UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, O-C. 20460
July 11, 1986
M.
Administrator
U.S. Environmental Prelection
Agency
Washington, D,c. 204SO
Dear Mr. Thonast
The Science Advisory Board's Environmental Health Ccmnittee has co^leted
its review of the Office of Research and Development's Health Assessment
Document for Nickel. The Committee carried out its review through its Metals"
Subcommittee'which net on March 24-25, 1986. The Subcoamittee's report is
attached.
The document appropriately characterizes the current scientific literature
on the carcinocjenicity of nickel compounds. Hi is current revised document
is much improved in a number of ways over the previous draft. The Subcamittee
identifies sane remaining revisers that the Agency staff should incorporate
into the final document before its final publication.
The Board thanks you- for the opportunity to present its scientific
ccmnents on this issue and requests that a formal Agency reply be prepared
in response to the attached report.
Sincerely,
K
Norton Nelson
Chairman
Science Advisory Board
Richard A. Grieseiner
Chainman
Eiwirontnental Health Ccnmittee
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D,C. 204SO
June 9, 1986 SAB-EHC-86-Q26
Dr. Richard A. Griesemer
Chair, Environmental Health Committee OFFICE or
Science Advisory Board THE ADMINISTR
U.S. Environmental Protection Agency
401 M street, sw
Washington, DC 20460
Dear Dr. Griesemer:
The Metals1 Subcommittee of the Environmental Health Committee met on March
24-25, 1986 in Farmington, Connecticut, to review the draft final Health
Assessment Document for nickel (EPA/600/8-83/01 2Py September, 1985)*
Subsequently^ members of the Subcommittee prepared individual comments.
This letter summarizes the Subcommittee's major conclusions.
The Environmental Health Committee reviewed a previous version of the
document in September, 1983» The Subcommittee agrees that the current
draft is responsive to our earlier comments. It now is clearer and more
comprehensive, and with the corrections suggested by the Subcommittee,
should be a scientifically accurate document* Since staff indicated that
further editing is underway, our detailed comments have been transmitted
directly to the Office of Research and Development (ORD). In addition,
the Subcommittee recommends that ORD resolve some technical problems that
remain in the three areas described below before the document is released
in final form.
(1) As the document notes repeatedly, different forms of nickel exhibit
different profiles of toxicity. Nickel subsulfide is appropriately ae~
knowledged as presenting the most serious carcinogenic hazard, but the
document lacks clarity beyond that conclusion. The scientific terminology
from section to section is not always consistent, the chemistry of nickel
is, at times, presented inaccurately, and the understanding of nickel
manufacturing processes is incomplete. Moreover, the nickel-ion hypothe-
sis, which asserts that the proximal carcinogenic form is divalent nickel
ion in solution, seems overstated, especially on page 8-210.
(2) The discussion of nickel absorption, distribution, metabolism and
elimination- -lacks a firm grasp of terminology and principles because of
numerous instances of confusing and imprecise phrasing. For example,
"clearance" and "elimination" are used interchangeably, but these are
different processes. The term, "retention time," is used in a confusing
way. The definitions and roles of metal binding proteins are presented
inaccurately. The understanding of the principles of inhalation toxicology
and of relevant empirical data seem limited, which leads in turn to incor-
rect assumptions and .conclusions about the role of respiratory mechanics
and function. AS with other assessment documents, body surface area is
used to correlate delivered doses between animals and humans. This is an
incorrect assumption for substances delivered by inhalation.
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-2-
(3) Heither the animal nor the European epidemiology data seem to b* used
properly for quantitative risk assessment. The animal data are seriously-
flawed and have limited utility for either extracting definitive conclu-
sions or assessing human risk. For example, little confidence can be
placed in a data set in which control animals exhibit 31* survival, The
epidemiology data lack reliable exposure estimates and do not reveal much
familiarity with the complexities of the manufacturing process. The
quantitative risk assessment based on European epidemiology relies on U.S.
cancer mortality rates for unexposed persons, despite the differences in
these rates for U.K. and Norwegian population studies. This inappropriate
adjustment could seriously bias the unit risk estimates derived from these
studies.
We appreciate the opportunity to comment on this public health issue and
hope that our comments are useful to the Science Advisory Board and the
Agency.
Sincerely yours,
Bernard Weiss, Ph.D*
Chair, Metals' Subcommittee
.'-' _.^ f 7
Ronald Wyzga, Sc.Dj/" / '/'
Vice-chair, Metals' Subcommittee
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U.S Environmental Protection Agency
Science advisory- Board
Environmental Health Committee
Metals' Subcommittee
March 25, 1986
Dr. Bernard Weiss [Chair], Professor, Division of "toxicology, P.O. Box
RBB, University of Rochester, School of Medicine, -Rochester, NY 14642
(716)275-3791
Dr* Bonald Wyzga [Vice-chair], Electric Power Research Institute, 3412
Hillview Avenue, P.O. Box 1041, Palo Alto, California 94303 (415)855-2577
Dr. Thomas Clarkson, Professor and Head, Division of Toxicology, University
of Rochester, School of Medicine, Pest Office Box RBB,, Rochester, New York
14642 (716)275-3911 ' ' -
Dr. Gary Diamond, Assistant Professor of Pharmacology, University of
Rochester School-of Medicine, Rochester, New York 14642 (716)275-5250
Dr* Edward F. Ferrand, Assistant Cotmiss ioner for Science and Technology,
New York City Department of Environmental Protection, 51 Astor Place, New
York, New York 10003 (212)566-2717
Dr. Itobert Coyer, Deputy Director, NIEHS, P.O. Box 12233, RTF, North
Carolina 27709 8-629-7620
Dr, Marvin Kuschner, Dean, School of Medicine, Health Science Center,
Level 4, State University of New York, Stony Brook, New York 11794
(516)444-2080
Dr. Brooke T. Mcssroan, Department of Pathology, The University of Vermont,
Medical Alumni Building, Burlington, Vermont 05405-0068 (802) 656-2210
Dr, Gunter Oberdoerster, Associate Professor, Radiation Biology and Biophysics
Division, University of Rochester, School of Medicine, 400 EJUwood Avenue,
Rochester, N.Y. 14642 (716) 275-3804
Dr. P. William Sunderman, Professor of laboratory Medicine and Pharmacology
and Head, Department of Laboratory Medicine, University of Connecticut
Health Center, Room C 2021, Farraington, Connecticut 06032 (203)674-2328
Executive Secretary
Dr. Daniel Byrd, III, Ejsecutive Secretary, Science Advisory Board [A-1Q1F],
U.S. Environmental Protection Agency, Washington, D.C. 20460 (202)382-2552
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UNIVERSITY OF ROCHESTER
School of Medicine and Dentistry
Department of Radiation Biology & Biophysics
DIVISION OF TOXICOLOGY
Toxicology Training Program
Environmental Health Sciences Center
April 28, 1986
Dr. Daniel M. Byrd III
Executive Secretary
Science Advisory Board
USEPA
401 M Street, S.W.
Washington, D.C. 20460
Dear Dr. Byrd:
Please find enclosed roy post-meeting comments on HftD - Nickel
Speciation. I am also forwarding a copy to Bernie Weiss.
