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WASHINGTON DC 29-160
July IS, 1988
SAB-F.HC-039
Honorable Lee M, Thomas
Administrator
U. S. Environmental Protection Agency
401 M Street, S.W.
Washington, D.C. 20460
Subject: Science Advisory Board's review of STYSENS health
criteria document
Dear Mr. Thomas:
The Drinking Water Subcommittee of the Science Advisory
Board's Environmental Health Committee' has completed its review'
of the Drinking Water Health Criteria Document for styrene dated
January 1988. The review was conducted February 4-5, 1988, at the
Washington Circle Hotel in Washington, D,C.
The Subcommittee made the following conclusions and
recommendations concerning this document on styrene i
- there is insufficient evidence to justify the reclassifica-
tion of styrene to EPA's category B2 a-i recommended continuation
of the category C classification?
- the study lay Quast et al should be discounted because it
was less than a lifetime study and the metabolism in the dogs is
poorly understood and may not be applicable to humans;
- the rationale for choosing the study used to quantify the
risk was unclear and needs to be more clearly articulated;
- all of the epidemiology findings should be included in the
analysis i and
- the exposure section needs to be changed to more
realistically reflect the existing situation.
A more detailed discussion of these points is attached.
Additional chapter-specific comments have already been forwarded
from individual members to the Office of Drinking Water.
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We appreciate the opportunity to conduct this p
scientific review. We request that the Agency forma
-o the scier.-ific livice crcvided here.
Sincerely,
Norton Nelson, Chairman
Executive Committee
Richard A. Griesemer, Chairman
Environmental Health Committee
Gary"?, Carlson, Chairman
Drinking Water Subcommittee
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SUBJECT; SCIENCE ADVISORY 30AED'S REVIEW OF THE STYRENE HEALTH
CRITERIA DOCJMSNT
SCIENCE ADVISORY BOARD COMMITTEE? DRINKING WATER SUBCOMMITTEE OF
THE ENVIRONMENTAL HEALTH COMMITTEE
DATE OF REVIEW: FEBRUARY 4-5, 1988
PLACE OF REVIEW: WASHINGTON CIRCLE HOTEL, WASHINGTON, O.C.
1. The subcommittee concludes that there is insufficient
evidence to justify the reclassification of styrene to SPA's
category B2, "probable human carcinogen." The subcommittee
recommends continuation of the category C classification.
Those conclusions are based on the subcommittee's being less
convinced than the EPA staff of the weight of evidence for
styrene carcinogenesis. EPA's evaluation of individual studies
properly acknowledged the studies' limitations such as
peculiarities of control animals, failure to demonstrate dose-
response in some cases, and the presence of tumors having a high
spontaneous incidence leading to marginal statistical
significance. Further, the data for styrene oxide, while
demonstrating cancer causation, are not clearly relevant to the .
estimation of the human cancer risk for styrene, because the
tumors at the site of application were most likely due to the
high dose of this most highly alkylating substance (i.e., styrene
oxide)» This effect is unlikely to be seen with the low doses of
the parent compound styrene which night be found in drinking
water. Also the data for styrene oxide in humans is for the
inhalation route which is not appropriate for ingestion analysis
and there is no information whether or not styrene oxide is the
direct carcinogenic metabolite of styrene.
The Subcommittee recognized that the EPA placed considerable
emphasis on supporting data (e.g., chromosome aberrations) in
workers? alkylation of DNA by styrene oxide) in its weight of
evidence analysis,' however, the subcommittee was less convinced
of the value of these data for. suggesting carcinogenic potential,
because of the confounding factors in studies of styrene and
because of the unclear relevance of the styrene oxide data to
human risk. The subcommittee recognized that styrene oxide is
quite reactiv* with biological tissue; however, the subcommittee
believes that such reactivity may be much less likely to lead
to pathology when styrene is administered at doses at which the
human body possesses adequate means of detoxification.
The subcommittee noted a difference in interpretation of the
Jersey study by EPA and the principal author of the study. We
found more persuasive the arguments of Dr. Jersey than those of
SPA, The EPA analysis relied on the published interpretation of
lymphosarcoma and leukemia in female animals by Dr. Jersey?
whereas, Dr. Jersey had discounted his earlier conclusions on the
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basis of more recent observations of much higher background tusaor
rates,
2, The data from paper by Quast et al (1979) used to
calculate the 10-day and longer-term health advisories ana the
lifetime DUEL caused the subcommittee concern for two major
reasons. Flmt the duration of the Quast study, conducted in
dogs, was less than 600 days, which is a relatively small percent
of the lifetime for this species and, consequently, does not
approximate lifetime exposure. Second, the metabolism of styrene
in this species is Known only poorly. It is unclear, for
example, whether styrene's metabolism in the dog more closely
approximates that of the rodent or that of humans, both of which
differ considerably. Rats conjugate styren* to form glucuronides
and mercapturic acids whereas, humans fora mandelic acid or
phenylglyoxylic acid. Consequently, the subcommittee recommends
that EPA discount this study in the formulation of health
advisories.
3. EPA properly summarized the toxicity data from which to
derive health advisories of varying durations? however, a
critical examination of those data to demonstrate convincingly
the selection and use of particular data sets was absent. The
strength of the health advisories rests in part on the ability to
extract salient and relevant knowledge and understanding from
diverse studies. If only one study of many is selected as a
basis for a health advisory, the relative value of that
particular data set aust be clearly articulated by EPA.
Considerations of major interest in drawing on relevant — albeit
incomplete -- studies include examination of (a) sensitive
measures of toxicity, (b) routes and durations of exposure
comparable to those of the governing health advisory, (c) dosage
regimens, and (d) species of interest.
4. 1PA concluded that the epidemiologic findings were
inconclusive. The subcommittee notes that not all epidemiologic
findings were included in its analysis and recommends that its
data set be supplemented with the additional information.
Further the subcommittee recommends that EPA. use the upper
confidence limits on those studies to estimate the upper estimate
of risk at the lower doses possible via tap water and to compare
this estimate with that derived by EPA from the laboratory animal
studies. Such a comparison would assist in defining some of the
degree of uncertainty incorporated in the EPA's current risk
estimates.
5. The section on human exposure to styrene creates an
erroneous impression of high exposure from ambient and indoor air
(as high as 70,000 ug/day). In fact, Table iv-l indicates levels
between 0.00 and 3300 ug/m . However, the text (page IV-4)
indicates that mean levels ranged up to only 16 ug/m3 in the
Bayonne/Elizabeth, NJ study. That table and accompanying text
should be modified to provide a more representative description
of actual exposures.
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6. As a source of drinking water contaminants and possible
health implications, little consideration has been given to
reactions of styrene with high concentrations of chlorine,
hydrogen chloride, chloramine, or ozone during disinfection.
Such probabl« reactions are presented below. The products (as
illustrated in Figure l), although possibly produced in low
concentration*, are prime alkylating agents capable of combining
with genetic and other essential biological materials to produce
cellular injury of varied physiological consequence, The
subcommittee thus recommends a vigorous research endeavor to
determine the existence of such byproducts and, if so, the
conditions and magnitude of occurrence.
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Figure 1,
r
C12/H20 > (1)
HC1—> (2)
C12/MH3 —> (3)
(1)
Cl
I
CSH5-CH-CH2-C1
OH
I
CsHg-CH-CH2-Cl
0
/\
•-> CSH5-CH-CH2
Cl
I
(2) C6HS-CH-CH3
NH-
H
N
/ '
(3) C6H5-CH-CH2-C1 —> G6H5-CH-CH2
(4) C6H5-CH-CH2
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