xvEPA
United States
Environmental Protection
Agency
Office of the Administrator
Science Advisory Board (A-1011
401 M Street, SW
Washington, DC 20460
October 1986
Review of 37 Office of
Drinking Water Health Advisories by
the Environmental Health Committee of
The Science Advisory Board
Metals Subcommittee: (SAB-EHC-87-004)
arsenic, barium, cadmium, chromium, cyanide, lead,
mercury, nickel, and nitrate/nitrite
Halogenated Organics Subcommittee: (SAB-EHC-87-005)
carbon tetrachloride, chlorobenzene, dichlorobenzene,
1,2-dichloroethylene, cis and trans 1,2-dichloroethylene,
1,1-dichloroethylene, epichlorohydrin, hexachlorobenzene,
polychlorinated biphenyls, tetrachloroethylene,
1,1,2-trichloroethylene, 1,1,1 ,-trichloroethylene,
and vinyl chloride.
Drinking Water Subcommittee: (SAB-EHC-87-006)
acylamide, benzene, p-dioxane, ethylbenzene,
ethylene glycol, hexane, Legionella, methylethylketone,
styrene, toluene, and xylene
-------
.
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON. D.C. 20460
24, 1986
Honorable Lee M." Thomas
Administrator ' OF<=,CEOF
U. S. Environmental Protection Agency THEAD-.N.STR
401 M Street, S. W.
Washington, D. C. 20460
Dear Mr. Thomas:
The Environmental Health Conmittee of EPA's Science Advisory Board
has completed its review, requested by the Office of Drinking Water (ODW),
of thirty-seven drinking water health advisories. The Committee accomplished
this task by assigning the review to three separate subcommittees: Metals,
Halogenated Organics and Drinking Water. The Science Advisory Board has
not previously reviewed health advisories, and its participation in this
program has been informative.
i
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 comments and
about 110 pages of detailed comments. The final comments are enclosed
with this letter as three Subcommittee 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 commendable 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 ODW 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
-------
- 2 -
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 summary numerical tables, as indicated in the current
drafts.- Instead, they recommend 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, Executive Committee
-------
MSC
-------
United States
Environmental Protection
Agency
Office of the Administrator
Science Advisory Board (A-101)
401 M Street, SW
Washington, DC 20460
SAB-EHC-87-004
October 1986
EPA
Review of Drinking Water Health
Advisories by the Metals
Subcommittee of The Environmental
Health Committee of
The Science Advisory Board
Arsenic
Barium
Cadmium
Chromium
Cyanide
Lead
Mercury
Nickel
Nitrate and Nitrite
-------
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON. D C 20460
September 20, 1986 SAB-EHC-87-004
Dr. Richard A. Griesemer OFFICE O
Chair, Environmental Health Committee THS*»""""
Science Advisory Board [A-101]
U.S. Environmental Protection Agency
401 M Street, SW
Wasington, DC 20460
Dear Dr. Griesemer:
On January 9-10, 1986 the Metals Subcommittee of the Environmental
Health Committee reviewed nine (9) draft health advisories for drinking
water in public session. The draft health advisories were prepared by
the Office of Drinking Water. The health advisories are not regulatory
documents but are intended to provide consistent, brief reference infor-
mation, particularly for technical personnel responsible for the operation
of water works or for state and local public health officials. During
the review of the health advisories, the Subcommittee utilized Drinking
Water Criteria Documents for these substances as support documents. The
Subcommittee recommends that the Criteria Document for Mercury undergo
further detailed scientific review, because this is the first attempt to
set forth the Agency's evaluation of ionic mercury, and some scientific
issues will be controversial.
Our comments below are divided into general advice, which is relevant
to all of the advisories reviewed by the Subcommittee, followed by advice
specific to each of the substances reviewed. Based on the general review,
the Subcommittee recommends that the Office of Drinking Water undertake
an updating of three guidance documents (issue papers) for use of inhala-
tion data, pharmacokinetics and multiple exposures (mixtures). Although
the guidance may be conceptually sound for organic substances, some in-
formation in the documents seems inappropriate to the toxicology of
metals. Because of the extensive nature of our comments, a Table of
Contents and some supporting appendices are included. We appreciate the
opportunity to become involved with this program and stand ready to
provide further advice, as requested.
Sincerely,
Bernard Weiss, Ph.D.
Chair, Metals Subcommittee
^^ /^/-^
/l_O-yi£Lc>ci C.
Ronald Wyzga, Sc.D.
Vice-chair, Metals Subcommittee
-------
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 recommendation for use.
-------
TABLE OF CONTENTS
I. GENERAL COMMENTS ON DRINKING WATER HEALTH ADVISORIES
II. SPECIFIC COMMENTS ON NINE HEALTH ADVISORIES
A. Arsenic 8
B. Barium 10
C. Cadmium 12
D. Chromium 14
E. Cyanide 16
F. Lead 18
G. Mercury 21.
H. Nickel 23
I. Nitrate and Nitrite 25
III. APPENDICES
Roster of the Subcommittee
List of comments received from the public
Federal Register notice of the January 14-17, 1986 meeting
Agenda for the meeting
An example of a narrative summary for cyanide
-------
I. GENERAL COMMENTS OF THE METALS SUBCOMMITTEE OF THE ENVIRONMENTAL HEALTH
COMMITTEE OF EPA'S SCIENCE ADVISORY BOARD REGARDING DRINKING WATER HEALTH
ADVISORIES
A. THE RELATIONSHIP BETWEEN AUDIENCE AND CONTENT NEEDS CLARIFICATION.
The format and content of the health advisories are inconsistent.with
the audience for which they are intended. Often the descriptions of studies
bear only a remote relationship to the aims of the health advisories. Lethal
doses in animals, or details of pathological surveys in rodents after high
doses, for example, are not usually necessary to convey the basis for the
"risk reference dose." A related problem with the health advisories is the
presentation of the information. Typically, a few papers are tersely ab-
stracted, with little attempt to integrate their contents. The nickel health
advisory, for example, lists nine studies under the heading, "longer-term
exposure." Two pages later, under the heading "longer-term health advisory,"
it states that no suitable studies were identified to derive the longer-term
health advisory. Not only were the nine studies not pertinent, but they
were described as if in an annotated bibliography, lacking any attempt to
integrate their findings. The health advisories should be made crisper and
clearer and feature only those data upon which the various calculations rely.
1
B. THE HEALTH ADVISORIES HAVE DIFFERENT UNCERTAINTIES.
Various health advisories have different degrees of uncertainty
associated with them. The uncertainty results from one or more of the
following:
No adequate data exist which can be used to derive a health advisory.
The health advisory for arsenic, for example, is based upon subjective opinions
about the best experimental data to use.
A health advisory is calculated from animal data, and it is unclear how
to extrapolate to humans. See, for example, the chromium health advisory.
Health effects data exist for another route of exposure, and it is un-
clear how and whether to extrapolate for exposure via another media. For
example, chromium (VI) is a reasonably well-established carcinogen associated
with respiratory cancers, yet the health advisory for chromium states that
there is inadequate evidence to determine whether or not oral exposure to
chromium can lead to cancer. In such situations, it is unclear whether and
how inhalation effects data can be used for health advisories. A different
example occurs in the derivation of the lifetime health advisory for mercury.
Effects following subcutaneous injection were used to estimate effects from
drinking water .exposure.
Exposure durations are .different for the health advisory and for the
study used to derive the advisory. For example, a 24-week study was used to
derive the 10-day health advisory for cadmium.
There is thought to be some difference in the toxicity of alternative
species of a,metal, but species-specific health advisories are not estimated.
Arsenic is an example here, where the trivalent species is believed to be
most toxic, but insufficient data exist to derive species-specific health
advisories.
-------
-2-
Different sensitivities were likely applied to alternative studies in
measuring health effects. For example, the ten-day health advisory for
chromium is based upon an increased incidence of "slight roughness of coat."
Other endpoints appear to reflect more severe response.
There may be conflicting information between two or more studies. For
example, the lifetime health advisory for mercury would differ by several
hundred fold if an alternative study were used to calculate it, Conflicting
studies may have different scientific merit. For example, one study may not
have a control group and another may have an incorrect statistical analysis.
There is considerable uncertainty in exactly how one should weigh the dif-
ferent merits of these studies.
A health advisory may be highly dependent on the design of the experiment
used to estimate the advisory. For example, the lifetime health advisory for
-cyanide is based upon a study undertaken at two dose levels. No effects were
found at either level, hence, the higher level is assumed to be the no-
-observed-effeet-level. If alternative dose levels were chosen for this
experiment, it is likely that both the no-pbserved-effeet-level and the
health advisory would differ from the current values.
The experimental design will also influence the power or ability of an
experiment to detect a statistically significant health response from in-
creased exposure to a toxic substance.
1 Doses in certain experiments were administered in media other than
water. If absorption varies by media, this will produce uncertainty for
developing advisories. For example, the lifetime health advisory for nickel
is based upon a study of nickel administered through milk.
The health risk depends on other sources of the metal, and these will
vary.
Interactions may occur between the substance of concern in the drinking
water and other substances.
A lack of understanding of the underlying biological mechanism can
impede the interpretation of experimental results.
The toxicologically critical organ and the critical effect are useful
concepts that need to be differentiated, or an uncertainty will be created.
The critical organ is the main target of a particular toxicant. The critical
effect is the earliest adverse effect to appear. For cadmium, the kidney is
the critical organ, whereas many toxicologists believe that beta-2-micro-
globulinemia is the critical effect. The health advisories should recognize
this distinction explicitly and address each accordingly.
To adjust for uncertainty, the health advisories usually reflect assump-
tions designed to err on the side of safety, and they utilise safety factors
in order to be protective of public health. The use of (and rationale for)
bias in the interpretation of assumptions and safety factors needs to be
clearly explained in the health advisories, in order for them to meet their
Stated purpose of providing useful information in the field. Without some
indication of the bias, operating personnel cannot distinguish between a
-------
-3-
decrease in the margin of safety and the imminent possibility of mortality
or morbidity in the consuming population. ; It would be useful, moreover, to
provide some indication of the Uncertainty associated with a health advisory*
The soapiest way to do this would be to indicate explicitly the nature of
the uncertainties. These could be taken, for example, from the above list.
Alternatively, the Agency could develop and incorporate a system to express
the levels of confidence associated with the health advisory. Such a system
has recently been incorporated into EPA's risk assessment guidelines for
mixtures. ' , , .
'C. BIOPROCESSING OF THE METALS NEEDS A CLEARER PRESENTATlCPJ.
The Subcommittee noted some Inconsistencies in the pharmacokinetics sections
between different health advisories for metals and inorganic substances. The
content and depth of the discussions varied considerably. In some advisories,
extensive animal data were presented without adequate interpretation (e.g*,
absorption of chromium), and in other places general interpretive statements
were presented without data (e.g., absorption of barium)* Also, -there ap-
peared to be inconsistencies in the definition of the various components of
the bioprocessing of metals (absorption, distribution* metabolism and ex-
cretion). Examples of this include the following*
Binding of chromium to iron-binding proteins is discussed in the section
on distribution, whereas binding of cadmium to metallothionein is discussed
in the section on metabolism.
Retention of cadmium is discussed in the section on absorption father
than in the section on excretion*
Renal processing of chromium is discussed in the section on distribution
rather than in the section on excretion*
» Transport of chromium is discussed in the section on metabolism rather
than the section on distribution.
* Retention of lead is discussed in the section on metabolism.
« The transfer of lead across the placenta is discussed in the section on
metabolism rather than in the section on distribution.
The transfer of nickel across the placenta is discussed in the section
on metabolism rather than in the section on distribution.
Inconsistencies such as those cited above confuse the reader* making it
difficult to abstract information fron the.documents and reducing confidence
in the documents, it would be helpful if a uniform set of definitipns of
each of these processes was adopted, and if information concerning each
process was categorized in the document accordingly. Also, statements in
the documents should be interpretive and should focus on the bioprocessing of
metals in humans. If this involves extrapolation from laboratory animal
data, the extrapolation should be indicated.
-------
-4-
The Subcommittee proposes the following, suggest ions for the content
of the various subsections of the pharmacbkinetics sections, of the health
advisories: ', : ' ; '-> '*'- ' :
."Absorption" refers to the*processes 'by which metals enter the internal
environment of the body. In this section all routes,of absorption that are
relevant to human exposure should be indicated, including inhalation of
volatile materials from drinking water sources and so forth. Factors that
influence the magnitude of gastrointestinal absorption should be indicated.
A quantitative estimate of the percent absorption from the gastrointestinal
tract in humans (or a range of values)' should be provided. The source of
the data from which the estimate was made should be indicated (e.g. human
data,, laboratory animal experiments or conjecture).
The "distribution" section should describe where the metal is located in
the human body. If human data is not available, the location may be inferred .
through data from laboratory ariimals or from analogy to similar substances.
If possible, a,quantitative description should be'provided of the distribution
of the body burden. This description should indicate the largest depots for
the metal .and the target tissues. Factors that influence the distribution
should be indicated (e.g., speciatibn, route of absorption or other substances),
Transfer of metals across the placenta to the fetus should be discussed in
this section. Mechanisms of entry of the metal into target tissues (e.g.
membrane transport)-, 'if discussed at' all,'should be reviewed in this section.
The "metabolism" section should describe the chemical conversions of the
metal that-are relevant to the absbrption, distribution, excretion, detoxifi-
cation and activation of the metal. This includes oxidation or reduction
reactions, binding to intracellular or extracellular proteins, and chelation
or complex formation with'inorganic components of bone. The significance of
metabolism to the overall distribution and' elimination of the metal and to
the toxicity of the metal should be discussed.
Under "excretion," a description of the elimination kinetics (e.g., bio-
logical half-life) should be presented in each health advisory. The routes
of excretion should be identified, and the relative contributions of each of
.the routes should be discussed. In discussing the fecal excretion of metals,
it is important to distinguish the excretion of ingested and nonabsorbed
metal from the excretion of-absorbed metal. Mechanisms of excretion (e.g.,
renal tubular transport), if discussed at all, should be reviewed in this
section. ;
D. BIOLOGICAL EFFECTS VARY WITH SPECIATION OF METALS.
In general, metals exist in a number of physical and chemical species.
Changes in oxidation state and the formation of organo-metallie compounds
(where the metal is covalently bound to at least one carbon atom) are forms
of speciation that may have a profound influence on the toxicity of the
metal. Speciation should'be considered in most of the sub-sections of the
health advisory.
-------
-5-
In the "occurrence" sections, the global cycle of the metal frequently
involves interconversion to more soluble or more volatile species of the
metal. The methylation of inorganic mercury in freshwater and oceanic sedi-
ments is a key step to the bioaccumulation of mercury in aquatic food chains.
The redox potential in water supplies may influence the species in drinking
water. The oxidation of trivalent to pentavalent arsenic occurs in well
oxygenated water supplies.
In the pharmacokinetics sections, essentially the same principles as
above will explain the ijnportance of species in the uptake, distribution,
metabolism and excretion of metals. Trivalent chromium crosses cell membranes
much more slowly than hexavalent chromium. The methylated forms of metals
usually are absorbed better than the inorganic species. Methylmercury must
first be demethylated before excretion can take place.
Metallic cations can form a wide variety of complexes with ligands in
cells and biological fluids. The induction of and binding to metallothionein
by cadmium explains the long-term accumulation of the metals in the kidney.
The formation of a glutathione complex in the liver is a key step in the
biliary excretion of mercury. The failure to secrete biliary glutathione
explains the lack of fecal excretion of mercury in suckling animals.
In the health effects sections, speciation will influence the occurence
of health effects both by affecting the pharmacokinetics of the metal or by
changing the chemical reactivity.and cellular toxicity of the metal. Tri-
valent arsenic binds to neighboring sulphydryl groups inhibiting sulphydryl
containing enzymes and co-factors, such as lipoic acid. Pentavalent arsenic,
in the form of anionic arsenates, follows the same metabolic pathway as
phosphates, causing uncoupling of high energy phosphate synthesis. Organic
metallic compounds such as methylmercury, tetramethyl lead and tetramethyltin
produce much more serious effects on the brain than their inorganic counter-
parts. Carcinogenic properties are well-established for nickel subsulfide
but not for soluble nickel compounds.
In the quantification of toxicological effects sections, speciation
becomes an important consideration in assessing the importance of different
routes of intake to total exposure to the metal and to decisions on using
toxicological data from experiments with different routes of exposure.
Inhalation studies indicating the carcinogenic effects of nickel subsulfide
in lung tissues are probably not relevant to dietary uptake of nickel that
will be present in food as a different chemical species. On the other hand,
studies on inhaled cadmium compounds may be relevant to dietary intake, if
kidney effects are the endpoint for both routes. The same species of cadmium
(inorganic divalent cadmium) is involved in renal uptake. The relative con-
tribution of air, water and food to total lead uptake can be directly compared
as inorganic lead is the common species. This is not the case with mercury.
Mercury vapor is the predominant species in air, methylmercury in food and
inorganic divalent mercury in drinking water. Mercury vapor in air and
inorganic mercury in food may be compared, if kidney damage is the endpoint.
None of these species are comparable if nerve damage is the health effect of
concern.
-------
-fi-
E. MULTIPLE SOURCES OF EXPOSURE INFLUENCE THE HEALTH ADVISORIES.
For most metals, the normal route of intake involves several sources
whose relative contributions differ. Often, food constitutes the predominant
source and this should obviously be taken into consideration when calculating
the health advisory, and it has been practiced in the present set of health
advisories. However, it is not clear how the values for source contributions
(X% food, mn-JTC water) were derived, and this should he stated for the
individual metal. In most cases, the source contribution factor mav -just be
a crude speculation, but even such conjectures usually have some basis.
A more serious concern arises when a major contribution and route of
exposure is via inhalation. This is of particular importance (a) when the
target organ is the respiratory tract and the chemical accumulates in or
affects the lung after it is absorbed fron the gastrointestinal tract; or
(b) when there is a well-defined target organ which is different from the
lung where the chemical accumulates once it is absorbed into the blood cir-
culation from either lung or gastrointestinal tract.
c
Case (a) might be a more hypothetical one, but for case (b)'several
examples can be given. Lead from automobile exhaust accimulates in the
central nervous system; mercury vapor released from dental fillings accumu-
lates as divalent mercuric ion in the kidney; and cadmium inhaled by cigarette
smoking accumulates in the kidney. In those cases, where the contribution
from inhalation can approach a significant or even major portion of the
daily intake, inhalation data must be taken into account and the health
advisory must be adjusted accordingly. This has to be evaluated for each
chemical individually and is exemplified further in the specific comments
for cadmium in this report.
The percentage of the population affected by additional inhalational
intake should be considered in a health advisory. For example, if only a
small percentage (less than 2%) of the population is exposed occupationally
by inhalation to a chemical, such that a major portion of the body burden of
the chemical is derived from this occupational activity, should this be
reflected in the health advisory? (Examples are workers exposed to manganese
dust, mercury vapor or cadmium aerosols in the workplace.) From a scientific
point-of-view, both occupational and environmental standards should consider
total exposure, unless the applied safety factor in the calculation of the
health advisory convincingly covers the additional intake by occupational
exposure (or the occupational standard covers environmental exposure). This
should then be stated.
If the percentage of people with inhalational exposure is significant,
this additional intake will affect the calcualtions in a health advisory.
One example, the impact on the cadmium health advisory of smokers in the U.S.
population, is described in the specific comments section. In summniary,
cigarette smoking alone can contribute as much or more than the daily recom-
mended dose that EPA estimates for non-smokers. Perhaps the applied safety
factor of 10 in the present health advisory is high enough to protect smokers
also. Nevertheless, a discussion about these relationships should be included
in the health advisory.
In any event, multiple exposure sources have to be taken into account
once it becomes obvious from knowledge of the pharraacokinetics of a chemical
-------
-7-
that lung absorption can significantly contribute to a target site dose.
Local authorities should be alerted to the fact that occupational exposure
can significantly add to the body burden. Possibly, a "secondary" health
advisory can be established for those situations taking into account occupa-
tional exposure. With this knowledge and information, local authorities
will be able to decide where to set their drinking water standard.
F. HEALTH ADVISORIES SHOULD DESCRIBE THE RELATIVE CONTRIBUTION OF DRINKING
WATER TO EXPOSURE.
For each metal, the Subcommittee suggests that a table (or summary
statement) be inserted into the health advisory detailing the relative
(intake) contributions for humans from different sources, including water.
The importance of this table is described in the specific comments for the
lead health advisory. An example of a table is given below for lead. EPA
also should consider adding an additional column which indicates "percent
absorbed." The resulting figure would represent a net contribution which
may mean more to the reader than quantity of source. For example,t lung
absorption for lead is about one hundred percent for the appropriate particle
size; for cadmium, it can be close to one hundred percent, whereas gastro-
intestinal tract absorption is ten to fifteen percent for both metals. Lead
absorption is higher in infants, but there is no infant data for cadmium.
Human Lead Exposure
2-year-old child Adult male
Source ug/day Total (%) ug/day Total (%)
Air 0.5 1 1.0 2
Food 18.9 40 35.8 59
Dust 21.0 44 4.5 8
Water 6.9 15 18.9 31
Total 47.3 100 60.2 100
Adapted from support documents for the lead health advisory.
-------
-8-
II. SPECIFIC COMMENTS OF THE METALS SUBCOMMITTEE ABOUT THE HEALTH ADVISORIES
FOR METALS AND ASSOCIATED SUBSTANCES
A. ARSENIC HEALTH ADVISORY
The health advisory for arsenic reasonably summarizes the pertinent infor-
mation available in the Criteria Document. Except for carcinogenic effects,
much of the available information on the toxicity of arsenic is anecdotal
and/or of limited value in calculating a health advisory. Animal experiments
were carried out at very high dose levels. Given the uncertainty about how
to extrapolate the outcome of these studies to humans at ambient level arsenic
concentrations, animal experiments could not be used to calculate the health
advisory values.
It was not possible to apply the formula in the section on quantification of
toxicological effects, or any other quantitative method, to derive health
advisory values. The result is the adoption of a National Academy of Sciences
recommendation. Therefore, more detail should be given to indicate the
rationale for this National Academy of Sciences recommendation. .In any
case, there is considerable uncertainty associated with the health advisory,
and this should be specifically indicated. Given the statements that data
or evidence exist which indicate that some species of arsenic are more toxic
than others, the Office of Drinking Water should consider the possibility of
a health advisory specific for an ionic species. Using different assumptions,
such as the human essentiality of arsenic, alternative estimates could have
been calculated.
