UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
OFFICE OF
THE ADMINISTRATOR
EPA-SAB-EHC-91-Q13
August 16,1991
Honorable William K. Reilly
Administrator
U.S. Environmental Protection Agency
401 M Street, S.W.
Washington, D.C. 20460
Subject: Science Advisory Board's review of the Office of Research and Development draft
document Response to Issues and Data Submissions._Qr\,Th.e... CarcinQgenfcitv of Tetra-
cnloroethvlene fPerchloroethvlenB." EPA/600/6-91/1 Q02A, dated February 1991
Dear Mr. Re!!r
On February 22, 1991, EPA's Office of Health and Environmental Assessment (OHEA) (a
component of the Office of Research and Development) asked the Science Advisory Board
(SAB) to review the above-referenced draft document OHEA wished to revisit issues and
data concerning the identification of hazard, i.e., the weight of the animal evidence bearing
on the potential for human carcinogenlcity of perchloroethylene (hereafter referred to as
"perc" or "PCE"), as well as other issues (noted below). Data have been submitted and
issues raised in public comment connected with a variety of recent Agency rule-making
actions, including action by the Agency's Office of Drinking Water.
Recently-generated laboratory data have led to the development of hypotheses about
the mechanisms of perc tumorigenesls, but the data are still equivocal as to the relevancy of
these hypotheses for human careinogenesis. Consequently, the Agency decided to seek a
new review by the SAB, In general terms, OHEA requested that the Board review the
technical adequacy of discussions concerning the animal cancer data and related ancillary
information, such as mutagenicity and metabolism, and the relationship of this Information
base to a hazard classification of PCE under the Agency's current cancer guidelines. The
Environmental Health Committee met in Bethesda, Maryland, on March 26,1991 to receive
briefings from Agency officials and the public, and to discuss specific issues as the initial
step in the preparation of a report.
The SAB last reviewed perc-related issues in late 1987. The Board's findings,
summarized in a letter to the Administrator (March 9,1988), were that the overall weight-of-
evidence positions perc on the continuum between categories B2 and C,
Printed on Recycled Paper
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It is the Committee's view that the major issues arising from the assessment of perc
have not changed over the past four years, and that SAB's previous response remains
appropriate. The available scientific evidence confirms that perchloroethytene should be
considered as an animal carcinogen, based on three endpoints in two species: liver tumors
in male and female mice, kidney tumors in male rats, and, possibly, mononuclear cell
leukemia in male and female rats. Complications within each study and in their biological
interpretations have made it difficult to categorize this compound. We do not consider the
evidence strong enough to classify this compound as a probable human carcinogen (i.e.,
B2); on the other hand, the evidence for carcinogenicity is stronger than for most other
compounds classified as possible human carcinogens (i.e., C). Therefore, in the spirit of the
flexibility encouraged by the Guidelines, our best Judgment places this compound on a
continuum between these two categories,
The SAB Executive Committee (EC) examined this conclusion at their July 23 meeting.
In particular, they discussed a concern of one Member that the EHC report arrived at a B2-
to-C classification by 'telescoping" the two-step qualitative and quantitative risk assessment
process into one, contrary to typical EPA and International Agency for Research on Cancer
(IARC) practice. However, both the EC and the EHC are aware that qualitative weight-of-
evidence decisions made by the Agency have risk management impacts beyond EPA.
Therefore, while risk management decisions are generally beyond the purview of the SAB,
we feel that it is important to be as precise as possible about our views on the classification
of this chemical, independent of quantitative considerations. In this case, that has meant
moving beyond the current classification system, which albeit simplistic, is useful in dealing
with the majority of chemicals.
Perchloroethylene, however, is an example of a chemical for which there is no com*
pelling evidence of human cancer risk, but for which reductions in unnecessary human
exposure might well be prudent. The available scientific information does not suggest to us
the same regulatory responses that would be appropriate for a chemical whose bioassay
responses were clearly relevant to human cancer.
The SAB is sensitive to the concerns of some that its recommended classification may
appear to place perc beyond the reach of regulation, but does not see this classification as
a retreat from pybli'c health concerns. As we noted to then-Administrator Thomas in a 1988
dialogue on perc,"... the distinction between the B2 and C categories can be an arbitrary
distinction on a continuum of weight-of-evidence... From a scientific point of view, it seems
inappropriate for EPA and other agencies to regulate substances that are classified 82 and
not to consider regulations of compounds classified as C, regardless of the level of human
exposure... A substance classified as C (limited evidence in animals) for which human
exposure is high may represent a much greater threat to human health."
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We recommend that the Agency continue its risk assessment effort on perchloroethyl-
ene, not only to improve the risk management for this widely-used solvent, but to serve as a
model for addressing other chemicals that present similar ambiguities of interpretation. It
would be especially helpful for future evaluations of such chemicals if the Agency focused
on the implications of recent findings concerning perc for the assessment of dose-response.
The quantitative assessment of the risk should include careful evaluation of the relevance of
the animal endpoints to humans, including species differences, the pharmacokinetlcs of
delivered dose to target organs and metabolite formation, and mechanistic information such
as effects on ceil proliferation. To the extent that such information suggests a departure
from low-dose linearity, as assumed in the linearized multistage model used by EPA as the
default procedure for dose-response assessment, appropriate alternative dose-response
models should be used to explore the implications of available scientific information for
human cancer risk.
