UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON. D,G, 20460
**t *«f«dctQber 24, 1986
Honorable Lee M.' Thomas
Administrator • •
U* S. Environmental Protection Agency -*
401 M Street, S. W,
Washington, D. C, 20460
Dear Mr. Thomass
The Environmental Health Committee of EPA's Science Advisory
has completed its review, requested by the Office of Drinking Water (QDW),
of thirty-seven drinking water health advisories. The Committee accomplished
this task by assigning the review to three separate subcommittees: Metals,
Halogenated Qrganics and Drinking Water. The Science Advisory Board has
not previously reviewed health advisories, and its participation in this
program has been informative*
The Agency's development of health advisories represents an important
component of its drinking water program. By seeking to improve their
scientific quality, EPA will better serve the needs of state and local
officials who have a legitimate need for the advisories.
In order not to delay the ODW's revision of the advisories, the three
subcommittees have already provided transcripts of their oral eoroents and
about 110 pages of detailed ctnronts. The final comments are enclosed
with this letter as three Subcoranittee reports. The major conclusions of
the review are as•follows;
* The Subcommittees found the health advisories uneven with respect
to their scientific quality. The Office of Drinking Water should
develop guidance to assure more consistent quality in the future.
« The Office of Drinking Water has made a coraendable effort to
provide exposure analysis information in the draft health advisories,
including the consideration of exposure from drinking water through
routes other than oral ingestion, and the utilization of inhalation
toxicologic data. The Subcommittees encourage OEW to perform even
more of this work.
• The major problem in reviewing the health advisories was to under-
stand the draft documents in relation to their intended audience(s).
According to the Office of Drinking Water, there are multiple
audiences with different skill and background levels, such as
operating personnel of waterworks and public health officials* As
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currently written, the health advisories have the appropriate format
and content to satisfy the needs of persons with expertise in
toxicology, such as health officials, but not operating personnel.
Therefore, the Subcommittees advise that the health, advisories
• not provide suronary numerical tables, as indicated in the current
drafts.- •Instead, they reccranend that each health advisory contain
a narrative summary, written in a style that can be understood by
lay persons,
* There will be less of a problem with communicating with various
audiences if the Office of Drinking Water adopts a three step
process to document drinking water contaminants. This process
includes developing Criteria Documents to support Agency
regulations; preparing health advisories for public health
authorities; and writing a narrative summary for operating
personnel of waterworks. The major role for the Science Advisory
Board within this process will be to review Criteria Documents
and selected health advisories.
The Science Advisory Board appreciates the opportunity to review
the health advisories. In behalf of the Board, we request that the
Agency formally respond to the scientific advice contained in the attached
reports.
Sincerely,
Richard Griesemer
Chairman, Environmental Health Committee
Science Advisory Board
Norton Nelson
Chairman, Exeoitive Committee
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Review of 37 office of Drinking Water Health Advisories
by the
Environmental Health Ccramittee
of the
Science Mvisory Board
* Metals Subcommittee; (SAB-EHC-87-OQ4)
arsenic, barium, cadmium, chromium, cyanide, lead, mercury,
nickel, and nitrate/nitrite
* Halogenated Organics Subcommittee: (SAB-EHC-87-005)
carbon tetrachloride, chlorobenzene, dichlorobenzene,
1,2-dichloroethane, cis and trans 1,2-dichlorGethylene,
l,l-dichloroethylener diehlorcraethane, dichloropropane,
dioxin epichlorohydrin, hexaehlorobenzene, polychlorinated
biphenyls, tetrachloroethylene, 1,1,2-trichloroethylene,
1,1,-trichloroethylene, and vinyl chloride.
* Drinking Water Subcommittee: (SAB-EHC-87-006)
acrylamide, benzene, p-dioxane, ethylbenzene, ethylene glycol,
hexane, legionella, methylethylketone, styrene, toluene,
and xylene
October 1986
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^ ,.
*
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C 20460
September 20, 1986 '
Dr. Richard A. Griesemer
Chair, Environmental Health Cemmittee TH
Science Advisory Board [A-101]
U.S. Environmental Protection Agency
401 M Street, SW ' • . .
Wasington, DC 20460
Dear Dr. Griesener:
on January 6-8, 1986 the Drinking Water Subcommittee of the Science
Advisory Board's Environmental Health Committee publically reviewed
eleven (11) draft health advisories for drinking water. Health advisories
are described by the Office of Drinking Water as nonregulatory documents
that are used to provide consistent, brief information to state and local
health officials and personnel operating water works. During the review,
the Subcommittee utilized Drinking Water Criteria Documents as support
information for all of the health advisories except for g-dioxane, ethylene
glycol, n-hexane and methyl ethyl hexane, for which the Subcommittee
received copies of key papers from the scientific literature that support
the calculations* The Subcommittee recommends that preparation of Criteria
Documents for these four substances receive priority, because collections
of key papers are not adequate support for the health advisories. Although
the papers have the essential data, the bare facts are neither evaluated
from EPA's perspective nor placed in logical context. EPA does not
presently have source {or core) documents for these four substances*
The comments are divided into general advice, which is relevant to
all of the advisories reviewed by the Drinking Water Subcommittee, fol-
lowed by scientific advice specific to each of the substances reviewed.
Because of the extensive nature of the comments, a Table of Contents and
some supporting appendices are included. We appreciate the opportunity
to becorae involved with this program and stand ready to provide further
advice, as requested.
Sincerely,
Robert Tardiff , Ph.D.
Chair, Drinking Water Subcommittee
Hersehel Griffin, M.D.
Vice-chair, Drinking Water Subcommittee
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EPA NOTICE
This report has been written as a part of the 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 a
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 does mention of trade names or commercial products constitute
endorsement or reccraniendation for use.
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TABLE OF CONTENTS
Subject ' • Page
I. GENERAL COMMENTS ON DRINKING WATER HEALTH ADVISORIES 1
II. SPECIFIC COMMENTS CM' ELEVEN HEALTH ADVISORIES 8
A, Aerylamide i' -B
8. Benzene 10
C. Dioxane 11
D, Ethylbenzene 13
E. Ethylene glycol 14
F, n-Hexane 16
G. Legionella 19
H. Methyl ethyl ketone 21
I. Styrene 22
K. Toluene ' 24
L. Xylenes (ortho-, meta- and para-xylene) 25
III. APPENDICES
Roster oE the Subconmittee
List of conments received £rom the public.
Federal Register notice of the January 6-8, 1986 meeting
Agenda for the meeting
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I, GENERAL COMMENTS OF THE LINKING WATER SUBCOMMITTEE OF THE EWIRQM»1ENTAL
HEALTH COMMITTEE OF EPA'S SCIENCE ADVISORY BOARD REGARDING DRINKING WATER
HEALTH ADVISORIES
A, THE OFFICE OF DRINKING WATER (DDK) NEEDS TO CONSIDER HOW HEALTH ADVISORIES
WILL BE USED,
Several groups of people will use health advisories, including state and
local health officials (physicians, toxicologists, and engineers)t water
purveyors, and the-general public, A physician will need clinical information,
such as which biological tests are the most sensitive, both in terms of
monitoring exposure and determining any potential health effects. Of particular
importance are potential developmental or reproductive effects, increased
sensitivity of a specific subpopulation, such as the young, and potential
dermal effects which may occur from bathing. Water purveyors will desire
concise statements of risk and "bottom line" numerical guidance for specific
situations they may encounter. In most situations, they will have to meet
the goal of the the lowest concentration, if the water is used for ingestion
purposes. The general public will want information in easy to understand
language and will want to know if it is "safe." The most useful format for
the health advisory will provide at least the minimum, roost basic information
for all of these groups.
As currently written, the health advisories are aimed primarily at
practicing toxicologists because of their fairly complete summaries of
scientific data. However, additional information should be provided on
dermal and inhalation exposures, since the ingestion route can easily be
eliminated for a short time period by substitution of an alternative water
supply. Guidance on showering and bathing is essential.
B, THE ONE WD TEN DAY ADVISORIES SHOULD BE RELATED TO EACH OTHER ACCORDING
TO A SCIENTIFIC RATIONALE.
The one and ten day advisories are of of limited use for providing
guidance for ingestion exposures. Public water supplies do not have milligram
per liter concentrations of organic chemicals unless a spill has occurred,
In those cases, the water source or the distributed water will not be' used
for drinking purposes for a short period of time. Moreover, if the contamina-
tion has just been found, no one will know how long people have been exposed
to it, or how much time will elapse before the contamination is removed.
Therefore, the long-term advisory will most often be used.
There are many examples in which the peak short-term concentration value of
a substance produces maximal effects (not the total amount). This situation
exists for some developmental effects, for example. On that basis, doubts
exist about the adequacy of dividing a ten day advisory into its component
parts.
For scute substances, insufficient data exist to generate a ten day
health advisory. There is no evidence in the literature of a repeated dose
study having been performed for several days duration. The use of the one day
health advisory as a starting point is in itself not wrong. Dividing by ten
assumes that either the substance, or its effect, are strictly cumulative,
which is the case for only a few substances. The health advisory level is
intended to protect against injury, but cumulative injury is not expected.
