I
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
EPA-SAB-EHC-91-002
OFFICE OF
THE AOMtNISTRATQR
November 26, 1990
Honorable William K. Reilly
Administrator
U.S. Environmental Protection Agency
401 H Street, s.w.
Washington, D.C, 20460
Subject: Science Advisory Board's review of issues relating to
the health effects of ingested pentachlorophenol
Dear Mr. Reilly.
The Science Advisory Board's Environmental Health Committee
met in Miami Beach, Florida, on February 15-16, 1990, to review
issues -relating to the health effects of ingested pentachloro-
phenol. The review was performed at the request of four offices
in the Agency; Office of Drinking Water, Office of Research and
Development, the Office of Pesticide Programs and Office of Solid
Waste. In addition, the Board considered this matter further at
the July 9-10, 1990 Executive Committee meeting and held a public
teleconference on August 29, 1990 to allow further opportunity
for public comment. As a result of these two meetings, the
committee found no reason to revise the substance of its report.
Four issues were considered in this review of the health
effects of ingested pentachlorophenol. The first issue concerned
interpretation of the observed relationship between mouse liver
toxicity and tumor incidence and, in particular, the choice of
the experimental evidence that should be used to describe the
carcinogenic potential of pentachlorophenol. The Committee
recommended that the dose-dependent increase in the incidence of
hepatocellular carcinomas and adenomas that was observed should
be considered a valid indicator of oncogen icity.i
In regard to the second issue, the relevance of the
observed increase in the incidences of mouse pheochromoeytomas to
humans, the Committee concluded that-the incidence and dose-
response pattern of such tumors in mice suggest that their
-------
Increased rate of occurrence was clearly related to the
administration of the test agent; however, the fact that the
increase was limited to benign and not malignant
pheochromocytomas led the Committee to question whether these
tumors are related to human cancer.
The third issue concerned the selection of the data set(s)
that should be used in formulating quantitative estimates of
human cancer risJc. The Committee recommended the use of the
observed dose-incidence data on hemangiomas and hemangiosarcomas
as the basis on which to assess the cancer risk for humans, since
these tumors are more likely than the others to be known human
cancers.
As concerns the final issuet whether a toxicity-equivalence-
factor approach should be considered for the liver tumors, the
Committee recommended that it not be used.
Based on the evidence presented the Committee concluded that
pentachlorophenol should be classified as a B2 carcinogen,
according to the EPA's weight-of-evidence scheme in its
carcinogen guidelines.
We appreciate the opportunity to conduct this particular
scientific review. We request that the Agency formally respond
to the scientific advice provided herein.
Sincerely,
Raymond C.
Chairman
Executive Committee
Arthur Upton
Chairman
Environmental Health Committee
-------
REPORT OF SCIENCE ADVISORY BOARD'S REVIEW OF ISSUES CONCERNING
THE HEALTH EFFECTS OF INGESTED PENTACHL0RQPHENQL
1.0 EXECUTIVE SOMMARY
The Science Advisory Board's Environmental Health Committee
reviewed issues relating to the health effects of ingested
pentachlarophenol. The review was performed at the request of
four offices in the Agency; office of Drinking Water, office of
Research and Development, Office of Pesticide Programs, and
Office of Solid Waste.
Four issues were considered in this review of the health
effects of ingested pentachlorophenol. The first issue concerned
interpretation of the observed relationship between mouse liver
toxicity and tumor incidence. The Committee recommended that the
observed dose-dependent increase in the incidence of
hepatocellular carcinomas and adenomas be considered a valid
indicator of the oncogenicity potential of the chemical.
In regard to the second issue, the relevance of the observed
increase in incidence of mouse pheochromocytomas to humans, the
Committee concluded that the incidence and dose~response pattern
of such tumors in mice suggest that their increased rate of
occurrence was related to the administration of the test agent to
mice.
The third issue concerned the selection of the data set(s)
that should be used in formulating quantitative estimates of
human cancer risk. The Committee recommended the use of the
observed dose-incidence data on hemangiomas and hemangiosarcomas
as the basis for the cancer risk for humans.
The final issue, whether a toxicity-equivalence-factor
approach should be considered for the liver tumors, the Committee
recommended that such a factor not be used.
2.0 Introduction
The Environmental Health Committee of the Science Advisory
Board of the U. S* EPA met in Miami Beach, Florida on February 15
and 16, 1990 to discuss the overall weight-of-evidence
classification appropriate for pentachlorophenol. In addition,
the Board considered the matter further at the July 9-10, 1990
Executive Committee meeting and held a public teleconference on
August 29, 1990 to allow further opportunity for public comment.