The greatest gap in our knowledge arises from the absence of interpretable
epidemiological data. The Agency should work with the relevant industries and other
institutions to assure that further research on the human health risks of exposure to
perchloroethylene is vigorously pursued.
The Science Advisory Board is pleased to have had the opportunity to review the draft
document and to offer its advice. We would appreciate your response to the major points
we have raised, particularly with regard to our position on flexibility in interpreting the current
guidelines.
Dr. Raymond Loelir, Chairman
Science Advisory Board
Or, Bernard Weiss, Acting Chairman
Environmental Health Committee
ENCLOSURE
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. United State* Scieow Admoiy BPA-SAB-mCai-oi3
Environmental Board (M 01) AugiM 1991
Protection Agency
&EPA HEALTH EFFECTS
ASSESSMENT OF
PERCHLOROETHYLENE
REVIEW OF THE OFFICE OF
RESEARCH AND DEVELOPMENT'S
DRAFT DOCUMENT: "RESPONSE
TO ISSUES AND DATA
SUBMISSIONS ON THE
CARCINOGENICITY OF
PERCHLOROETHYLENE
(EPA/600/6-91/002A) BY THE
ENVIRONMENTAL HEALTH
COMMITTEE
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ABSTRACT
On March 26, 1991, EPA's Science Advisory Board (SAB) reviewed the draft Office
of Health and Environmental Assessment (QHEA) document "Response to Issues and
Data Submissions on The Carcinogenicity of Tetrachloroethylene (Perchloroethyiene),"
EPA/600/6-91/1002A, dated February 1991. The Board reviewed the technical adequacy
of discussions concerning animal cancer data and related ancillary information, such as
mutagenicity and metabolism, and the relationship of this information base to a hazard
classification of PCE under the Agency's current cancer assessment guidelines.
It is the Committee's view that the major issues arising from the assessment of
perchloroethylene (perc) have not changed over the past four years, and that SAB's
previous response (SAB-EHC-87-018, January 1987) remains appropriate. The available
scientific evidence confirms that perchloroethylene should be considered as an animal
carcinogen, based on three endpoints in two species: liver tumors in male and female
mice, kidney tumors in male rats, and, possibly, mononuclear cell leukemia in male and
female rats. However, each of these endpoints is problematic with respect to its relevance
for human cancer. The Committee found that the evidence does not warrant designation
of perc as a probable human carcinogen, but noted that the evidence for Carcinogenicity
is stronger than for most other compounds classified as possible human carcinogens.
Therefore, in ih*j spirit of the flexibility encouraged by the Guidelines, the Committee
places this compound on a continuum between these two categories.
Further research, particularly on the epidemiology of human occupational exposure,
is recommended.
KEYWORDS:carcinogen; alpha-2u-globulin; peroxisome proliferation; carcinogen assess-
ment guidelines; perchloroethylene; perc; PCE; liver tumors; mononuclear cell leukemia.
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U, a ENVIRONMENTAL PROTECTION AGENCY
NOTICE
This report has been written as a part of thi activities of the Science Advisory Board, a
public advisory group providing extramural scientific information and advice to the
Administrator and other officials of the Environmental Protection Agency. The Board is
structured to provide balanced, expert assessment of scientific matters related to problems
facing the Agency. This report has not been reviewed for approval by the Agency and,
hence, the contents of this report do not necessarily represent the views and policies of the
Environmental Protection Agency, nor of other agencies in the Executive Branch of the
Federal government, nor does mention of trade names or commercial products constitute a
recommendation for use.
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ENVIRONMENTAL PROTECTION AGENCY
SCIENCE ADVISORY BOARD
ENVIRONMENTAL HEALTH COMMITTEE
Perchloroethylene Review Panel
ACTING CHAIRMAN
Dr. Bernard Weiss, University of Rochester School of Medicine
MEMBERS & CONSULTANTS
Dr, Gary Carlson, School of Pharmacy, Purdue University
Dr. David Gaylor, National Center for Toxicological Research, Department of Health & Human
Services
Dr. Michael A. Gallo, Department of Environmental and Community Medicine, UMDNJ-Rofoert
Wood Johnson Medical School
Dr. Richard A. Griesemer, National Institute of Environmental Health Sciences
Dr, Joe H. Grisham, School of Medicine, University of North Carolina
Dr. Marshall Johnson, Jefferson Mfcuical College
Dr. Nancy K, Kim, New York Department of Health
Dr. D. Warner North, Decision Focus Inc.
