UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
EPA-SAB-DWC-90-016
OFFICE £>F
May 15, 1S90 THE ADMINISTRATOR
Honorable William K, Reilly
Administrator
CJ.S. Environmental protection Agency
401 M Street, S*W,
Washington, D.C. 20460
Subject: Science Advisory Board's re^evaluation of issues
concerning the health effects of styrene.
Dear Mr. Reilly,
The Toxicology Subcommittee 'of the Science Advisory Board's
Drinking Water Committee (DWC) met in Washington, D.C. on
February 1-2, 1990, to discuss, among other issues, the re-
evaluation of the health effects of styrene as requested by the
Office of Drinking Water {ODW5 and the Office of Research and
Development (ORD). The charge to the Committee was to answer two
questions:
1. Based on the available data, what is the appropriate weight-
of-evidence classification for styrene?
2. what are the appropriate data and procedures to be used for,
the calculation of the Reference pose for non-
carcinogenic effects?
In the attached report, we reaffirm our previous position
that styrene should be classified in weight-of-evidence category
C (limited animal evidence; inadequate evidence in humans), not
category B2 (sufficient evidence in animals? inadequate evidence
in humans)» We also find that the study entitled "Chronic
foxicity and Three-Generation Reproduction Study of Styrene
Monomer in Drinking Water of Rats" by Beliles et al, (1985),
which is in agreement with previous studies, could be used
appropriately in establishing a Reference Dose for. non-
carcinogenic effects.
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The Committee continues to maintain that the effects of
atyrene oxide are not relevant to generating a standard for
styrene because of its rapid metabolism*
We appreciate the
scientific review. We
to the scientific advice
opportunity to conduct this particular
request that the Agency formally respond
e provided herein.
Sincerely,
Raynrnd C. Loehr
Chairman
Executive Committee
William H.
Chairman
Drinking Water
Committee
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FPA U.S. Environmental Washington, DC
CrM Protection Agency EPA-SAB-DWC-9Q-Q1i
Report of the Drinking Water
Committee (DWC) of the Science
Advisory Board (SAB)
Science Advisory Board Reevaluation
of Issues Concerning the Health
Effects of Styrene
A SCIENC1 ADVISORY BOARD REPORT MAY 1990
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1. EXECUTIVE SUMMARY
The Drinking Water Committee reaffirms its previous position
(see Science Advisory Board report SAB^lHC-88-039 dated July 19,
1988) that styrene be classified in EpA's weight-o£-evidence
category cr rather than 82. It also finds that the study
entitled "Chronic Toxicity and Three-Generation Reproduction
Study of Styrene Monomer in Drinking Water of Rats" by Beliles et
al. (1985) could be used appropriately in establishing a
leference Dose (RfD) foe non-carcinogenic effects.
2, INTRODUCTION-
The Toxicology Subcommittee of the Science Advisory Board's
Drinking Water Committee (DWC) met in Washington, D.C. on
February 1^2, 1990, to discuss, among other issues, the re-
evaluation of the health effects of styrene as requested by the
Office of Drinking Water (ODW) and the Office of Research and
Development (ORD). The charge to the committee was to answer two
questions;
a. Based on the available data, 'what is the appropriate weight-
of-evidence classification for styrene?
b. what are the appropriate data and procedures to be used for
the calculation of the Reference Dose for non-
carcinogenic effects?
Background information on these matters was contained in a
briefing paper provided by the ODW.
Both questions in the charge had been previously addressed
in a report of the Environmental Health Committee (originating in
its Drinking Water Subcommittee) that was issued in July, 1988
(SAB EHC-88-Q39), following a public meeting held 'in Washington,
D.C. in February, 1988.
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3.0 RE-EVALUATION OF THE HEALTH EFFECTS OF STYRENE
The principal items of new information presented at the
meeting were two studies; Conti et al. (1988) and Bellies et al,
(1985). In addition, written public comments from the Styrene
Information and Research Center, the National Resources Defense
Council, and the Cincinnati Water Works were supplied.
3.1 carcinogenic effects
Styrene provides an interesting example of the problems
involved in using the EPA guidelines for classifying carcinogens.
