vvEPA
United States
Environmental Protection
Agency
Office of Water
Regulations and Standards
Criteria and Standards Division
Washington DC 20460
EPA 440/5-80-060
October 1980
Ambient
Water Quality
Criteria for
Nickel
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AMBIENT WATER QUALITY CRITERIA FOR
NICKEL
Prepared By
U.S. ENVIRONMENTAL PROTECTION AGENCY
Office of Water Regulations and Standards
Criteria and Standards Division
Washington, D.C.
Office of Research and Development
Environmental Criteria and Assessment Office
Cincinnati, Ohio
Carcinogen Assessment Group
Washington, D.C.
Environmental Research Laboratories
Corvalis, Oregon
Duluth, Minnesota
Gulf Breeze, Florida
Narragansett, Rhode Island
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DISCLAIMER
This report has been reviewed by the Environmental Criteria and
Assessment Office, U.S. Environmental Protection Agency, and .approved
for publication. Mention of trade names or commercial products does not
constitute endorsement or recommendation for use.
AVAILABILITY NOTICE
This document is available to the public through the National
Technical Information Service, (NTIS), Springfield, Virginia 22161.
jjjH J , f.'j _ .- . _,. -,._,. » ,' 1 '4 -"**'
ii
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FOREWORD
Section 304 (a)(l) of the Clean Water Act of 1977 (P.L. 95-217), requires
the Administrator of the Environmental Protection Agency to publish
criteria for water quality accurately reflecting the latest scientific
knowledge on the kind and extent of all identifiable effects on health and
welfare which may be expected from the presence of pollutants in any body of
water, including ground water. Proposed water quality criteria for the 65
toxic pollutants listed under section 307 (a)(l) of the Clean Water Act were
developed and a notice of their availability was published for public
comment on March 15, 1979 (44 FR 15926), July 25, 1979 (44 FR 43660), and
October 1, 1979 (44 FR 56628). This document is a revision of those proposed
criteria based upon a consideration of comments received from other Federal
Agencies, State agencies, special interest groups, and individual scien-
tists. The criteria contained in this document replace any previously
published EPA criteria for the 65 pollutants. This criterion document is
also published in satisfaction of paragraph 11 of the Settlement Agreement
in Natural Resources Defense Council. et_a1. vs. Train, 8 ERC 2120 (D.D.C.
1976), modified, 12 ERC 1833 (D.D.C. 1979).
The term "water quality criteria" is used in two sections of the Clean
Water Act, section 304 (a)(l) and section 303 (c)(2). The term has a
different program impact in each section. In section 304, the term
represents a non-regulatory, scientific assessment of ecological effects.
The criteria presented in this publication are such scientific assessments.
Such water quality criteria associated with specific stream uses when
adopted as State water quality standards under section 303 become en-
forceable maximum acceptable levels of a pollutant in ambient waters. The
water quality criteria adopted in the State water quality standards could
have the same numerical limits as the criteria developed under section 304.
However, in many situations States may want to adjust water quality criteria
developed under section 304 to reflect local environmental conditions and
human exposure patterns before incorporation into water quality standards.
It is not until their adoption as part of the State water quality standards
that the criteria become regulatory.
Guidelines to assist the States in the modification of criteria
presented in this document, in the development of water quality standards,
and in other water-related programs of this Agency, are being developed by
EPA.
STEVEN SCHATZOW
Deputy Assistant Administrator
Office of Water Regulations and Standards
111
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ACKNOWLEDGEMENTS
Aquatic Life Toxicology:
Charles E. Stephan, ERL-Duluth
U.S. Environmental Protection Agency
John H. Gentile, ERl-Narragansett
U.S. Environmental Protection Agency
Mammalian Toxicology and Human Health Effects:
Magnus Piscator (author)
Karolinska Institute, Sweden
Christopher T. DeRosa (doc. mgr.)
ECAO-Cin
U.S. Environmental Protection Agency
Jerry F. Stara (doc. mgr.) ECAO-Cin
U.S. Environmental Protection Agency
A. F. Crocetti
New York Medical College
Philip E. Enterline
University of Pittsburgh
D. W. Gaylor
U.S. Food and Drug Administration
Richard Jacobs
U.S. Food and Drug Administration
Steven D. Lutkenhoff, ECAO-Cin
U.S. Environmental Protection Agency
0. J. McKee, ECAO-RTP
U.S. Environmental Protection Agency
S. Shibko
U.S. Food and Drug Administration
F. W. Sunderman
University of Connecticut
Edward Calabrese
University of Massachusetts
Dr. Chung
U.S. Food and Drug Administration
Joe Cirvello
U.S. Environmental Protection Agency
Patrick Ourkin
Syracuse Research Corporation
Warren Galke, ECAO-RTP
U.S. Environmental Protection Agency
R. Norton, HERL
U.S. Environmental Drotection Agency
Si Duk Lee, ECAO-Cin
U.S. Environmental Protection Agency
E. Mastromatteo
Inco Limited, Toronto, Ontario
Paul Mushak
University of North Carolina
Donald Stedman
University of Michigan
Technical Support Services Staff: D.J. Reisman, M.A. Garlougn, E.L. Zwayer,
P.A. Daunt, K.S. Edwards, T.A. Scandura, A.T. Pressley, C.A. Cooper,
:O1. Denessen.
Clerical Staff: C.A. Haynes, S.J. Faehr, L.A. Wade, D. Jones, B.J. Sordicks,
3.J. Quesnel!, T. Highland, 8. Gardiner, R. Swantack.
IV
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TABLE OF CONTENTS
Page
Criteria Summary
Introduction A-l
Aquatic Life Toxicology B-l
Introduction B-l
Effects B-2
Acute Toxicity B-2
Chronic Toxicity B-7
Plant Effects B-5
Residues B-8
Miscellaneous B-8
Summary B-10
Criteria B-ll
References B-30
Mammalian Toxicology and Human Health Effects C-l
Introduction C-l
Exposure C-4
Ingestion from Water C-4
Ingestion from Food C-4
Inhalation C-ll
Dermal C-16
Other Modes of Exposure C-16
Pharmacokinetics C-19
Absorption C-20
Distribution C-26
Metabolism C-63
Excretion C-66
Effects C-68
Acute, Subacute, and Chronic Toxicity C-68
Allergenic Response C-76
Chronic C-90
In Vitro and In Vivo Studies C-91
Synergism and/or Antagonism C-101
Teratogenicity C-103
Gametotoxic Effects of Nickel C-104
Carcinogenicity C-105
Experimental Carcinogenesis C-105
Epidemiology C-112
Criterion Formulation C-130
Existing Guidelines and Standards C-130
Current Levels of Exposure C-130
Special Groups at Risk C-130
Basis for Derivation of Criterion C-130
References C-139
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CRITERIA DOCUMENT
NICKEL
CRITERIA
Aquatic Life
For total recoverable nickel the criterion (in vg/1) to protect fresh-
water aquatic life as derived using the Guidelines is the numerical value
. (0.76[ln(hardness)l+1.06) 0. , . ..
given by e as a 24-hour average, and the concen-
tration (in ug/1) should not exceed the numerical value given by e(0''°l'n-
(hardness)]+4.02) . .. _. n j. i_ _i ^ ,-« -,,>«
at any time. For example, at hardnesses of 50, 100, and
200 mg/1 as CaC03 the criteria are 56, 96, and 160 yg/1, respectively, as
24-hour averages, and the concentrations should not exceed 1,100, 1,800, and
3,100 wg/l» respectively, at any time.
For total recoverable nickel the criterion to protect saltwater aquatic
life as derived using the Guidelines is 7.1 pg/1 as a 24-hour average, and
the concentration should not exceed 140 ug/1 at any time.
Human Health
For the protection of human health from the toxic properties of nickel
ingested through water and contaminated aquatic organisms, the ambient water
criterion is determined to be 13.4 ug/1.
For the protection of human health from the toxic properties of nickel
ingested through contaminated aquatic organisms alone, the ambient water
criterion is determined to be 100 yg/1.
VI
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INTRODUCTION
Nickel has an atomic weight of 58.71 and its atomic number is 28. It
has a boiling point of 2,732°C and a melting point of 1,453°C. At 25°C the
metal has a specific gravity of 8.902. The commonly occurring valences of
nickel are 0, +1, +2, and +3, with +4 rarely encountered (Weast, 1975; Wind-
holz, 1976). Approximately 0.018 percent of the earth's crust is composed
of nickel, the chief sources of nickel are minerals containing copyrite,
pyrrhotite, and pentlandite (Windholz, 1976). Certain secondary silicate
minerals contain nickel, which also substitutes for magnesium in various
primary minerals (e.g., olivine, hypersthene, hornblende, biotite) (Kirk and
Othmer, 1967). Although elemental nickel is seldom found in nature and is
not soluble in water as the pure metal, many nickel salts are highly soluble
in water (Mckee and Wolf, 1963). At temperatures between 18 and 25°C, solu-
bilities of nickel compounds were: less than 1 g/1 for nickel hydroxide,
nickel monosulfide, and nickel oxide; 1 to 100 g/1 for nickel chloride,
nickel nitrate, and nickel sulphate. Nickel metal, nickel carbonate (bas-
ic), and nickel subsulfide are among the least soluble nickel compounds in
water at temperatures and pH values normally found in nature. Highly toxic
nickel carbonyl is soluble in water to the extent of less than 1 g/1 at
9.8°C ("International Agency for Research on Cancer (IARC), 1976].
Nickel is most likely to occur in natural waters as a divalent cation
and has geochemical behavior similar to that of cobalt. Nickel is probably
strongly sorbed to iron amd manganese oxides (Hern, 1975), although nickel
oxides, hydroxides and carbonates are probably common in natural waters,
especially those of high pH. In-tests reported here, nickel is added as Ni,
not as the salt.
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REFERENCES
Hem, J.D. 1975. Study and interpretation of the chemical characteristics
of natural water. 2nd ed. Geo. Surv. Water-Supply Paper, U.S. Govern.
Printing Office, Washington, D.C.
International Agency for Research on Cancer. 1976. IARC monograph on the
evaluation of carcinogenic risk of chemicals to man. II. Cadmium, nickel,
some epoxides, miscellaneous industrial chemicals, and general considera-
tions on volatile anesthesis. Int. Agency Res. Cancer, Lyon, France.
Kirk, R.E. and D.F. Othmer. (eds.) 1967. Encyclopedia of Chemical Tech-
nology. John Wiley and Sons, Inc., New York.
McKee, J.E. and H.W. Wolf. 1963. Water duality criteria. Pub. No. 3-a.
Calif. State Water Res. Control Board, Sacramento.
Weast, R.C. 1975. Handbook of Chemistry and Physics. 5th ed. CRC Press,
Cleveland, Ohio.
Windholz, M. 1976. The Merck Index, 9th ed. Merck and Co., Rahway, New
Jersey.
A-2
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Aquatic Life Toxicology*
INTRODUCTION
Nickel is a common component of natural freshwaters and usually occurs
at concentrations less than 1 wg/1 in areas impacted to a minimal degree by
+2
man. As with other divalent heavy metals, free nickel ion (Ni ) may
participate in various types of aqueous chemical reactions such as sorption,
precipitation, and complexation. Since the chemical form of nickel is
changed in these processes, its toxicity may also be changed.
Equilibrium calculations using various chemical components common to
natural freshwaters reveal that very few known reactions with nickel would
be expected to occur to any great extent with anions such as sulfate, chlo-
ride, and carbonate. For example, chloride is not an important complexing
agent, since its concentration would have to be greater than that of typical
sea water to form the nickel chloride complex. Sulfate concentrations would
have to approach about 10'2M, which is an unlikely natural condition, be-
fore approximately one-half of the nickel would be complexed. Although pre-
cipitation by carbonate is possible, this reaction is also relatively unim-
portant since conditions conducive to its occurrence appear unlikely.
With respect to more reactive substances, complexation by organic agents
such as aminopolycarboxylic acids is possible, but equilibria with natural
substances such as suspended clays, humic acids, and microorganisms are gen-
erally poorly understood. Therefore, as a first approximation, the most
*The reader is referred to the Guidelines for Deriving Water Quality Cri-
teria for the Protection of Aquatic Life and Its Uses in order to better un-
derstand the following discussion and recommendation. The following tables
contain the appropriate data that were found in the literature, and at the
bottom of each table are calculations for deriving various measures of tox-
icity as described in the Guidelines.
B-l
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prevalent form of nickel in water with low concentrations of suspended
solids and total organic carbon is estimated to be the free ion, Ni .
Of the analytical measurements currently available, a water quality cri-
terion for nickel is probably best stated in terms of total recoverable
nickel, because of the variety of forms of nickel that can exist in bodies
of water and the various chemical and toxicological properties of these
forms. The forms of nickel that are commonly found in bodies of water and
are not measured by the total recoverable procedure, such as the nickel that
is a part of minerals, clays and sand, probably are forms that are less tox-
ic to aquatic life and probably will not be converted to the more toxic
forms very readily under natural conditions. On the other hand, forms of
nickel that are commonly found in bodies of water and are measured by the
total recoverable procedure, such as the free ion, and the hydroxide, car-
bonate, and sulfate salts, probably are forms that are more toxic to aquatic
life or can be converted to the more toxic forms under natural conditions.
Because the criterion is derived on the basis of tests conducted on soluble
inorganic salts of nickel, the total nickel and total recoverable nickel
concentrations in the tests would probably be about the same, and a variety
of analytical procedures would produce about the same results. Except as
noted, all concentrations reported herein are expected to be essentially
equivalent to total recoverable nickel concentrations. All concentrations
are expresses as nickel, not as the compound tested.
EFFECTS
Acute Toxicity
The data base for nickel and freshwater animals has 75 acute values, but
more than half are for two species (Table 1). On the other hand, acute val-
ues are available for 22 species from 18 different taxonomic families that
perform a variety of ecological functions.
B-2
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Forty of the acute values for nickel are for eleven species of fresh-
water invertebrates from ten taxonomic families (Table 1), although over 70
percent of these values are for two daphnids. At comparable water hardness
values of 45 and 40 mg/1, the acute values range from a low of 510 vg/1 for
Daphnia magna to a high of 33,500 ug/1 for the stonefly. Except for the two
daphnids, all tests with invertebrates were conducted in dilution water with
a hardness value of 50 mg/1 or less.
Lind, et al. (Manuscript) examined the effects of hardness, alkalinity,
pH, and total organic carbon on the toxicity of nickel to Daphnia pulicar-
^£. Hardness was the water quality parameter most highly correlated with
the first 16 acute values from Lind, et al. (Manuscript) listed in Table 1.
The last seven of the listed acute values were a study of the effect of add-
ed calcium and magnesium on the toxicity of nickel in Lake Superior water.
Both calcium and magnesium reduced the toxicity of nickel.
Chapman, et al. (Manuscript) investigated the effects of water hardness,
at nominal hardness values of 50, 100 and 200 mg/1, on the acute toxicity of
nickel to Daphnia magna (Table 1). They found that nickel was more toxic at
lower hardness values.
Thirty-five LCgg values for eleven freshwater fish species from eight
families have been reported for nickel (Table 1). Almost half of these val-
ues are for the fathead minnow. The acute values ranged from a low of 2,480
yg/1 for the rockbass (hardness » 26 mg/1) to a high of 46,200 yg/1 for the
banded killifish (hardness - 53 mg/1). The only acute value for a salmonid
fish was 35,000 ug/1, but the hardness was not reported (Hale, 1977).
Pickering and Henderson (1966) examined the toxicity of nickel to the
fathead minnow and bluegill in static tests using soft (hardness - 20 mg/1)
and hard (hardness - 360 mg/1) dilution water. The arithmetic means of dup-
B-3
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licate LC5Q values determined with the fathead minnow were 4,880 ug/1 and
43,450 ug/1, respectively. The mean of duplicate LC50 valuer, determined
with the bluegill in soft water was 5,270 ug/1, and for one test in hard
water the LC5Q value was 39,600 ug/1.
Lind, et al. (Manuscript) examined the effect of hardness, alkalinity,
pH, and total organic carbon on the toxicity of nickel to the fathead minnow
in flow-through tests. Hardness was the variable which best correlated with
the LC5Q values, which ranged from 2,920 ug/1 (hardness = 28 mg/1) *o
17,700 ug/1 (hardness » 89 mg/1). The LC50 value for the test in the
hardest dilution water (91 mg/1) was 8,620 ug/1.
An exponential equation was used to describe the observed relationship
of the acute toxicity of nickel to hardness in freshwater. A least squares
regression of the natural logarithms of the acute values on the natural log-
arithms of hardness produced slopes of 1.23, 0.49, 0.91, and O.,70, respec-
tively, for Daphnia magna, Daphnia pulicaria, fathead minnow, arid the blue-
gill. The first three slopes were significant, but the last was not. The
arithmetic mean acute slope (0.76) was used with the geometric mean toxicity
value and hardness for each species to obtain a logarithmic intercept for
each of the 22 freshwater species for which acute values are available for
nickel. The species mean acute intercept, calculated as the exponential of
the logarithmic intercept, was used to compare the relative acute sensitivi-
ties (Table 3). Both the most sensitive and the least sensitive species are
invertebrates. A freshwater Final Acute Intercept of 56 ug/1 was obtained
for nickel using the species mean acute intercepts listed in Table 3 and the
calculation procedures described in the Guidelines. Thus the Final Acute
Equation is e(0-76nn(hardness)] + 4.02).
B-4
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Acute toxicity studies in salt water have been performed with two fish
and many invertebrate species. The most sensitive invertebrate species was
a mysid shrimp (Heteromysis formosa) with an LC50 of 152 u9/l» and the
least sensitive species was the mummichog fish (Fundulus heteroclitus) with
an LC5Q of 350,000 ug/1. The Atlantic silverside (Menidia menidia) was
the more sensitive fish species with an LC50 of 7,960 ug/1 (U.S. EPA.
1980b). Clam larvae (Mercenaria mercenaria) were the most sensitive larvae
with an LC50 of 310 tfg/l (Table 1). Adult polychaetes, clams, starfish,
and crabs were among the least sensitive to nickel with LC50 values
ranging from 17,000 to 320,000 ug/1. The copepods had a range of sensitivi-
ty from 600 ug/1 for Nitocra spinipes. to 9,670 ug/1 for Eurytemora af-
finis. A saltwater Final Acute Value of 137 wg/l was obtained for nickel
using the species mean acute values in Table 3 and the calculation proce-
dures described in the Guidelines.
Chronic Toxicity
The data base for chronic toxicity of nickel to freshwater animal spe-
cies (Table 2) includes eight chronic values and six acute-chronic ratios.
Life-cycle tests are available for a cladoceran, caddisfly, and the fathead
minnow, whereas early life-stage tests are available for the rainbow trout
and fathead minnow. The chronic values range from a low of 14.8 wg/1 for
Daphnia magna in soft water (51 mg/1 hardness) to a high of 530 ug/1 for the
fathead minnow in hard water (210 mg/1 hardness).
Life-cycle tests (Chapman, et al. Manuscript) have been conducted with
Daphnia magna in water having hardness values of 51, 105, and 205 mg/1
(Table 2). The chronic values ranged from a low of 14.8 ug/1 in soft water
to 354 ug/1 in hard water. The acute-chronic ratios for these studies
ranged from 83 in soft water to 14 in hard water.
B-5
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A life-cycle test (Pickering, 1974) and an early life stage test (Lind,
et al. Manuscript) have been conducted with the fathead minnow (Table 2).
The chronic values were 527 ug/1 (hardness - 210 mg/1) and 109 yg/1 (hard-
ness » 44 mg/1), respectively. The acute-chronic ratios for these two
chronic tests were very similar, 50 and 48, respectively, in both soft and
hard water Daphnia is a more sensitive species than the fathead minnow. On
the other hand, with daphnids the acute-chronic ratio changes with hardness,
but with fathead minnows it apparently does not.
Nebeker, et al. (Manuscript) conducted an early life-stage test with the
rainbow trout, and the chronic value was 350 ug/1, at a hardness of 50
mg/1. An acute value is not available for the calculation of an acute-
chronic ratio for this species. The rainbow trout was a more resistant spe-
cies than the fathead minnow in a soft water of similar hardness value.
As with acute values, an exponential equation was used to describe the
observed relationship of the chronic toxicity of nickel to hardness in fresh
water. The least squares regression produced slopes of 2.30 and 1.01,
respectively, for Daphnia magna and fathead minnow. The first slope was not
significant, and the last could not be tested because only two values were
available. The three available species mean acute-chronic ratios are 49,
27, 5.5 (Table 3) resulting in a Final Acute-Chronic ratio of 19.4. Thus
the Final Chronic Intercept of 2.89 ug/1 is obtained by dividing the Final
Acute Intercept of 56 ug/1 by the Final Acute-Chronic Ratio of 19.4 (Table
3). The Final Chronic Equation is e(0.76[ln(hardness)] + 1.06).
A chronic life-cycle test on nickel was performed with the saltwater my-
sid shrimp, Mysidopsis bahia, with a control survival after 36 days of 73
percent. The effect of nickel was assessed on several reproductive re-
sponses. The first spawn occurred at 20 days at 141 ug/1, with no spawns
B-6
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occurring at 297 wg/l. The total young and total spawns produced per con-
centration followed a similar pattern, with marked decreases occurring at
141 ug/1 and no spawns and consequently no young at 297 ug/l. Statistical
comparisons were conducted on the ratios of total young/available female
spawning day and total spawns/available female spawning day. No significant
differences were detected (p<0.05) between the control, 30 ug/1 and 61
ug/1. Differences were observed at 141 ug/1 and 297 ug/1. Thus the chronic
limits are 61 ug/1 and 141 wg/l and the chronic value is 92.7 yg/l. The
corresponding 96-hour LC50 for this species in a static measured test was
508 ug/1 resulting in an acute-chronic ratio of 5.5 (Table 2).
Division of the saltwater Final Acute Value by the Final Acute-chronic
Ratio of 19.4 results in a saltwater Final Chronic Value of 7.1 ug/1.
Plant Effects
Hutchinson (1973) and Hutchinson and Stokes (1975) observed reduced
growth of several freshwater algal species at concentrations ranging from
100 to 700 ug/1 (Table 4), but the hardness of the test waters used was not
stated. Although a decrease in diatom diversity was observed by Patrick, et
al. (1975) to occur at concentrations as low as 2 ug/1 (Table 6), the sig-
nificance of this is uncertain because the occurrence of slight changes in
diversity due to nickel may or may not be deleterious to ecological func-
tions and biomass production. The values in Table 4 are higher than the
chronic data on fish and invertebrate species, and so algae should not be
affected by nickel at concentrations that do not chronically affect fish and
invertebrates.
Two saltwater algal species (Macrocystis pyrifera and Phaeodactylum tr_U
cornutum) have been exposed to nickel (Table 4). A 50 percent reduction in
photosynthesis occurred in Macrocystis at a nickel concentration of 2,000
ug/1, whereas reduced growth was reported for Phaeodactylum at 1,000 ug/1.
8-7
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Residues
The available bioconcentration factors for freshwater organisms are 9.8,
100, and 61 for alga, Daphnia magna. and the fathead minnow, respectively
(Table 5).