The Science Advisory Panel was represented at the February review
by Dr. Edward BresnicJc (see list at the end of this report) . The
-------
review was performed at the request of four offices in the
Agency; Office of Drinking Water, Office of Research and
Development, Office of Pesticide Programs, and Office of Solid .
Waste. The major emphasis was on data, reported in 1989, of
studies conducted in male and female B6C3F1 nice by the National
Toxicology Program. These studies examined both technical grade
pentachlorophenol and Dowicide EC-7 pentaehlorophenol given in
the feed for two years,
From these studies the NTP concluded that there was clear
evidence of carcinogenic activity for male mice fed diets
containing the technical grade pentachlorophenol as evidenced by
increased incidences of adrenal medullary and hepatocellular
neoplasms. There was also some evidence of carcinogenic activity
in female mice administered the technical grade pentachlorophenol
as evidenced by increased incidences of iiemangiosareomas and
hepatocellular neoplasms. There was clear evidence of
carcinogenic activity for male mice exposed to EC-7
pentachlorophenol, as shown by increased incidences of adrenal
medulla and hepatocellular neoplasms. There was clear evidence
of carcinogenic activity for female mice given the EC-7
pentachlorophenol, as shown by increased incidences of adrenal
medullary and hepatocellular neoplasms and hemangiosarcomas.
Based on the above evidence the Committee concluded that
pentachlorophenol should be classified as a B2 carcinogen,
according to the EPA's weight-of-evidence scheme in its
carcinogen guidelines. The guidelines were issued September 24,
1986 by the U.S. Environmental Protection Agency.
Four issues were presented to the Committee for comment and
recommendations. Issue 1 concerned whether the liver toxicity
found in virtually all of the exposed mice may have contributed
to the incidence of liver tumors and thus compromised the
validity of the study for extrapolation to low dose levels where
toxicity is greatly reduced or absent. The question was whether
or not there was evidence to demonstrate a causal relationship
between the liver toxicity and the liver tumors.
Issue 2 concerned the possibility that the pheochromocytomas
seen in rats may have reflected a reaction to stress and
therefore may not be relevant to the carcinogenicity at low dose
levels* The question asked was whether there was sufficient
evidence to support the same conclusion in mice and thus to
discount the relevance of the mouse pheochromocytomas to humans.
These guidelines can be found in the Federal Register, 51
FR 33992 or in a separate EPA publication "The Risk Assessment
Guidelines of 1986", EPA/600/8-87/045, U.S. Environmental
Protection Agency, Washington, D.C., 20460.
-------
Issue 3 concerned the selection of the data set that should
be used in the quantitative assessment of cancer risk? i*e.r
which tumor types should be included, which sexes .should be
included, which grades of pentachlorophenol should be considered,
and whether it was appropriate to take averages across the sexes
or grades of pentachlorophenol. Four options were presented,
including 1) taking an average of unit risks from female mice
exposed to technical grade pentachlorophenol and female mice
exposed to EC-7 pentachlorophenol, 2} using the unit risk from
female mice exposed to EC*-7 pentachlorophenol, 3) using the unit
risk from male nice exposed to technical grade pentachlorophenol,
and 4) taking an average of the unit risks across both sexes and
both grades of pentachlorophenol.
Issue 4 concerned the question of whether a toxicity-
equivalence-factor approach should be considered for the liver
tumors, in view of the fact that the principal impurities
identified in the pentachlorophenol preparations used (namely
chlorinated dibenzo-p-dioxins, diben?ofurans and
hexachlorobenzene) were those for which such an approach has been
used in the past. This approach wight seem desirable since
hexachlorobenzene and some dioxins cause liver tumors in mice,
but these chemicals have not been associated with the other two
tumor types observed in the studies on pentachlorophenol.
3.0 Issue 1
In regard to Issue 1, on the relationship between mouse
liver toxicity and tumor incidence, the Committee recommends that
the dose-dependent hepatocellular carcinomas and adenomas be
considered as valid indicators of the oncogenic potential of
pentachlorophenol, especially since they were accompanied by the
presence of tumors in other organs. In regard to hepatotoxieity,
since the liver normally has a low rate of cell turnover, usually
the Committee considers that it must usually undergo a toxic
reaction prior to the development of neoplasia. An exception to
this generalization may exist, however, in the case of the
peroxisomal proliferates. Although most hepatocarcinogens may
be hepatotoxins, not all hepatotoxins are necessarily
hepatocarcinogens2. The Committee also wishes to point out the
unusual sensitivity of the B6C3P1 mouse to hepatoeareinogenesis,
which suggests that its liver may already conceivably be primed
for tumor development. For this reason, the Committee recommends
that the incidence of hepatocellular carcinomas and adenomas in
these mice be consid-
ered less important than the appearance of hemangiosarcomas.