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A health advisory level based on the peak concentration of exposure would
depend upon the half-life of the compound, If data are available, elimination
rate needs to be considered. If the half -life is very short, the factor of
ten may be excessive, especially in view of the safety factor already built
into the one day health advisory* If the half -life of the chemical is long,
or if accumulation is known to occur, the use of a factor of ten could be
warrantedt However, it would be peculiar to generate a ten day health advisory
level lower than the longer term health advisory, adjusting for the fact that
the ten day for health advisory is set for a child and the longer term health
advisory for an adult.
C, THE FOOTING ASSUMPTION THAT TWENTY PERCENT OF TOTAL HUMAN EXPOSURE DERIVES
DRINKING WATER IS UNWARRANTED,
An explanation is needed to address the default assumption that drinking
water contributes a certain fraction of total exposure, where no data are
available for a specific substance. The Subcommittee understands that the
Office of Drinking Water often has to develop health advisories with inadequate
(or absent) information. However, the current default assumption of a
twenty percent contribution is particularly inappropriate for children and
infants, on whom the one day and ten day advisories are based. The body
surface area to body weight ratio is markedly different between infants and
adults. Skin thickness (and dermal exposure) also may differ significantly
between children and adults.
The automatic use of a twenty percent contribution from drinking water
sources appears to be arbitrary. Further confusion results when the assumption
of a twenty percent contribution is applied in some cases and not in others*
The health advisories provide no explanations for these exceptions or for
the default cases. For those cases where data are available regarding the
possibility of exposure in the general public, a contribution calculated
from these data should be used. The resulting contribution might be either
higher or lower than twenty percent.
The Office of Drinking Water needs to consider inhalation and dermal
exposures as additional confounding factors* These exposures could result
frcm the use of water for purposes other than drinking, such as showering
or cooking* Even for these factors, there are data for many of the compounds
reviewed in this set of health advisories. These data include volatility
and inhalational toxicity results. In a few cases dermal absorption rates
also may be known. For many of these compounds the toxicity via the dermal
route is known. In many cases these data are available from material safety
data sheets. There may also be data available on the irritant properties of
these substances.
D. THE ASSUMPTION OP A TEN KILOGRAM CHILD FOR EXTRAPOLATION TO INFANTS REQUIRES
SOME MODIFICATION.
Just as children may respond very differently from adults, infants can
be found to react very differently from children. This is particularly
important when one considers that pediatric practice is able to sustain and
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achieve survival of increasingly younger premature infants. In many instances,
these children carry out in the incubator the kinds of developmental events
that are more characteristic of in utero life, and they can be markedly more
sensitive to exogenous agents than postnatal individuals* The way to solve
these latter two problems is simply to add a general warning to alert the
unwary reader that-a health advisory based on adults or children might not
be directly extrapolatable to increasingly younger and immature individuals.
E. BIQDEGRADATIQN INFORMATION NEEDS A GREATER EMMAS IS.
The health advisories, in general, have a paucity of biodegradation infor-
mation, which might be among the more valuable knowledge for officials of
municipalities in dealing with specific contamination situations. Efforts
to obtain such information from the literature should be carefully pursued
in each instance, and no usable data should be ignored. In some cases, the
Subcommittee does not know whether such information exists, or if the health
advisory preparation process does not facilitate its aquisition.
F. OCCURRENCE MD TOXICITY DATA SHOULD BE CONSIDERED TOGETHER,
Most chemical substances are utilized in industry for a variety of pur-
poses and are produced in varying amounts. A good example is the case of
ethyl benzene, for which there is no Criteria Document and limited data for
the health advisory. Ethyl benzene is manufactured in the amount of approxi-
mately 3*3 million tons per year. As a screen for deciding when to develop
health advisories and/or Criteria Documents, OEW should make some attempt to
correlate the occurrence and usage data of a compound with its potential as a
hazardous substance. ODW can subsequently assign priority to those chemicals
which have high usage or occurrence data. The Subcommittee understands that
this is a complex matter. For example, in the case of a synthetic intermediate,
there is little chance o£ public exposure from routine use, but substantial
exposures can occur after accidental releases.
G. SOME PHYSIOLOGICAL ENDPOINTS MERIT INCLUSION.
In considering the adverse effects produced by a substance, it is impor-
tant not to dismiss toxicological effects as simply being physiologic changes.t
In the draft health advisories, certain changes were reported that appeared
to be physiological responses or adaptations. For example, in the case of
xylenes, ultra-structural changes were observed in the liver, but were considered
as toxicologically insignificant. In other cases, increases in cytcchrome
P-45Q were considered to be a toxicological endpoint. Toxicologists have
debated the significance of such changes for years without developing a
scientific consensus. In some cases, increases in the toxicity (activation)
of a compound are observed and, in other cases, a decrease' in the toxicity
(detoxification) occurs. The problem with the current set of health advisories
is a lack of consistency. Office of Drinking Water staff should decide how to
carry out the evaluation of such physiological changes, and should use this
policy consistently in the health advisories.
t V.AI Newill, "Regulatory Decision-Making: The Scientist's Role," J. Wash*
Acad. Sci., 64: 31-48, (1974).
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H. 'PfiARMACQiaNETIC ANALYSIS IS IMPORTANT IN THE HEALTH ADVISORIES.
The Office of Drinking Water should attempt to provide pharmacokinetic
data with the most recent references as well as the best references. Although
the advisories generally compare animal data to human data and, in particular,
where metabolites are thought to be responsible for toxicity, each advisory
also should provide a careful assessment of the qualitative and quantitative
differences. If different endpoints of toxicity exist in lower animals and
humans, metabolic.differences must be carefully considered. If the data base
is sparse, this deficiency should be stated explicitly, at the beginning of
the section in the health advisory,
I. THE ADVISORIES SHOULD NOTE ODOR THRESHOLDS.
Where odor and taste thresholds are Icwer than recetnmended levels, a
note should be inserted in the health advisory to indicate that water potability
or aesthetics may be an important consideration for field consideration, in
addition to safety considerations. Each health advisory also should note where
a particular substance present in the water is subject to sensory determination
(odor, smell, color), or is determined analytically to be present and usually
accompanied by other substances of equal or greater toxicity.
J. THE OFFICE OF DRINKING WATER SHOULD DEVSIDP GUIDANCE, PERHAPS IN THE FORM
OP AN ISSUE PAPER, ABOUT THE SELECTION OP DATA TO SET THE LEVEL OP AN
ADVISORY.
Three subjects discussed by the Subcoratdttee relate to the concept of a
hierarchy of data to be used in selecting studies for use in calculating
advisory values. These include:
* Inconsistency in how no-observed-adverse-effect-levels "were selected
for different substances.
» Criteria to select pivotal studies.
* Use of information prepared by other organizations, such as the
American Conference of Governmental Industrial Hygienists.
The Subcommittee recommends that a general and flexible hierarchy be
formulated and followed consistently through the health advisory program.
Specific points raised by the Subcommittee include:
* Advisories should be developed from data of appropriate exposure
length and frequency. However, this should not lead one to calculate
a "longer-term" or "lifetime" value substantially larger than a one
day or ten day value.
* Oral exposure data should take preference over that from other
routes, and drinking water studies are preferred over gavage
studies. This is particularly true for gavage studies utilizing
oil as a vehicle to attain large concentrations, and in particular
where the vehicle alters absorption/pharmacokinetics.
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* OEW states that the health advisories are based on the most-sensitive-
observed-effects. It should characterize and state its views more
clearly on the nature and significance of these effects. This decision
will often be specific to the material for which the advisory is
developed. For example, consideration of toxic effects from substances
of similar structure or from studies of different duration may support
selection of the "sensitive effect" as toxic.
« After it develops values for health advisories of different durations
for a substance, the Office of Drinking Water should review the entire
data base to determine the consistency of individual calculations with
each other* A prior description of the underlying logic for •which
such decisions are made will be useful guidance for preparing, advisories,
• For some materials, (e.g. benzene, hexane) there are human toxicity
and/or exposure data by other than oral routes. These data may be
considerable, involving a good estimate of body burden, and may provide
additional data for a no-observed-adverse-effect-level or lowest-
observed-adverse-effeet-level evaluation. The Environmental Health
Cownittee and its Subcommittees have consistently urged the Agency to
take advantage of these kinds of "experience checks."
• The American Conference of Governmental Industrial Hygienists has been
active for many years in the setting of Threshold Limit Values.
Threshold Limit Value is a registered trade mark of American; Conference
of Governmental Industrial Hygienists (ACGIH). AOGIH frequently
reevaluates these values and publishes the scientific basis of each
one. They may be considered concensus values based on the best available
published datat While there is some hesitancy to use the Threshold
Limit Values because the route of exposure is frequently by inhalation,
they often are based on human data. It would be interesting to deter-
mine how many of the health advisories cite the same references as
those given for the Threshold Limit Values. The Office of Drinking
Water might initiate a health advisory with this set of references
for purposes of efficiency. The Threshold Limit Value documentation
also frequently contains other useful pieces of information. For
example, they may cite the lowest doses associated with mortality or
other signs or symptoms of toxicity. In addition, they may contain
inforjnation on irritancy and odor threshold.
