UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
September 20, 1986 SaB-EBC-S7-Q04
Dr. Richard A, Griesemer • OFFICE o
Chair, Environmental Health Committee ™£ *°M'*'«•"
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
Subconroittee 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 seme scientific
issues will be controversial.
Our ccmments 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, phannaeokinetics and multiple exposures (mixtures)* Although
the guidance may be conceptually sound for organic substances, sane in-
formation in the documents seems inappropriate to the toxicology of
raetals. Because of the extensive nature of our comnents, a Table of
Contents and some supporting appendices are included* We appreciate the
opportunity to became involved with this program and stand ready to
provide further advice, as requested.
Sincerely
Bernard Weiss, Ph*D*
Chair, Metals Subcommittee
Ronald Wyaga, Sc.D, (/ ff
Vice-chair, Metals Subcowiittee
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EPA NOTICE
This report has been written as a part of the activities of the Science
Advisory Board, a public advisory group providing extramural scientific
information and advice to the Administrator and other officials of the
Environmental Protection Agency* The Board is structured to provide a
balanced expert assessment of scientific matters related to problems
facing the Agency. Ihis report has not been reviewed for approval by
the Agencyf 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 recommandation for use.
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TABLE OF CONTENTS
Subject " - Page
I, GENERAL COMMENTS ON DRINKING WATER HEALTH ADVISORIES 1
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 ccraments 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
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I. GENERAL COMMENTS OF THE METALS SUBCOMMITTEE OF THE ENVIRDNMEOTM, HEALTH
COMMITTEE OF EPA'S SCIENCE ADVISORY BOARD REGARDING LINKING 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.
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 {¥!} 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.
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* 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-observed-effect~*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.
• 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 utilize 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
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decrease in the margin of safety and the iitwdnent possibility of mortality
or morbidity in the consuming population. It would be useful, moreover, to
provide seme indication of the uncertainty associated with a health advisory.
The simplest 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. BIOPKQCESSING OF THE METALS NEEDS h CLEARER PBESENTATICM. •
The Subccnroittee noted some inconsistencies in the phannacokineties sections
between different health advisories for metals and inorganic substances. The
content and depth of the discussions varied considerably. In some advisories,
extensive aniraal 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 rather
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 from the documents and reducing confidence
in the documents. It would be helpful if a uniform set of definitions 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 bicprocessing of
metals in humans. If this involves extrapolation from laboratory animal
data, the extrapolation should be indicated.
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The SubcaiTOittee proposes the following suggestions for the content
of the various subsections of the pharmaeokinetics sections of the health
advisories: .
» "Absolution" 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 animals 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., speciation, 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 absorption, distribution, excretion, detoxifi-
cation and activation of the metal. TMs includes oxidation or reduction
reactionsr 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
raetal front 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 fozms
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.
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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 phatmacokinetics sections, essentially the same principles as
above will explain the importance of species in the uptake, distribution,
metabolism and excretion of metals. Trivalent chromium crosses cell membranes
jmieh more slowly than hexavalent chromium. The methylated forms of metals
usually are absorbed better than the inorganic species. Methylmereury 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 pharrnacdkinetics 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, methylmereury 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.
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E. M,JI..TIH.E SOURCES OF J5XP08IJRE INOTENCF 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
(XI food, inn-W 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-) t*hen 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 *Mch is different from the
lung where the chemical accumulates once it is absorbed into the blood cir-
culation from either lung or gastrointestinal tract.
Case (a) might be a more hypothetical one, but for case (b) several
examples can be given. Lead from automobile exhaust accumulates 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 aeeimulates 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 he 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 he 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 cadniuru aerosols in the workplace.) From a. scientific
poitit-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 sumnroary,
cigarette smoking alone can contribute as ranch 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, ipultiple exposure sources have to be taken into account
once it becomes obvious from knowledge of the pharmacokinetics of a chemical
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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
be able to decide where to set their drinking water standard.
