TECHNICAL REPORT DATA
fftttte rttd liutructtont on the reverse btfort compltnnfl
'1. REPORT NO.
EPA/600/8-89/097
a.
4. TITLE AND SUBTITLE
Updated Health Effects Assessment for
Trichloroethylene
3. RECIPIENT? ACCESSION NO
PB90-142498/AS
ft. REPORT DATE
. PERFORMING ORGANIZATION CODE
. AUTHOR(S)
. PERFORMING ORGANIZATION REPORT NO.
B. PERFORMING ORGANIZATION NAME AND ADDRESS
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT NO.
12. SPONSORING AGENCY NAME AND ADDRESS
Environmental Criteria and Assessment Office
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati. OH 45268
. TYPE OF REPORT AND PERIOD COVERED
14. SPONSORING AGENCY CODE
EPA/600/22
IS SUPPLEMENTARY NOTES
16. ABSTRACT
This report summarizes and evaluates information relevant to a preliminary interim
assessment of adverse health effects associated with specific chemicals or compounds.
The Office of Emergency and Remedial Response (Superfund) uses these documents in
preparing cost-benefit analyses under Executive Order 32991 for decision-making under
CERCLA. All estimates of acceptable intakes and carcinogenic potency presented in
this document should be considered as preliminary and reflect limited resources
allocated to this project. The intent in these assessments is to suggest acceptable
exposure levels whenever sufficient data are available. The interim values presented
reflect the relative, degree of hazard associated with exposure or risk to the
chemical(s) addressed. Whenever possible, two categories of values have been
estimated for systemic toxicants (toxicants for which cancer is not the endpoint of
concern). The first, RfDs or subchronic reference dose, is an estimate of an exposure
level that would not be expected to cause adverse effects when exposure occurs during
a limited time interval. The RfD is an estimate of an exposure level that would not
be expected to cause adverse effects when exposure occurs for a significant portion
of the lifespan. For compounds for which there is sufficient .evidence of
carcinogenicity, qi*s have been computed, if appropriate, based on oral and
inhalation data if available.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
b.IDENTIFIERS/OPEN ENDED TERMS
c. COSATi Field/Croup
. DISTRIBUTION STATEMENT
Public
It. SECURITY CLASS (This Report!
Unclassified
21. NO. OF PAGES
20. SECURITY CLASS
Unclassified
22. PRICE
EPA Fan* 2220-1 (Rev. 4.77) PREVIOUS BDITION is OMOLKTB
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EPA/600/8-89/097
February, 1988
HEALTH EFFECTS ASSESSMENT
FOR TRICHLOROETHYLENE
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
CINCINNATI. OH 45268
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DISCLAIMER
This document has been reviewed In accordance with the U.S. Environ-
mental Protection Agency's peer and administrative review policies and
approved for publication. Mention of trade names or commercial products
does not constitute endorsement 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 In this document should be considered as preliminary and reflect
limited resources allocated to this project. Pertinent toxlcologlc and
environmental data were located through on-Hne literature searches of the
TOXLINE, CANCERLINE and the CHEMFATE/DATALOG data bases. The basic litera-
ture searched supporting this document 1s current up to May, 1987. Secon-
dary sources of Information have also been relied upon In the preparation of
this report and represent large-scale health assessment efforts that entail
extensive peer and Agency review. The following Off1ce . of Health and
Environmental Assessment (OHEA) sources have been extensively utilized:
U.S. EPA. 1980a. Ambient Water Quality Criteria for TMchloro-
ethylene. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincin-
nati, OH for the Office of Water Regulations and Standards, Wash-
ington, DC. EPA 440/5-80-077. NTIS PB 81-117871.
U.S. EPA. 1981. The Carcinogen Assessment Group's Carcinogen
Assessment of Trlchloroethylene. Prepared by the Office of Health
and Environmental Assessment, Carcinogen Assessment Group, Wash-
ington, DC. Internal draft.
U.S. EPA. 1982. Hazard Profile for Trlchloroethylene. Prepared
by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of
Solid Waste, Washington, DC.
U.S. EPA. 1983. Review of Tox1colog1cal Data In Support of Evalu-
ation for Carcinogenic Potential of Trlchloroethylene. Prepared by
the Office of Health and Environmental Assessment, Carcinogen
Assessment Group, Washington, DC for the Office of Solid Waste and
Emergency Response, Washington, DC.
U.S. EPA. 1985. Health Assessment Document for Trlchloroethylene.
Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Research Triangle Park, NC. EPA
600/8-82-006F. NTIS PB 84-162882.
U.S. EPA. 1987. Integrated Risk Information System (IRIS). Risk
Estimate for Carcinogens for Trlchloroethylene. On line.
(Preparation date: 2/18/87). Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincin-
nati, OH.
111
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The Intent 1n these assessments Is to suggest acceptable exposure levels
for noncarclnogens and risk cancer potency estimates for carcinogens
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.
Nevertheless, the Interim values presented reflect the relative degree of
hazard or risk associated with exposure to the chemical(s) addressed.
Whenever possible, two categories of values have been estimated for
systemic toxicants (toxicants for which cancer Is not the endpolnt of
concern). The first, RfD$ (formerly AIS) or subchronlc reference dose, Is
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 llfespan).
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 In ambient air or water where lifetime
exposure Is assumed. Animal data used for RFD§ 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. These
values are developed for both Inhalation (RfD$i) and oral (RfD$0)
exposures.
The RfD (formerly AIC) Is similar In concept and addresses chronic
exposure. It 1s an estimate of an exposure level that would not be expected
to cause adverse effects when exposure occurs for a significant portion of
the llfespan [see U.S. EPA (1980b) for a discussion of this concept]. The
RfD 1s route-specific and estimates acceptable exposure for either oral
(RfDo) or Inhalation (RfDi) with the Implicit assumption that exposure
by other routes Is Insignificant.
Composite scores (CSs) for noncarclnogens have also been calculated
where data permitted. These values are used for Identifying reportable
quantities and the methodology for their development Is explained 1n U.S.
EPA (1984).
For compounds for which there Is sufficient evidence of carclnogenlcHy
RfD$ and RfD values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980b). Since cancer Is a
process that Is not characterized by a threshold, any exposure contributes
an Increment of risk. For carcinogens, q-j*s have been computed, If appro-
priate, based on oral and Inhalation data If available.
1v
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ABSTRACT
In order to place the risk assessment evaluation 1n 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
Interpretation 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.lxKT2 (mg/kg/day)"1 has been computed.
Trlchloroethylene has been shown to be carcinogenic In mice by Inhala-
tion exposure 1n three strains and 1n rats In one experiment. Human
ep1dem1olog1cal studies are Inadequate to assess the potential carclno-
genlclty of trlchloroethylene 1n humans.
U.S. EPA (1987b) used mouse data based on the Incidence of lung tumors
and the corresponding metabolized dose from the mouse Inhalation studies to
estimate a unit risk for Inhalation exposure. Data concerning the pharma-
coklnetlcs of trlchloroethylene 1n animals and humans was utilized to
estimate effective dose levels. The resulting unit risk was 1.7xlO~6
(yg/m3)"1. Trlchloroethylene has been classified as a B2 carcinogen
(U.S. EPA, 1987b).
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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. Dr. Christopher DeRosa and Karen
Blackburn were the Technical Project Monitors and John Helms (Office of
Toxic Substances) was the 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, Jacky Bohanon and Kim Davidson
Environmental Criteria and Assessment Office
Cincinnati, OH
v1
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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
HEIGHT OF EVIDENCE
REGULATORY STANDARDS AND CRITERIA
Page
. . . . 1
. . . . 3
, . . . 3
, . . . 3
. . . . 4
. . . 4
, . . . 4
, . . . 8
, . . . 11
, . . . 11
, . . . 12
. . . . 13
... 13
, . . . 15
, . . . 15
... 17
... 17
, . . . 17
... 17
... 18
, . . . 18
... 23
... 26
... 33
... 40
... 41
V11
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TABLE OF CONTENTS (cont.)