• 'Where the Office of Drinking Water hesitates to use the human inhala-
tion data from a Threshold Limit Value or chooses to use animal oral
data, it might be useful to compare the two values. However, the
Subcommittee is of a divided opinion regarding the desirability of such
calculations. A value based on human inhalation data could be calculated
by extrapolating from inhalation to oral route. The difference-, in
safety factors for animals versus humans would also have to be considered,
and Threshold Limit Values are established for eight hours per day
exposure of healthy workers. Threshold Limit Values should be used
only for non-route specific target organ effects. For example, it is
not appropriate to set a drinking water value for a metal which causes
fume fever when inhaled. Beyond this specific caveats, some members
of the Subcommittee urge caution in extrapolating from human occupational
inhalation standards to environmental standards for the general population
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since the workplace standards often are developed from experience at
existing occupational exposures. Thus, the Theshold Limit Values
often have an empirical, tentative status and are subject to downward
revision as more experience accumulates. In such a situation,
comparison to an environmental standard mean to provide safety for the
general population can be misleading.
K. TEE PRESENCE OP.CERTAIN COMPOUNDS IN DRINKING WATER CAN INDICATE THE
PRESENCE OF OTHER SUBSTANCES FROM A COMMDNLY OCCURRING MIXTURE.
Sane of the ccwpounds for which health advisories exist are most likely
to be found as part of a mixture. Hexane will probably be found as a component
of gasoline, and other components, such as benzene, toluene, xy^lenes, and
ethyl benzene, also may be present. In this case, hexane serves as'an indicator
or sentinel substance. The health advisory for each of the components should
mention this possibility and present some guidance as to how the presence of
the total mixture should be evaluated. For exanple, in the health advisory
for toluene, a note might be added that when toluene is found, the reader
should also examine the monitoring data for the possible presence of other
compounds found in gasoline. If found, the reader should review the health
advisories for gasoline related substances, such as benzene, followed by a
listing of the gasoline related substances for which advisories exist. The
Office of Drinking Water should consider the devlopment'of a health advisory
for gasoline.
L. THE EXiQSURE ANALYSES THAT SUPPORT HEALTH ADVISORY CALCULATIONS MERIT
SOME MODIFICATION.
The health advisories only consider ingestion of two liters of water as
the route of exposure. Drinking water contamination can also lead to inhala-
tion and dermal exposure. The advisories should consider these two routes of
exposure especially when they address high contaminant levels.
Exposure to contaminants in drinking water occurs not only through the two
liters of water that QDW assumes a person drinks in one day. Exposure from
drinking water also occurs through dermal absorption and through inhalation
of volatile compounds. Because the average per capita use of domestic water
approximates 120 liters, which is more than the two liters estimated in the
health advisory for oral consumption, these other exposure routes are potentially
significant on a mass balance basis. Moreover, if drinking water is obtained
from contaminated ground water, the indoor air quality in homes above the
ground water can be affected.
Human exposure to some of the compounds considered in the health advisories
occurs not only through water but through the air, food, soil and dust. When
deriving health advisory values, these other routes of exposure must be
considered, and the entire Acceptable Daily Intake can not be allocated to
drinking water. In most cases, exposure information will not be complete.
Even though an estimate of the known exposure may be possible, ODW should
make allowances to ensure that the Acceptable Daily Intake is not exceeded.
Therefore, the health advisory should include information on whether or not
the compound is absorbed through the skin and whether or not it is a skin
irritant.
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Users need the one and ten day health advisories to make decisions and
provide infonnation on whether or not the water is suitable for bathing and
showering purposes since the ingestion route can be avoided for limited time
periods by issuing a bottled water order. EPA should consider providing seme
advice on not using a contaminated raw water source when possible, especially
if the contamination is the result of a spill and the source is not essential.
If substantial differences exist in the health effects of a substance
when exposure occurs through inhalation rather than ingestion, .the health
advisory should indicate this difference. If the compound contributes to
indoor air pollution, this information should be stated explicitly.
If a health advisory number derives from an acute or subacute effect,
EPA should consider basing the number only on a child or infant, not an
adult. If a study of chronic effects (lifetime study) drives the value of a
health advisory, EPA should develop only the value for an adult*
M. ODW SHOULD IMPROVE THE EDITORIAL QUALITY AND CONSISTENCY OP THE DRAFT
HEALTH ADVISORIES.
Overall, the Subcommittee found a high level of proofreading and citation
errors. The health advisories did not describe the properties of the substances
in a consistent manner, and factual matters, such as molecular weights, were
misquoted with a high frequency. In addition, the Subcommittee has pointed
out many errors in the calculations. The Subcommittee has not provided a
comprehensive technical editing for the health advisories* Therefore, it
recommends that the Office of Drinking Water provide for a thorough technical
editing before it releases the final versions.
The Office of Drinking Water provided constructive cements on the use of
health advisories by states and localities. Both the Subcommittee and EPA
have concerns about potential misuse of the health advisories. For example,
if the terminology regarding developmental effects is not articulated clearly,
the health advisories will be counter-productive of embryonic well-being by
tending to generate unwarranted elective abortions. The label "teratogen"
refers more often to the dose at which exposure occurred in an animal study
than to some intrinsic property of the chemical itself. The current practice
tends not to emphasize selective effects on the conceptus. The Subcommittee
recommends that the Office of Drinking Water use the terminology of "develop-
mental toxicity" instead of "teratology." Teratology is but one of the four
signs of developmental effects.
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II. COMMENTS OP THE DRINKING WATER SUBCCMMlTTiB ON HEALTH ADVISORIES EDR
SPECIFIC SUBSTANCES
ft. ACRYIAMIDB HE<H ADVISORY
The Criteria -Document is dated October, 1985, but it fails to include
some relevant recent data, including key papers published in 1983. The
health advisory, which closely reflects the contents of the Criteria
Document, also lacks these references. They may not be important for
calculating safe exposure levels but, because they relate to seme of the
more subtle effects and mechanisms of toxicity, they possess implications
for the assessment of long-term adverse effects. To update the" references,
the Subcommittee recommends the use of some standard computerized litera-
ture retrieval service. The Subcommittee provided a printout to Office
of Drinking Water staff as an example. The health advisory also has a
large number of editorial and typographical errors. For example, the
chemical structure of acrylamide is in error.
The Criteria Document for Acrylamide is not an integrative, critical
review, but largely consists of a series of descriptions of individual
studies. For this reason, it misses a significant aspect of the acryl-
amide literature: the consistent reports that, first, sensory systems
are damaged before motor systems and, second, that detection of functional
impairment (behavioral, electrophysiological , neurochemical) often precedes
histological damage .
Both the Criteria Document and the health advisory do not adequately
discuss the question of dose-duration relationships. They assert that
evidence of acrylamide neurcpathology is manifest after a cumulative
dose of 100-150 mg/kg, but this conclusion is warranted only within a
narrow range of dose rates. In some experiments, a single dose of 50'
mg/kg to rats inhibited nerve terminal sprouting. This work was not
reviewed in the health advisory. In contrast, a dose rate of 1 mg/kg* day
induced clinical signs of neurotoxicity in monkeys only after 18 months
of treatment and a presumed cumulative dose of about 400 rag/kg. Enough
data are available in the literature to calculate a relationship between
dose rate and toxicity.
The time dependency of acrylamide dose is deceptive. The pharmacokinetie
half -life is between 2 to 5 hours, but metabolites last longer, and the
toxic behavioral effects are inconsistent with the pharmacokinetics.
One to two weeks after a 10 mg/kg dose in the cat, symptoms appear. At
1 mg/kg* day, symptoms appear after 18 months. Extrapolation based on
pharmacokinetie analysis is unwarranted. The exposure calculations would
be modified slightly by basing them on 1982 data indicating behavioral
effects after a single dose of 10 mg/kg to rats. Collateral neurochemical
data also yield the same dose level as at least a lowest-observed-adverse-
-ef feet-level. The description of absorption should reflect that acryl-
amide can be absorbed through unbroken skin as well as through mucous
membranes and lungs.
The section on synonyms is incomplete. The Subcommittee recommends that
the Office of Drinking Water use a standard source, and it has provided the
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program with a printout from a standard cenmercial source. The section
on uses also is incomplete. The health advisory could add data on
solubilities in chloroform and benzene, since there is no available
octanol/water partition coefficient.
In the short-term exposure section, the analysis should reflect that
McCollister used female rats, male guinea pigs and rabbits of both sexes.