Technically, when the rules in the guidelines are applied to one
study at a time, one may come to the conclusion that styrene
should be classified D (inadequate evidence in animals;
inadequate evidence in humans) in the weight-of-evidence
categori2ation. However, when all the data are considered
together and scientific judgment is applied, some scientists have
come to the conclusion that it should be classified as a category
C carcinogen (limited evidence in animals; inadequate evidence in
humans). The DWc came to this latter conclusion in its 1988
review of the issues relating to the health effects of ingested
styrene (SAB-SHC-88-039)'. 0DW and OKD have asked the Committee
to review its previous conclusion in light of some newer data,
A recent study by Conti et al, (1988) indicated that styrene
administered via inhalation, but not via intraperitoneal
injection or orally by gavage, caused an increase in total
(benign and malignant) tumors of the mammary gland in female
rats. These results are difficult to evaluate for four reasons.
First, as noted, tumors did not increase in number for all routes
of administration, second, there are no values given for the
number of animals that finished the study since the authors do
not indicate the number of animals that died* Third, there is no
statistical analysis of the data, and only percentages are given,
There does not seem to be a well-defined dose-response effect,
and the controls demonstrated an incidence of 56.7 percent,
Fourth, the paper was not peer reviewed.
The EPA briefing document again fails to evaluate critically
the epidemiology data base and does not discuss the negative
studies. While the Drinking water Committee would tend to agree
with 1PA that the data do not support the classification as a
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human carcinogen, it is important that SPA a) more carefully and
formally analyze the positive and negative studies and b)
consider the overall data in its totality; i.e., a meta-analysis.
EPA's overall assessment of the human data may have been too
easily dismissed in favor of the animal studies,
The supporting evidence for styrene as a mutagen is not
strong. Styrene itself, according to the results of the majority
o£ the well conducted studies, is neither mutagenic nor
clastogenic.
The EPA appeared to misinterpret the DWC's earlier comments
on styrene oxide. There is no doubt that this chemical is
mutagenic in the S a 1 mone 11 a typhjlinurium (Ames) assay or that it
is capable of causing tumors in the rat forestomach. The real
question is whether oc not such information is biologically
relevant to what would be expected from the ingestion of styrene.
The Committee continues to maintain that it is not relevant.
Certainly at levels of exposure that would be possible via
drinking water and in consideration of the ability of the cat and
probably man to rapidly detoxify reasonable levels of the styrene
oxide formed in vivo from styrene, the effects of styrene oxide
are not particularly germane to the setting of a MCLG for
styrene. (see the document entitled "A Review of Styrene
Pharmacokinetics and carcinogenicity" provided to the committee
by canTox inc., Qakville, Ontario and prepared for SIRC, Shell
Canada Ltd., Calgary, Alberta,Canada for mote details.)
Consideration of metabolism of a parent compound which may
lead to potentially toxic metabolites is usually a necessary
ingredient in hazard assessment. Thus, studies conducted with
styrene oxide may be'considered in'the weight-of-evidence
approach. However/ these studies are interpreted by this
Committee with a great deal of caution. Certain principles
pertain. First, the rate of formation and the rate of further
metabolism of styrene oxide, itself, must be considered.
Secondly, the transport and storage of styrene oxide and its
metabolite must be considered. Lastly, the sites of formation
and the clearance from the sites 'of formation are important
factors.
There are a number of substances which are known to be
metabolized in, vivo to reactive metabolites that may be
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potentially carcinogenic, in addition, the metabolite may even
form DNA abducts in vitro studies, and yet the parent compound
administered in drinking water is not carcinogenic. One such
compound is methanol, which is metabolized to formaldehyde.
Methanol does not produce cancers in acute or long term studies
and its initial metabolite, formaldehyde, is rapidly metabolized
to formate in all species. However, if formaldehyde is
administered at high levels by inhalation, it can produce nasal
tumors in rats. Thus, formaldehyde can act locally much the same
as styrene oxide doeaj i.e. produce tumors at the site of
administration. But methanol cannot be considered as a
carcinogen simply because it is metabolised to formaldehyde. The
formaldehyde formed systemically is of little concern because of
its rapid rate of metabolism.' The same can be said for ethanol
which is metabolized to acetaldehyde, another reactive compound
that can also produce nasal tumors if administered at high dose
by inhalation. Thus, the argument that, because a reactive
metabolite or a potentially carcinogenic metabolite is formed,
the parent compound should be considered carcinogenic is not
necessarily valid. For methanol and ethanol, it is invalid. In
the case of styrene, the lack of.a strong demonstration of
carcinogenicity in the many studies performed thus far may be due
to the capacity of the animals to dispose of the metabolite
generated in an adequate fashion.