Dr. Martha J. Radike, Medical Center, University of Cincinnati
Dr. Stephen M. flappaport, School of Public Health, University of North Carolina
Dr. Thomas S, Wallsten, University of North Carolina
Dr. Ronald Wyzga, Electric Power Research Institute
SCIENCE ADVISORY BOARD STAFF
Mr. Samuel Rondberg, Designated Federal Official, Environmental Health Committee
Science Advisory Board, U.S. Environmental Protection Agency
Ms. Mary L. Winston, Staff Secretary, Environmental Health Committee, Science Advisory
Board
Mr. A, Robert Flaak, Assistant Staff Director, Science Advisory Board
Dr. Donald G. Barnes, Staff Director, Science Advisory Board
in
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TABLE OF CONTENTS
1. EXECUTIVE SUMMARY 1
2. INTRODUCTION » , ..... . 3
2.1 Background .......... ....................... 3
2,2. Charge To The Committee ..,,,,,....,. ,... , 3
a SPECIFIC FINDINGS . 5
3.1 Classification of Fere .. , 5
3.1,1 Classification Issues .. 5
3.1.2 Data for Classification ............. 6
3,1.3 Further Issues re Classification . 7
3.2 Peroxisome Proliferation and Perehloroethylene 9
3.3 AIpha-2-u Globulin , 10
3.4 Epidemiological Data and Issues 11
3.5 Tumor Responses to Perchloroethylene 11
3.6 Developmental Effects of Perchloroethylene 12
4. CONCLUSIONS AND RECOMMENDATIONS ... 14
4.1, Conclusions , , % , 14
4.2 Recommendations ...........V; , 14
5. REFERENCES 16
IV
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1. EXECUTIVE SUMMARf
It Is the Committee's view that the major issues arising from the assessment of
perchloroethyiene (perc) have not changed over the past four years, and that SAB's
previous response (SAB-EHC-87-Q18) remains appropriate. The available scientific
evidence confirms that perchloroethyiene should be considered as an animal carcinogen,
based on three endpoints in two species: liver tumors in male and female mice, kidney
tumors in male rats, and, possibly, mononuclear cell leukemia in male and female rats.
However, each of these endpoints is problematic with respect to its relevance for human
cancer. It is the Committee's judgment that the evidence does not warrant designation of
perc as a probable human carcinogen; note however, that the evidence for carcino-
genlcity j§ stronger than for most other compounds classified as possible human carcino-
gens. Therefore, in the spirit of the flexibility encouraged by the Guidelines, our best
judgment places this compound on a continuum between these two categories.
Perchloroethyiene is typical of a widely used and economically important chemical for
which there is no compelling evidence of human cancer risk. Reductions in unnecessary
human exposure might well be prudent, but the available scientific information does not
mandate the same regulatory actions that would be appropriate if the bioassay responses
were clearly relevant to human cancer.
The Committee is sensitive to concerns that its recommended classification may seem,
to some observers, to place perc beyond the reach of regulation, but does not see its
classification as a retreat from public health concerns. We are convinced that it will
stimulate further research (see below), and ultimately, lead to risk estimates that are
sufficiently precise and dependable to offer a sound basis for risk management by EPA.
In addition, as noted by the SAB in a 1988 letter on perc to then-Administrator Thomas,
"From a scientific point of view, it seems inappropriate for EPA and other agencies to
regulate substances that are classified B2 and not to consider regulations of compounds
classified as C, regardless of the level of human exposure... A substance classified as C
(limited evidence in animals) for which human exposure is high may represent a much
greater threat to human health."
We recommend that the Agency continue Its risk assessment effort on perchloroethyi-
ene in order to improve the risk management for this widely-used solvent. The Agency
should produce a comprehensive health assessment update document summarizing re-
cent findings and their implications for assessment of dose- response. The quantitative
assessment of the risk should include careful evaluation of the relevance of the animal
endpoints to humans, including species differences, the pharmacokinetics of delivered
1
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dose to target organs and metabolite formation, and mechanistic information such as
effects on cell proliferation. To the extent that such information suggests a departure from
low-dose linearity as assumed in the linearized multistage model used by EPA as the
default procedure for dose-response assessment, appropriate alternative dose-response
models should be used to explore the implications of available scientific information for
human cancer risk.
Continued research to resolve uncertainty in the health effects of perc is highly
desirable, particularly in the area of epiderniological data. The Agency should work with
the relevant industries and other institutions to assure that further research on the human
health risks of perchloroethylene is vigorously pursued.
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2. INTRODUCTION
2.1 Background
On February 22, 1991, EPA's Office of Health and Environmental Assessment (QHEA)
(a component of the Office of Research and Development) asked the Science Advisory
Board (SAB) to review the draft document Response to Issues and Data Submissions on
The Cardnogenicity of Tetmchloroethylene (Perchlomethylene), EPA/600/6-91 /1Q02A,
dated February 1991. OHEA wished to revisit issues and review data concerning the
identification of hazard, i.e., the weight of the animal evidence bearing on the potential for
human carcinogenicity of perchloroethylene (hereafter referred to as "pere" or "PCE"),
Data have been submitted and issues raised in public comment connected with a variety
of recent Agency rule-making actions, including action by the Agency's Office of Drinking
\Afeter, In general terms, OHEA requested that the Board review the technical adequacy
of discussions concerning the animal cancer data and related ancillary information, such
as mutagentcity and metabolism, and the relationship of this information base to a hazard
classification of PCE under the Agency's current cancer guidelines,
The subject of a potential cancer hazard from PCE is not a new on© in terms of past
Science Advisory Board /EPA dialogue. The most recent exchange was a letter of advice,
dated March 9, 1988, from the Board to the Administrator regarding the Board's perspec-
tives on this topic; prior to that, in 1986, the Board reviewed a draft addendum to the
Health Assessment for perc, and provided a report (SAB-EHC-87-018, January 1987) to
(then) Administrator Thomas. Since the 1988 interchange, the Agency has continued to
conduct research and to gather data on perc. Recently-generated laboratory data have
led to the development of hypotheses about the mechanisms of perc tumorigenesis, but
the data are still equivocal as to the relevancy of these hypotheses for human carcinogen-
esis. Consequently, the Agency decided to seek a new review by the SAB, the SAB
accepted the request, and the Environmental Health Committee met in Bethesda,
Maryland, on March 26, 1991 to receive briefings from Agency officials and the public, and
to discuss the specific issues (see below) as the initial step in the preparation of a report.