Pryor reported an acute LDsg of 203 ragAg and subchronic values of (5
days/week/4weeks). LD$Q of 32 mg/kg and subchronic (5 days/week/15weeks)
LD5Q of 17 mg/kg. In the longer-tern exposure section, the advisory should
provide a reference for the value cited in the first section, and move the
second/ fourth and sixth sections to the section on short-term exposure
to reflect the dosing. McCollister reported additional no-observed-adverse-
effect-level data for rats, cats and monkeys that are not reflected in
the health advisory. The drinking water equivalent level calculation
should be based on 0,0002 rag/kg'day instead of 0.002 rag/kg*day* Ihere is
an error in the calculation. The EPA standard given in the Criteria Document
is 0.05%, not 0,05 ug/L.
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B. BEN2EME HEALTH AWISORY
The benzene health advisory effectively organizes data frcm diverse
sources and places them into perspective. However/ the status of the
Criteria Document is not clear, and it differs in places with the health
advisory. The Criteria Document appears to be a preliminary draft because
of the inconsistent styles between each section and because the logic
wanders. The two documents also are inconsistent. For example, the
Criteria Document does not mention ground water in extent or significance,
but the health advisory states that benzene is released to the ground,
binds somewhat to the soil, slowly migrates to ground water and .retains
stable there.
Several synonyms often are confused with benzene, such as benzin or
benzol, and they merit inclusion* Where information exists on mixtures
containing benzene, the health advisory should use it. For example, the
Criteria Document mentions that the simultaneous treatment with both
benzene and toluene or piperonyl butoxide increases the excretion of
benzene in breath. The odor threshold for benzene is of considerable
importance. No mention is made of the metabolites of benzene, which
include phenolf catechol and hydroxyquinone.
The preponderant scientific evidence suggests that benzene is
metabolized through formation of an epoxide, which contrasts with the
inconclusive statement in the health advisory that different metabolic
pathways are involved. For risk assessment, it is ictportant to note that
47% of benzene inhaled was absorbed, 301 retained and 16% exhaled unchanged,
when exposed to 52-62 ppm for 4 hours, and was the same for both sexes.
Benzene absorbed frcm ingested drinking water or inhaled from drinking
water sources will be subject to these, pathways. More detailed informa-
tion on dermal absorption is needed. The Criteria Document also mentions
three elimination phases for humans versus the biphasic results described
elsewhere. This descrepancy should be resolved.
Neither the study by Dosken nor that by Chang states that the lowest
level of benzene to produce platelet effects in workers was 10 ppm, .which
represents a modelled result. The description of short-term health studies
by Wblfe and coworkers should include a description of duration of exposure.
The description of the Occupational Safety and Health Administration
standard as 3.2 itiicrogram/L is in error. The standard is 32
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C. DIOXANE HEALTH ADVISORY
The health advisory for 1,4-dioxane constitutes a useful document,
but seme errors merit correction. The range of dioxane concentrations
found in drinking water needs to include a perspective on these data
based on the hazard information in the health advisory, The Subcommittee
suggests that the "health advisory point out that 1,4-dioxane is a synthetic
organic compound with no known natural sources. Dioxane is mixable with
water at all concentrationsf and it may be that its nobility in soil is
directly proportional to water passage through the soil.
Given the importance of biodegradation and/or spontaneous ^degradation
information, the Subcommittee recommends a further search of the literature.
The current review appears out of date. Degradation by chlorination,
which will occur in many drinking water supplies, results in products
which are more toxic than the parent compound. The fact that the test
material nay become chlorinated and thereby become markedly more toxic
than the parent compound is not a valid basis for not determining a
health advisory. The fact of potential chlorination, with or without
altered molar toxicity, is relevant, however, to other aspects of an
health advisory, i.e., other criteria, guidance and standards. Since
this detail is reported in the longer-term health advisory section, many
operating personnel may miss it.
The health advisory tor dioxane assumes one hundred percent absorption
from the gut. The Subcommittee recommends the addition of a discussion
about the cutaneous and pulmonary routes as well,
Covalent binding of 1,4-dloxane was higher in the nuclear fraction than
in other cell fractions. The Subcommittee suggests adding a perspective
on the extent or absence of covalent binding with DMA and its implications.
Metabolism of dioxane is dose-dependent and saturable. The relevant
data are cited but not interpreted. The first sentence of the excretion
section speaks of "animals," but if reports from species other than the
rat exist, they should be reported. The rate, as well as the form of
excretion, constitutes important information.
The health advisory cites the 1979 National Institute of Occupational
Safety and Health Registry to provide the oral LD5Q values in several
species. Some of the references of the Registry also report effects at
lower doses and, if these were reported, one would have information
significantly more useful than isolated LDsg values. The discussion
of acute pathology is very limited, and there may be additional published
target organ toxicity information available. The description of the work
of Fairley and coworkers with rabbits is difficult to understand. It
merits not only rewriting but also expansion. Overall, the slopes of
dose-reponse curves should be given, where possible.
The nature of the tumors reported in the study of Kociba and coworkers
merits discussion.
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Several studies in chickens may be useful in evaluating the developmental
aspects of 1,4-dioxane, A mouse study of sore utility existst. There
are numerous examples of solvents that represent significant hazards to repro-
duction. Structure activity relationships for reproductive (but not
developmental) effects also are possible in some limited instances, such
as alkylating agents and seme classes of hormones. This information sierits
a renewed literature search for relevant data.
Several reports of in vitro mutagenieity tests of l,4-^3ioxane occur in
the literature that are not cited in the health advisory, and the Subcom-
mittee recefiroends further searching for similar studies.
The relevance of the calculation of no-observed-adverse-effect levels
for a substance with carcinogenic potential, such as dioxane, fieri ts
discussion in addition to the retrospective predictive ability of the
formula presented. The use of body weight is an essential component of
such calculations, but they fail to account for the marked differences
among individuals based on age alone. The consumers who take in the
largest relative volume of liquid are infants. Awareness of this factor
could be one of the qualifiers applied to this calculation. The dangers
of extending the mg/kg calculation to the newborn or prematurely delivered
infant merits mention. Hew was the safety factor of 100 for "animal
data" arrived at? Retrospectively, how proper has it proven?
With respect to the one day advisory, it is difficult to consider how
intravenous dose groups of one aniraal, each with effects seen in the
animal treated at the lowest dose, leads to a useful lowest-observed-
adverse-effect-level without carefully reviewing supporting -data.
However, such an extended rationale is not available in the health
advisory. The extrapolation needs a discussion (or citation for a support-
ing explanation) of its range of limitations. The Subcommittee prefers
the use of an acute oral toxicity study to an intravenous study, given
the scant knowledge of pharmacokinetics of dioxane.
The fact that an acceptable study for calculating a ten-day health advisory
was not located does not justify dividing the one-day health advisory by
ten. There are instances where it is not the area under the curve that
is proportional to response, but instead the peak level attained that
exceeds a threshold of response.
The absence of acceptable data to set a short-terra standard and the
possibility of enhanced toxicity after biodegradation do not constitute
valid reasons to set aside the development of a longer-term health advisory,
In other advisories, the Office of Drinking Water has developed longer
term health advisories for substances with carcinogenic potential, and
some consistency is needed. The data of Kociba and eoworkers will support
the development ot both longer term and lifetime health advisories.
The Subcommittee suggests further literature searches on the topics of
movement in ground water and other water degradation, biologic half-time
and perhaps bioaccumulation potential.
A degree of value judgment and/or guidance is merited in the analysis
section* The paragraph offered is not meaningful in guiding the reader
to the appropriate technique.
t See Toxicology letters 12: 191-198 (1982).
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D. ETHYLBENZEME HEALTH ADVISORY
With the exceptions noted below, the health advisory is consistent with
information presented in the Drinking Water Criteria Document for Ethyl-
benzene. Overall, acceptable daily intake calculations are consistent
with guidance provided in the issue papers for such calculations.
The health advisory should include "tobacco smoke constituent" as a
source of exposure to ethylbenzene since this source results in the
highest exposure Amounts in ambient air. Similarly, motor vehicle
exhaust may reasonably be expected to result in exposure.
The pharntacokineties section needs modification. The Criteria Document
should include several important referencest published in 1984 that
provide new information on the metabolism and excretion of ethylbenzene
in rats.
The uncertainty in human health effects reported at 100 ppn is not prop-
erly presented. The report of Bardodej and Bardodejova states that the
total number of volunteers was 18, The authors report that exposure to
100 ppm caused no ill effects. Duration of exposure was not specified
in the Criteria Document, but an increase in exposure resulted in reported
symptoms of sleepiness, fatigue, headache and mild eye and respiratory
irritation. The authors did not report the increase in exposure that
caused these symptoms.
This report does not attain the sane quality as information considered
in establishing and maintaining the present American Conference of
Governmental Industrial Hygienists Threshold Limit Value of 100 ppn.
Most available information indicates that 100 ppm-8 hour exposure
represents a no-adverse-effect-level, not an effect level*
The ntutagenicity section needs improvement because the health advisory
fails to cite the work of Dean and coworkers* which reports that ethyl-
benzene is not mitagenic in Salmonella typhjjtiuriurof JLcoli/ S. cervisiae
and in the recessive lethal chromosome assay in Drosophila.