The health advisory should be placed in perspective. Assuming an adult
drinks 2 liters of water a day, the total consumption of arsenic is about
0.1 rag/day at the health advisory concentration. This level of ingestion
should be contrasted with the oral intake of arsenic from diet and other
sources.
Two different formulae are given for sodium arsenite. The second should
be sodium arsenate.
In the health effects section, the health advisory notes that the toxicity
of arsenic depends on its chemical form, yet the summary of health effects
.information does not support this statement, implying that some relevant
information is not mentioned. Descriptions of the animal studies include
material on As+^ that hardly seem worthwhile given the statements that the
toxic species is As"1"^. The studies which support the conclusions about
species-specific toxicity in this section should be cited. A slightly expanded
summary in the health effects section would result in a better investment of
the reader's time.
The Criteria Document raises questions about the Zaldevar study in the longer-
term exposure section. For example, it notes that "the decrease in cutaneous
lesions seemed to be too rapid following installation of the water-treatment
plant". Accordingly, some qualification should be given to this study in the
health advisory, noting that the decrease of some symptoms seemed to be too
dramatic as arsenic concentrations decreased to 0.08 mg/L.
-------
-9-
The health advisory should mention that the study of Tseng and coworkers
has been heavily criticized because of the presence of confounding factors in
the study population. The Office of Drinking Water also should note the
comments of Andelman and Barnett in the article cited in the health advisory.
Many of the U.S. studies may have been negative because of the small size of
the study populations and their correspondingly low power to detect a sig-
nificant increase in health effects.
It is ironic that the same advisory value is calculated for short-term and
long term exposure given the statement that toxicity is duration-dependent.
The review of carcinogenicity omits human data from Argentina.
-------
-10-
B. BARIUM HEALTH ADVISORY
The arguments for determining the uncertainty factors for barium are not
convincing. Why was the uncertainty factor dropped from 1000 to 100? How
was a factor of 10 derived as a quantitative Treasure of the effects of the
defined diet on hypertension? There is no critical evaluation of the calcu-
lated lifetime health advisory (for example, possible sources of error,
subpopulations to which the calculated health advisory may not apply, and
information that is unavailable but critical to improving the calculation).
Should not a factor similar to the one for defined diet be included that
quantifies differences in gastrointestinal absorption of barium in young
animals?
The document states that there were no signs of toxicity at any barium dose
level. This statement is not correct since hypertension was evident in rats
given 100 ppm barium in the study of Perry and coworkers. Indeed, the hyper-
tensive effects of barium are used to calculate the lifetime health advisory.
Although, in the lifetime health advisory, an increase in blood pressure of 4
to 7 mm (Hg) was not large enough to be considered an adverse effect, eleva-
tions of this magnitude traced to lead exposure are considered by EPA to be
a significant public health problem. The evaluation of the study by Tardiff
and coworkers concludes that no conclusive signs of barium toxicity were
observed. This evaluation should be reconsidered since blood pressure was
not measured in this study. Perhaps the evaluation should state that there
were no additional signs of toxicity at any dose of barium.
It is not clear why the lowest-observed-adverse-effect-level was established
as 5.1 rag/kg.day rather than 0.51 mg/kg-day. The study by Perry and coworkers
demonstrated significant elevation of blood pressure in rats given 0.51 mg
Ba/kg-day for 8 months. In the same study, hypertension was evident in rats
given 5.1 mg Ba/kg.day for only 1 month. Thus, the results of this study
support a lowest-observed-adverse-effect-level that may be as low as 0.51
Ba mg/kg*day.
EPA reported several other changes in rats given 100 ppm barium that could
be considered as evidence of barium-induced toxicity, such as decreased
content of adenosine triphosphate and phosphocreatinine in myocardium,
decreased rates of cardiac contraction and depressed electrical activity
of the myocardium. In the study by Schroeder and Mitchener, increased
proteinuria was observed in rats exposed to approximately 0.25 mg 8a/kg-day
for 173 days. The acute toxic threshold dose that is cited in the Criteria
Document is 2.9 to 71 mg/kg, whereas the health advisory cites a value of
2.9 to 7.1 mg/kg. Which value is correct?
Citations of scientific literature to support certain statements in the
document are missing. Literature citations to support statements concerning
the solubility of barium compounds in water and the effects of pH on solu-
bility should be provided. Literature citations to support statements con-
cerning the natural abundance of barium compounds, sources of contamination
of drinking water and levels of barium in drinking water should be provided.
The information provided in the document ranges from detailed and highly
-------
-11-
technical to vague. Similarly, the document will be improved by using con-
sistent units to describe barium concentration.
The sections about pharmacokinetics were difficult for the Subcommittee to
understand. It is not clear what is meant by the statement that substitution
of barium for strontium and potassium ions is common. The metabolism of
barium should be described in greater detail, particularly the incorporation
of barium into bone. Statements concerning the similarities between the
skeletal metabolism of barium and calcium do not summarize the skeletal
metabolism of calcium and provide useful information only to those individuals
who are knowledgeable about calcium. While data obtained from studies of
laboratory animals by Lengemann suggest that barium absorption in young
animals may be significantly greater than in adult animals, information is
currently inadequate to determine if this applies to humans. Only the mouse
data is analyzed in the distribution section. This section should summarize
the human autopsy data and the data on retention of barium in humans that is
presented in the Criteria Document.
Information about the relative magnitudes of fecal and urinary excretion
could be presented. The role of diet is discussed too tersely and is con-
fusing. No mention is made of the magnitude of excretion of barium in mater-
nal milk. The Criteria Document reports that 10% of an intravenously admin-
istered dose of barium is excreted in the milk of lactating cows. If. this
applies to humans, excretion of absorbed barium in maternal milk could be a
more significant excretory route in lactating females than is excretion in
urine.
-------
-12-
C. CADMIUM HEALTH ADVISORY
The data base for cadmium appears to be fairly complete, although information
on cadmium intake via smoking is missing. The acceptable daily intake cal-
culations seem to be correct. However, the ten day advisory is based on
values from a study of 24 week duration. The calculations for the longer-
-term health advisory of 18 ug/L value are not given. How is it derived?
The basis for the uncertainty factor of ten, rather the more ususal value of
one hundred, should be explained. A rationale exists in the narrow, measurable
range of cumulative doses that cause renal disease. There is no critical
evaluation in the health advisory of possible sources of error, subpopulations
to which the calculations may not apply or information that is unavailable
but critical for improving the calculation. The dose of cadmium might be
expressed per kg body to facilitate comparisons with other data in the text.
The basis for using 10 kg or 70 kg for body weight in the calculation of
health advisory should be explained. Similarly, the calculation of the
longer-term health advisory for a child of 5 ug/L is not explained.
The risk reference dose (RRFD) of 35 ug/d approximately equals the current
U.S. daily intake of cadmium from all sources (mostly food). Using conservative
assumptions, the Friberg model yields 352 ug/d as the minimum daily dose
that would result in an adverse effect (renal tubular dysfunction). No need
exists for an additional safety or uncertainty factor because these data
arise from the most sensitive human subpopulation. Many scientists believe
that a risk reference dose of about 200 ug/d is adequate protection for
humans. The World Health Organization and the European Economic Community
have set their standards at this level. However, if EPA retains the current
risk reference dose, the Agency should communicate it to the U.S. Food and
Drug Administration and the Department of Agriculture, as changes in the
pattern of food consumption will be required.
The general question of including effects of widely practiced social
labits should be addressed. Specifically, the intake of toxicants by cigar-
stte smoking should be considered. For example, the health advisory is
jased on the assumption that the risk reference dose is 0.5 ug cadmium per
-.g'day or 35 ug/day for a 70 kg man. The statement that food appears to
be the major route of exposure for cadmium should be modified for smokers.
Cigarette smokers constitute approximately 30% of the population, and they
will take in an additional amount equal to or exceeding the dietary intake.
The health advisory assumes that drinking water contributes 25% of total
cadmium intake with the remainder derived from food, which gives a lifetime
health advisory of 5 ug/L. It is not entirely clear how the contribution
from smoking will affect this calculation, but perhaps it will be lower by a
factor of two.
The effects of other metals affecting cadmium absorption should be mentioned,
particularly zinc. Lung absorption is not described, although it is important
and is discussed in the Criteria Document, and absorption calculations will
be in error if this contribution is not included. The main reason for the
long half-time of cadmium in the body should be described, i.e., retention
in the kidney. Statements about the retention of radiolabelled cadmium
chloride do not belong in the absorption subsection. In the study by McLellan
and coworkers, the retention of orally administered cadmium was used to
-------
-13-
estimate the gastrointestinal absorption of cadmium, but the statement in
the advisory about this study does not indicate what was learned about ab-
sorption from the study. Perhaps the results of the studies of gastrointestinal
absorption of cadmium in humans and studies of laboratory animals that are
described in the Criteria Document should be summarized. The statement that
cadmium does not cross the skin is vague. Can a quantitative expression be
used to describe the absorption of cadmium across the skin? Is data available
on the absorption of cadmium across skin in humans?
The whole section on health effects should., be reorganized to present a
clearer summary, with a emphasis on the kidney as a target organ, rather than
a loosely linked series of annotated references. The health effects of
cadmium occur as a sequence of events, in which beta-2-microglobulinemia is
an earlier indicator. The reference to Itai-Itai disease should note that it
appeared in elderly, multiparous women. This disease may not be a sole
consequence of high levels of cadmium exposure. Instead, cadmium may be an
etiological factor. The symptoms described for humans are for oral exposure.
Similarly, for animal data, it is not clear whether described effects are for
oral exposure or also after other routes of cadmium administration (injection).
If the latter is the case, inhalation effects also ought to be included. The
epidemiology study by Thun and coworkers should be cited in the subsection
about humans. A better explanation should be provided to support the state-
ment that data on cadmium carcinogenicity are not thought relevant to the
consumption of cadmium in drinking water. Effects of cadmium on the respira-
tory system are not discussed or recognized as human health concerns in the
health advisory. This may mislead readers who are not knowledgeable about
these aspects of cadmium toxicology.
Friberg and coworkers estimated the daily intake of cadmium that would result
in the accumulation of 200 ug cadmium/g renal cortical tissue after 50 years
of continuous exposure. Roels and coworkers have shown that this level of
cadmium occurs in human kidneys that exhibit symptoms pf renal impairment.
The health advisory should summarize this information.
Testes exhibit toxic effects after parenteral administration of cadmium. The
Subcommittee is divided on the importance of this phenomenon. The results
do show that testes of the rat are a sensitive organ for cadmium. However,
the pathological effects occur only after massive parenteral doses and after
necrosis in blood vessels leading to the testes. Thus, these observations
do not have public health significance.
Since the Threshold Limit Values established by the American Conference of
Governmental Industrial Hygienists are given, the Occupational Safety and
Health Administration's workplace exposure limits should also be described,
since these are the legally binding limits for cadmium as dust (0.2 mg/itP)
or fume (0.1 mg/m^).
What is the evidence to support the statement that commercial use of cadmium
has not resulted in the contamination of ground and surface waters? Does
this mean that all cadmium in ground and surface water (1-10 ug cadmium/L)
is derived from natural sources?
-------
-14-
D. CHROMIUM HEALTH ADVISORY
Most of the health advisory evaluation of chromium is accurate, complete
and in agreement with the Criteria Document. However, the section on health
effects does not adequately reflect the body of the evidence presented in
the Criteria Document and is open to question on the evaluation of both
carcinogenic and non-carcinogenic effects.
Both the Criteria Document and the health advisory make efforts to dis-
tinguish between chromium (III) and chromium (VI). This distinction is
important as the toxicity of chromium has been attributed primarily to
chromium (VI). The main difficulty with this advisory concerns the appraisal
of the carcinogenicity of chromium (VI). The health advisory states that
there is inadequate evidence to determine whether or not oral exposure to
chromium can lead to cancer. While this is true, there is strong evidence
that inhalation of chromium (VI) increases the risk of cancer (most notably
for the lung), although there is no direct evidence of carcinogenicity from
oral exposure. The advisory concludes that the carcinogenicity of inhaled
chromium (VI) has no bearing on risk following oral exposure. This statement
is not well justified.
The Criteria Document notes that the International Agency for Research
on Cancer concluded that chromium falls into its Group 1 category (meaning
that sufficient evidence exists to demonstrate that the chemical is carcino-
genic in humans). However, this categorization was not included in the
advisory. Further, EPA's Health Assessment Document for Chromium reviews
this evidence and reaches agreement with the International Agency for Research
on Cancer's categorization. Although the categorization results primarily from
inhalation data, it seems reasonable to include it in the advisory (with the
associated caveats on inhalational versus oral data). There is one animal
study on ingestion of chromium by Ivankovic and Preussman, but it involved
chromium (III) not chromium (VI).
The Criteria Document does not attempt to reach either a qualitative or
quantitative conclusion on the carcinogenic risk from oral exposure through
drinking water based on the inhalation data. Nevertheless, it is critical
to consider the caroinogenicity of chromium (VI) from oral exposure in light
of the inhalation data, the pharmacokinetics, metabolism and mutagenic
effects of chromium (VI). A supporting issue paper reviews the use of
inhalation data to develop acceptable exposure levels in drinking water and,
therefore, a policy basis exists for the Office of Drinking Water to make
this extrapolation for the sake of consistency. However, the Metals Subcommittee
recommends that the Office of Drinking Water not use this exact method,
since this issue paper is in need of revision.
A secondary concern involves the assessment of the noncarcinogenic health
effects in humans. In presenting the evidence, the advisory gives strong
weight to a report on the effect of drinking water containing 1 mg/L of
chromium (VI) in one family of four persons, based on a physical exam. This
report is anecodotal and has little scientific value. Neither was a control
family studied nor were details given on health effects measured. In contrast,
the health advisory notes that chronic inhalation of dust or air containing
chromium (VI) may cause respiratory problems. However, these risks seem
understated as the Criteria Document describes at least three well designed and
-------
-15-
controlled epidemiologic studies which conclude that chronic inhalation of
air containing chromium (VI) causes respiratory problems.
Animal studies on non-carcinogenic effects of chromium are listed but
not reviewed. Conclusions such as "no adverse health effects were reported,"
are not particularly helpful. The emphasis on chromium (VI) is appropriate,
but this description might precede the pharmacokinetics section.
A more critical evaluation of the health advisory calculations would be
desirable by, for example, reviewing possible sources of error, subpopulations
to which the calculated health advisory may not apply, or information that
is unavailable but would be critical for improving the calculation.
-------
-16-
E. CYANIDE HEALTH ADVISORY
The health advisory for cyanide suffers from a haphazard literature review.
For example, in the excretion section, three statements are presented. One
is a summary statement about the major route of elimination, one refers to
rats, and one describes an apparent human suicide attempt. A similar lack
of critical interpretation appears in the section on longer-term exposure.
TWo dog studies are reported. In one, no signs of toxicity apparently were
found after 3 mgAg'day administration for thirty days. In the second,
histopathological changes (in a site described as "ganglion cells of the
CNS" with no other clarification) were found after 0.27 mgAg'day for 15
months. In the first study, the cyanide was administered in the diet, in
the second, as a capsule. Could the different findings be ascribed to the
mode of administration? The text fails to discuss the differences.
The health advisory should add synonyms of prussic acid and hydrocyanic acid.
The use of cyanides in electroplating and the need to check for cyanides in
business closings are of concern but have been emitted. The section on
occurrence should start with a definition of free cyanide. Many organic
compounds exist, such as nitriles, which contain the cyanide functional
group. Few nitriles disassociate to liberate the cyanide ion. Unless the
definition of cyanides is limited to the cyanide ion and hydrocyanic acid,
statements in the health advisory about pharmacokinetics should be modified.
Is it valid to apply potassium cyanide data to the case of hydrocyanic acid
(or cyanide gas) when discussing percent absorption and time to death? The
data of Getter and Baine would be better converted to cyanide ion as is done
in the Criteria Document. Free cyanides absorb readily, and hydrocyanic acid
is absorbed and distributed more rapidly than potassium cyanide. The distri-
bution of cyanide depends upon the time before exposure and death; volatil-
ization of hydocyanic acid from samples should be suspected when the ana-
lytical values are low. The wide range in the concentrations found in human
organs in cases of fatal poisoning may be affected by these factors. The
rapid distribution of cyanide throughout the organs of the body following
ingestion or inhalation is an important fact in characterizing its effects.
Yamamoto's data seem to indicate a greater tendency of cyanide to distribute
to the liver and spleen by ingestion as sodium cyanide than by inhalation as
cyanide gas.
The section on distribution needs to distinguish between the distribution of
radioactivity and the distribution of cyanide. The accumulation of cyanide
within erythrocytes is mainly due to the oxidation of iron in methemoglobin
and the formation of cyanomethemoglobin. The section on metabolism should
note that cyanocobalomin is a form of vitamin B-12. This nomenclature
should be clarified for the non-expert reader. The effectiveness of dif-
ferent sulfur compounds that detoxify cyanide ion by forming thiocyanate is
dependent upon the presence of a free sulfur atom adjacent to another sulfur
atom in the the molecule as is the case with thiosulfate.
The discussion of human epidemiological studies in the section about health
effects has omitted data on electroplaters.
-------
-17-
The.health advisory- should note that animals can tolerate higher doses of
cyanide when administered in-the diet'or in drinking water during longer-term
exposures (20-90 days) than when the same dose is given over a much shorter
period such as 1 day. The compound used in the study by Howard and Hanzal
was hydrocyanic acid. The average concentrations were 76 mgAg of diet and
190 mg/kg of diet, instead of 100 mg/kg and 300 mg/kg as described in the
health advisory.
Why is Cyanide classified as a carcinogen? The health advisory reports
that there is inadequate evidence for such a conclusion. Elsewhere, the
health advisory states that there are no pertinent data available. This is
contradictory.
The rate at which cyanide is absorbed, distributed and detoxified is
important in evaluating the health effects of cyanides. For example, in the
study by Palmer and Olson (see data below), it is not clear how much of the
effect on liver is caused by greater total uptake of cyanide and how much by
faster rate of absorption or distribution. This evaluation will affect the
choice of data for calculation of the 1-day health advisory.
Compound No-observed-ef feet-level Duration of study
KCN diet 8 rog(CN-)/kg '(body weight)-day 21 days
HCN diet " 10.4 mg(CN-)Ag (body weight)'day 104 weeks
KCN water 12 mg/kg (body weight)*day 21 days
The Subcommittee could not find a rationale in the health advisory for the
extra 5-fold factor in the safety factor. If this value relates to absorption
characteristics, it would be;better to describe it separately than to combine
it with the traditional safety factor.
The Subcommittee has written a prose summary of the cyanide health advisory
(See appendix) to illustrate the advantage of narrative for the reader lacking
prior training in toxicology in comparison to the summary table of numerical
data that the health advisory currently presents.
-------
-18-
F. LEAD HEALTH ADVISORY
The recommended lifetime health advisory of 20 ug/day can be supported by
present information about lead metabolism and toxicity. The calculations are
correct, but the selection of values of a blood lead level of 15 ug/dl and a
safety factor of 5 could be challenged. Although past evidence may have seemed
inconclusive, the current literature supports an even lower level than 15 ug/dl,
as discussed later in this review. The recommended standard represents a
reduction in the interim EPA water standard for lead, currently 50 ug/liter.
The Subcommittee also agrees that one day and ten day health advisories are
not appropriate for lead. The health advisory generally is consistent with
the Criteria Document. However, it does not have a clear focus and would not
be especially useful to someone not thoroughly familiar with the lead literature.
An overall statement or description is needed on the range of health effects
of lead, from the most mild to the most severe, associated with the corresponding
blood levels. A summary statement about the significance of these findings
should accompany the table.
In discussing absorption, the health advisory does not note the underlying
reasons for enhanced absorption by children. This is a peculiar omission
because of regulatory efforts to protect the young. The discussion of distri-
bution is devoted solely to lead in blood and does not present information on
where else lead may be found, for example, in kidney and bone. In the section
on short-term exposure, several statements are made about the blood levels
needed to achieve an effect and the .possible latency to effects. These esti-
mates are rather arbitrary and subject to change given current research find-
ings. The statement that it takes 35 days for blood levels to reach a certain
value is difficult to understand. The Criteria Document quotes evidence that
it takes 100 days to attain a steady state level,
Because the health advisory does not describe complete dose-effect relation-
ships, it is difficult to make sense of the biochemical, behavioral, neuro-
physiological and reproductive effects that are listed. The manner in which
the health advisory chooses a single value of 15 ug/dl seems arbitrary. The
change in blood pressure at approximately this level is similar in size to the
elevation produced by barium, an elevation estimated to account for over 7,000
myocardial infarctions annually. In the health advisory for barium these data
were not taken into account to lower the level.
The studies cited to illustrate the sensitivity of the fetus and child to lead
need to be updated. The recent EPA-supported meeting in Edinburgh contained
several reports indicating significant adverse effects in the offspring of
mothers with blood lead values that previously would have been deemed low or
modest. Some of these data, moreover, have been published. Research groups
at the University of Cincinnati, Children's Hospital in Boston, and elsewhere
have obtained data to indicate a direct relationship between maternal blood
levels and lower birthweight, minor malformations, and reduced scores on psycho-
logical tests that persist for at least two years. Such data make the calcula-
tion of a threshold a tenuous proposition. Although impaired heme synthesis
in children may occur at blood lead levels exceeding 10 ug/dl, the health
significance of this effect is less clear.
-------
-19-
For adults, as for children, earlier data suggested few significant effects
on peripheral nerve function at blood leads below 40 ug/dl. Recent data
support the occurence of such effects, but the case is not as clear, and the
statement in the health advisory about nerve dysfunction should be made more
provisional.
The proportionality constant between lead intake in the diet and blood lead
needs to be reviewed in terras of diet contents such as other minerals. The
statement about the World Health Organization European standard for lead of
100 ug/dl in blood should be re-examined to determine if it is cited correctly.
The Subcommittee questions the validity of the statement about the mutagenicity
of lead. Because lead causes toxicity prior to mutagenicity does not mean no
genotoxicity will result. In EPA's Air Quality Criteria Document, lead
is described as decreasing the fidelity of replication, inhibiting RNA synthesis,
causing an S-phase specific cell cycle block that indicates lead will interfere
with normal synthesis and replication of DMA, and causing induction of DMA
repair synthesis. Human carcinogenesis studies also can be cited in support
of the genotoxicity of lead.