2.21 Charge To Tfce Committee
The "Response to Issues..." document provided to the Committee for review has a
relatively narrow purpose (as noted in its Introduction), compared to the more typical
comprehensive health assessment document that the Committee usually reviews for
OHEA. OHEA's primary objective for the SAB review of the document was to revisit
issues and review data concerning the weight of the animal evidence bearing on the
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potential for human earcinogenieity. An earlier version of this response document is
currently -in the docket for the recently promulgated National Primary Drinking Vfeter
Standard for Tetrachloroethylene as published in the Federal Register on January 30,
1991.
In general terms, QHEA requested that the Committee review the technical adequacy
of discussions in their document concerning the animal cancer data and related ancillary
information, such as mutagenicity and metabolism, and the relationship of this information
base to a hazard classification of PCE under the Agency's current cancer guidelines.1
More specifically, the Committee was requested to focus on the topics and questions
listed below.
a. Technical adequacy of discussions about the three animal bioassay tumor
endpoints.particularly regarding the relevance of these tumor endpoints to
the potential for human hazard at some dose,
b. Technical adequacy of discussions about ancillary information for mutagenic-
ity and metabolism considerations and the appropriate use of this informa-
tion in providing a better understanding of the animal bioassays or the
relevance of these to the potential for human hazard.
c. Have all important issues been identified and appropriately considered,
recognizing that many more fundamental scientific questions may exist but
which may not be developed adequately to meaningfully discuss in a risk
assessment context?
d. The soundness of the rationale used to weigh the evidence, from each
endpoint and in the aggregate for human hazard potential. This topic relates
to the logic of weighing animal evidence including the relevance of ancillary
data to that process.
1 It is important to note that th* concept of "w«ight-otovid»nc«* under EPA'» Cancer Risk Astesament Guideline Idenflfie* an
agent's potential t
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3. SPECIFIC FINDINGS
3.1 Classification of Pere
3.1.1 Classification Issues
There are two issues associated with the classification of perc and other potentially
carcinogenic compounds. First of all, any scheme used for such classification must be
flexible and cannot escape the need for the introduction of scientific judgment into any
specific determination. Secondly, risk management actions are often predicated upon a
chemical's classification status. Other decision criteria, such as the extent of potential
exposures, may be more important or equally important in determining risk management
strategies, and these should be factored into risk management decisions.
One objective of the hazard identification step of risk assessment is to assess the
likelihood that a compound is a potential human carcinogen. The hazard identification
step was defined in the National Academy of Sciences 1983 report, Risk Assessment in
the Federal Government Managing the Process, as
... the process of determining whether exposure to an agent can cause an
increase in the incidence of a health condition (cancer, birth defect, etc.), It
involves characterizing the nature and strength of the evidence of causation,
Although the question of whether a substance causes cancer or other adverse
health effects is theoretically a yes/no question, there are few chemicals on which
the human data are definitive. Therefore, the question is often restated in terms of
effects in laboratory animals or other test systems, e.g.,"Does the agent induce
cancer in test animals?' Positive answers to such questions are typically taken as
evidence that an agent may pose a cancer risk for any exposed humans, (p. 19)
The current Agency Guidelines for Carcinogen Risk Assessment (EPA/6QQ/8-87/045)
state that:
The ... hazard identification part of risk assessment contains a review of the
relevant biological and chemical information bearing on whether or not an agent
may pose a carcinogenic hazard, (Federal Register, 51:33994 (1986))
EPA's Guidelines stress that the following information should be reviewed as part of
the hazard identification process:
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a. physical-Chemical properties and routes and patterns of exposure
b. structure-activity relationships
c. metabolic and pharmacokinetic properties
d. toxicologic effects
e. short-term tests
f. long-term animal studies.
g. human evidence
We agree fully with this position that hazard identification should indude a broad
review of relevant biological and chemical information. We are concerned that Agency
practice tends to weight the results from long-term animal studies most heavily and at
times appears to ignore the other available Information.
The current Guidelines also indicate that for long-term animal studies, "Carcinogenic
responses under conditions of the experiment should be reviewed carefully as they relate
to the relevance of the evidence to human carcinogenic risks." They further state,
"Judgments about the weight-of-evidenee involve considerations of the quality and
adequacy of the data and the kinds and consistency of responses induced by a suspect
carcinogen,"
These Guidelines recommend the evaluation of all available evidence and imply that
considerable judgment is required within the hazard identification component of risk
assessment The portion of the Guidelines responding to public and Science Advisory
Board comments devotes a whole section to mouse liver tumors and the need for
judgment in interpreting this endpoint. Rat mononuclear cell leukemia and male rat kidney
tumors involving the alpha-2-microgIobulin mechanism are other endpoints for which
judgment is required to assess the relevance for human cancer risk.