The National Cancer Institute has not yet initiated a bioassay for car-
cinogenicity of ethylbenzene. Activity is at the design cownittee stage.
No rationale exists to support the establishment of a ten day health
advisory value through the procedure of dividing the one day value by
ten, when ethyl benzene (1) appears to have a threshold, and (2) seems to
be rapidly metabolized and cleared from the body. A consortium of ethyl-
benzene producers is currently conducting 28-day inhalation probe studies
in mice, rats and rabbits. These studies should provide better data for
calculating short-term health advisories.
No data are presented to support the conclusions about treatment of water.
t K. Engstrom, "Urinalysis of Minor Metabolites of Ethylbenzene and m-Xylene,"
Scan. J. »orkt Env. Health 10: 75-81 (1984),- K. Engstrom, "The Metabolism
of Inhaled Ethylbenzene in Rats," Scan, J. Work. Env. Health 10; 83-87 (1984);
K, Engstrom and Cowordersr Int. Arch. Qccup, Env. Health 54; 355-363 (1984).
* B.J. Dean and Coworkers, "Genetic Toxicology Testing of 41 Industrial
Chemicals," Mutation Research 153: 57^77 (1985).
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E, ETHYLENE GLYCQL HEALTH ADVISORY
No Drinking Water Criteria Document is available for ethylene glycol*
The health advisory derives from a number of key references and, in
general, adequately reflects the contents of the journal articles cited.
The studies by Mason are correctly transcribed, but it is not clear how
thoroughly the pathology portion of the study was conducted, other than
the tumor counts, . For example, what is meant by selected tissues? How
carefully were the kidneys examined?
The only study reported under the section of developmental and repro-
ductive effects is that of Elis and Raskova. However, their report
lacks experimental detail.
The study by Blood and coworkers represents a key reference and is used
in the calculation of the longer-term health advisory* This study used
only three monkeys, and the experimental details in the report are sketchy.
Another study which EPA should consider is that of Roberts and Seibold
which also studied monkeys at various doses although for shorter periods
of time.-'- This study found kidney damage in the absence of calcium
oxalate crystals which required a dose of 15 ml/kg or greater for formation.
The study of Laug and coworkers adequately describes the acute effects
in a variety of animals, but the study by Reif is questionable. It does
not constitute a well controlled study but merely reported observations
on one individual • More information on humans is available/ including
a number of studies in the literature on the toxicity of ethylene glycol,
These studies are addressed in reviews and texts, 2 Also, studies of
individual cases have demonstrated a wide range of sensitivity among humans
to the toxic effects of ethylene glyeol. The paper by Reif may not be
adequate to estimate percentages of metabolites. Ethylene glycol elimination
is a very dose dependent process which has been documented well in animal
studies, such as those by Marshall. 3 Dose dependency of elimination works
strongly against the use of high doses to make estimates on long term,
low level exposures.
EPA should review a number of other multiple dose studies in animals,
such as that of Rajagopal and Ramakrishnan,^ which also list other
J,A. Roberts and H,R. Seibold, "Ethylene Glycol Toxicity in the Monkey,"
Toxicology and Applied Pharmacology, 15: 624-631 (1969),
2 $ee, for example, Haddan and Winchester, Clinical Management of Poisoning
and Drug Overdose; R.W. Moriarty and R.H* McDonald, "The Spectrum of Ethylene
Glycol Poisoning. Clinical Toxicology," 7_: 583-596 (1974); C*D. Peterson and
Coworkers, "Ethylene Glycol Poisoning: Pharmacokinetics during Therapy with
Ethanol and Hemodialysis," Mew England Journal of Medicine 3Q4i 21-23 (1981)*
3 T.C. Marshall, "Dose-dependent Disposition of Ethylene Glycol in the Rat
After Intravenous Administration," Journal of Toxicology and Environmental
Health 10; 397^409 (1982).
4 G. Rajagqpal and S. Ramakrishnan, "Effect of Ethylene Glycol Toxicity on
Hepatic Carbohydrate Metabolism in Rats," Toxicology and Applied__JPharroacolQgy
46; 507-515 (1978).
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-15-
relevant references. The study by Gessner arid coworkers on metabolism
and the study o£ Marshall also are germane. .
Another inportant factor is the literature base used to develop the
Threshold Limit Value by the American Conference of Governmental Industrial
Hygienists. Although many of the data relate to studies conducted by
using the inhalation route, there are a number of good studies referenced.
In summary, the Health Advisory on ethylene glycol represents a reasonable
distillation of the references used. However, it suffers from the .emission
of useful data generated in the last decade and underestimates what is
already known about the toxicity of this compound in humans. In addition,
recent incidents will generate new data on human exposure by ingestion.
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F. n-HEXflNE HEALTH M^ISORY
Since no Drinking Water Criteria Document for n-hexane exists,
the health advisory is based on a collection of supporting papers. Hie
health advisory omits recent references dealing with metabolism and
toxicity, especially with the agents responsible for toxicity. It also
lacks some papers dealing with toxicity and mechanisms.
The 1290 mg/kg dose used as the basis of most calculations is difficult
to justify. With a substance producing an irreversible toxicity it is
necessary to understand the mechanism, the metabolite responsible and
the rate at which humans might be expected to produce the metabolite.
If this kind of explanation cannot be provided for n-hexane, EPA should
explore this issue and provide a rationale for the method though which
it calculates the safety levels.
In the study by Heshkowitz and cowoiters, the exposures averaged 650 ppn
with peaks up to 1,300 ppnw instead of ranging between these two levels.
In the study by Krasavage and coworkers, it is not clear that the 1,140
mg/kg dose was administered for 120 days. The paper could be interpreted as
indicating that the 1,140 iwj/kg dose was given for 90 days. ODW should
re-evaluate if the dose of n-hexane in the study by DiVincenzo and coworkers
may be 250 mg/kg and not 450 mg/kg.
Nerve conduction velocities may be one of the more sensitive indicators
of impairment by n-hexane. The experiments used to calculate the health
advisories were not based on these endpoints, nor was this mentioned in
the health advisory.
The health advisory mentions furan and valerolactone derivatives as
metabolites of n-hexane. In discussing metabolites of methyl n-butyl
ketone, DiVincenzo and coworkers indicate that a furan derivative may
be formed in the gas chromatograph and may not actually be a metabolite
of methyl n-butyl ketone. The same artifact may occur with n-hexane and
its cyclic derivatives. The level of 2-hexanol referred to in the excretion
section section should be 0.5 mg/liter and not 0.05 rag/liter. The hexane
used was commercial hexane and not pure n-hexane. The study by Bus and
coworkers shows that n-hexane and its metabolites reach the fetus. The
reproductive section should state this conclusion.
The Subcommittee suggests that, given the amount of information available
about human industrial exposures and abuse, the advisory could base the
calculations directly on the human data. The drinking water issue paper
by Khanna, which discusses the conversion of inhalation data into drinking
water standards, provides one means of doing so. Also, it would be
useful to apply such a technique to the Threshold Limit Value. At a
minimum, a calculation based on human data can compare with the current
calculation as an "experience check." Information on respiratory uptake
and retention of hexane also would be useful, if EPA extrapolates between
the oral and inhalation route. Inhalation experiments indicate that
continual exposure may be more toxic than intermittent exposure. In
addition, Perbellini and coworkers suggest that humans may be more
susceptible to n-hexane than experimental animals based on the different
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ratios of metabolites among the species. The advisory should address
these possibilities as part of the experience check.
EPA should incorporate into the health advisory the issue of the toxicity
of mixtures of which n-hexane is a constituent. The paper referred to
in the health advisory reports that the hepatotoxicity of chloroform is
greatly enhanced when simultaneous exposure to n-hexane occurs. Water
supplies are unlikely to be contaminated with only n-hexane, and the
health advisory indicates that the major source of hexane in the environ-
ment will be gasoline. Howeverf the health advisory does not mention
how this should be factored into the use of the values given.
Since other gasoline components will accompany n-hexane contamination
roost of the time, additional guidance on how the health advisories-should
be altered for the complex mixture would prove valuable. It may be
worthwhile to note that some gasoline components have been associated
with carcinogenic effects and that gasoline itself is probably is car-
cinogenic for humans. Office of Drinking «ater staff should consider
whether it may be a better strategy to issue a health advisory for
gasoline, rather than deal with possible problems in a piecemeal fashion.
For a volatile substance like n-hexane, the greatest need for the one-
and ten-day advisories will be to provide guidance as to whether or not
the water can be used for bathing and to provide information on the
adverse impact on indoor air quality. The exposure scenarios only use
ingestion as the route of exposure, which can easily be eliminated by
issuing an advisory against the use of the contaminated water source for
drinking and cooking purposes, or in the case of the one-day advisory,
not using the contaminated raw water source and using stored water.
Information on whether or not hexane is absorbed dermally would provide
some indication of the potential for exposure while bathing.