Page
RISK ASSESSMENT ......................... 42
6.1. SUBCHRONIC REFERENCE DOSE (RfDs) ............ 42
6.2. REFERENCE DOSE (RfD) .................... 42
6.3. CARCINOGENIC POTENCY (*) ............... 42
6.3.1. Oral ....................... 42
6.3.2. Inhalation .................... 44
7. REFERENCES ............................ 51
APPENDIX: Summary Table for Trlchloroethylene Using the Mouse ..... 64
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LIST OF TABLES
No. Title Page
3-1 Effects of Subchronlc Trlchloroethylene Exposure 5
4-1 CarclnogenlcHy of Trlchloroethylene 19
4-2 Disposition of 14C-Tr1chloroethylene 72 Hours After Single
Oral Doses to Hale Osborne-Mendel and W1star-Derived Rats
and to Male B6C3F1 and Swiss Mice 28
4-3 Metabolism of Trlchloroethylene 1n B6C3F1 Mice: Effect of
Chronic Dosing 29
4-4 Disposition of l4C-Tr1chloroethylene Radioactivity for
72 Hours After Single Oral Dose (200 mg/kg) to Rats and
Mice (NMRI) 30
4-5 Metabolism of Radlolabeled Trlchloroethylene In Rats
and Mice Following a 6-Hour Exposure Period 33
4-6 Predicted Relationship Between Inhalation Exposure Level
and Trlchloroethylene Metabolites 39
6-1 Incidence Rates of Hepatocellular Carcinomas 1n Male
and Female Mice In the NTP (1982) and NCI (1976) Gavage
Studies 43
6-2 Estimated Slope Values (q-j*) Based on Extrapolation
from Data on Male and Female Mice 45
6-3 Summary of Estimated Metabolized Dose from the Animal
Bloassays, Corresponding Human Equivalent Dose (HED)
and Tumor Incidence for the Mouse Bloassays 47
6-4 Summary of Estimated Metabolized Dose from the Rat
Bloassay, Corresponding Human Equivalent Dose (HED)
and Tumor Incidence 48
6-5 Human q-|* Estimates per (mg metabolized dose/kg/day) 50
1x
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LIST OF FIGURES
No. Title Page
4-1 Relationship between administered single oral doses of
14C-TC1 to rats and mice and amount of dose metabolized
1n 24 hours, expressed as mg/kg bw, as calculated from
l4C-rad1oact1v1ty excreted 1n urine, feces, and expired
air (other than unchanged 14C-TC1) 32
4-2 Relationship 1n the mouse of the doses of TCI (po mg/kg:
Inhalation mg eq/kg) and the amount of total TCI metabo-
lized (TTCIM mg eq) 34
4-3 Relationship In the Rat of the Doses of TCI (po mg/kg:
Inhalation mg eq/kg) and the Amount of Total TCI Metabo-
lized (TTCIM mg eq) as Predicted by Using Data from
Tables 4-2 and 4-5 35
4-4 Relationship 1n the Rat Between Airborne Concentrations
of TCI and Total Amount of TCI Metabolized (TTCIM mg eq)
Obtained by Computer Simulation 37
4-5 Relationship In the Mouse Between Airborne Concentrations
of TCI and Total Amount of TCI Metabolized {TTCIM mg eq)
Obtained by Computer Simulation 38
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LIST OF ABBREVIATIONS
ADI Acceptable dally Intake
BCF B1oconcentrat1on factor
CAS Chemical Abstract Service
CS Composite score
Koc Soil sorptlon coefficient
Kow Octanol/water partition coefficient
LOAEL Lowest-observed-adverse-effect level
NOAEL No-observed-adverse-effect level
ppm Parts per million
RfD Reference dose
RfDj Inhalation reference dose
RfD0 Oral reference dose
RfD$ Subchronlc reference dose
RfD$i Subchronlc Inhalation reference dose
RfD$o Subchronlc oral reference dose
SNARL Suggested no-adverse-response level
STEL Short-term exposure limit
TCA TMchloroacetlc add
TCE TMchloroethanol
TLV Threshold limit value
TWA Time-weighted average
v/v Volume/volume
x1
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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: halogenated aliphatic hydrocarbon
(purgeable halocarbon)
Molecular weight: 131.4
Vapor pressure: 57.9 mm Hg at 20°C (Callahan et al., 1979)
Water solubility: 1100 mg/l at 20°C (Callahan et al., 1979)
Log Kow: 2.42 (Hansch and Leo, 1985)
Soil mobility: 1.6 (Wilson et al., 1981)
(predicted as retardation
factor for soil depth of
140 cm and organic carbon
content of 0.087%)
Koc: 87-150 (NLM, 1987)
BCF: 17 (1n blueglll, Lepomls macrochlrus)
(U.S. EPA, 1980a)
Half-lives In
A1r: 4-5 days (U.S. EPA, 1982; NLM, 1987)
Water: 1-4 days (river) (Zoeteman et al., 1980)
30-90 days (lake) (Zoeteman et al., 1980)
The primary removal mechanism for trlchloroethylene In the atmosphere Is
reaction with photochemically generated hydroxyl radicals. Products of this
reaction are phosgene, dlchloroacetyl chloride and formyl chloride. In
photochemical smog situations, trlchloroethylene degrades rapidly with a
half-life on the order of hours (NLM, 1987).
The primary removal mechanism for trlchloroethylene In water Is expected
to be volatilization. B1oaccumulat1on In aquatic organisms and adsorption
to suspended solids and sediments are not expected to be Important fate
processes (NLM, 1987).
0046H -1- 08/26/87
-------
The half-life of trlchloroethylene In soil was not located 1n the avail-
able literature. Trlchloroethylene 1s expected to volatilize rapidly from
soil surfaces. The half-life for evaporation from soil should be longer
than Us evaporation half-life from water (Wilson et al., 1981). In sub-
surface soil, no significant degradation Is expected to occur under aerobic
conditions, although some blodegradatlon may occur In anaerobic soils (NLH,
1987). Trlchloroethylene Is expected to be fairly mobile 1n soil as
Indicated by Us K and the retardation factor (velocity of water through
soil divided by apparent velocity of the compound through soil). Undegraded
residue 1s expected to leach Into groundwater. Detection of this compound
In a number of groundwater supplies supports this prediction (NLH, 1987).
0046H -2- 08/26/87
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2. ABSORPTION FACTORS IN HUMAN AND EXPERIMENTAL ANIMALS
2.1. ORAL
Rats and mice were given single 10, 500, 1000 or 2000 mg/kg doses of
tr1chloro[14C]ethylene In corn oil by gavage (Prout et al., 1984). Deter-
mination of radioactivity In the urine, feces, expired air and carcass after
24-72 hours showed that 92-100% of the doses were absorbed. Similar data
were reported In an earlier study with rats (Daniel, 1963). Data are not
available on the extent of gastrointestinal absorption of trlchloroethylene
by humans. See Section 4.3.2. for selected pharmacoklnetlc data.
2.2. INHALATION
In humans, absorption of trlchloroethylene through the lungs Is rapid,
and complete tissue equilibrium 1s achieved after ~8 hours of exposure (U.S.
EPA, 1985). See Section 4.3.2. for selected pharmacoklnetlc data.
0046H -3- 01/11/88
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3. TOXICITY IN HUHANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. Tucker et al. (1982) added trlchloroethylene 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 trlchloro-
ethylene 1n 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
tMchloroethylene was lost from the drinking water solution 1n a 3- to 4-day
period. It 1s not clear whether the authors Included this loss of tr1-
chloroethylene with time 1n their calculations; however, using the dose
levels reported, the lowest dose levels, 18.4 mg/kg/day In males and 17.9
rog/kg/day In females, produced no observed effects In the mice. The next
dose level of 216.7 mg/kg/day 1n males and 193.0 mg/kg/day In females caused
an Increase In the liver-to-body weight ratio In males only. At a dose
level of 393.0 mg/kg/day 1n males and 437.1 mg/kg/day 1n females, ketone and
protein levels were elevated 1n the urine of males but not females, and the
relative liver weight remained higher 1n males but was not Increased In
females. At the highest dose levels used 1n 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 1n the urine (Tucker et al., 1982).
In an associated study, groups of male CD-I mice were given 24 or 240
mg/kg bw trlchloroethylene by gavage once a day for 14 days (Sanders et al.,
1982). Cell-mediated Immune response to sheep erythrocytes was signifi-
cantly Inhibited at both dose levels compared to vehicle controls. Humoral
Immune response to sheep erythrocytes was unaffected by treatment.
0046H -4- 12/29/87
-------
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Immune status was also evaluated 1n male and female CD-I mice that were
administered trlchloroethylene In the drinking water for 4 or 6 months
(Sanders et al., 1982). Reported average doses for 6 months were 0, 18.4,
216.7, 393.0 or 660.2 mg/kg/day for males and 0, 17.9, 193.0, 437.1 or 793.3
mg/kg/day for females. Parameters evaluated Included humoral Immunity,
cell-mediated Immunity, lymphocyte responsiveness, bone marrow function and
macrophage function. Treatment-related effects Included suppressed humoral
response to sheep erythrocytes at >437.1 mg/kg/day after 4 months but not
after 6 months In the females (this was supported by concommltant Increases
In hemagglut1nat1on tHer), suppressed cell-mediated Immune response to
sheep erythrocytes at >17.9 mg/kg/day after 4 months and at 793.3 mg/kg/day
after 6 months In the females. Bone marrow stem cell colonization was
significantly Inhibited In females at all dose levels after 4 and 6 months
and In males at all doses after 4 months.