F. HEALTH ADVISORIES SHOTID DESCRIBE THE RELATIVE CCMTRIBUTIOSI OF DRINKING
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, 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 LeadExposure
2-year-old child Mult 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 frcm support documents for the lead health advisory.
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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
ca$ef 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 sane species of arsenic are raore 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 mg/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 As4^ that hardly seem worthwhile given the statements that the
toxic species is As+3. 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 2aldevar study in the longer-
term exposure section. For example, it notes that "the decrease in cutaneous
lesions seeraed 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 seaaed to be too
dramatic as arsenic concentrations decreased to 0.08 rog/L.
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the health advisory should mention that the study of Tseng arid ccworkers
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 emits human data f ran Argentina,
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B* B&RIOM HEALTH ADVISORY
The arguments for determining the uncertainty factors for barium are not
convincing* Why was the uncertainty factor dropped frcm 1000 to 100? How
was a factor of 10 derived as a quantitative measure 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 ram. (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 ware
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 tog/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 sane 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-effset-level that may be as low as 0,51
Ba rag/kg-day.
EPA reported several other changes in rats given 100 ppro barium that could
be considered as evidence of barium-induced toxicity, such as decreased
content of adenosine triphosphate and phosptocreatinine 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 Ba/kg-day
for 173 days. The acute toxic threshold dose that is cited in the Criteria
Document is 2.9 to 71 rag/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 missir*g. 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
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technical to vague. Similarly, the document will be unproved by using con-
sistent units to describe barium concentration.
Hie 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 cannon, 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.
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C. CamiUM 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^
dilations 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-
-tem 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 ccnparisons 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 (RFFD) 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
habits should be addressed. Specifically, the intake of toxicants by cigar-
ette smoking should be considered. For example, the health advisory is
based on the assumption that the risk reference dose is 0.5 ug cadmium per
kg»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 radiolataelled 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
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estimate the gastrointestinal absorption of cadmium, but tile 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 tite 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
cleaj^er summary, with a emphasis on the kidney as a target organ, rather than
a loosely linked series o£ annotated references. The health effects of
cadmium occur as a sequence of events,, in which beta-2-^ctiicroglobulineitiia is
an earlier indicator. The reference to Itai-Itai disease should note that it
appeared in elderly, multiparous wcraen. Ihis 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 Than 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.
Fribecg and coworkers estimated the daily intake of cadmium that would result
in the accumulation of 200 ug eadmium/g renal cortical tissue after SO years
of continuous exposure. Roels and coworkers have shown that this level of
cadmium occurs in human kidneys that exhibit symptoms of renal impairment.
The health advisory should summarize this information.
Testes exhibit toxic effects after parenteral administration of cadmium. The
Subccradttee 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 rag/m^)
or fume (0,1 mg/m3),
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 raean that all cadmium in ground and surface water (1-10 ug cadmium/L)
is derived from natural sources?
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D. CHBOMIUM HEALTH ADVISORY
Most of the health advisory evaluation of chromium is accurate, couplets
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 an the evaluation of both
carcinogenic and non-carcinogenic effects.
Both the Criteria Document and the health advisory make efforts to dis-
tinguish between chronium (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 JPreussman, but it involved
chromium (III) not chromium (VI).
The Criteria Document does not attenpt 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 carcinogenicity of chromium (VI) from oral exposure in light
of the inhalation data, the phannacokinetics, metabolism and mutagenic
effects of chrcmium (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 Subccramittee
reccnmends that the Office of Drinking Mater 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
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controlled epidenriologic studies which conclude that chronic inhalation of
air containing chranium (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 chranium {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.
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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 suranary 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 mg/kg*day administration for thirty days. In the second,
histopathological changes {in a site described as "ganglion cells of the
CMS" with no other clarification) were found after 0.27 mg/kg*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
rood® of administration? Ihe 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 omitted. 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* Pew 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 erythroeytes is mainly due to the oxidation of iron in metheraoglobin
and the formation of cyanomethemoglobin. The section on Htetabolisra 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.