Sincerely,
Tom Clarkson
Professor
tw/cmkb
enc.
Mailing address: University of Rochester School of Medicine,
P.O. Box RBB • Rochester, New York
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HAD - NICKEL - SPECIATION
TOM eiARKSON
POST MEETING COMMENTS
INTRODUCTION
The HAD Is well written and addresses the key issues raised in previous SAP
reviews. These post-meeting comments are directed towards the speciation of
nickel and its compounds - the physical and chemical species that contain
nickel,
Speciation is a theme that permeates this document. Indeed the previous SAB
review stressed its importance in all aspects of the HAD, One of the major
issues - the "nickel ion" hypothesis for careinogenesis devolves around the
speciation of nickel. This brief post-meeting review will be presented under a
number of sub-headings.
TERMINOLOGY
The public comments from INCO indicated ambiguities in the HAD. Sometimes the
word "nickel" is used to indicate the element, sometimes to refer generically
to all forms of nickel, clearly this problem is common to all HAD's dealing
with metals. In the case of mercury, the problem was solved by using the terms
metallic mercury or elemental mercury when referring to the element. I do not
regard this as an important issue but "down the line" it would be useful to
develop consistent terms for all the metal HMJS.
Public comments at the meeting drew attention to the many physical forms of
nickel oxide. One of the public written comments (INCO) used the term "oxidic
Nickel", unfortunately some of the original publications do not always
identify the specific physical form used in the study. Questions were also
raised at the meeting on the use of the designation "chemical compound* for
nickel oxides or complex oxides of nickel and other metals such as copper as
the atomic proportions are variable. It was suggested that the word substance
be used, I do not think this issue is sufficiently important to justify a
complete check of all the publications on "nickel oxide" used in the HftD. The
on-going "Nickel Speciation Research Project" in which the EPA is participating
would help clear up this ambiguity for any future documents on nickel.
THE MANUFACTURING PROCESS
A thorough knowledge of the manufacturing process is essential to identifying
each species of nickel of importance to human exposure. The public comments
from one of the manufacturers emphasizes this point - "The retrospective
estimation of environmental conditions can be done only by people familiar with
the plants and processes and with access to industries records and personnel".
Clearly the authors of the HAD are at a disadvantage in having to use
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"second-hand" and frequently incomplete information in the published
literature. It is obvious from the written comments and from those given at
the meeting that the HAD has not identified all the species of nickel and other
substances involved in human exposure at various stages of the manufacturing
process, in this respect, the comments from the two principal manufacturers -
INCO and Falconbridge - are specially important. Their detailed written
comments on nickel species that exist at stages of the manufacturing process
should be used to improve both the accuracy and scope of the HAD's treatment of
speciation during manufacture, e.g., Table 8-1 is clearly incomplete. INCO's
comments on speciation are too numerous to be detailed here.
ATMOSPHERIC NICKEL
The public comments agree with the HAD that currently available methods do not
allow speciation of nickel at concentrations of total nickel found in the
ambient atmosphere. Calculations made at the meeting indicate that direct
speciation will remain unattainable in the foreseeable future. This lack of
information is a critical gap in our knowledge in view of the controversy over
which species of nickel may be regarded as carcinogenic.
HAD has attempted through one of its contractors to calculate the most probable
species from themodynamic and other considerations - in all, 19 species were
identified. The public comments urge that a more practical approach could be
made by measuring the forms of nickel in the undiluted emission sources to the
atmosphere. Techniques are available to speciate nickel into water soluble
forms, Ni,S2, metallic nickel and "nickel oxide". in addition, it will be
necessary tb know the relative contributions from the different emission
sources and the residence time of each species in the atmosphere. These
estimates clearly cannot be included in the current HAD but should remain an
important objective for the future.
TOXICITY AND CAECINOGENICITY
The HAD adequately covers the importance of speciation in determining toxicity
and carcinogenicity. Some of the earlier papers may not have satisfactorily
identified the precise species of nickel, e.g. the specific fora of nickel
oxide.
Theories on mechanisms of carcinogenesis are appropriately mentioned in the HAD
but it remains for future research to further elucidate these mechanisms. The
so-called "nickel-ion" hypothesis is at best vague and interpreted differently
by different people as at the meeting. One interpretation is that the nickel
ion reacts directly with DMA. to initiate the carcinogenic process. However, as
noted by Nieboer, many other divalent metal ions react with DNA but do not
produce cancer. So what is special about nickel ions? Theories on
bioaccumulation must be added to account for carcinogenesis. To further
complicate the picture, Nieboer has presented evidence that a soluble small
molecular complex of nickel can cause the cellular machinery to produce
"di-oxygen free radicals" that have mutagenic properties. The HAD correctly
describes this putative mechanism as a hypothesis in the main text but
unfortunately mentions it in the important summary paragraph on page 8 - 210 in
an attempt to justify classifying "all compounds of nickel" as "potential human
carcinogens". Instead, it is suggested that the first paragraph of section 8-5
should be rephrased. The text starting "However, there is a reasonable
-------
probability,..to the end of the paragraph..."is not well understood" should be
deleted and replaced by "The question of the carcinogenicity of other nickel
compounds remains open and is therefore an important subject for further
investigations."
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Chapter 3. Nickel Background Information
General Comments
The background information should be directed more strongly
towards those nickel compounds and their special properties which
may have some relevance to health effects. Thus, the physical
and chemical properties of nickel subsulfide, nickel carbonyl and
nickel oxides should be featured.
The electronic structures of nickel and nickel ions and the
effects which they have on the properties of the metal and the
compounds and complexes of nickel should be explained,
The use of nickel metal in fi.nely divided form as a catalyst in
the hydrogenation of oils should be mentioned. The possibility
of nickel entering the food chain via this route should be
evaluated, -Nickel's ability to serve as a catalyst in these
reactions may be important evidence in understanding some of its
biological interactions,
Nickel metal atoms have two 4s electrons and eight 3d electrons,
two of which are unpaired. Formation of the nickel II ion
involves the loss of two 4s electrons. The two unpaired
electrons in the 3d shell of the metal and nickelous ion give
rise to paramagnetism. There are indications that catalytic
hydrogenation by hydrogen in the presence of nickel metal in
finely divided form entails the dissociation of hydrogen
molecules into atoms within the nickel metal luttice. The
decrease in paramagnetism as hydrogen gas is absorbed by the
metal is evidence that the unpaired elections in the nickel atoms
are being paired with those in the dissociated hydrogen atoms.