Preliminary subchronlc studies for NTP (1986) carc1nogen1c1ty bloassays
were conducted In which groups of 10 ACI, August or Marshall rats/sex were
exposed to trlchloroethylene 1n corn oil by gavage, 5 days/week for 13
weeks. Male ACI and male August rats were administered doses of 0, 125,
250, 500, 1000 or 2000 mg/kg. Female August and female ACI rats were admin-
istered doses of 0, 62.5, 125, 250, 500 or 1000 mg/kg. Male Marshall rats
were treated with 0, 268, 308, 495, 932 or 1834 mg/kg, and female Marshall
rats were treated with 0, 134, 153, 248, 466 or 918 mg/kg. With the excep-
tion of three male August rats that were given 2000 mg/kg, all rats survived
to termination of the study. Reduced final mean body weights In excess of
10% of control group weights occurred In males of all strains at the high
doses; body weight depression ranged from 12.1% 1n Marshall rats to 17.1% 1n
ACI rats. There were no treatment-related behavioral or hlstopathologlcal
effects 1n any of the groups.
0046H -7- 01/11/88
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In preliminary subchronlc studies for the NCI (1976) bloassay, 0, 562,
1000, 1780, 3160 or 5620 mg/kg doses of trlchloroethylene In corn oil were
administered to groups of five Osborne-Mendel rats/sex, 5 days/week for 8
weeks. Groups of five B6C3F1 mice/sex were treated similarly with doses of
0, 1000, 1780, 3160, 5260 or 10,000 mg/kg. Body weight gains of all treated
groups of rats were reported to be below that of the control group, and were
quantified as >20% for females at doses >1780 mg/kg and males at doses >3160
mg/kg. Abnormal clinical signs at >1780 mg/kg and 100% mortality at 5620
mg/kg also occurred In male and female rats, but there were no treatment-
related hlstopathologlcal effects. There were no treatment-related effects
on body weight or histology 1n the mice, but mortality occurred at 5260
mg/kg (80%) and 10,000 mg/kg (100%).
Results of 13-week preliminary subchronlc studies for a NTP (1982)
bloassay of trlchloroethylene with F344 rats and B6C3F1 mice were not
Included 1n the available summary (U.S. EPA, 1985) of this bloassay.
3.1.2. Inhalation. In an earlier study, Adams et al. (1951) reported
that exposure to trlchloroethylene vapor 7 hours/day, 5 days/week for ~6
months decreased body weights 1n guinea pigs at a dose level of 200 ppm. At
a dose level of 400 ppm, rats had Increased liver and kidney weights, and
guinea pigs and rabbits had Increased liver weights. Male rats and male
guinea pigs had depressed body weights at a dose level of 400 ppm (Adams et
al., 1951). Rats exposed to 55 ppm trlchloroethylene vapor Intermittently
for 14 weeks (see Table 3-1) had Increased liver weights, but no hlsto-
pathology was reported (Klmmerle and Eben, 1973). Hepatic and renal
physiology, as well as clinical hematologlcal values, appeared normal.
Prendergast et al. (1967) did not see any effects associated with continuous
Inhalation of 35 ppm trlchloroethylene by rats, guinea p1gs» monkeys or
0046H -8- 12/29/87
-------
dogs. Depressed body weight was observed 1n rabbits. 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.
Rats that were exposed continuously to 320 ppm trlchloroethylene for 30
or 90 days had altered fatty add composition of cerebral cortex
ethanolamlne phosphoglycerlde (Kyrklund et al., 1985 abstract only).
Several Unolelc add derived fatty adds were Increased and Unolenlc add
derived fatty add were decreased. The effects were partially reversed
after 30 days rehabilitation and not observed after 5 days of exposure.
Continuous exposure to 60 or 300 ppm trlchloroethylene for 3 months followed
by a recovery period of 4 months had Inconclusive effects on brain S100
protein or DNA content In gerblls (Haglld et al., 1981 abstract only).
Groups of 10-20 NMRI mice of both sexes were exposed to 0 or 150 ppm
trlchloroethylene continuously for 2, 5, 9, 16 or 30 days (Kjellstrand et
al., 1981). Groups of 10-24 rats and 8-24 gerblls were similarly exposed to
150 ppm for 30 days. Relative liver weights were Increased 1n all species
and treatment groups, but the effect was more pronounced In the mice (60-80%
enlargement) than the rats or gerblls (20-30%). Examination of mice 5 and
30 days after cessation of treatment Indicated that liver weights had
decreased but were still significantly higher than controls. Pathological
examinations were not conducted.
In a related study, liver weights and plasma butyrylchollnesterase
(BuChE) activity were evaluated In NMRI and nine other strains of mice of
both sexes that were exposed to 150 ppm trlchloroethylene continuously for
30 days (Kjellstrand et al., 1983b). Unexposed mice of each strain were
used for controls. Liver weights were significantly Increased 1n treated
mice of all strains and plasma BuChE activity Increased 1n males of all
0046H -9- 12/29/87
-------
strains and 1n females of two of the strains (A/sn and NZB). Pathological
examinations were not conducted.
Relative liver weight and BuChE activity were also evaluated In groups
of NMRI mice of both sexes that were exposed to 0, 37, 75, 150 or 300 ppm
trlchloroethylene continuously for 30 days (Kjellstrand et al., 1983a).
Group sizes were 20 (10/sex) at 37 ppm and 10 (5/sex) ar the higher concen-
trations. Liver weights were significantly Increased and concentrations-
related 1n all groups (-25% Increase at 37 ppm), and BuChE activity was
significantly Increased In males at 75 and 150 ppm and both sexes at 300
ppm. Intermittent exposure 30-day experiments In which exposures ranged
from 225 ppm for 16 hours/day to 3600 ppm for 1 hour/day, providing average
dally concentrations of 150 ppm, suggested that liver weight Increases were
Independent of exposure schedule. Hlstologlcal examination of the livers
from an unspecified number of mice showed that continuous exposure to
trlchloroethylene caused alterations, Including enlarged and vacuolated
hepatocytes, at all concentrations. The hlstologlc alterations generally
were more pronounced following Intermittent exposure to the higher
concentrations of trlchloroethylene. Liver weights and serum BuChE activity
were not significantly Increased In mice 120 days after continuous exposure
to 150 ppm for 30 days. The liver became hlstologlcally similar to controls
during the rehabilitation period except for changes 1n cellular and nuclear
sizes, suggesting reversibility of the hepatic effects.
The results of a study In which groups of 13 Sprague-Dawley rats were
exposed continuously to trlchloroethylene concentrations of 0, 50, 200 or
800 ppm for 12 weeks were reported by Nomlyama et al. (1986). Increases 1n
liver weight and hepatic Indices apparently occurred 1n all of the treatment
groups (1t was reported that effects were noted "especially" 1ri the 800 ppm
0046H -10- 01/11/88
-------
group). Hepatic Indices measured Included total protein, albumin/globulin
ratio, SGPT, trlglycerldes, cholesterol and chollnesterase. Unspecified
pathological examinations appear to have been unremarkable.
3.2. CHRONIC
3.2.1. Oral. In the NCI (1976) cardnogenlclty bloassay, technical grade
trlchloroethylene was administered by gavage to groups of 50 Osborne-Mendel
rats/sex at TWA doses of 869 or 1739 mg/kg, 50 male B6C3F1 mice at TWA doses
of 1169 or 2339 mg/kg and 50 female B6C3F1 mice at TWA doses of 869 or 1739
mg/kg, 5 days/week for 78 weeks, with 12 weeks (mice) or 32 weeks (rats) of
observation (Section 4.2.1.). Vehicle controls consisting of 20 animals/
sex/species were maintained. Treated 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 poor survival and It Is difficult to determine the Impact of trl-
chloroethylene on survival. The mice did not have decreased body weights or
survival times after treatment with trlchloroethylene. Treated rats of both
sexes had an Increased Incidence of chronic nephropathy, compared with
controls. No noncancerous hlstopathologlcal changes were described In mice
(NCI, 1976).
In the NTP (1982) bloassay, F344 rats of each sex were treated by gavage
with 0, 500 or 1000 mg/kg trlchloroethylene, 5 days/week for 103 weeks
(Section 4.2.1.). B6C3F1 mice of each sex were treated similarly at a dose
level of 1000 mg/kg. Treatment-related nonneoplastlc effects Included
reduced weight gain In the low and high dose male and female rats, decreased
survival 1n the low and high dose male rats and toxic nephrosls (character-
ized as cytomegaly) 1n 98% of treated male and 100% of treated female rats.
Effects In the mice Included reduced body weight gain and decreased survival
i
0046H -11- 12/29/87
-------
1n the males, and cytomegaly In the kidney of 90% of the treated males and
98% of the treated females. It should be noted that there were neoplastlc
effects In the kidneys of the rats and liver of the mice (Section 4.2.1.).