3.1.2 Data for Classification
In the case of perchtoroethylene the Environmental Health Committee reviewed the
available information and examined in detail the characteristics of the various long-term
animal studies. Complications within each study and in their biological interpretations
have made it difficult to categorize this compound. We do not consider the evidence
strong enough to classify this compound as a probable human carcinogen (Le.» B2); on
the other hand, the evidence for carcinogenicity |§ stronger than for most other com-
pounds classified as possible human carcinogens (i.e., C). Therefore, in -the spirit of the
flexibility encouraged by the Guidelines, our best judgment places this compound on a
continuum between these two categories.
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3.1.3 Further Issues re Classification
This experience with perchloroethylene suggests that when the Guidelines are revised,
their flexibility should be endorsed and strengthened, and that exceptions to a strict
categorization are a practical necessity. It is particularly important to convey any uncer-
tainty or deviation from a strict categorization scheme because many risk management
practices are narrowly tied to the category in which a compound is placed. Tne SAB is
uncomfortable with this practice and believes that deviations from a strict categorization
scheme are appropriate and can help to convey a better sense of the scientific weight-of-
evidence and associated uncertainties to risk managers.
In his tetter of August 3, 1987 to the Science Advisory Board, requesting a reevalua-
tion of the classification of perchloroethylene, Administrator Lee Thomas also expressed
concern about the linkage between weight-of-evidence categorization and risk manage-
ment practice by EPA and other regulatory agencies;
it is important to understand that a decision on the classification of any
compound under the cancer .guidelines is not an EPA decision to regulate
that compound; however, it does weigh heavity on the type or extent of the
possible regulation, especially under certain environmental statutes. A
decision to regulate a compound represents a statement of potential hazard
in the absence of other factors such as exposure. A regulatory decision by
EPA on whether to control the sources of a specific compound, and the
degree of control must necessarily weight hazard, potency, exposure and
other factors. It is clear, however, that EPA's classification of a compound
has major ramifications beyond its use in EPA's own decision making
process. Rightly or wrongly, state environmental decisions and public
perceptions of risk are often triggered by an EPA determination to classify a
compound as a B2 carcinogen. This black-white interpretation of the
classification system is troubling.
As noted earlier, the Science Advisory Board carried out further review of perchloro-
ethylene and responded to the Administrator with a letter report dated March 9, 1988.
The Board provided its advice on hazard identification and weight-of-evidence classifica-
tion of perchloroethylene in responding to the second of three specific questions. This
question and SAB's response were as follows;
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Question 2. What is the Board's view of the approach taken by EPA in
using its guidelines to infer human carcinogenic potential from the total
body of scientific evidence on perchloroethylene?
SAB Response. The issues regarding the application of the risk assess-
ment guidelines appear not to represent disagreement among scientists
about scientific evidence but, rather, the consequence of attempting to fit
the weights of evidence into necessarily arbitrary categories of risk.
Since the weights of evidence, and uncertainties associated with such
evidence, for perehtoroethytene and other compounds fall within a range
of scientifically defensible choice, it may not be possible, in some in-
stances, to fit them neatly into only one risk category. Moreover, the
more incomplete the data, the less precision one can expect in classify-
ing a compound within EPA's cancer guidelines. In addition, the type of
evidence that places a compound in a particular category may vary
considerably from substance to substance within that category. For
perchloroethylene, as with trichloroethylene, the Science Advisory Board
concludes that the overall weight of evidence lies on the continuum
between the categories B2 and C of EPA's risk assessment guidelines
for cancer.
As perchloroethylene illustrates, the distinction between the B2 and
C categories can be an arbitrary distinction on a continuum of weight of
evidence. The "black-white interpretation" that you referred to in your
letter is indeed troubling. From a scientific point of view, it seems
inappropriate for EPA and other agencies to regulate substances that
are classified B2 and not to consider regulations of compounds classi-
fied as C, regardless of the level of human exposure; In the case of B2,
B1, or even A category compounds where exposure levels are low, EPA
may, with scientific justification, decline to regulate because the potential
health effects appear to be trivial in magnitude. A substance classified
as C (limited evidence in animals) for which human exposure is high
may represent a much greater threat to human health.
EPA and other agencies (including those In state governments) may,
therefore, wish to take steps to reduce high exposures to substances in
the C category whenever there appears to be a potentially significant
threat to human health (in the sense that the plausible upper bound
estimate of potency times lifetime exposure is above the threshold where
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regulation may be judged appropriate). Indoor exposure to perchloro-
ethylene, such as might be found in dry cleaning establishments not
using the equivalent of good industrial hygiene practices, could merit
action under this criterion. So might high levels of exposure to other
solvents, pesticides, or industrial chemicals that have been considered
by the public as "safe" in the absence of sufficient evidence of carcino-
genicity in animals. In many instances, this appearance of safety results
from not yet having the results from well-designed bioassays such as
those conducted by the National Toxicology Program.