Two species of saltwater bivalve molluscs are capable of accumulating
nickel (Table 5) to high levels. The highest bioconcentration factor was
obtained with Mytilus edulis when exposed to 5 pg/1 (BCF » 416), and with
both species tested, the higher bioconcentration factors were observed at
the lower nickel concentrations. Oassostrea virginica. when exposed to 5
vg/1 had a BCF of 384 as compared to 299 at a nickel concentration of 10
yg/1. Mytilus edulis had BCF values of 416 and 328 when exposed to 5 and 10
ug/1, respectively.
No final Residue Value can be calculated for either freshwater or salt-
water because no maximum permissible tissue concentration is available for
nickel.
Miscellaneous
The results of many additional tests of the effects of nickel on fresh-
water aquatic organisms are listed in Table 6. Some of these are acute
tests with non-standard durations for the organisms used. Many of the other
acute tests in Table 6 were conducted in dilution waters which were known to
contain materials which would significantly reduce the toxicity of nickel.
These reductions were different from those caused by hardness, and not
enough data exist to account for these in the derivation of the criteria.
For example,' Lind, et al. (Manuscript) conducted tests with Daphnia puli-
caria and fathead minnow in waters with concentrations of TOC ranging up to
34 mg/1. Until chemical measurements which correlate well with the toxicity
8-8
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of nickel in a wide variety of waters are identified and widely used, re-
sults of tests in usual dilution waters, such as those in Table 6, will not
be very useful for deriving water quality criteria.
Beisinger and Christensen (1972) conducted a life-cycle test with Daphn-
ia magna at a hardness of 44 mg/1, but did not measure the concentration of
nickel in the test solutions. The lower and upper chronic endpoints were 30
and 95 wg/l for a chronic value of 53 ug/1 and and acute-chronic ratio of
9.6. As noted earlier, at a hardness of 51 mg/1, Chapman, et al. (Manu-
script) obtained a chronic value of 14.8 ug/1 and an acute-chronic ratio of
83 for the same species (Table 2).
Nebeker, et al. (Manuscript) initiated an early life stage chronic expo-
sure using eyed embryos of rainbow trout. The effect level of 3,660 ug/1
was much larger than that of 350 ug/1 (Table 2) when the exposure was
started with two-day-old embryos.
Birge (1978) and Birge, et al. (1978) studied the toxicity of nickel to
embryos and larvae of five species of aquatic vertebrates (Table 6). Renew-
al exposure was maintained from fertilization through four days post-hatch.
Grossly anomalous survivors were counted as lethals. The LC5Q values
ranged from 50 ug/1 for rainbow trout and toad to 2,140 yg/1 for goldfish.
The LC50 value of 50 vg/l in water with a hardness value of 93 to 105 mg/1
was about one-seventh of the effect level for the rainbow trout in water
with a hardness value of 50 mg/1 (Table 2).
Among saltwater organisms, nickel has an affect on molluscan larval
growth. Calabrese, et al. (1977) reported that growth of 50 percent of the
Crassostrea virginica larvae was inhibited by 1,210 ug/l afrer 12 days
treatment, whereas 5,710 ug/1 inhibited the growth of 50 percent of the
Mercenaria larvae after 8 to 10 days treatment. This study should not be
confused with earlier studies by Calabrese et al. (1973) and Calabrese and
B-9
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Nelson (1974) in which LC50 values for acute toxicity of nickel to Oasso-
strea virginica and Mercenaria mercenaria larvae were reported (Table 1).
In these studies, embryonic development (up to 48 hours) was used as an in-
dicator of toxicity, whereas in the 1977 study growth of 48-hour larvae was
used as an indicator.
Petrich and Reish (1979) reported that the 96-hour and 7-day LC5Q val-
ues for the polychaete, Capitella capitata were above 50,000 ug/1 (Table 6),
whereas the 4-day LC5Q for the polychaete Ctenodrilus serratus was 17,000
ug/1 (Table 1). In the same study, they observed no deaths but complete in-
hibition of reproduction when the polychaete, Ctenodrilus serratus, was ex-
posed for 28 days (one complete life cycle) to a nickel concentration of
2,000 ug/1 (Table 6).
Using sea urchin embryos (Lytechinus pictus), Timourian and Watchmaker
(1972) observed delayed and abnormal development after 20 hours treatment
with 58 and 580 ug/1, respectively. Waterman (1937) using Arbacia punctu-
lata embryos (sea urchin) obtained greater than 50 percent mortality after
42 hours treatment with 17,000 ug/1.
Summary
The data base for nickel and freshwater animals includes 75 acute values
for 22 species from 18 different taxonomic families. These values range
from 510 ug/1 for Daphnia magna to 46,200 ug/1 for banded killifish. The
relationship between the toxicity of nickel and water hardness was developed
from four species. The mean of the slope of the regression equation was
0.76.
Chronic data are available for two invertebrate species and two fish
species. The species chronic values range from 14.8 ug/1 for Daphnia magna
8-10
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in soft water to 530 ug/1 for fathead minnow in hard water. The three
acute-chronic ratios for Daphm'a magna range from 14 to 83. The two ratios
for fathead minnow are 50 and 48.
The plant data indicate that algae are affected by nickel at concentra-
tions as low as 100 wg/l. The residue data for whole fish produced a bio-
concentration factor of 61.
The acute values for saltwater species ranged from 152 ug/1 for a mysid
shrimp to 350,000 ug/1 for the mummichog fish. A chronic toxicity test was
conducted with the mysid shrimp and an adverse effect was observed at 141
wg/1, but not at 61 wg/1, producing and acute-chronic ratio of 5.5 for this
species. A reduction in growth and photosynthesis was obtained in algal
species at 1,000 and 2,000 ug/1, respectively. The oyster and mussel are
relatively good accumulators of nickel, with bioconcentration factors from
299 to 416. Delayed embryonic development, suppressed reproduction, and in-
hibition of larval growth were caused by nickel in a bivalve mollusc, poly-
chaete worm, and sea urchin, respectively.
CRITERIA
For total recoverable nickel the criterion (in ug/1) to protect fresh-
water aquatic life as derived using the Guidelines is the numerical value
given by e(0-76[ln(hardness)] + i-06) as a 24-hour average, and the con-
centration (in ug/1) should not exceed the numerical value given by
e(0.76[ln(hardness)] + 4.02) at any time> For exampiej at hardnesses of
50, 100 and 200 mg/1 as CaC03 the criteria are 56, 96, and 160 ug/1. re-
spectively, as 24-hour averages, and the concentrations should not exceed
1,100, 1,800, and 3,100 ug/1, respectively, at any time.
For total recoverable nickel the criterion to protect saltwater aquatic
life as derived using the Guidelines is 7.1 ug/1 as a 24-hour average, and
the concentration should not exceed 140 ug/1 at any time.
B-ll
-------
Table I. Acut* values for nickel
Species
Method*
Chemical
Hardness
(ng/l as LC50/EC50"
CaCO,) (ug/l)
Species Mean
Acute Value**
(yg/l) Reference
FRESHWATER SPECIES
Rotifer,
Philodlna acutl cornus
Rotifer,
Philodlna acutl cornus
Brlst leworm,
Nals sp.
Snail (adult),
Amnlcola sp.
Cladoceran,
Daphnla magna
Cladoceran,
Daphnla magna
i_, Cladoceran,
10 Daphnla magna
Cladoceran,
Daphnla magna
Cladoceran,
Daphnla magna
Cladoceran,
Daphnla magna
Cladoceran,
Daphnla magna
Cladoceran,
Daphn la pull car i a
Cladoceran.
Daphnla pul 1 carl a
Cladoceran,
Daphn i a pu 1 1 car 1 a
s,
s,
s.
s,
s.
s,
s,
s.
s.
s.
s.
s,
s.
s.
u
u
M
u
u
M
M
M
M
M
M
M
M
M
Nickel
chloride
Nickel
su 1 fate
Nickel
nitrate
Nickel
nitrate
Nickel
chloride
Nickel
chloride
Nickel
chloride
Nickel
chloride
Nickel
chloride
Nickel
chloride
Nickel
ch lorlde
Nickel
su 1 fate
Nickel
su 1 fate
Nickel
su 1 fate
25
25
50
50
45
51
54
100
104
206
45
48
48
44
2,900
7,400
14,100
14,300
510
1,810
645
2,340
1,940
4,960
865
2,180
1^810
1,840
Bulkema, et al.
Bulkema, et al.
Rehwoldt, et al.
1974
1974
1973
Rehwoldt, et al. 1973
Bleslnger 4
Chrlstensen, 1972
Chapman, et al.
Manuscript
Chapman, et al.
Manuscript
Chapman, et al.
Manuscript
Chapman, et al.
Manuscript
- Chapman, et al.
Manuscript
U.S. EPA, 1980a
Llnd, et al.
Manuscript
_ Llnd st 3!.
Manuscript
Lind, et al.
Manuscript
-------
Table 1. (Continued)
w
1
H1
U)
Species
Cladoceran,
Daphnla pul Icarla
Cladoceran,
Daphnla pul Icarla
Cladoceran,
Daphnla pul Icarla
Cladoceran,
Daphnia pul Icarla
Cladoceran,
Daphnla pul Icarla
Cladoceran,
Daphnla pul Icarla
Cladoceran,
Daphnla pul Icarla
Scud,
Gammarus sp.
Mayfly,
Ephemeral la subvarla
Stonef ly.
Acroneurla ly cor las
Damsel fly.
(unidentified)
Midge,
Chlronomus sp.
Caddlsf ly.
(unidentified)
Amer 1 can ee 1 ,
Angul 1 la rostrata
Amer 1 ca 1 ee 1 ,
Angul 1 la rostrata
Method*
S,
s,
s,
s.
s.
s.
s.
s.
s.
s.
s.
s.
s.
s.
s.
M
M
M
M
M
M
M
M
U
U
M
M
M
M
M
Chemical
Nickel
sulfata
Nickel
su 1 fate
Nickel
su 1 fate
Nickel
su 1 fate
Nickel
sulfate
Nickel
su 1 fate
Nickel
su 1 fate
Nickel
nitrate
Nickel
su 1 fate
Nickel
su 1 fate
Nickel
nitrate
Nickel
nitrate
Nickel
nitrate
Nickel
nitrate
Nickel
nitrate
Hardness
(wg/l as
CaCOO
44
94***
144«*«
244***
94****
144**»*
244****
50
42
40
50
50
50
53
55
LC50/EC50"
(wa/l)
1,900
3,160
3,830
3,300
2,470
2,470
2,410
13,000
4,000
33,500
21,200
8,600
30,200
13,000
13,000
Species Mean
Acute Value"
(ug/l) Reference
Llnd, et al.
Manuscript
Llnd, et al.
Manuscript
Llnd, et al.
Manuscript
Llnd, et al.
Manuscript
Llnd, et al.
Manuscript
Llnd, et al.
Manuscript
Llnd, et al.
Manuscript
Rehwoldt, et al.
War nick & Bell,
Warnlck & Bell,
Rehwoldt, et al.
Rehwoldt, et al.
Rehwoldt, et al.
Rehwoldt, et at.
Rehwoldt, et al.
1973
1969
1969
1973
1973
1973
1971
1972
-------
Table 1. (Continued)
Species
Rainbow trout,
Salmo galrdnerl
Goldfish,
Carasslus auratus
Fathead minnow,
Plmephales promelas
Fathead minnow,
Plmephales promelas
Fathead minnow,
Plmephales promelas
Fathead minnow,
Plmephales promelas
Fathead minnow,
W Plmephales promelas
£> Fathead minnow,
Plmephales promelas
Fathead minnow,
Plmephales promelas
Fathead minnow,
Plmephales promelas
Fathead minnow,
Plmephales promelas
Fathead minnow,
Plmephales promelas
Carp,
Cyprlnus carplo
Carp,
Cyprlnus carpio
Method*
FT, M
s,
FT,
FT,
s,
s.
FT,
FT,
s.
s,
s.
s.
s.
s.
u
M
M
U
M
M
M
U
U
U
U
M
M
Chemical
Nickel
nitrate
Nickel
chloride
Nickel
sulfate
Nickel
su 1 fate
Nickel
chloride
Nickel
chloride
Nickel
chloride
Nickel
chloride
Nickel
chloride
Nickel
chloride
Nickel
chloride
Nickel
chloride
Nickel
nl trate
Nickel
nitrate
Hardness
(mg/l as
CaCOx)
-
20
45
44
210
210
210
210
20
20
360
360
53
55
LC50/EC30"
(UO/I)
35,500
9,820
5,210
5,160
27,000
32,200
28,000
25,000
5,180
4,580
42,400
44,500
10,600
10,400
Species Mean
Acute Value"
(ufl/l) Reference
Hale, 1977
Pickering &
Henderson, 1966
Llnd, et al.
Manuscr 1 pt
Llnd, et al.
Manuscript
Pickering, 1974
Pickering, 1974
Pickering, 1974
Pickering, 1974
Pickering &
Henderson, 1966
Pickering &
Henderson, 1966
Pickering &
Henderson, 1966
Pickering &
Henderson, 1966
Rehwoldt, et al.
Rehwoldt, et al.
-------
Table 1. (Continued)
Species
Banded kllliflsh,
Fundulus diaphanus
Banded killlflsh,
Fundulus diaphanus
Guppy,
Lebistes reticulatus
White perch,
Morone amerlcanus
White perch,
Morone amerlcanus
Striped bass,
Morone saxat 1 1 is
Striped bass,
I Morone saxatllis
<-n Rock bass,
Ambloplltes rupestrls
Pumpklnseed,
Lepomls glbbosus
Pumpklnseed,
Lepomls glbbosus
Bluegl 1 1,
Lepomis macrochlrus
B 1 ueg i 1 1 ,
Lepomis macrochlrus
B 1 ueg III,
Lepomls macrochirus
Method*
s,
s,
s,
s,
s,
s,
s,
FT,
s,
s,
s,
s.
s.
M
M
U
M
M
M
M
M
M
M
U
U
U
Chemical
Nickel
nitrate
Nickel
nitrate
Nickel
ch lorlde
Nickel
nitrate
Nickel
nitrate
Nickel
nitrate
Nickel
nitrate
Nickel
su 1 fate
Nickel
n 1 trate
Nickel
nitrate
Nickel
chloride
Nickel
chloride
Nickel
chloride
Hardness
Cmg/l as
CaCO,)
53
55
20
53
55
53
55
26
53
55
20
20
360
LC50/EC50**
(lig/U
46,200
46,100
4,450
13,600
13,700
6,200
6,300
2,480
6,100
6,000
5,180
5,360
39,600
Species Mean
Acute Value**
(ug/l) Reference
Rehwoldt, et al.
Rehwoldt, et al.
Pickering &
Henderson, 1966
Rehwoldt, et al.
Rehwoldt, et al.
Rehwoldt, et al.
Rehwoldt, et al.
Und, et al.
Manuscript
Rehwoldt, et al.
Rehwoldt, et al.
Pickering &
Henderson, 1966
Pickering &
Henderson, 1966
Pickering &
1971
1972
1971
1972
1971
1972
I97J
1972
Henderson, 1966
-------
Table I. (Continued)
Species
Polychaete,
Ctenodr i 1 us serratus
Polychaete,
Neanthes arenaceodentata
Sand worm,
Nereis vlrens
American oyster (larva),
Crassostrea virgin lea
Hard clam (larva),
Mercenar la mercenar la
Soft shell clam,
m My a arenarla
1
I1 Copepod,
°^ Acartia clausi
Copepod ,
Eury femora affinls
Copepod ,
Tlgrlopus Japonlcus
Copepod,
Nltocra splnlpes
Mysld shrimp,
Heteromysis formosa
Mysid shrimp,
Mysldopsls blgelowl
Mysld shrimp,
Mysldopsls bah la
Method*
Chemical
Hardness
(mg/l as LC50/EC50**
CaCO,) (ug/l)
Species Mean
Acute Value**
(ug/l) Reference
SALTWATER SPECIES
s,
s,
s,
s,
s,
s,
s,
s,
s,
s,
s,
s,
s.
u
u
u
u
u
u
u
u
u
u
M
M
M
Nickel
chloride
Nickel
chloride
Nickel
ch lor 1 de
Nickel
chloride
Nickel
ch lor Ida
Nickel
chloride
Nickel
chloride
Nickel
chloride
Nickel
chloride
Nickel
chloride
Nickel
chloride
Nickel
chloride
Nickel
ch lor 1 de
17,000
49,000
25,000
1,180
310
320,000
2,080
9,670
6.360
600
152
634
508
17,000
49,000
25,000
1,180
310
320,000
2,080
9,670
6,360
600
152
634
508
Petrlch & Reish, 1979
Petrlch & Relsh, 1979
Elsler & Hennekey,
1977
Calabrese, et al.
1973
Calabrese & Nelson,
1974
Elsler & Hennekey,
1977
U.S. EPA, 1980b
U.S. EPA, 1980b
U.S. EPA, 1980b
Bengtsson, 1978
U.S. EPA, 1980b
U.S. EPA, 1980b
U.S. EPA, I980b
-------
Table 1. (Continued)
ou
1
M
-J
Species
Crab,
Pagurus longlcarpus
Starfish,
Aster 1 us forbesl
Munrolchog,
Fundulus heteroci Itus
Atlantic si Iverslde,
Men Id la menldia
Method*
S. U
S. U
S, U
S, U
* S = static, FT = flow-through, U
** Results are expressed as nickel,
**« Calcium added
Magnesium added
Freshwater
Hardness
(g/l as
Chemical CaCO})
Nickel
chloride
Nickel
chloride
Nickel
chloride
Nickel
chloride
= unmeasured, M = measured
not as the compound.
Species Mean
LC50/EC50** Acute Value**
(uo/l) (wo/1)
47,000 47,000
150,000 150,000
350,000 350,000 '
7,960 7,960
Reference
Elsler & Hennekey,
1977
Elsler & Hennekey,
1977
Elsler & Hennekey,
1977
U.S. EPA, 1980b
Acute values vs. hardness
Daphnla magna: slope = 1.23, Intercept = 1.95, r = 0.88, p = 0.01, N = 7
Paphnla pullcarla; slope = 0.27, Intercept = 6.57, r = 0.72, p = 0.05, N = 10
* -
Fathead minnow: slope = 0.83, Intercept = 5.76, r = 0.98, p = 0.01, N = 10
Blueglll: slope = 0.70, Intercept = 6.48, r = 0.99, not significant, N = 3
Arithmetic mean acute slope = 0.76
-------
Table 2. Chronic values for nickel
Chemical
Hardness
(mg/l as Limits*" Chronic Value**
cacop (ug/» (yg/»>
Reference
00
1
CO
apociv* I.*""1.
Cladoceran, LC
Daphnia magna
Cladoceran, LC
Daphnia magna
Cladoceran, LC
Daphnia magna
Caddlsfly, LC
Cllstoronla magnlflca
Rainbow trout, ELS
Salmo gairdnerl
Fathead minnow, ELS
Plmephales promelas
Fathead minnow, LC
Plmephales promelas
Mysld shrimp, LC
Mysldopsls bahla
FRESHWATER SPECIES
Nickel 51 10.2-21.4 14.8
ch lor 1 de
Nickel 105 101-150 123
ch lor 1 de
Nickel 205 220-570 354
chloride
Nickel 50 295-734 465
chloride
Nickel 50 230-535 350
chloride
Nickel 44 109-433 109
chloride
Nickel 210 380-730 527
chloride
SALTWATER SPECIES
Nickel 61-141 92.7
chloride
Chapman, et
Manuscript
Chapman, et
Manuscr 1 pt
Chapman, et
Manuscr 1 pt
Nebeker, et
Manuscript
Nebeker, et
Manuscript
Lind, et al
Manuscript
Pickering,
al.
al.
al.
al.
al.
1974
U.S. EPA, 1980b
* LC = life cycle or partial life cycle; ELS = early life stage
"Results are expressed as nickel, not as the compound.
Freshwater
Chronic value vs. hardness
Daphnia magna; slope = 2.29, Intercept = -6.16, r = 0.99, not significant, N = 3
Fathead minnow: slope * 1.01, intercept = 0.88, r = 1.0, N = 2
«
Arithmetic mean chronic slope = 1.65
-------
Table 2. (Continued)
Acute-Chronic Ratios
00
1
t '
VO
Species
Cladoceran,
Daphnla magna
Cladoceran,
Daphnla magna
Cladoceran,
Daphnta magna
Fathead minnow,
Plmephales proroelas
Fathead minnow.
Plmephales promelas
Mysld shrimp.
Mysldopsls bah la
Chemical
Nickel
chloride
Nickel
chloride
Nickel
chloride
Nickel
chloride
Nickel
chloride
Nickel
chloride
Hardness
(mg/l as
(CaCOjl
51
105
205
210
44
-
Acute Value
-------
Table 3. Species Man acute Intercepts and values and acute-chronic ratios for nickel
Species Mean Species Mean
Acute Intercept Acute-Chronic
Rank* Species (ug/l) Ratio
Od
I
to
o
22
21
20
19
18
17
16
15
14
13
12
11
10
9
FRESHWATER
Banded kill Ifish,
Fundulus dlaphanus
Stonef ly,
Acroneur 1 a 1 ycor 1 as
Caddisfly.
(unidentified)
Damsel fly,
(unidentified)
Goldfish,
Carasslus auratus
Snail,
Ann 1 col a sp.
Brlst leworra,
Nals sp.
Scud,
Gamnarus sp.
White perch,
Horone amerlcanus
American eel,
Angu Ilia rostrata
Bluegill,
Lepomls macrochlrus
Carp,
Cyprlnus carplo
Guppy,
Poecll la ret leu Iota
Midge,
Chlronomus sp.
SPECIES
2,230
2,030
1,540
1,080
1,010
730
720
665
659
627
509
507
457
440
-
-------
Table 3. (Continued)
CO
I
to
H-
Rank*
8
7
6
5
4
3
2
1
Rank*
17
16
15
14
Species
Fathead minnow,
Plmephales promelas
Rotifer,
Ph 1 1 od 1 na acut 1 cornus
Pumpkinseed,
Lepomls glbbosus
Striped bass,
Moron e saxatl lus
Mayfly,
Ephemerella subvaria
Rock bass,
Ambloplltes rupestrls
Cladoceran,
Daphn la pu 1 1 car 1 a
Cladoceran,
Daphn la magna
SALTWATER
Species
Mummichog,
Fundulus heterocl Itus
Soft shell clam,
Mya arenaria
Starfish,
Aster lus forbesl
Polychaete,
Species Mean
Acute Intercept
(UQ/I)
440
401
388
302
234
208
78.5
54.0
SPECIES
Species Mean
Acute Value
(i»a/l)
350,000
320,000
150,000
49,000
Species Mean
Acute-Chronic
Ratio
49
27
Species Mean
Acute-Chronic
Ratio
-
Neanthes arenaceodentata
-------
Table 3. (Continued)
DO
I
NJ
to
Rank*
13
12
11
10
9
8
7
6
5
4
3
2
1
Species
Crab,
Pagurus long! carpus
Sand worm.