The Subcommittee suggests some additional references as a basis to
initiate revision of the health advisory;
Baker and Rickert, "Dose-dependent uptake, distribution and elimination
of inhaled n-hexane in the Fischer-344 rat," Tpjticology andApplied Pharmacology,
61: 414-422 (1981).
T.A. Marks, et al, "Influence of n-hexane on embryo and fetal development
in mice," Drug and Chemical Toxicology 3; 393-406 (1980),
Raje, "In vitro toxicity of n-hexane and 2,5-hexanedione using isolated
perfused rabbit heart," J. Tox. and Env. Health 11; 879-884 (1983).
Lungarella et al, "Respiratory tract lesions induced in rabbits by short-
term exposure to n-hexane," Res. Connu in Chenu Path, and Pharm. 29:
129-139 (1980).
Kronevi et al,, "Histopathology of skin, liver, and kidney after epicu-
taneous administration of five industrial solvents to guinea pigs," Env.
Res, 19: 56-69 (1979).
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Jakobson et al., "Intake via the blood and elimination of 1Q organic
solvents following epicutaneous exposure of anesthetized guinea pigs,"
Tox. and App. Pharm. j53: 181-187 (1982).
Howd et al, "Relation between schedules of exposure to hexane and plasma
levels of 2,5-hexanedione," Neurobehayioral Tox. and Teratology,. _4;
87-91 (1982).
Court and Milks, "Toxieity and metabolism of the neurotoxic hexacarbons
n-hexane, 2-hexanone, and 2,5-*hexanedionef" jyin. Bev. Pharraacol. Tbxicol.
2^; 145-166 (1982).
Calvender et al, "A 13-week vapor inhalation study of n-hexane in rate
with emphasis on neurotoxic effects," Fund, and Agp_* Tox. 4_: 191-201
(1984).
Bravaccio and Anmendola, "H-reflex behavior in glue (n-hexane) neuropathy.
Clinical Tox. 18: 1369-1375 (1981),
Graham et al, Tox. Appl. Pharm. 64; 415-422 (1982).
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G. LEGIQNELIA HEALTH ADVISORY
The Subcommittee questions the classification of potential bacterial
pathogens in water as toxic substances on the basis that bacterial cells
are complex, dynamic entities, capable of replication. Placing them
into the same group as toxic substances may not be appropriate.
The format of the health advisory, for t^gionella differs from that
ot the chemical substances, perhaps in recognition of the incongruence.
However, EPA should articulate the rationale for the difference, and the
Subcommittee recommends that the enphasis of the final health advisory be
placed on surveillance of respiratory illness, not drinking water.
Twenty-three recognized species of Legionella exist, twelve of which have
been implicated by culture techniques as sources of pneumonia. One species,
L.pneumophila, causes approximately 85% of these cases. With only one
exception (I,. feeLsiJL), L. pneumophila has been implicated as an agent
for Pontiac Fever, although no isolates of legionellae have been obtained
from patients with Pontiac Fever. Thus, grouping all legionellae as
pathogens with equivalent virulence cannot be justified at this time.
Most public health officials would agree that an advisory on legionellae
is needed at this time, because of numerous inquiries by the public,
especially engineering personnel and health officials given the respon-
sibility of taking appropriate measures to prevent the spread of Lagionella
from water in their facility. However, the advisory should emphasize
that epidemics and sporadic cases should be dealt with on a case-by-^case
basis. The beginning of the advisory should state the following: (1)
The source for the spread of legionellosis or Pontiac Fever should be
determined epidemiologically before intervention. It does not make
sense to attempt widespread eradication of mostly nonpathogenic organisms,
when the pathogenic strain can be traced. (2) Environmental strains
implicated as a cause of disease should be matched with patient isolates.
(3) Routine monitoring of water for Lsgipnella is not reccranended. (4)
There is no all encompassing disinfection procedure that can be recommended
each time.
Although the health advisory is not legally enforceable, the Subcommttee
understands that it will be accepted by seme workers as policy for in-
stallation and maintenance of plumbing systems. The guidance in the
health advisory focuses on how to deal with a problem once it is recog-
nized, rather than how to decide when one has a problem. The Subcommittee
recommends the following sequence of investigation as more appropriate;
* Given the impossible task of eradicating legionella, legionellosis
appears selective for high risk individuals. The attention of clinical
and public health workers should focus initially on surveillance for
respiratory illness, especially in high risk patients. If an increase
is detected, they should attempt to establish the etiology, not by cul-
turing the water but by culturing the patients and by performing serologic
studies. Microbiological analysis of clinical specimens is as rapid as
culture of environmental specimens, and preliminary information can be
gleaned from acute-phase serological specimens.
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is implicated in an outbreak of clinical illness,
public health officials should attempt to culture environmental sources.
They may undertake temporary measures designed to control environmental
legionellae, while using modern molecular techniques to determine if the
source has, in fact, been identified correctly, If all the data suggest
a clinical problem, and that it is probably associated with a 'particular
environmental source, continuing effort should be directed at that source
because past experience suggests that the problem may recur,
* Maintenance of decontamination procedures should occur in a way to
minimize clanger to individuals and damage to the plumbing systems. A care-
ful program of microbiologic monitoring of the environment and clinical
monitoring of human disease represents an integral part of that" program because
it cannot be assumed that the problem has been controlled indefinitely. A
focus on a few problem sites makes rouch more sense than a dilution of
effort by attacking all potable water systems, when dilution of effort
occurs, the likely result is that none of the sites is treated optimally*
* The Subcommittee also has several technical corrections to improve the
accuracy of the final health advisory, as follows:
» The importance of matching the patient isolate with the environmental
isolate frcm a source iinplicated by epidemiologic data should be discus-
sed in more detail. Also, grouping and characterization of L. pneuntophila
strains by isoenzyme profiles may be more definitive than monoclonal
subgrouping.t
* The contamination of a water system by new distribution components
is not well documented.
* Since legionellae can reside in cold water pipes, disinfection of a
plumbing system by heat treatment alone is not as effective as the com-
bination of heat treatment and chlorination. Chlorination without heat
treatment has been effective in several cases. Growth of legionellae
raay theoretically be enhanced on the cold water side of a hot-cold water
mixing valve in a heat-treated plumbing system.
* Since the overall cost of using heat for disinfection is greater when
considering all of the costs such as personnel time to monitor heat treatment,
cost of the heating, costs 'for precautionary measures taken against scalding,
and the cost of periodic treatments, this factor should be discussed when
comparing the advantages and disadvantages of chlorination versus heating.
• The health advisory should state that ozone, ultraviolet, and ethylene
oxide methods for disinfection of legionellae have not proven effective
in field tests. The advisory should note the difficulties of controlling
manual batch chlorination and the availability of devices that continually
monitor and adjust chlorine levels.
* Information on the specific types of gaskets and fittings that support
the colonization of legionellae is not well documented. More research is
needed to confirm published reports, and make recommendations on acceptable
materials.
t R.K.Selander and Coworkers, "Genetic Structure of Populations of Legionella
pneumophilia," J. Bacterial. 163: 1021-1037 (1985).
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H« METHYL ETHYL KSTQNE HEALTH ADVISORY
The Office of Drinking Water has not prepared a Criteria- Docunent for
methyl ethyl ketone. Instead, it included key references for calculating
the health advisory values. Although the data base for methyl ethyl
ketone is meager, it appears adequate for the purpose of calculating
these values. The evaluation of the literature is reasonable, and the
values correct, except that the lack of a ten day advisory is inconsistent
with the use of subchronic data.
Similar to the situation with n-hexane, the mixtures problem needs to be
addressed especially since methyl ethyl ketone enchances the neuro-
toxicity of n-hexane. That combination is suspected as responsible for
the outbreak of neuropathies among substance abusers in Vfest Berlin who,
until the addition of methyl ethyl ketoner seemed to suffer relatively
mild toxicity.
Although the advisory makes statements concerning the dermal absorption
and the qualitative nature of certain metabolites, the Subcommittee is not
aware of adequate studies dealing with distribution and metabolism. "Ehe
lack of adequate studies merits greater emphasis and should preceed the
paragraphs on absorption and metabolism.
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I. STYRENE HEALTH ADVISORY
The health advisory has addressed the major scientific issues in the Criteria
Document on Styrene, Except as noted below and in the general comments
sections, it has appropriately summarized and drawn sound conclusions.
The styrene health advisory notes that experiments in humans support the
use of no-observed-^effeet-levels based on central nervous systsn effects.
The one-day exposure level, however, derives from a study that relied on
hepatotoxic endpoints- It also seems inconsistent that the longer term
acceptable daily intake is equivalent to the IQ^day health advisory for a
child and quite close to the one-day health advisory. The health advisory
should offer some explicit cautions.
In the section on distribution, the radioactivity detected was styrene
or its metabolites. The health advisory should also specify where in the
molecule the ^C ]_abei Was located,
In the section on transplacental transfer, the measurement of transferrred
styrene was made on cord blood. This does not imply a one-way transfer
but rather a selective concentration on the fetal side of the placenta,
This could be the result of'an equilibrium in a two-way transfer
situation.