3.2 Peroxisome Proliferation and Perchloroethylen©
The EPA document on perc has an excellent section on the possible role of
peroxisome proliferation in mouse liver tumorigenesis. The rationale that perc's major
metabolite, trichloroacetic acid (TCA), may be involved is supported by the data being
generated within EPA by DeAngelo and co-workers (1989), The rationalizations that
the higher rate of metabolism in mice (compared to humans) and the ability of this
pathway to brnome saturated lend support to the belief that it is unlikely that humans
would metu- /':''.& perehloroethytene to trichloroacetic acid in sufficient quantities to
cause liver tumors. While this concept of a threshold may be difficult for EPA to
accept from a regulatory perspective, it has been used in Its scientific publication for
dichloroacetic acid (DeAngelo et a!., 1991), The document also does a credible job in
emphasizing that even under in vitro conditions, hepatocytes from mice are more
sensitive to perchloroethylene than are those from rats or humans (albeit from limited
data). The argument is made that, if peroxisome proliferation and carcinogenicity are
causally linked, then there should be a better correlation between the activity of
compounds as peroxisomal prollferators and their efficacy as hepatocarcinogens.
While it would be gratifying to be able to make such a simple comparison, it tends to
ignore other effects that these compounds may have such as cytotoxicity. The
additional question of genotoxicity independent of peroxisomal proliferation is an
important one. However, results presented at the Committee meeting suggest that
the positive effects reported for single-strand breaks in DNA must be approached with
caution since they may not be repeatabie or may be re-lated to some protocol
variation which needs verification. Although there is some discussion (pages 26 and
27 of the draft "response" document) of the relevance of peroxisome proliferation in
humans to tumor formation In a generic sense, the Committee recommends that the
EPA take a much closer and more thorough look at this generic issue since its
resolution applies to many substances other than perc, and to more than issues of
classification. In this regard, since the problem also applies to a number of drugs, it
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may be advantageous to evaluate the approach taken by the FDA in dealing with
peroxisome proliferators.
In addition, the Committee recommends that EPA should initiate or continue
research efforts in two areas. One is the question of whether or not TCA has direct
effects on DNA. The Agency should try to resolve discrepancies that now exist in the
literature. The second is to continue to evaluate the role of peroxisomal proliferation
in tumorigenesis, A great many studies are currently underway throughout the world
which may provide information useful in evaluating this relationship.
3.3 Alpha-2-u Globulin
Exposure to perc is associated with an increased incidence of kidney tumors, but
only in male rats. Similar results have been obtained with other agents, such as
unleaded gasoline. The specificity of this outcome has stimulated considerable
investigation. The mechanism most clearly identified begins with the binding of the
chemical to alpha-2u-globulin, a protein synthesized by male rats, predominantly in
the liver. AIpha-2-u-glohulin accounts for about 30% of total urinary protein excreted
by male rats, but its ft-MUion remains undetermined.
Chronic exposure to perc, gasoline, and the other chemicals inducing male rat
kidney tumors leads to a syndrome termed hyaline droplet nephropathy (hyaline
droplet is a descriptive term for intercellular vacuoles containing amorphous material
by light microscopy), prior to the development of tumors. Hyaline droplet nephropa-
thy, which is virtually unique to the male rat, histotogically features an accumulation of
protein droplets (now known to represent alpha-2u-globutin) in the lysosomes of
proximal tubule epithelial cells. Chemically modified alpha-2u-globulin accumulates
apparently because the chemical-alpha-2u-g!obulin complex is less easily hydrolvzed
(and more slowly excreted) than is the unbound protein. Accumulation of the protein
droplets is correlated with increased cell turnover and the production of tumors, which
appear, to be triggered by increased cell proliferation, and not by direct genotoxiclty
from perc exposure.
Although proteins belonging to the alpha-2u-g!obulin protein superfamily are found
in other species, including humans, the narrow specificity of the renal tumor-protein
accumulation In male rats indicates a questionable relevance to human susceptibility,
which should be carefully evaluated in risk classification. The "Response to Issues,.."
document notes the data implicating such accumulation and its consequences, but
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also argues that events Independent of this process play a role, perhaps the predomi-
nant role, in the perc carcinogenetic response.
The Committee urges EPA to explore further its argument that perc carcino-
genieity is independent of the process described above, consulting with investigators
actively engaged in alpha-2u-globulin research to determine how the discrepant views
might be reconciled.
3.4 EpidemiologicaJ Data and Issues
There are few epidemiologica! data addressing perc. Brown and Kaplan (1987)
conducted a retrospective cohort mortality study of 1690 workers employed in the dry
cleaning industry, in their study, there appears to be an increase in mortality from
cancer of the intestine and cancer of the urinary bladder with Increasing time since
first employment in dry cleaning shops using perc. Also, mortality from cancer of the •
intestine and cancer of the bladder appear to increase with length of employment.
Since dry cleaning workers may be exposed to other petroleum solvents, these
effects cannot b© attributed solely to perc, and there does not appear to be adequate
evidence to establish perc as a hi-v*an carcinogen,
3.5 Tumor Responses to Perchtoroethylene
Three putative tumor responses to perc were reviewed-mononuclear cell leukemia
in F344/N rats, renal tumors in male rats,,and hepatocellular tumors in both sexes of
mice.
The evidence for mononuclear cell leukemias in F344/N rats, one of three putative
tumor responses to perc exposure (along with renal tumors in male rats and hepato-
cellular tumors in male and female mice) now seems to be somewhat weaker than in
the 1987 SAB review, because the incidence of leukemia in control rats was consider-
ably higher in the cited National Toxicology Program (NTP) study (TR 311, 1986} than
expected on the basis of NTP historic data (See Table 1, following). The consistently
higher control rates of this tumor type in the study laboratory, coupled with widely
variable incidence (in comparison with other NTP laboratories) weakens the signifi-
cance of the findings. The findings cannot be disregarded, however.