Nereis vlrens
Polychaete,
Ctlnodrllus serratus
Cope pod,
Eurytemora af finis
Atlantic si Iverslde,
Man Id la men Id la
Copepod,
Tlgrlopus Japonlcus
Copepod,
Acartla clausl
American oyster,
Crassostrea virgin lea
Mysld shrimp,
Mysldopsls blgeloxl
Copepod,
Nltrocra splnlpes
Mysld shrimp,
Mysldopsls bah la
Hard clam,
Mercenar la mercenar la
Mysld shrimp.
Species Mean
Acute Value
(wa/D
47,000
25,000
17,000
9,670
7,960
6,360
2,060
1,180
634
600
508
310
152
Spec left Mean
Acute-Chronic
Ratio
5.5
Heteroroysls formosa
-------
Table 3. (Continued)
* acX? .eor^afui!" f° * SenSlt'Ve Specles «P~'« «
I
f^>
freshwater
Final Acute Intercept = 56 ug/l
natural logarithm of 56 = 4.02
acute slope = 0.76 (see Table 1)
Final Acute Equation = e(0<76( In(hardness) 1+4.02)
Final Acute-Chronic Ratio = 19.4 (Table 2)
Final Chronic Intercept = (56 ug/l)/19.4 - 2.89 yg/l
natural logarithm of 2.89 = 1.06
Final Chronic Equation = e(0'761 In(hardness) 1 + 1.06)
Saltwater
Final Acute Value = 137 pg/l
Final Acute-Chronic Ratio = 1.94
Final Chronic Value = (137 ug/l)/1.94 = 7.1 ug/l
-------
Tablo 4. Plant values for nickel
Species
Alga (green),
Chlamydomonas eugameros
Alga (green),
Chloral la vulgarls
Alga (green),
Haematococcus capensls
Alga (green),
Scenedesmus acumlnata
Alga (green),
Scenedesmus acuminata
ffl
^ Giant kelp,
*» Macrocystls pyrlfera
Alga,
Phaeodacty 1 urn tr 1 cor nu turn
Chealcal
Nickel nitrate or
nickel sulfate
Nickel nitrate or
nickel sul fate
Nickel nitrate or
n Ickel su 1 fate
Nickel nitrate or
n Ickel sul fate
Nickel nitrate or
nickel sulfate
Hardness
(«g/l as
CaCO,)*
FRESHWATER
50
50
50
50
50
SALTWATER
-
Effect
SPECIES
Reduced growth
Reduced growth
Reduced growth
Reduced growth
Reduced growth
SPECIES
50* Inactlvatlon
of photosynthesis
Reduced growth
Result"
tug/D
700
500
300
500
too
2,000
1,000
Reference
Hutch inson, 1973
Hutchlnson, 1973
Hutchlnson, 1973
Hutchlnson & Stokes,
1975
Hutch inson, 1973
Clendennlng & North,
1959
Skaar, et al. 1974
* Ca.lculated from concentrations of calcium, magnesium, and ferrous Iron in growth medium.
"Results are expressed as nickel, not as the compound.
-------
Table S. Residues for nickel
Species
Alga (green),
Scenedesmus acumlnata
C 1 adoceran ,
Daphnla magna
Fathead minnow,
Plaephales prone las
Tissue
Cells
Whole body
Whole body
Chealcal
FRESHWATER
Nickel nitrate or
nickel sulfate
"NI in
O.W HCI
Nickel
chloride
Bloconcentratlon
Factor
SPECIES
9.8
100
61
Duration
(onvs)
6
2-4
30
Reference
Hutch Inson A Stokes,
1975
Hall. 1978
Llnd. et al.
Manuscript
SALTWATER SPECIES
American oyster,
Crassostrea virgin lea
American oyster,
Crassostrea virgin lea
CO Mussel,
f'j Mytllus edulls
tn
Mussel.
Mytllus edulls
Soft parts
Soft parts
Soft parts
Soft parts
Nickel
su 1 fate
Nickel
su 1 fate
Nickel
su 1 fate
Nickel
sulfate
384
299
416
328
84
84
84
84
U.S. EPA. I980b
U.S. EPA, 1980 b
U.S. EPA, 1980 b
U.S. EPA, 1980b
-------
Table 6. Other data for nickel
cd
i
to
en
Species
Alga,
(mixed population)
Snail (embryo),
Amnicola sp.
Cladoceran,
Daphnla magna
Cladoceran,
Daphnla magna
C ladoceran,
Daphnla magna
Cladoceran,
Daphnla magna
Cladoceran,
Daphnla magna
Cladoceran,
Oaphnia pul 1 car la
Cladoceran,
Daphnia pul i car la
Cladoceran,
Daphnla pul i car la
Cladoceran,
Daphnia pul 1 car la
C 1 adoceran ,
Daphnla pul icaria
Cladoceran,
Daphnla pul icaria
Chemical
Hardness
(«g/l as
CaCOx)
Duration
Effect
Result*
(ug/l)
Reference
FRESHWATER SPECIES
Nickel
nitrate
Nickel
nitrate
Nickel
chloride
Nickel
chloride
Nickel
chloride
Nickel
su 1 fate
Nickel
su 1 fate
Nickel
su 1 fate
Nickel
sul fate
Nickel
su 1 fate
Nickel
su 1 fate
Nickel
su 1 fate
Nickel
su 1 fate
87-99
50
44
44
60***
60***
89
89
114
120
29
28
^53 days
96 hrs
64 hrs
48 hrs
21 days
9 days
9 days
48 hrs
48 hrs
48 hrs
48 hrs
48 hrs
48 hrs
Decrease In
diatom diversity;
population shift
to blue and blue-
green algae
LC50
Immobi 1 ization
LC50
Reproductive
Impairment
LC50
Growth Inhibition
EC 50
EC50
EC50
EC50
EC50
EC50
2-8.6
1 1 ,400
<317
1,120**
30-95
500
too
2,040
2,720
3,160
3,610
697
1,140
Patrick, et al. 1975
Rehwoldt. et al. 1973
Anderson, 1948
Blesfnger &
Christensen, 1972
Bleslnger &
Christensen, 1972
Hall, 1978
Hall, 1978
Llnd, et al.
Manuscript
Llnd, et al.
Manuscript
Llnd, et at.
Manuscript
Lind, et al.
Manuscript
Lind, el ai.
Manuscript
Llnd, et al.
Manuscript
-------
Table 6. (Continued)
CO
I
to
Species
Cladoceran,
Daphnla put(carIa
Cladoceran,
Daphnla pulI car Ia
Cladoceran,
Daphnla pullcar I a
Cladoceran,
Daphnla pulI car Ia
Cladoceran,
Daphnla pulI car Ia
Cladoceran,
Daphnla pirl I car I a
Cladoceran,
Daphnla pulI car I a
Rainbow trout (embryo),
Salmo galrdnerl
Rainbow trout,
Salmo galrdnerl
Rainbow trout,
Salmo galrdnerl
Rainbow trout,
Salmo galrdnerl
Brown trout,
Salmo trutta
Brook trout,
Salvelinus fontinalis
Lake trout,
Saivelinus namayctisb
Chemical
Nickel
su I fate
Nickel
sulfate
NJckel
su 1 fate
Nickel
su 1 fate
Nickel
su 1 fate
Nickel
sulfate
Nickel
sulfate
Nickel
chloride
Nickel
su 1 fate
Nickel
chloride
Nickel
sul fate
Nickel
su 1 fate
Nickel
su 1 fate
Nickel
su 1 fate
Hardness
-------
Table 6. (Continued)
td
1
10
CO
Species
Goldfish (embryo),
Carasslus auratus
Fathead minnow,
Plmephales promelas
Fathead minnow,
Pimephales proms las
Fathead minnow,
Plmephales promelas
Fathead minnow,
Plmephales promelas
Fathead minnow,
Plmephales promelas
Fathead minnow,
Plmephales promelas
Carp (embryo),
Cyprlnus carplo
Carp (larva),
Cyprlnus carplo
Carp ( larva),
Cyprlnus carplo
Channel catfish,
Ictalurus punctatus
Blueglll,
Lepomis macrochlrus
Largemouth bass (embryo),
Mlcrooterus sal mo Ides
Chemical
Nickel
chloride
Nickel
sulfate
Nickel
su 1 fate
Nickel
su 1 fate
Nickel
sulfate
Nickel
sulfate
Nickel
su 1 fate
Nickel
sulfate
Nickel
sulfate
Nickel
sulfate
Nickel
sulfate
Nickel
sulfate
Nickel
chloride
Hardness
(a/I as
CaCO,)
195
29
28
77
89
91
86
128
128
126
42
42
93-105
Duration
7 days
95 hrs
96 hrs
96 hrs
96 hrs
96 hrs
96 hrs
72 hrs
72 hrs
257 hrs
48 hrs
48 hrs
8 days
Effect
LC50
LC50
LC50
LC50
LC50
LC50
LC50
LC50
LC50
LC50
LC50
LC50
LC50
Result*
(ug/l)
2,140
2,920
2,920
12.400
17,700
8,620
5,380
6,100
8,460
750
36,800
110,000
2,020
Reference
Blrge, 1978
Llnd, et al.
Manuscript
Lind, et al.
Manuscript
Llnd, et al.
Manuscript
Lind, et al.
Manuscript
Lind, et al.
Manuscript
Llnd, et al.
Manuscript
Blaylock & Frank, 1979
Blaylock & Frank, 1979
Blaylock & Frank, 1979
Ml II ford, 1966
Will ford, 1966
Blrge. et al. 1978
-------
Table 6. (Continued)
Species
Toad (embryo),
Gastrophryne carol inensis
Salamander (embryo),
Ambystoma opacum
Oyster (larva),
Crassostrea virgin lea
Hard clam (larva),
Mercenaria mercenaria
Polychaete,
Capltel la capitata
00 Polychaete,
1 Ctinodrilus serratus
*° Shrimp,
Panda lus montagul
Sea urchin (embryo),
Lytechlnus p Ictus
Sea urchin (embryo),
Lytechlnus p Ictus
Sea urchin (embryo),
Arbacla punctalata
Green crab,
Carcinus maenus
Chemical
Nickel
chloride
Nickel
chloride
Nickel
chloride
Nickel
chloride
Nickel
chloride
Nickel
chloride
Nickel
chloride
Nickel
chloride
Nickel
chloride
Nickel
chloride
Nickel
chloride
Hardness
(9/1 as
CatXK) Duration
195 7 days
93-105 8 days
SALTWATER SPECIES
12 days
8-10 days
96 hrs
7 days
28 days
48 hrs
20 hrs
20 hrs
42 hrs
48 hrs
Effect
LC50
LC50
EC50 on larval
growth
EC50 on larval
growth
LC50
LC50
No deaths, no
reproduction
LC50
Delayed
development
Abnormal
development
>50% embryo
mortality
LC50
Result*
(ug/l)
50
420
1,210
5,710
>50,000
>50,000
2,000
200,000
58
580
17,000
300,000
Reference
Blrge, 1978
Blrge, et al. 1978
Calabrese, et al. 1977
Calabrese, et al. 1977
Petrlch & Relsh, 1979
Petrlch & Relsh, 1979
Portmann, 1968
Timourlan & Watchmaker,
1972
Timourlan & Watchmaker,
1972
Waterman, 1937
Portmann, 1968
* Results are expressed as nickel, not as the compound
** Animals were fed during test.
***Hardness calculated from data given
-------
REFERENCES
Anderson, B.C. 1948. The apparent thresholds of toxicity to Daphnla magna
«
for chlorides of various metals when added to Lake Erid water. Trans. Am.
Fish. Soc. 78: 96.
Bengtsson, Bengt-Erik. 1978. Use of harpacticoid copepod in toxicity
tests. Mar. Pollut. Bull. 9: 238.
Biesinger, K.E. and G.M. Christensen. 1972. Effects of various metals on
survival, growth, reproduction, and metabolism of Daphnia magna. Jour.
Fish. Res. Board Can. 29: 1691.
Birge, W.J. 1978. Aquatic Toxicology of Trace Elements of Coal and Fly
Ash. In; J.H. Thorp and J.W. Gibbons (eds.), Energy and Environmental
Stress in Aquatic Systems. DOE Sumposium Series (CONF-771114), Natl. Tech.
Inf. Ser., Springfield, Virginia.
Birge, W.J., et al. 1978. Embryo-larval Bioassays on Inorganic Coal Ele-
ments and Jto Situ Biomonitoring of Coal-waste Effluents. lr±: D.E. Samuel,
et al. (eds.), Surface Mining and Fish/Wildlife Needs in the Eastern United
States. FWS/OBS-78/81.
Blaylock, B.G. and M.L. Frank. 1979. A comparison of the toxicity of
nickel to the developing eggs and larvae of carp (Cyprinus carpio). Bull.
Environ. Contam. Toxicol. 21: 604.
B-30
-------
Brown, V.M. and R.A. Dalton. 1970. The acute lethal toxicity to rainbow
trout of mixtures of copper, phenol, zinc and nickel. Jour. Fish Biol.
2: 211.
Buikema, A.L., Jr., et al. 1974. Evaluation of Philodina acuticornis
(Rotifera) as a bioassay organism for heavy metals. Water Resour. Bull.
Am. Water Resour. Assoc. 10: 648.
Calabrese, A., et al. 1973. The toxicity of heavy metals to embryos of
the Atlantic oyster (Crassostrea virgim'ca). Mar. Biol. 18: 162.
Calabrese, A. and D.A. Nelson. 1974. Inhibition of embryonic development
of the hard shell clam, Mercenaria mercenaria, by heavy metals. Bull. En-
viron. Contam. Toxicol. 2: 92.
Calabrese, A., et al. 1977. Survival and growth of bivalve larvae under
heavy metal stress. Mar. Biol. 41: 179.
Chapman, et al. Effects of water hardness on the toxicity of metals to
Daphnia magna. (Manuscript)
Clendenning, K.A. and W.J. North. 1959. Effects of Wastes on the Giant
Kelp, Macrocystes pyrifera. In: E.A. Pearson (ed.), Int. Conf. on Waste
Disposal in the Mar. Environ. Berkeley, California Proc.
B-31
-------
Eisler, R. and R.J. Hennekey. 1977. Acute toxicities of Cd2+, Cr2*,
Hg , Niz+, and Zn2+ to estuarine macrofauna. Arch. Environ. Contain.
6: 315.
Hale, J.G. 1977. Toxicity of metal mining wastes. Bull. Environ. Con-
tarn. Toxicol. 17: 66.
Hall, T. 1978. Nickel uptake retention and loss in Daphnia magna. M.S.
Thesis. Univ. Toronto, Toronto, Ontario.
Hutchinson, T.C. 1973. Comparative studies of the toxcity of heavy metals
to phytoplankton and their synergistic interactions. Water Pollut. Res.
(Canada). 8: 68.
Hutchinson, T.C. and P.M. Stokes. 1975. Heavy metal toxicity and algal bi-
oassays. ASTM STP 573, Am. Soc. Test. Mater, p. 320.
Lind, D., et al. Regional copper-nickel study, Aquatic Toxicology Study,
Minnesota Environmental Quality Board, State of Minnesota. (Manuscript)
Nebeker, A.V., et al. Effects of copper, nickel, and zinc in the life cyc-
le of the caddisfly Clisbronia magnifica (Limnephilidae). (Manuscript)
Nebeker, A. V., et al. Rainbow trout early life stage testing: Sensitivity
to nickel chloride. (Manuscript)
B-32
-------
Patrick, R., et al. 1975. The role of trace elements in management of
nuisance growth. U.S. Environ. Prot. Agency, EPA-600/2-75-008
Petrich, S.M. and D.J. Reish. 1979. Effects of aluminum and nickel on sur-
vival and reproduction in polychaete annelids. Bull. Environ, contam. Tox-
icol. 23: 698.
Pickering, Q.H. 1974. Chronic toxicity of nickel to the fathead minnow.
Jour. Water Pollut. Control Fed. 46: 760.
Pickering, Q.H. and C. Henderson. 1966. The acute toxicity of some heavy
metals to different species of warmwater fishes. Air Water Pollut. Int.
Jour. 10: 453.
Portmann, J.E. 1968. Progress report on a programme of insecticide analy-
sis and toxicity-testing in relation to the marine environment. Helogolan-
der wiss. Meeresunters. 17: 247.
«
Rehwoldt, R., et al. 1971. Acute toxicity of copper, nickel and zinc ions
to some Hudson River fish species. Bull. Environ. Contam. Toxicol. 6: 445.
Rehwoldt, R., et al. 1972. The effect of increased temperature upon the
acute toxicity of some heavy metal ions. Bull. Environ. Contam. Toxicol.
8: 91.
Rehwoldt, R., et al. 1973. The acute toxicity of some heavy metal ions
toward benthic organisms. Bull. Environ. Contam. Toxicol. 10: 291.
B-33
-------
-------
Mammalian Toxicology and Human Health Effects
INTRODUCTION
Assessment of the risk posed by nickel to public health in the
United States entails consideration of two general facets of the
issue: sources of exposure relevant to U.S. populations at larqe
and population response.
There are some obvious questions about the exposure aspects of
nickel. (1) What are the environmental sources of nickel in the
United States? (2) What are the various routes by which nickel
enters the body?
Nickel, in common with other metallic elements, is a multi-
media contaminant. Thus, one needs to have a clear understanding
of fractional contributions to total body burden in humans through
various routes of exposure before one can assess the relative sig-
nificance of any given avenue of intake. A second complicating
factor is the impact of a primary route of environmental entry on
other compartments of the environment. For example, to what degree
does airborne nickel contribute to contamination of water and soil
via fallout?
Some aspects of the problem of human population response to
nickel include: (1) the relevant human biological and pathophysio-
logical responses to nickel; (2) subgroups of the U.S. population
that can be identified as being at particular risk to effects of
nickel by virtue of either exposure setting or some ohysiological
status imparting heightened vulnerability; (3) the magnitude of the
risk to these subgroups in terms of the numbers exposed and as can
best be determined by available population data.
C-l
-------
A discussion of the various effects of nickel on man includes
dose-effect and dose-response relationships and the various para-
meters that are of utility in assessing both magnitude of exposure
and the extent of response.
"Dose" is the amount or concentration of a substance which is
presented over a defined time to the specific site where a given
effect is elicited. In man, it is rarely feasible to assess this
directly, and one must depend on some other means which reflects
the target-site level of the toxicant. Usually, one must select
levels of the agent in urine, blood, hair, etc. as indices of in-
ternal exposure, and these levels are integrated reflections of the
total contributions from various external exposures.
"Effect" is a physiological change resulting from exposure to
a toxic substance, while "adverse health effect" is taken to mean
an impairment of either the organism's ability to function opti-
mally or the organism's reserve capacity to cope with other sys-
temic stresses.
A dose-effect relationship is a quantitative statement of the
relationship between changes in the quantity of an agent and ob-
served gradations of severity in effect resulting therefrom. Dose-
response refers to the frequency with which a given effect occurs
within a copulation at a defined dose.
Furthermore, Nordberg (1976) has defined the concept of criti-
cal organ, critical concentration, and critical effect. "Critical
organ" is that organ which first obtains the critical concentration
of a metal under defined conditions. "Critical concentration" is
that mean concentration of the toxicant in the critical organ at
C-2
-------
which adverse effects are first manifested. That point in the
dose-effect relationship at which an adverse effect exists is
termed the "critical effect".
Nickel enters the environment via both natural and anthropo-
genic activity, and a detailed description of sources and preva-
lence of nickel in the environment is given in the comprehensive
National Academy of Sciences (NAS) review (1975).
In 1972, U.S. consumption of nickel, exclusive of scrap, was
estimated to total about 160,000 tons (Reno, 1974). The estimate
consisted mainly of commercially pure nickel (about 110,000 tons).
The main uses for this commercially pure nickel were stainless
steel, various other alloys, and electroplating. Presumably, the
commercial utility of nickel is such that growth in the use of
nickel is assured.
From the total consumption of nickel in the United States, it
is difficult to determine what fraction of each of the end uses is
dissipated into the environment in ways that are relevant to gen-
eral population exposure assessment. Similarly, the relative con-
tribution of naturally emitted nickel cannot be precisely stated,
although the relative impact of this source is not as great as that
arising from man's activities.
The approach taken in this document is to give attention to
the various media by which the general peculation comes into con-
tact with nickel and to define the nickel levels therein: ambient
air, water, foodstuffs, soil, and other exposure sources.
03
-------
EXPOSURE
Ingestion from Water
The values for nickel levels in 969 U.S. public water supplies
for 1969 to 1970 are presented in Table 1. The survey includes
eight metropolitan areas (NAS, 1975). The average value, taken at
the consumer tap, was 4.8 pg/1, with only 11 systems of this total
exceeding 25 ug/1. The highest level was, in one supply, 75 jjg/1.
It should be noted that tap water levels include any nickel added
in processing and distribution.
Since the data in Table 1 do not furnish any measure of the
number of people consuming drinking water of variable nickel con-
tent, the nickel levels for water supplies of the ten largest U.S.
cities have been listed in Table 2. This table is based on the data
of Durfor and Becker (1964) .
The values for New York City, Chicago, and Los Angeles do not
appear to be markedly at variance with the value of 4.8 yg/1 from
Table 1.
Ingestion from Food
The route by which most people in the general population re-
ceive the largest portion of daily nickel intake is through foods.
The assessment of average daily nickel intake in 1:ood can be
done either by considering the aggregate nickel content of average
diets in the population or by fecal nickel determinations. Al-
though fecal nickel levels would be more meaningful than diet anal-
ysis, given the very small gastrointestinal absorption of nickel in
man, such data have been sparse in the literature in terms of rep-
resentative groups of individuals.
C-4
-------
TABLE 1
Nickel Levels in U.S. Drinking Water
1969-1970a'b
Ni Concn, No. of Ni Frequency
mg/1 Samples (percent of samples)
0.000 543 21.69
0.001-0.005 1,082 43.22
0.006-0.010 640 25.57
0.011-0.015 167 6.68
0.016-0.020 46 1.84
0.021-0.025 14 0.56
0.026-0.030 4 0.16
0.031-0.035 2 0.08
0.036-0.040 1 0.04
0.041-0.045 1 0.04
0.046-0.050 1 0.04
0.051-0.055 1 0.04
0.075 1 0.04
Total 2,503 100.00
aSamples from 969 water systems
bSource: NAS, 1975
C-5
-------
TABLE 2
Nickel Levels of Drinking Water
of 10 Largest U.S. Cities3
City Nickel Level, ug/1
New York City 2.jb
Chicago 7.4°
Los Angeles 4.8
Philadelphia 13.Ob
Detroit 5.6b
Houston 4.5°
Baltimore 4.7C
Dallas 5.2°
San Diego 7.8
San Antonio Not detected
tabulation adapted from NAS, (1975); values
for 1962 survey of Durfor and Becker (1964)
r_
In storage
°Post-treatment
C-6
-------
Some representative nickel values for various foodstuffs,
adapted from data in the HAS Nickel Report, are given in Tables 3,
4, and 5. These values have been obtained by different laborato-
ries using different methods and may be dated in some cases. Total
daily dietary intake values may range up to 900 yg nickel, depend-
ing on the nature of the diet, with average values of 300 to 500 yg
daily (NAS, 1975).