OEM should expand the section on metabolism to include a more extensive
treatment of styrene oxide, which is is a highly reactive chemical, a
carcinogen and a mutagen. It would be valuable to know what percentage
of styrene gets metabolized to styrene oxide and how this might vai^
frcm organ to organ. The effect of dose on metabolism should also be
described. Many studies on mercapturic acid formation have not been
included.
In the developmental and reproductive effects section, the advisory
should comment that the doses studied were 300 rag/kg*day or less, and
that these were comparatively low doses. Effects are possible at higher
doses. Perhaps it would suffice to add a parenthetical statement at the
end of the paragraph noting comments on the comparatively low doses. The
dose of styrene oxide should be specified and noted as a source of concern.
In the Finnish study the control incidence was 81 and the exposed 15%. The
control incidence is the unusual finding, since in many comparable studies,
it is 15%.
Considerably more evidence about the autagenicity of styrene oxide exists
than is described in the health advisory. It would be valuable to add
information about mutagenicity in other systems including mammalian
cells. Activity as measured with a number of other endpoints, which are
not necessarily mutagenic but related, might also be noted, such as
sister chrcwatid exchanges, chromosomal abnormalities, and so forth.
The data regarding the carcinogenicity of styrene is complicated and
deserves somewhat more discussion in this section. The statement about
excessive mortality suggests that the study by Pononarkov and Tomatis was
done poorly. Instead, there were many early deaths related to treatment
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-23-
In this study, and among the animals dying early there were an excess of
lung tumors including a disproportionate share of malignant tumors.
More discussion of these issues is warranted. The advisory should also
include some information about the carcinogenieity of styrene oxide,
since it is a major metabolite and an active chemical which could relate
to the possible careinogenicity of styrene.
In the one-day Health Advisory,, the data cited is from the article by
Das and ccworkers, not Srlvastava and coworkers. Some explanation is also
needed to justify using the study by Das in preference to that:of Agarwal,
which snowed effects on dopamine receptors at 200 rog/kg/day.
OCW should extend the paragraph on the assessment of carcinogenic
activity to provide a clearer explanation of why it chose this study
and selected lung tumors for the evaluation. Because of the com-
plexity of the data in this study, it is uonportant for ODK to provide
a wQte explicit description of how it used the data and factored early
deaths with tumors into the estimate.
The last section concerns the possible biodegradation of styrene by
oxidation. Since styrene oxide is a possible oxidation product and
an active chemical, it should be considered here. Will styrene oxide be
formed by this process? if so, what is the stability of styrene oxide in
water, particularly at the range of pH of water caning from treatment
plants» It is most important that the efforts to reduce the concentration
of detectable styrene not be acheived by the generation of a different,
but more active and more hazardous byproduct.
As noted in the discussion of n-hexane, styrene is a corponent of gasoline
and some discussion of its presence as part of a mixture should be included.
A large number of typographical and editorial errors occur in the health
advisory* For example, the melting point for styrene is -30.6*^, while
the value of 145«C is the boiling point. The density listed is incorrect.
The statement about pulmonary absorption should be reworded to avoid the
impression that the lungs were removed to measure retentions as might
happen in studies of animals.
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J. TOLUENE HEALTH
The toluene health advisory has a high level of typographical and
editorial errors. For example, it incorrectly states the molecular formula,
The reference dose, calculation appears to have a hundred-fold error
(stated as 28,8 rag/kg -day but calculated as 0.288 rag/kg -day). The health
advisory states an LD^Q for toluene that is ten-fold higher than that
described in the Criteria Document.
The health advisory should refer to synonyms of methacide. .and methylbenzol.
The Office of Drinking Water should refer to the Agency's Health Assessment
Document for Toluene for information on uses. The Criteria Document lacks
any information on this subject, and the three uses cited in the health
advisory, while correct, orait other significant uses. Similarly , the
Criteria Document lacks information on occurence, while the health advisory
does not cite the sources of information on occurence.
In the section on phannacokinetics, the health advisory has correctly
referred to information from the 1974 paper of Nomiyama and Nomiyaraa, but
a numer of inconsistencies occur with the Criteria Document, which misquotes
the data from this source.
The health advisory and the Criteria Document differ with respect to
sources of toluene exposure. The health advisory refers to intentional
abuse plus laboratory and occupational settings as the usual sources of
exposure, whereas the Criteria Document cites drinking water, food,
ambient air occupational settings and consumers products as sources of
exposure to toluene,
The health advisory should briefly describe what is known about the
mechanism of toxicity. The Subcommittee recommends that the health
advisory provide a clearer statement of the human health effects of
toluene. The health advisory refers to effects on the liver at 200 to
800 ppm, whereas the Criteria Document cites hematological effects as-
sociated with benzene contamination of toluene.
The data base is not up-to-date and should be compared against a standard
reference data base.
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K. XYLENES HEALTH ADVISORY (ORTHO-xyLENE, META-XYLEN1B AND PARA-XYLENE)
The health advisory for xylenes generally follows the Criteria Document
for these compounds* The studies selected for establishing the known
effects arid for the" calculations appear appropriate. For the health
advisory on xylenes, the allowable exposures are based primarily on gross
toxicity rather than the primary central nervous system effects. This way
be necessary for the calculations, but the reader should be warned. The
Subcommittee understands the difficulty created by the lack of oral
administration data in the published literature. , • • .
While the health advisory correctly cites the amounts of xylene found in
water, it does not recognize that other studies have occasionally found
higher concentrations* An additional problem stems from the fact that
values in the health advisory for the physical characteristics of the
xylenes do not agree with those in the Criteria Document, notably the
solubilities and the octanol/water partition coefficients. This appears
to result from the use in the health advisory of an older version of the
reference for these values (Verschueren),
A greater emphasis in the health advisory on metabolic profile studies
actually conducted in humans would be more appropriate. These include
work by Ogata, Riihiachi and Sedivec and Flek, The health advisory
cites the latter in a different context. The health advisory may have
used older references that are not adequately updated, but the Criteria
Document has more recent data.
The health advisory may underestimate the possibility of effects on the
liver. The studies by Tetrai and Ungvary cited in the Criteria Document
suggest that this may be a sensitive target organ. The studies of Horley
support this view, albeit in humans high levels of exposure were
encountered. The epidemiological studies are equivocal. In this regard,
EPA should consider the numerous studies on the capacity of these agents
to induce drug metabolism.
The advisory acknowledges the study of Bowers and coworkers but
dismisses it froti consideration as the basis for the calculation. However,
if material were lost by evaporation in this study, it would tend to
underestimate the toxicity of the xylenes, not overestimate it* Furthermore,
the lack of examination of other tissues is a moot point since positive
effects were observed in the liver. The Criteria Document is not much
help on this point since it tends to argue somewhat teleologically that
the ultrastructural changes observed were adaptive in nature. However, one
could also argue that the significance of these changes observed by
electron but not by light microscopy is unknown.
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The section on teratology is overly brief considering the number of
available studies. The Criteria Document tends to emphasize that pregnant
women may represent a sensitive population, but the health advisory does not
address this issue fully, this lack of concern may be justified in view of
the recent review, of the complete literature commissioned by EPA, which
reviewed the various studies from the perspective of dose and concluded
that xylenes jaay be embryotoxic and maternally toxic but only at high
doses.*
study by Jenkins is hard to reconcile with that of Carpenter. In
the Jenkins study, rats died at 3,358 mg/M3, so it is difficult for the
Subcommittee to accept Carpenter's no-observed-effect-levels of 2,000
and 3 ,500 mg/M3,
The lack of a ten day health advisory conflicts with the position
in the Criteria Document. Both the health advisory and the Criteria
Document make the calculations using the sane formula and data frcm the
same study. Both documents arrive at the same values. However, the
Criteria Document describes this calculation as a ten-day advisory,
whereas the health advisory uses it as a long-term (not lifetime)
advisory, t»4iich a water works official might use as a temporary ten-day
advisory.
The calculations assume that 20% of human exposure to xylene arises from
drinking water. This assumption is not supported by the data presented
in the Criteria Document that demonstrates that only a very small amount
(0.1 to 3,9 ug/kg/day) would be expected from air with essentially no
intake frem food. Thus, the inclusion of this factor is highly question-
able.
The calculations of values for advisories should use the minute volume
for the species from which the effect level is derived. Staff can then
extrapolate the effect level for this species to humans.
Xylene is a component of gasoline and should be evaluated as part of this
mixture, as discussed above in the comments on n-hexane.
* R.D. HOOD and M.S. OTTLEY, "Developmental Effects Associated with Exposure
to Xylene: A Review," Djcug_ and Chemical Toxicology. _8; 281-297 (1985).