The formation by Ntll of stable complexes with cyanide ion also
occurs with loss of paramagnetism*
Ground rules should be established for use of the word nickel so
that it is always clear whether the reference is to the elemental
state or a compound or ion of the element.
The information should be presented in a more direct manner - the
writing style needs to be changed to accomplish this. For
example, the first two paragraphs on p.3-13 could be rewritten in
a more concise manner.
"Brief has described several methods which range in sensitivity
from 0.008 to 0.10 g for the determination of nickel carbonyl
(Brief et al, 1965). A chemiluminesience method base.d upon the
reaction between nickel carbonyl and ozone is faster and
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sensitive down to parts per billion (Stedman et al., 1979}."
There is a considerable amount Of material included which out of
context of the source documents provides little useful
information and is sometimes intelligible only to readers who are
already thoroughly familiar with the subject.
P.3-1
Comments on Specific Material in Chapter 3
"... nickel content of some nickel-containing minerals" is
redundant.
Has or has not native metallic nickel in a pure form been
observed? (What does rarely, if ever, imply?)
Elemental nickel dissolves in diulte acids, not only dilute
oxidizing acids. The statement that "even oxidizing salts
do not "corrode nickel because the metal is made passive, or
incapable of displacing hydrogen, by formation of a
surficial oxide filin" is taken out of context and requires
further explanation.
The existence of a true -1 state of nickel, that is, nickel
acting as a nonmetal by adding electrons does not make
chemical sense.
P»3-2 Table 3-1
Nickel Arsenite should be Nickel Arsenate
According to the text in p.3-3, the basic salt
2NiCO33Ni(OH)24HzO "is the roost important form11 yet it does
not appear in the table (Is it the most important commercial
form?)
The melting point and boiling points given for nickel
nitrate hexahydrate are highly questionable; decomposition
rather than melting and boiling are involved.
P.3-3
Greater attention should be given to the formation of nickel
oxide which is an important process because of its relevance
to the nickel emitted into the environment as a result of
combustion.
The nickel-ammonia complex is Ni(NH3)64"1" in solution - the
hydroxide ion is not part of the complex in solution.
"When dissolved ... and is rendered soluble" is redundant.
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Cations form complexes with ligands
P. 3,8 Section 3.2
This section would be easier to write and easier to read if
it were organized in a different manner.
1. Sampling methods
2. Preparation of samples for instrumental or,
colorimetric analysis
3, instrumental analysis
Analysis of most air, water or soil samples are currently
performed by atomic absorption with the use of inductively
coupled plasma spectroscopy expanding. After the sample
preparation step, the measurement of the nickel
concentration in the prepared solutions is essentially the
same regardless of the type of environmental sample.
Particulate matter may be solid or liquid. Nickel compounds
occur in the atmosphere as particulate matter - they do not
necessarily have to be associated with other atmospheric
pollutants. Referring to nickel as having to be associated
with particulate emissions is confusing.
3.9
The melting and boiling points-of nickel are 1455*C and
2920*C; referring to nickel as a volatile trace element in
streams at temperatures up to 500'C is inappropriate.
High volume samplers are used for ambient air monitoring.
Because of instability it is not likely to find nickel
carbonyl in the ambient atmosphere.
3.2.2
The phrase "in its elemental state" implies presence of
nickel as the metal which is not the intent of the
statement.
The meaning of the third sentence is not clear as stated.
Identification of the nickel compounds present in an ambient
air sample is very difficult because of the very small
amounts usually present mixed in with a complex matrix of
other particulate matter and the changes that attempts to
separate trace amounts often have on the nature of the
compounds present.
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P. 3.13
The discussion on sampling should either be expanded by
providing a better description of the sampling methods or
shortened by providing more detailed references. I suggest
the latter.
The statement; "Any of the following three methods are
recommended; "is misleading, The state: "The sample is
removed by a valve regulating flow from a clean Teflon line
inserted into the sampling bottle. " is awkward - valves do
not remove samples and samples are not removed from the
sampling bottle.
P.3.14
The discussion of preeoncentration does not belong under
sampling,
Under 3,2.2 (Air) the detection limit of the AAF method is
given is 0.005 ug/ral? under 3*2.4 the detection limit is
given as 0.05 mg/1 (U.S. EPA 1979}
"Standard Methods for the Examination of Water and
Wastewater (1985)" gives a detection limit of 0.02 ug/ml by
flame and 0.001 ug/ml by graphite furnace.
Because the detection part of the analysis of either air
samples or water samples by atomic absorption involves the
same procedure, the discussion of atomic absorption should
be given in one place with these obvious discrepancies
resolved.
P. 3-15
The first two sentences in 3.2,7 say very little and should
be eliminated.
P. 3-16
The heading of Section 3.3 should be "Sources of Atmospheric
Nickel" rather than "Nickel in Ambient Air". The text is
concerned predominantly with sources and not ambient air.
The information in Section 3.3 should be summarized in
tabular form with references. The five main groups of
sources together with the nickel species emitted and
emission factors. (Amounts of nickel emitted per unit
activity), where available, would be the components of the
table. The discussion would focus on the table and could be
considerably shortened.
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The availability of emission factors for different types of
operations is of great importance to environmental control
work because they provide major guidance in the allocation
of the resources dedicated to the elimination of a problem.
See the discussion in Section 3.6.1* Note the estimate of
up to 80% of nickel from human activities as coming from
fossil fuel combustion.
P. 3-24
Table 3-2 would be more appropriately placed in section
3.3.2 than under analytical procedures.
The statement is made that neutron activiation analysis is
not performed on atmospheric nickel samples "because no
suitable states exist in the nuclei of nickel isotopes".
How is this statement reconciled with the discussion of NAA
on P. 3-11?
P. 3-25
The return to another discussion of the same five source
groups and the separation of "Nickel Species in Water" from
"Concentration of Nickel in Ambient Waters" repeats the
organization under air. This argues for a restructuring of
chapter 3 which unifies discussion of sources that release
nickel into the environment, their impact on air, water and
soil and the pathways into the human body then represent.
3-26/3-34
The author continues to have problems identifying nickel
species in the ionic state. Soluble nickel salts,
especially in highly dilute solutions exist as ions which
are relatively independent of each other* Statements such
as "This nickel is likely to be discharged as the Ni+2 ion
or as dissolved nickel salt {sulfate chloride, etc.)" imply
incorrectly that Ni+^ can exist either as the independent
ion or in solution as
The map legend (p. 3-33) does not indicate the significance
of the counties which are shown without coloring.
in the text the Southeast basin is said to have means
ranging from 85.1 to 754 ug/1 while in Table 3-3, the range
of means is 45.4 to 77,6. The Northeast had a maximum of
9,140 ug/1 in 1980 but its 85th percentile was 105 compared
to one of 173 for the southeast which had a maximum of only
900. This shows the desireability of frequency distribution
statistics for such data sets.