Schroeder, et al. (1962) calculated an average oral nickel in-
take by American adults of 300 to 600 yg/day, while Louria and co-
workers (1972) arrived at a value of 500 yg/day. Murthy, et al.
(1973) calculated the daily food nickel intake in institutionalized
children, 9 to 12 years old, from 28 U.S. cities at an average value
of 451 yg/day. In a related study, Myron, et al. (1978) determined
the nickel content of nine institutional diets in the U.S. and cal-
culated an average intake of 165 yg/day.
Food processing methods apparently add to the nickel levels
already present in foodstuffs via (1) leaching from nickel-contain-
ing alloys in food-processing equipment made from stainless steel,
(2) the milling of flour, and (3) catalytic hydrogenation of fats
and oils by use of nickel catalysts.
Several studies have reported daily fecal excretions of nick-
el. Nodiya (1972) reported a fecal excretion average of 258 yg in
Russian students. Horak and Sunderman (1973) determined fecal ex-
cretions of nickel in ten healthy subjects and arrived at a value
of 258 yg/day, identical to the Russian study.
A bioconcentration factor (BCF) relates the concentration of a
chemical in aquatic animals to the concentration in the water in
C-7
-------
TABLE 3
Nickel Content of Various Classes
of Foods in U.S. Diet*
Food Class and Examples
Nickel Content,
ppm, Wet Weight
Grains/grain products
Wheat flour, all-purpose
Bread, whole-wheat
Corn, fresh frozen
Rice, polished American
Rye flour
Rye bread
Fruits and vegetables
Potatoes, raw
Peas, fresh frozen
Peas, canned
Beans, frozen
Beans, canned
Lettuce
Cabbage, white
Tomatoes, fresh
Tomato juice
Spinach, fresh
Celery, fresh
Apples
Bananas
Pears
Seafood
Oysters, fresh
Clams, fresh
Shrimp
Scallops
Crabmeat, canned
Sardines, canned
Haddock, frozen
Swordfish, frozen
Salmon
Meats
Pork (chops)
Lamb (chops)
Beef (chuck)
Beef (round)
0.54
1.33
0.70
0.47
0.23
0.21
0.56
0.30
0.46
0.65
0.17
0.14
0.32
0.02
0.05
0.35
0.37
0.08
0.34
0.20
1.50
0.58
0.03
0.04
0.03
0.21
0.05
0.02
1.70
0.02
Not detected
Nbt detected
Not detected
*Source: NAS, 1975
C-8
-------
TABLE 4
Nickel in Liquids*
Nickel Cone., ppm
(freah wt.)
Milk, evaporated 0.03
Tea, orange pekoe 7.60
Cocoa 5.00
Ginger ale 0.01
Cider 0.55
Cider vinegar 0.22
Beer, canned 0.01
Mineral water, bottled, Arkansas 0.01
Coffee, green "Robusta" 0.26
Coffee, green "Colombian" O.iO
Tea, Chinese 0.51-0.65
Wine, white, Slovakian 0.09
Wine, red, Moravian 0.12
*Source: NAS, 1975
C-9
-------
TABLE 5
Nickel in Condiments*
,. ,_ Nickel Cone., ppm
Condiment (fresh wt<)
Salt, table 0.35
Pepper, black 3.93
Baking powder 13.40
Sugar, cane 0.03
Yeast, dry active 0.48
Cinnamon 0.74
Nutmeg l.j.7
Allspice 0.79
Bay leaves 0.88
Cloves, whole O.iO
*Source: NAS, 1975
C-10
-------
which they live. An appropriate BCF can be used with data concern-
ing food intake to calculate the amount of nickel which might be
ingested from the consumption of fish and shellfish. Residue data
for a variety of inorganic compounds indicate that bioconcentration
factors for the edible portion of most aquatic animals is similar,
except that for some compounds bivalve molluscs (clams, oysters,
scallops, and mussels) should be considered a separate group. An
analysis (U.S. EPA, 1980a) of data from a food survey was used to
estimate that the per capita consumption of freshwater and estua-
rine fish and shellfish is 6.5 g/day (Stephan, 1980). The per
capita consumption of bivalve molluscs is 0.8 g/day and that of all
other freshwater and estuarine fish and shellfish is 5.7 g/day.
Bioconcentration factors of 384 and 299 were obtained for
nickel with the American oyster, whereas 416 and 328 were obta.ned
with a mussel (U.S. EPA, 1980b) . The geometric mean BCP for bi-
valve molluscs is 354, but no data are available for appropriate
tissues in other aquatic animals. Based on the available data for
copper and cadmium, the mean BCF value for other species is proba-
bly about one percent of that for bivalve molluscs. If the values
of 354 and 3.5 are used with the consumption data, the weighted
average bioconcentration factor for nickel and the edible portion
of all freshwater and estuarine aquatic organisms consumed by Amer-
icans is calculated to be 47.
Inhalation
Perhaps the most comprehensive assessment of ambient air lev-
els of nickel in the U.S. is that of the National Air Surveillance
Network. Tabulation of air nickel levels for the period 1964
C-ll
-------
through 1969 are contained in the NAS Nickel Report (NAS, 1975) for
231 urban and 47 nonurban localities. More recent figures are
available for the period 1970 to 1974 (U.S. EPA, 1976).
Table 6 tabulates the air nickel averages for urban stations
for the period 1970 to 1974. For 1974, the most recent entry, the
arithmetic mean level was 9 ng/m .
Table 7 presents the corresponding values for all nonurban
stations for the same period. Again for 1974, the arithmetic mean
level was 2 ng/m .
It may be seen from Tables 6 and 7 as well as earlier surveys
in the NAS Nickel Report, that there is a clear difference in urban
versus nonurban nickel levels, with urban values being around 3- to
4-fold higher.
Trends in air metal level changes for urban and nonurban areas
have been assessed for a number of elements including nickel (Faoro
and McMullen, 1977). Figure 1 depicts the trend in the 50th per-
centile at urban sites of annual air nickel averages for the period
1965-1974. Nickel shows a downward trend over this period, that is
most pronounced in the latter half of the survey period with an
approximate drop of 40 percent from the 1970-71 to the 1973-74 val-
ues. Nickel is one of the metals associated with fuel combustion,
particularly oil. This relationship is based on documented season-
dependent gradients in air levels with highest levels in the winter
quarter when space heating is at a maximum.
Sulfur regulations which have been in effect over the period
1965 to 1974 appear to be the major factor in lower air nickel lev-
els, particularly in the northeastern United States. Sulfur re-
C-12
-------
TABLE 6
Urban Cumulative Frequency Distributions
of Ambient Air Nickel Levelsa'b
o
1
Year
1970
1971
1972
1973
1974
No. of
sites
797
717
708
559
594
Percentilec
Min.
0.001
0.001
0.001
0.001
0.001
10
0.001
0.001
0.001
0.001
0.001
50
0.001
O.OOi
0.001
0.001
0.001
99
0.127
0.126
0.100
0.133
0.057
Arithmetic Mean
(SD)
0.015
0.015
0.011
* 0.014
0.009
(0.028)
(0.028)
(0.023)
(0.037)
(0.029)
Contracted tabulation from U.S. EPA data (1976).
Lower detection limit for analyses, 0.001 yg/m .
c
Values under given percentile indicate the percentage of stations below air level.
Values in
-------
TABLE 7
Uroan Cumulative Frequency Distributions
of Ambient Air Nickel Levels
a,b
o
Year
1970
1971
1972
1973
1974
No. of
Sites
124
97
137
100
79
Percentile
Min.
0.001
0.001
0.001
0.001
0.001
10
0.001
0.001
0.001
0.001
0.001
1,0
0.001
0.001
0.001
0.001
O.OOi
99
0.076
0.046
0.076
0.188
0.020
Arithmetic Mean
(SD)
0.005
0.003
0.004
0.011
0.002
(0.024)
(0.011)
(0.012)
(O.OJ7)
(0.004)
Contracted tabulation from U.S. EPA data (1976).
°Values under given percentile indicate the percentage of stations below the given air level,
Values in
-------
0.1
o
H
4*
at
U
p
O
8
O
u
0.01
0.001
JII I I t I I I
65 66
67 68 69 70
Year
71 72 73 74
FIGURE 1
Trend in the 50th Percentile at Urban Sites of Average for Nickel
Source: Faoro and McMullen, 1977
C-15
-------
moval from residual oil necessitated by these regulations indirect-
ly removes nickel as well (Faoro and McMullen, 1977).
How long this trend to lower air nickel values in urban areas
will continue, in view of the above, will depend primarily on the
future status of sulfur regulations as well as the level of fuel
oil consumption. Even though the pattern suggested in Figure 1 may
be partially due to changes in analytical technique or sensitivity,
at very least these data suggest that levels of environmental nick-
el in the atmosphere are not going up.
Dermal
The discussion of nickel exposure routes so far has focused on
intake and systemic absorption from various media: air, food, and
water. External contact with nickel is associated with clinically
defined skin disorders. (For further discussion of the dermal ef-
fects of nickel, see the Allergenic Response section.) There is an
extensive list of commodities which contain nickel and through
which the general population can be externally exposed. In partic-
ular, the use of stainless steel kitchens, nickel-plated jewelry,
and various other nickel-containing materials has created a wide-
spread problem for nickel-sensitive individuals.
Other Sources of Exposure
Soil nickel levels are considered in this section chiefly from
the aspect of the influence of soil nickel on man's food chain:
plants 4 animals fr man.
Soils normally contain nickel in a wide range of levels, 5 to
500 ppm, and soils from serpentine rock may contain as much as
C-16
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5,000 ppm (NAS, 1975). While these levels may appear high in some
instances, nickel content of soils as such is less important for
plant uptake than such factors as soil composition, soil pH, organ-
ic matter in soil, and the classes of plants grown therein.
Natural levels of soil nickel may be added to by contamination
from human activity such as atmospheric fallout in the areas of
nickel-emitting industrial activities or auto traffic as well as
treatment of agricultural lands with nickel-containing super phos-
phate fertilizers or municipal sewage sludge.
Ragaini, et al. (1977), in their study of trace metal contami-
nants of soil and grasses near a lead-smelting operation in Idaho,
found that surface soil nickel levels are enriched 39-fold in sam-
pling sites in the vicinity of the smelter.
Contamination of roadside soil with nickel, leading to in-
creased nickel content of grasses, has been noted by Lagerwerff and
Specht (1970). There was an increase in grass nickel levels from
1.3 to 3.8 ppm dry weight, dependent on the distance from the road-
side. Sources of roadside nickel were presumed by the authors to
arise from fuel combustion as well as from external abrasion of
nickel from auto parts.
In a study on the uptake of nickel by the edible portions of
food crops such as bush beans, cabbage, onions, tomatoes, and pota-
toes grown in test pots in municipal sludge from Ithaca, M.Y. ,
Purr, et al. (1976) observed: (1) at first-year harvest, nickel
levels in the above food crops were increased 2- to 3-fold compared
to control soil, the corresponding soil pH levels being 7.1 for
sludge-amended samples and 5.3 for control soils; (2) at second
C-17
-------
harvest, the increases seen in the first harvest did not recur, ex-
cept for about a 2-fold increase in onions and tomatoes.
John and Van Laerhoven (1976) determined the effect of apply-
ing sludge at various loading rates on trace metal uptake by grow-
ing romaine lettuce and beets on amended soil with and without lim-
ing. Sludge used with unlimed soil significantly increased nickel
levels in lettuce, did not affect the element level in beet tops,
and reduced the nickel content of beet tubers. On the other hand,
liming led to increases of nickel in all plant tissues at a 25 g/kg
loading rate for one type of sludge (Milorganite) but. not with a
second type produced at a local treatment plant.
Cigarette smoking can contribute significantly to man's daily
nickel intake by inhalation and nickel from this source probably
exceeds the amount absorbed by breathing ambient air. An indivi-
dual smoking two packs of cigarettes a day would inhale 1 to 5 mg of
nickel per year or about 3 to 15 ug nickel daily (^AS, 1975). The
possible existence of nickel in cigarette smoke as nickel carbonyl
suggests that there would be a net daily absorption of about 1.5 to
7.5 yg into the bloodstream (NAS, 1975; Kasprzak and Sunderman,
1969) . This may be contrasted to the markedly smaller amounts
taken in by inhalation of nickel in ambient air (vide supra).
Several studies indicate that nickel can pass the placental
barrier in animals (Phatak and Patwardhan, 1950; Lu, et al. 1976;
Sunderman, et al. 1978) and man (Creason, et al. 1976) leading to
fetal exposure. Effects of nickel in utero are discussed in the
teratogenicity section of this document.
C-18
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PHARMACOKINETICS
Routes of nickel intake for man and animals are inhalation,
ingestion, and percutaneous absorption. Parenteral exposure is
mainly of importance in experimental animal studies.
The relative amount of inhaled nickel which is absorbed from
various compartments of the pulmonary tract is a function of both
chemical and physical forms. Pulmonary absorption into the blood
stream is probably greatest for nickel carbonyl vapor, with animal
studies suggesting that about half of the inhaled amount is ab-
sorbed. Vickel in particulate matter is absorbed from the pulmo-
nary tract to a considerably lesser degree than nickel carbonyl.
Smaller particles are lodged deeper in the respiratory tract and
the relative absorption is greater than with larger particles.
Lung model and limited experimental data suggest several percent
absorption. While insoluble nickel compounds may undergo limited
absorption from the respiratory tract, their relative insolubility
has implications for the carcinogenic character of nickel, as will
be noted in the following discussion.
Absorption of dietary nickel from the gastrointestinal tract
is on the order of 1 to 10 percent in man and animals from both
foodstuffs and beverages.
Percutaneous absorption of nickel occurs and is related to
nickel-induced hypersensitivity and skin disorders. The extent to
which nickel enters the bloodstream by way of the skin cannot be
stated at the present time.
Absorbed nickel is carried by the blood, although the extent
of partitioning between erythrocyte and plasma cannot be precisely
stated. In any event, Plasma or serum levels reflect the blood
C-19
-------
burden. Normal serum nickel values in man are 2 to 3 yg/1. Albumin
is the main macromolecular carrier of nickel in a number of spe-
cies, inciudina man. In man and rabbit, there also appear to be
nickel-specific proteins.
Tissue distribution of absorbed nickel appears to be dependent
on the route of intake. Inhaled nickel carbonyl leads to highest
levels in lung, brain, kidney, liver, and adrenals. Parenteral
administration of nickel salts usually results in highest levels in
the kidney, with significant uptake shown by endocrine glands,
liver, and lung.
Based on animal studies, nickel appears to have a half-time of
several days in the body. There is little evidence for tissue
accumulation.
The main excretory route of absorbed nickel in man and animals
appears to be through the urine, with biliary excretion also occur-
ring in experimental animals. While hair deposition of nickel also
appears to be an excretory mechanism, the relative magnitude of
this route, compared to urinary excretion, is not fully known at
present.
A number of disease states or other physiological stresses can
influence nickel metabolism in man. In particular, heart and renal
disease, burn trauma, and heat exposure can either raise or lower
serum nickel levels.
Absorption
The major routes of nickel absorption are inhalation and in-
gestion via the diet. Percutaneous absorption is a less signifi-
cant tactor for nickel's systemic effects but is important in the
:-20
-------
allergenic responses to nickel. Parenteral administration of nick-
el is mainly of interest to experimental studies and particularly
helpful in the assessment of the kinetics of nickel transport, dis-
tribution, and excretion in addition to maximizing the physiologi-
cal parameters for nickel's effects.
The amounts of nickel absorbed by organisms are determined not
only by the quantities inhaled or ingested, but also by the chemi-
cal and physical forms of nickel. Other factors, such as the
nutritional and physiological status of the host organism, also
play a role, but this has been studied little outside of investiga-
tions directed at an essential role for nickel.
Gastrointestinal intake of nickel by man is surorisingly high,
relative to other toxic elements, which is at least partly account-
ed for by contributions of nickel from utensils and equipment in
processing and home preparation of food.
Collectively, the data of Tedeschi and Sunderman (1957) , Perry
and Perry (1959), Nomoto and Sunderman (1970), Nodiya (1972), and
Horak and Sunderman (1973) indicate that 1 to 10 percent of dietary
nickel is absorbed.
One question that arises in considering the dietary intake and
absorption of toxic elements has to do with the bioavailability of
the agent in solid foodstuffs versus water and beverages. Ho and
Furst (1973) observed that intubation of Ni in dilute acid solu-
tion leads to 3 to 6 percent absorption of the radiolabeled nickel
regardless of the dosing level. It does not appear, then, that
nickel in simple aqueous solution is absorbed to any greater extent
than that incorporated into the matrix of foodstuffs.
C-21
-------
Percutaneous absorption of nickel is mainly viewed as impor-
tant in the dermatopathological effects of this agent, ssuch as con-
tact dermatitis, and absorption viewed this way is restricted to
the passage of nickel past the outermost layers of skin deep enough
to bind with apoantigenic factors.
Wells (1956) demonstrated that divalent nickel penetrates the
skin at sweat-duct and hair-follicle ostia and binds to keratin.
Using cadaver skin, Kolpokov (1963) found that nickel (II) accumu-
lated in the malpighian layer, sweat glands, and walls of blood
vessels. Soruit, et al. (1965) have shown that nickel penetrates
to the dermis.
Values for the amounts of nickel passing through outer layers
of skin relative to amounts applied have not been determined.
Samitz and Pomerantz (1958) have reported that the relative extent
of nickel penetration is enhanced by sweat and detergents.
Mathur and his co-workers (1977a) have reported the systemic
absorption of nickel from the skin using nickel sulfate at very
high application rates. After 30 days of exposure to nickel at
doses of 60 and 100 mg Ni/kg, a number of testicular lesions were
observed in rats, while hepatic effects were seen by 15 days at
these exposure levels. It is not possible to calculate any absorp-
tion data from this study.
Respiratory absorption of various forms of nickel is probably
the major route of nickel entry into man under conditions of occu-
pational exposure. Of these forms, nickel carbonyl is one that has
been found to be toxic.
C-22
-------
Nickel carbonyl/ Ni(CO)4, is a volatile, colorless liquid
(b.p. 43°C). Armit (1908) judged its relative toxicity to be 100-
fold higher than that of carbon monoxide. More recently, the
threshold limit value (TLV) for a work day exposure has been set at
50 ppb. In contrast, the corresponding value for hydrogen cyanide
is 10 ppm, 200-fold greater [American Conference of Governmental
Industrial Hygienists (ACGIH), 1978]. Occupational health hazard
of Ni(CO)« has been recognized since the development of the Mond
process of nickel purification in its processing (Mond, et al.
1890). A detailed discussion of the toxicological aspects of nick-
el carbonyl poisoning is included in the NAS report on nickel
(1975) as well as a recent review by Sunderman (1977).
Studies of nickel carbonyl metabolism by Sunderman and his co-
workers (Sunderman and Selin, 1968; Sunderman, et al. 1968) indi-
cate that pulmonary absorption is both rapid and extensive, the
agent passing the alveolar wall is intact Ni(CO)4. Sunderman and
Selin (1968) observed that rats exposed to nickel carbonyl at 100
mg Ni/1 air for 15 minutes excreted 26 percent of the inhaled
amount in the urine by four days post-exposure. On taking into
account the exhaled quantity, as much as half of the inhaled amount
could have been initially absorbed.
Few data on the pulmonary absorption of nickel from particu-
late matter deposited in the lung exist. The International Radio-
logical Protection Commission (IRPC) Task Group on Lung Dynamics
(1966) has advanced detailed deposition and clearance models for
inhaled dusts of whatever chemical origin as a function of particle
size, chemical properties, and compartmentalization within the pul-
C-23
-------
monary tract. Nickel oxide and nickel halides are classified as
Class W compounds, i.e., compounds having moderate retention in the
lungs and a clearance rate from the lungs of weeks in duration.
While the model described above has limitations, it can be of
value in approximating deposition and clearance rates for nickel
compounds of known particle size. For example, Natusch, et al.
(1974) in a detailed study of eight coal-fired cower plants, found
that nickel is one of a number of elements emitted from these
sources. It is found in the smallest particles of escaped fly ash,
about 1 to 2 um mass median aerodynamic diameter (MMAD). This is a
size that penetrates deepest into the pulmonary tract. According
to the approaches of the IRPC model, particles of 1 um undergo a
total deposition percentage of 63 percent, with 30 percent in the
nasopharyngeal tract, 8 percent in the tracheobronchial part, and
25 percent in the pulmonary compartment. The absorption rate of
deposited particulate matter in the IRPC model is based on chemical
homogeneity of the particulates, however, and one can only approxi-
mate such absorption if heterogeneous particles are considered.
According to Natusch, et al. (1974), nickel-enriched particles in
fly ash have much of the nickel on the particle surface. If one
approximates the absorption rate by assuming that particles en-
riched in nickel in the outer portions of the particle are handled
by the model lung in a fashion similar to a homogenous particle of,
say, nickel, then one obtains a total approximate absorption of
about 6 percent, with major absorption calculated as taking Place
from the pulmonary compartment, 5 percent.
C-24
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Wehner and Craig (1972) , in their studies of the effect of
nickel oxide aerosols on the golden hamster, observed that inhala-
tion by these animals of nickel oxide particles in a concentration
of 2 to 160 yg/1 (2 to 160 mg/m ) and particle size of 1.0 to 2.5 ym
MMAD led to a deposition of 20 percent of the total amount inhaled.
After six days post-exposure, 70 percent of the nickel oxide re-
mained in the lungs, and even after 45 days approximately half the
original deposition was still present. Since no material increase
in nickel levels of other tissues had occurred, it appeared that
absorption in this interval was negligible. In a later, related
study (Wehner, et al. 1975), co-inhalation of cigarette smoke had
no apparent effect on either deposition or absorption.
Leslie and co-workers (1976) have described their results with
exposure of rats to nickel and other elements contained in welding
fumes. In this case, the particle size vs. nickel content was
known precisely, highest nickel levels being determined in parti-
cles 0.5 to 1.0 ym in diameter at an air level of 8.4 ym Ni/m .
While the authors did not determine the total nickel deposition in
the lungs of these animals, they observed that essentially no ab-
sorption of the element from the lung had occurred by 24 hours, nor
were there elevations in blood nickel, suggesting negligible ab-
sorption. In contrast, Graham, et al. (1978) , using nickel chlor-
ide aerosol and mice (^ 3 ym diameter, 110 ug Ni/m ) found about 75
percent absorption by day four post-exposure. The rapid absorption
of the nickel halide was probably due to its solubilitv relative to
the oxide.
C-25
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In addition to nickel exposure in man due to inhalation of
ambient and workplace air, cigarette smoking constitutes a possible
significant source among heavy smokers. Studies by Sunderman and
Sunderman (1961a), Szadkowski, et al. (1969), and Stahly (1973)
indicate that 10 to 20 percent of cigarette nickel is carried in
mainstream smoke, with better than 80 percent of this amount being
in gaseous, rather than particulate, form. Since it is quite pos-
sible that nickel carbonyl constitutes the gaseous fraction (Sun-
derman and Sunderman, 1961a) , one must assume that the relative
absorption of nickel from cigarette smoke is proportionately great-
er than that from airborne nickel particulates, and with heavy
smokers may be the main source of nickel absorbed via inhalation.