Groups of 50 ACI, August, Marshall or Osborne-Mendel rats/sex were
administered tMchloroethylene by gavage at doses of 0, 500 or 1000 mg/kg, 5
days/week for 103 or 104 weeks (NTP, 1986). The final body weights of all
dosed groups, except for high dose female Osborne-Mendel rats, were somewhat
lower than those of the control groups, but reductions >10% occurred at 1000
mg/kg In.ACI, August and Osborne-Mendel males and Marshall females, and at
500 mg/kg In ACI males. Treatment-related decreased survival occurred In
ACI males and Marshall females at both doses and 1n ACI females and Osborne-
Mendel females at 1000 mg/kg. Nonneoplastlc pathologic effects Included
cytomegaly of renal tubular cells and toxic nephropathy In dosed rats of all
strains; Incidences ranged from 82-98% and 17-80% for the two types of
lesions, respectively. Treatment-related neoplastlc renal lesions also
occurred (Section 4.2.1.).
3.2.2. Inhalation. A number of epldemlologlc studies with occupational
exposure to trlchloroethylene, primarily oriented toward carclnogenldty,
have been reviewed by U.S. EPA (1985) and Axelson (1986). The more
extensive review and evaluation was performed by U.S. EPA (1985). Of the
epldemlologlc studies, two (Axelson et al., 1978; Tola et al., 1980)
reported the total number of observed deaths from all causes compared with
the number of expected deaths based on national statistics (for Sweden and
Finland, respectively). In neither study did the number of observed deaths
significantly exceed the number expected, and In most cases the number
observed was substantially below the number expected.
0046H -12- 12/29/87
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3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. Pertinent data regarding teratogenldty resulting from oral
exposure to trlchloroethylene could not be located 1n the available
literature.
Reproductive function was assessed In groups of ten 70-day-old male
Long-Evans rats that were treated with trlchloroethylene 1n corn oil by
gavage at doses of 0, 10, 100 or 1000 mg/kg, 5 days/week for 6 weeks (Zenlck
et al., 1984). Copulatory behavior and semen evaluations (sperm count,
motlllty and morphology) were conducted after 1 and 5 weeks of treatment and
at 4 weeks postexposure. Impaired copulatory behavior, characterized by
neglect of females and Incomplete genital contact, occurred 1n the 1000
mg/kg group only after 1 week of exposure. It was suggested that these
effects may be attributed to the narcotic properties of trlchloroethylene,
as they were not apparent after 5 weeks of treatment because of presumed
tolerance.
Groups of 22 or 23 female Long-Evans rats were exposed to trlchloro-
ethylene 1n corn oil by gavage at doses of 0, 10, 100 or 1000 mg/kg for 2
weeks before mating through day 21 of pregnancy (Hanson et al., 1984).
There were no effects on length of estrus cycle or fertility 1n any of the
groups. Maternal toxldty (Increased mortality and decreased weight gain)
and decreased neonatal survival, which were primarily due to deaths at the
time of birth, occurred at 1000 mg/kg.
Trlchloroethylene that was mlcroencapsulated In a gelatln/sorbltol shell
was administered 1n the diet to CD-I mice In a continuous breeding fertility
study that consisted of a 7-day prematlng exposure period, a 98-day cohabi-
tation period and a 21-day segregation period (George et al., 1986a). Diet
concentrations of 0, 0.15, 0.30 and 0.60% provided respective approximate
trlchloroethylene Intakes of 0, 64, 248 and 653 mg/kg/day during the first
0046H -13- 02/29/88
-------
week, 0, 53, 266 and 615 mg/kg/day during the second week and 0, 188, 375
and 750 mg/kg/day during the remainder of the study. Thirty-five pairs of
untreated and 17-19 pairs of treated mice were tested. Final Utters from
the control and high dose-groups were raised to sexual maturity and bred.
There were no treatment-related effects on fertility or reproductive
performance 1n either the FQ or F, mice but sperm motmty was reduced
by 45% 1n the high dose FQ males and by 18% In the F^ males. Effects In
high-dose F, offspring Included Increased testls and epldldymldls weights
and a 2-fold decrease In perinatal (days 0-21) but not postweanlng survival.
Hlstologlcal examination of tissues revealed treatment-related lesions In
the liver and kidneys (but not 1n the reproductive tracts) In the high-dose
FQ and F, mice.
A similarly designed fertility study with mlcroencapsulated trlchloro-
ethylene was conducted with F344 rats (George et al., 1986b). This study
used the same diet concentrations as the mouse study (Intake estimates were
not reported) and similar numbers of animal pairs, but differed with respect
to the segregation period (28 days as opposed to the previously used 21
days). Treatment at all concentrations had a marginal effect on numbers of
live Utters per pair and live pups per Utter, but no effect on fertility
or other measures of reproductive performance. Rats 1n the high concentra-
tion group had Increased testls and epldldymls weights, but sperm evalua-
tions, testls histology and histology of other tissues were normal. There
were no effects on fertility, reproductive performance, histology or open
field behavioral performance In the F, generation. The effects Indicated
In the George et al. (1986b) study were attributed to generalized toxldty
rather than a specific effect on the reproductive system because decreased
body and organ weights occurred 1n both FQ and F, rats.
0046H -14- 02/29/88
-------
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 1n mice. Decreased maternal weight gain
occurred In the rats.
Healy et al. (1982) exposed 32 mated Wlstar rats to trlchloroethylene at
100 ppm 4 hours/day on days 8-21 of gestation. A group of 31 similarly
treated mated rats served as controls. Examinations performed on gestation
day 21 revealed no evidence of teratogenldty, but fetotoxldty was mani-
fested as an Increase In the Incidence of dams with complete Utter resorp-
tlons, reduced fetal body weight and delayed ossification. No mention was
made of maternal toxlclty.
When pregnant rabbits were exposed to trlchloroethylene vapor at a con-
centration of 500 ppm 7 hours/day, 5 days/week on days 6-21 of gestation,
days 0-21 of gestation or beginning 3 weeks before mating continuing through
gestation, the offspring were reported to have an Increased Incidence of
external hydrocephalus (Bellies et al., 1980). While the Incidence was not
statistically significant, the authors felt that 1t was biologically
significant. Other, less definitive, teratogenldty 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
and body size and delayed ossification.
3.4. TOXICANT INTERACTIONS
Because trlchloroethylene 1s bloactlvated by liver mlcrosomal enzymes,
substances that stimulate liver mlcrosomal enzymes may potentiate trlchloro-
ethylene toxldty, and substances that depress liver mlcrosomal enzymes may
0046H -15- 02/29/88
-------
decrease trlchloroethylene toxldty (U.S. EPA, 1985). In addition, Inter-
actions with alcohol (Bardodej and Vyskoch, 1956; Seage and Burns, 1971.;
Cornish and Adefuln, 1966; Ferguson and Vernon, 1970; Gessner and Cabana,
1970) and carbon tetrachloMde (Pessayre et al., 1982) enhance the toxldty
of trlchloroethylene. Trlchloroethylene potentiates the effect of eplneph-
rlne on the myocardium (Dhumer et al., 1957; Defalque, 1961).
0046H -16- 02/29/88
-------
4. CARCINOGENICITY
4.1. HUMAN DATA
4.1.1. Oral. Although trlchloroethylene has been reported as a contami-
nant of various human water supplies (Zlgllo et al., 1983), pertinent data
regarding carclnogenlclty In humans from oral exposure to trlchloroethylene
were not located In the available literature.
4.1.2. Inhalation. Three retrospective epidemlologic studies Investi-
gating human exposure to trlchloroethylene 1n the workplace and subsequent
tumor development (Axelson et al., 1978; Blair et al., 1979; Tola et al.,
1980) were reviewed 1n U.S. EPA (1985). Individuals 1n these studies were
assigned to exposure categories on the basis of the amount of tMchloro-
acetlc add, a trlchloroethylene metabolite, In 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 tetrachlorlde 1n conjunction with trlchloro-
ethylene. The relative amounts of each chemical during exposure were not
determined. The other two studies (Axelson et al., 1978) did not find an
Increased Incidence or rate of cancer development 1n Individuals exposed to
trlchloroethylene.
A more recent study (Shlndell and UlMch, 1985), which Is reviewed 1n
detail In U.S. EPA (1987b), reports the results of a cohort study In a manu-
facturing plant where trlchloroethylene was used as a degreaslng agent.
This study failed to demonstrate any cause-specific excess mortality.
However, data concerning exposure level, duration of exposure and follow-up
were Inadequate. The conclusions of U.S. EPA (1987b) were that these data
were Inadequate to fully evaluate the absence of an effect.
