I UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
J WASHINGTON. O.C. 204^0
March 9, 1988
HOn. I*e M, Thomas SAB-EHC-S8-012
Administrator
U.S. Environmental Protection
Agency rH
401 M Street, SW
Washington, D.C. 20460
Bear Mr- Thomas^
The Halogenated Grganics Subcommittee of the Science Advisory Board's
Environmental Health Conmittee met on August 13-14 1987 to evaluate the
scientific adequacy of the Office of Research and Development's July 1987
Draft Addendum to the Health Assessment Document for Triehloroethylene.
The attached report completes the Subcommittee's evaluation of this
document.
The Subcommittee's conclusions and reccnmendations for the major issues
in the review include the following?
o In general, the document has evaluated the relevant studies and present-
ed their strengths and weaknesses in a balanced manner.
o Die evidence for the carcinogenieity of triehloroethylene in animals
is appropriately discussed in the draft Addendum. However, the Addendum
should place greater emphasis upon such issues as: the inconsistency
among many experiments because of the number of apparent negative as well
as positive results; the possibility that the parent compound is a tumor
inducing agent: and, in the context of metabolism and pharmaeokinetic
data, discussion of the _in vitro and in vivo data that suggest that
triehloroethylene is a weakly genotoxic agent.
o The overall weight of evidence lies on the continuum between the
categories 62 and C of EPA's risk assessment guidelines for cancer.
The Subecratdttee's major concern with the Addendum, and with the
classification system of the guidelines, is that the relatively
moderate tumor responses and the uncertainties regarding most of the
assumed endpoints are not adequately presented.
o Triehloroethylene has the potential to cause cancer in humans, but its
potency is low. Current scientific evidence reports liver tumors in
two strains of mice by two routes of administration, lung tumors in
mice by inhalation and renal tumors in rats following gavage. There
is also limited evidence for lymphonas in rats and mice, forestomaeh
tumors in mice and testicular interstitial cell tumors in rats.
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We appreciate the opportunity to conduct a scientific evaluation of
this compound. In behalf of the Subccramittee, we request that the Agency
formally respond to the scientific advice provided in the attached report,
Sincerel
,
Norton Nelson, Chair
Executive Committee
Halogenated Cftrganics
idtmittee
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Report of the Halegenated Qrganics Subcommittee of the
Office of Research and Development's July 1987 Draft
Addendum to the Health Assessment Document for Trichloroethylene
Major Conclusions and Recoirngndatigrg
1. The draft addendum appropriately evaluated the relevant studies and
presented their strengths and weaknesses. The scientific evidence for the
carcinogenicity of trichloroethylene in animals is appropriately discussed
in the draft addendum.
2. Current scientific evidence reports liver tumors in two strains of
mice by two routes of administration {oral and inhalation)* ihere is also
evidence of lung tumors in mice by inhalation, for renal tumors in rats
following gavage, limited evidence for lymphoraas in rats and mice* fore-
stcmaeh tumors in mice and testieular interstitial cell tunors in rats.
The draft addendum needs to place greater emphasis upon the inconsis-
tency among reported observations across many experiments. U\ere are as many
negative as positive study results, and interpretation of the results re-
quires careful examination of factors such as: the varying purity of the test
substances (sate contain epichlorhydrin, for example); the difficulty in
setting a maximum tolerated dose (MTD) because of cumulative and delayed
toxic effects (many studies used dose rates that were either too high or
too low); varying ages at the start of exposure; differing durations of
exposure? lack of adjustment for early mortality; and under reporting of
the extent of histopathological examinations. As a result, it is not clear
from the draft addendum if the scattered reports of leukemias and testicular
and forestcmach tumors are false positive errors or indicators of widespread
effects.
The endpoints with the most biological plausibility, based upon what
is known about the effects of structurally related compounds, are liver
and lung tumors in mice and renal tumors in rats. liver tumors (benign
and malignant) in mice appear unequivocally related to compound administra-
tion by two routes of exposure in one inbred and one outbred strain of mice.
The incidences in the fJational Ibxicology Program (NTP) 1982 assay are 76 per
cent in male mice compared to about 35 per cent expected (some male control
groups yield 55 or 60 per cent tumors) and 39 per cent in female mice compared
to 10 per cent as an approximate expected rate. While clearly in excess, they
do not approach the incidence of 100 per cent that occurred for chloroform,
for example. This suggests a lower or more moderate potency for trichloro-
ethylene* Three other studies in mice gave negative results, although all
were flawed to sane degree. The flaws involve small group sizes, testing
in only one sex, short duration of treatment, overdosing and unexpectedly
lew tumor incidences in control mice.
Dang tumors did not increase in Swiss mice (slight increase in the low
dose males but not in the high dose males), while in the B6C3F1 mice increases
in the males were observed only at the high dose (if adencmatous hyperplasia
is combined). In a replicate study in the same laboratory, increases were
observed in high dose female but not in male mice. Hie Subcommittee considers
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these types of results as suggestive but not definitive for the mouse lung.
Renal tumors in rats are reported for F344 and s-D rats but not for CM rats.
In F344 male rats, renal adencmas or carcinomas were 0/48 in controls, 2/49
in low dose and 3/49 in the high dose group, in S-D rats, only 5 of 129 high
dose male rats had renal tumors. The Subcommittee does not view these reported.
results as indicative of a potent effect, and recommends that this viewpoint be
expressed in the draft addendum.