Individuals smoking two packs of cigarettes daily can inhale up to
5 mg nickel annually (NAS, 1975). By contrast, an individual in an
urban U.S. area having an air level of Ni of 0.025 yg/nT1 (NAS, 1975)
for regional average values of airborne nickel, and breathing 20 m
daily would inhale somewhat less than 0.2 mg. The relative signif-
icance for absorption would be even greater (vide supra).
Distribution
The kinetic processes governing the transport and distribution
of nickel in various organisms are dependent upon the modes of
absorption, the rate and level of nickel exposure, the chemical
form of nickel and the physiological status of the organism.
Blood is the main vehicle for transport of absorbed nickel.
While it is difficult to determine from the literature the exact
partitioning of nickel between erythrocytes and plasma or serum for
unexposed individuals, serum levels are rather good reflections of
C-26
-------
blood burden and exposure status (NAS, 1975) . In unexposed indivi-
duals, serum nickel values are approximately 0.2 to 0.3 yg/dl. Ow-
ing to the analytical difficulties of assessing nickel in whole
blood, it would be difficult to arrive at accurate determinations
of plasma/cell ratios for blood nickel. It would be desirable to
have good data on plasma to whole blood ratios; however, this data
is currently not available.
Distribution of serum-borne nickel among the various biomolec-
ular components has been discussed in some detail in recent review
(NAS, 1975) , and it will mainly be noted here that serum albumin is
the main carrier protein in sera of man, the rabbit, the rat, and
bovines. Furthermore, there exists in sera of man and rabbits a
nickel-rich metalloprotein identified as an <=K ,-macroglobulin
(nickeloplasmin) in rabbits and in man as a 9.5 S *<,-glvcoprotein.
Sunderman (1977) has suggested that nickeloplasmin may be a complex
of the
-------
TABLE 8
Serum Nickel in Healthy Adults of Several Species'
Species (N)
Nickel Concentration,
ug/ib
Domestic horse (4)
Man (47)
Jersey cattle (4)
Beagle dog (4)
Fischer rat (11)
British goat (3)
New Hampshire chicken (4)
Domestic cat (3)
Guinea pig (3)
Syrian hamster (3)
Yorkshire pig (7)
New Zealand rabbit (24)
Maine looster (4)
2.0 (1.3-2.5)
2.6 (1.1-4.6)
2.6 (1.7-4.4)
2.7 (1.8-4.2)
2.7 (0.9-4.1)
3.5 (2.7-4.4)
3.6 (3.J-3.8)
3.7 (1.5-6.4)
4.1 (2.4-7.1)
5.0 (4.2-5.6)
5.3 (3.5-8.3)
9.3 (6.5-14.0)
12.4 (8.3-20.1)
Source: Sunderman, et al. 1972a
3Mean (and range)
C-28
-------
have observed elevated, rapidly cleared levels of nickel in lungs,
brain, kidney, and liver of various animal species (Barnes and
Denz, 1951; Sunderman, et al. 1957; Ghiringhelli and Agamennone,
1957; Sunderman and Selin, 1968; Mikheyev, 1971).
Sunderman and Selin (1968) have shown that one day after expo-
sure to inhaled Ni, nickel carbonyl, viscera contained about half
of the total absorbed label with one-third in muscle and fat. Bone
and connective tissue accounted for about one-sixth of the total.
Spleen and pancreas also appear to take up an appreciable amount of
nickel. Presumably, nickel carbonyl crosses the alveolar membrane
intact from either direction, inhalation or injection, suggesting
that its stability is greater than has usually been assumed (Kas-
przak and Sunderman, 1969; Sunderman, et al. 1968; Sunderman and
Selin, 1968). Retained nickel carbonyl undergoes decomposition to
carbon monoxide and nickel of zero valency in the erythrocyte and
tissues, followed by intracellular oxidation of the element to the
divalent form with subsequent release into serum.
In human subjects acutely exposed to nickel carbonyl vapor,
highest nickel levels were found in the lung, followed by kidney,
liver, and brain (NAS, 1975).
A number of reports in the literature describe the tissue dis-
tribution of divalent nickel following parenteral administration of
nickel salts. These studies have been of two types: tissue nickel
content assessment or studies measuring the kinetics of nickel
deposition and clearance within a modeling framework. The data are
summarized in Table 9.
C-29
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TABLE 9
Tissue Distribution of Nickel (II) After Parenteral Administration*
Species
Dosage
Relative Distribution of 63Ni
Reference
Mouse
Rat
6.2 mg/kg
(one i ntraperi tones 1
injection
o
to
o
Guinea pig
Rabbit
Rabbit
617
(one intravenous
injection
(subcutaneously
for 5 days)
240 M9A9
(one intravenous
injection)
4.5 Mg/kg
(intravenously for
34-38 days)
Kidney >lung >plasma >liver >erythrocyte
spleen >bladder> heart> brain >carcass
(muscle, bone, and fat)
Kidney >lung > adrenal> ovary > heart > gastro-
intestinal tract >skin>eye> pancreas>
spleen - liver) muscle> teeth> bone>
brain - fat
Kidney > pituitary >lung >liver > spleen > heart)
adrenal > testis) pancreas >medulla
oblongata » cerebrum » cerebellum
Kidney >pituitary> serum> whole blood > skin>
lung >heart > testis > pancreas > adrenal)
duodenum) bone > spleen >liver> muscle)
spinal cord >cerebellum )medulla oblongata »
hypothalamus
Kidney >pituitary > spleen >lung > skin ) testis)
serum * pancreas adrenal sclerae duodenum «
liver > whole blood ) heart > bone > iris ) muscle)
cornea » cerebellum hypothalamus ) medulla
oblongata ) spinal cord >retina ) lens ) vitreous
humor
Nase, et al.
Smith and
UacKley
(196B)
Clary
Parker and
Sunderman
U974)
Parker ana
Sunderman
(1974)
Source: HAS, 1975
-------
It can be generally stated that nickel administered this way
leads to highest accumulation in kidney, endocrine glands, lung,
and liver. Relatively little nickel is lodged in neural tissue,
consistent with the observed low neurotoxic potential of divalent
nickel salts. Similarly, there is relatively slight uptake into
bone, consistent with other evidence that nickel is rather rapidly
and extensively cleared from organisms, with little retention in
soft or mineral tissue.
Onkelinx, et al. (1973) studied the kinetics of iniected 63Ni
metabolism in rats and rabbits. In both species, a two-compartment
model of clearance could be discerned, consisting of fast and slow
components. In the rabbit, better than 75 percent of the dose was
excreted within 24 hours, while comparable clearance in the rat
required three days. In a later study, Onkelinx (1977) reported
whole body kinetics of Ni in rats. The time course of plasma
nickel levels entailed first-order kinetics analyzable in terms of
a two-compartment model. The major portion of nickel clearance is
accounted for by renal excretion.
Chausmer (1976) has measured exchangeable nickel in the rat
using Ni given intravenously. Tissue exchangeable pools were
directly estimated and compartmental analysis performed by computer
evaluation of the relative isotope retention versus time. Kidney
tissue had the largest labile pool within 16 hours with two intra-
cellular compartments. Liver, lung, and spleen pools could also be
characterized by two compartments, while bone tissue fits a one-
compartment model. Corresponding half-times for the fast and slow
components were several hours and several days, resoectively.
C-31
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Oral exposure of experimental animals to nickel with regard to
absorption and tissue distribution appears to be dependent upon the
relative amounts of the agent employed. Schroeder, et al. (1974)
could find no uptake of nickel in rats chronically exposed to nick-
el in drinking water (5 ppm) over the lifetime of the animals.
Phatak and Patwardhan (1952) reported the effects of different
nickel compounds given orally to rats in terms of tissue accumula-
tion. Among the three chemical forms of nickel used, i.e., carbon-
ate, nickel soaps, and metallic nickel catalyst, tissue levels were
greatest in the groups fed the carbonate. O'Dell and his co-work-
ers (1971) fed calves supplemental nickel in the diet at levels of
62.5, 250, and 1,000 ppm. While levels of nickel were somewhat
elevated in pancreas, testis, and bone at 250 pom, pronounced in-
creases in these tissues were seen at 1,000 ppm. whanger (1973)
exposed weanling rats to nickel (acetate) in the diet at levels up
to 1,000 ppm. As nickel exposure was increased, the nickel content
of the kidneys, liver, heart, and testes was also el»vated, with
greatest accumulation in the kidneys. Spears, et al. (1978) ob-
served that lambs given tracer levels of Ni orally with or with-
out supplemental nickel in diet had the highest levels of the label
in the kidneys, the relative levels in the kidneys, lungs, and
liver being less for the low-nickel group.
Comparing the above studies suggests that a homeostatic mecha-
nism exists to regulate low levels of nickel intake, e.g., 5 ppm,
but such regulation is overwhelmed in the face of larqe levels of
nickel challenge.
C-32
-------
The blood values for nickel, as shown in Table 10, are limited
to those utilizing atomic absorption spectrometry. The data are
taken from the report by the NAS (1975) and expanded by the addi-
tion of three relevant later studies.
The values agree well with the exception of the earliest
study, that done by Schaller, et al. (1968). The mean value re-
ported for the H^getveit and Barton study (1976) is of interest,
since the authors report in another publication (H^getveit and
Barton, 1977) : "These figures today (1977) appear hiqh. There has
been a distinct lowering of plasma nickel levels...partly due to
improved laboratory reliability...more recent tests of 21 unexposed
adults...revealed an average plasma nickel level of 0.21 ug/dl in
contrast to the previous control group of 0.42 ug/dl."
Age and sex do not appear to be associated with nickel blood
levels, as authors frequently report mean values for the total
group only because they have found no significant differences by
age or sex. There are no data for this population segment or about
lifespan gradient.
Other variables such as race, residence, and geographic loca-
tion similarly cannot be evaluated, and further, there are no data
for "unacculturated" populations who are not exposed to industrial
pollution. The only study addressing the question of differences
in mean blood nickel levels for normal populations living in envi-
ronments with differing degrees of pollution due to the absence or
presence of nickel refineries is that of McNeely, et al. (1972).
He examined normal adults who were not occuoationally exposed to
nickel in Sudbury, Ontario, the location of North America's laroest
C-33
-------
TABLE 10
"Normal" Blood Nickel Concentrations
Author
Method
Area
Sheets or^asmi *ickel Concentration ot
and Sex (P) Mean (+ SO) Range
O
I
ui
Schaller, et al. (1968)
Nomoto and Sunderroan (1970)
McNeely, et al. (1972)
Pekarek and Hauer (1972)
Nomoto (1971)
H0getveit and Barton (1977)
Spruit and Bongaarts (1977a)
Atomic absorption Germany 26
Atomic absorption Connecticut 40.
Atomic absorption Connecticut 26
Atomic absorption Washington, D.C. 20
Atomic absorption Japan - 23
Atomic absorption Norway 3
Atomic absorption Holland 10
P 2.4. U.bU-j. 70
S 0.2b U.ii-0.40
S 0.2b U. Otl-O.L>2
S A.50 (+ O.i)
S 0.21 (+ O.li)
P 0.42 O./0-O.oO
P O.J.6
-------
nickel refinery, and compared them to adults from Hartford, Conn.
The Sudbury mean serum nickel level for 25 adults was 0.46 + 0.14
with a range of 0.20 to 0.73 yq/dl, while respective values for
Hartford were 0.26 + 0.09 (range 0.08 to 0.52 yg/dl).
It should also be noted that smoking status of the individuals
tested has not been considered systematically in these reports.
The NAS report (1975) cites several studies which showed "that 10
to 20 percent of the nickel in cigarettes is released in the main-
stream smoke." The authors conclude that an individual smoking two
packs per day may inhale between 1 and 5 mg of nickel a year. There
is some evidence that about four-fifths of the nickel in mainstream
smoke is in the gaseous phase (Szadkowski, et al. 1969). Further,
there is inferential evidence that this gaseous nickel is in the
form of nickel carbonyl (Kasprzak and Sunderman, 1969; Stahly,
1973) , which has a very high degree of retention in the resoiratory
tract. It would seem quite possible that regular smoking of one or
more packs of cigarettes a day would contribute the manor fraction
of daily inhaled nickel in the general population.
Data from three studies reporting values of nickel in blood
for occupationally exposed persons and nonexposed controls show
significant differences. Clausen and Rastogi (1977) report on a
study in which atomic absorption spectrometry was used to determine
blood nickel levels in a qrouo of Danish qarage mechanics as well
as a control group of laboratory workers and blood donors. The
mean whole blood level of the group of workers was for nickel 5.3 +
4.8 ug/dl, while the 54 controls showed a mean of 1.7 + 1-5, range
0.4 to 5.4 ug/dl. The difference was significant at o<0.01.
C-35
-------
H^getveit and Barton (1976) reported on the results of moni-
toring blood plasma Ni levels in workers in the Falconbridge nickel
refinery. They found Ni plasma values of 0.74 yg/dl for 701 sam-
ples from 305 workers while controls showed an average value of
0.42 ug/dl in 86 samples. Atomic absorption spectrometry was used
in the analyses. The plasma levels for workers at different work
stations showed that 179 electrolysis department workers had a mean
blood nickel concentration of 0.74 yg/dl while 126 roasting-smelt-
ing workers averaged 0.60 yg/dl. Workers engaged in electrolysis
operations were found to be exposed to soluble nickel salts in
aerosol form while the workers in roasting-smelting operations were
exposed to largely insoluble compounds in dust (H0getveit and
Barton, 1977). Figure 2 shows the nickel plasma averages for the
two groups of workers as a function of date of initial employment
in the industry. Two levels of nickel exposure are evident, as is
the finding that levels reflect intensity of exposure and not dura-
tion, i.e., blood plasma levels appear to reflect current exposure.
Spruit and Bongaarts (1977a) tested for blood plasma nickel
levels in eight occupationally exposed volunteers and found average
levels of 1.02 and 1.11 yg/dl at different periods during the work
year, but 0.53 yg/dl after the annual two-week holiday. The con-
trols, patients from the dermatology service without occupational
exposure, showed plasma levels of 0.16 and 0.20 yg/dl for 10 males
and 14 females, respectively. These data support the H^getveit and
Barton (1976) finding that Plasma concentrations reflect current
exposure and, further, provide evidence that there is very quick
response to exposure.
C-36
-------
1
a
7
6
0
1
u>
6
t
1 1 1 1 1 1 1
~~ ^^^*""~^----"
ELECTROLYSIS WORKERS
*~~
O ^ , *-o~*- O^
o *
A ^*^» ^_ _,_ .1
ROASTINa/SMELTINQ
WORKERS .
0
1 1 I 1 1 1 1
1843- 1848 1053- IflliB 1B63- 1061- 1971- AFTER
47 62 67 62 67 70 72 JAN 1.1&73
FIGURE 2
Average Plasma Nickel Levels in Employees According to Year Beginning Employment
Source: H^geveit and Barton, 1976
-------
The specific effects on blood levels of nickel in exposed
workers who smoke, practice faulty hygiene, and fail to observe
safety regulations have either not been evaluated or, if evaluated,
have not been reported. However, there is one case study of a re-
calcitrant worker (HjzJgetveit and Barton, 1977) who showed a plasma
nickel level of 10.0 ug/dl. Ten days after safety measures were
enforced the worker's plasma nickel level had drooped to 3.75 ug/dl
and he was given sick leave for three weeks. During this leave, the
worker's plasma nickel level dropped to 1.0 yg/dl. After he re-
turned to work, his nickel level rose steadily until safety en-
forcement brought about a reduction once more.
The data presented for urinary nickel levels are subject to
the same strictures as those for blood nickel levels. The analytic
technique is subject to considerable error, and the selection of
subjects varies from volunteers to clinic patients "not occuoation-
ally exposed." The criteria for determining nonexposure and re-
cruitment and selection of volunteers and other "normals" are not
specified. Several of the studies evaluating urine nickel concen-
trations appear in Table 10 for plasma and serum concentrations as
well.
The available data for nickel concentrations present a further
problem, namely the comparability of values for single samples or
24-hour collections. Spruit and Bongaarts (1977a) reported nickel
urine concentrations for different samples collected on consecutive
days and found considerable unexplained variation as shown in Fig-
ures 3, 4, and 5.
C-38
-------
30
8 16 0 8 16 0 8 16 0 8 16 0 8 16 0
Wednesday Thursday Friday Saturday Sunday
FIGURE 3
Urine Ni Concentrations in Consecutive Determinations
of Urinary Nickel from a Healthy, Nonallergic Volunteer
Mean Ni Content: 2.2 jig Ni/1 Urine
Source: Spruit and Bongaarts, 19?7a
C-39
-------
z o f-^-CP
6 12 1w w « - .
Tuesday.June 15 Wednesday. June 16 Thursday .June 17
18 0 6 12 18
Monday Tuesday June 22
0 6
Wednesday June 23
FIGURE 4
Urine Ni Concentration of Two Nonallergic Patients
Showing Influence of Toothache and Extraction
Source: Spruit and Bongaarts, 1977a
C-40
-------
Z 0
work
A ^B«working hours
16 0 8 16 0 8 16 0 8 16 0
8 16
Friday Saturday Sunday MondayJune21 Friday Saturday Sunday
_fe
work
work
ALJB
work
0 8 16 0 8 16 0
Monday TuesdayJune 29
ALJ8 ALJ8
work work
FIGURE 5
Urine Ni concentration in an occupationally exposed, nonaller-
gic volunteer. Mean value: 6.0 ug Ni/1 urine and peak values up to
40 vig Ni/1 urine during working hours
Source: Spruit and Bongaarts, 1977a
C-41
-------
H0getveit and Barton (1976) state that they consider urine Mi
concentrations an undesirable monitoring method since only 24-hour
collection totals are indicative of atmospheric nickel concentra-
tions. The authors point out that 24-hour collections require co-
operation by workers and avoidance of urine contamination during
sample collection.
while some investigators present data for both single samples
and 24-hour urine collections, many did not collect 24-hour urine
samples. In addition, the calculation of nickel concentration
relative to creatinine to control for renal function is not em-
ployed or reported by most investigators.
Finally, the number of subjects in most studies is quite
small, and the effects of sex and age cannot be evaluated. Equal-
ly, there are no data to assess the association between race,
urban-rural residential status, geographical location,, degree of
industrialization, and urine Ni levels, so that these variables
cannot be examined. There are no data for children and effect of
the age gradient cannot be determined for urine concentrations.
The values presented in Table 11 show six findings of remark-
able agreement ranging from 0.20 to 0.27 ug/dl for mean values.
There is no, obvious explanation for the other disparate values
found, although analytical problems may have played a part.
Bernacki, et al. (1978) determined urine concentrations by
volume and creatinine ratio for workers with different environment-
al exposures. Table 12 shows the findings for exposed, nonexposed,
and control subjects as well as air concentrations for seven work
environments. There is only partial concordance between atmospher-
C-42
-------
TABLE 11
Nickel Concentrations in Human Urine
O
I
Authors
Sunderman (1965)
Nomoto and Sunderman (1970)
Lehnert, et al. (1970)
McNeely, et al. (1972)
H0getveit and Barton (1976)
Spruit and Bongaarts (1977a,b)
Mikac-Devic, et al. (1977)
Bernacki, et al. (1978)
Ader and Stoeppler (1977)
Method
Atomic absorption
Atomic absorption
Atomic absorption
Atomic absorption
Atomic absorption
Atomic absorption
Atomic absorption
Atomic absorption
Atomic absorption
Area No> of
Acea Subjects
Pennsylvania
Connecticut
Germany
Connecticut
Norway
Netherlands
Connecticut
Connecticut
a
17
26
15
20
a
10
a
19
a
Nickel Concentration, pg/dl (pg/ciayj
Mean
1.8 (19.8)
0.23 (2.4)
«9.i)
0.20 (2.5)
2.i
0.06
0.27
0.27b
0.2
Range
0.4-J.i
0. iU-O.bz (i.O-b.o)
(5.7-J.2.7)
0.07-0.40 (O.Ub-b.U)
0.3-4.2
a
a
0.04-0.bib
a
Not specified.
Ni:2.b + 1.3 pg/g creatine (range 0.7-5.7 pg/g creatine); all samples with specific gravity <1.012 discarded.
-------
TABLE 12
Nickel Concentrations in Urine Specimens From Workers in Twelve Occupational Groups'
Group
A
B
C
D
E
? *
*»
* G
H
I
J
K
L
Occupation
Hospital workers
Nonexposed industrial
workers
Coal gasification
workers
Buffers/polishers
External grinders
Arc welders
Bench mechanics
Nickel battery
workers
Metal sprayers
Electroplaters
Nickel platers
Nickel refinery
workers
No. of
Subjects
and Sex
19 (15M.4F)
23 120M.3F)
9M
7 (6M.1F)
9 (7M,2F)
10 (7M,2F)
8 (4M,4F)
6 (5M,1F)
5 (4M,1F)
11M
21M
15M
Description
Physicians, technologists, and
clerks
Managers, office workers and
storekeepers
Ni-catalyzed hydrogenation
process workers
Abrasive buffing, polishing and
deburring aircraft pacts made of
Ni-alloys
Abrasive wheel grinding of exteriors
of parts made of Ni alloys
DC arc welding of aircraft parts
made of Ni alloys
Assembling, fitting, and finishing
parts made of Ni alloys
Fabricating Ni-Cd or Ni-Zn electri-
cal storage batteries
Flame spraying Ni-containing pow-
ders in plasma phase onto aircraft
parts
Intermittent exposure to Ni in com-
bined electrodeposition operations
involving Ag, Cd, Cr, or Cr plating
as well as Ni
Full-time work in Ni plating
operations
Workers in a nickel refinery that
employs the electrolytic process
j
Atmospheric Ni
Cone, ug/m °
Not measured
Not measured
Not measured
2t>+48
(0705-129)
1.6+3.0
(2.1-8.8)
6.0+14.3
(0.7-46)
52+94
(0.1+252)
Not measured
2.4+2.0
(0.54-6.5)
0.8+0.9
(0.4-2.1)
Not measured
489+560
(20-2,200)
Urine M
-------
ic concentrations and urine values. In view of H0getveit's find-
ings of the role of* different nickel compounds in elevation of
plasma levels, it seems that total nickel concentrations in air are
not the most useful indicator of variation in exposure effects, ano
that concentrations of specific compounds might be required to ex-
plain associations.
Hjrfgetveit and Barton (1976) found an average urine nickel con-
centration of 8.9 ug/dl for 729 samples from 305 workers, while the
value for controls was 2.1 yg/dl. The data for average urine con-
centrations for different work sites and exposure to different
nickel compounds are not given.
Figure 6 shows the effect of occupational exposure over a 40-
day period for both plasma and urine concentrations in two tempo-
rary employees, while Figure 7 shows the data for a control subject
over a period of 4.5 months. The values showed variation between
individual determinations but the range remains below occupational
exposure levels.
Spruit and Bongaarts (1977a) found a mean nickel urine concen-
tration of 1.8 yg/dl for seven occupationally exposed individuals
and 0.06 ug/dl for ten unexposed males. After a two-week vacation
period, the mean value for the exposed workers had gone down to
0.18 yg/dl.