The lifetime health advisory for lead is less than levels sometimes found in
air, food, and water. In the Criteria Document for lead, the lifetime health
advisory is considered in terms of relative source data. This type of discus-
sion might be included in the health advisory to reconcile the recommended
level with actual intakes occurring for most Americans today.
For example, the following calculation for an adult ingestion level can be
made using the relationship between blood lead levels and water lead levels
derived by Pocock and coworkers.
__ (15 ug/dl) _ = 48 ug/day
[(1 ug/dl)/(0.062 ug/day)](5)
where:
(a) 15 ug/dl = blood lead level at which no adverse effects are thought to be
observed, and
(b) 5 = an uncertainty factor, which should have a rationale.
Using this maximum ingestion level dividing by an estimate of water consumption
per day, a maximum level of lead in water is obtained. For example, if the
estimate is two liters of water consumed per day by an adult, calculation is as
follows :
48 ug/day = 24ug/l
2
Data on the relative sources of lead and how they contribute should be con-
sidered. The above calculations assume that 100% of an adult's lead exposure
comes from drinking water. However, studies of other routes of lead exposure
in adults show that air-borne lead, lead in food, and dust ingestion also
-------
-20-
contribute. Drinking water contributes about 30% of total intake in adults of
about 100 ug/day. Therefore, the calculation should be modified as follows:
(0.30) (48 ug/day) = 7.2 Ug/l
2 I/day
For this reason, a summary of the relative source contributions for adults
and children will enhance the health advisory.
-------
-21-
G. MERCURY HEALTH ADVISORY
The health advisory generally is consistent with the guidance in the Office
of Drinking Water issue papers. The acceptable daily intake calculations
are arithmetically correct. However, correcting the acceptable daily intake
for intake of mercury from sources other than drinking water poses a difficult
problem.
The decision to subtract mercury intakes for food and air from the total
acceptable daily intake for inorganic mercury assumes that various forms of
mercury are toxicologically equivalent.
The data in the health advisory support the conclusions in the context of a
number of assumptions. The judgments reflect those in the Criteria Document.
The major decision is to accept the experiment by Druet and coworkers as the
basis of calculating the acceptable daily intake. The data of Fitzhugh and
coworkers also are listed in the health advisory but not used. If they were
used, the acceptable daily intake could be 240 times higher than that calcu-
lated in the health advisory. Human data on kidney effects frcm exposure to
mercury vapor are not used. This is also true of the Criteria Document.
Human data are variable in the case of mercury because humans react to mercury
as an antigen, and the data may be difficult to evaluate for purposes of
safety levels. However, human data are preferred, and there is a large data
base for humans. The health advisory also neglects a rather sizable litera-
ture in children relating to Pink Disease (Acrodynia), which, despite its
flaws, is still a better basis for quantification than the data from rats.
The assumptions and uncertainties are not clearly described, but it might
require considerably more text to do this. The most important assumptions
and decisions to be described are as follows:
The rationale for choosing the data of Druet and coworkers versus those
of Fitzhugh and coworkers.
The assumption that all forms of mercury-mercury vapor in air, methyl-
mercury in food and inorganic compounds in drinking water are toxico-
logically equivalent.
The decision not to consider mercury intake frcm dental amalgams.
The approach to adjusting for other sources of mercury in the health advisory
is to subtract the average total air and food intake of all forms of mercury
from the total acceptable daily intake calculated for inorganic mercury.
This calculation gives the acceptable daily intake for drinking water.
Another approach is to estimate the fraction of daily intake of total mercury
contributed by each medium - air, food and drinking water - as estimated for
the general "non-exposed" population and then to apportion the acceptable
daily intake in the same proportion. For example, if drinking water accounts
for 20% of total mercury, the acceptable daily intake for drinking water
would be 20% of 11 ug/day of total mercury or approximately 2 ug/day, given a
maximum concentration in drinking water of 1 ug/1, which is in agreement
with the value derived by the World Health Organization.
-------
-22-
A third approach is to consider the three major forms of mercury as
toxicologically independent. Thus, the acceptable daily intake for inorganic
mercury would be allocated almost entirely to drinking water, giving a maximum
concentration in drinking water of 5 ug/1 inorganic mercury.
Some data on mercury are missing from the health advisory that might better
be included, such as:
Information on intakes from food, air and water. These data should be
described in the section on general information and properties.
Intake from dental amalgams. This information also is missing from the
Criteria Document.
Concentrations of mercury found in commonly used indicator media, such
as blood and urine, for the non-exposed general population. However,
this information also is not present in the Criteria Document.
The health advisory is generally consistent with the Criteria Document.
Thj problems of assessment reside mainly in the Criteria Document.
Mercury represents a special problem in its diverse toxic forms and how
they differ in different media. In addition, this is the first attempt by any
public health organization to evaluate the effects of ionic mercury in the
context of total mercury intake. The Subcommittee has recommended that the
Criteria Document for mercury undergo additional scientific and editorial
review. Detailed comments on the Criteria Document by one Subcommittee
member, which also suggest that the Criteria Document requires additional
review, have been sent directly to the Office of Drinking Water.
-------
-23-
H. NICKEL HEALTH ADVISORY
Sane Subcommittee members have reservations about the proposed lifetime
health advisory of 150 ug/1 for nickel in drinking water (350 ug/1 assuming
that all nickel exposure occurs through drinking water) which is higher than
the nickel concentrations that usually are encountered in public water supplies.
However, EPA's Health Assessment Document for Nickel (Draft final; September,
1985) cites the results of the Agency's STORET data base as a range from <5
ug/1 to >1,000 ug/1 and gives values of 700 ug/1 for the Ohio river. Other
Subcommittee members think that setting the lifetime health advisory close to
the usual drinking water concentrations is overly stringent and will result in
frequent enforcement actions with no clear health benefits. These members
recommend further EPA research on nickel carcinogenicity, sensitization and
uptake in relation to chemical form (species).
The range of nickel concentrations in ambient surface water is not clear.
In another study of 2503 water samples from 969 public water supplies in the
United States during 1969-1970, nickel concentrations averaged 4.8 ug/1. The
nickel concentrations were < 20 ug/1 in 99.0% of the water supplies and < 50
ug/1 in 99.9%. The highest observed nickel concentration was .75 ug/liter.
Similarly, in running tap water from 20 public water supplies in Sweden and 10
European cities, the nickel concentrations ranged from 3 to 7 ug/1 and 5 to 8
ug/1, respectively. In running tap water from 41 public water supplies in the
environs of Copenhagen, Denmark, nickel concentrations were < 35 ug/1 with two
exceptions (91 and 120 ug/1). In Ontario, Canada, at the Sudbury site of the
world's largest nickel deposits, mines and refineries, higher nickel concen-
trations have been reported in drinking water. Nickel concentrations in seven
samples of running tap water collected in Sudbury during 1971-1972 averaged 200
ug/1 (range = 141 to 264 ug/1), while corresponding values for five samples
collected in Hartford, Connecticut, were 1.1 ug/1 (range = 0.8 to 1.5 ug/1).
Differences in ambient exposures to nickel were reflected by differences in the
respective urinary excretions of nickel, which averaged 7.9 ug/day (5.9 ug/g
creatinine) in 19 hospital workers who resided in Sudbury, compared to 2.5
ug/day (2.3 ug/g creatinine) in 20 hospital workers who resided in Hartford.
There is no current evidence to suggest that a carcinogenic response is
induced in humans or laboratory animals by the ingestion of nickel compounds.
However, the Criteria Document emphasizes that there are no bioassays for
carcinogenesis of nickel by the oral route at concentrations greater than 5
mg/1. Until adequate oral carcinogenesis bioassays of nickel compounds in
drinking water have been conducted, the question of nickel carcinogenicity
remains open. This is one practical reason for selecting a lifetime health
advisory level for nickel in drinking water close to the prevalent nickel
concentrations in public water supplies in the U.S.
A second reason to set the health advisory level close to the levels observed
in water is that hypersensitivity to nickel occurs in a significant portion of
the general population, and clinical evidence suggests that oral ingestion can
exacerbate nickel allergy. The Criteria Document summarizes the literature
through 1982 on exacerbation of nickel contact allergy following oral intake
and describes the occurrence of positive dermal patch test results from nickel
in 7 to 11% of adult women and 0.2 to 2% of adult men. Because of the frequency
of nickel hypersensitivity in the population, an additional margin of safety
-------
-24-
may be appropriate in setting the health advisory level for nickel in drinking
water.
A third reason to set the health advisory level closer to the levels
observed in water is the growing evidence that bioavaliability of nickel from
drinking water may be greater than from foods and beverages. Solomons and
coworkers have studied the effects of foods and beverages on gastrointestinal
absorption of nickel in five healthy human subjects following an oral dose of
5 mg, administered as nickel sulfate hexahydrate. No significant post-prandial
increases of plasma nickel concentration occurred after consumption of nickel
added to beans or eggs, whereas prompt and sustained elevations of plasma
nickel concentrations occurred when the same quantity of nickel was consumed
as an aqueous solution by fasting subjects. Increases in plasma nickel concen-
tration also were suppressed when 5 mg of nickel (as nickel sulfate) was
dissolved in milk, coffee, tea, or orange juice. These studies indicate
that certain foods and beverages reduce or prevent the absorption of divalent
nickel from the alimentary tract. Foulkes and McMullen also have found that
divalent nickel ion uptake from the lumen of the perfused rat jejunum is
significantly inhibited by divalent zinc ion and by skimmed milk, supporting
the view that certain dietary constituents reduce the bioavailability of
nickel.
A fourth reason to set the health advisory level close to the levels
observed in water arises from the methodological deficiencies of some published
studies on reproductive effects of nickel salts, administered to rats in diet
or drinking water. The limitations of these studies are discussed in the
Criteria Document. A two-generation reproduction and fertility study of
nickel chloride administered to rats in drinking water at three dosage levels
is underway at the Research Triangle Institute under EPA sponsorship. The
results of this study should soon be available. The outcome of this study is
likely to influence the value of the lifetime health advisory for nickel in
drinking water.
Oral carcinogenesis tests of nickel compounds added to drinking water might
influence the level of the life-time advisory, as well as comparisons of the
bioavailability and toxicity of nickel salts administered to rodents in
drinking water. Until these data are available, EPA's criteria for regulating
oral exposures to nickel in drinking water will remain controversial.
The health advisory does not contain an adequate discussion of nickel as an
essential element. The statements in the health advisory about carcinogenicity
are somewhat disconnected and mostly irrelevant. An interpretive summary
would be far better.
-------
-25-
I. NITRATE AND NITRITE HEALTH ADVISORY
The nitrate and nitrite health advisory is well-written and essentially
complete. The health advisory fairly reflects the contents and conclusions
of the Criteria Document. It is appropriate to recognize the infant as the
most vulnerable organism.
The main thrust of the health advisory is that nitrate is not toxic per se,
'but must be converted to nitrite to be toxic. Nitrate reduction to nitrite
is proposed to occur in salivar which is then swallowed. Nitrate and nitrite
are absorbed through the gastrointestinal tract. Nitrate is recycled by
excretion into saliva, where conversion to nitrite occurs once again. Nitrite
reacts predominantly with red cell hemoglobin to form methemoglobin and
nitrate.
Nitrate and nitrite also produce profound vasodilation and cardiovascular
collapse. The mechanism of vasodiliation is not clear. B'ormation of S-nitroso
vasodilator compounds has been proposed as one mechanism, but is not mentioned
in the Criteria Document. An alteration in chloride transport is another
mechanism based on the competition of nitrate and nitrite with iodide and
other monovalent cations.
The health advisory focuses on methemoglobin formation as the most significant
health effect on the basis that infants suffer from methemoglobinemia after
drinking nitrate contaminated water, milk or formula. For the purposes of the
health advisory, methemoglobinemia in infants is the most appropriate endpoint.
The calculated values assume a 10% conversion of nitrate to nitrite in the
bucal cavity and 100% absorption of nitrite. The no-observed-adverse-effect-
-level selected from the studies reported in the Criteria Document is
appropriate. The studies selected as the basis for the no-observed-adverse-
-effect-level are also appropriate. The calculations do not have arithmetic
errors.
A major problem exists in the lack of data on the chronic health effects of
nitrate. The lifetime multigeneration study of Newbern is controversial due
to the intrepretation of the histopathology. The most recent cancer bioassay
with Fisher 344 rats also is confusing due to the 100% tumor rate in both
control and exposed animals.
No data are now available on the cardiovascular effects of chronic exposure to
nitrate. Given the profound vasodilator effects of nitrates (some of which
are used clinically) independent of the development of methemoglobinemia, this
aspect of the toxicity of nitrate and nitrite deserves further investigation.
A more pressing problem is the question of the carcinogenicity of nitrate.
The Subcommittee agrees with the health advisory conclusion that, under the
Agency's proposed guidelines for carcinogen risk assessment, the current data
fit best into category D (not classifiable). A major health concern, however,
arises from the evidence that simultaneous ingestion of nitrite (or nitrate
with amines) results in cancers of many organ systems. N-nitroso compounds
are presumed to be the ultimate carcinogenic substances. The calculated excess
cancer risk from the combined exposure to a nitrosatable compound and nitrite
-------
-26-
can be significant. It is not possible to calculate the risk, if any, from
nitrate or nitrite alone.
The Office of Drinking Water should devise a plan to develop appropriate ex-
perimental data to clarify this problem. Clearly a number of carcinogenic,
nitrosatable compounds exist in drinking water or foods which, if ingested with
nitrate or nitrite-contaminated drinking water, will result in formation of the
carcinogens and excess cancer risk. Lacking better data, the Subcommittee
agrees that a better estimate of human cancer risk can not now be provided,
but the public is left uncertain if the present health advisory for nitrate
provides adequate protection from this incremental risk.
Some of the difficulty arises from the legislative direction regulating drinking
water standards. Like other health risk legislation, drinking water legislation
is oriented to specific chemicals; e.g. nitrate rather than N-nitroso carcinogens.
The Office of Drinking Water should consider and document how the current
health advisory provides or does not provide a means of indirectly regulating
human exposure to N-nitroso carcinogens.
The health advisory slips into jargon from time to time. The most glaring
ex^.^le is in the introduction, where the third paragraph refers to the "Health
Adv.sory numbers". Clearly, this intended to mean the "Health Advisory values".
This health advisory is better integrated than the other advisories for metals
and related substances.
-------
U.S. Environmental Protection Agency
. Science Advisory Board
Environmental Health Committee
Metals Subcommittee
January 9-10, 1986
Dr. Bernard Weiss [Chair], Professor, Division of Toxicology, P.O. Box RBB,
University of Rochester, School of Medicine, Rochester, NY 14642
Dr. Ronald Wyzga [Vice-chair], Electric Power Research Institute, 3412
Hillview Avenue, P.O. Box 1041, Palo Alto, California 94303
Dr. Ronald Brookmeyer, Department of Biostatistics, School of Hygiene and
Public Health, Johns Hopkins University, 615 N. Wolfe Street, Baltimore,
MD 21205
Dr. Thomas Clarkson, Professor and Head, Division of Toxicology, University
of Rochester, School of Medicine, Post Office Box RBB, Rochester, New York
14642
Dr. Gary Diamond, Assistant Professor of Pharmacology, University of Rochester
School of Medicine, Rochester, New York 14642
Dr. Edward F. Ferrand, Assistant Commissioner for Science and Technology,
New York City Department of Environmental Protection, 51 Astor Place, New York,
New York 10003
Dr. Robert Goyer, Deputy Director, NIEHS, P.O. Box 12233, RTP, North Carolina
27709
Dr. Marvin Kuschner, Dean, School of Medicine, Health Science Center, Level 4,
State University of New York, Stony Brook, New York 11794
Dr. Daniel Menzel, Director and Professor, Pharmacology and Medicine, Director,
Cancer Toxicology and Chemical Carcinogenesis Program, Duke University Medical
Center, Durham, North Carolina 27710
Dr. Brooke T. Mossman, Department of Pathology, The University of Vermont,
Medical Alumni Building, Burlington, Vermont 05405-0068
Dr. Gunter Oberdoerster, Associate Professor, Radiation Biology and Biophysics
Division, University of Rochester School of Medicine, 400 Elmwcod Avenue,
Rochester, NY 14642
Dr. F. William Sunderman, Professor of Laboratory Medicine and Pharmacology
and Head, Department of Laboratory Medicine, University of Connecticut Health
Center, Room C 2021, Farmington, Connecticut
Executive Secretary
Dr. Daniel Byrd, III, Executive Secretary, Science Advisory Board, [A-101F],
U.S. Environmental Protection Agency, Washington, D.C. 20460 (202) 382-2552
-------
COMMENTS SUBMITTED TO THE METALS SUBCOMMITTEE
BY THE PUBLIC REGARDING THE SCIENCE ADVISORY BOARD'S
REVIEW OF DRAFT DRINKING WATER HEALTH ADVISORIES
National Audubon Society
National Capital Office
645 Pennsylvania Avenue, S.E.
Washington, D.C. 20003
Date: December 24, 1985
Chemical Manufacturers Assoc.
2501 M Street, N.W.
Washington, D.C. 20037
Date: December 26, 1986
Natural Resources Defense
Council Inc.
122 East 42nd Street
New York, N.Y. 10168
Contact: Chuck Pace
Contact: Geraldine V. Cox
Contact: Robin Whyatt
Wendy Gordan
Date: November 29, 1986
Water Quality Association Contact: Danna M. Cirolia
1518 K Street, N.W.
Suite 401
Washington, D.C. 20005
Date: November 22, 1985
The New Jersey Dept. of Health Contact: Bonnie L. Bishop
and The New Jersey Dept. of
Environmental Protection
Date: August, 1985
State of Connecticut Contact: David R. Brown
Department of Health Services
Date: December 12, 1985
Michigan Pure Water Council Contact: Martha Johnson
Date: December 12, 1985
-------
-2-
POSTMEETING COMMENTS RECEIVED
National .Audubon Society Contact: Chuck Pace
National Capital Office
645 Pennsylvania Avenue, S.E.
Washington, D.C. 20003
Date: January 27, 1986 :
-------
U.S. Environmental Protection Agency
Science Advisory Board
Environmental Health Committee *
Metals Subcommittee
Open Meeting
Under Public Law 92-463, notice is hereby given that a
two-day meeting of the Metals Subcommittee of the Environmental
Health Committee of the Science Advisory Board will be held
on January 9-10, 1986, in Conference Room 451 of the Joseph
Henry Building; National Academy of Sciences; 2122 Pennsylvania
Avenue, N.W.; Washington, DC. 20037. The meeting will start
at 9:00 a.m. on January 9 and adjourn no later than 4:00
p.m. on January 10.
The purpose of the meeting will be to discuss, draft
drinking water Health Advisory documents for the following
substances:
Arsenic Lead
Barium Mercury
Cadmium Nickel
«
Chromium Nitrate/Nitrite
Cyanide
The Metals Subcommittee will not receive oral comments
on the Health Advisory documen-ts 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]; U.S. Environmental Protection Agency;
401 M Street, S.W.; Washington, DC; 20460.
-------
- 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 above 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 nail to: Science Advisory.Board (A-101F);
401 M Street, S.W.; Washington, DC: 20460, no later than
c.o.b. on December 20, 1985.
Yosie
)irector
October 15, 1985 V^/Scie^qb Advisory Board
Date
-------
U.S. ENVIRONMENTAL PROTECTION AGENCY
SCIENCE ADVISORY BOAPD
ENVIRONMFNTAJ, HEALTH COMMITTEE
METALS SUBCOMMITTEE
Conference Room 451
Joseph Henry BuiIding
National Academy of Sciences
212.2 Pennsylvania Avenue, NW
Washington, DC 20037
January 9-10, 1986
ORDER OF BUSINESS
REVIEWS OF DRAFT DRINKING WATER HEALTH. ADVISORIES
Opening Remarks Dr. Weiss
Administrative Matters Dr. Pyrd
Introduction Dr. Crisp
Dr. Weiss
*Tentative Sequence of Reviews, beginning Thursday, January Q, 1986
Substance (Manager) Reviewers
Arsenic (Marcus) Drs. Wyzga and Goyer
Lead (Marcus) Drs. Goyer and Olarkson
Nickel (Bathija) Drs. Sunderman and Rrookmeyer
tfariun (Bailey) Drs. Diamond and Sunderman
Padmium (.Bailey) Drs. Mossman and Diamond
Chromium (Ba iley) Drs. Brookmeyer and Mossman
On Friday, January 10, 1986
Merctiry (Khanna) Drs. Clarkson and Wy?.ga
Cyanide (Bathija) Drs. Ferrand and Knschner
Nitrate (Bailey) Drs. Menzel and Ferrand
At the conclusion of the reviews
*Completion of reviews (previously deferred) Dr. Weiss
General comments . Dr. Weiss
Nomination of Criteria Documents for further review Dr. Weiss
Other Subcommittee Business
Concluding remarks Dr. Weiss
Dr. Byrd
ADJOURNMFOT
* The sequence in which the Subcommittee reviews Health Advisories for different
substances and the time allocated to each review are at the discretion of the Chair.
-------
CYANIDE
DEFINITION
For the purposes of this document cyanide refers to hydrogen cyanide and
its water soluble salts, primarily sodium and potassium. Organic compounds
called nitriles because they contain a cyano, (-CN), functional group are
sometimes referred to as cyanides. These are not included because they do
not readily dissociate to form cyanide ion. Cyanide ion has a tendency to
combine with certain cations to form complexes. Their contribution to the
"free" cyanide measured in water solution depends on their stability and the
analytical procedure.
Pure hydrogen cyanide is a colorless liquid with a bitter almond taste which
biols near room temperature (25.7° C) and is miscible in all proportions with
water. Sodium and potassium salts are colorless, crystalline solids which
are quite soluble in water where they are converted to hydrogen cyanide to an
extent dependent upon the acidity of the water.
SOURCES OF CYANIDES
Cyanides are used by the chemical industry in the manufacture of pesticides,
rodenticides, photographic and metal polishing products and in the preparation
of other chemicals such as nitriles and plastics. Wastes from the manufacture
or use of cyanide products, for example, from electroplating and case hardening
operations are potential sources of cyanide contamination of water supplies.
Cyanide, at the concentrations normally found in drinking water supplies,
ordinarily is not an important contributor to the body intake. Therefore, it
is not a public health problem in the United States. A survey reported in
1970 of 2595 samples collected from over 800 water supplies found a maximum
concentration of 0.008 mg per liter. Nevertheless, the possibility of cyanide
in water supplies by accidental or intentional contamination requires that
monitoring programs or at least an anlytical capability should be maintained
by water suppliers.