*Hoel, D.G., Baseman, J.K., Hogan, M, D,, Huff, J*, and
McConnell, E., The impact of toxic,ity on-carcinogenicity studies:
implications for risk assessment, Carcinogenesis, .9t2045-2052,
1982,
-------
4.0 Issue 2
As concerns Issue 2, whether there was sufficient evidence
to discount the relevance of mouse pheochromocytomas to humans,
the Committee finds that the increased incidence and dose-
response pattern of pheochromocytomas in these studies suggest
that the tumors-were related to the administration of the test
agents, even though there was no increase in the number of
malignant pheochromocytomas.
5 .'o Issue 3
In regard to Issue 3, as to which data set(s) should be used
in the quantitative estimate of the cancer risk, the Committee
reeommendsthe use of the hemangiomas and the hemangiosarcomas as
the tumors on which to base the risk assessment. These tumors
were related to the administration of the pentachlorophenol
formulations tested, occurred in.a dose-response manner in the
treated animals, and are morphologically related to known fatal
human cancers t.hat are induced by xenobiotics. It should also be
noted that the development of hemangiosarcomas was related to the
incidence of multifocal hematopoietic proliferation in control
animals (TG-eontrols, male 6%, females 14%; EC-F controls, male
3%, females 59%).
Ample consideration was given to the questions of the liver
tumors and the pheochromocytomas. The Committee's recommendation
of using the data on hemangiosarcoraas in preference to the data
on the other tumors does not negate the association of the liver
tumors and pheochromocytomas with the administration of the
formulations of pentachlorophenol. However, the committee
recognizes the controversies surrounding the pathogenesis of
these lesions and the difficulty in extrapolating these results
in order to estimate human risk.
In the case of the liver tumors, it was recognized that the
concurrent hepatotoxicity may have played a key role in the
formation of the tumors. As noted above, to the best of our
knowledge, few rodent hepatocarciogens (with the notable
exception of peroxisome proliterators) induce their effects
without hepatotoxicity. In point-of-fact, what may actually be
occurring is promotion and progression of spontaneous tumors in
the liver. The committee recommends that EPA address the generic
issue of promotion of liver tumors as soon as possible, it
should be noted that the classic rodent liver promotion models
utilize hepatotoxicity as the means to enhance development of
tumors.3
3 Solt, D,S. and Farber, E,, Nature, 263:701, 1976.
-------
The Committee had similar reservations about utilizing the
pheochromocytomas as the underpinning of the classification of
pentachlorophenol containing formulations. There is genuine
disagreement in the interpretation of the meaning of these tumors
in rodents and, in addition, there is controversy in the
diagnosis of the lesions. The lesions in mice and in rats may or
may not be similar in pathogenesis but in neither case is it
fatal nor does it invade other tissue. The Committee recommends
that IPA support research on the biogenesis of this lesion in
mice, including the study of similarities between
pheochromocytomas in mice and rats.
The Committee further recommends that the q,*» for
pentachlorophenol be estimated from derivations using the
linearized multistage model (LMS) as well as the time-to-tumor
model. The reason for this recommendation is that most, if not
all, other qt*s have been developed using IMS and the Agency is
urged to be consistent. In so recommending, the Committee is not
saying that other models are not appropriate. It further
recommends that the Agency continue to examine alternative models
for estimating risk.
In summary, the Committee recommends that the q,* be based
on the development of tumors most relevant to human cancer and to
the most unique tumors in this study, namely the
hemangiosarcomas. Under these circumstances it is reasonable to
average across grades of pentachlorophenol as tested, but
averaging across tumors types and genders (no hemangiosarcomas in
males) should not be done. The Committee agreed that, using the
weight-of-evidence scheme from the EPA's carcinogen guidelines,
pentachlorophenol should be classified as a B2 carcinogen.
Further the Committee recommends;
a that EPA and other interested parties initiate
research on the biogenesis and interpretation of
pheochromocytomas in mice,
b that other toxicity studies be conducted to
determine the shape of the dose-response curve for
hepatotoxicity of pentachlorophenol in rats and mice,
c) that EPA address the questions of hepatic tumor
promotion with agents that are both hepatotoxic and
contain contaminants that are structurally related to
tumor promoters,
d) that EPA (perhaps through NIEHS/NTP programs) refine
its definition of MTD in light of the difficulty of
inducing hepatocarcinogenicity without hepatotoxicity,
e) that NTP design its studies to be used in
-------
risk assessment, rather than to take the position that
NTP studies stand alone and are not designed for risk
assessment.