The same authors report on the urine and plasma concentrations
in a healthy, nonexposed volunteer after ingestion of 5 mg of nick-
el as a solution of nickel sulfate. Figure 8 shows these concen-
trations during the first eight days after ingestion. Plasma and
urine concentrations do not follow the same pattern of response.
C-45
-------
400
320
WO-
WO
OPERATOR AT
IRON PRECIPITATION
(FILTER PRESSES <
TCMMtTrO
CM»U9n«Nr
I
I
OPERATOR AT
CEMENTATION
DAY
FIGURE 6
Plasma and Urine Nickel Values in Two Temporary
Workers Tested Every 10 Days
Source: H0geveit and Barton, 1976
C-46
-------
O
I
*>.
300
200
180
160
140
120
100
BO
60
40
20
16
I I I I I I I I I I I I I I I I I I I I
i i i i i i i i i i i i i i V*?ELL.A i i i
«»« ft » fl ft » 1H»f ₯ t ₯ * f ₯ ₯ f
FIGURE 7
Plasma and Urine Nickel Concentrations in a Student Volunteer
Source: H0geveit and Barton, 1976
-------
FIGURE 8
Blood plasma and urinary Ni content of a healthy, nonallergic
volunteer after oral consumption of 5 mg Ni (solution of nickel
sulfate) at time 0. Mean of 11 urine determinations during the
first 48 hrs. 10.9 ug Ni/1 urine; mean of 8 plasma determinations
during the first 48 hrs. 13.5 ug Ni/1 plasma.
Source: Spruit and Bongaarts, 1977a
C-48
-------
As in the case of plasma and serum concentrations, studies of
urine concentrations in occupationally exposed persons have not re-
ported smoking status or age. The effect of smoking, consequently,
cannot be examined at this time. Age as a variable in nickel urine
concentrations cannot be assessed at this time, since there are no
available data. It should be pointed out that H^getveit and
Barton's data (1976) showing employment cohorts cannot serve as a
surrogate variable for age cohorts. Kreyberg's (1978) analysis of
lung cancer in workers from that nickel refinery found that post-
World War II employees were considerably older at the start of
their employment than the prewar groups and that age cannot be
assumed from employment cohort membership.
The use of hair in assessing toxic metal exposure has several
»
appealing features: hair sampling represents a rapid, noninvasive
means of assessing internal exposure and involves a matrix which
can be stored indefinitely in sealed containers. Also, segmental
analyses along the length of the hair samples should provide some
sort of chronological index of chronic and episodic acute exposure
to an agent.
One of the most vexing problems associated with determination
of hair nickel levels is that of external contamination, not only
from airborne and water-borne nickel but also from the use of hair
preparations which may contain appreciable amounts of nickel.
Thus, the relative effectiveness of chemical debridement methods
will markedly influence the resulting nickel levels. Cleaning
techniques which not only remove surface nickel but penetrate the
matrix of the hair may yield values that are too low. Conversely,
C-49
-------
ineffective cleaning will yield nickel levels from both internal
and external exposure. A second problem is the sampling from dif-
ferent places along the hair shaft by different laboratories.
It would appear that standardization of cleaning and sampling
techniques is urgently required before hair nickel levels from var-
ious laboratories can be compared and conclusions made regarding
the exposure-hair level relationship.
Table 13 shows hair nickel values from studies employing atom-
ic absorption spectrometry techniques. Samples for the Schroeder
study were of unspecified length and were collected from a barber-
shop. Nechay"s samples consisted of hair obtained 5 cm from the
scalp. The Eads study obtained samples from barbershops and beauty
shops but the location and length of the hair fibers are not speci-
fied. Spruit reports taking hair samples at about 1 cm from the
scalp.
In the Schroeder study, the hair was washed in tetrachloride.
Eads reports elimination of "obviously bleached and dyed hair,". 48-
hour soaking and several rinses in deionized water, one-hour soak,
repeated rinses in methanol, and drying in a draft oven at 110 C.
Nechay states that hair was washed in nonionic detergent, and
Spruit gives no information on washing procedures.
All authors except Nechay and Sunderman (1973) report signifi-
cant differences in values for men and women. In view of the dif-
ferences in sample collection, washing techniaues, and details of
analytic procedures, it is impossible to reach conclusions about
the nickel content of hair from adults without occupational expo-
sure.
C-50
-------
TABLE 13
Nickel Concentrations in Human Hair
Authors
O
1
(ji
I1
Schroeder
and Nason
(19b9)
Eads and Lambdin (1973)
Nechay and Sunderman (1973)
Spruit and
Bongaarts
(19776)
Method
Atomic
Atomic
Atomic
Atomic
absorption
absorption
absorption
absorption
New
Area
Hampshire
Texas
Connecticut
Netherlands
No. and Sex
of Subjects
79H
25F
19M
21F
2QM
10M
14F
Nickel Concentration, ppm
Mean Range
0
3
1
3
0
0
i
.97
.b9
.9 0.9-7.,*
.4 0.7-7.b
.22 O.U-O.bi
.b
.0
-------
Chattopadhyay and Jervis (1974) reported hair nickel values
for 76 rural subjects, 45 urban subjects, and 121 subjects from
urban regions near refineries. The hair samples were taken bv
clipping "close to the head," and the samples were washed sequen-
tially with ether, alcohol, and distilled water, and then analyzed
by nuclear activation techniques. Precision and accuraicy for nick-
el determination as evaluated by the National Bureau of Standards
and Environmental Protection Agency-NBS standard materials analy-
ses were good: the value for orchard leaves was 1.27 + 0.08 ppm
compared to the NBS value of 1.3 +0.2 ppm and the value for fly ash
was 96.9 + 3.2 compared to the EPA-NBS concentration of 98 +_ 3 ppm.
The median and range for the rural subjects were 2.1 (1.6 to 17)
pom; for the urban subjects 2.4 (1.2 to 20) ppm; and 3.6 (1.1 to 32)
ppm for the subjects from urban regions near refineries.
Creason, et al. (1975) investigated hair nickel concentrations
in adults and children in communities within the New York metro-
politan area. The communities had different levels of nickel in
the environment as measured in dustfall, home dust, and soil. The
hair samples were contributed by the subjects as they obtained a
"normal hair cut or trim". Dry ashing and emission spectroscopy
were used as the analytic method. Hair was washed in a detergent
solution. Nickel concentrations observed showed no significant
differences for children (0 to 15 years old) and adults ^ 16 years
old. The concentrations were: for 265 children, a geometric mean
of 0.51, + 0.20 to 1.30 geometric SD, range of 0.036 to 11.0 ppmj
for 194 adults, the results were 0.74 geometric mean, + 0.27 = 2.07
geometric ^D, range 0.045 to 11.0 ppm. ^or nickel, environmental
C-52
-------
exposure gradients were significantly associated for children but
not for adults.
The role of hair as an excretion tissue for nickel is compli-
cated by the findings for nickel concentrations in scalp hair and
pubic hair of women studied for maternal-fetal levels of trace ele-
ments. Creason, et al. (1976) used dry ashing and emission spec-
troscopy as the method for nickel concentration assessment. The
mean for 63 samples of scalp hair was 1.7 yg/g and the geometric
mean 1.0 yg/g, while 110 samples of cubic hair showed 0.7 and 0.4
yg/g, respectively, The differences in these values are not ex-
plained, and the question of the relative role of scalp hair as an
indicator of secretion in relation to exposure and body burden re-
mains unanswered.
The excretion of trace metals such as nickel via hair has been
demonstrated in the above studies. However, the data available for
nickel concentrations in various "normal" populations are too
sparse to permit one to reach conclusions. Most investigators have
found significant differences between male and female hair nickel
concentrations (Table 13).
Spruit and Bongaarts (1977b) reported the mean hair nickel
concentration for eight occupationally exposed men as 14.5 ppm.
The value for nonexoosed males was reported as 0.6 ppm.
Hair nickel determinations are not usually carried out with
industrial population assessment and such studies aooear to re-
strict themselves to evaluation of blood and urine nickel levels,
since these are more reflective of current exposure.
C-53
-------
Crucial to the assessment of the effects of nickel on human
populations is the necessity of determining key tissue levels of
the element and, where possible, total body burden. It is gener-
ally not feasible to assess these levels in humans other than
through autopsy studies, and several investigators have carried out
such surveys of nickel levels in selected orqans. These studies
can be roughly classed into case studies concerned with specific
diseases or population studies, as discussed below. No iri vivo
studies for nickel have been reported, though Harvey, et al. (1975)
performed such a study using neutron-activation analysis for cad-
mium.
It is necessary to point out some limitations of the data ob-
tained from autopsy studies. The cases coming to autopsy do not
really constitute a representative sample of a given population.
The requirements for performing an autopsy vary from country to
country, and different population segments differ siqnificantly in
their willingness to consent to autopsies not legally required. Tt
is also well known that this attitude is related to social status,
occupation, and housing, all of which are factors associated with
different degrees of exposures to pollutants as well as with nutri-
tional and health status. The technical problems of speed, collec-
tion of information retrospectively, and the proportion of dead
with no living contacts all add to the difficulty of obtaining re-
liable data needed to analyze and interpret findings. Finally,
there is the problem of defining "normal" or "healthy" individuals.
Usually, accidental death victims are defined as "normal" or
"healthy" subjects, and the quality of the examination of accident
0-54
-------
cases to determine this status may also vary. In the case of inves-
tigations of nickel in tissue from cadavers, there is the problem
of the effect of pathology, stress, or traumas, all of which can
change nickel levels.
There are very few data in the literature concerning nickel
tissue levels and total body burden. The NAS report (1975) summa-
rized the findings from the work by Tipton and her group and con-
cluded that the total nickel content in a normal man is approxi-
mately 10 mg. Table 14 is derived from the NAS report presenting
Schroeder's findings.
Bernstein, et al. (1974) reported results for 25 autopsies of
subjects aged 20 to 40 years from New York City, with a diagnosis of
sudden death and no indication of illness. Tissues taken from the
right lung and paratracheal, peribronchial, and hilar lymph nodes
were ashed in nitric acid and analyzed with atomic absorption spec-
trometry. Mean values were 0.23 + 0.06 pg Ni/g wet weight for lung
tissue and 0.81 + 0.41 ug net weight for lymph nodes. Numeric val-
ues for concentrations found in the liver, kidneys, blood, and bone
(three vertebrae) were not reported, and Figure 9 shows means and
standard deviations.
Sumino, et al. (1975) reported on heavy metals in tissues from
autopsies of 30 persons who lived in the same Prefecture in Japan.
The causes of death were trauma, suffocation, overdoses of sleeping
pills, and carbon monoxide intoxication. Ages ranged from 10 to
}60 for the 15 males and 10 to ^ 60 for the 15 females. Twenty
different types of tissue were removed but not all types from each
subject so that the number of samples for different tissues vary.
C-55
-------
TABLE 14
Nickel Concentrations in Kidney and Liver, by Geographic Region*
O
I
en
Kidney
, Mean Nickel
£p£. ""STS-iiS"'
United States 161 7
Alaska 2 35
Honolulu 5 4
Non-U.S. subjects 146 12.4
Frequency of
Nickel
Occurrence, %
27
100
40
58.2
Liver
M - Nean Nickel Frequency of
SnDles Concentration, Nickel
p PPM of Ash Occurrence, »
163 6 i'i
1 36 J.UU
54 40
141 il.O 44.0
Source: NAS, 1975
-------
13
f
L
0
:n
NcW
>
r-.
Hh
r-i
i-
6on
FIGURE 9
Distribution of Nickel in Human Tissues
Source: Bernstein, et al. 1974
057
-------
Nickel concentrations for those tissue samples with detectable
amounts were reported. The analytic method of nickel was dry ash-
ing, residue digestion, and flame atomic absorption spectroscopy.
The detection level was not stated, but the report of the nickel
concentrations in the different tissues indicates that not all sam-
ples showed detectable amounts of nickel. Table 15 shows some of
the nickel concentrations. The total body burden for nickel was
calculated as ^5.7 yg of nickel for a body weight of 55 kg.
The NAS report (1975) contains Sunderman's data (1971) ob-
tained by an atomic absorption method from material from four
autopsies (Table 16).
Nickel concentrations in lung tissue for 15 control subjects
in a study of bituminous coal miners were reported by Sweet, et al.
(1974). Emission spectroscopy was employed for nickel analysis.
The mean nickel concentration was 0.6 yg/g dry weight.
Creason, et al. (1976) reported maternal and fetal tissue lev-
els of nickel. Dry ashing and emission spectroscopy analysis was
employed for nickel determinations. Placental tissue from 160
women yielded an arithmetic mean of 3.4 and a geometric mean of 2.2
yg/100 g with 10 percent of the samples giving values below the
detection limit of the method employed.
The data available for nickel concentrations in normal human
tissue are very limited and analytic procedures differ. At this
time, it seems unwise to draw conclusions as to concentrations
within various organs or total body burden in normal populations.
An age gradient does not seem likely, but adequate data are not
available to assess that aspect either.
C-58
-------
TABLE 15
Nickel Concentrations in Japanese Human Tissues*
o
1
Organ
Lung
Liver
Kidney
No. of Cases
30
27
28
Nickel Concentration, yg/g Wet Weight
0
0
0
Mean +
.16 +
.078 +
.098 +
SD
0.094
0.046
0.070
Median
0
0
0
.16
.068
.081
0
0
0
Range
.038-0
.028-0
.012-0
.44
.22
.30
vo
*Source: Sumino, et al. 1975
-------
TABLE 16
Nickel Concentration in Human Tissues*
Nickel Concentration,
Subject No,
1
2
o
1
o 3
4
Sex Age, Years Cause of Death
M 44 Stab wounds
F 40 Barbituate
poisoning
M 18 Hanging
F 22 Carbon monoxide
poisoning
Mean
Wet Weight
Lung
2.40
2.20
0.81
0.96
1.59
Liver
0.52
0.86
0.76
1.32
0.87
Heart
0.62
0.57
0.43
0.83
0.61
yg/lOOg
Dry Weight
Lung
14.6
12.1
3.3
4.3
8.6
Liver
2.1
3.2
2.b
4.8
3.2
Heart
2.3
2.4
i.b
3.0
2.3
*Source: Sunderman, et al. 1971
-------
Indraprasit, et al. (1974) reported nickel concentrations in
tissues obtained from 220 random autopsies. On the basis of clini-
cal findings the patient population was divided into three groups.
The first group was classified as "controls" (based on serum crea-
tinine ^1.5 mg percent) and consisted of 116 patients. The other
groups, consisting of 104 patients, were equally divided into those
with acute renal failure and those with chronic renal failure at
time of death. Freeze-dried tissue samples were analyzed by emis-
sion spectroscopy. The limit of detection for nickel was 0.5 ppm.
Renal cortex tissue was obtained for all 220 subjects, but liver
and spleen tissue was collected for only the last 144 subjects.
The 220 cases were obtained by random sampling of cadavers during
one calendar year. Table 17 shows the results of the analysis for
the three organs for the three groups. The authors state that the
limit of detection and the consequent low percentages of tissues
with detectable limits preclude any significant findings of rela-
tionships between renal failure and nickel concentrations, but it
seems worthy of note that there is a consistent gradient of detect-
ability for the three disease categories, i.e., levels of nickel
rising to detectability.
There is little in the literature reporting autopsy tissue
studies of nickel refinery workers, except from cases of fatal
nickel carbonyl poisoning (NAS, 1975) , where highest levels of
nickel are seen in lung, with lesser amounts in kidneys, liver, and
brain. In a study of coal workers' pneumoconiosis (CWP), nickel
content of lung tissue of bituminous coal miners with CWP showed
significantly higher nickel concentrations in lung tissue when com-
061
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TABLE 17
Nickel Concentrations in Renal Cortex, Liver, and Spleen for
Normals and Patients with Acute or Chronic Renal Failure3
Kidney
o
i
ro
Percent
Detectability
Normal5 27
ARFC 39
CRFd 34
Mean
Ni, ppm
Dry wt.
1.82
1.86
1.82
Liver
Percent
Detectability
16
39
43
Mean
Ni , ppm
Dry wt.
1.85
2.14
1.05
Spleen
Percent
Detectability
16
38
40
Mean
Ni, ppm
Dry wt.
1.72
2.11
i.y7
b
Source: Indraprasit, et al. 1974
Normal: no acute or chronic renal failure present at time of death
'ARF: acute renal failure present at time of death
CRF: chronic renal failure present at time of death
-------
pared to values obtained for nonoccupationally exposed males and
females residing in the area (Sweet, et al. 1974) . The nickel con-
centrations for coal miners with CWP ranged from 5.0 uq/g dry
weight to 0.5 jjg/g for six groups of disease severity. The mean for
the entire group was 2.5 yg/g dry weight and the mean value for con-
trols was 0.6 pg/g.
Metabolism
A number of disease states and other physiological stresses
are reported to alter the movement and tissue distribution of nick-
el in man as well as experimental animals. Furthermore, rn vivo
movement of nickel may be deliberately altered to enhance nickel
removal from the organism to minimize toxicity in cases of exces-
sive exposure, specifically via the use of nickel chelating agents
in the clinical management of nickel poisoning.
In man, increased levels of serum nickel are seen in cases of
acute myocardial infarction (D'Alonzo and Pell, 1963; ^underman, et
al. 1972a; McNeely, et al. 1971), such alterations presently being
considered as secondary to leukocytosis and leukocytolysis (Sunder-
man, 1977).
Serum nickel levels are also elevated in acute stroke and ex-
tensive burn injury (McNeely, et al. 1971), while reduction is seen
in hepatic cirrhosis or uremia, possibly secondary to hypoalbumine-
mia.
Palo and Savolainen (1973) report that hepatic nickel was in-
creased 10-fold over normal values in a deceased patient with as-
partylglycosaminuria, a metabolic disorder characterized by re-
duced activity of aspartyl-^-glucosaminidase.
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Other stresses appear to have an effect on nickel metabolism.
Significant reduction in serum nickel has been seen in mill workers
exposed to extremes of heat (Szadkowski, et al. 1970), probably due
to excessive nickel loss through sweating, as was noted earlier.
While tissue nickel levels are reported to be elevated in rats dur-
ing pregnancy (Spoerl and Kirchqessner, 1977), no comparable data
are available for man.
The use of various classes of chelating agents to expedite the
removal of nickel from man and animals has been reported with the
goal of developing efficient chemotherapeutic agents for use in
nickel poisoning. The data have been reviewed (NAS, 1975; Sunder-
man, 1977) and will only be summarized in this section.
On the basis of reported clinical experience, sodium diethyl-
dithiocarbamate (dithiocarb) is presently the drug of choice in the
management of nickel carbonyl poisoning, being preferable overall
to EDTA salts, 2,3-dimercaptopropanol (BAL), and oenicillamine. In
all cases, the agents work to accelerate the urinary excretion of
absorbed amounts of nickel before extensive tissue iniury can re-
sult.
There is a growing body of literature that establishes an es-
sential role for nickel, at least in experimental animals. The
earlier studies have been reviewed (NAS, 1975; Nielsen and Sand-
stead, 1974; Nielsen, 1976; Spears and Hatfield, 1977; Sunderman,
1977).
Mertz (1970) has spelled out criteria for essentiality of
trace elements as micronutrients, and this discussion will focus
primarily on one of the most critical of these: demonstration of
C-64
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specific deficiency-related syndromes which are prevented or cured
by the element alone.
Earlier workers in trace-element nutritional research could
not demonstrate any consistent effects of nickel deficiency (NAS,
1975; Spears and Hatfield, 1977) owinq in part to the technical
difficulties of controlling nickel intake because of its ubiquity.
Later workers have demonstrated adverse effects of nickel depriva-
tion in various animal models.
Nielsen and Hiqqs (1971) have shown a nickel-deficiency syn-
drome in chicks fed nickel at levels of 40 to 80 ppb (control diet:
3 to 5 ppm) characterized by swollen hock joints, scaly dermatitis
of the legs, and fat-depleted livers. Sunderman, et al. (1972b)
observed ultrastructural lesions such as perimitochondrial dila-
tion of rough endoplasmic reticulum in hepatocytes of chicks fed a
diet having 44 ppb nickel. Nielsen and Ollerich (1974) also noted
hepatic abnormalities similar to those reported by Sunderman, et
al. (1972b). Nickel is also essential in swine nutrition; pigs fed
a diet having 100 ppb exhibited a decreased growth rate, impaired
reproduction, and a rough hair coat (Anke, et al. 1974).
Growth responses to nickel supplementation have also been re-
ported for rats (Schnegg and Kirchgessner, 1975a; "'chroeder, et al.
1974). Rats maintained on nickel-deficient diets through three
successive generations showed a 16 percent weight loss in the first
and 26 percent weight loss in the second generation compared to
nickel-supplemented controls (Schnegg and Kirchgessner, 1975a).
Effects on reproduction have been documented in rats (Nielsen,
et al. 1975) and swine (Anke, et al. 1974; ^chneaq and Kirchaess-
C-65
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ner, 1975a), mainly in terms of increased mortality durinq the
suckling period in rats and smaller litter size.
Nickel appears to be essential also for ruminant nutrition
(Spears and Hatfield, 1977). Spears and Hatfield (1977) demon-
strated disturbances in metabolic parameters in lambs maintained on
a low-nickel diet (65 ppb), intraperitoneal dosing yields lung car-
cinomas in mice (Stoner, et al. 1976) when nickel acetcite is used,
while nickelocene, an organonickel "sandwich" structure, induces
sarcomas in rats and hamsters when given intramuscularly (Haro, et
al. 1968; Furst and Schlauder, 1971).
Schnegg and Kirchgessner (1975b,1976) demonstrated that nick-
el deficiency leads to reduced iron contents in organs and iron de-
ficiency anemia, resulting from markedly impaired iron absorption.
Nickel appears to pertain also to other criteria for essen-
tiality (Mertz, 1970) : apparent homeostatic control and partial
transport by specific nickel-carrier proteins (see Metabolism sec-
tion) . Furthermore, Fishbein, et al. (1976) have reported that
jackbean urease is a natural nickel metalloenzyme, and it is also
possible that rumen bacterial urease may also have a specific nick-
el requirement (Spears, et al. 1977).
Excretion
The excretory routes for nickel in man and animals depend in
part on the chemical forms of nickel and the mode of nickel intake.
Unabsorbed dietary nickel is simply lost in the feces. fUven
the relatively low extent of gastrointestinal absorption (vide
supra), fecal levels of nickel roughly approximate daily dietary
intake, 300 to 500 pg/day in man.
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Urinary excretion in man and animals is usually the major
clearance route for absorbed nickel. Normal levels in urine vary
considerably in the literature, and earlier value variance probably
reflects methodological limitations. More recent studies suggest
values of 2 to 4 ug/1 (McNeely, et al. 1972; Anderson, et al. 1978).
While biliary excretion is known to occur in the rat (Smith
and Hackley, 1968), the calf (O'Dell, et al. 1971), and the rabbit
(Onkelinx, et al. 1973) , its role in nickel metabolism in man is
unknown.
Sweat can constitute a manor route of nickel excretion. Hohn-
adel and co-workers (1973) determined nickel levels in the sweat of
healthy subjects sauna bathing for brief periods at 93°C to be 52 +
36 yg/1 for men and 131 + 65 yg/1 for women.