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The text is again at variance with the table. "... for the
Southeast Basin in 1980 where the maximum reported value was
1500 ug/1 but 85 percent of the remaining samples contained
less than 130 ug/l"» Table 3-3 shows 900 and 173 for the
same statistics.
3-34/3-38
Oil and coal used for space and hot water heating should be
included with power utilities as sources of nickel in soil.
Space and hot water heating emissions usually occur at lower
altitudes with less opportunity for dispersion that those
from tall stacks, incineration of urban wastes also should
be cited as a source of soil contamination.
in Section 3-6.1 it is reported that combustion of oil alone
accounts for 83% of atmorpheric nickel from human
activities. Space and hot water heating are major
contributors.
P. 3-40
Nickel in Food - Should restrict the discussion to the
nickel content of different foods. Section 4.1,2,
"Gastrointestual Absorption of Hickel", is the proper place
to discuss the relationship between intaJce and fecal
excretions of nickel.
P. 3-42 Section 3.6
The last sentence in the first paragraph should be
rewritten.
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F, WILLIAM SUNOERMAN, JR.. M.D.,
Qtpartments of Labaracofy Medicine and Pharmacology, University of Connecticut School of Medicine
283 Fgrmington Avenue, Farmington, Connecticut. 06032. Telephone 203/674-2328
10 March 1986
Mr, Daniel Byrd
Executive Secretary
Science Advisory Board (A-101F)
U.S. Environmental Protection Agency
401 M Street, S.W.
Washington, DC 20460
Dear Dan:
In preparation for the meeting on 25 March 1986 of the EPA Metals Subcommittee
to consider the Health Assessment Document for Nickel, I have prepared the
following line-by-line citations of some points in the document that may need
clarification or correction;
p1v, 1(2, line 11. The word "brain" should be omitted, unless the statement
is modified to specify nickel carbonyl.
p xiv, line 23. My initial "F." should be placed before "William",
p 2-4, fl. Soya beans and soya products contain an average of 5,5 mg
Ni/kg (range 1.1 to 7.8) and cocoa contains 9.8 mg Ni/kg
(range 8.2 to 12), according to Nielsen and Flyvholm
(1984).
p2-4, |2. Volcanic emissions may be cited as an additional natural
source of atmospheric nickel.
p 2-4, 1(3. Human parenteral exposures to nickel are of importance in
relationship to iatrogenic sources, such as implanted
orthopedic pros-theses, hemodialysis treatment, and
injections of nickel-contaminated drugs and X-ray contrast
media.
p 2*9, 13, line 5 The statements on post-partum hypernickelemia should be
and p 2-12» 1J6, deleted from the summary. The original observations of
line 5.Rubanyi et_aK (1982) are dubious, owing to analytical
prob 1 emsy~post-partum hypernickelemia has not been
observed in a follow-up study by Nomoto et al. (1983).
p 2-13, Jlt line 1. Is there evidence that family history is predictive of
susceptibility to nickel sensitization, on the basis of
hereditary predisposition?
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(2)
p 2-13, |2»1ast The measurements by Sutenmann etal. (1982) of nickel in
2 lines. cigarette smoke do not agree withearlier measurements
(Menden et al. 1972, Wescott and Spincer, 1974, Perinelll
and Carcigno, 1978), This matter Is unsettled and further
research is needed. Studies by Alexander et al. (1983) do
indicate that the nickel in mainstream smoke is not
present as nickel carbonyl. The statement that "nickel in
mainstream smoke is "minimal" is imprecise and
controversial and should be deleted.
p 3-11, If2, line 6. The unit should be 'ii 1" rather than "ml".
p 3-15, |4, lines The statement that "neutron activation analysis and
Z-3'. "colorimetric procedures are also used" is incorrect and
should be deleted. Instead, a statement can be inserted
that "anodic-stripping voltametry and isotope-dilution
mass spectrometry are also used".
p 3-16, |1, line 14. The reference to Nomoto and Sunderman (1970) is
out-of-date. More up to date references are Stoeppler
(1981,1984) and Sunderman (1984).
p 3-23. 1f2, line 3.
p 3-4Q, |4-6, and
1able "3-8".
p 3-42.
p 3-42, 14.
p 4-1, fl, line 6,
p 4-9. HI.
p 4-18. Table 4-2.
The importance of nickel exposures from mold-making in
glass bottle factories should be mentioned (Raithel et al.
1981,1985). ~~
Except for the study by Myron ^ a1. (1978)> the cited
studies on nickel concentratioffs"irf foods are out-of-date.
More recent references are Ellen et al. (1978), Nielsen
and Flyvholm (1984), and Flyvholm et al. (1984).
A paragraph on nickel in bacteria and other microorganisms
might be appropriate at the end of section 3,5.
The citation of Weast (1980) (CRC Handbook on Chemistry
and Physics) can be deleted; the paper by Hassler (1983)
refers to an unpublished report; the paper by Sutenmann et^
al. (1982) refers to nickel in smoke from tobacco grown on
municipal sludge-amended soil. Additional references that
may be cited are given above,
Parenteral exposures of humans to nickel from prostheses,
medications, hemodialysis, etc,, should be mentioned, as
discussed by Sunderman et al. (1986).
The discussion of nickel in cigarette smoke should be
modified, as indicated for p 3-42, f4.
The dosages given for the mouse experiment of Oskarsson
and Tjalve (1979) are erroneous (4.6yg Ni/kg). Moreover,
the footnotes of the NAS table have been omitted. The
footnotes, which specify the intervals between last
injection of SSnnc^ and death, are necessary for
interpretation of these experimental data.
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(3)
p 4-20 to 4-22, Nickel concentrations in human milk might be discussed
(Mingorance and Lachica, 1985; Feeley et al., 1983).
p 4-24, 1(4. Evident analytical problems in the study by Rubanyi et al
(1982) should be mentioned, and the contrary findings of
Nomoto st._tlt (1983) should be discussed.
p 5-8, 12, Jine_!_,_ DL-alanine (not alaline).
p 5-13, f4. Additional cases of cancers at the sites of implanted
nickel-containing prostheses have been reported (see
references cited by Linden et al., 1985).
p 5-23, |4. The findings of Hopfer et al. (1985), showing that the
erythrocytosis is mediated by enhanced erythropoietin
production should be mentioned,
p 8-116, |2. The word "tested" should be changed to "found".
line 22,
p 8-157, footnote. Change "cm3" to "m3".