Renal tumors in male rats have been consistently associated with exposure to
chlorinated hydrocarbons. The incidence from exposure to perc was not greatly ele-
vated (P value of 0.07) but such tumors are uncommon in control rats and included
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CONTROL CONTROt
MALES,, FEMAL
OBSERVED S6% 36%
EXPECTED IN THE 47% ±15% . 29% ±6%
LABORATORY
EXPECTED IN NTP 29% ±12% 12% ±7%
STUDIES
Table i INCIDENCE OF LEUKEMIA, IN F344/N RATS (NTP STUDY TR 311,19%)
two carcinomas (4%) In the high dose group which were not found in untreated
control rats. A possible association with alpha~2u»glGbulin hyaline droplet nephropathy
was discounted. Although hyaline droplets were reported to be found after exposure
to 1,000 ppm for 28 days by inhalation, no hyaline droplets were found at the
carcinogenic doses of 200 and 400 ppm. For these reasons the evidence for renal
tumors was judged to be stronger than in the previous review; it must be noted,
however, that the failure to observe hyaline (fii^plets may be due to the lack of
sensitivity of the crude method used to deteu*droplets. At the same time, more
evidence has accumulated to strengthen the alpha-2u-globulin argument.
Hepatoctllular tumors with greatly exaggerated responses were found in male
and female mice in two studies by inhalation and oral routes of exposure (NCI, 1977
and NTP, 1986), The possibility of association with peroxisome proliferation, (which
was the best hypothesis in 1986) is now less certain. Peroxisome proliferation is not
dose-related, and other mechanisms, including mediation through recently Identified
peroxisome receptors, are possible, it was concluded that the evidence for hepato-
cellular tumors in mice is still strong.
In summary, the available evidence indicates that exposure to tetrachloroethyiene
results in hepatic tumors in male and female mice, renal tumors in mate rats, and,
equivocally, in mononucltar cell leukemia in male and female rate.
3.6 Developmental Effects of Perchloroethylene
The relevant issues regarding perchloroethylene do not involve reproductive or
developmental concerns. Moreover, unlike the assumptions that govern carcinogenio-
"rty, developmental and reproductive toxiclty evaluation assumes that there are
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exposures below which no detectable adverse effects are anticipated. Perc has not
been adequately tested, but, thus far, has not demonstrated the reproductive system
or its support organs to be a primary target, ft is among that group of chemicals that
apparently have little If any propensity to produce terata.
Schwetz et al. (1975) exposed pregnant rats and mice to 300 ppm of perc for 7
hours a day from days 7-15 of pregnancy, and made standard evaluations of the term
fetuses. No frank congenital malformations were produced by this protocol, although,
some mouse fetuses were smalt for gestational age.
Nelson et al. (1980) exposed pregnant rats to 900 ppm perc for 7 hours a day
from days 7-13, as well as to 100 ppm on days 14-20 of pregnancy. Clear maternal
toxicity was evident at 900 ppm. Postnatal sensory, motor, and behavioral measure-
ments of the offspring were made. No consistent postnatal effects were evident,
although brain acetylcholine levels were reduced in the young of 900 ppm treated
mothers at weaning. No effects were reported in mothers or offspring at the 100 ppm
exposure level.
No useful human epidemiological studies of the efft^cl of perc exposure during
gestation were located. Also, apparently absent from the published literature, are
studies examining effects of perc specifically on either male or female reproductive
performance. The topics of reproductive and developmental toxicity quite properly
were not a focus of the EPA's issues for review, and were not addressed in the draft
response document, in that adult systemic target organ toxicity is the real issue.
Addressing reproduction and development in the document, at least In passing, ,
would be useful to complete the picture, and, particularly, in view of the large data
gaps, the undetermined No Observed Adverse Effects Level (NQAEL) for some
aspects of development, and significant human exposure potential. Perc should not
be listed as a teratogen at any level of exposure yet studied.
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4. CONCLUSIONS AND RECOMMENDATIONS
4.1 Contusions
Based on our review of EPA's draft issue paper, Response to Issues ancl Dafa
Submissions on the Carcinogenicity of Tetrachloroethylene (Perchlofoethylene)
EPA/600/6-91/002A, and the discussion at the public meeting March 26,1991, we
believe that the major issue has not changed over the past four years, and that SAB's
previous response remains appropriate. The scientific evidence that has emerged
over the past four years has confirmed that perchloroethytene should be considered
as an animal carcinogen based on three endpoints in two species: Jiver tumors in
male and female mice, rat kidney tumors in male rats, and, possibly, mononuclear cell
leukemia in rats. Each of these endpoints is problematic with respect to its relevance
for human cancer. It is the Committee's judgment that the evidence does not warrant
designation of perchloroethytene as a probable human carcinogen, with the implica-
tion that such a designation carries for federal and state regulation.
Perchloroethytene is a prototype of a widely used and econorr ;\!Sy Important
chemical for which there is no compelling evidence of human cer^c,; 'risk, accompa-
nied by animal data of carcinogenlcity whose extrapolation to humans is ambiguous.