The role of nickel deposition in hair as an excretory mecha-
nism in man has prompted a number of studies. The use of hair nick-
el levels in assessing overall nickel body burdens as well as expo-
sure chronology remains to be widely accepted. Its utility in epi-
demiological studies is discussed elsewhere. Schroeder and Nason
(1969) have reported sex-related differences in nickel levels of
human hair samples, female subjects having nickel levels (3.96
yg/g, S.E.M. = + 1.06) about 4-fold those of men (0.97 ug/g,
S.E.M. = + 0.15). Such a difference, however, was not encountered
by Nechay and Sunderman (1973) nor were their average sample values
as high. The differences in these two studies serve to point out
some of the difficulties in establishing quantitative relationships
for the role of hair levels in nickel metabolism.
C-67
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In experimental animals, urinary excretion is the main clear-
ance route for nickel compounds introduced parenterally.
Animals exposed to nickel carbonyl by inhalation exhale a part
of the respiratory burden of this agent within two to four hours
while the balance is slowly degraded in vivo to divalent nickel and
carbon monoxide, with nickel eventually undergoing urinary excre-
tion (Sunderman and Selin, 1968; Mikheyev, 1971).
EFFECTS
Acute, Subacute, and Chronic Toxicity
The purpose of this section of the document is to discuss
those biological and adverse health effects which have been report-
ed for nickel in man and animals. It is not the purpose of this
treatment to assemble a thorough review of the literature on nick-
el, but rather to focus on those reported effects which have more
direct relevance for ultimate evaluation of health risks in man as
posed by nickel in its various forms and under varying exposure
conditions.
Comparatively speaking, the major concern with nickel on human
health effects has centered on nickel carcinogenesis and nickel's
allergenic properties; thus, for emphasis, these two areas are dis-
cussed separately from the systemic toxicity of nickel.
Unlike the case with toxic elements such as cadmium, lead, and
mercury, there appears to be an increasingly strong case for nickel
being an essential element, at least in animals, as well as a toxi-
cant. Thus, the ultimate use of exposure regulation and health
benefit/health cost balance is made more complicated, in that
desirable nickel intake must lie somewhere between amounts adequate
C-68
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to serve essentiality and not enough to precipitate adverse ef-
fects. The data pertinent to nickel's role as a probable essential
element are discussed in the final segment of this chapter.
Since the systemic toxicity of an agent is a macroscopic re-
flection of the deleterious interactions of the substance at the
molecular, organellar, and cellular level, it is helpful to discuss
those studies that characterize effects at these levels of func-
tional and structural organization. This approach of course is an
arbitrary, if widely used, device to elaborate the range and types
of toxicant effects. In reality, the overall response of an orga-
nism to a toxic agent is a complex integration of discretely deter-
mined phenomena. In some cases, it is more appropriate to discuss
subcellular and cellular effects with the associated systemic ef-
fects and hence, the cellular level is not covered here.
The toxicity of nickel to man and animals is a function of the
chemical form of the element and the route of exposure.
With regard to oral intake, nickel metal is comparatively non-
t^vic, dogs and cats being able to tolerate up to 12 mg Ni/kg daily
for up to 200 days without ill effects (Stokinger, 1963). Nickel
carbonate, nickel soaps, or nickel catalysts given to young rats at
levels UD to 1,000 ppm in diet for eight weeks had no effect on
growth rate (Phatak and Patwardhan, 1952); similarly, these forms
of nickel at 1,000 ppm when fed to monkeys for up to six months did
not affect growth, behavior, or hematological indices (Phatak and
Patwardan, 1952).
The gross toxicity of a number of inorganic and organometallic
complexes of nickel in terms of dose versus lethality percentages
have been tabulated (NAS, 1975).
C-69
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Exposure to nickel by inhalation or parenteral administration
as well as cutaneous contact is of greater significance to the pic-
ture of nickel toxicology and the discussion of nickel effects on
various systems in man and animals mainly relates to these routes
of exposure.
In terms of human health effects, probably the most acutely
toxic nickel compound is nickel carbonyl, Ni(CO)4, a volatile,
colorless liquid formed when finely divided nickel comes into con-
tact with carbon monoxide, as in the Mond process for purification
of nickel (Mond, et al. 1890). The threshold limit value (TLV) for
a work day is 1 ppb (ACGIH, 1978).
A sizable body of literature has developed over the years
dealing with the acute exposure of nickel processing workers to
nickel carbonyl by inhalation [NAS, 1975; National Institute for
Occupational Safety and Health (NIOSH), 1977; Sunderman, 1977].
Since much of this information is relevant mainly to occupational
medicine rather than general environmental health, it is not appro-
priate to accord it detailed discussion in this document.
According to Sunderman (1970) and Vuopala, et al. (1970), who
have studied the clinical course of acute nickel carbonyl poisoning
in workmen, clinical manifestations include both immediate and
delayed symptomology. In the former, frontal headache, vertigo,
nausea, vomiting, insomnia, and irritability are commonly seen,
followed by an asymptomatic interval before the onset of insidious,
more persistent symptoms. These include constrictive chest pains,
dry coughing, hyperpnea, cyanosis, occasional gastrointestinal
symptoms, sweating, visual disturbances, and severe weakness. Aside
C-70
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from the weakness and hyperpnea, the symptomology strongly resem-
bles that of viral pneumonia.
The lung is the target organ in nickel carbonyl poisoning in
man and animals. Pathological pulmonary lesions observed in acute
human exposure include pulmonary hemorrhage and edema accompanied
by derangement of alveolar cells, degeneration of bronchial epithe-
lium, and formation of fibrinous intra-alveolar exudate. Roent-
genological follow-up on patients surviving the acute episode of
exposure frequently indicates pulmonary fibrosis.
The pronounced pulmonary tract lesion formation seen in ani-
mals acutely exposed to nickel carbonyl vapor strongly overlaps
that reported for cases of acute industrial poisoning, and these
have been tabulated in Table 18.
As in man, the lung is the target organ for effects of nickel
carbonyl in animals regardless of the route of administration. The
response of pulmonary tissue is very rapid, interstitial edema
developing within one hour of exposure. There is subsequent pro-
liferation and hyperplasia of bronchial epithelium and alveolar
lining cells. By several days post-exposure, severe intra-alveolar
edema with focal hemorrhage and pneumocyte derangement has oc-
curred. Death usually occurs by the fifth day. Animals surviving
the acute responses show regression of cytological changes with
fibroblastic proliferation within alveolar interstitium.
Adverse effects in animals by inhalation of other forms of
nickel have been reported. Bingham, et al. (1972) exposed rats to
aerosols of both soluble (as the chloride) and insoluble (as the
oxide) nickel at levels in the region of those acceptable for human
C-71
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TABLE 18
Acute Pulmonary Effects of Nickel Carbonyl Exposure in Animals
Animal
RdDDit
Dosing
Inhalation
1.4 mg/1. ,
50 min
Effects
Intra-alveolar hemorrhages, edema
and exudate; alveolar cell degen-
eration oy days ±-5
Reference
Armit,
1908
Rat
o
Rat
Rat, dog
Rat
Rat
Inhalation
0.9 mg/1.,
30 min
Inhalation
0.24 mg/1.,
30 min
Inhalation
1 mg/1.,
30 min
I.V.
65 mg/kg,
single dose
I.V.
65 mg/kg,
single dose
At 2-12 hr, capillary congestion
and interstitial edema; at 1-3 hr
days, intra-alveolar edema; 4-10
days, pulmonary consolidation and
interstitial fibrosis
At 1 hr, pulmonary congestion and
edema; at 12 hr-6 days, interstitial
pneumonitis with focal atelectosis
and peribronchial congestion
At 1-2 days, intra-alveolar edema
and swelling of alveolar lining
cells; at 3-5 days, inflamation,
atelectases and interstitial fibro-
lytic proliferation
At 1-4 hr, perivascular edema; at
2-5 days, severe pneumonitis with
intra-alveolar edema, hemorrhage
sub-pleural consolidation, hyper-
trophy and hyperplasia of alveolar
lining cells
Ultrastructural alterations, includ-
ing edema of endothelial cells at
b hr and massive hypertrophy of
membranes and granular pneumocytes
at 2-6 days
Barnes and Denz,
1951
Kincaid, et al.
1953
Sunderman, et al,
i9ol
Hackett and Sunderman,
1967
Hackett and Sunderman,
1969
-------
industrial exposure. Hyperplasia of bronchiolar and bronchial epi-
thelium with peribronchial lymphocytic infiltrates was seen. Port,
et al. (1975) noted that intratracheal iniection of a suspension of
nickel oxide (5 mg, particle size < 5 urn) into Syrian hamsters
first treated with influenza A/PR/8 virus 48 hours previously sig-
nificantly increased mortality versus controls. Surviving animals
at this dosing and lesser doses showed mild to severe acute inter-
stitial infiltrate of polymorphonuclear cells and macrophages sev-
eral weeks later. Additional pathological changes included bron-
chial epithelial hyperplasia, focal proliferative pleuritis, and
adenomatosis.
A number of studies have been directed to the effects of nick-
el on endocrine-mediated physiological processes. As noted in the
previous section dealing with nickel metabolism, exposure of ani-
mals to nickel especially parenterally consistently shows marked
jjptake of the element in endocrine tissue: pituitary, adrenals,
and pancreas. Thus, disturbances in function might be anticipated.
Various laboratories have cited effects of nickel on aspects
of carbohydrate metabolism in different animal species. Bertrand
and Macheboeuf (1926) reported that parenteral exposure of rabbits
or dogs to nickel salts antagonized the hypoglycemic action of
insulin. Later workers (Kadota and Kurita, 1955; Clary and Vig-
nati, 1973; Freeman and Langslow, 1973; Horak and Sunderman,
1975a,b) observed a rapid, transitory hypergloycemia after paren-
teral exposure of rabbits, rats, and domestic fowl to nickel (II)
salts. In several reports, Horak and Sunderman (1975a,b) noted the
effects of nickel (II) on normal, adrenalectomized, and hypophysec-
C-73
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tomized rats. Injection of nickel chloride (2 or 4 mg/kq) produced
prompt elevations in plasma glucose and glucagon levels with a re-
turn to normal two to four hours afterwards, suggesting that hyper-
glucagonemia may be responsible for the acute hyperglycemic re-
sponse to divalent nickel (Horak and Sunderman, 1975a). Nickel had
the most pronounced hyperglycemic effect when this element was
studied versus effects of other ions given in equimolar amounts.
Concurrent administration of insulin antagonized the hyperglycemic
effect (Horak and Sunderman, 1975b). Kadota and Kurita (1955) ob-
served marked damage to alpha cells and some degranulation and
vacuolization of beta cells in the pancreatic islets of Langerhans.
Ashrof and Sybers (1974) observed lysis of pancreas exocrine cells
in rats fed nickel acetate (0.1 percent).
Human endocrine responses to nickel have been poorly studied,
although Tseretili and Mandzhavidze (1969) found pronounced hyoer-
glycemia in workmen accidentally exposed to nickel carbonyl.
Nickel apparently has an effect on the hypothalamic tract in
animals, enhancing the release of prolactin-inhibiting factor (PIF)
therby decreasing the release of nrolactin from bovine and rat
pituitary glands (LaBella, et al. 1973a). Furthermore, intravenous
administration of small amounts of nickel to urethane-anesthetized,
chlorpromazine-treated rats produces significant depression of
serum prolactin without any effect on growth hormone or thyroid-
stimulating hormone, although the _in vitro release of pituitary
hormones other than PIF have been demonstrated for bovine and rat
pituitary (LaBella, et al. 1973b).
C-74
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Dormer, et al. (1973) and Dormer and Ashcroft (1974) have
studied the in vitro effects of nickel on secretory systems, parti-
cularly the release of amylase, insulin, and growth hormone. Nick-
el (II) was seen to be a potent inhibitor of secretion in all three
glands: parotid (amylase), islets of Langerhans (insulin), and
pituitary (growth hormone). Inhibition of growth hormone release
at nickel levels comparable to those which LaBella, et al. (1973b)
observed actually to enhance release may reflect differences in
tissue handling prior to assay. Dormer, et al. (1973) suggested
that nickel may block exocytosis by interfering with either secre-
tory-granule migration or membrane fusion and microvilli formation.
Nickel-induced nephropathy in man or animals has not been
widely documented. Acute renal injury with proteniuria and hyaline
casts were observed by Azary (1979) in cats and dogs given nickel
nitrate. Pathological lesions of renal tubules and glomeruli have
been seen in rats exposed to nickel carbonyl (Kincaid, et al. 1953;
Hackett and Sunderman, 1967). Gitlitz, et al. (1975) observed
aminoaciduria and proteinuria in rats after single intraperitoneal
injection of nickel chloride, the extent of the renal dysfunction
being dose-dependent. Proteinuria was observed at a dose of 2
mg/kg, while higher dosing occasioned aminoaciduria. nitrastruc-
turally, the site of the effect within the kidney .appears to be
glomerular epithelium. These renal effects were seen to be transi-
tory, abating by the fifth day.
In man, nephrotoxic effects of nickel have been clinically
detected in some cases of accidental industrial exposure to nickel
carbonyl (Brandes, 1934; Carmichael, 1953). This takes the form of
renal edema with hyperemia and parenchymatous degeneration.
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Nickel compounds appear to possess low neurotoxic ootential
save for fata, acute exposures to nickel carbonyl (MAS, 1975;
NIOSH, 1977). Neural tissue lesion formation in the latter case if
profound, including diffuse punctate hemorrhages in cerebral, cere-
bellar, and brain stem regions, degeneration of neural fibers, and
marked edema.
Intrarenal injection of nickel subsulfide in rats elicits a
pronounced erythrocytosis (Jasmin and Riopelle, 1976; Morse, et al.
1977; Hopfer and Snderman, 1978), the erythrogenic effect being
apparently unrelated to the carcinogenicity of the compound (Jasmin
and Riopelle, 1976). Morse, et al. (1977) showed that the erythro-
cytosis is dose-dependent, is not elicited by intramuscular admin-
istration and is associated with marked erythroid hyperplasia of
bone marrow. Hopfer and Sunderman (1978) observed a marked inhibi-
tion of erythroctyosis when manganese dust was co-admiriistered.
Effects of nickel on thyroid function have been noted by Les-
trovoi, et al. (1974). Nickel chloride given orally to rats (0.5
to 5.0 mg/kg/day, two to four weeks) or by inhalation (0.05 to 0.5
mg/m3) significantly decreased iodine uptake by the thyroid, such
an effect being more pronounced for inhaled nickel.
Allergenic Response
Since allergenic responses to contact with nickel containing
compounds has been a major focus of research effort, discussion of
this topic is presented as a unified body of information in this
section of the document.
^ V
Nickel dermatitis and other dermatological effects of nickel
have been extensively documented in both nickel worker populations
C-76
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and populations at large (NAS, 1975). Originally considered to be
a problem in occupational medicine, the more recent clinical and
epidemiological picture of nickel sensitivity offers ample proof
that it is a widespread problem in individuals not having occupa-
tional exposure to nickel but encountering an increasing number of
nickel-containing commodities in their everyday environment.
Occupational sources of nickel that have been associated with
nickel sensitivity include mining, extraction, and refining of the
element as well as such operations as plating, casting, grinding,
polishing, and preparation of nickel alloys (NAS, 1975). Although
the frequency of nickel dermatitis has considerably abated owing to
advances in both control technology and industrial medicine, it may
still persist in electroplating shops (NAS, 1975).
Nonoccapational exposure to nickel which may lead to dermati-
tis includes nickel-containing jewelry, coinage, tools, cooking
utensils, stainless steel kitchens, prostheses, and clothing fas-
teners. Women appear to be particularly at risk for dermatitis of
the hands, which has been attributed to their continous contact
with many of the nickel-containing commodities noted above (Malten
and Spruit, 1969).
It is not possible to say at the present time that women are
physiologically more susceptible to nickel hypersensitivity than
are men, and it is quite likely that women are simply at greater
risk by virtue of increased contact with nickel commodities.
Nickel dermatitis in nickel miners, smelters, and refiners is
known as "nickel itch" and usually begins as itching or burning
papular erythema in the web of the fingers, spreading to the fin-
C-77
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gers, wrists, and forearms. Clinically, the condition is usually
manifested as a papular or papulovesicular dermatitits with a ten-
dency toward lichenification, having the characteristics of atopic
rather than eczematous dermatitis.
Citing a large number of cases, Calnan (1956), stated that
nickel dermatitis has a unique topographical distribution pattern:
(1) primary: areas in direct contact with the element; (2) secon-
dary: spreading of the dermatitis in a symmetrical fashion; and
(3) associated: afflicted areas having no relation to contact
areas. Furthermore, the affliction may persist some time after re-
moval of obvious sources of exposure.
A clear relationship between atopic dermatitis and that elic-
ited by nickel has been confused by conflicting reports in the
literature. Watt and Baumann (1968) showed that atopy was present
in 15 of 17 young patients with earlobe nickel dermatitis, but
other workers (Wilson 1956; Marcussen, 1957; Caron, 1964; Calnan,
1956) have failed to demonstrate any connection between the two
disorders. Juhlin, et al. (1969) demonstrated elevated immunoglo-
bulin (IgE) levels in atopy patients while Wahlberg and Skog (1971)
saw no significant increases of IgE in patients having nickel and
atopic dermatitis histories.
The occurrence of pustular patch test reactions to nickel sul-
fate has been considered significant in connecting nickel and atop-
ic dermatitis. Uehara, et al. (1975) have reported that pustular
patch test reactions to five percent nickel sulfate were regularly
produced in patients with atopic dermatitis, but only when applied
to areas of papulae, erythema, lichenification, and minimal trauma;
C-78
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such response seldom occurred on normal-appearing skin surface.
Furthermore, traumatizing the test areas in control as well as der-
matitic subjects furnished positive responses. These workers sug-
gest that pustular patch testing is primarily a primary irritant
reaction.
Christensen and Moller (1975a) found that of 66 female oa-
tients with hand eczema and nickel allergy, 51 had an eczema of the
pompholyx type; i.e., a recurring itching eruption with deeply
seated fresh vesicles and little erythema localized on the palms,
volar aspects, and sides of fingers. Of these, 41 had pompholyx
only, while the remainder had at least one additional diagnosis:
allergic contact eczema, irritant dermatitis, nummilar eczema, or
atopic dermatitis. These workers also found that the condition was
not influenced by any steps taken to minimize external exposure.
Subsequently, these investigators (Christnesen and Moller (1975b)
discovered that oral administration of nickel in 9 of 12 of the
earlier subjects aggravated the condition, while intense handling
of nickel-containing objects was without effect.
While Kaaber, et al. (1978) found little correlation between
nickel excretion and the status of dermatitis in their patients,
Menne and Thorboe (1976) have reported elevated urinary nickel lev-
els during flare-ups in the dermatitis. De Jongh, et al. (1978)
found limited correlation between plasma nickel level, urinary ex-
cretion of nickel and the clinical activity of the condition in a
patient followed during two periods of five and six weeks each.
Internal exposures to nickel associated with nickel sensiti-
vity and arising from prosthesis alloys have been reviewed (NAS,
C-79
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1975; Samitz and Katz, 1975; Fisher, 1977), and much of these data
are summarized in this section.
The most common prosthesis alloys are stainless steel or
cobalt-chromium (Vitallum), which may contain nickel in amounts up
to 35 percent, generally in the range of 10 to 14 percent (Samitz
and Katz, 1975).
Instances of allergic reactions as well as urticarial and
eczematous dermatitis have been attributed to implanted prosthesis
with resolution of the condition after removal of the devices (NAS,
1975; Samitz and Katz, 1975). Apparently, sufficient solubiliza-
tion of nickel from the surface of the material occurs to trigger
an increase in dermal response. In support of this, Samitz and
Katz (1975) have shown the release of nickel from stainless steel
prosthesis by the action of blood, sweat, and saline.
Fisher (1977), in his review, has counseled caution in inter-
preting the reports and has recommended specific criteria for proof
of nickel dermatitis from a foreign body, to include evidence of
surface corrosion and sufficient corrosion to give a positive nick-
el spot test.
Determination of nickel dermatitis classically involves the
use of the patch test and site response to a nickel salt solution or
contact with a nickel-containing obiect. ^he optimal nickel con-
centration in patch test solution is set at 2.5 percent (nickel
sulfate). Patch test reactions may be ambiguous, in that they can
reflect a primary irritation rather than a pre-existing sensitivity
(Uehara, et al. 1975). Intradermal testing as described by Epstein
(1956) has also been employed, but the procedure appears to offer
no overall advantage to the conventional method (NAS, 1975).
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The induction of nickel sensitivity in human subjects has been
claimed by Haxthausen (1936) and Burckhardt (1935). In their sub-
jects, prior sensitivity was not ruled out. Furthermore, the con-
centraiton of the sensitizing solution, 25 percent, may easily have
induced an irritation response. More recently, Vandenberg and
Epstein (1963) successfully sensitized nine percent of their clini-
cal subjects.
One area of controversy with regard to nickel dermatitis in-
volves the question of hypersensitivity to groups of metals, i.e.,
cross sensitivity, and various sides of the issue have been re-
viewed (NAS, 1975). Of particular concern is the existence of
hypersensitivity to both nickel and cobalt, as the elements occur
together in most of the commodities with which susceptible indivi-
duals may come in contact.
The underlying mechanisms of nickel sensitivity presumably
include (1) diffusion of nickel through the skin, (2) subsequent
binding of nickel ion with protein(s) and other skin components,
and (3) immunological response to the nickel-macromolecule complex
(NAS, 1975) . In the section on nickel metabolism, the fact that
penetration of the outer skin layers by nickel does occur was
noted. Jansen, et al. (1964) found that nickel in complex with an
amino acid (D,L-alaline) was a better sensitizer than nickel alone,
while Thulin (1976) observed that inhibition of leukocyte migration
in ten patients with nickel contact dermatitis could be elicited
with nickel bound to bovine and human serum albumin or human epi-
dermal protein, but not with nickel ion alone. Hutchinson, et al.
(1975) noted nickel binding to lymphocyte surfaces from both sensi-
C-81
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tive and control subjects; thus, nickel binding, per se, is not the
key part of the immunological response (lymphocyte transformation).
Useful experimental animal models of nickel sensitivity have
only slowly been forthcoming, and only under very specialized con-
ditions.
Nilzen and Wilstrom (1955) reported the sensitization of gui-
nea pigs to nickel via repeated topical application of nickel sul-
fate in detergent solution. Samitz and Pomerantz (1958), however,
have attributed this to local irritation rather than true aller-
genic response. Samitz, et al. (1975) were unable to induce sensi-
tization in guinea pigs using any nickel compound from complexation
of nickel ion with amino acids or guinea pig skin extracts.
Wahlberg (1976) employed intradermal injection of nickel sul-
fate in highly sensitive guinea pigs. The reactions to the chal-
lenge were statistically greater than with control animals. Turk
and Parker (1977) reported sensitization to nickel manifested as
allergic-type granuloma formation. This required the use of
Freund's complete ad-iuvant followed by weekly intradermal injec-
tions of 25 yg of the salt after two weeks. Delayed hypersensitiv-
ity reactions developed in two of five animals at five weeks by use
of a split-adjuvant method. Interestingly, these workers also ob-
served (Parker and Turk, 1978) suppression of the delayed hypersen-
sitivity when intratracheal intubation of nickel sulfate was also
carried out on these animals.