In general, the present document fs substantially improved, in comparison
to earlier drafts. Unless you disagree, I do not believe that the specific
points that are mentioned in this letter need detailed consideration by the
Metals Subcommittee. I suspect that our discussions in Farmington will
be centered upon the controversial proposition that "there is a reasonable
probability that the ultimate carcinogenic form of nickel is nickel ion" and
that "on this basis, all compounds of nickel might be regarded as potential
human carcinogens , . ." (p 8-210).
Looking forward to seeing you on 24 March, and with cordial regards, I am,
Sincerely yours.
F. William Sunderman Jr., M.D.
Professor of Laboratory Medicine
and Pharmacology
/ms
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(4)
References that are not cited In the Document
Ellen, G., van den Bosch-Tibbesma, S.» & Douma, F.F. (1978) Nickel content of
various Dutch foodstuffs. Z. Lebensin. Unters. Forsch, 166, 145-147,
Feeley, R.M., Eitenmiller, R.R., Jones, J.B., Jr., & Barnhart, H. (1983)
Manganese, cobalt, nickel, silicon and aluminum in human railk during early
lactation. Fed. Proc., 42, 931.
Flyvholm, M.A., Nielsen, G.D., & Andersen, A. (1984) Nickel content of food
and estimation of dietary intake. Z> Lebensro. Unters. Forsch., 179, 427-431.
Hopfer, S.M., Sunderman, F.W., Jr., & Goldwasser, E. (1985b) Effects of
unilateral intrarenal administration of nickel subsulfide to rats on
erythropoietin concentrations in serum and in extracts of both kidneys. In:
Brown, S.S. & Sunderman, F.W., Jr., eds,» Progressin Nickel Toxicology,
Oxford, Blaekwell, pp 97-100. ""
Linden, J.V., Hopfer, S.M., Gossling, H.R., & Sunderman, F.W., Jr. (1985)
Blood nickel concentrations in patients with stainless-steel hip prostheses.
Ann. Clin. Lab. Sci., 15, 459-463.
Menden, E.E., Ella, V.J., Michael, L.W. and Petering, H.G. (1972) Distribution
of cadmium and nickel of tobacco during cigarette smoking. Environ. Sci.
Techno1., £:83Q-832.
Mingorance, M,D. & Lachica, M. (1985) Direct determination of some trace
elements in milk by electrothermal atomic absorption spectrometry. Anal.
Lett., 18. 1519-1531.
Nielsen, G.D. & Flyvholm, M. (1984) Risks of high nickel intake with diet.
In: Sunderman, F.W., Jr., ed.-in-chief, Nickel in the Human Environment, Lyon,
Intern. Agency Res. Cancer, pp 333-338.
Perinelli, M.A., and Carugno, N, (1978) Determination of trace metal in
cigarette smoke by fTameless atomic absorption spectrometry. Bertr. Tabakfors.
Intern. 9:214-216. ~~ "~^
Nomoto, $,, Hirabayashi, T., & Fukuda, T. (1983) Serum nickel concentrations
in women during pregnancy, parturition, and post-partum. In: Brown, S.S. &
Savory, J., eds., ChemicalToxicology and Clinical Chemistry of Metals, London,
Academic Press, pp 351-352.
Raithel, H.J., Mayer, P., Schaller, K.H., Mohrmann, W., Weltle, D.f and
Valentin, H. (1981) Untersuchungen zur Nickel-Exposition bei Beschaftigten in
der Glas-Industrie. Zbl. Arbeltsmed., 31_;332-339.
Raithel, H.J., Kress, W.t Schaller, K.H., Weltle, D.t & Valentin, H. (1985)
Toxicological and occupational medical investigations concerning nickel-
exposure in different industrial areas in the FRfi. In: Brown, S.S. &
Sunderman, F.W., Jr., eds., Progress in Nickel Toxicology, Oxford, Blackwell,
pp 219-222.
Stoeppler, M. (1981) General analytical aspects of the determination of lead,
cadmium, and nickel in biological materials. In: Facchetti, S., eds.,
Analytical Techniques for Heavy Metals in Biological _F1 inds, Amsterdam,
Elsevier,pp 133-154.
-------
(5)
Stoeppler, M. (1984) Analytical chemistry of nickel. In: Sunderman, F.W.,
Jr., ed.-in-chief. Nickel In the Human Environment, Lyon, Intern, Agency Res.
Cancer, pp 459-468.
Sunderman, F.W., Jr. (1984) Nickel, In: Vercruysse, A., ed., Hazardous
Metals in Human Toxicology, Amsterdam, Elsevier, pp 279-306.
Sunderman, F.W,, Jr., A1t1o» A., Morgan, L.G., & Norseths T. (1986) Biological
monitoring of nickel. Toxicology and Indust. Health (1n press).
Wescott, D.T. and Splncer, 0. (1974) The cadmium, nickel and lead content of
cigarette smoke. Belt. Tabakfors. 7:217-221.
-------
EPRI
Electrie Power
Research Institute
April 14, 1986
Dr. Daniel Byrd
Science Advisory Board
US/EPA A-1Q1F, Rm 508
Washington, DC 20460
Dear Dan:
I have reviewed the Nickel Health Assessment Document and
offer the following comments about the quantitative risk
assessment.
Animal Studies.
The data from the Ottolenghi et al. study were used to
undertake a quantitative risk assessment for nickel, r have
great concern about using these data for two reasons. First
of allr one-half of the control and treated- anamals were
injected intravenously with hexachlorotetra-flourobutane, an
agent used to induce pulmonary infarction. There is no
available information to indicate whether there may be any
synergism or antagonism resulting from the simultaneous
exposure of this drug and nickel subsulfide* which also
largely affected the lungs. At a minimum the Ottolenghi et
al. data set should be subdivided into two groups for risk
assessment purposes. Those animals injected with
hexachlorotetrafluorobutane and those which received no
injection, if the risk assessment results are similar, the
data could be concerned.
I am also very uncomfortable with the very high mortality
rate in the nickel-exposed and control groups in this
study. Apparently only 5% of the exposed group and 31% of
the control group survived. It would be useful to have some
guidelines about minimally acceptable survival rates before
a data set is subjected to a quantitative risk assessment*
3412 Hillview Avenue, Post Office Box 10412, Palo Ate, CA 94303 Telephone (415) 855-2000
Washington Office: i860 Massachusetts AM., NW, Suits 700, Washington, DC 20036 (202) 872-9222
-------
Dr. Daniel Byrd, 4/14/86
Page 2
In addition, clearly-articulated caveats should be attached
to any quantitative results using this study — even if the
results are only used to compare the "best" animal study
with epidemiology results. The comparison may not be
meaningful.