0046H -17- 03/01/88
-------
4.2. BIOASSAYS
4.2.1. Oral. In the NCI (1976) study, groups of -50 B6C3F1 mice/sex and
similar numbers of Osborne-Mendel rats were given trlchloroethylene 1n corn
oil by gavage, 5 days/week for 78 weeks (Table 4-1). The mice were 5 weeks
old at their first treatment and the rats were 7 weeks old. The tMchloro-
ethylene was >99% pure but contained epoxlde stabilizers, Including 0.09%
eplchlorohydrln. The experiments were terminated after 90 weeks (mouse) and
110 weeks (rat). The doses specified 1n Table 4-1 are TWA doses calculated
for the 5 days/week of treatment (the doses were changed during the course
of the experiments). No compound-related carcinogenic effects were seen 1n
the rats, but high mortality rates within all groups of rats significantly
detracted from the usefulness of the conclusions (U.S. EPA, 1985). There
was a significant Increase In the Incidence of hepatocellular carcinomas In
male mice at both dose levels. Females had a significantly Increased Inci-
dence of hepatocellular carcinomas, but only at the high dose level. The
carcinogenic effect of trlchloroethylene was greater 1n males than females.
The rate of hepatocellular tumor development was dose-dependent, being
greater 1n the male animals exposed to the high dose level (NCI, 11976).
The National Toxicology Program (NTP, 1982) recently completed a cancer
bloassay using Fisher 344 rats. The trlchloroethylene used had a purity
>99.9% and eplchlorohydrln was not detected 1n 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 trlchloro-
ethylene, 1000 mg/kg trlchloroethylene. Trlchloroethylene was administered
In corn oil by gavage, 5 days/week for 103 weeks.
A dose-related reduction 1n survival was noted In male rats (NTP, 1982).
Both the low and high dose groups were significantly different from the
vehicle control group using survival probabilities estimated by the Kaplan
0046H -18- 02/29/88
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and Meier technique. High dose males showed a significant (p<0.05) Increase
In kidney tubular adenocardnomas (3/16) compared with vehicle controls
(0/33) at terminal sacrifice by life table (p=0.028) and Incidental tumor
(p=0.028) tests. The Cochran-Armltage test for linear trend was also
significant (p=0.038). Historical control data showed a renal tumor Inci-
dence of 3/748 for this strain of rat; however, the comparison of kidney
adenocardnomas between high dose males and vehicle controls did not show a
significant difference using the Fisher Exact test. Other treatment-related
Increases 1n tumor Incidence were not apparent. The high dose used 1n this
study appears to have exceeded the maximally tolerated dose as defined by
NCI. Despite the Increase 1n renal adenocarclnomas, NTP has concluded that
this study 1s Inadequate for judging the carclnogenldty of trlchloroethy-
lene.
B6C3F1 mice were also tested 1n this study (NTP, 1982). A single gavage
dose of 1000 mg/kg/day trlchloroethylene 1n corn oil, 5 days/week for 103
weeks was used. Fifty males and 50 females were assigned to the untreated
control, vehicle control and trlchloroethylene 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 1n the vehicle and treated groups, respectively. The corre-
sponding Incidences In males were 8/48 and 30/50. In addition, hepatocellu-
lar adenoma Incidence was significantly (p<0.05) Increased 1n female mice by
the life table, Incidental tumor and Cochran-Armltage and Fisher Exact
tests, while 1n males significance was only found using life table analysis.
Historical control data Indicated hepatocellular tumor Incidence of 18% and
2.9% for males and females, respectively. These results confirm those of
the NCI (1976) study that reported an Increased Incidence of hepatocellular
0046H -22- 02/29/88
-------
carcinoma In male and female B6C3F1 mice given trlchloroethylene stabilized
with eplchlorohydrln and other epoxldes. These results Indicate that the
epoxldes were not a requisite factor 1n the response.
Groups of 50 ACI, August, Marshall or Osborne-Mendel rats/sex were
administered eplchlorohydrln-free trlchloroethylene In olive oil by gavage
at doses of 0, 500 or 1000 mg/kg, 5 days/week for 103 or 104 weeks (NTP,
1986). Treatment was associated with significantly Increased Incidences of
renal tubular cell adenomas In the low dose male Osborne-Mendel rats and
Interstitial cell tumors of the testls 1n high dose male Marshall rats. NTP
(1986) concluded that these bloassays were Inadequate for assessing either
the presence or absence of cardnogenlclty because of chemically Induced
toxldty and reduced survival (see Section 3.2.1.), and deficiencies 1n the
conduct of the studies as revealed by data audits.
Maltonl et al. (1986) treated male and female Sprague-Dawley rats by
gavage with trlchloroethylene (99.9X pure) 1n olive oil at 50 or 250 mg/kg,
4-5 days/week for 52 weeks. The rats were observed until death. There was
a dose related Increase 1n the Incidence of leukemia and 1mmunoblast1c
lymphosarcomas In males, with no Increased tumor Incidence In females. The
rats were 13 weeks old before trlchloroethylene treatment began. As a part
of a much larger experiment, Van Duuren et al. (1979) treated 30 male and 30
female ICR/Ha Swiss mice by gavage with 0.5 mg trlchloroethylene 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 a bloassay conducted from 1975-1977
at Industrial Bio-Test Laboratories, Inc. In this study, mice and rats were
exposed to 100, 300 or 600 ppm of trlchloroethylene 6 hours/day, 5 days/week
for 24 months (see Table 4-1). No carcinogenic effect was seen In rats.
Hepatocellular carcinoma occurred In mice. In males, the Incidence of
0046H -23- 02/29/88
-------
hepatocellular carcinoma was greater at each dose level than 1n females and
occurred 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
trlchloroethylene 7 hours/day, 5 days/week (Fukada et al., 1983) (see Table
4-1). Exposure began for both mice and rats at 7 weeks of age. No signifi-
cant effects on body weight or mortality were produced by trlchloroethylene.
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 In
rats occurred frequently, the only tumor type that occurred significantly
more frequently 1n treated compared with control animals was lung adeno-
cardnoma 1n mice. The development appeared dose-related and species-
specific 1n that 150 and 450 ppm trlchloroethylene caused an Increased
Incidence of pulmonary adenocardnomas 1n mice only (Fukada et al., 1983).
After exposure to 100 or 500 ppm of trlchloroethylene, 6 hours/day, 5
days/week for 18 months, no effect on the body weights of rats, mice or
hamsters was observed, and Increased mortality was observed only 1n the mice
(Henschler et al., 1980) (see Table 4-1). Age of the animals at the start
of exposure was not reported. The only statistically significant effect
(p<0.05) was an Increased Incidence and rate of development of malignant
lymphomas In female mice. The response was greater, but apparently not
significantly greater, In the high dose than In the low dose animals. The
0046H -24- 02/29/88
-------
authors suggested that Immunosuppresslon 1n the female mice was a contribut-
ing factor In the Increased rate and Incidence of the malignant lymphomas,
but they provided no experimental basis for the suggestion. The control
mice In the Henschler et al. (1980) study 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 treatment with 24 or 240 mg/kg of trlchloroethylene by
gavage decreased the Immune response In male CD-I mice.
Maltonl et al. (1986) conducted a number of Inhalation studies In which
rats or mice were exposed to trlchloroethylene at 0, 100, 300 or 600 ppm, 7
hours/day, 5 days/week. Exposure of Sprague-Dawley rats by this regimen for
8 weeks (observed for 164 weeks) did not result 1n Increased tumor
Incidences. A slight but nonsignificant Increase 1n hepatomas was observed
1n male but not female Swiss mice exposed to trlchloroethylene for 8 weeks,
with a total observation period of 134 weeks.
Exposure of groups of 130 Sprague-Dawley rats of each sex to
trlchloroethylene by this regimen for 104 weeks (observed for 150 weeks)
resulted 1n a significant dose-related Increase In testlcular Leydlg cell
tumors (Maltonl et al., 1986). Slight Increases In leukemia, especially
Immunoblastlc lymphosarcomas, and renal adenocardnomas were also noted
among the exposed males. Tumor Incidences were not Increased among female
rats.
Maltonl et al. (1986) also exposed groups of 90 male and 90 female Swiss
mice, similar groups of B6C3F1 (NCI) mice, and groups of 90 male B6C3F1
(CRL) mice to trlchloroethylene by this regimen for 78 weeks (observed for
154 weeks). Increased Incidences of hepatomas (4, 2, 9 and 14%) and lung
tumors (11, 12, 26 and 30%) occurred 1n some of the treated groups of male
Swiss mice. The Incidences were significantly Increased at the high and
0046H -25- 02/29/88
-------
mid-exposure concentrations for lung tumors, and at the high concentration
for liver tumors. Although lung tumors were not significantly Increased In
female Swiss mice, the Incidence data (15/90, 15/89, 13/90, 20/89) suggested
a trend. Incidences of hepatomas (2/90, 4/90, 4/89, 9/89) and pulmonary
tumors (2/90, 6/90, 7/89, 14/87) were Increased among treated female B6C3F1
(NCI) mice, but the only Increase that was statistically significant was
pulmonary tumors In the high dose group. The Increase 1n total number of
malignant tumors among the females was statistically significant at all
exposure levels. The study In male B6C3F1 (CRL) mice was conducted because
survival of the male B6C3F1 (NCI) mice was reduced due fighting. Among male
B6C3F1 (CRL) mice, tumor Incidences were not Increased at any of the
exposure levels when compared with controls.