There are other contributors to the body burden which should be considered if
cyanide is a concern. Unusual diets, smoking habits and occupational exposures
can be more important contributors than drinking water. Individuals with a
metabolic defect in the enzyme system that converts cyanide to less toxic
thiocyanate, with a vitamin B12 deficiency or with defective B12 metabolism or
with an iodine deficiency, as well as fetuses in utero of smoking mothers, are
at greater risk than the normal population.
There is no available evidence pertaining to the carcinogenicity of cyanides.
ADVERSE HEALTH EFFECTS
Cyanide acts as an asphyxiant by preventing body tissues from using the
oxygen transported to them by the blood. Thus, the inhalation, ingestion or
absorption through the skin of high concentrations of cyanide can cause
serious damage to the tissues of many organs. Hydrogen cyanide is absorbed
most rapidly by inhalation.
-------
2 -
Studies relating cyanide exposures to adverse health effects indicate that a
daily intake of up to 0.021 mg of cyanide per kg of body weight over an
extended period will not cause observable adverse effects to the health of
children. If all exposure comes from drinking water, then to avoid exceeding
the daily dose, the concentration of cyanide in the water supply must not
exceed 0.21 mg per liter of water. This value is based upqn the assumption
of a 10 kg child who drinks an average of 1 liter per day:
0.21 rcg CN" x 10 k9 n 0,
kg (bw) day __ = u'2i mg CN
liter
1 liter
day
A 70 kg adult drinking 2 liters per day from this same water supply will
receive a considerably smaller daily exposure per kg of body weight.
0.21 mg CN~ x 2 liter
J _ liter _ day 0>006 mg CN'
kg (bw) day
70 kg (bw)
REMOVAL OF CYANIDE FROM WATER SUPPLIES
Cyanide ion, CN~, in water is in equilibrium with hydrocyanic acid (HCN)
with the equilibrium concentrations dependent upon the pH of the water:
HCN (gas)
I
CN~ + H20 = HCN (aq) + OH~
At pHs less than 7, over 99% will be in the HCN (aqueous) form. Therefore,
in an open body of water there will be a tendency to lose cyanide slowly by
^aporation as gaseous HCN. Chlorination of the water supply or use of other
oxidizing substances for disinfection will convert some cyanide to the less
toxic isocyanate form.
ANALYSIS OF WATER FOR CYANIDES
Free CN~ can be measured: by titration with silver ion using a silver sensitive
indicator; by colorimetry based upon conversion to cyanide chloride using
chloramine followed by formation of a dye, or by cyanide-selective electrode.
Depending on the pretreatment method used in the analysis, anything from free
cyanide to total cyanide, including insoluble and complex cyanides, can be
determined.
REFERENCES
-------
HOSC
-------
United States Off ice of the Administrator SAB-EHC-87-005
Environmental Protection Science Advisory Board (A-101) October 1986
Agency 401 M Street, SW
Washington, DB 20460
Review of Drinking Water Health
Advisories by the Halogenated
Organic Subcommittee of
. «
The Environmental Health Committe
of The Science Advisory Board
V
Carbon tetrachloride
Chlorobenzene
Dichlorobenzenes (ortho, meta and para)
1,2-Dichloroethane
cis-Dichloroethylene
trans-Dichloroethylene
Vinylidene chloride
Dichloromethane
Dichloropropane
2,3,7,8-Tetrachlorodibenzo-p-dioxin
Epichlorohydrin
Hexachlorobenzene ^
Polychlorinated biphenyls
Tetrachloroethylene (perchloroethylene)
1,1,1-Trichloroethane (methylchloroform)
1,1,2-Trichloroethylene
Vinyl chloride
-------
i UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
'.U
* WASHINGTON. O C 20460
SAB-EHC-87-005
September 20, 1986
Dr. Richard A. Griesemer
Chair, Environmental Health Committee
Science Advisory Board [A-101]
U.S. Environmental Protection Agency
401 M Street, SW
Washington,. DC 20460
Dear Dr. Griesemer:
On January 14-17, 1986 the Halogenated Organics Subcommittee of the
Science Advisory Board's Environmental Health Committee reviewed fifteen
(15) draft health advisories for drinking water in public session. The
draft health advisories were prepared by the Office of Drinking Water.
The health advisories are not regulatory documents but are intended to
provide consistent, brief reference information, particularly for tech-
nical personnel responsible for the operation of water works or for state
and local public health officials. During the review, the Subcommittee
utilized Drinking Water Criteria Documents as support information for all
of the health advisories except for 1,2-dichloroethane, for which the
Subcommittee made use of the Agency's Health Assessment Document, supple-
mented by a Quantitative Toxicological Evaluation for drinking water.
Some of the Criteria Documents merit detailed review in the future.
Our comments below are generally divided into general advice, which
is relevant to all of the advisories reviewed by the Halogenated Organics
Subcommittee, followed 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 ap-
preciate the opportunity to become involved with this program and stand
ready to provide further advice, as requested.
Sincerelv.
__all, M.D., Ph.D.
Chair, Halogenated Organics Subcommittee
Seymour Abrahanson, Ph.D.
Vice-chair, Haloeenated Oreanics Subcommittee
-------
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 recommendation for use.
-------
TABLE OF CONTENTS
Subject
I. GENERAL COMMENTS ON DRINKING WATER HEALTH ADVISORIES
II. SPECIFIC COMMENTS ON SEVENTEEN HEALTH ADVISORIES
A. Carbon Tetrachloride 6
B. Chlorobenzene 10
C. Dichlorobenzenes (ortho, meta and para) 11
D. 1,2-Dichloroethane 13
E. Dichloroethylenes (cis, trans and vinylidene chloride) 15
F. Dichloromethane .18
G. Dichloropropane 21
H. 2,3,7,8-Tetrachlorodibenzo-g-dioxin 22
I. Epichlorohydrin 23
J. Hexachlorobenzene 24
K. Polychlorinated Biphenyls 26
L. Tetrachloroethylene (perchloroethylene) 28
M. 1,1,1-Trichloroethane (methyl chloroform) 31
N. 1,1,2-Trichloroethylene 3 3
O. Vinyl Chloride 35
III. APPENDICES
Roster of the Subcommittee
List of comments received from the public.
Federal Register notice of the January 14-17, 1986 meeting
Agenda for the meeting
-------
I. GENERAL COMMENTS OF THE HALOGENATED ORGANICS SUBCOMMITTEE OF THE
ENVIRONMENTAL HEALTH COMMITTEE OF EPA'S SCIENCE ADVISORY BOARD
REGARDING DRINKING WATER HEALTH ADVISORIES
The Subcommittee recommends that each halogenated organic health advisory
provide the CAS number after the chemical name on the first page to facilitate
referencing, and that each health advisory provide access information (such as
a name and telephone number) for the chemical manager or health advisory
manager.
The Subcommittee suggests that the health advisories cite a date through
which the literature has been searched comprehensively, and give preference to
the use of primary literature citations, whenever they are available. If
relatively inaccessible references, such as EPA documents or in-house memo-
randa, must be used, the health advisory should explain how to obtain them.
Citation of abstracts or personal communications should generally be avoided.
English translations of any critical foreign language documents used in the
health advisory should be .made available upon request. Whenever primary
reference documents, such as Criteria Documents or International Agency for
Research on Cancer publications, are cited, EPA should provide specific page
numbers in the reference section. Otherwise, the health advisory as a quick
reference will lose value, because a large number of volumes would have to be
searched.
The Subcommittee recommends that the Office of Drinking Water provide a
consistent and uniform list of physical and chemical properties for each
substance. These properties should be presented in a uniform system of units,
and should contain factors for converting concentrations between different media.
If the literature does not include one or more properties, the health advisory
should indicate this absence, rather than omit the property from the list.
The Office of Drinking Water should add a glossary of definitions, abbrevia-
tions, and acronyms. Situations will occur in which the analytical measure-
ment of the concentration of a substance in water exceeds its solubility
when, for example, the water sample contains undissolved substance or when
other contaminants enhance solubility. However, it will be worthwhile to
compare the levels recommended in each health advisory to the solubility of
a substance in pure water since, in some cases, the former exceed the latter.
The description of the occurrence and use of a chemical should include
a single primary reference. Whenever available, sections on use and human
exposure should be included in the Criteria Documents and health advisories.
Occurrence information should be put into perspective with health effects
information in the health advisories. Uses listed in the health advisories
should be categorized as "past" versus "current," when applicable, but both
should be included.
Pharmacokinetic sections should include the half-life of the chemical
in humans and/or animals, and the rates of absorption and excretion, where
known. This information will be helpful in assessing blood levels which
correspond to toxic endpoints. It will also enable the reader to be aware of
the persistence of the chemical in the biological system being discussed.
Most of the Criteria Documents for halogenated organic chemicals contain this
information for some route of administration.
-------
A default assumption of a 20% source contribution of drinking water to
total human exposure should not be made: (1) if available exposure estimates
indicate that air and/or food are not a major source of exposure, or (2) if
the physico-chemical properties of a compound make one or both alternative
sources of exposure (food or air) unlikely.
The rationale for the 20% assumption is an estimate of the generic contri-
bution of water to total dose. The assumption of 100% source contribution is
appropriate for substances for which exposure occurs mostly through drinking
water ingestion, as in the two circumstances above.
The health advisories should indicate that calculations are based on the
assumption that the only increase in exposure occurs through drinking water.
There may be additional exposure by other routes such as inhalation of vapors
frcm the boiling of water, through showering and by dermal absorption when
bathing. Boiling water, except outdoors, should not be recommended for
decontamination purposes, since boiling water will transport a halogenated
organic material from drinking water into indoor air, where it recirculates,
changing the route of administration to inhalation and possibly increasing
exposure. Non^water sources of exposure may include food and air. Health
advisory recommendations should take into consideration these additional
sources of exposure.
The sections about health effects should be reorganized. Human health
effects should be presented first, followed by discussion of health effects
in animals. Each health advisory should categorize the effects derived from
human and animal data in parallel structures. An example is presented below:
(1) Human evidence:
(a) Acute (brief) exposure or toxicity
(b) Repeated short-term exposure or toxicity
(c) Chronic (long-term) exposure or toxicity
(d) Specific organ system effects and/or mechanism
(e) Carcinogenicity and mutagenicity
(f) Reproductive and developmental effects
(2) Animal and other evidence:
(a) Acute (brief) exposure or toxicity
(b) Repeated short-term exposure or toxicity
(c) Chronic (long-term) exposure or toxicity
(d) Specific organ system effects and/or mechanism
(e) Carcinogenicity and mutagenicity
(f) Reproductive and developmental effects
Each of the above categories should include the exposure levels known to
cause and not to cause effects. The human evidence category should include
experience from the medical, poison control, occupational, and epidemiological
literature. In particular, the health advisory should emphasize studies of
-------
-3-
groups exposed to contaminated water. Mutagenesis data should be preceded
by a statement indicating that positive results may indicate the potential
of the chemical to initiate genetic changes that may lead to cancer but may
not indicate developmental or reproductive risks.
The Subcommittee recommends that when a health advisory uses data from a
particular study for a calculation of the no-observed-adverse-effect-level
or lowest-observed-adverse-effeet-level, this use should be highlighted as the
study is discussed. Otherwise, the user has to flip back and forth in a
health advisory and can not easily refer to the data on which the health
advisory was based.
Determining a lowest-observed-adverse-effect-level or no-observed-
adverse-effect-level from an oral exposure study, especially oral exposure
through drinking water, is preferred to a determination using data from
other routes of exposure. For some chemicals, oral exposure data may not be
available, making it necessary to rely on data derived from other routes of
exposure, such as inhalation. When data from an inhalation study are used,
factors such as the body weight, tidal volume and respiratory rate of the
animal should be considered in the calculation of the total absorbed dose.
An uncertainty factor can then be applied to the animal estimate to calculate
the health advisory level. Inhalation data also can be used to increase
confidence in the calculations derived from drinking water studies. It
might be remembered, however, that pharmacokinetic factors, such as differ-
ences in absorption rate and first pass effects, may produce predictable
differences among different routes of exposure, which in the absence of data
on comparable blood levels must be interpreted with caution. Development of
a data base comparing the toxicity of halogenated organic chemicals at simi-
lar blood levels from studies using different routes of exposure would be
desirable; comparisons could be made between various hydrocarbons and between
different routes of exposure. Where the appropriate data are not available,
EPA should consider these issues as research needs.
In assigning a lowest-observed-adverse-effect-level or a no-observed
-adverse-effect-level, EPA should consistently use a dose-related endpoint
for a particular effect. Thus, the use of one toxicological endpoint in one
health advisory should be consistent within the same advisory as well as
between advisories. If a decrease in body weight is used as an endpoint,
significant weight loss should not be ignored in other advisories'. Similar
arguments apply to other endpoints, such as serum enzyme levels, histopatho-
logical changes and organ weight changes.
The Subcommittee recommends that the definition of the term "longer-term
advisory" include the length of time covered, i.e. month to years. An advisory
that recommends a lower level of a substance for a 10-day health advisory
than for a longer term (or life-time) exposure level contradicts a principle .
of toxicology. From the managerial view, once people are exposed to a low
level of a substance in drinking water, a higher long-term health advisory
value implies that exposed persons will be safer, if they would continue
drinking the contaminated water. For most substances, a greater effect is
manifest as the duration of an exposure increases. Either interpretation,
acute or chronic, could be in error. For certain substances, especially those
causing neurotoxic effects, a phenomenon of tolerance can occur. However,
-------
-4-
tolerance usually is induced by increasing the dose over time. Even with a
substance causing tolerance, safety levels should not be based on the chronically
exposed animal, if exposure to this level would cause toxic effects in the
previously unexposed person. The problem of health advisory values that are
inconsistent with time of exposure may arise when different routes of exposure,
different species or different endpoints of toxicity are used for the development
of the various health advisories for a substance. In these situations, EPA
should explicitly state when the inconsistency arises from the choice of
safety (or "uncertainty") factors. The Subcommittee suggests that in these
instances the levels derived for longer-term or lifetime health advisories
should be used to calculate 10-day and 1-day health advisories.
The Subcommittee believes that the mathematical calculations of health
advisory levels are informative, where directly relevant. .However, for sub-
stances where argument is developed by analogy to another compound, discussion
should focus on the strength or weakness of the analogy. Illustrative calcu-
lations in these circumstances do not communicate the uncertainty involved
in the analogy, and they imply the possession of information that does not
actually exist. The health advisory should present alternative analogies and
emphasize their comparative strengths and weaknesses.
Statements regarding potential carcinogenic risks should clearly state
that the values given represent an estimated plausible upper bound on the
possible true risk. For example, a health advisory introduction should state
that, for given concentrations of the contaminant, the actual risks are
unlikely to exceed the projected excess lifetime cancer risks calculated by
EPA. In the section about evaluations of carcinogenic potential, the health
advisories should note that the exposure levels provided are unlikely to pose
a carcinogenic risk in excess of the stated values. Under "Other criteria,
guidance, ..." risks of 10~5, should be changed to "estimated upper limits of
10~5, ...". The intended readers of the health advisories, including operating
personnel of water works, probably do not have the technical background to
supply the appropriate perspective themselves, which may prove crucial in
some decisions.
The Subcommittee requests that the Drinking Water Subcommittee and/or
the Environmental Health Committee comment on the revisions of the classifi-
cation levels of cancer in the Federal Register on pages 46884-46885 as 40
CFR Part 141.142. EPA has moved all group B probable human carcinogens (both
group Bl and B2) into a new category 1 of known or probable human carcinogens,
which receive equal treatment. Both the International Agency for Research on
Cancer categories and EPA's guidelines for carcinogen risk assessment distin-
guish probable human carcinogens from known human carcinogens. Strict use of
the new classification approach might treat a substance as an aqueous carcinogen
based on an evaluation of positive inhalation data, with contradictory data
for drinking water. Such might be the case with arsenic, for which the
Agency has evaluated the literature differently for drinking water.
Health advisories include standards derived by other groups, such as
the Occupational Safety and Health Administration, National Institute of
Occupational Safety and Health, American Conference of Government Industrial
Hygiensts, World Health Organization and National Academy of Sciences.
-------
5
References to these standards will be of greater value to readers if each
health advisory supplies the assumptions made and/or constants used in the
derivation of quoted standards. A statement could be made for each standard
concerning the endpoints(s) on which the standard was based, the estimated
risk and the date the standard was issued. Conversion of such standards to
dimensions equivalent to those of drinking water exposures would facilitate
comparison. However, some members of the Environmental Health Committee
caution that such comparisons can mislead the reader if not properly explained.
The Subcommittee also recommends that the health advisories cite Science
Advisory Board reviews and the EPA reports where the substance in question
was previously reviewed. Otherwise, state and local public health officials
will not be aware of the context in which the Board's comments are made.
EPA needs a source document for polychlorinated biphenyls. The Subcom-
mittee has provided a detailed scientific review of the Drinking Water Criteria
Document for Polychlorinated biphenyls to the Office of Drinking Water, which
included thirty detailed comments and thirteen minor comments. The final
draft of this document is dated March, 1985. The data and papers which are
included, and some of the interpretations, are highly inadequate. Some of
the issues, which have not been thoroughly discussed or even acknowledged,
include the following:
Recent papers indicate that Yusho poisoning is primarily related to the
toxic polychlorinated dibenzofurans and not the polychlorinated dioxins in
contaminated rice oil. Thus, a discussion of the human health effects of
polychlorinated biphenyls should not use "Yusho" as an example. Industrial
exposure data more accurately reflect human health effects.
The discussion of chemical analysis of polychlorinated biphenyls and the
complexity of polychlorinated biphenyl mixtures-is out of date, and any
revised document should recognize important new advances in this field.
A multitude of important papers on structure-activity relationships for
polychlorinated biphenyls have been published but are not cited in the com-
ment. For polychlorinated biphenyls, this is a critical issue which must be
thoroughly discussed.
The mechanism of action of polychlorinated biphenyls has been extensively
reviewed but is not covered adequately in the Criteria Document. [See,
for example, CRC Crit Rev. Tox 13; 319 (1985), Environ. Health. Perspect..
JiO: 47 (1985) or Environ. Health. Perspect. _61: 21 (1985)]. Thes'e sections
of the Criteria Document are out of date and need revision.
In view of the above comments, as well as those made beginning on page 26,
the Subcommittee strongly recommends that the Drinking Water Criteria
Document for Polychlorinated biphenyls be extensively revised and updated.
The revised document could serve as an Agency-wide source document.
-------
-6-
II. SPECIFIC COMMENTS OF THE HALOGENATED ORGANICS SUBCCMMITTEE ON SEVENTEEN
CRAFT DRINKING WATER HEALTH ADVISORIES
A. CARBON TETRACHLORIDE HEALTH ADVISORY
The health advisory for carbon tetrachloride is not a legally enforce-
able federal standard. However, any EPA guideline that quantifies risks
will be used as policy by Federal, state and local officials, as well as the
public, including the affected industries. In a very practical way, they
also become the reference points in litigation proceedings. It is, therefore,
desirable that the EPA initially examine a complete data base in preparing
the carbon tetrachloride health advisory, although the health advisory
does not need to cite the complete literature. The criterion applied is
whether the health advisory cites the literature that is crucial to the
calculations. Evaluation, interpretation and ultimate utilization of data
must be done in an objective way, if the health advisory is to have credi-
bility. The Criteria Document should provide much of the evidence for
such a process. However, critical data are excluded in the case of the
carbon tetrachloride health advisory.
The support document for the health advisory is the final draft Criteria
Document prepared by Life Systems, Inc., which is dated January, 1985.
This document represents a condensed version of the more comprehensive,
and supposedly multimedia, Health Assessment Document, which was published
by EPA in September of 1984. As the Subcommittee understands it, the
Health Assessment Document contains data from the health effects literature
up to March 1983, and was based in part on the Criteria Document, which
appeared in draft. One would assume that the Criteria Document would be
more up-to-date, but it contains about one-half as many references as does
the Health Assessment'Document. It should be pointed out that since March
1983, there have been over one thousand citations in the toxicologic
literature related to carbon tetrachloride. Several of these new articles
are pertinent to the health advisory and should be incorporated. Where
appropriate, references to recent key studies are provided in these comments.
EPA' recently issued a final rule for a Recommended Maximum Contam-
inant Level for carbon tetrachloride at the level of zero based on a B2
carcinogenicity classification with evidence from three animal species by
the oral route. The same rulemaking reports that carbon tetrachloride has
been detected in drinking water supplies in concentrations ranging from
0.5 to 30 parts per billion (ppb). The Agency's cancer risk estimate (parts
per billion) corresponding to an upper bound of 10~-> risk) given in the rule-
making is 0 - 2.7 cases. The Office of Drinking Water should note the upper
bound nature of the risk estimate. EPA also proposed a Maximum Contaminant
Level for carbon tetrachloride (Federal Register, pp. 46902-46933, November
14, 1985) at 0.005 ppm. This rulemaking also proposes 5 ppb as the practical
quantitative level of detection of carbon tetrachloride in water. The
above numerical estimates of carbon tetrachloride risk or numerical contam-
inant levels need to be acknowledged, accounted for, and explained in the
drinking water health advisory, if the advisory is to be useful for state
and local public health officials.
-------
7
The above comments serve to indicate^that the Criteria Document 'is
incomplete. The resulting drinking::.water health'advisory-, therefore,
is not based on all of the readily available data-and merits^revision:
The Subcommittee recommends either a -further scientific .review of the
Criteria.Document, or (better) an updating of the-Health'Assessment -
Document,, perhaps by a memorandum-(or:-"quantitative-toxicological-evaluation")
and use of the combined Health Assessment Document .and .memorandum-as the
reference (or source) document to support the*;drinking.;water-.Thealth;
advisory.
In the section on "general, information'and properties,:," the synonyms
section should omit "carbon- tetrachloride,-," and add-. "methane-,-tetrachloride"
and "perchloromethane". Under "properties," the-odor threshold may notbe
known, but .the odor is sweetish, aromatic, and moderately strong.; .The
odor of carbon tetrachloride is characteristic. Under "occurrence,"
after the first two paragraphs the remainder :of'this section runs together
and should be revised to state how carbon tetrachloride gets to air, to
water, etc. How much is found in an environmental sink, how-long does
it stay, and what are the major concerns? There are no references
provided in this section of the drinking water health advisory. The
Criteria Document has. no section on occurence. This section needs a few
key citations to support the statements, judgements, assumptions and
uncertainties in this section.