Epidemiology Studies
Four data sets were used for these analyses. The
Huntington, W.Va. data are taken from a study by Enterline
and Marsh, an apparently carefully undertaken study. The
analyses derived from this data set are reasonable and
clearly articulated.
Data from Copper Cliff, Ontario were the second data set
analyzed. I have two concerns with the analyses of these
data. First of all, exposure is poorly characterized and
rough exposure estimates are used in the analyses. Since
the selection of exposure values can influence the results,
I suggest that there be some type of sensitivity analysis
undertaken for this study showing how risk (potency)
estimates vary as exposure estimates vary. Secondly, the
analysis used a background lung cancer rate of .036, derived
from U.S. white male data. There is some difference between
the U.S. and Canada as seen from the attached figure; but of
greater concern is the increase over time in lung cancer
rates. A recent EPA publication (U.S.Cancer Mortality,
Rates and Trends, EPA600-1-83-015A) shows that the lung
cancer mortality rate for white males in the U.S. has
increased from 29.6 (1950-59) to 46.8 (1960-69) to 64.0
(1970-79) per 100,000. Given this volatility, it is
important that the correct background rate Pa be used in the
risk assessment calculation for the Copper Cliff data. The
use of .036 may be incorrect.
The third study used in the analysis was from Clydach,
Wales. The analysis of these data suffer from similar
problems as the Ontario data except the extrapolation of a
U.S. background rate to Wales may be more questionable than
extrapolation to Canada. Figure 1 demonstrates how much
higher male lung cancer mortality rates are in England and
Wales over the U.S. This study may also suffer from some
confounding of exposure as practically all of the lung
cancer deaths apparently were exposed to arsenic. The
analysis should show how any arsenic exposure would impact
the risk estimates.
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Dr. Daniel Byrd, 4/14/86
Page 3
The final study analyzed is of a Kristiansand, Norway
population. Concerns about this analysis are similar to
those for the Copper Cliffs analysis. The attached figure
demonstrates the extrapolation of U.S* background lung
cancer mortality rates to Norway may be dangerous, as
Norwegian rates appear to be considerably lower than U.S.
rates. The analysis for this study is also not clearly
articulated. A table analagous to Table 8-47 would be
helpful here so that the assumptions made in the analysis
would be clearer.
Overall Comment
I am somewhat troubled by the use of "median of the range"
risk estimate. Since this apparently turns out to be the
average of the highest and lowest risk estimates, it is
dominated by the larger number. A better approach might be
to derive a median estimate for each study and take the
median of the medians.
I hope the above are useful. Obviouslyf if any
clarifications are desired, please let me know.
Sincerely,
Dr» Ronald Wyzga
Technical Manager
Environmental Risk Assessment
Enclosure
cc; Bernie Weiss
HEW/acc
-------
Dr. Daniel Byrd, 4/14/86
Enclosure
FIGORE 1
- :GURE !6. AGE-ADJUSTED MORTALITY RATES FOR MALIGNANT NEOPLASMS
OF THE LUNG, BRONCHUS, AND TRACHEA IN VARIOUS COUNTRIES,-
1966-1967,
MALE
t
Scotland
England i Wales
Netherlands
Austria
Belgium
U. S., Non-wnit
North. Ireland
Germany, F.H,
U. S>. Whits
New Zealand
Australia
South Africa
Denmark
Switzerland
Ireland
Italy
France
Chile
Norway
Jaoan
33 40 SO
RATE PSR 100.000 POPULATION
Seoiland
England & Wales
Ireland
Denmark
U.S.. NOn-whrte
North, trelarnj
Sou in Africa
U.S,.Wnile
Aystfta
Chile
Canada
New Zealand
GarfrWrty, F.R.
Japan
Australia
Italy
Belgium
Finland
France
Netherlands
Switzerland
Norway
Portugal
80
0 10
RATE PER 1QO.Q00
POPULATION
Source: Levin, D. (1975) Cancer Rates and Risksr
2nd. edition, U.S.H.E.W. NIH 75-691.
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THE UNIVERSITY OF ROCHESTER
601 ElMWQQO AVENUE
MEDICAL CENTER
™BK 14M2
SCHOOL OF MEDICINE AND DENTISTRY * SCHOOL OF NURSING
STRONG MEMORIAL HOSPITAL
DEPARTMENT OP PH AKMACOI.OGV
March 27, 1986
Dr. Daniel Byrd
Executive Secretary
Science Advisory Board (A-101F)
U.S. Environmental Protection Agency
401 M Street, S.W,
Washington, D.C,
Dear Dr. Byrd:
I have prepared a list of comments on the Health Assessment Document for
Nickel. These comments relate specifically to sections 4,2.1 - 4.4 of the
document. Evaluation of the remaining portion of section 4 is being
conducted by Dr, Qberdoerstei:.
General Comments on Sections 4.2.1 ^ 4.4
1. In view of the controversy over the "Ni+ hypothesis", it seems
appropriate to include a discussion of the jpetabolism of nickel compounds to
Ni in tissues, is there evidence for Ni being a common metabolite of
nickel compounds? Reference is made to this possibility in section 4,2.2.
(P3) where the conversion of nickel carbonyl to Ni is mentioned.
2. when possible, the elimination half times should be stated precisely,
as these values are very useful,
3. The expressions "clearance", "retention" and "intake" are used
incorrectly in places.
4. A uniform set of units should be selected to express concentrations
of nickel.
Specific Comments OT Sections 4.2.1 - 4.4 :
4.2.1 Nickel in Blood i
1. Pl, 1.1 s The meaning of the statement "Blood is the main vehicle
for transport of absorbed nickel." is not at all clear. How is the term
"absorbed nickel" defined? Is nickel that enters the epithelial cells of the
intestine by crossing the mucosal weiabrane considered to have been absorbed?
Is it meant that blood is the predominant route by which nickel is
distributed to other tissues (e.g. rather than lywph)? Can the relationship
-------
between the concentration of nickel in blood or serum and the body burden of
nickel be stated in precise terms?
2- ?2j_ LJ, : Change "no" to "not".
3- p3> 1.-2 : Change "clearance" to "elimination". The term "clearance"
has a very specific meaning. It refers to the volume of a compartment from
which a substance is removed over a given length of time. Thus, the units of
clearance are volume per unit of time (e.g. ml/tain). It should not be
confused with rates of elimination, rate constants for elimination processes
or with half-times for elimination. There are several places in the text
where this discrepancy occurs. It is a minor point, however, for
consistency, a uniform terminology should be used,
3. P4, 1.1 ; Change "clearance of nickel" to "kinetics of elimination
of nickel".