Such situations may occur with some frequency, and they should not cause paralysis
in regulatory action. For such chemicals, pollution prevention and reductions In
unnecessary human exposure could be prudent measures to take now to safeguard
public health. However, at this time the available scientific information does not
mandate the same regulatory actions as would be appropriate if the bioassay
responses were clearly relevant to human cancer.
We wish to note here that the Committee is sensitive to concerns that its recom-
mended classification may seem, to some observers, to place perc beyond tie reach.
of regulation. As we noted to then-Administrator Thomas in a 1988 dialogue on perc,
"... the distinction between the B2 and C categories can be an arbitrary distinction on
a continuum of weight of evidence.,., From a scientific point of view, it seems inappro-
priate for EPA and other agencies to regulate substances that are classified B2 and
not to consider regulations of compounds classified as C, regardless of the level of
human exposure... A substance classified as C (limited evidence in animals) for which
human exposure is high may represent a much greater threat to human health."
The Committee's mandate, however, is to provide objective scientific advice; risk
management is the Agency's function and domain. In light of the above comments,
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the Committee does not believe that its classification is a retreat from public health
concerns. On the contrary, it is convinced that it will stimulate further research (see
below), and ultimately, lead to risk estimates that are sufficiently precise and depend-
able to offer a sound basis for risk management
4.2 Recommendations
We recommend that the Agency continue its risk assessment effort on perchloro-
ethylene in support of risk management for this widely-used solvent. The Agency
should produce a comprehensive health assessment update document that summa-
rizes recent additions to scientific knowledge and their implications for evaluation of
dose-response. The quantitative assessment of the risk should include careful
assessment of the relevance of the animal endpoints to humans, including species
differences, the pharmacokinetics of delivered dose to target organs and metabolite
formation, and mechanistic information such as the effects of cell proliferation. To the
extent that such information suggests a departure from low-dose linearity as assumed
in the linearized multistage model used by EPA as the default procedure for dose-
response assessment, appropriate alternative dose-response models should bo used
to explore the implications of available scientific information for human cancer risk.
The extensive information on the mechanisms by which perchloroethyiene leads to
tumors in mice and rats comes in large part from research sponsored by the chemi-
cal industry. Continued research to resolve uncertainty concerning the health effects
of perchloroethylene appears highly desirable, particularly with regard to obtaining
better epidemiological data. The Agency should take steps to work with the relevant
industries and other institutions to assure that further research to illuminate the human
health risks of perehloroethylene is vigorously pursued.
Three specific areas warrant emphasis: (a) We need to address the question of
whether or not TCA, the principle metabolite of perc, has direct effects on DNA
structure and attempt to resolve discrepancies that now exist in the literature; (b) The
evaluation of the role of peroxisomal proliferation in tumorigenesis should be contin-
ued; and (c) Addition research should address the involvement of perchloroethylene
in the etiology of kidney disease in humans, Perc, in conjunction with other solvents
has been reported to cause membranous nephropathy in humans, but this lesion is
quite distinct in mechanism of development, morphology, and function from the
tubular lesions produced in male rats (Ehrenreich, Yunis and Churg, 1977).
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I *
5. REFERENCES
Brown, _; and Kaplan, _,; (1987) Retrospective cohort mortality study of dry cJeaner
workers using perchloroethylene. J. Occupational Med. 29, 535-541.
DeAngelo, A.B.; Daniel, F.B,; McMillan, L; Wernsing, P.; Savage, R.E. Jr.; (1989)
Species and strain sensitivity to the induction of peroxisome proliferation by chloro-
acetic acids. Toxicol. Appl. Pharmacol, 101, 285-298.
DeAngelo et al.; (1891) Carcinogenicity of dichbroacetic acid in the mate B6C3F1 rat.
Fundam, Appl. Toxicol, 16, 337-347.
Ehrenreich, T.; Tunis, S.L; and Churg, J.; (1977) Membranous nephropathy following
exposure to volatile hydrocarbons. Environ. Res. 14:35-45
NCI, (1977) Bioassay of tetrachloroethylene for possible careinogenieity. Technical
Report Series #13, U.S. HEW, NIH 77-813.
Nelson, B. K.; Tayior, B. I.; Setzer, I, V. and Homung, R. W. (1980). Behavioral
teratology of perchloroethylene in rats. Journal of Environmental Pathology and
Toxicology 3, 233-250.
NTP. (1986) Toxicology and carcinogenesis of tetrachtoroethyfene (perchloroethylene)
(CAS No. 127-18-4) in F344/N rats and BiCSFl mice (inhatation studies) NIH publication
No. 86-2567. NTP TR311.
Schwetz, B. A.; Leong, B. M. I.; and Gehring, B. I. (1975). The effect of maternally
inhaied trichtoroethylene, perchloroethylene, methyl chloroform and methylene chloride on
em*bryonal and fetal development in mice and rats., Toxicology and Applied Pharmacolo-
gy 32, 84-96.
Science Advisory Board, U.S. EPA (1987) Review of the Draft Addendum to the Health
Assessment Document for Tetraehloroethylene (Perchloroethylene), EPA-SAB-EHC-018,
January, 1987.
U.S. EPA. (February11991 Draft) Response to Issu&s and Dala Submissions on the
Cardnogenicily of Tetrachloroethylene (P&rchlQroethylene}(EPA/60QI6-91JQQ2A)>
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