4.2.3. Selected Pharmacok1net1cs Relevant to Dose-Response Estimates. A
complete discussion of the pharmacoklnetlcs of tHchloroethylene Is outside
the scope of this document. The pharmacoklnetic data are extensively
reviewed 1n U.S. EPA (1985). A brief summary of the data relating to satu-
ration kinetics Is Included here since these data are an Integral part of
dose estimates used for quantitative risk assessment for trlchloroethylene.
Experimental data Indicate that the magnitude of trlchloroethylene
metabolism 1s dose-dependent 1n rodents, showing saturation kinetics 1n both
the mouse and rat at high dose levels. The dose required for saturation
appears to be -2000 mg/kg 1n mice and between 500 and 1000 mg/kg 1n rats.
Experimental evidence Indicates that metabolic pathways for trlchloro-
ethylene are qualitatively similar among mice, rats and humans (U.S. EPA,
1985).
Studies regarding trlchloroethylene metabolism considered by U.S. EPA
(1985) to be most relevant to Interspedes dose-response extrapolation are
summarized In the following paragraphs.
0046H -26- 03/08/88
-------
Prout et al. (1985) administered l4C-tr1ch1oroethylene 1n corn oil as
single 1ntragastr1c doses of 10, 500, 1000 and 2000 mg/kg to male Osborne-
Mendel and W1star-der1ved 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 are shown In 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 In 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.
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 quan-
tifying urinary metabolites (TCA and TCE-glucuron1de). These data are shown
In Table 4-3. The fractional metabolism appeared to be constant across time
although the ratio of TCA to TCE-g1ucuron1de Increased. These data Indi-
cated that trlchloroethylene did not accumulate significantly with repeated
dally dosing.
DeKant et al. (1984), using balance studies, compared the metabolism of
trlchloroethylene In female Wlstar rats and female NHRI mice. A single
gavage dose of 200 mg/kg l*C-tr1chloroethylene was administered to each
animal. Radioactivity was measured 1n urine, feces, carcass and exhaled air
for 72 hours after administration. Virtually complete oral absorption was
apparent. Data are shown 1n Table 4-4. The amount of trlchloroethylene
0046H -27- 03/08/88
-------
: o"
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TABLE 4-3
Metabolism of TMchloroethylene In B6C3F1 Mice:
Effect of Chronic Dos1nga (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
bBased on experimental weight of mice averaging 30 g, the dally dose per
mouse equals 30 mg 1n 0.5 corn oil.
0046H -29- 03/08/88
-------
TABLE 4-4
Disposition of 14C-Tr1chloroethylene Radioactivity for 72 Hours
After Single Oral Doses (200 mg/kg) to Rats and Mice (NMRI)a
Mice (average of 3)b
Absolute dose 5.1 mg/an1mal
mg equivalent per animal
Rats (average of 2)D
Absolute dose 48 mg/anlmal
mg equivalent per animal
Expired
Unchanged
Metabolized
i*C02
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
bfiased on experimental weight of animals: female rats, 140 g; female mice,
25.5 g.
0046H
-30-
03/08/88
-------
metabolized by rats and mice, as estimated by U.S. EPA (1985), Is also shown
In Table 4-4. Based on these data, U.S. EPA (1985) estimated the ratio of
metabolized trlchloroethylene as 5.05 for rattmouse. This ratio agrees well
with the estimated surface area ratio for the two species [(240/24.4)
= 4.46].
Buben and 0'Flaherty (1985) examined trlchloroethylene metabolism In
male Swiss-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 for
doses In the range of 0-1600 mg/kg trlchloroethylene. At higher doses,
saturation of metabolism 1s Indicated by an abrupt plateau.
The data of Prout et al. (1985) which were presented In Table 4-2 are
Illustrated graphically 1n Figure 4-1. Using least square regression, these
data were fitted to a M1chaels-Meten type equation of: amount metabolized
(H)=594.1 mg x administered dose (d 1n units of mg/day) * [702.97 mg + d].
This equation was utilized to estimate the animal metabolized doses for each
administered dose 1n the NTP (1982) and NCI (1976) cancer bloassays 1n mice.
Using the conclusions previously discussed, the animal metabolized doses
were then converted to human metabolized doses using a surface area ratio.
U.S. EPA (1987b) utilized a similar approach for the development of an
Inhalation unit risk for trlchloroethylene. In this document the data of
Prout et al. (1985) (see Table 4-2) were combined with that of Stott et al.
(1982) shown In Table 4-5. The pooled data from the Inhalation and oral
exposures were evaluated using linear regression and the resultant relation-
ships between trlchloroethylene exposure (TCI) In units of mg/kg and total
trlchloroethylene metabolites (TTCIM) 1n mgs are shown for rats and mice In
Figures 4-2 and 4-3, respectively.
0046H -31- 03/08/88
-------
MO
1*00
00
«00
1000 1UO
TCI DOSAGE,
FIGURE 4-1
Relationship between administered single oral doses of 14C-TC1 to rats
and mice and amount of dose metabolized 1n 24 hours, expressed as mg/kg bw,
as calculated from l4C-rad1oact1v1ty excreted 1n urine, feces and expired
air (other than unchanged 14C-TC1). Each data point represents four rats
or mice.
Source: U.S. EPA, 1985
-------
TABLE 4-5
Metabolism of Radlolabeled Trlchloroethylene 1n Rats
and Mice Following a 6-Hour Exposure Period*
ppm
Rats
10
600
Mice
10
600
Total uptake
(mg/rat)
1.18
35.31
0.36
14.4
Exhaled
(mg)
0.03
7.46
0.003
0.346
Metabolized
(mg)
1.15
27.82
0.36
14.0
'Source: U.S. EPA, 1987b
Data of Stott et al., 1982
0046H -33- 03/08/88
-------
1
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2 sis
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1-1 £«
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0046H
-34-
03/08/88
-------
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i
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60 o«
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a
co
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0046H
-35-
03/08/88
-------
Transformation of these curves Into ppm exposure vs. metabolized dose
are shown 1n Figures 4-4 and 4-5 for rats and mice, respectively. These
curves were constructed by first estimating the amount of trlchloroethylene
Inhaled using estimated ventilating volumes. These curves Illustrate a two-
compartment solution with a log-log solution 1n the first compartment and a
L1neweaver-Burk solution for the second compartment.
The data from Figures 4-4 and 4-5 are presented In tabular form 1n Table
4-6. It Is these metabolized dose estimates which form the basis for the
quantitative risk estimates for Inhalation exposure.
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-
genlclty caused by contaminants, purified trlchloroethylene has been tested.
Purified trlchloroethylene caused Increased mutagenesls In Salmonella typhl-
murlum (Bartsch et al., 1979; Baden et al., 1979; Simmon et al., 1977), and
In Saccharomyces cerevlslae, strains D4 and 07 {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 In Drosophlla melanoqaster. Trlchloroethylene did not Induce dominant
lethal mutations 1n NMRI-Han/BGA mice (Sladk-Erben et al., 1980). Results
of mutagenlcHy testing In the mouse spot test, however, were positive
(Fahrlg, 1977).
Negative results were observed 1n mouse skin painting and subcutaneous
Injection studies with trlchloroethylene (Van Duuren et al., 1979) and
trlchloroethylene epoxlde (Van Duuren et al., 1983).
0046H -36- 03/08/88
-------
II
o
I/I
=
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o ^
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a
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N
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bU «^
oe < « «/>
SS
c« =
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*' ^B
** i^ O
«0 ^ CO
86 o
^"
lo
11
I I I I I I I
^ n N * .O
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o
4-«
0,2
Si
s
un o £ <:
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0046H
-38-
01/11/88
-------
TABLE 4-6
Predicted Relationship Between Inhalation Exposure
Level and Trlchloroethylene Metabolites*
Airborne TCI
Concentration
(ppm)
600
450
300
150
100
50
10
Predicted TTCIM
Rat (200 g)
21.81
18.19
13.85
8.83
5.85
3.57
0.96
(mq)
House (30 g)
10.2
7.87
5.45
2.91
1.74
1.08
0.25
*Source: U.S. EPA, 1987b
0046H
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4.4. WEIGHT OF EVIDENCE
Inhalation of trlchloroethylene has caused pulmonary adenocarclnomas
(Fukada et al., 1983); lymphomas (Henschler et al., 1980) In female mice,
and hepatocellular carcinomas 1n both male and female mice (Bell et al.,
1978) and leydlg cell tumors 1n male rats. Oral exposure to trlchloro-
ethylene has caused hepatocellular carcinomas 1n both male and female mice
(NCI, 1976; NTP, 1982). This constitutes sufficient evidence of cardno-
genldty In animals since carclnogenldty has been demonstrated for multiple
strains of mice exposed by Inhalation or gavage treatment. The evidence for
cardnogenlclty In humans Is Inadequate to demonstrate or refute a carcino-
genic potential. Based on EPA carcinogen risk assessment guidelines (U.S.