6.0 Issue 4
In regard to Issue 4, whether or not "a toxieity-eguivalence-
factor approach should be considered for the liver tumors, the
Committee recommends that toxicity-equivalent factors not be
applied to assessing the carcinogenic potential of
pentaehlorophenol, for several reasons:
a) Bioassay data are available for two mixtures which are
similar in purity but differ somewhat from mixtures
marketed today in regard to their specific impurities.
Toxicity estimates for the two tested mixtures are likely
to bracket those for the mixtures to which the public is
currently exposed,
b) Individuals are exposed to mixtures and if data are
available for the same or similar mixtures they should be
used to estimate toxicity. For more details see the Risk
Assessment Guidelines for Chemical Mixtures,
c) Toxicity-equivalent-factors for dioxin are likely to
change and are currently based, among other things, on
induction of the All receptor associated with acute
toxicity data in rat liver; the pentachlorophenol data are
based on their response data in mice,
d) The Committee recommends that quantitative risk estimates
be based upon the hemangiosarcoma data for female mice.
There is little difference between mixtures in risk for
this effect, suggesting that the risk estimate varies
relatively little with variability in mixture
formulations. Moreover, these tumors have not been
associated with the identified impurities in
pentachlorophenol.
-------
U. S. ENVIRONMENTAL PROTECTION A61NCY
SCIENCE ADVISOR! BOARD
ROSTER OF THE ENVIRONMENTAL HEALTH COMMITTEE
CHAIRMAN
Dr. Arthur Upton
New York University Medical Center
Institute of Environmental Medicine
550 First Avenue
Room M-S-B-213
New York, New York 10016
MEMBERS/CQMSPM'AKTS
Dr. Edward Bresnick
Professor and Chairman
Department of Pharmacology and Toxicology
Dartmouth Medical School
Hanover, NH Q£756
c/o Harriet McCollum
Office of Pesticides Programs
Fifra Scientific Advisory Panel
Crystal Mall No, 2
Room S20C, H-750C
Dr. Gary Carlson
Department of Pharmacology and Toxicology
School of Pharmacy
Purdue University
west Lafayette, Indiana 47907
Dr. Michael Gallo
Biology Department
Redfield Laboratory
Woodshole Oceanographic Institution
Woodshole, Massachusetts 02543
Dr. Rogene Henderson
Lovelace ITRI
P.O. Box 5890
Albuquerque, New Mexico 87185
Dr. Kenneth Jenkins
Director, Molecular Ecology Institute
California State University
Long Beach, CA 90840
-------
Dr. Marshall Johnson
Professor, Department .of Anatomy
Jefferson Medical College
1020 Locust Street
Philadelphia, Pennsylvania 19107
Dr, Nancy Kim
Director, New York Department of Health
Division of Environmental Health
2 University Plaza '
Albany, New York 12203
Dr. Morton Lippwann
Institute of Environmental Medicine
New York University
Lanza Laboratory
Long Meadow Road
Tuxedo, New York 10987
Dr. Martha Radike
Department of Environmental Health
Medical Center
University of Cincinnati
3223 Eden Avenue, ML #56
Cincinnati, OH 45267
Dr, Stephen M. Rappaport
Department of Biomedical and Environmental
Health Sciences
Earl Warren Hall, Room 317
School of Public Health
University of California
Berkeley, CA 94720
Dr. Paul Schulte
NIOSH
4676 Columbia Parkway
Mail Stop R-13
Cincinnati, OH 45226
Dr. Bernard Schwetz
NIIHS
P.O. Box 12233
MD-D4Q2
Research Triangle Park, NC 27709
-------
Dr» Jan stolwijk
Department of Epidemiology
Public Health
Yale University
School of Medicine
60 College street
P.O. Box 3333
New Haven, Connecticut 06510
Dr. Bernard Weiss
Professor of Toxicology
Environmental Health Sciences Center
P.O. Box EHSC
University of Rochester
School of Medicine
Rochester, NY 14642
Dr. Jerry WesolowsJci
Air and Industrial Hygiene Laboratory
California Department of Health
2151 Berkeley Way
Berkeley, CA 94704
Dr. Eonald Wyzga
Electric Power Research Institute
3412 Hillview Avenue
P.O. Box 1041
Palo Alto, CA 54303
Executive Secretary
Dr. c. Richard Cothern
Environmental Protection Agency
401 M Street, S.W., A-101F
Washington, D.C. 20460
Staff Secretary
Darlene A, Sewell
Environmental Protection Agency
401 M Street, S.W., A-101F
Washington, D.C* 20460
Staff Director
Donald G* Barnes
Environmental Protection Agency
401 M Street, S.W., A-101
Washington, D,C. 20460
------- |