The pharmacokinetics section illustrates 'the desirability of
providing succinct, meaningful summaries. The paragraph provided
could be replaced with one which states that, based mostly on animal
studies, carbon tetrachloride has been shown to absorb readily through
the respiratory tract, the gastrointestinal tract, and the skin. The
subsections about distribution, metabolism, and excretion should be
revised to provide the basis of the information citedj if the health
advisory is to be useful for health professionals.
In the health effects section, the following additional ref-
erences, which are not covered in the drinking water health advisory
and/or Criteria Document for chloroform, should be reviewed and
utilized in the overall toxicological evaluation:
(a) Amacher, D.E. and Zelljadt, I., "The morphological transformation
of Syrian hamster embryo cells by chemicals reportedly nonmutagenic
to Salmonella typhimurium," Carcinogenesis (Lond.) 4_: 291-296 -
(1983).
(b) Cans, J.H. and Korson, R., "Liver nuclear DNA synthesis in mice
following carbon tetrachloride administration or partial
hepatectomy," Proc. Soc. Exp. Bio. Med. 175; 237-42 (1984).
(c) Mirsalis, J.C.; Tysn, C.K.; Loh, E.N.; Spek, O.K. and Spalding,
J.W., "Induction of hepatic cell proliferation and unscheduled
DNA synthesis in mouse hepatocytes following in vivo treatment,"
Carcinogenesis 6; 1521-4 (1985).
-------
-8-
Shank, C. and Barrows, L.R., "Toxicological effects on carcino-
genesis," in Toxicological Risk Assessment, Vol. I of Biological
and Statistical Criteria, D.B. Clayson, D. Krewski, and
I. Munro, eds., CRC Press, (1985), p. 93.
Sina, J.F.; Bean, C.L.; Dysart, G.R.; Taylor, V.I. and Bradley,
M.O., "Evaluation of the alkaline elution/rat hepatocyte assay as
a predictor of carcinogcnic/mutagenic potential," Mutat. Res.
113; 357-91 (1983).
Uemitsu, N.; Minobe, Y. and Nakayosho, H., "Concentration-time-
response relationship under conditions of single inhalation of
carbon tetrachloride," Toxicology and Applied Pharmacology 77;
260-266 (1985).
VanStee, E.W.; Boorman, G.A.; Moorman, M.P. and Sloane, R.A.,
"Time-varying concentration profile as a determinant of the
inhalation toxicity of carbon tetrachloride," J. Tox. Enviro.
Health 10; 785-795 (1982).
Wilkcosky, C.; Checkoway, H.; Marchall, E.G. and Tyroler, H.A.,
"Cancer mortality and solvent exposures in the rubber industry,"
Am. Ind. Hyg. Assoc. J. 45; 809-811 (1984).
The human exposure section of the Criteria Document was unavailable
for review and comment.
The entire section on "quantification of toxicological effects"
rests upon data derived from an EPA sponsored study performed by J.V.
Bruckner and co-workers. The paper was recently published in Fundamental
and Applied Toxicology 6; 16-34 (1986). It was only accepted for
publication in May 1985, but EPA has used it in risk assessments for
carbon tetrachloride for more than a year. A copy of this paper was
obtained and reviewed by one member of the Subcommittee. This paper
presents primarily clinical chemistry data for rats that were dosed for
nine days or twelve weeks. Many methodology problems were immediately
evident. Only male rats were used. Dosing was discontinuous (i.e.,
for 9 days: 5 on, 2 off, 4 on); for 12 weeks: 5 on, 2 off, .for duration).
Animals were not fasted; dosing was conducted at night (initial part
of active cycle) because the authors determined that this period is
when non-fasted rats are most sensitive to carbon tetrachloride hepato-
toxicity. No signs of toxicity or body weight data were provided.
Carbon tetrachloride was administered by gavage in corn oil. The
Science Advisory Board previously has noted the controversy about the
significance tor environmental standards of data obtained using corn
oil as vehicle. No chemical analyses were provided for carbon tetra-
chloride, corn oil, or feed. The results were based exclusively on
liver enzyme and pathology data.
In the section about quantification of toxicological effects, the
data of Bruckner may be appropriate for calculating the 1 and 10 day
drinking water health advisories, but they should not be used for the
longer term health advisory. There are papers, cited in the Health
-------
-9-
Assessment Document, by Smyth and coworkers (1936), Adams and coworkers
(1952) and Prendergast and coworkers (1967), which are as suitable
as the Brucker data for the calculations, since there is some validity
in extrapolating from inhalation to oral exposure. (See !K. iKhanna,
"Use of Inhalation Data for Estimating Acceptable Exposure Levels in
Drinking Water," draft, September .12, 1985, EPA issue paper).
The .section on quantification of toxicological effects presents
health advisories for one day (based on a ten kg child), ten days
(based on a ten kg-child), and longer term (for both a ten :kg child
and a seventy kg adult). Health advisories for one-day and ten-days
for a 70 kg adult are missing. The Criteria Document includes these
calculations, and they should be included in the health advisory.
There is inconsistent use of data in calculating the RRfd, :DWEL,
and unit risk estimate for carcinogenic potential. The first two
are based on Bruckner's data. The latter values derive from four
studies which by EPA's own admission, are "less than ideal for risk
estimation for continuous daily exposure over a lifetime."1 EPA has
chosen to estimate unit risk by the geometric mean of the estimates
frcm each of the studies (two in mice, one in the rat and one in the
hamster). This is a poor estimate because the geometric mean of
four poor estimates is still a poor estimate. EPA should make an
effort to provide a more accurate evaluation of carcinogenic potential,
or it should describe the uncertainty in the estimate in more detail.
The lifetime health advisory, whether revised or not, should be
placed into perspective with the levels of carbon tetrachloride
expected in water and other environmental media.
In the section about other criteria, guidance and standards, para-
graphs 1, .2, 3 and 4, should be combined or discussed in the section
on evaluation of carcinogenic potential (section V).
Since apparently suitable data now are available (i.e., those of
Bruckner), what do the calculations in paragraph 5 of section V mean?
A better explanation needs to be provided.
Since SNARLS have been replaced by RRfd's, why include them? Over-
loading the drinking water health advisory with numbers is not helpful.
-------
-10-
B. CHLOROBENZENE HEALTH ADVISORY
The spectrum of chlorobenzene induced acute and chronic toxic
effects is well-documented in animal experiments for different
routes of exposure. Limited human data indicate similarities between
man and various animal models. There is also some evidence that
chlorobenzene causes necplastic nodules in male rats, leading to its
classification as a Group C carcinogen under EPA's proposed carcinogen
risk assessment guidelines. The Science Advisory Board reviewed the
Criteria Document for Monochlorobenzene in public session on July
23-24, and a detailed written report is in progress.
In the section about quantification of toxicological effects, the
advisory notes that numerous correlations exist between the toxicities,
such as liver necrosis and porphyria, versus subcellular events,
such as enzyme induction, covalent binding and glutathione depletion.
However, in the light of conflicting results, the mechanistic meaning
of these correlations ought to be viewed with caution.
An appropriate 10-day (and 1-day) health advisory for chlorobenzene
was developed based on an inhalation study. This is compatible with
a regulatory philosophy of public health prudence, since after
inhalation exposure less of the material goes directly to the liver
to undergo metabolism. Thus, there is less of a "first pass" effect,
and the inhalation data are likely to represent a more toxic route
of exposure than oral administration. The selection of the Battelle
studies for both the long term health advisory and the life time
health advisory appears sound, as does the quantification of car-
cinogenic effects.
The criteria document is inconsistent with the health advisory in
places, and the health advisory makes inconsistent statements regarding
the mouse studies.
The Subcommittee questions why data were not used from the 14-day
toxicity study sponsored by the National Toxicology Program. If
these values are used, and if animal factors (not human factors) are
applied to the animal data, then the shorter term health advisories
become consistent with the longer term. Further, if the National
Toxicology Program data are used, problems with the absorption
fraction are resolved. The Subcommittee notes that the National
Toxicology Program usually performs histopathology analyses as part
of its 14-day studies.
The Office of Drinking Water should clarify why 125 mg was chosen
as a no-observed-effect-level, when growth retardation occurred with
the male mouse at 60 mg.
Sane perspective will be useful in statements about biodegradation,
perhaps by comparing chlorobenzene to other substances, such as
hexachlorobenzene, which biodegrades about 1,000 times more slowly.
A direct statement of the half-life ot chlorobenzene would be useful.
-------
-11-
C. DICHLOROBENZENES (OKTHO-DICHLOROBENZENE, META-DICHLOROBENZENE
AND PARA-DICHLOROBENZENE) HEALTH ADVISORIES
',»..!.( ''''.,.
The health effects section notes that a reasonably well
developed data base 'exists for the toxicity of dichlorobenzenes from
animal experiments. Data from various groups of investigators
suggest that the spectrum of toxic effects is similar with the three
isomers in various species. Limited human data also suggest simi-
larities between man and animals in the manifestations from acute
or chronic exposure to dichlorobenzenes. State-of-the-art develop-
mental and reproductive toxicity studies did not reveal any adverse
effects. National Toxicology Program carciriogenicity studies in
two rodent species indicated a lack of tumorigenic effects of o-di-
chlorobenzene. Dichlorobenzenes are not mutagenic in animal studies
and in some other commonly used mutagenicity assays, but they
show some mutagenic effects in onion, fungal and yeast
systems.
The pharmacokinetics and disposition of the three isomers also are
quite similar with the exception that substantial amounts of mercap-
turic acids are formed frcm o-dichlorobenzene and m-dichlorobenzene
but not from the para-isomer. Both o- and p_-dichlorobenzene cause
similar toxicities at comparable dosage levels. O-dichlorobenzene
depletes glutathione levels, whereas j>-dichlorobenzene does not
affect glutathione levels. Thus, it is unlikely that glutathione
depletion represents a major mechanism of dichlorobenzene toxicity.
To the contrary, the data indicate that the mechanism of toxicity
of dichlorobenzenes has little, if anything, to do with glutathione
depletion or related oxidative stress. Similar problems exist with
attributing any role in dichlorobenzene-induced toxicity to reactive
intermediates. Considering the high doses required to induce sub-
chronic and chronic toxicity, it is more reasonable to assume that
nonspecific membrane effects or interference with hormonal homeo-
stasis is involved in the induction of toxicity, as has been shown
for some other chlorinated benzenes. Since specific evidence for
dichlorobenzenes is lacking for the latter contention, it must be
concluded that the mechanism of action of these compounds is unknown.
In the section about quantification of toxicological effects,
development of drinking water health advisories for dichlorobenzenes
has been conducted according to EPA's issue paper. Selection of the
Battelle studies for the recommended 1-day and 10-day health advisory
levels and for acceptable daily intake calculations is reasonable
because these bioassays are scientifically adequate. Studies of
Varshavskaya indicating orders of magnitude lower no-observed-effect-
-levels for dichlorobenzenes contrast with a larger number of inves-
tigations which yield consistent but different results. Because
the details of this study are very sketchy, this study should not
be used for health advisories. It is also prudent to use oral
gavage data rather than inhalation data to derive recommendations
for health advisories because chemicals that are readily metabolized
may have vastly different toxicities when administered by these
-------
-12-
two routes. Furthermore, in the Battelle studies, diehlorobenzenes
were administered in corn oil which leads to essentially complete?
absorption. However, chlorinated benzenes administered in aqueous
solutions are absorbed to a much lesser extent, this" introduces a
further conservative element into the estimation of the no-observed--
effect-level.
The solubility noted in the health advisory is' in error.
The health advisory should use ah absorption fraction' of 60% to be
consistent with the available information on absorption.
The term "relatively high absorption" could be better stated: in
quantitative terms.
-------
-13-
D. 1,2-DICHLOROETHANE HEALTH ADVISORY
The Science Advisory Board previously reviewed the health effects
data for 1,2-dichloroethane in a report of January 4, 1985, which
the Halogentated Organics Subcommittee prepared. Since the Health
Assessment Document that the Subcommittee reviewed is a multimedia
source document to meet Agency-wide needs, the health advisory was
based on .this information, updated in an appropriate way by a memo-
randum titled "quantification of toxicological effects." However,
the support document distributed to the Subcommittee was the April,
1984, external review draft and not the September, 1985, final
report and, as such, did not incorporate EPA's revisions in response
to the Subcommittee's review. Certain of the Subcommittee's comments
(below) repeat those in its previous report.
Overall, the health advisory generally is in agreement with the
Health Assessment Document, which is appropriate data on which to
base the advisory.
In the general information and properties section, the health
advisory should note which uses of dichloroethane no longer occur.
The rest of the uses should be divided into major and minor categories.
The reader for whom the health advisory is intended can not be
expected to supply this information, and information on obsolete
uses may lead water works personnel to implicate sources which no
longer exist.
Sane physical properties (solubility, boiling point and density)
cited in the health advisory are in conflict with those in the
Health Assessment Document.
The sources of release of ethylene dichloride need to be clarified
further. The data in the document indicate that the major release
in air is from dispersive uses, such as lead scavenging, paint
coating and adhesives. The health advisory indicates metal cleaning
is the major source of release. Comments by the Chemical Manufac-
turers Association sent to the Subcommittee indicate that ethylene
dichloride no longer is used for the above mentioned purposes.
In the section on pharmacokinetics, the qualitative statements
about absorption are a representative summary of the information
available, but the Subcommittee believes that a correlation between
oral dose, inhalation dose and blood levels can be easily built.
This will provide a better quantitative basis than the speculation
in the health advisory based on physical and chemical properties.
The absorption fraction of 30%, which is assumed in the calculations,
needs a rationale, if retained in the light of the above comment.
ODW should modify the statements about distribution to indicate
the amount of the dose which remains in the biological system at the
termination of the distribution study. For example, this section
might read as follows: "Within 48 hours after dosing, 96% of the
administered radioactivity of a single oral dose of 150 mg/kg was
-------
-14-
eliminated fron the body in various metabolised forms." Distribution
studies in these animals reveal that the liver and kidneys contained
the highest concentration of the radioactivity. Reitz and coworkers
showed that successively lower concentrations occurred in the
forestonach, stomach and spleen.
Most information about "acute poisoning and toxicity" of humans
in the health effects section originates from Russian studies. The
Subcommittee has doubts about the veracity of these data, and the
level of detail is skimpy. EPA should consider omitting these
descriptions.
As opposed to the acute effects results for humans from the Russian
literature, the Subcommittee suggests that the mutagenicity studies
by Rappaport are credible.
The short term exposure data for animals are LD5Q, not LD2Q results.
Negative mutagenic activity of 1,2-dichloroethylene in Salmonella
typhimurium was reported by McCann and coworkers in 1975.
The carcinogenicity bioassay data appear not to have been audited,
and their validity may be in doubt. Deficiencies in the 1978 Nation-
al Cancer Institute study were summarized in the comments presented
to the Subcommittee by the Chemical Manufacturers' Association.
The Subcommittee argued in the previous Science Advisory Board
report on ethylene dichloride that the structure-activity analogy
with ethylene dibromide could be misleading in interpreting the
metabolism of ethylene dichloride, especially in regard to possible
reactive intermediates. However, a structure-activity analogy may
be more appropriate in interpreting possible qualitative carcinogenic
and nutagenic effects ot ethylene dichloride than for metabolism.
In the section about quantification of toxicological effects, the
units in the long-term health advisory should be ug/L, not mg/L.
If the Agency bases conclusions about pharrnacokinetics on correla-
tions between blood levels versus oral or inhalation doses, then a
more reasonable basis will exist to use inhalational bioassay results.
-------
-15-
E. DICHLOROETHYLENES [CIS-DICHLORQETHYLENE, TRANS-DICHLOROETHYLENE AND
1,1-DICHljQROETHYLENE (VINYLIDENE CHLORIDE)] HEALTH ADVISORIES
The information in the drinking water health advisories reflects
the criteria documents for dichloroethylenes fairly accurately. All
three advisories could be written better from the standpoint of more
clearly delineating the differences between non-carcinogenic concen-
trations and that concentration which relates to carcinogenesis.
These three health advisories should use wording similar to that
found in the trichloroethylene advisory to distinguish acute from
chronic toxicity.
In the sections about quantification of toxicological effects, the
definitions of adverse effects for the three dichloroethylenes are
inconsistent, as illustrated below:
In the one day health advisory for cis-dichloroethylene, an
elevated alkaline phosphatase is considered an adverse but not a
life-threatening effect. In the trans-dichloroethylene one day
health advisory, increased incidence of degeneration of the liver
lobule and lipid accumulation by the Kupffer cells of the liver is
not considered an adverse effect. In the one day health advisory
for 1,1-dichloroethylene, a doubling of liver alkaline phosphatase
and an 80% reduction in liver glucose-6-phosphatase is considered
an adverse effect.
In the longer term health advisory for 1,1-dichloroethylene,
increased cytoplasmic vacuolization of hepatocytes in livers of
both sexes is not considered an adverse effect. In the longer
term health advisory for cis-dichloroethylene, an increased cyto-
plasmic vacuolization of hepatocytes is considered an adverse
effect. In the longer term health advisory for trans-dichloro-
ethylene, a trend towards increased fatty deposition in the liver
was considered an adverse effect.
Vinylidene chloride may not be an appropriate toxicologic analog
of the 1,2-dichloroethylenes. The Subcommittee has compared them,
as follows:
1,2-Dichloroethylenes Vinylidene chloride
Oral LD5Q = 1300 mg/kg Oral LD5Q = 200 mg/kg
No observed effects Pathology seen at 10 ppm
at >1,000 ppm for 6 hours
Liver and kidney not affected Liver and kidney affected
200 ppm TLV 5 ppm TLV
Not mutagenic in host- Mutagenic for Salmonella
mediated Salmonella assay with metabolic activation
A bioassay in Salmonella is not adequate mutagenicity testing. A
computerized data base on this subject, such as that of the Environ-
mental Mutagen Information Center, needs to be consulted.
-------
-16-
COMMENTS SPECIFIC TO CIS-1,2-DICHLOROETHYLENE
The cis-dichloroethylene health advisory identified a no-observed
-effect-level of 10 ing/kg, when the 5 rag/kg dose actually gave a
decreased kidney to body weight ratio. If this decision was based
on the absence of decreased kidney to body weight ratio at 10 rag/kg,
a more complete description of the judgment is necessary.
In the longer term health advisory, a lowest-observed^adverse-effect
-level is given for 100 ppm, rather than a no-observed-effect-level
at 50 ppm.
If contaminated water is the main source of cis-1,2-dichloroethylene,
why does the health advisory assume that drinking water supplies are
only 20% of the exposure in the longer term health advisory?
In the pharmacokinetics section, almost all of the information
is based on analogy. Therefore, some language changes seem desirable
for the advisory to avoid confusing the reader. For example, the
health advisory could state that "cis-dichloroethylene should be
absorbed rapidly," or that "cis-dichloroethylene would be expected
to be found in liver and kidney," or that "if similar to vinylidene
chloride in excretion, then cis-dichloroethylene will be excreted
relatively rapidly."
It is important to note in the health effects section that
cis-dichloroethylene is well-tolerated as an anesthetic in man and
animals, in addition to describing its anesthetic properties.
The subsection about health effects in animals reports that no data
are available, but the American Conference of Government and Industrial
Hygienists reports that no exposure related changes occurred from a
mixture of 60% trans-dichloroethylene and 40% cis-dichloroethylene
at 500 or 1000 ppm in rats, rabbits, guinea pigs, or dogs exposed
for seven hours daily, five days each week for six months. Parameters
studied included growth, mortality, organ and body weights, hematology,
clinical chemistry, and gross and microscopic pathology.
In the section about other criteria, guidance and standards, the
Threshold Limit Value (TLV) given is 200 ppm (790 ug/m3). The health
advisory states that, in view of the finding that the no-observed-
effect-level in animals after prolonged inhalation is at least 1000
ppm, and the supporting information by other routes of administration,
the TLV of 200 ppm and the short term exposure limit of 250 ppm may
be too conservative. The Office of Drinking Water should note that
200 ppm is equivalent to 790 mg/m3, 790 mg/m3 x 10 m3/day = 8,000
mg/day, and 8,000 mg/70 kg = 112 mg/kg/day. This suggests that the
lifetime health advisory value, based on analogy to 1,1-diethylene,
is too low.
The American Conference of Government Industrial Hygienists reports
that liver and kidney injury do not appear to be important endpoints
of cis-dichloroethylene exposure.
-------
-17-
COMMENTS SPECIFIC TO TRANS-1,2-DICHLORQETHYLENE
The human health effects discussion does not decribe the
experience of human exposures without adverse effects.
The subsection addressing effects in animals reports that the
oral LD50 is l/6th of intraperitoneal U%Q, which might suggest
that a metabolite arises after the first pass that is responsible
for the acute toxicity. If so, why does the advisory make a predic-
tion of liver and kidney toxicity when no changes in organ weight
were seen after 220 mg/kg by gavage for 14 days? Comparison of the
inhalation data with the gavage study involves different endpoints,
biochemical for the former and organ weight for the latter. If this
difference is the basis of the choice of an inhalation study in
preference to a gavage study, the health advisory needs to
describe the rationale for the choice.
In the section about quantification of toxicological effects, an
alternative derivation of the one-day drinking water health advisory
based on inhalational data might be compared to the value of 2.7
mg/L in the health advisory, as follows: 200 ppm x 3.97 mg/m-vppm
x 0.00438 m3/hr/rat x 1 rat/0.190 kg x 8 hrs x 30% absorption x
10 kg child/Liter/day x 0.01 (uncertainty factor) = 43.8 mg/L
Some relevant papers were not cited in the reference section,
such as that by Jenkins and coworkers (1976), and some were incomplete,
such as those of Olsen and Gehring (1976) or Lehmann and coworkers
(1936).
COMMENTS SPECIFIC TO VINYLIDENE CHLORIDE
In the reference section, a recent review of long-term studies
in Environmental Health Perspectives and the Agency's Health Assessment
Document on Vinylidene Chloride should be cited.
-------
-18-
F. DICHLOROMETHANE (METHYLENE CHLORIDE) HEALTH ADVISORY
The support document for the health advisory is a final draft Criteria
Document prepared by Life Systems, Inc., which is dated June, 1985.