3. Hie significant body of _in vitro and in vivo data that suggest that
trichloroethylene is, at best, only weakly genotoxic have not received approp-
riate weight of evidence consideration, particularly when considered in the
context of metabolism and pharmacokinetic data, Ihe draft addendum has also
not seriously evaluated several significant studies implicating the potential
role of hepatic peroxisctne proliferation in mediating trichloroethylene car-
cincgenicity. Instead, it stresses the view of direct acting genotoxic mech-
anisms of carcinogenicity. &n expanded presentation of these points should
be included.
4. Although there is an impressive weight of evidence implicating the
metabolites of trichloroethylene in tumor induction, the possibility should
not be discounted that the actual tumor inducing agent is the parent com-
pound. Ho enhance the completeness of the draft addendum, this possibility
should be discussed at greater length.
5. Unpublished experimental data should either be subjected to quality
assurance checks and external peer review or used in only a limited way, if
at all, as a basis for quantitative risk assessment. Ihe report of studies by
Maltoni using trichloroethylene are incomplete and, thus, of questionable
value. However, his observations of lung tumors in mice, Lsydig cell tumors
in rats and kidney tumors in rats may be considered to be in agreement with
the tfenschler and Fukuda mice studies and the NIP rat studies,
6. Ihe Subcommittee has also reviewed the draft addendum with respect
to genotoxicity (mutagenicity, chromosome aberations and ENA damage) end-
points, Ihe very limited additional data does not lead to a clearer under-
standing of potential genotoxicity than previously existed.
7» Ihe Subccmmittee concludes that trichloroethylene has the potential
to cause cancer in humans, but that its potency is lew. The conclusion in
the draft addendum should be qualified by stating the moderateness of the
tumor responses and the uncertainties of most of the supposed endpoints. It
should be emphasised that chlorinated hydrocarbons are difficult to test
because of the cumulative effects of toxicity and that the weight of evidence
is not necessarily an either/or judgment among the current categories of EPA's
risk assessment guidelines for cancer. Ihe Subccmmittee concludes that the
interpretation of the weight of evidence falls on the continuum between suf-
ficient and limited evidence and could be reasonably judged either way. in
the case of tetrachloroethylene, the mouse liver tumor response was more
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exaggeirated, and a committee of the International Agency for Research on Cancer
(IMC) judged it to have sufficient evidence for carcinogenicity. The same
committee concluded that the animal evidence for trichloroethylene was limited,
although it is not clear whether all of the studies reviewed by EPA were consider^
ed by IMC.
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U.S. Environmental Protection Agency
Science Advisory Board
Environmental Health Ccnroittee
Halogenated Organies Subcomnittee
Roster for August 13-14, 1987 Review of the Draft
Addendum to the Health Assessment Document for Trichloroethylene
Dr. John Doull, Chairman, Professor of Pharmacology and Toxicology, Univer-
sity of Kansas Medical Center, Kansas City, Kansas 66103
DC. Seymour Abrahamson, Vice-chairman, Professor of Zoology and Genetics,
Efepartinent of Zoology, University of Wisconsin, Madison, Wisconsin 53706
Subcommittee Members and Consultants
Dr. Linda Birnbaum, National institute of Environmental Health Sciences, P.O.
Box 12233, Research Triangle park, North Carolina 27709
DC. George T. Bryan, Efepartment of Hunan oncology, University of Wisconsin,
K-4, Room 528, 608 Clinical Science Center, 600 Highland Ave.» Madison,
Wisconsin 53792
Dr. James Bus, Pathology and Toxicology Research, Upjohn Company, Kalamazoo,
Michigan 49001
Dr. Robert Dedrick, Chief, Chemical Engineering Section, National institutes
Hfealth, Building 13, BOOT 3W13, Bethesda, Maryland 20892
DC. David Gaylor, National Center for Toxicologieal Research, Jeffersonf
Arkansas 72079
Dt. Ronald D. Hood, Professor and Coordinator, Cell and Developmental Biology
Section, Department of Biology, University of Alabama, and Principal
Associate, R.D, Hood and Associates, Consulting Toxicolccjists, P.O. 1927,
University, Alabama, 35486
Dr. K, Roger Hornbrook, Department of Pharmacology, P.O. Box 26901, University
of Oklahoma, Oklahoma City, Oklahoma 73190
Dr. Curtis Klaassen, Professor of pharmacology and Toxicology, university of
Kansas Medical Center, 39th and Rainbow Blvd., Kansas City, Kansas 66103
Dr. Karl K. Roman, Department of Pharmacology, Toxicology and Therapeutics,
University of Kansas, Kansas City, Kansas 66103
Dr. Stephen Safe, Department of Veterinary Medicine, Physiology and Pharmacology,
College of Veterinary Medicine, Texas MM University, College Station, Texas
77843-4
Or, Robert Squire, 1515 Labelle Ave., Ruxton, Maryland 21204
Dr. Ihomas Starr, CUT, P.O. Box 12137, Research Triangle Park, North Carolina
27709
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Members of the Environmental Health Ccnroittee
Br. Richard A. Griesemer, Biology Division, Oak Ridge National laboratory,
Martin Marietta Energy Systems, Inc., P.O. Box Y, Oak Ridge, Tennessee
37831
dr. D. Warner North, Principal, Decision Focus Inc., los Altos Office
" Center, Suite 200, 4984 El Candno Real, IDS Altos, California 94022
Or. C. Richard Cothern, Executive Secretary , Environmental Health CowRittee,
Science Advisory Board (A™ 10 IF) , U.S. Environmental Protection Agency,
401 M Street, SW, Washington, D.C. 20460
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