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U.S. Environmental Protection Agency
Science Advisory Board
Environmental Health Cotmittee
Drinking Water Subcommittee
January 6-8, 1986
Dr. Robert Tardiff, [Chair], Principal, Environ Corporation, 1000 Potomac
St., N.W., Terrace Level, Washington, D.C. 20007
Dr. Herschel E* Griffin, [Vice-chair], Professor of Epidemiology, Graduate
School of Public Health, 650S Mvarado Road, San Diego State University,
San Diego, California 92182-0405
Dr. Larry Andrews, Celanese Corp., 1211 Avenue of the Americas, 13th Floor,
Mew York, m 10036
Dr. James Barbaree, Center for Disease Control, Chief of Epidemic Investigations
Laboratory Respiratory Disease Laboratory, Center for Infectious Diseases Bldg.
1 Room B-360, 1600 Clifton Road, Atlanta, Georgia 30333
Dr. Paul Brubaker, Jr., Paul E. Brubaker Associates Inc., 3 Halstead load,
Mendham, New Jersey 07945
Dr. Gary Carlson, Department of Pharmacology and Toxicology, School of Pharmacy,
Purdue University, West Lafayette, Indiana 47907
Dr. Rose Dagirmanjian, • Professor, Department of Pharmacology and Toxicology,
University of Louisville, Louisville, Kentucky 40292
Dr. Marshall Johnson, Professor, Department of Anatomy, Jefferson Medical
College, 1020 Locust Street, Philadelphia, PA 19107
Dr. David Kaufman, Department of Pathology, University of North Carolina,
Room 515 Brinkhous-Bullitt, Chapel Hill, North Carolina 27514
Dr. Nancy Kim, Director, New ¥ork Department of Health, Bureau of Toxic
Substance Assessment, Roan 359, Tower Building, Enpire State Plaza,
Albany, NY 12037
Dr. Verne Ray, Medical Research Laboratory, Pfitzer, Inc. Groton, CT 06340
Dr. Thomas Tephly, Professor, Department of Phaoaacology, The Bowen Science
Building, University of Iowa, Iowa City, Iowa 52242
Dr. Bernard Weiss, Professor, Division of Toxicology, P.O. Box IBB, University
of Rochester, School of Medicine, Rochester, NY 14642
Dr. Washington C« Winn, Jr., University of Vermont, Medical Center Hospital,
Medical Alumni Building, Burlington, Vermont 05405-0068
Executive Secretary: Dr. Daniel Byrd, III, Executive Secretary* Science Advisory
Board (A-101P), U.S. Environmental Protection Agency, Washington, D.C. 20460
(202) 382-2552
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COMETS SUBMITTED TO TOE DRINKING WATER SUBCOMCTTEE
BY THE PUBLIC REGARDING THE SCIENCE ADVISORY 'BOARD'S
REVIEW OF DRAFT DRINKING WA1ER HEALTH ADVISORIES
National Audubon Society
National Capital Office
645 Pennsylvania Avenue, S.E,
Washington, D.C. 20003
Date; December 24, 1985
Contact: Chuck Pace
Chemical Manufacturers Assoc.
2501 M Street, N.W.
Washington, D.C. 20037
Date: December 26, 1986
Contact: Geraldine V. Cox
Natural Resources Defense
Council Inc.
122 East 42nd Street
New York, N.Y. 10168
Date: November 29, 198fi
Contact: Robin Whyatt
Wendy Gordan
Water Quality Association
1518 K Street, N.W.
Suite 401
Washington, D.C. 20005
Date: November 22, 1985
Contact: Danna M. Cirolia
Diamond Shamrock Corporation
World Headquarters
717 North Harwood Street
Dallas, Texas 75201
Date: December 2, 1985
Contact: Ross E. Jones
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-2-
Cyanatnid Company Contact: Linda Dulak
One Cyanamid Plaza
Wayne, New Jersey 07470
Date; November 27, 1985
The Society of the Plastics Contact; Hugh Toner
Industry, Inc.
1025 Connecticut Ave.
Washington, D.C, 20036
Date; December 16, 1985
The New Jersey Dept. of Health
and The New Jersey Dept* of Contact Bonnie L. Bishop
Environmental Protection
August, 1984
State of Connecticut
Department f Health Services Contact: David R« Brown
Date: December 12, 1985
Michigan Pure Water Council
Educat ional, Non-Prof it
Non-Political thru Investigation, Contact: Martha Johnson
Research
December 12, 1985
Synthetic Organic Chemical
Manufacturers Assn. Contact; Alan W. Rautio
1330 Connecticut Avenue
Washington, D. C. 2U036
November 27, 1985
Ethylbenzene Producers' Association
1330 Connecticut Avenue Contact: Eric A. Clark
Washington, D. C. 20036
November 27, 1985
Synthetic Organic Chemical
Manufacturers Association , Contact: Alan W» Rautio
1330 Connecticut Avenue
Washington, D, C. 20036
December 18, 1985
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POST MEETING COMMENTS RECEIVED
National Audubon Society
National Capital "Office Contact: Chuck Pace
645 Pennsylvania Avenue, S. E.
Washington, D. C. 20003
Date: January 27, 1986
Hazco
5301 Lee Highway Contact: Redmond Clark
Arlington, Virginia 22207
Date: March 14, 1986
Chemical Manufacturers
Association Contact: Ann M. Mason
2501 M Street, N. W.
Washington, D. C, 20037
Date; April 30, 1986
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U.S. Environmental Protection Agency
Science Advisory Board
Environmental Health Committee
Drinking Water Subcommittee
OpenMeeting
Public Law 92-463, notice is hereby given that a
three-day meeting of the Drinking Water Subcommittee of the
Environmental Health Committee of the Science. Advisory Board
will be held on January 6-3, 1986, in Conference Room 451 of
the Joseph Henry Building; National Academy of Sciences;
2122 Pennsylvania Avenue, N.w.r Washington, DC. 20037. The
meeting will start at 9:00 a.m. on January n and adjourn no
later than 4;00 p.m. on January 3,
The purpose of the meeting will be to discuss draft
drinking water Health Advisory documents for the following
substances:
Acrylamide Legionella
Benzene Methylethylketone
p_-Dioxane Styrene
Ethylbanzene Toluene
Ethylene giycol Xylene
Hexane
The Drinking Water Subcommittee will not receive oral
comments on the Health Advisory documents at the meeting.
Written comments on any of the specific substances should be
delivered within forty (40) days from the date of this notice
to Manager-, Health Advisory Program; Criteria and Standards
Division [WH-550]; ti,S, Environmental Protection Agency; 401
M Street, S.W.: Washington, DC; 20460,
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- 2 -
EPA's Office of Drinking Water prepared" the" draft Health
Advisory documents. They are neither regulations nor regula-
tory support. To obtain copies of the draft health Advisory
documents for specific substances please write to the Manager
of the Health Advisory Program at the abo_ve address *
The meeting will be open to the public. Any member of
the public wishing to attend or to obtain further information
should contact either Dr. Daniel Byrd, Executive Secretary
to the Committee, or Mrs. Brenda Johnson, by telephone at
(202)382-2552 or by mail to; Science Advisory Board (A-101F);
401 M Street, S.w.; Washington, DC; 20460, no later than
c*o.b. on December 20, 1985.
le
ector
.dvisory Board
X—/ I /
October 15, 1985
Date
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SCIENCE ADVISORY BQSBD
ENVIRONMENTAL HEALTH CQMMITTFE
DFINKING WftTER SUBODfWITTEE
Conference Roan 451
Joseph Henry Building
National Academy of Sciences
2122 Pennsylvania Avenue, NW
Washington, DC 2003?
January 6-8, 1986
ORDER OF BUSINESS
REVIEWS OP DRAFT DRINKING WftOER HEALTH ADVISORIES
Opening Remarks .................. or- Tardiff
Administrative Matters or. Byrd
Introduction Dr. Crisp
Dr. Tardiff
*Tentative Sequence of Reviews, beginning Monday, January 6, 1986
substance (Manager) Beviewers
j>-Dioxane (Khanna) Drs. Johnson and
Ethylbenzene (lhanna) ....,...,».,....., Drs. Andrews and Ray
Ethylene glycol (Khanna} Drs. lay and Johnson
Toluene (Khanna) Drs. Griffin and Dajimanjian
Benzene (Marcus) Drs, Brubaker and Kim
Styrene (Marcus) .................. Drs. Kaufman and,Andrews
Xylene (Patel) Drs. Carlson and Griffin
Methylethylketone (Patel} Drs. Tephly and Brubaker
On Tuesday, January 1, 1986
Legionella (Berger) Ors. larbaree and winn
On.Wednesday, January 8, 1986
Acrylawide (Crisp) Drs. Dajirmanjian and Weiss
Hexane (Patel) Drs, Kim and Tephly
At the conclusion of the reviews
Completion of reviews (previously deferred) Dr. Tardiff
General comments Or. Tardiff
Nomination of Criteria Documents for further review Dr. Tardiff
Other Subconmittee Business
Concluding remarks Dr. Tardiff
Dr. Byrd
ADJOURNMENT
* The sequence in which the Subcommittee reviews Health Advisories Cor different
substances and the time allocated to each review are at the discretion of the Chair.
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