4*« H/ iil ' Can the elimination half-times be stated precisely here?
5. P6, 1,3 ;. Change "may be the factor..." to "may be an important
factor in the transfer of nickel from blood to other tissues.". Blood is a
tissue.
6. P7, 1.7 : Change "histidine may serve to..." to "histidine may
facilitate the movement of nickel from the serum into other tissues.".
7• Mi Iii ' Change "labeled nickel" to "radiolabeled nickel".
8« PS? 1-3 : What is alpha-2-nickolplasmin? Is this the same as
nickelplasmiiFTp. 4-13, 1.30)?
9. P9, 1.2 j Change "which reflect" to " that my reflect". Is this
range of TbTnding of nickel to serum albumin the result of differences in
binding characteristics of serum albumin or does it reflect differences in
the binding characteristics or amounts of other binding ligands in the serum
(e.g. nickelplasnin, histidine)?
!
4.2.1*1. Tissue Distribution of Nickel; Human Studies
1, P3, 1.11 ; Change "that the element..." to "that the accumulation of
nickel does not increase with increasing age.".
2* E3, 1^.18 * Change "ppm" to "ug/g". It would help if similar units
for concentration were used throughout the document.
3- ?6,_ 1.5 ? Does this mean that accumulation of nickel in lung, but
not other tissues, increases with increasing age? If so why not state this
precisely?
4.2.2.2 Animal Studies ;
-------
1* ffv 1.3 : What is meant by the expression "elevated, rapidly cleared
levels of nickel"? is it meant that the levels of nickel in these tissues
were elevated in animals that inhaled nickel carbonyl vapor and that the
accumulated nickel was eliminated quickly?
2. P3, 1.5 t The basis for this presumption is not clear,
3. P3, 1.9 : is this pathway of metabolism of nickel carbonyl a ,
hypothesIs~oFTias it been established? it is highly relevant to the "Ni
hypothesis" that nickel compounds can undergo conversion to the divalent ion
in tissues. Also change "erythrocytes and tissues" to "erythrocytes and
other tissues".
4- P6.A 1,.2 : Change "metal transport protein" to "metal binding
protein", A role for metallothionein in the "transport" of metals has not
been established. This is to distinguish metallothionein from other proteins
(e.g. transferrin) that have been shown to function in the transport of
metals in the extracellular or intracellular compartments.
5. P6, 1,4 : Convert the units "mmol/Kg" to "ug/Kg" for consistency
with other notations.
6. P7, 1,10,12,13 : Convert these values to a consistent set of units.
7. BB : What mechanism could regulate nickel intake? Is it meant that
absorption of dietary nickel Erott the gastrointestinal tract is regulated or
that the levels of nickel in tissue are maintained constant as the amount of
nickel in the diet is increased?
4.JU3 Subcellular distribution of Nickel :
PS, 1.9 ; it is not at all clear why endocytosis would deliver
insoluble nickel adjacent to the nucleus. What is meant by this statement?
4.3 Retention and Excretion of Nickel in Kan and Animals :
P2 j Is the term "retention half-time" synonyaous with "elimination
half-time"? What is meant by the term "retention rate"? Does this mean that
30% of the ingested nickel (400 ug Ni/day) is absorbed from the
gastrointestinal tract? If so, the elimination half-time o£ 1200 days seems
to be very high. What is menat by the term "retention time"?
F3» JUB : What is meant by the term "daily intake retention figure"?
The information that is discussed in P2 and P3 are very important and need to
be presented very clearly by using precise terminology to describe the
elimination Kinetics.
p§ : Change "major clearance route" (1.1) to "major excretory route1**
&lso,~Tt is-not clear why variations in the concentration of nickel in urine
-------
are the result of analytical limitations. The "urine flow rate vries 50 to
100 fold as function of body water content and diet. If the rate of urinary
excretion of nickel was relatively constant in humans of agiven sise or age,
the concentration of nickel in urine would also vary by this amount.
P6, 1»1 j Change "clearance route" to "excretory route".
P6, 1*8 : Change "clearance" to "excretion".
P8, 1.2 : Is the measurement of nickel in hair a useful indicator of
the body burden of nickel or is it not?
j?9_r 1,1 ; Change "clearance" to "excretion" or "eliaiination'1.
pip, 1,2 : Change "clearance" to "elimination".
Pll, 1.7 ! Can the elimination half times be stated precisely?
P12,_ 1.1 : What is meant by the expression "the pattern of
labeleBPnicTtel urinary excretion"? Also, what is i»eant by a "ligating
moiety"?
Eespeetfully,
.•"? *•
^__X_ S',/'
^•t^-y
Gary L» Diamond, Ph.D.
GliD/lm
-------
THE UNIVERSITY OF ROCHESTER „
n j. I-r*t I ,-* A • X-xr-lk i-r-i-i-fc ROCHESTER, NEW YORK 14642
MEDICAL CENTER AREA CODE 716
SCHOOL OF MEDICINE AND DENTISTRY • SCHOOL OF NURSING
STRONG MEMORIAL HOSPITAL
DEPARTMENT OF RADIATION BIOLOGY
AND BIOPHYSICS
May 28, 1986
Dr. Daniel M. Byrd, III
Executive secretary
Science Advisory Board
US EPA
401 M Street, S*W.
Washington, DC 20460
Dear Dan:
Thank you for your letter of May 21 with the draft committee and sub-
committee letter reports on the review of the nickel IAD* Unfortunately, I
had overlooked an error on page two of my comments: The formula should read:
At - i (1 - .-<*)
I apologize for this oversight and I would like to ask you to correct it
before submitting it to the SAB, I have no further comments on the draft
letter. Your memo and letters did reach me on fuesday, May 27,
With kind regards,
Sincerely yours,
GOnter Oberdocsc&rr D.V.M., Ph.D.
Associate Professor of Toxicology
-------
THE UNIVERSITY OF ROCHESTER ^ ELMWOOO
.._.—^.j^.. A i— n .-r-r-r-i ROCHESTER, NEW YORK 14642
MEDICAL CENTER AREA CODE 7i6
SCHOOL OF MEDICINE AND DENTISTRY • SCHOOL OF NURSING
STRONG MEMORIAL HOSPITAL
DEPARTMENT OF RADIATION SiOLOGY
AND BIOPHYSICS
April 23, 1986
Dr. Daniel Byrd III
Executive Secretary
Science Advisory Board
US - EPA
410 M Street, S.W.
Washington, D.C. 20460
Dear Dan: - •_
Please accept my apologies for sending these comments on the Ni document -
as requested by you and Bernie Weiss - so late. I hope the people working on
the document can use my comments, if they or you need additional
clarification, please contact me.
Sincerely yours.
Gunter OberdSrster, D.V.H., Ph.D.