EPA, 1986a), the overall weight of evidence for cardnogenlclty of
trlchloroethylene was classified In Group 82 - Probable Human Carcinogen.
This classification system and ranking Is contained In several recent Agency
analyses (U.S. EPA, 1985, 1986b,c, 1987a,b).
U.S. EPA (1987b) also noted that a metabolite of trlchloroethylene, TCA,
has been shown to Induce liver carcinomas In male mice, thus further
supporting the Group B2 classification.
0046H -40- 03/08/88
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5. REGULATORY STANDARDS AND CRITERIA
The current OSHA (1985) standards for occupational exposure to trl-
chloroethylene are air concentrations of 100 ppm as an 8-hour TWA and 200
ppm as a celling. The acceptable maximum peak above the acceptable celling
concentration Is 300 ppm for 5 minutes In any 2 hours. Trlchloroethylene Is
regarded as a potential carcinogen by OSHA. NIOSH has proposed an 8-hour
TWA of 25 ppm for trlchloroethylene {Page and Arthur, 1978). The ACGIH
(1986) currently recommends a TWA-TLV of 50 ppm (270 mg/m3) and an STEL of
200 ppm (1080 mg/m3) for trlchloroethylene.
A 10~5 risk level ambient water concentration of 27 yg/i was
derived by the U.S. EPA (1980a). This value assumes a dally Intake of 2 I
water and 6.5 g fish and shellfish with a BCF of 10.6, and was calculated
from a q * of 1.26xlO~2 (mg/kg/day)"1 that was derived from the NCI
(1976) bloassay. More recently, U.S. EPA (1986b) estimated a concentration
of 2.8 yg/i In drinking water associated with an excess cancer risk of
10~6 using the recent EPA approach, which 1s discussed In Chapter 6.
U.S. EPA (1985) estimated a unit risk for trlchloroethylene 1n air of
1.3xlO~6 (wg/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 bio-
assays. The oral q * was converted to an Inhalation unit risk based on
human pharmacoklnetic data. U.S. EPA (1987b) has provided a unit risk
estimate for Inhalation of 1.7xlO~* (vg/m3)"1 based upon more recent
Inhalation data.
0046H -41- 03/08/88
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6. RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfDc)
x>
Trlchloroethylene 1s a chemical that 1s demonstrated to be a carcinogen
In experimental animals, and data are sufficient for estimation of carcino-
genic potencies by both the oral and Inhalation routes. It Is Inappro-
priate, therefore, to calculate an oral or Inhalation Rfl)_ for this
chemical.
6.2. REFERENCE DOSE (RfD)
Trlchloroethylene 1s a chemical that 1s demonstrated to be a carcinogen
1n experimental animals, and data are sufficient for estimation of carcino-
genic potencies by both the oral and Inhalation routes. Based upon the
guidelines for this series of documents, an oral or Inhalation RfD for this
chemical 1s not calculated. It should be noted that an RfD for the non-
carcinogenic effects of trlchloroethylene 1s currently under review by the
Reference Dose Workgroup of the U.S. EPA.
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 (1980b) for the data from both the NCI (1976)
and NTP (1982) studies. These data are shown In Table 6-1.
Metabolized doses (see Table 6-1) were calculated from doses administered
to rodents based on the data from Prout et al. (1984) using a "Mlchaeles-
Menton" type equation, M=a x (d/bnl): d represents the experimental 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 In terms of
0046H -42- 03/08/88
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TABLE 6-1
Incidence Rates of Hepatocellular Carcinomas In Hale and Female Mice
1n the NTP (1982) and NCI (1976) Gavage Studies8
Study
NTP
NCI
NTP
NCI
Continuous Human
Equivalent (animal
nominal) Doses
(mg/kg/day)b
0
47.39b
0
45.11
85.80
0
45.62
0
31.65
61.43
(0)
(1000)
(0) H
(1169)d
(2339)d
(0)
(1000)
(0) A
(869)d
(1739)d
Animal
Metabolized
Dose
(mg/day)
MALE
0
31.98C
0
30.90C
58.77C
FEMALE
0
28.17C
0
18.49C
35.89C
Incidence Rates
No. with Tumor/Total
(%)
8/48 (17%)
30/50 (60%)
1/20 (5%)
26/50 (52%)
31/48 (6554)
2/48 (4%)
13/49 (27%)
0/20 (0%)
4/50 (8%)
11/47 (23%)
aSource: U.S. EPA, 1985
bAll 95% upper-limit slopes q-j* calculated using continuous human equiv-
alent doses.
Equivalent human dosage
(Wa/70)1}3
animal metabolized dose x 5/7 days x lc/Lc
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.
Lc, the length of experiment, = 2 years and lc, the duration of
exposure, 1s 2 years for the NTP study and 1.5 years for the NCI study.
°Determ1ned using data from Prout et al. (1984) and a "MUhaeles-Menton"
type equation by U.S. EPA (1985)
dTWA gavage dose over 78-week treatment period.
0046H
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metabolized dose using a surface area approximation. Human q,*s In 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).
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.lxKT2 (mg/kg/day)'1. This value has been verified and
1s available on IRIS (U.S. EPA, 1987a).
6.3.2. Inhalation. U.S. EPA (1985) estimated a unit risk for tMchloro-
ethylene In air of 1.3x10"* (vg/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 jig/m3 of trlchloroethylene In
air.
The median amount metabolized by four subjects exposed to 70 ppm for 4
hours 1s 439 mg. Assuming that the dose metabolized 1s linearly related to
the level and duration of exposure, the dose corresponding to 1 vg/m3 of
trlchloroethylene In air was estimated as:
439 mg x (24 hours/4 hours)
^ - -
. ...
dose/1 ,..-.,-
70 ppm x 5475 mg/m3/ppm
= 6.9xlO~3 (mg/dayMvg/m3)'1
= 6.9xlO~3/70 kg = 9.9xlO~5 (mg/kg/day)~^
Therefore, the unit risk for trlchloroethylene 1n air Is 1.3xlO~2 (mg
metabolized trlchloroethylene/kg/day)'1 x 9.9xlO~5 (mg metabolized
trlchloroethylene/kg/day/vg/m3) = 1.3x!0~* (vg/m3)'1 expressed
1n terms of ambient concentration.
0046H -44- 03/08/88
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TABLE 6-2
Estimated Slope Values (q-|*) Based on Extrapolation from
Data on Hale and Female M1cea»D
Study
Geometric mean
q-l*
(Animal)
(mg metabolized
dose/kg/day)'1
1.0xlO~3
q-,*
(Human)
(mg metabolized
dose/kg/day)'1
1.3xlG~2
(Human)
(mg administered
dose/kg/day)"1
NTP
male mice
female mice
NCI
male mice
female mice
1.8xlO~3
7.5xlO'4
1.6xlO~3C
5.0xlO~«c
2.2xlO"2
9.5xlO~3
2.1xlO'2
6.9xlO"3
1.9xlO~2
8.0xlO"3
1.8xlO~2
5.8xlO~3
l.lxlO'2
aSource: U.S. EPA, 1985
bq-j* 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 because the
was less than the Hfespan of the test animal.
duration of the experiment
0046H
-45-
03/08/88
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In a more recent assessment, U.S. EPA (1987b) utilized animal Inhalation
bloassays to calculate a unit risk for Inhalation exposure. The data sets
chosen for quantitative analysis were: Leydlg cell tumors In male rats
(Maltonl et al., 1986); liver and lung tumors 1n male Swiss mice (Maltonl et
al, 1986); lung tumors 1n female swiss mice (Maltonl et al., 1986), liver
and lung tumors In female B6C3F1 mice (Maltonl et al., 1986) and lung tumors
In female ICR mice (Fukada et al., 1984).
Animal metabolized doses were estimated for each experimental exposure
condition utilizing the data shown 1n Table 4-5. Extrapolation from the
doses shown 1n Table 4-5 to those shown In Table 6-3 Involved First extrap-
olating to animals of different body weight by multiplying the dose from
Table 4-5 by the 2/3 power of body weight. The doses were then corrected
for a 7-hour vs. a 6-hour exposure by multiplying by 7/6. In addition the
animal doses were converted Into estimated human equivalent metabolized
doses by using the ratio of the body weights to the 2/3 power. These doses
were further adjusted by multiplying by the percent of the animals lifetime
that the experimental time period represented. An animal lifetime of 28
months was assumed for this calculation. As a result, the human HEDs In
Table 6-3 derived from studies using Swiss and B6C3F1 mice were multiplied
by 0.133 to account for 78 weeks of exposure, 5 days/week, 7 hours/day and
the HEDs derived from the study using ICR mice (107-week exposure) were
multiplied by 0.183.