The Criteria Document represents another version of the more comprehensive
Health Assessment Document, which was published by EPA in February
of 1985, and the Addendum to the Health Assessment Document, which
was published in August of 1985. Several articles and other information
have appeared subsequently (cited below) that are pertinent to the
health advisory, and this material should be incorporated into the
health advisory.
EPA has received detailed comments from the Halogenated Solvents
Industry Alliance on December 16, 1985 which focus on the carcino-
genicity, non-carcinogenic health effects, exposure and risk assess-
ment of dichloromethane (EPA/Docket No. OPTS-62045). At the same
time, the Food and Drug Administration proposed in the Federal
Register on December 17, 1985, to ban dichloromethane as an'ingredient
in all cosmetic products, citing studies showing that inhalation of
the chemical causes cancer in rats and mice and poses a possible
cancer risk to humans. The same notice did not propose a ban on
use of dichloromethane in coffee decaffeination. The responses to
both the EPA and FDA proposals need to be evaluated and used, as
appropriate, in preparing the final versions of the health advisory
and Criteria Document.
Some old business needs completing before the Criteria Document and
health advisory are finalized. The health advisory merits revision
on the basis that the data base is incomplete, as detailed below.
The Criteria Document also is deficient and needs further detailed
review or perhaps replacement by the Health Assessment Document and
its Addendum. Specific comments include:
In previous reports, the Science Advisory Board has requested that
EPA provide sensitivity analyses of the Agency's risk estimates.
EPA has decided to have an independent review of the Kodak epi-
demiology studies, which will be important to the Agency's
reviews of available human data.
EPA reviews of DMA-binding data submitted by the European Council
of Chemical Manufacturer's Federation should be completed, if the
Agency is to clarify the relative toxicity of the different di-
chloromethane reactive intermediates.
The health advisory and Criteria Document need to be reinterpreted
in the light of the Agency's proposed guidelines for risk assess-
ment, which the Science Advisory Board has reviewed, and which
are operational within the Agency. Reinterpretation will be
particularly important for dichloromethane with respect to benign
versus malignant tumors and to weight of the evidence for carcino-
genicity.
-------
-19-
The Agency's interpretation of the pharmacokinetics and comparative
metabolism of dichloromethane needs additional peer review, par-
ticularly in regard to the use of this information in a risk
assessment.
An EPA report of May 1, 1984, authored by Cothern, Coniglio and
Marcus, which assesses carcinogenic risk to populations from
dichloromethane via the ingestion, inhalation and dermal routes,
is not mentioned in the health advisory or Criteria Document.
In the section on general information and properties, add methylene
bichloride under synonyms.
In the subsection about occurrence, the Subcommittee notes that
the health advisory says that there are no natural sources, whereas
the Criteria Document says that possibly there are natural sources.
The question of potential natural sources may be important. The
production figure in the health advisory appears to be more up to
date than that in the Criteria Document. This conflict needs to be
resolved. The remaining paragraphs in this subsection are presented
as categorical statements of fact with no references cited; neither
is any information provided in the Criteria Document. This needs to
be corrected so that data are available to support the statements,
judgments, assumptions, and uncertainties in this section.
In the section about pharmacokinetics the most recent pharmacokinetics
and comparative metabolic data relative to the interpretation of the
findings on the animal studies need to be reviewed in detail by the
EPA. In response to the October 17, 1985 Advanced Notice of Proposed
Rulemaking, EPA has received comments and new experimental data.
In addition to the Halogenated Solvents Industry Alliance commments
mentioned previously, EPA has received detailed information (including
two publications and five preprint manuscripts) from the National
Coffee Association. These papers present pharmacokinetic modelling
of data fron orally administered dichloromethane to rats and mice.
(EPA Docket No. OPTS-62045).
In the health effects section, two drinking water studies are
mentioned under long-term exposure, but there is no reference to the
Dow chronic inhalation studies. This is also true of the Criteria
Document. The Office of Drinking Water draft issue paper by K.
Khanna ("Use of Inhalation Data for Estimating Acceptable Exposure
Levels in Drinkng Water," September 12, 1985) explains the validity
of extrapolating fron inhalation to oral exposure. The Dow studies
may, therefore, be useful.
The subsection on teratogenic/reproductive effects should be
revised to emphasize that the studies were not dose-response designs
and that high doses were tested. Furthermore, EPA has received a
copy of a report by Nitschke, Eisenbrandt, and Lomox (1985), which
describes negative results in a two-generation inhalation study in
Fischer 344 rats.
-------
-20-
In the National Coffee Association submission, a detailed review by
Broome and Sivak of mutagenicity data on dichloromethane is included.
This paper suggests that a genetic rational for a carcinogen risk
assessment of dichloromethane is inappropriate. EPA should examine
this paper and evaluate the assertions made.
Reference to the National Toxicology Program chronic oral study
should be deleted in the carcinogencity subsection since the Board
of Scientific Counselors has disavowed this study with respect to
providing background information on the forthcoming publication of
their inhalation study. The pertinent sections in the Criteria
Document (pages V-28-V-30 and V-40-V-41) should likewise be deleted.
The carcinogenicity subsection contains a detailed summary of
the Hazelton Laboratories chronic drinking water bioassay. However,
page six of the health advisory states that EPA (1985) performed an
independent assessment of the data frcm this study and concluded
that "the 250 ng/kg/day dose was borderline for carcinogenicity in
Fischer 344 rats." No details of that assessment are provided in
either the text of the health advisory or the Criteria Document,
and there is no 1985 citation given in the References section. The
reasons for this conclusion should be presented before the reader can
understand the overall interpretation.
In the carcinogenicity subsection, EPA accepts the National Toxi-
cology Program two-year inhalation data to provide evidence of
carcinogenicity. The same studies, however, are not mentioned in
the advisory for longer-term exposure. Perhaps, the Agency needs
to combine the two subsections for longer-term exposure and carcino-
genicity into one.
The human exposure section of the Criteria Document was unavailable
for review and comment.
The section on quantification of toxicological effects presents
health advisories for a 10 kg child exposed for one day or for ten
days. Health advisories are missing for 70 kg adults exposed for
one day or ten days. These calculations are included in the. Criteria
Document and should be included in the health advisory. Also missing
from both the health advisory and Criteria Document is a calculation
of a longer-term exposure health advisory. It is stated that no
data were available for the calculation. EPA needs to reexamine
the literature and make the calculations.
Concerning the evaluation and calculation of carcinogenic potential,
the National Toxicology Program chronic oral study should be deleted
from the data base, and this section should be reworked because the
study has not been accepted by the National Toxicology Program Board
of Scientific Counselors. The lifetime health advisory should be
placed into context with levels of dichloromethane in water and other
environmental media. Perhaps the Advanced Notice of Proposed Rulemaking
will provide this perspective.
-------
-21-
G. 1,2-DICHLOROPROPANE HEALTH ADVISORY
The health advisory contains information that is not provided in
the Criteria Document. The quality of the Criteria Document needs
to be upgraded to contain the missing information.
In the section about general information and properties, the infor-
mation about occurrence is not found in the Criteria Document.
The Criteria Document contains no information on the extent of
absorption. The statement that "90% of the orally administered
dose is absorbed" lacks justification.
The metabolism information provided in the advisory is misleading.
The study described by Jones and Gibson (1980) indicates that two
metabolites represent only 25-35% of the administered dose. Structures
and contributions of other potential metabolites were not determined.
The human health effects information provided in the health
advisory is not accurate and was presented with no details. For
example, one abstract was cited as describing the toxicity of a
cleaning substance which contained substances other than dichloropropane.
In the section about quantification of toxicological effects, the
ten day health advisory is based mainly on information from two
Russian abstracts. Because the experimental design, data and results
are questionable, EPA's conclusions based on this information may be
in some doubt.
In the reference section (literature citations), National Toxicology
Program (1983) information is available in the Criteria Document.
However, the information provided on this report may change pending
auditing of the experimental data and issuance of final report by
National Toxicology Program. Is this final report available?
-------
-22-
H. 2,3,7,8-TETRACHIX)RODIBENZO-p-DIQXIN HEALTH ADVISORY
There is a relatively good correspondence between the data and
conclusions presented in both the health advisory ,and Criteria
Document for 2,3,7,8-tetrachlorodibenzo-p_-dioxin. However, there is
one important consideration which has not been addressed in either
document: the problem of human exposure not only to 2,3,7,8-
-tetrachlorodibenzo-p_-dioxin (TCDD) but to other polychlorinated
dibenzofuran (PCDF) and dibenzo-p-dioxin (PGDD) isomers and congeners.
Recent studies by Rappe and coworkers, and others, have demonstrated
that a number of highly toxic PCDDs and PCDFs bioaccumulate in
human adipose tissue (Chemosphere 14; 933, 1985; Chemosphere 14;
697, 1985) and in most cases, TCDD is a minor component of these
toxic mixtures. There are several studies that demonstrate the
value of using "tetrachlorodibenzo-p_-dioxin equivalents" for describing
the potential adverse human and environmental health effects of
2,3,7,8-tetrachlorodibenzo-p_-dioxin and related compounds, and this
concept should be noted in the health advisory. It is likely that
in the future there will be an increase in the number of reports
which confirm the presence of other toxic PCDDs and PCDFs in 'humans,
and it would be prudent to recognize this possibility in both documents.
The Uses section should be retitied Uses and Occurrence, and this
section should note identification of TCDD in fly ash as a by-product
of combustion.
The formula of TCDD should be properly drawn.
The Pharmacokinetics section should include recent studies which have
identified 2,3,7,8-tetrachlorodibenzo-p_-dioxin and related compounds
in human tissues (Chemosphere 14; 697, 1985; Chemosphere 14; 933, 1985).
The metabolism section should note that the metabolite profiles are
consistent with an arene oxide intermediate. The covalent interaction
of TCDD with cellular macronolecules is minimal. A statement like this
would summarize the likely route of oxidative metabolism and also point
out that covalent modification of DMA, RNA and protein is not significant.
Although TCDD is a mouse teratogen it is not "teratogenic in all
strains of mice tested." A study by Poland and Glover (Mol. .Pharmacol.
r?: 86, 1980) reported that at a dose level of 30 ug/kg the CBA/J,
AKR/J, SWR/J and 129/J strains were resistant to the teratogenic effects
of TCDD.
TCDD is fetotoxic and a reproductive toxin in rats, but it is not
generally regarded as rat teratogen.
While the Criteria Document is well written and provides supporting
evidence for the health advisory, there are a number of sections which
merit modification. Detailed comments on some recommended changes have
been sent directly to the Office of Drinking Water by individual
Subcommittee members.
-------
-23-
I. EPICHLORDHYDRIN HEALTH ADVISORY
The ten day drinking water health advisory for a child is 0.14
mg/kg/day (or other equivalent), and the lifetime drinking water
health advisory (and/or DWEL) for an adult is 0.15 mg/day. These
values appear inconsistent, perhaps due to an error in accounting
for body weight, and merit additional conment in the advisory.
Is there a consistent carcinogen risk policy? Is a risk of approxi-
mately 2 x 10~5 an acceptable EPA upper limit of risk? While de facto
risk may be orders of magnitude lower than the stated value, what is the
rationale for this maximum risk value for epichlorohydrin?
Synonyms should be checked with the Criteria Document and the
Epichlorohydrin Health Assessement Document Final Report. For
example, chloronethyl oxirane is not listed there, but chloromethyl
ethylene oxide is.
A vapor pressure of 12 mm at 20°C is given, but a pressure of 1.0 mm
at 16.6°C and 22 mm at 30°C appears in EPA's final report.
In the section on mutagenicity, the Subcommittee suggests that tihe
fourth sentence read as follows: "Epichlorohydrin also induces gene
mutations and very likely chromosomal aberrations in mouse cell
culture studies (Moore-Brown and Clive, 1979) and chromosome breakage
in human lymphocytes in vitro (Keicerova and coworkers, 1976)."
Through in vivo studies, Sram (1976) demonstrated a clear dose-
response relationship in mouse bone marrow studies.
A study by Laskin was used to set the DWEL. Tumors occurred after
six weeks, and their incidence suggests a dose-response relationship.
A separate section on organoleptic properties would make the health
advisory more useful.
-------
-24-
J. HEXACHLOROBENZENE HEALTH ADVISORY
In the section about general information and properties, it is worth
noting that hexachlprobenzene has an extremely low water solubility
of 5 ug/1 :(not 0.05 ing/1).
.-'I . .
Hexachlorobenzene has no natural sources. Use of hexachlorobenzene
as a fungicide has been discontinued. Hexachlorobenzene is a contaminant
of some pesticides. The low water solubility implies rapid partition to
soil following releases to the environment with a half-life of 3-6
years. Hexachlorobenzene bioaccumulates in fish. It has been
detected at 0.005 ug/L in two drinking water supplies and in some
foods at ppb levels. Diet probably is the major route of exposure.
! In the pharmacokinetics section, gastrointestinal absorption of
hexachlorobenzene occurs primarily through lymphatic channels, which
route is dependent on solvent vehicle. In olive oil, 80% is absorbed;
in aqueous solution, less than 20%. This difference is not accounted
for in the calculations, so the health advisory will overestimate
the internal exposure via drinking water.
Hexachlorobenzene is lipophilic, accumulates in adipose tissues and
crosses the placenta.
Hexachlorobenzene undergoes slow metabolism, with the parent compound
excreted in feces (more than 90% of dose) and the metabolites in urine.
In the health effects section, it should be noted that exposure
of humans in Turkey occurred via consumption of contaminated wheat seed.
A more specific description of the human effects in the Turkish
episode would be desirable. F'or example, very high mortality (95%)
occurred in children under 1 year of age. The "few" patients quoted
in the health advisory actually was 15/161, almost 10%; the greater than
50% actually was 78% hyperpigmentation, 83% scarring. Thyroid enlargement
in 60% of the exposed females is not mentioned. In the Criteria Document,
thyroid tumors in 60% of females are described. Hexachlorobenzene also
causes hypothyroidism in animals (Rozman and coworkers, "Reduced Serum
Thyroid Hormone Levels in Hexachlorobenzene Induced Porphyria," Toxicology
Letters 30; 71-78 [1986]).
Both the health advisory and the criteria document report signifi-
cant increases in liver and kidney weights in several species of treated
animals. But Table V-l and the rest of the subchronic toxicity section
indicates an effect on kidney weights only in rats. Has the Criteria
Document been checked for internal consistency?
Increased mortality plus hepatic and renal lesions occur in rodents.
Histopathologic effects occur in monkey ovaries. The most prominent
effect is increased porphyrin levels in liver and urine, to which
females are more sensitive than males. Hexachlorobenzene causes
-------
-25-
accumulation of beta-H-steroids. (not para-H-steroids), which induce
porphyrin synthesis. PentaGhlorophenol, a hexachlorofe>enzene metabo-
lite (but not hexachlorobenzene itself) inhibits uroporphyrinogen
decarboyxlases, but only above 1.0"^ M. Hexachlorobenzene also
induces; cytochromes and hepatic microsomal enzymes.
Hexachlorobenzene occurs in the milk' of nursing dams. Reduced
fertility, litter size, hepatomegaly a^d cpnj>rpinise,d survival of
pups, occur on exposure. Developmental effects, such as, cleft palate,
occur: in mice but not rats.
Hexachlorobenzene is not mutagenic in Salmonella strains with or
without metabolic activation, does not induce dominant lethal
mutations in rats, but is mutagenic in ye.ast.
Hexaehlorobenzene is carcinogenic in hamsters, rats, and mice.
Most often liver tumors occur, with some adrenal, kidney, thyroid,
and parathyroid tumors. The study of Lambrecht and coworkers
(19:83) is only mentioned in this section, although it is the data
set used by EPA to estimate carcinogenic potency.
In the section about quantification of toxicological effects, diets
with hexachlorobenzene in corn oil probably overestimate internal
dose versus equivalent exposure in drinking water. A no-observed-
-adverse-effeet-level of 0.6 mgAg/day was found for female rats (a
transient increase in liver porphyrin levels four weeks after re-
moval of hexachlorobenzene). Higher doses yielded increased por-
phyrin levels in liver, kidney and spleen; increased liver to body
weight ratios, decreased survival, and so forth. Ten-day drinking
water, health advisories for child and adult are 50 and 175 ug/L,
respectively, which are 10 and 35 times higher than hexachlorobenzene
solubility in water.
Based on the study by Arnold and coworkers in 1983, in utero ex-
posure followed at 28 days by dietary exposure at parental levels
for 130 weeks, the health advisory derives a no-observed-effect-level
of 0.32 ppm. Periportal glycogen depletion occurred, only in Fl
generation males at 1.6 ppm, so 1.6 ppm also can be observed as a
no-observed-effect-level. At 8 ppm and higher exposures, hexa-
chlorobenzene resulted in increased hepatic centrilobular basophilic
chromogenesis, pup morbidity, peribiliary lympocytosis and fibrosis,
severe, chronic nephrosis in males, adrenal pheochromocytomas in
females and parathryoid tumors in males.
One and six-tenths ppm equals 0.08 mg/kg/day on average, which also
yields an adult DWEL of 28 ug/L, the same value as- the lifetime
acceptable daily intake given in the criteria document. This value
is more than five times greater than the solubility of hexachloro-
benzene in water.
-------
-26-
K. POLYCHLORINATED BIPHENYLS HEALTH ADVISORY
The pharmacokineti.es discussion should broadly summarize the data
on polychlorinated biphenyls. This section focuses primarily on
results from a single paper and is not representative of the facts.
The draft health advisory for polychlorinated biphenyls also is
inconsistent with the Criteria Document. The section on excretion
is an example. The health advisory states that no data were available.
It would seem that the major elimination pathway through urine could
be inferred from the 1975 data of Yoshimura and Yamamoto, which are
quoted in the Criteria Document and which show small percentages of
polychlorinated biphenyls excreted in the feces. This inference is
supported by two other studies cited in the Criteria Document which
report that excretion of specific polychlorinated biphenyls occurs
increasingly in the feces as the degree of chlorination of the
biphenyl portion of the molecule increased (and as metabolism pre-
sumably was increasingly inhibited). In addition, several studies
that are cited as dealing with polychlorinated biphenyl metabolites
found a negative correlation between rapid urinary excretion and
degree of chlorination of the mono- through hexa-chloro isomers.
Matthews and Anderson also found that excretion half-life appeared
to be negatively correlated with increasing chlorination. Other
investigators, such as Muehlebach and Bickel, have reported half-
-life data. Felt and coworkers (1977) reported polychlorinated
biphenyl elimination rates in rhesus monkeys, and Chen and coworkers
reported similar data for humans. These studies are summarized in
the Criteria Document.
The brief discussion of metabolism is incomplete. This section
should note the importance of (a) degree of ring chlorination, (b)
substituent orientation and (c) the availability of adjacent unsub-
stituted carbon atoms.
In the section on short-term exposure, depending on what was meant
by "asymetrical skull" and taking into consideration other factors,
such as the developmental stage at the time of abortion, such a
finding in aborted fetuses may have little toxicological significance.
The discussion of effects of short term exposure to polychlorinated
biphenyls on the immune system does not correspond with that found
in the Criteria Document. The specific references, findings, timing,
doses at which a response was seen, and so forth, differ between
the health advisory and the criteria document.
In the analysis of data from Allen and coworkers, although it is
true that the menstrual cycles were irregular and serum levels of
sex steroids were depressed, the monkeys had "extreme weight loss."
Therefore, the hormonal problems may have occurred secondarily to
other toxic effects.
The useage of "isomers" and "cogeners" should be corrected. Poly-
chlorinated biphenyls are not mixtures of isomers but mixtures of
isomers and congeners.
-------
-27-
The health effects section suggests that the short-term human exposure
of Yusho poisoning is representative of polychlorinated biphenyl
toxicosis. Recent studies indicate that the major etiologic agents
in Yusho were polychlorinated dibenzofurans rather than polychlorinated
biphenyls.
At least three papers have reported the immunotoxicity of several
polychlorinated biphenyl isomers and congeners (Clark et al, Immuno-
pharmacol. 6: 143, 1983, Silkworth et al, Toxicol. Appl. Pharmacol.
65: 109, 1982 and 75: 156, 1984).
The analysis section is out of date. It is possible to analyse
polychlorinated biphenyls by congener-specific capillary gas chromato-
graphy using all 209 polychlorinated biphenyls as standards. This
procedure will eliminate the guessing from future polychlorinated
biphenyl analytical methods and ultimately will permit risk assess-
ment to be based on individual compounds that are present.
EPA needs a source document for polychlorinated biphenyls. The Sub-
committee has provided detailed scientific comments on the Drinking
Water Criteria Document for Polychlorinated Biphenyls to the Office
of Drinking Water, which included thirty major comments and thirteen
minor caranents. The final draft of the Criteria Document gives a
date of March, 1985; whereas the document is out-of-date. The data
and papers which are included and some of the interpretations are
highly inadequate. Some of the issues have not been thoroughly
discussed. In view of the comments below, the Subcommittee strongly
recommends that the Drinking Water Criteria Document for Polychlor-
inated Biphenyls be extensively revised and updated. Specific comments
include: , ,
Recent papers indicate that Yusho poisoning is primarily re-
lated to the toxic polychlorinated dibenzofurans and not the
polychlorinated dioxins in contaminated rice oil. Thus, a
discussion of the human health effects of polychlorinated
biphenyls should not use "Yusho" as an example. Industrial
exposure data more accurately reflect human health effects.
The discussion of chemical analysis of polychlorinated 'biphenyls
and the complexity of polychlorinated biphenyl mixtures is
out of date, and any revised document should recognize important
new advances in this field.
A multitude of important papers on structure-activity relation-
ships for polychlorinated biphenyls have been published but
are not cited in the document. For polychlorinated biphenyls,
this is a critical issue which must be thoroughly discussed.
The mechanism of action of polychlorinated biphenyls has been
extensively reviewed but is not covered adequately in the
Criteria Document. [See, for example, CRC Crit. Rev. Tox. 13;
319 (1985), Environ. Health. Perspect. 60: 47 (1985) or
Environ. Health. Perspect. ej^: 21 (1985)]. These sections
of the Criteria Document are out of date and need revision.
-------
-28-
L. TETRACHLOROETHYLENE HEALTH ADVISORY
The health advisory states that the major sources of exposure to
perchloroethylene result from contaminated water and to a lesser
extent, air. The Agency's Health Assessment Document states the
opposite. The idea that a main source exists in comparison to a
secondary source may be misleading.