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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 my/kg of diet and
190 rag/kg of diet, instead of 100 mg/k§ and 300 rag/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
infjortant in evaluating the health effects of cyanides* For exaraple, 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 l-
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F. LEAD HEALTH
The recommended lifetime health advisory of 20 ug/day can be supported by
present information about lead Metabolism and toxicity. The calculations are
correct f 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 nay 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 thaired herne synthesis
in children may occur at blood lead levels exceeding 10 ug/dl, the health
significance of this effect is less clear.
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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 imitagenicity
of lead. Because lead causes toxicity prior to mutagenicity does not mean no
genotoxicity will result. In EPA's Mr 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 nonmal synthesis and replication of DNA, and causing induction of OSft.
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 tears 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 nost .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, vtfiich 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 consuired per day by an adult, calculation is as
follows:
48 ug/day = 24uq/l
~
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
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-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/1
2 1/ctay .
For this reason, a summary of the relative source contributions for adults
and children will enhance the health advisory.
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G. MERCURY HIMLTH AWISQRY '
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 from 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 (Acrcdynia), 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 Pitzhugh and coworkers.
* The assumption that all forms of mercury-inercury vapor in air, methyl-
mercury in food and inorganic compounds in drinking water are toxico-
logically equivalent.
* The decision not to consider mercury intake from 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.
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A third approach is to consider the three major forms of mercury as
toxicologieally 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 connonly 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.
The 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
jteraber, which also suggest that the Criteria Document requires additional
review, have been sent directly to the Office of Drinking Water.
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H. NICKEL HEALTH ADVISORY
Sore Subcommittee members have reservations about the proposed lifetime
health advisory of ISO 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 STQRET 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
Subeomittee 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
reccnanend 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 sanples
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 eaphasizes 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
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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 bioavailability of nickel from
drinking water may.be greater than from foods and leverages. 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 ing, 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 prcnpt and sustained elevations, of plasma
nickel concentrations occurred when the same quantity of nickel wa's 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 fron 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 bioavaliability 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 SPA 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 carcincgenesis tests of nickel ccnpounds added to drinking water might
influence the level of the life-time advisory, as well as comparisons of the
bioavaliability 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.
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I. NITRATE AND NITRITE HEALTH AWISORY
The nitrate and nitrite health advisory is well-written and essentially
cotplete* 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 saliva, 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. Formation 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 roethernoglobin formation as the most significant
health effect on the basis that infants suffer frcm methemoglobinemia after
drinking nitrate contaminated water, milk or formula* For the purposes of the
health advisory, methemoglobinemia in infants is the roost 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-*3ffect-
-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 anijmals.
No data are now available on the cardiovascular effects of chronic exposure to
nitrate. Given the profound vasodilator effects of nitrates (acne 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 earcinogenicity 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
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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 conpounds exist in drinking water or foods which, if ingested with
nitrate or nitrite-contaminated drinking water, will result in fomation 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 chemicalsj 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 itteans of indirectly regulating
human exposure to N-nitroso carcinogens*
The health advisory slips into jargon from time to tiros. The most glaring
example is in the introduction, where the third paragraph refers to the "Health
Advisory 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.
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U.S. Environmental Protection Agency
Science Advisory Board
Environmental Health Coranittee
Metals Subccstraittee
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]t 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 Coyer, Deputy Director, NIEHS, P.O. Box 12233, RTP, North Carolina
27709
Dr. Marvin Kusehner, .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. Mossnan, 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 Elitwood 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, tA-lQIFj,
U.S. Environmental Protection Agency, Washington, D.C. 20460 (202) 382-2552
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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
Contact: Chuck Pace
Contact: Geraldine V. Cox
Natural Resources Defense
Council Inc.