With regard to the animal studies cited by EPA as evidence
for the reclassification of styrene from C to B2, the Drinking
Water Committee sees no compelling arguments presented to shift-
from its original position. That is, there were difficulties in
the interpretation of the published studies. These have been
articulated previously. The use of historical control data
|e,g., Jersey et al, (1978) and National Toxicology Program (NCI,
1979)], the expectance of dose-response relationships (NCI,1979),
and the requirement of adequate experimental design [which is
missing in the Ponomarkov and fomatis (1978) study, in which the
dosing schedule was highly unusual and the doses used were
certainly toxic] are entirely reasonable. The criterion
necessary for inclusion in class B2, "sufficient evidence in
animals", is not met. The data are not clear cut either for rats
or for mice* At best, the data are equivocal based on the faulty
experimental designs and/or interpretation of the results. They
do, however, support a class C designation, "limited animal
evidence". (According to the EPA cancer risk assessment
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guidelines. Class C evidence includes "tumor responses of
marginal statistical significance in studies having inadequate
design or reporting"; cf», the Conti et al study in which the
number of deaths is not given.) This recommendation is made with
the knowledge that the International Agency for Research on
Cancer (IARC) has classified styrene as 2B i'n its scheme. Mote
that the IARC 2B category is defined differently from the B2
category of EPA. Also, the procedures for using the data in
reaching classification decisions are different in the two
organisations; cf./ lARC's strength-of-evidence judgment vs.
EPA's weight-of-evidence judgment.
3.2 Non-carcinogenic effects
in the study of Beliles et al. (1985} the styrene was
administered in the drinking water for two years, and the results
are negative in regard to tumorigenicity, although this has less
weight since the study was not designed as a eareinogenicity
study. The highest level of styrene administered, 250 ppm, was
close to the level of saturation of styrene in water.
The study of Beliles et al, (1985) for rats is suitable for
the establishment of a Reference Dose (RfD) for non^cancer
endpoints. it is especially relevant because of the oral route
of administration. An RfD of 1,6 mg/L is consistent with the
data for chronic' toxicity. The RfD of 0.14 mg/L which was
derived from the study of Quast et al. (19793 in dogs has been
adjusted downward by EPA by an additional factor of ten because
of styrene's being in class C weight-.of-evidence category. This
is over and above the 1000 uncertainty factor which was
appropriately used. It is interesting to note that if the
additional factor of ten is not included, the value would be 1.4
mg/L/ very close to the 1,6 mg/L value from the rat study by
Beliles et al, (1985). Conversely, if the additional uncertainty
factor of ten were used with the Bellies study (assuming a
classification as a C carcinogen), an RfD of 0,16 mg/L would
result.
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3.3 conclusion
in summary, the Drinking Water committee reaffirms its
previous position and recommends that styrene retain its
classification in category C and not be reclassified B2» This
conclusion is based on scientific judgment after looking at all
the evidence relating to this decision together. The Committee
also finds that the study of Bellies et al* (1985) could be used
appropriately in establishing an RED for chronic toxicity.
REFERENCES
Bellies, R.P., J.H. Butala, C.R. Stack and S. Makris. 1985.
"Chronic Toxicity and Three-Generation Reproduction Study of
Styrene Monomer in Drinking Water of Rats", Fundamental and
Applied .Toxicology, 5:855-868, (1985).
Conhi, B. , C, Maltoni, G. Perino and A. Ciliberti. June, 1988.
"Long-Term Carcinogenicity Bioassays on Styrene Administered
by ingestion in Sprague-Dawley Rats, and para-Methylstyrene
Administered by ingestion in Sprague-Dawley Rats and Swiss
Mice", Annals of the New York Academy of Sciences, pp. 203-
234,
jersey, G.C., M.F. Balmer, J.F, Quast, C.N. Park, D.J. Schuetz,
J.E. Beyer, J.K. Olson, S.B. McCollister and L»W, Rampy,
1978. "Two-year chronic inhalation Toxicity and
Carcinogenicity Study of Monomeric styrene in Rats", Final
Report, DOW chemical Company, Midland, Michigan.