Sane health advisory statements are potentially misleading, such
as: "the accumulated human inhalation data indicate that there is a
minimal effect on motor coordination at 100 ppm". The time frame
is omitted. Similarly, the exposure range at which inebriation
first appears is 300-475 ppm, and effects appear to vary with the
time of prior exposure. This perspective is more informative than
simply noting that inebriation is seen. A related problem occasionally
occurs when abbreviated statements of fact are made. For example,
in describing the distribution of perchloroethylene, the health
advisory states "in rats," whereas a better description might be
"in rats previously exposed to perchloroethylene by inhalation at
1340 mg/nr for 6 hrs/day and 4 days, the perchloroethylene concentra-
tion on the fifth day is highest in perirenal fat. Exposure to the
same perchloroethylene concentration on the sixth day showed that..."
When such terms as SCOT are used as a measure of toxicity, information
on the relationship to liver damage should be included. Most readers
will not know the significance of increased serum SCOT.
Some other synonyms could be added, such as ethylene tetrachloride,
Nema, Tetracap, Tetropil, Perclene, Ankilostin, Didakene.
The properties section should note that perchloroethylene is a
colorless liquid. For specific gravity, add a superscript of 15
and a subscript of 4. Also, the document should note that the partition
coefficient (water/air) is 1.22 (20°C), that perchloroethylene is
nonflammable, and that the odor threshold in water is 50-300 ug/1.
The health advisory should note that perchloroethylene degrades in
the presence of sunlight and moisture.
If degradation to trichloroethylene and vinyl chloride is not a
usual route, then the conditions, such as laboratory rather than
ambient, should be discussed or the reference should be omitted.
The health advisory should include the annual production of per-
chloroethylene .
The section on absorption should note that ninety-eight percent of
a single oral dose of 189 mg/kg perchloroethylene administered.to
rats was excreted in expired air (Daniel, 1963). In mice given a
single oral dose of 500 mg/kg 14C-labeled perchoroethylene, approxi-
mately 85% was recovered in expired air with total recovery of 96.8% in
72 hours (Schumann and coworkers, 1980).
-------
-29-
The 25% perchloroethylene absorption figure given for humans in the
health advisory does not appear in the Criteria Document. The
health advisory states that 25% of inhaled perchloroethylene was
absorbed during a four-hour exposure at 72 or 144 ppm. Also, the
description of exposure as "72 to 144" ppm implies a variable
exposure within a range, whereas the actual conditions were either
72 or 144 ppm exposure.
The Subcommittee has general concerns about the assumption of values
for absorption fractions without clearly stating when they are based
on reference studies and when they constitute arbitrary assumptions.
For perchoroethylene, the 50% value contrasts with the values assumed
for other substances, like trichloroethylene, for which a 35% value
is used. Perhaps a better systematic approach is to base the values
on physical solubility measurements.
The statement about three distinct half-times for perchloroethylene
exhalation need clarification and amplification.
The health advisory needs a more extensive description of saturation
kinetics of perchloroethylene and the implications of saturation
kinetics. It also may be useful to cite recent studies about protein
binding of metabolites.
The health advisory should note that trichloroethanol is a human
metabolite of perchloroethylene because trichloroethanol is thought
to be the active metabolite in some of the hypothetical mechanisms
proposed for perchloroethylene effects.
The discussion of the "proposed metabolic pathway" is incorrect.
This sentence should state that oxidative metabolism is proposed to
proceed through an epoxide intermediate, which can lead to the
major metabolite, trichloroacetic acid.
The problem with some of the effects data is that the length of
exposure was quite variable. In the study of Rowe and coworkers
(1952), effects are associated with a single exposure ranging in
time from two minutes to two hours. The study of Stewart and coworkers
(1961) noted an impaired ability to maintain a normal Romberg test
after a 30-minute exposure of volunteers to 190 ppm. Either the
second paragraph is misleading or else these studies should be included
as short-term effects. The study of Stewart and coworkers (1970)
involved exposures of 7 hours per day for 5 days. In 1974 Stewart's
group also exposed 19 volunteers to perchloroethylene at 20 to 150
ppm for a 5 week period and noted deleterious effects at 100 ppm but
not at 20 ppm. These data provide a basis for a 10-day advisory.
Results of the study of Schwetz and coworkers (1975) were
characterized by fetotoxicity, not developmental effects, and these
results would be better placed in the health effects section.
-------
-30-
The Subcommittee does not have a general consensus about the
use of develprnental toxicity data in which maternal toxicity is
observed. However, current EPA practice is to use effects information
at an exposure for which less than 10% maternal mortality is observed.
Obtaining maternal mortality at the highest dose in such studies
is not considered inappropriate. OEW should consider performing
a comprehensive re-evaluation of the literature on the developmental
toxicity of perchloroethylene.
The carcinogenicity section should be updated to include the
papers by Van Duuren and coworkers (See J. Natl. Cancer Inst. 63;
1433, 1979). Moreover, a recent paper by this group (Cancer Res.
43; 159, 1983) reports the carcinogenicity of chloroalkene oxides
and their parent olefins after topical or subcutaneous administration.
Perchloroethylene oxide, presumably the metabolically activated
perchloroethylene metabolite, did not significantly increase tumor
incidence after subcutaneous injection but did produce benign skin
tumors in mice at a low frequency.
The route of administration, dose (or doses), purity, and target
organs or tissues should be stated in describing the chronic studies
for perchloroethylene.
National Cancer Institute chronic bioassay data suggest that per-
chloroethylene may be acting as a carcinogenic promoter. The Dow
Chemical Study by Rampy and coworkers (1978) merits some mention in
the drinking water health advisory. Perhaps it was excluded because
it was an inhalation study. However, the results in Sprague-Dawley
Spartan substrain rats were negative and can be useful in placing
limits on the risk estimates.
In calculating the total absorbed dose, the conversion of a 5-day
exposure to a 10-day exposure was omitted.
A recommendation to the public of boiling water to remove perchloro-
ethylene seems dubious, unless it is made clear that the water is to
be boiled outdoors.
The Subcommittee suggests that the key to interconverting bioassay
data for perchloroethylene administered by different routes of
administration is to correlate blood levels with exposure (or dose)
for different species. Sufficient data is available for perchloro-
ethylene, including humans, to adopt this approach.
-------
-31-
I. 1,1,1-TRICHIDROETHANE (METHYL CHLOROFORM) HEALTH ADVISORY
With the exceptions described below, the drinking water health
advisory is generally consistent with the information presented in
the Criteria Document.
The drinking water health advisory states that the major source of
methyl chloroform results from its use as a metal degreaser. Entrance to
the environment is from evaporation and dumping of the grease con-
taminated chemical into landfills, open ground or sewers. Due to the
costs of methyl chloroform and changes in environmental standards,
most methyl chloroform is recovered and recycled. Although the
evaporation problem continues, current disposal practices are pro-
bably not contributing to ground water levels at this time. Much of
the existing ground water problem is apparently due to past practices.
The drinking water health advisory also states that the major source
of human exposure is through the water supply and, to a lesser extent,
air. There is no clear indication of source predominance for methyl
chloroform on a site-by-site basis. According to the Criteria
Document, exposure in water predominates over air only at drinking
water levels above 84 ug/L, which are levels to which less than
0.1% of the population are exposed.
The 1,1,1-TCE abbreviation might be changed to avoid confusion with
trichloroethylene, or else use the synonym "methyl chloroform" as
in the present conments.
The discussion of pharmacokinetics lacks data on the elimination
rate. Although the Criteria Document does not present a half-life
after acute exposure, 44% of an inhaled dose is excreted within one
hour, suggesting a short half-life, but these data receive little
attention. There is the possibility of accumulation in tissue
during chronic exposure, with one study showing trace amounts of
methyl chloroform still present one month after chronic exposure.
There is an apparent error in referring to the study of Monster and
coworkers (1979), where the health advisory states that very small
amounts of methyl chloroform are excreted unchanged by the lungs.
Although lung excretion will depend on dose, the lungs are the major
route, with the parent compound accounting for almost all of the
excretion. Perhaps the health advisory is referring to the metabolic
product, trichloroethanol, which accounts for less than 1% of the
total dose of methyl chloroform administered.
The study by Hake and coworkers (1960) suggests that about 3% of
methyl chloroform is metabolized by rats. Actually this study
showed that 98% of the radioactivity was associated with the un-
changed compound and 0.5% as CC^. About 50% of the remainder
was associated with metabolites, while the other 50% was lost to
evaporation. Thus, less than 1% was metabolized.
-------
-32-
The description of the human data needs expansion. A concentration
(68 mg/L) producing death by central nervous system depression is
known. The sensitization of the heart to catecholamines and the
sudden deaths due to the cardiovascular effects of methyl chloroform
are not mentioned. Central nervous system functional impairment
has been demonstrated with concentrations of methyl chloroform as
low as 250 ppm in air. Upper respiratory irritation and the un-
pleasant odor also observed at low concentrations are not mentioned.
The study by Vainio and coworkers (1976) should be placed in perspec-
tive. The 1.4 g/kg dose that depressed microsornal metabolism is about
25% of the H>50 and well above the dose that induces anesthesia.
A 1983 National Toxicology Program is presented, but the results
of the study are not discussed.
The health advisory uses the studies of McNutt and coworkers (1975)
to calculate a lifetime advisory of 200 ug/L. The health advisory
uses a lowest-observed-adverse-effect-level of 250 ppm for mice and
values for humans into the appropriate formula. If, instead, mouse
body weight and ventilation rate are taken into consideration, a
10-fold higher advisory will result.
Skin absorption is not considered in detail. There is some skin
absorption with methyl chloroform, but it does not appear to be a
major contributor to exposure, based on data in the Criteria Document.
There is considerable data available on human toxicity of methyl
chloroform, but little of this data is mentioned in the health
advisory.
The analysis of mutagenicity results needs further clarification
with respect to the actual material tested, presence of contaminants,
and so forth. In particular, the analysis should consider the
possibility of action on spindle fibers and resulting clastogenic
action.
If methyl chloroform is classified under EPA's new guidelines as a
category D carcinogen, the health advisory should not refer to
a q-^ for carcinogenic potency.
The health advisory should reference and consider two potentially
confusing aspects: (1) the 1-day advisory is approximately the same
as the advisory for "longer-term" adult exposure, and (2) the sol-
ubility of methyl chloroform in water is less than the advisory
levels. Further explanation of these apparent inconsistencies is
desirable.
-------
-33-
N. 1,1,2-TRICHLDK)ETHYLENE HEALTH ADVISORY
In general, the information in the drinking-water health advisory
for trichloroethylene accurately "reflects the criteria document.
The health advisory for tricholoroethylene more clearly delineates
the differences between non-carcinogenic concentrations and the
concentration which relates to carcinogenesis than do other advisories.
However, the trichloroethylene health advisory does not use the Criteria
Document for trichloroethylene for all the source material. In many
cases, the drinking water health advisory material cited is more
recent than that cited in the Criteria Document.
In the section about general information and properties, some other
synonyms for trichloroethylene could be added, such as ethinyl
trichloride; Tri-Clene; Trielene; Trilene; Trichloran; Trichloren;
Algylen? Trimar; Triline; Tri; Trethylen; Trethylene; Westrosol;
Chlorylen; Gemalgene; Germalgene.
The description of physical properties is not complete, and the
Subcommittee suggests adding the following additional information,'
which may be of value and which was obtained from Patty's Industrial
Hygiene and Toxicology (Vol. IIB, 1981).
Vapor Pressure 75 mm Hg (25°C)
Water Solubility O.lg/100 ml(H20, 20°C)
Boiling Point 8.7°C (760 mm Hg)
Density 1.456 (25°C)
Physical State Colorless Liquid
Nonflammable
Autoignition Temperature 410°C
CAS # 79-01-6.
% in Saturated Air 10.2 (25°C)
Conversion Factors 1 ppm in air = 5.38
at 25°C, 760 mm Hg
1 mg/L = 185.8 ppm
According to the comments received by the Subcommittee, trichloro-
ethylene is generally recovered from degreasing residues and recycled,
while the dumping of trichloroethylene on the ground has been prohibited.
Thus, contamination of ground water is likely to be a result of past
disposal practices. The health advisory should state whether the
Agency agrees with these comments.
Trichloroethylene is degraded in the presence of light and moisture.
The section about pharmacokinetics should note that after excretion
in human urine, Soucek and Vlachova (1959) reported the ratio of
trichloroethylene metabolites to be 1:5:12 (monochloroacetic acid:
trichloroacetic acid: trichloroethanol). More recent studies with
humans are reported in the Criteria Document, although results are
similar. Based on total trichlorocompounds in the urine of factory
-------
-34-
workers, the biological half-life of trichloroethylene was calculated
to be approximately 41 hours (Ikeda and Imamura, 1973). Trichloro-
ethylene does not bioaccumulate.
Acute exposure to trichloroethylene is associated with liver damage
and cardiac irregularities. After longer exposures, the most cannon
complaints of exposed workers involve central nervous system
disturbances.
Inhaled trichloroethylene (500 ppm) "depressed myocardial activity in
dogs (Aviado and coworkers, 1976).
The health advisory should note that Tucker and coworkers (1982)
found that pale, spotty and granular livers developed in all groups
of male and female mice exposed for six months to trichloroethylene
in drinking water at 100, 1,000, 2,500 and 5,000 mg/L.
The health advisory does not describe developmental effects bioassays
in which no positive results were found, or summarize any of the
information about reproductive effects. For example, Zenick and
coworkers (1984) found no trichloroethylene-related effects on the
sperm of male rats after oral administration, and Manson and coworkers
(1984) found no fertility and pregnancy effects in female rats.
Reproductive effects were not found in four epidemiology studies.
The health advisory omits reference to a 1980 National Cancer
Institute bioassay. Doses of trichloroethylene should be listed
for all carcinogenicity studies.
The study by Kimmerle and Eben (1973) does provide a reasonable
basis for the calculation of a EWEL, but it should be noted that
increased liver weight was found after 14 weeks exposure (5 days/wk)
to 55 ppm by inhalation, which indicates a toxic response in the
liver. The advisory might report the number of animals per group,
effects on body weight, and any other endpoints that were reported
by Kimmerle and Eben.
The RRfD value reflects a calculational error.
The Subcommittee recommends that Agency staff carefully review the
available chronic bioassay data for possible pathological changes,
such as organ weight changes, that could be used to calculate effects
levels.
-------
-35-
0. VINYL CHLORIDE HEALTH ADVISORY
The health advisory and the Criteria Document contradict each other
about population exposures. The health advisory states that little
or no exposure is expected from food, whereas; the Criteria Doeumant-
states that the principal source of vinyl chloride exposure for
most Americans is probably from polyvinyl chloride food' containers,
which contribute approximately 1 ppb to the diet.
The difference in -^C-vinyl chloride distribution between the study
by Bolt and coworkers (1976) compared to those of Watanabe and
coworkers (1976a,b) is not a time difference in distribution^but a
difference in the time of -^C assay, after administration of the.
labeled compound (72 hours post-administration compared to immed-
iately). The Bolt article is also misquoted.
The information about the model of Withey and Collins (1976) relates
to absorption instead of excretion.
In the section about human health effects, the actual exposure con-
ditions of 40-900 ppm in air should be cited, rather than describe
them as "high." These values might be compared to the U.S. Occupa-
tion Safety and Health Administration standard of 1 ppm.
The description of carcinogenic effects should be placed in the sec-
tion on human health effects, should refer to Tabershaw and Gaffey
(Journal of Occupational Medicine, 1979) and should begin with note
on the work of Creech and Johnson (Journal of Occupational Medicine,
1974). It may be worthwhile to point out the. high risk and specificity
of association with a rare tumor.
Although the studies by Infante on birth defects have been in dispute,
they should be mentioned. Dominant lethal studies have been negative,
as reported by Purchase and coworkers (Lancet, 28; 410, 1975).
The health advisory describes the data of Torkelson and coworkers
(1960) as a 7 hour daily exposure, but the Criteria Document describes
the same study as a 2 hour daily exposure. If the latter value is
correct, a difference of 3.5 is introduced into the calculation of
the 10-day advisory. A 10-day advisory also could be calculated
from the inhalation study of Torkelson and coworkers (1961), using
the calculation of Withers and Collins (1976), as follows:
. lOOppm x _1_ x ^ x 20mg/L x 40ml/day/rat = 33 mgAg/day
24 7 2 ppm 250 gram/rat
The data of Feron (1981) and Til (1983) are misdescribed. Feron
found no angiosarcomas at 1.7 mg/kg/day and at 5 mg/kg/day found
a significant excess of angiosarcomas in male rats and a significant
excess of hepatocellular cancers in female rats. Til found no
significant excess of hepatocellular cancer at 1.7 mgAg/day in
female rats, but did in males. Til also found a nonsignificant
increase in the incidence of angiosarcona at 1.7 mq/kq/day for
either sex of rat.
-------
-36-
0
5
0
0
0
0
16
0
0
0
0.017
12
0
0
0
0.17
15
n
0
0
1.7
23
3
3
1
Data of Feron (1981)
The data of both studies can be summarized, as follows:
Male Effects Data of Til (1983)
Dose
Basophilic Foci
Neoplastic Nodule
Hepatocellular Cancer
Aneiosarcoma
Male Effects
Dose
Basophilic Foci
Neoplastic Nodule
Hepatocellular Cancer
Angiosarcoma
Female Effects
Dose
Basophilic Foci
Neoplastic Nodule
Hepatocellular Cancer
Angiosarcoma
Female Effects
Dose
Basophilic Foci
Neoplastic Nodule
Hepatocellular Cancer
Angiosarcoma
n
8
0
0
0
Data of Til (1983)
0
19
0
1
0
0
7
0
0
0
0.017
17
1
0
0
0,
31
1
1
0
17
Data of Feron (1981)
0
2
0
0
0
1.7
18
1
1
0
1.
32
10
3
2
1.
33
26
4
0
5
21
7
2
6
5
17
39
19
2
14.1
22
23
8
27
14.1
28
44
29
9
-------
U.S. Environmental Protection Agency
Science Advisory Board
Environmental Health Committee
Halogenated Organics Subccranittee
January 14-17, 1986
Dr. John Doull, [Chair], Professor of Pharmacology and Toxicology, University
of Kansas Medical Center, Kansas City, Kansas 66103
Dr. Seymour Abrahamson, [Vice-chair], Professor of Zoology and Genetics,
Department of Zoology, University of Wisconsin, Madison, Wisconsin 53706
Dr. Ahmed Ahmed, Department of Pathology and Pharmacology, University of
Texas Medical Branch at Galveston, Galveston, Texas 77550
Dr. K. Roger Hornbrook, Department of Pharmacology, P.O. Box 26901,
University of Oklahoma, Oklahoma City, OK 73190
Dr. Ronald D. Hood, Professor and Coordinator, Cell and Developmental Biology
Section, Department of Biology, The University of Alabama, and Principal
Associate, R.D. Hood and Associates, Consulting Toxicologists, P.O. Box 1927,
University, Alabama 35486
Dr. John G. Keller, National Medical Advisory Service, 7315 Wisconsin Avenue,
Suite 802 West, Bethesda, MD 20814
Dr. Steven Lamm, President, Consultants in Epidemiology and Occupational Health
Inc., 2423 Tunlaw Road, N.W., Washington, D.C. 20007
Dr. Don E. McMillan, Chairman, Department of Pharmacology, Mail #638, University
of Arkansas, Medical Sciences, 4301 West Markham Street, Little Rock, Arkansas 72205
Dr. Martha Radike, University of Cincinnati Medical Center, Department of
Environmental Health, 3223 Eden Avenue - M.L. #56, Cincinnati, Ohio 45268
Dr. Karl K. Rozman, Department of Pharmacology, Toxicology and Therapeutics,
University of Kansas, 39th and Rainbow Blvd., Kansas City, KS 66103
Dr. Stephen Safe, Department of Veterinary Physiology and Pharmacology, Texas
A&M University, College of Veterinary Medicine, College Station, TX 77843-4466
Dr. Tom Starr, CUT, P.O. Box 12137, Research Triangle Park, NC 27709
Executive Secretary
Dr. Daniel Byrd, III, Executive Secretary, Science Advisory Board, (A-101F),
U.S. Environmental Protection Agency, Washington, D.C. 20460 (202) 382-2552
-------
COMMENTS SUBMITTED TO THE HALOGENATED ORGANICS SUBCOMMITTEE
BY MEMBERS OF THE PUBLIC REGARDING THE REVIEW OF
DRAFT DRINKING WATER HEALTH ADVISORIES
National Audubon Society Contact: Chuck Pace
National Capital Office
645 Pennsylvania Avenue, S.E.
Washington, D.C. 20003
Date: December 24, 1985
Chemical Manufacturers Assoc. Contact: Geraldine V. Cox
2501 M Street, N.W.
Washington, D.C. 20037
Date: December 26, 1986
Natural Resources Defense Contact: Robin Whyatt
Council Inc. Wendy Gordan
122 East 42nd Street
New York, N.Y. 10168
Date: November 29, 1986
Water Quality Association Contact: Danna M. Cirolia
1518 K Street, N.W.
Suite 401
Washington, D.C. 20005
Date: November 22, 1985
Halogenated Solvents Industry Contact: Paul A. Cammer
Alliance
1330 Connecticut Ave. N.W.
Suite 300
Washington, D.C, 20036 ,
Date: December 9, 1986
Diamond Shamrock Corporation . Contact: Ross E. Jones
World Headquarters
717 North Harwood Street'
Dallas, Texas 75201
Date: December 2, 1985
-------
-2-
The Society of the Plastics Industry, Inc. Contact: Hugh Toner
1025 Connecticut Ave. : "
Washington, D.C. 20036
Date: December 16, 1985
The New Jersey Dept. of Health Contact Bonnie L. Bishop
and The New Jersey Dept. of
Environmental Protection
Date: August, 1984
State of Connecticut Contact: David R. Brown
Department of Health Services
Date: December 12, 1985
Michigan Pure Water Council Contact: Martha Johnson
December 12, 1985
POST MEETING COMMENTS RECEIVED
National Audubon Society Contact: Chuck Pace
National Capital Office
645 Pennsylvania Avenue, S.E.
Washington, D.C. 20003 ,
Date: January 27, 1986
Chemical Manufacturers Association Contact: Ann M. Mason
2501 M Street, NW
Washington, DC 20037
Date: April 30, 1986
-------
U.S. Environmental Protection Agency
Science Advisory Board
Environmental Health Committee
Halogenated Organics Subcommittee
Open Meeting
Under Public Law 92-463, notice rs here'by >g>i'vehthat a
four-day meeting of -the Halogenated Organics Suto'cSiTimdtfeee of
the Environmental Health Committee of the Sciene'e Advisory
Board will be. held on-January 14-17, 19'86, in Cohferehc'is
Room 390:6-3i908 at Waterside Mall; U.S. Ehvironlnental Protection
Agency; 401 M.Street, S.W.; Washington, DC; 204#0i the meeting
will start at 9:00 a.m. on January 14 and adjourn no later
than 4:00 p.m. on January 17.