Similarly, the data for metabolized dose and human equivalent dose for
Sprague-Dawley rats are shown In Table 6-4. For this 104-week study,
exposure time adjusted doses could be calculated by multiplying by 0.178.
The U.S. EPA (1987b) then calculated slope estimates (q^) utilizing
the multistage model for each of these data sets. Slope estimates were
0046H -46- 03/08/88
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TABLE 6-3
Summary of Estimated Metabolized Dose from the Animal Bloassays,
Corresponding Human Equivalent Dose (HED) and
Tumor Incidence for the Mouse Bloassays*
Trlchloroethylene
Exposure
Swiss
Swiss
B6C3F1
Mice, Male (47
600
300
100
0
Mice, Male (40
600
300
100
0
Mice, Female (
600
300
100
0
ICR Mice, Female (40
450
150
50
0
Metabolized
Dose (mq)
Animal
grams)
16.1
8.59
2.74
grams)
14.4
7.71
2.46
32 grams)
12.4
6.64
2.12
grams)
11.1
4.12
1.53
HED
2148
1148
367
2148
1148
367
2148
1148
367
1658
613
227
Lung Liver
Tumor Tumor
Incidence Incidence
27/90 13/90
23/89 8/89
11/89 2/89
10/89 4/88
20/89
13/90
15/89
15/90
14/87 9/89
7/89 4/89
6/90 4/90
6/90 3/90
11.46
13/50
5/50
6/49
Reference
Maltonl
et al.,
1986
Maltonl
et al.,
1986
Maltonl
et al..
1986
Fukada
et al.,
1983
'Source: Adapted from U.S. EPA, 1987b
0046H
-47-
03/08/88
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TABLE 6-4
Summary of Estimated Metabolized Dose from the Rat Bloassay,
Corresponding Human Equivalent Dose (HED)and Tumor Incidence*
TMchloroethylene
Exposure
600
300
100
0
Metabolized
Dose (mq)
Animal HED
52.0 1289
33.0 818
13.9 346
Leydlg
Cell Tumor
Incidence
31/129
30/130
16/130
6/135
Reference
Fukada
et al.,
1983
*Source: Adapted from U.S. EPA, 1987b
0046H
-48-
03/08/88
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calculated both by using body weight as the scaling factor and by using
2/3
estimated surface area ((weight) ) as the scaling factor. The estimates
seemed to be 1n closer agreement when a surface area assumption was uti-
lized. These data are shown 1n Table 6-5. The slope estimates are all In
the same range as that calculated by U.S. EPA (1985), 1.3xlO~2, based upon
mouse gavage studies.
The geometric means of the mouse potency estimates were 8.7xlO~3 and
1.7xlO~2 (mg/kg/day)"1 for the liver and lung, respectively. The higher
of the two values was chosen for use 1n subsequent extrapolations. This
value was chosen over that based upon the Leydlg cell tumors 1n male rats
for several reasons: the fact that It reflects a first pass effect
resulting from Inhalation and because 1t 1s based on a response seen In
multiple mouse strains and In both sexes (U.S. EPA, 1987b).
This q * was then converted Into a unit risk for Inhalation exposure
by utilizing the same data base described In Section 6.3.2. where H was
estimated that exposure of humans to air containing 1 yg/m3 should
result In a metabolized dose of lxlO~4 mg metabolized trlchloroethyl-
ene/kg/day. Therefore the unit risk for Inhalation exposure to trlchloro-
ethylene was calculated as follows:
[1.7xlO~2(mg metabol1zed/kg/day)~l]x[lxlO~« mg metabol1zed/kg/day/vg/m3]
= 1.7xlO~« (vg/m3)'1
0046H -49- 03/08/88
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TABLE 6-5
Human q-j* Estimates per (mg metabolized dose/kg/day)*
Data
Hale Rats
Leydlg cell
Swiss Hale Mice
Liver
Lung
Swiss Female Mice
Lung
B6C3F1 Female Mice
Liver
Lung
ICR Female Mice
Lung
qi*
2.7xlO~
1.1x10"
2.4x10"
9xlO~3
7.1x10"
1.3x10"
2xlO"3
3
2
S
a
2
*Source: Adapted from U.S. EPA, 19875
0046H -50- 03/08/88
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Luz, A. 1977. The range of Incidence of spontaneous neoplastlc and
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0046H -57- 03/08/88
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QQ46H -58- 03/08/88
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0046H -59- 03/08/88
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0046H -60- 03/08/88
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U.S. EPA. 1983. Review of lexicological Data In Support of Evaluation for
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"Evaluation of Potential Cardnogenlclty of Trlchloroethylene." Prepared by
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Washington, DC. December, 1986 Draft.
0046H -61- 03/08/88
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2/18/87). Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH.
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ethylene: Updated Carclnogenldty Assessment for Trlchloroethylene. EPA
600/8-82/006FA. External Review Draft.
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genldty of halogenated oleflnlc and aliphatic hydrocarbons 1n mice. J.
Natl. Cancer Inst. 63: 1433-1439. (Cited 1n U.S. EPA, 1981)
Van Duuren, B.L., S.A. Kline, S. Melchlonne and I. Seldman. 1983. Chemical
structure and carclnogenldty relationships of some chloroalkane oxides and
their parent aleflns. Cancer Res. 43: 159-162. (Cited 1n U.S. EPA, 1985)
Wilson, J.T., C.G. Enfleld, W.J. Dunlop, R.L. Cosby, D.A. Foster and L.B.
Baskln. 1981. Transport and fate of selected organic pollutants 1n a sandy
soil. J. Environ. Qual. 10: 501-506.
York, R., B. Sowry, L. Hastings and J. Hanson. 1981. Evaluation of the
prenatal toxldty of methyl chloroform. Tox1colog1st. 1(1): 28 (abstract).
(CHed In U.S. EPA, 1980a, 1982)
Zenlck H., K. Blackburn. E. Hope. N. Rlchdale and M.K. Smith. 1984.
Effects of trlchloroethylene exposure on male reproductive function 1n rats.
Toxicology. 31(3-4): 237-250.
0046H -62- 03/08/88
-------
Z1gl1o, G., G.M. Fara, G. BeltramelH and F. Pregllasco. 1983. Human
environmental exposure to tMchloro- and tetrachloroethylene from water and
air In Milan, Italy. Arch. Environ. Contam. Toxlcol. 12(1): 57-64.
Zoeteman, B.C.J., K. Harmsen, G.B.H.J. Llnders, C.F.H. Horra and W. Slooff.
1980. Persistent organic pollutants 1n river water and groundwater of the
Netherlands. Chemospnere. 9: 231-249.
0046H -63- 03/09/88
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for Carcinogens for TMchloroethylene. On-Hne. (Preparation date:
2/18/87). Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH.
U.S. EPA. 1987b. Addendum to the Health Assessment Document for TMchloro-
ethylene: Updated CardnogenlcHy Assessment for TMchloroethylene. EPA
600/8-82/006FA. External Review Draft.
Van Duuren, B.L., B.M. Goldschmldt, G. Lowengart, et al. 1979. Cardno-
genlcHy of halogenated oleflnlc and aliphatic hydrocarbons 1n mice. J.
Natl. Cancer Inst. 63: 1433-1439. (Cited 1n U.S. EPA, 1981)
Van Duuren, B.L., S.A. Kline, S. Melchlonne and I. Seldman. 1983. Chemical
structure and carclnogenlcUy relationships of some chloroalkane oxides and
their parent aleflns. Cancer Res. 43: 159-162. (Cited 1n U.S. EPA, 1985)
Wilson, J.T., C.G. Enfleld, H.J. Dunlop, R.L. Cosby, D.A. Foster and L.B.
Baskln. 1981. Transport and fate of selected organic pollutants 1n a sandy
soil. J. Environ. Qua!. 10: 501-506.
York, R., B. Sowry, L. Hastings and J. Hanson. 1981. Evaluation of the
prenatal toxldty of methyl chloroform. lexicologist. 1(1): 28 (abstract).
(Cited 1n U.S. EPA, 1980a, 1982)
Zenlck H., K. Blackburn, E. Hope. N. Rlchdale and H.K. Smith. 1984.
Effects of trlchloroethylene exposure on male reproductive function 1n rats.
Toxicology. 31(3-4): 237-250.
0046H -62- 03/08/88
-------
Zlgllo, G., G.H. Fara, G. Beltramelll and F. Pregllasco. 1983. Human
environmental exposure to tMchloro- and tetrachloroethylene from water and
air In Milan, Italy. Arch. Environ. Contam. Toxlcol. 12(1): 57-64.
Zoeteman, B.C.3., K. Harmsen, J.B.H.J. Llnders, C.F.H. Morra and W. Slooff.
1980. Persistent organic pollutants In river water and groundwater of the
Netherlands. Chemosphere. 9: 231-249.
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