Associate Professor of Toxicology
GO/jh
Attachment
-------
COMMENTS ON NICKEL HAD (<32nter Oberdorster)
Chapter 4; Metabolism.
It may be useful to include a general diagram of the metabolic model of
Ni-kinetics. I have attempted a draft of such a model, and if possible, EPA
could put some number of transfer rates into this model. It gives the reader
a quick and general idea of major metabolic pathways and points out the target
sites.
Specific comments:
p. 4-1: relative solubilities of Ni-compounds in biologically relevant
media are discussed. While these are useful to have, they may not as easily
be useable for predicting in vivo, elimination rates as it is stated on page
4-1. It is known, for example, that insoluble CdO is rapidly solubilized in
the lung, and probably the most important mechanism for this is the
solubilization in the lysosoraes of the alveolar macrophages. This was
recently shown by Lundborg _et_ _al_. (1984, 1985) for Mn02f and the low pa of
the lysosome (pB4) may account for this. Thus, more emphasis should be placed
on the in vivo solubility; in addition, particle size plays an important role
in this process, for 2 reasons: (1) the phagocytosis is dependent on the
particle size, (2) the solubilization rate is slower for larger particles.
p. 4-4: The conclusion drawn from the Wehner and Craig study (1972) -
that absorption of NiO in the period of 45 days was negligible - should be
judged under the experimental conditions: the concentrations being used were
2-160 mg/m3, and this may lead to a decrease in lung clearance of particles
and possibly also of HiO particles. For example, we showed that exposure for
several weeks to 50 pg/»3 Of Nio - a very low concentration - led to a
highly significant decrease of the lung clearance of particles in the rat
(OberdSrster et_ _ajU, 1980, ins Nickel Toxicology, p. 125, Academic Press}.
We also showed that lung retention of inhaled NiO has a half time of 36 days.
this could possibly be included in the document.
p. 4-5s The term "dose-lung deposition relationship* (line 1) is
unclear. Is it exposure - lung deposition relationship?
On the following pages, the terms clearance rate - which is the amount
being eliminated per unit time - and retention half-time - which is the time
during which 50 percent of the initial amount is eliminated using a
monoexpoential model -are used indiscriminately such as "clearance half-time*
or even "clearance rate half-time.* This should be changed.
p. 4-7: Clearance rate is given as 72 hours (last paragraph); it should
be retention half time. This number was derived from urinary excretion, based
on the Corvaiio and aiemer study (1982). However, the Ni compounds used in
the 2 studies were different, and it can be expected that intratracheally
instilled "moderately* soluble Ni-carbonate will be cleared to a large extent
into the Gl-tract and is then excreted through the feces. Therefore, the T
1/2 of 72 hours is in all likelihood lower.
-------
Page Two
p. 4-8: First paragraph; It can be expected that accumulation of NiO in
the lymph-nodes of the lung will be seen when the lung is overloaded. This is
not spegifio foe Nio, but for any particle, as has been shown for Ti02 by
Ferin et al. (1980) when the lung was burdened with too much TiQj. What is
"retro-ciliary" removal? {second paragraph) -probably meant is mueo-eiliary.
I don't see that a half time of 34 and 21 days for dissolution of Ki
subsulf ide in vitro is "roughly equivalent* to an in vivo retention T 1/2 of
12 days, it is not, and it shows - as mentioned earlier - that in vit.ro.
dissolution rates cannot simply be extrapolated to in vivo dissolution rates.
In this context, it might be mentioned again that the rate of solubiliiation
is of importance in addition to the solubility per se.
Chapter 8.3. Risk estimates based on animal studies.
p. 8-156; I am not certain - and it needs some better justification - how
the duration of the experiment (Le) should be included in the formula at the
bottom of the page. The dose retained in the lung over an exposure period
depends very much on the biological half time of the compound; Cor example, if
f 1/2 is longer* than the total dose (expressed here by total exposure) it is
very much different than it would be if the T 1/2 is shorter. So, I believe,
the retention of Ni in the lung should be included in the formula. This could
be done according to
where At is the amount retained at time t, a is the amount being deposited
each day and b is the elimination rate (b = . ,.).
p. 8-157! first paragraph deals with a completely water-soluble gas or an
aerosol and a poorly water-soluble gas. Ni carbonyl is insoluble in water,
its T 1/2 in air is only about 100 seconds. To which category does it belong
here? Aerosols are not absorbed proportionally to the amount of air breathed
in, factors like particle size will affect deposition and subsequent
absorption. Therefore, Nij 32 cannot reasonably be expected to be
absorbed (?) (probably meant - deposited) proportionally to breathing rate*
The distinction between "absorption" (-leading to an effective dose) and
"deposition* (resulting in a deposited dose) of an aerosol should clearly be
made. (I attach a copy of pages 8-157 and 8-158, from which some handwritten
suggestions for changes can be taken).
p. 8-161; Line 2 - it should be 970 yg/JG^ nickel subsulfide. Likewise,
in the table on this page the compound is nickel subsalf ide.
p. 8-162: Calculation of equivalent lifetime continuous exposure (top of
page) for calculation of equivalent human dosage cannot be done without taking
into account and knowing retention of inhaled Ni in rats and humans {see
comments for p. 8-156).
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Page Three
A few general remarks on the extrapolation of experimental animal data to
humans seem in place. In this and other Health Assessment Documents, body
surface area is used to correlate delivered doses in humans and animals. It
would be more appropriate to use lung surface area, more specifically
bronchial and alveolar surface area in rats and humans for calculating a
"surface area dose,1 Enough information on lung morphometry is available to
attempt those calculations. There is probably a difference in tumor sites
between the animals and humans, namely bronchial cancer in Hi-exposed workers
and possibly more peripheral tumors in the rats. The significance of this
difference for extrapolating from animal studies to human could be pointed
out, i.e., stating that such extrapolations are not well supported and will
limit an estimation of tumor risk for humans derived from animal studies. The
clearance of inhaled dust in the bronchial region is normally very fast,
unless bronchial clearance mechanisms are impaired. This could happen during
a high exposure situation or - at lower exposure concentrations - when there
is a toxic effect on bronchial clearance mechanisms, it is also possible to
calculate the deposited alveolar dose in humans and compare it to a calculated
bronchial dose.* This then could be compared to the respective doses in
animals for the same particle size* The result will show that bronchial and
alveolar doses are different in man and animals after inhalation of the same
particle size. Prom such calculations a particle size for animal studies can
be estimated that would approximate the human lung dose and that should be
used in planned animal studies.
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NICKEL METABOLISM
Skin Deposition
Inhalation
Inqestion
Lung
Gl-tract
Blood
Liver
jr
System I
Urine
Feces
Critical or target organs
4,
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