The purpose of the meeting will be to discuss draft
drinking water Health Advisory documents for the following
substances:
Carbon tetrachloride Dibxin
. Chlorobenzene Epichlorohydfin
Dichlorobenzenes . Hexachiorbberizene
1,2-Dichloroethane Pblychloririated bipheriyls
1,2-Dichloroethylenes Tetrachlorbethylene
1,1-Dichloroethylene 1,1,1-Trichlorbethahe
Dichloromethane frichlbroethylene
Dichloropropane Vinyl chloride
The Halogenated Organics 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
. i
Division [WH-550]; U.S. Environmental Protection Agency; 401
M Street, S.W.; Washington, DC; 20460.
-------
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 above 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. Srenda 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.
Yosie
lirector
October 15. 1985 '^/Scielnc^ Advisory Board
Date
-------
U.S. ENVIRONMENTAL PROTECTION AGENCY
SCIENCE ADVISORY BOARD
ENVIRONMENTAL HEALTH COMMITTEE
HALOGENATED ORGANICS SUBCOMMITTEE
Conference Room 3906-3908
Waterside Mall
401 M Street, SW
Washington, DC 20460
January 14-17, 1986
ORDER OF BUSINESS
REVIEWS OF DRAFT DRINKING WATER HEALTH ADVISORIES
Opening Remarks
Administrative Matters
Introduction
Dr. Doull
Dr. Byrd
Dr. Crisp
Dr. Doull
*Tentative Sequence of Reviews, beginning Tuesday, January 14, 1986
Subs tance (Manager)
Carbon tetrachloride (Anderson)
Tr ichloroethylene (Khanna)
Dichloromethane (Khanna)
Dichloroethylenes (Crisp)
Methylchloroform (Patel)
Dichloropropane (Patel)
PolychlorobiphenyIs (Khanna)
Tetrachloroethylene (Khanna)
1,2-Dichloroethane (Khanna)
Dioxin [TCCD] (Anderson)
Vinyl chloride (Anderson)
Chlorobenzene (Anderson)
Epichlorohydrin (Anderson)
Dichlorobenzenes (Anderson)
Hexachlorobenzene (Anderson)
Reviewers
Drs. Keller and Ahmed
Drs. Radike and Hombrook
Drs. Keller and Hood
Drs. Hombrook and Lamm
Drs. McMillan and Keller
Drs. Ahmed and McMillan
Drs. Hood and Safe
Drs. Radike and Safe
Drs. Ahmed and Abrahamson
Drs. Safe and Hood
Drs. Lamm and Radike
Drs. Rozman and Abrahamson
Drs. Abrahamson and Starr
Drs. Rozman and Starr
Drs. Starr and Rozman
At the conclusion of the reviews
*Completion of reviews (previously deferred)
General comments
Nomination of Criteria Documents for further review
Other Subcommittee Business
Concluding remarks
Dr. Doull
Dr. Doull
Dr. Doull
Dr. Doull
Dr. Byrd
ADJOURNMENT
* The sequency in which the Subcommittee reviews Health Advisories Eoc different
substances and the time allocated to each review are at the discretion of the
Chair.
-------
-------
United States Office of the Administrator AB-EHC-87-006
Environmental Protection Science Advisory Board (A-101) October 1986
Agency 401 M Street, SW
Washington, DC 20460
EPA Review of Drinking Water Health
Advisories by The Drinking Water
Subcommittee of The Environmental
Health Committee of
The Science Advisory Board
Acrylamide
Benzene
Dioxane
Ethylbenzene
Ethylene glycol
n-Hexane
Legionella
Methyl ethyl ketone
Styrene
Toluene
Xylenes (ortho, meta- and para-xylene)
-------
ICE O I-1
'i UNITED STATES ENVIRONMENTAL PROTECTION AGENCV
o .
/ . WASHINGTON D.C. 20460
' September 20, 1986
SAB-EHC-87-006
Dr. Richard A. Griesemer
Chair, Environmental Health Committee T.<£ ADV1,,,,STt,a ,o;,
Science Advisory Board [A-101]
U.S. Environmental Protection Agency
401 M Street, SW
Wasington, DC 20460
Dear Dr. Griesemer:
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 p_-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 become involved with this program and stand.ready to provide further
advice, as requested.
Sincerely,
Robert Tardiff, Ph.D.
Chair, Drinking Water Subcommittee
Herschel Griffin, M.D.
Vice-chair, Drinking Water Subcommittee
-------
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 recommendation for use.
-------
TABLE OF CONTENTS
Subject Page
I. GENERAL COMMENTS ON ERINKING WATER HEALTH ADVISORIES 1
II. SPECIFIC COMMENTS ON ELEVEN HEALTH ADVISORIES .8
A. Acrylamide " 8
B. 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 of the Subcommittee
List of comments received from the public.
Federal Register notice of the January 6-8, 1986 meeting
Agenda for the meeting
-------
I. GENERAL COMMENTS OF THE DRINKING WATER SUBCOMMITTEE OF THE ENVIRONMENTAL
HEALTH COMMITTEE OF EPA'S SCIENCE ADVISORY BOARD REGARDING DRINKING WATER
HEALTH ADVISORIES
A. THE OFFICE OF DRINKING WATER (ODW) 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), 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, most 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 AND 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 some 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.
-------
-2-
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,
or1 if accumulation is known to occur, the use of a factor of ten could be
warranted. 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 ROUTINE ASSUMPTION THAT TWENTY PERCENT OF TOTAL HUMAN EXPOSURE DERIVES
FROM 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
fron 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
from 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 OF 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
-------
-3-
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. BIODEGRADATION INFORMATION NEEDS A GREATER EMPHASIS.
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 acquisition.
F. OCCURRENCE AND 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, ODW 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 of 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 cytochrome
P-450 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.A. Newill, "Regulatory Decision-Making: The Scientist's Role," J. Wash.
Acad. Sci., 64: 31-48, (1974).
-------
-4-
H. PHARMACOKINETIC 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 lower than recommended 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 DEVELOP GUIDANCE, PERHAPS IN THE FORM
OF AN ISSUE PAPER, ABOUT THE SELECTION OF DATA TO SET THE LEVEL OF AN
ADVISORY.
Three subjects discussed by the Subcommittee 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.
-------
-5-
i ODW 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.
i 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.
i 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-effect-level evaluation. The Environmental Health
Committee 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). ACGIH frequently
reevaluates these values and publishes the scientific basis of each
one. They may be considered concensus values based on the best available
published data. 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
information 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
-------
-6-
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. THE PRESENCE OF CERTAIN COMPOUNDS IN DRINKING WATER CAN INDICATE THE
PRESENCE OF OTHER SUBSTANCES FROM A COMMONLY OCCURRING MIXTURE.
Some of the compounds 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, xylenes, 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 example, 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 EXPOSURE 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 ODW 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.
-------
-7-
Users need the one and ten day health advisories to make decisions and
provide information 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 some
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 OF 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 comments 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.
-------
-8-
II. COMMENTS OF THE DRINKING WATER SUBCOMMITTEE ON HEALTH ADVISORIES FDR
SPECIFIC SUBSTANCES
A. ACRYLAMIDE HEALTH 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 some 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, electro-physiological, 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 neuropathology 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 mg/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 pha'rmacokinetic
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
pharmacokinetic 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-
-effeet-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
-------
-9-
program with a printout from a standard commercial 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 LD50 of 203 mg/kg and subchronic values of (5
days/week/4weeks) LD50 of 32 mg/kg and subchronic (5 days/week/15weeks)
LD5Q of 17 mg/kg. In the longer-term 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 mg/kg-day instead of 0.002 mgAg'day- There is
an error in the calculation. The EPA standard given in the Criteria Document
is 0.05%, not 0.05 ug/L.
-------
-10-
B. BENZENE HEALTH ADVISORY
The benzene health advisory effectively organizes data from 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 remains
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 phenol, 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 important to note that
47% of benzene inhaled was absorbed, 30% retained and 16% exhaled unchanged,
when exposed to 52-62 ppm for 4 hours, and was the same for both sexes.
Benzene absorbed from 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 Wolfe and coworkers should include a description of duration of exposure.
The description of the Occupational Safety and Health Administration
standard as 3.2 microgram/L is in error. The standard is 32 milligrams/M^.
-------
-11-
C. DIQXANE HEALTH ADVISORY
The health advisory for 1,4-dioxane constitutes a useful document,
but some 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 concentrations, and it may be that its mobility 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 may 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 for 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-dioxane 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 DNA 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 LD$Q 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.
-------
-12-
Several studies in chickens may be useful in evaluating the developmental
aspects of 1,4-dioxane. A mouse study of some 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 some classes of hormones. This information merits
a renewed literature search for relevant data.
Several reports of in vitro mutagenicity tests of 1,4-dioxane occur in
the literature that are not cited in the health advisory, and the Subcom-
mittee recommends 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, merits
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. How 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 animal, 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-term standard and the
possibility of enhanced toxicity after bicdegradation 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 coworkers will support
the development of 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).
-------
-13-
D. ETHYLBENZENE HEALTH ADVISORY
With the exceptions noted below, the health advisory is-consistent with
information presented in the. Drink ing. Water Criteria: Document., for Ethyl-
benzene. Overall, acceptable daily intakecalculations^ are consistent
with guidance, provided in the issue papers for such calculations^.
The health advisory should include, "tobacco., smoke: constituent"7 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 pharmacpkinetics section needs-modification. The-;/Criteria Document
should include., several impprtant references-t published, in 1984'that
provide new,, information on the.metabjolism and excretion of-r ethylbenzene
in rats.
The. uncertainty in. human health effects.- reported at-100 ppm-is- not- prop-
erly presented. The report of Bardodej and Bardbdejpya-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 same quality as information considered
in establishing and maintaining the present American-Conference of
Governmental Industrial Hygienists Threshold Limit-Value of;100 ppm?
Most available information-indicates that 100 ppm-8 hour exposure
represents a no-adverse-effect-level, not an effect level.
The mutagenicity section needs.:improvement because-the-health advisory
fails to cite the work of Dean and coworkers*-which reports that ethyl-
benzene is not mutagenic in Salmonella ^ typhimur.ium-, E;coli/ 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 committee 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 frcm: the body. . A consortium of ethyl-
benzene producers is currently conducting 28-day inhalation probe studies
in mice, cats 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. Engstron, "Urinalysis of Minor Metabolites of Ethylbenzene and m-Xylene,"
Scan. J. Work. Env. Health 10; 75-81 (1984); K. Engs.trom, "The Metabolism
of Inhaled Ethylbenzene in Rats," Scan. J. Work. Env. Health 10; 83-87 (1984);
K. Engstrom and Coworders, Int. Arch. Occup. Env. Health 54; 355-363 (1984).
* B.J. Dean and Coworkers, "Genetic Toxicology Testing of 41 Industrial
Chemicals," Mutation Research 153: 57-77 (1985).
-------
-14-
E. ETHYLENE GLYCOL 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.-1- 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 glycol. 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,4 which also list other
^Tj.A. Roberts and H.R. Seibold, "Ethylene Glycol Toxicity in the Monkey,"
Toxicology and Applied Pharmacology, 15; 624-631 (1969).
2 See, 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," !_ 583-596 (1974); C.D. Peterson and
Coworkers, "Ethylene Glycol Poisoning: Pharmacokinetics during Therapy with
Ethanol and Hemodialysis," New England Journal of Medicine 304; 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. Rajagopal and S. Ramakrishnan, "Effect of Ethylene Glycol Toxicity on
Hepatic Carbohydrate Metabolism in Rats," Toxicology and Applied Pharmacology
46: 507-515 (1978).
-------
-15-
relevant references. The study by Gessner and:coworkera on metabolism
and the study of Marshall, also are germane.
Another important 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 fron the omission
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.
-------
-16-
F. n-HEXANE HEALTH ADVISORY
Since no Drinking Water Criteria Document for n-hexane exists,
the health advisory is based on a collection of supporting papers. The
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 coworkers, the exposures averaged 650 ppm
with peaks up to 1,300 ppm, 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 mgAg 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
-------
-17-
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. However, 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
most 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 Water 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," Toxicology and Applied 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. Comm. in Chem. 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).
-------
-18-
Jakobson et al., "Intake via the blood and elimination of 10 organic
solvents following epicutaneous exposure of anesthetized guinea pigs,"
Tox. and App. Pharm. j>3: 181-187 (1982).
Howd et al, "Relation between schedules of exposure to hexane and plasma
levels of 2,5-hexanedione," Neurobehavioral Tox. and Teratology, 4:
87-91 (1982).
Couri and Milks, "Toxicity and metabolism of the neurotoxic hexacarbons
n-hexane, 2-hexanone, and 2,5-hexanedione," Ann. Rev. Pharmacol. Toxicol.
_22: 145-166 (1982).
Calvender et al, "A 13-week vapor inhalation study of n-hexane in rate
with emphasis on neurotoxic effects," Fund, and App. Tox. 4: 191-201
(1984).
Bravaccio and Ammendola, "H-reflex behavior in glue (n-hexane) neuropathy."
Clinical Tox. 18: 1369-1375 (1981).
Graham et al, Tox. Appl. Pharm. 64: 415-422 (1982).
-------
-19-
G. LEGIONELLA 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 Legionella differs from that
of the chemical substances, perhaps in recognition of the incongruence.
However, EPA should articulate the rationale for the difference, and the
Subcommittee recommends that the emphasis 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 (L. feeleii), 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 Legionella
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 Legionella is not recommended. (4)
There is no all encompassing disinfection procedure that can be recommended
each time.
Although the health advisory is not legally enforceable, the Subcommittee
understands that it will be accepted by some 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.
-------
-20-
If Legionella 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 danger 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 much 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 fron a source implicated by epidemiologic data should be discus-
sed in more detail. Also, grouping and characterization of L. pneumophila
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
may 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
oneumoohilia," J. Bacteriol. 163: 1021-1037 (19851,
-------
-21-
H« METHYL. ETHYL KETQNE HEALTH. ADVISORY.
The Office, of. Drinking: Water has not prepared; -a Criteria^ Document 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; Mete, of a teni day .advdisory/ iis; inconsistent
with! the use: of subchronic;
Similar to. the' situation with, nrhexane;,, the; mixtures; problem; needs to be
addressed! especially since: methyl', ethyl, fcefeone; enehances. the; neuror-
toxicity of n-hexane. That combination' is- suspected' as; responsible: for
the: outbreak, of neuropathies among? substamce abusers; in>. West Berlin: who?,,
until the addition of: methyl. e.thy.3i ketone;,. seemed! to;- suffer, relatively
mild toxic ity.
Although the advisory makesj statements; coneern'ing; the? derma-H absorption
and the quantative nature; of certain. metaboiLites:-,,- the, Subcommittee; is not
aware, of adequate studies dealing with, distribution, and. metabolism1. The'
lack of. adequate studies- merits greater emphasis- and: shoul'd. preceed, the
paragraphs; on. absorption and metabolism.
-------
-22-
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-effect-levels based on central nervous system 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 10-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 label 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.
ODW 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 vary
from 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 mgAg*clay 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 8% and the exposed 15%. The
control incidence is the unusual finding, since in many comparable studies,
it is 15%.
Considerably more evidence about the mutagenicity of styrene oxide exists
than is described in the health advisory. It would be valuable to add
information about mutagenicity in other systems including mammmalian
cells. Activity as measured with a number of other endpoints, which are
not necessarily mutagenic but related, might also be noted, such as
sister chromatid 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 Poncmarkov and Tonatis was
done poorly. Instead, there were many early deaths related to treatment
-------
-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 carcinogenicity of styreme oxide,
since it is a major metabolite and an active chemical which could relate
to the possible carcinogenicity of styrene.
In the one-day Health Advisory, the data> cited is from the article by
Das and coworkers, not Srivastava and coworkers. Some explanation is also
needed to justify using the study by Das in preference to that of Agarwal,
which showed effects on dopamine receptors at 200
ODW 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 important for ODW to provide
a more explicit description of how it used the data and factored early
deaths with tumors into the estimate.
The last section concerns the possible bicdegradation 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 coming 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 component 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 -30.69C, while
the value of 145*0 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.
-------
-24-
J. TOLUENE HEALTH ADVISORY
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 mg/kg*day but calculated as 0.288 mgAg*dav)« The health
advisory states an LD50 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, omit 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 pharmacokinetics, the health advisory has correctly
referred to information from the 1974 paper of Nomiyama and Nomiyama, but
a numer of inconsistencies occur with the Criteria Document, which misquotes
the data fron 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.
-------
-25-
K. XYLENES HEALTH ADVISORY (ORTHO-XYLENE,. METAT-XYEENE; AND. PARA-XYLENE)
The health advisory for xylenes. generally follows the Criteria Document
for these conpounds. The studies selected, for'establishing; the known
effects and 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 may
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 coeff.relents. 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 Morley
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 from 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.
-------
-26-
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 fron the perspective of dose and concluded
that xylenes may be embryotoxic and maternally toxic but only at high
doses.*
The 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 rag/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 same formula and data from 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/ which 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 from 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," Drug and Chemical Toxicology. 8: 281-297 (1985).
-------
U.S. Environmental Protection Agency
Science Advisory Board
Environmental Health Committee
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, 6505 Alvarado Road, San Diego State University,
San Diego, California 92182-0405
Dr. Larry Andrews, Celanese Corp., 1211 Avenue of the Americas, 13th Floor,
New York, NY 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 Road,
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 York Department of Health, Bureau of Toxic
Substance Assessment, Room 359, Tower Building, Empire State Plaza,
Albany, NY 12037
Dr. Verne Ray, Medical Research Laboratory, Pfitzer, Inc. Groton, CT 06340
Dr. Thomas Tephly, Professor, Department of Pharmacology, The Bowen Science
Building, University of Iowa, Iowa City, Iowa 52242
Dr. Bernard Weiss, Professor, Division of Toxicology, P.O. Box RBB, 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-101F), U.S. Environmental Protection Agency, Washington, D.C. 20460
(202) 382-2552
-------
COMMENTS SUBMITTED TO THE DRINKING WATER SUBCOMMITTEE
BY THE PUBLIC REGARDING THE SCIENCE ADVISORY BOARD'S
REVIEW OF DRAFT DRINKING WATER .HEALTH ADVISORIES
National Audubon Society -Contact: -.Chuck^Race
National Capital Office
645 Pennsylvania'Avenue, S.E.
Washington, .D.C. 20003
Date: December .24, 1985
Chemreal Manufacturers Assoc. Contact: -Berald/ine *>V. ,Gox
2501 M Street, N.W.
Washington, .D.C. 20037
Date: December 26, 1986
Natural Resources Defense Contact: jRob'inIWhyaCt
Council Inc. '.Wendy Gordan
122 East 42nd Street
New York, N.Y. 10168
Date: November 29, 1986
Water Quality Association Contact: :Danna :M. Cirolia
1518 K Street, N.W.
Suite 401
Washington, D.C. 20005
Date: November 22, 1985
Diamond Shamrock Corporation
'Contact:: rRoss IE. .Jones
World Headquarters
717 North Harwood Street
Dallas, Texas 75201
Date: December .2, 1985
-------
American Cyanamid Company Contact: Linda Dulak
One Cyanaraid 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. .20036
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
-------
POST MEETING COMMENTS RECEIVED
National Audubon Society
National Capital Office
645 Pennsylvania Avenue, S. E.
Washington, D. C. 20003
Date: January 27, 1986
Contact: Chuck Pace
Hazco
5301 Lee Highway
Arlington, Virginia 22207
Date: March 14, 1986
Contact: Redmond Clark
Chemical Manufacturers
Association
2501 M Street, N. W.
Washington, D. C. 20037
Date: April 30, 1986
Contact: Ann M. Mason
-------
U.S. Environmental Protection Agency
Science Advisory Board
Environmental Health Committee
Drinking Water Subcommittee
Open Meeting
-Urrder Public Law 92-463, notice is hereby given that a
three-day meeting of the Drinking Water Subcommittee o.f 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.: Washington, DC. 20037. The
meeting will start at 9:00 a.m. on January 6 .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
Ethylbenzene Toluene
Ethylene glycol 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]; [J.S. Environmental Protection Agency; 401
M Street, S.W.: Washington, DC; 20460.
-------
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 above, 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.
October 15, 1985
Date
E/f/tfosie
Director
iencje Advisory Board
-------
U.S. ENVIRONMENTAL PROTECTION AGENCY
SCIENCE ADVISORY BOARD
ENVIRONMENTAL HEALTH COMMITTEE
DRINKING WATER SUBCOMMITTEE
Conference Roan 451
Joseph Henry Building
National Academy of Sciences
2122 Pennsylvania Avenue, NW
Washington, DC 20037
January 6-8, 1986
ORDER OF BUSINESS
REVIEWS OF DRAFT DRINKING WATER HEALTH ADVISORIES
Opening Remarks Dr. Tardiff
Administrative Matters Dr. Byrd
Introduction Dr. Crisp
Dr. Tardiff
^Tentative Sequence of Reviews, beginning Monday, January 6, 1986
Substance (Manager) Reviewers
Pj-Dioxane (Khanna) Drs. Johnson and Ray
Ethylbenzene (Khanna) Drs. Andrews and Ray
Ethylene glycol (Khanna) Drs. Ray and Johnson
Toluene (Khanna) Drs. Griffin and Dajirmanjian
Benzene (Marcus) Drs. Brubaker and Kim
Styrene (Marcus) Drs. Kaufman and Andrews
Xylene (Patel) Drs. Carlson and Griffin
MethylethyIketone (Patel) Drs. Tephly and Brubaker
On Tuesday, January 7, 1986
Legionella (Berger) Drs. Barbaree and Winn
On Wednesday, January 8, 1986
Acrylamide (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 Dr. Tardiff
Nomination of Criteria Documents for further review Dr. Tardiff
Other Subcommittee Business
Concluding remarks Dr. Tardiff
Dr. Byrd
ADJOURNMENT
* The sequence in which the Subcommittee reviews Health Advisories for different
substances and the time allocated to each review are at the discretion of the Chair.
------- |