122 East 42nd Street
New York, N.Y. 10168
Date; November 29, 1986
Water Quality Association
1518 K Street, N.W.
Suite 401
Washington, D.C. 20005
Date: Novewber 22, 1985
Contact: lobin Whyatt
Wendy Gordan
Contact: Danna M. Cirolia
The New Jersey Dept. of Health
and The New Jersey Dept. of
Environmental Protection
Date; August, 1985
Contacts Bonnie L. Bishop
State of Connecticut
Department of Health Services
Date; December 12, 1985
Michigan Pure Water Council
Date; December 12, 1985
Contact: David R. Brown
Contact: Martha Johnson
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POSIMEFTING COMMENTS RECEIVED
National Audhibon Society .Contact: Chuck Pace
National Capital Office
645 Pennsylvania Avenue, S.H,
Washington, O.C, 20003
Date: January 9.7, 1986
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0.S. Environmental Protection Agency
Science Advisory Board
Environmental Health Committee -
Metals Subcommittee
OpenMeeting
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 9-10f 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 tead
Barium Mercury
Cadmium Nickel
f
Chromium Nitrate/Nitrite
Cyanide
The Metals Subcommittee will not receive oral comments
on the Health Advisory docuraen-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-55QJ- U.S. Environmental Protection Agency;
401 M Street, S.W.; Washington, OC; 20460.
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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.ta. on December 20, 1935.
Yosie
sirector
3-5, 1985 N^/Science Advisory Board
Date
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O.S.
L PROTECTION AGJiNCY
SCIENCE ADVISORY, ROAPD
, FFALTH CCWITTEE
MFTALS STJBCCWtlTTEE
Conference fioom 451
Joseph Henry Gilding
National Aeadeiw of Sciences
2122 Pennsylvania Avenue, NW
Washington, DC 20037
'Januar 9-10
ORDER OF BUSINESS
REVIEWS OF DRAFT DRINKING WATFR HEALTH ADVISORIES
Opening Remarks ,...,»...... ____ , , . Dr. Weiss
Administrative Matters ,,.«»...,. ......... Dr. Byrd
Introduction ,»...........».,,,« Dr. Crisp
Dr. Weiss
*Tentative Sequence of Reviews, beginning Thursday, January Q, 1986
Substance (Manager) ^evie^grs
Arsenic (Marcus) Drs» Vyzaa and Goyer
I.,ead (Marcus) ...... . ..... ,.„,,,» Drs. Goyer and Clarkson
Nickel ( Bath i la) Drs. Sunderman and Brookneyer
(Bailey) .......... *..**.... Drs. Biamcrid and Sunderman
, (Bailey) . Drs. Mosswan and Diancsnd
(Bailey) ..... . ........ ..... Drs. BrooVmeyer and f-^ossinsn
On_ Friday, January 10, 1986
Mercury (Khanna) _ Drs. Clarkson and Wyzea
Cyanide (Bathija) ...,»»^, ........... Drs, Ferrand and Kuscbner
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 fiubcotnrottte.e_Bnsiness
Conduct ing remarks ---- .....,,,., ..... Dr. Weiss
Dr. 'Byrd
* The sequence in v^iiich the Subcomnittee reviews Health Advisories for different
substances and the time allocated to each review are at the discretion of the Chair.
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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 fora 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 alnond 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 CIANIDES
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 frott 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 HEftLTH 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.
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""* £*
Studies relating cyanide exposures to adverse health effects indicate that a
daily intake of up to 0.021 ag 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 roust not
exceed 0.21 mg per liter of water. This value is based upon the assumption
of a 10 kg child who drinks an average of 1 liter per day;
°"21
0.21
ing CN x
kg (bw) day
1 liter
day
10 kg (bw)
liter
A 70 kg adult drinking 2 liters per day from this sains water supply will
receive a considerably smaller daily exposure per kg of body weight.
0 21 mg_. CN~ x 2 liter
liter day - 0.006 2S_2f
kg (bw) day
70 kg (bw)
REMOVAL OF CYANIDE FSOM WftTSR 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)
CM" + 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
evaporation 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 WTER FOR CYANIDES
Free OT 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
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