National Cancer Institute. 1979. "Bioassay of Styrene for
possible Carcinogenicity.", Department of Health, Education
and Welfare, publication No, NIH 79-1741, Tech. lep. Sec.
No. 185:42, Washington, D.C,
ponomarkov, v. and L. Tomatis. 1978. "Effects of Long-term Oral
Administration of Styrene to Mice and Rats", Scand, J, Work
Environ. Hlth. 4(Suppl. 2) i!27-135.
Quast, J.F., C.G. Humiston, R.V. Kalnins, K.J. Olson, S.B.
Mccollister, c.i. Wade, J.E. Beyer and B.A. Schwetz. (July
31, 1979). "Results of a Toxicity Study of Monomeric
Styrene Administered to Beagle Dogs by Oral Intubation for
19 Months", MCA No. STY 1.2-fOX-Gav-DOW, Dow Chemical
company, Midland, Michigan.
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ENVIRONMENTAL PROTECTION AGENCY
SCIENCE ADVISORY BOARD
DRINKING WATER COMMITTEE
NOVEMBER, 1989
CHAIRMAN
Dr. William H. Glaae
Department of Envr„ Sci. & Etigr.
CB# 7400, Rosenau Hall
University of North Carolina
Chapel Hill, NC 27599-7400
VICE CBAIR
Dr. verne Ray
Medical Research Laboratory
Pfizer Inc.
Groton, CT 06340
MEMBERS
Dr. Richard Bull
College of pharmacy
Washington State University
Pullman, Washington 99164-6510
Or. Kenneth cantor
National .Cancer institute
6130 Executive Boulevard
Executive Plaza North, Soora 443
Bethesda, MD 20892
Dr. Gary Carlson
Department of Pharmacology and Toxicology
school of pharmacy
Purdue university
West Lafayette, IN 47907
Mr. Keith E. earns
Director of Water Quality
East Bay Municipal Utility District
2130 Adeline Street
P.O. Box 24055
Oakland, CA 94607
or. David Kaufman •
Department of pathology
University of North'Carolina
Brinkhoup-Bullitt, Room 515
Chapel Hill, NC 27514
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Dr. Nancy Kin, Director
Division of Environmental Health Assessment
New York State Department of Health
Room 350, 2 university Place
Albany, NY 12203-3313
Mr. Ramon G. Lee, system Director
Water Quality Research
American Water Works Service company/ inc.
1025 Laurel oak Road
P.O. BOX 1770
Voorhees, New Jersey 08043
Dr. Betty Olson
Program in Social Ecology
University of California
Irvine, CA 92717
Dr. Edo D. Pellizaari, vice president
Research Triangle institute
P.O. Box 12194
Research Triangle Park, NC 27709
Dr» vern Snoeyink
Department of Civil Engineering Lab
3230 Newmark civil Engineering Lab
university o,f Illinois
205 Mathews Avenue
urbana, IL 61801
Dr. Mark D, Sobsey
Department of Environmental Sciences and Engineering
School of Public Health
University of North Carolina
Chapel Hill, NC 27599
Dr. James Symons, Professor
Department of Civil and Environmental Engineering
University of Houston
Houston, Texas 77204-4791
Dr, Thomas Tephlyf Professor
Department of Pharmacology
The Bowen Science Building
University of lowa
Iowa City, IA 52242
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or, R, Rhodes Tcussell
Vice president
James M. Montgomery,
Consulting Engineers, Inc.
P.O. BOX 7009
Pasadena, CA 91109-7009
EXECUTIVE SECRETARY
Dr. C. Richard Cothern
Environmental Protection Agency
Science Advisory Board, A101P
Drinking Water Committee
Washington, D.C. 20460
STAFF SECRETARY
Darlene A. Sewell
Environmental Protection Agency
Science Advisory Board, A-10IP
Washington, D.C.' 20460
STAFF DIRECTOR
Donald G* Barnes
Environmental Protection Agency
401 M Street, S.W., A-101
Washington, DC 20460
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