There are no studies of general populations which relate nick-
el exposures or levels in tissues and fluids to physiological, sub-
clinical or clinical changes. The studies oreviously cited do not
C-82
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cover properly designed and executed samples of either total popu-
lations or selected population segments which would permit projec-
tion of findings to the total population from which subjects were
selected. Only occupationally exposed worker populations have been
surveyed or monitored in any statistically adequate manner, and
these studies will be reported later in connection with nickel car-
cinogenesis. The literature on adverse health effects in relation
to nickel exposure by the general population is limited to the
investigation of nickel dermatitis and nickel sensitivity, with
only occasional reports related to other diseases or conditions.
There has not been a single population survey to determine the
incidence or prevalence of this allergic condition and its clinical
manifestation. The literature is limited to studies of patient
populations, and this provides an unreliable basis for projection
to the general population. Clinic populations in specialty clinics
are self-selected and represent individuals who have decided that
their condition is severe enough to require medical care or who
have access to medical care and have been referred to specialty
clinics. The perception of need for medical care for specific
health problems varies significantly by socio-demographic charac-
teristics. For example, a hairdresser or manicurist with dermati-
tis of the hands will seek medical care, while a factory worker or
clerk with the same condition may not do so simply because there
are no clients who object. The data presented here, therefore, are
of limited value.
The survey conducted by the North American Contact Dermatitis
Group (1973) covered 1,200 subjects from ten cities in the United
C-83
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States. The subjects were selected from outpatient clinics and the
private practices of the 13 participating dermatologists. The spe-
cific method of selection was not reported, and therefore the pro-
portions of private and clinic patients is not ascertainable from
the published report. There are no data on age distribution, but
it is probable that all subjects were adults since children are not
mentioned. The group used a standardized patch test consisting of
16 allergens and read results in a standardized manner. The nickel
allergen was 2.5 percent nickel sulfate. Table 19 shows the re-
sults reported as derived from the group's report. The rates of
positive reactions are higher for females than for males and the
overall reaction rate was 11.2 percent for the 1,200 individuals.
The overall rate of reactivity found in data by the International
Contact Dermatitis Group (Fregert, et al. 1969) was compared with
these data. The allergen used in the International group data was
5 percent nickel sulfate, and 4,825 white individuals t»sted showed
a 6.7 percent rate of positive reaction, males showing a reaction
rate of 1.8 percent and females 9.9 percent. It is important to
point out that both sets of data found nickel sensitivity most fre-
quent in females. The North American study testing 16 allergens
found that nine other allergens had higher positive reeiction rates
than nickel in white males, while the data for the International
Contact Dermatitis Group testing 11 allergens found seven allergens
with higher positive reaction rates than nickel for the male sub-
jects. Black females in the North American group data showed the
highest reaction rate to nickel (Table 19) .
C-84
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TABLE 19
North American Contact Dermatitis Group Patch Test Results for
2.5 Percent Nickel Sulfate in 10 Cities*
o
CD
Subjects
Black
White
All
Females
Males
Total
Females
Males
Total
Females
Males
Total
Positive Reactions
Total No.
79
64
143
612
445
1,057
691
509
1,200
NO.
14
6
20
89
22
111
103
28
131
Percent
17.7
9.3
14.0
12.7
4.4
10.5
14.9
5.5
11.2
*Source: North American Contact Dermatitis Group, 1973
-------
Brun (1975) reported on 1,000 cases of contact dernictcitis from
the University Hospital Clinic in Geneva. Each patient was patch
tested with a standard group of 13 allergens including nickel as 3
percent nickel sulfate. The rate of positive reaction to nickel
for females was significantly higher than for males. The reaction
rates by sex are not reported, but the rate for the total patient
group was given as 12.2 percent. Turpentine, with a positive reac-
tion rate of 14.8 percent for the total population exceeded the
nickel reaction rate. Hexavalent chrome, the allergen showing the
third highest reaction rate, was statistically significantly more
frequent in males than females. Comparison with data from the
International Contact Dermatitis group by specific European cities
shows nickel sensitivity is by no means the leading allergen in
each location.
The differences in nickel sensitivity rates are not strictly
comparable, since the International group tested with 5 percent
nickel sulfate solution while the North American group used a 2.5
percent and Brun used a 3 percent nickel sulfate solution.
Spruit and Bongaarts (1977a) investigated the relationship of
nickel sensitivity to nickel concentrations in plasma, urine, and
hair and found no association. The role of atopy, either personal
or familial, in nickel-sensitive and nonsensitive dermatitis cases
was examined by Wahlberg (1975). No differences of rates of per-
sonal or familial atopy were found for nickel-sensitive and nonsen-
sitive oatients with hand eczema. All cases were ladies hairdress-
ers; they showed a positive reaction rate of 40 percent to nickel
sulfate (five percent) solution.
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Both Spruit and Bongaarts (1977b) and Wahlberq (1975) reported
that positive reaction to nickel sulfate occurs at very low dilu-
tion levels in some individuals. Wahlberg found 5 of 14 positive
reactors sensitive to ^_0.039 percent nickel sulfate solution.
Spruit and Bongaarts (1977b) found one female patient with a posi-
tive reaction when the solution was 0.001 percent Mi"1"1".
Nickel sensitivity is prevalent among women, and nickel con-
tact dermatitis occurs frequently not only among women but also
among men who are exposed. Nickel is extremely common in the arti-
cles and substances found in the home and in metals used for jewel-
ry, metal fasteners of clothing, coinage, etc. Some preparations
used in hair dressing contain nickel and consequently hairdressers
exhibit nickel dermatitis. The consequences of nickel contact der-
matitis seems to vary with the surrounding social factors: male
factory workers appear not to be handicapped by it (Spruit and Bon-
gaarts, 1977b) and continue in their work; hairdressers leave their
occupation when they develop dermatitis (Wahlberq, 1975).
The impact of nickel dermatitis on the health of the total
U.S. population cannot be assessed at this time since the preva-
lence of this condition in the population is unknown. Also, there
are no data on the range of severity and the consequences or the
costs of the condition.
Stainless steel, chrome, and other metal alloys used in pros-
theses and other surgical devices frequently contain proportions of
nickel that have proved to cause reactions in patients ranging from
itching to dermatitis to tissue breakdown, requiring replacement of
the device. The NAS report (1975) lists the following devices and
C-87
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prostheses reported in the literature as associated with adverse
reactions to their nickel contents: wire suture materials: metal-
lic mesh for nasal prostheses; heart valves; intrauterine contra-
ceptive devices; batteries for implanted pacemakers; alloys for
dental castings and fillings; and orthopedic implants.
The alloys, contrary to general assumption, appear not to be
biologically inert and produce adverse reactions in some of the
individuals sensitive to nickel. Two cases of cancer in humans at
the site of steel plate implantation were reported. These cancers
developed 30 years after implantation in both cases. In both cases
the alloys of the plates and screws differed and possibly electrol-
ysis and metallic corrosion may have occurred.
Deutman, et al. (1977) reported on metal sensitivity before
and after total hip arthroplasty in 212 cases from their orthopedic
service in Gronigen, Netherlands. They instituted their study be-
cause recent literature contains reports of reactions to orthopedic
implants including loosening of total ioint prostheses. The auth-
ors studied the pre-operative sensitivity status of 212 patients
scheduled for total hip replacement and followed up these patients
to ascertain if sensitivity developed after the insertion. Pour-
teen patients were sensitive to one or more of three metals tested
and 11 of these were sensitive to nickel. The allergens used were
those recommended by the International Contact Dermatitis Group,
that is, for nickel sensitivity, a 2.5 percent nickel sulfate solu-
tion was employed in the patch test. (The nickel sulfate solution
standard has been changed since the time of the European work re-
ported previously in the Allergenic Response section.) The
C-88
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past experience with metallic appliances for bone surgery was found
to be 173 cases without previous experience, 17 cases with less
than total joint replacement, 16 with total ioint replacement and
subsequent loosening and reoperations, and six with stable McKee-
Parrar prostheses. Of the 11 nickel-sensitive patients, three had
previous implants. Histories of nickel sensitivity showed five
cases of eczema due to jewelry or garters and two cases with pre-
vious implants where the eczema appeared over the scar tissue of
the site of the implant. Four individuals with positive reaction
to the nickel allergen did not have a previous history of eczema.
In addition, there were five patients with a history of sensitivity
but not a positive reaction to the patch test.
A second phase of the study consisted of six or more post-
operative patch-tests of 66 of the 198 patients without pre-opera-
tive sensitivity to patch tests. There were 55 women and 11 men,
average age 69.5 years, in this group. Four of these 66 showed
metal sensitivity, three to nickel and one to cobalt. This includ-
ed one woman with a negative pre-operative patch test but a history
of eczema from garters who was positive on post-operative patch
test. None of the 66, regardless of sensitivity status, had shown
pain, loosening of the prosthesis, infection, or skin symptoms dur-
ing the post-operative period of approximately two years. This
represents a conversion rate of six percent within up to about two
years post-operatively. A sensitivity rate of 4.6 percent to nick-
el by patch test was found in the 173 patients without previous
bone surgery.
C-89
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While nickel sensitivity in persons receiving orthopedic im-
plants puts them at higher risk of complications, this does not
represent a health problem to the peculation in general and is not
related to exposure due to the presence of nickel in environmental
media.
Chronic
In contrast to acute effects of nickel carbonyl exposure in
man, little has been reported for effects of chronic exposure to
this agent. Sunderman and Sunderman (1961b) have described one
case of chronic inhalation of nickel carbonyl at low levels, in
which the patient had developed asthma and Loffler's syndrome.
Adverse pulmonary effects in man due to other nickel com-
pounds, are noted below and discussed elsewhere in regard to occu-
pational carcinogenicity. Russian workers (Tatarskaya, 1960; Kuch-
arin, 1970; Sushenko and Rafikova, 1972) have observed chronic
rhinitis and nasal sinusitis in workers engaged in nickel electro-
plating operations where chronic inhalation of nickel aerosols,
such as of nickel sulfate, had occurred. Associated findings com-
monly encountered were anosmia and nasal mucosal injury including
nasal septum perforation. Asthmatic lung disease in nickel plating
workers has been documented by Tolot, et al. (1956) and McConnell,
et al. (1973). Based on various animal studies as described else-
where, inhalation of nickel particulate matter is likely to olay a
role in chronic respiratory infections in nickel workers via ef-
fects on the activity of alveolar macroohages.
The role of oral nickel in dermatitic responses has also been
demonstrated by Kaaber, et al. (1978), who investigated the effect
C-90
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of a low nickel diet in patients with chronic nickel dermatitis
presented as hand eczemas of dyshidrotic morphology. Of 17 sub-
jects in the clinical trial, nine showed significant improvement
during a period of six weeks on a low nickel diet. Of these nine
showing improvement, seven had a flare-up in their condition when
placed on a normal diet. Furthermore, there was no correlation
apparent between the level of urinary nickel and the degree of
improvement following the diet. These authors recommend limitation
in dietary nickel as a help in the management of nickel dermatitis.
In this connection, also, Rudzki and Grzywa (1977) described an
individual having chronic flare-ups in nickel dermatitis whose
chronicity of condition was traced to the nickel content of marga-
rine, Polish margarine having a rather high nickel content, up to
0.2 mg Ni/kg.
IN VITRO AND IN VIVO STUDIES
Subcellular and Cellular Aspects of Nickel Toxicity
A thorough discussion of the available information on the
interactions of nickel at the molecular level is beyond the purpose
of this document and consideration will be given mainly to data
that are more germane to both the adverse and beneficial effects of
nickel in vivo.
Nickel, in the form of the common divalent ion, is known to
bind to a variety of biomolecular species such as nucleic acids and
proteins as well as their constituent units: nucleotides, nep-
tides, and amino acids (MAS, 1975). Of the various ligand groups
for divalent nickel, strongest binding occurs to form chelate
structures with sulfhydryl, aza, and amino groups, with amido-N
(peptide group) and carboxyl group binding also being possible.
C-91
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In the previous section dealing with nickel metabolism, it was
noted that serum albumin is the main carrier protein for macromole-
cular-bound nickel in a number of animal species including man. It
was pointed out that in man and rabbit, there also appears to be a
specific nickel protein differing as to structure, such proteins
possibly being evidence for an essential role for nickel.
A number of relevant reports in the literature have appeared
discribing in, vivo and in vitro effects of various nickel compounds
on enzyme systems, nucleic acid and protein synthesis, as well as
related effects in experimental animals. Data obtained in vivo are
tabulated in Table 20, while jji vitro effects are presented in
Table 21.
A number of investigators have studied the effects of nickel
compounds on indueible enzyme systems in liver and other organs
that are involved in the metabolism and detoxification of drugs and
other foreign substances.
In the rat, nickel carbonyl inhibits the phenothiazine induc-
tion of benzopyrene hydroxylase in lungs and liver (Sunderman,
1967a), the cortisone induction of hepatic tryptophan pyrrolase
(Sunderman, 1967b) the phenobarbital induction of hepatic cyto-
chrome (Sunderman, 1968), and phenobarbital induction of aminopy-
rine demethylase (Sunderman and Leibman, 1970). Nickel carbonyl
inhibition of benzopyrene hydroxylase activity probably reflects
reduced enzyme biosynthesis, since iri vitro exposure to the agent
had no effect. Nickel sulfate, however, at levels greater than
1 mM does inhibit the enzyme jji vitro (Dixon, et al. 1970). Since
benzopyrene is a carcinogen, it has been suggested that a mechanism
C-92
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Ni(CO),
Ni(CO),
TABLE 20
In Vivo Biochemical Effects ot Nickel Compounds
Compound
NilCO)4
Ni(CO)4
Ni(CO)4
O
t£> Ni(CO),,
OJ *
N1(CO)4
Ni(CO)4
Ni(CO)4
Animal Dosing Conditions
Rat i.V. 20 rag/kg
Inhalation
0.20 rog/1 air
Rat I.V. 20 rag/kg
Rat I.V. 20 ntg/kg
Rat I.V. 22 rag/kg
Rat i.V. 22 mg/kg
Rat i.v. 22 Mg/kg
Rat I.V. 22 Mg/kg
Effects
Inhibition of phenothiazine
Induction of benzopyrene hydroxy-
lase in lungs and liver
Inhibition of cortisone induction
of hepatic tryptophan pyrrolase
Inhibition of phenobarbital induc-
tion of hepatic cytochrome
Inhibition of RNA polymer ase in
hepatic nuclei
Incorporation of ( C)-orotic acid
into hepatic RNA
Inhibition of RNA synthesis by
hepatic chroma tin - RNA polynerase
complex
Inhibition of phenobarbital
Reference
Sunder man, i967a
Sunder man, iyoVo
Sunder man, i^btt
Sunderman ana Esrahani,
1968
Beach and Sunder man,
1969
Beach and Sunderman,
1970
Sunder man and Leiuman.
Rat
Rat
I.V. 22 mg/kg
I.V. 22 Mg/kg
induction of aminopyrene
demethylase
Slight inhibition of leucine incor-
poration into liver microsomal
proteins
Elevated liver ATP level
a.970
Sunderman, 1970
Sunderman, it'lL
-------
TABLE 20 (continued)
o
Compound
Ni(CO)4
N1C12
NiSO4
Nickel (II)
ion
NiCl2
Animal Dosing Conditions
Rat I.V. 22 «g/kg
Rat S.C. 16 mg/kg
Rat I. P. mg/kg
daily. 30-90
days
Young
mouse
Rat I. P. 19 mg/kg.
single dose
oral 225 ppm
long term, water
Effects
Inhibition of RNA synthesis in liver
but not lungs
Reduced liver ALA-synthetase, reduced
porphyrin, cytochrome P-450, and total
heme; heme oxygenase elevation in
liver, kidney and cardiac tissue
At 60 to 90 days, succinic dehydrogen-
ase reduced in liver and kidney;
at 30, 60, and 90 days, ATP-ase activity
elevated in testes
Inhibition of cytochrome oxidase, iso-
citric and malic dehydrogenases in
liver, kidney and heart and inhibition
of heart muscle phosphor ylase
4-fold increase in serum glucose,
hyper lipidemia and insulin resistance
elevated serum triglycerides
Reference
Witschi, 1972
Maines and Kappas,
1977
Mathur, et al. I977b
Weber and Reid, 19btt
Clary and Vignati,
1973
NiCl2
Rat
Rat
I. P. 250 mg/kg,
single dose,
3-6 hrs before
sacrifice
I.M.
ATP-ase activity in brain capillaries
abolished
Glyceraldehyde-3-phosphate dehydro-
genase inhibited} Glucose-fa-
phosphate dehydrogenase elevated
within 6 hr.
Joo,
Joo, 1969
Uasrur and Swierenga,
1970
-------
TABLE 21
In Vitro Biochemical Effects of Nickel Compounds
Compound
System
Exposure
Effects
Reference
Ni(ll) ion
Ni(II)ion
Ni(II)ion
Rat liver microsomes
Raboit liver and
lung microsomes
DNA polymerase from
avian myeloblastosis
Up to 100 MM Ni
Up to 50 MM Ni
Up to 8 mM Ni
0
1
kO
en
Ni(II) ion
Ni (Il)ion
Ni(II)ion
Ni (II) ion
Ni (II) ion
Ni (II) ion
(6JNi, -
vi L us
DNA polymerase from 5 mM Ni
E. coli
Rat brain synapto- Up to 300 pM Ni
somes
Rat hepatic micro-
somes
Cilia of Tetrahymena 5 mM Ni
pyriformis
Sheep alveolar 1 mM Ni
macrophages
Sheep alveolar 0.5 mM Ni
macrophages
Rat embryo muscle
Ni
JS,
culture
Activity of benzopyrene
hydroxylase reduced to half
at 0.5 umolar Ni; total
inhibition at 10 timoles
N-oxidase activity enhanced
30 percent at 1 mM (liver)
and 5 mM (lung), respectively.
N-oxidase activity inhibited
above 10 mM
Fidelity of Mg-activated
DNA synthesis altered
Fidelity of DNA synthesis
altered
ATP-ase activity inhibited
20 percent at 100 pM
ATP-ase activity inhibited
ATP-ase activity inhibited
ATP-ase activity inhibited
ATP-creatine phosphotrans-
ferase activity inhibited
Inhibition of aldolase,
G-6-PD, LDH, and glyceralde-
hyde-3-phosphate dehydrogenase
Thompson, et al.
1974
Devereux and Fouts,
1974
Sirover and Loeb,
197V
Miyaki, et al.
1977
Prakash, et al.
1973
Federchenko and Petru,
1969
Raff and Blum,
1969
Mustafa, et al.
197i
U'Sullivan ana Morrison,
19b3
Basrur and Swierenga,
1970
-------
for at least co-carcinogenicity of nickel relates to increased re-
tention of the hydrocarbon, particularly in the case of heavy ciqa-
rette smokers (Dixon, et al. 1970; Sunderman, 1967a).
Maines and Kappas (1977) have reported effects of nickel (II)
injection in rats, including reduced heme levels and enhanced heme
oxygenase activity. These effects could be abolished if nickel was
complexed to cysteine .prior to injection. In a related study,
Maines and Kappas (1976) demonstrated no effect of nickel (II) ion
on hepatic heme oxygenase activity jjn vitro at levels? of 12.5 to
250 viM, indicating that direct activation of preformed enzyme does
not occur in vivo.
Inhibition of RNA symthesis in the rat, probably via an effect
on RNA polymerase (Sunderman and Esfahani, 1968; Beach and Sunder-
man, 1969, 1970; Witschi, 1972) has been demonstrated with nickel
carbonyl. Moderate inhibition by this agent of hepatic protein
synthesis has also been noted (Sunderman, 1970).
The inhibition of ATPase by nickel salts ir\ vitro and in vivo
has been reported for the enzyme from different sources (Prakash,
et al. 1973; Federchenko and Petru, 1969; Raff and Blum, 1969;
Mustafa, et al. 1971; Joo, 1968, 1969). In contrast, Mathur, et
al. (1977a) found that ATPase activity is elevated in rat testicu-
lar tissue for all time points (30, 60, and 90 days) when rats are
given Ni intraperitoneally at 3 mg/kg daily. Sunderman (1971) has
suggested that the inhibition of ATPase and other ATP-requiring en-
zymes likely involves binding of divalent nickel to ATP, making it
unavailable for subsequent utilization since it is known that nick-
el can form a stable complex with ATP (Sigel, et al. 1967).
C-96
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Tn vitro and ir\ vivo studies of nickel subsulfide (Ni.,^) on
muscle tissue (Basrur and Swierenqa, 1970) revealed impairment of
glycolytic enzyme activity.
Sirover and Loeb (1977) have demonstrated alteration of mag-
nesium-activated DNA synthesis fidelity at 8 mM levels of nickel
(II) ion and using DNA polymerase from avian myeloblastosis virus.
Similar effects also are noted with E. coli DNA polymerase (Miyaki,
et al. 1977).
Sunderman and Sunderman (1963) found that nickel carbonvl in-
halation in the rat led to increases in enzyme activity of micro-
somal and supernatant fractions of lung and liver homoqenates.
Webb and co-workers (1972) have found that 70 to 90 percent of the
nickel in nickel-induced rhabdomyosarcomas is found in the nucleus.
Of the total nuclear nickel burden, about half is present in the
nucleolus, with the remainder equally distributed between nuclear
sap and chromatin. Furthermore, nickel binding to RNA and DNA was
observed in nuclei of rhabdomyosarcomas from rats given nickel sub-
sulfide intramuscularly (Heath and Webb, 1967). In mouse dermal
fibroblasts grown ir\ vitro and exposed to various Ni-labeled com-
pounds, Webb and Weinzierl (1972) noted a similar distribution.
These data are consistent with the findings of Beach and Sunderman
(1970) that nickel is bound to the RNA polymerase-chromatin comolex
obtained from rat liver nuclei after nickel carbonyl exposure. De-
cently, Jasmin and Solymoss (1977) have reported that intrarenal
administration of nickel subsulfide in the rat led to the highest
relative amounts in the nuclear fraction of kidney homoqenate with
smaller amounts in the mitochondria and microsomes.
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Moffitt, et al. (1972) observed that alterations in the normal
subcellular distribution of nickel in rat tissue occvjr with the
acute administration of benzopyrene (8 mg intratracheally). By
three days post-exposure, significant reductions of nickel content
were seen in nucleus, mitochondria, and microsomes.
Changes in ultrastructure have been reported for various
organellar components from animals exposed to nickel compounds.
In rats exposed intravenously to nickel carbonyl (65 mg/kg),
ultrastructural alterations in hepatocytes included nuclear dis-
tortion by 24 hours, dilation of rough endoplasmic reticulum at one
to four days, and cytoplasmic inclusion bodies at four to six days
(Hackett and Sunderman, 1969).
A number of studies of the action of nickel subsulfide have
included the observation of ultrastructural effects. Tumor cells
from nickel subsulfide-induced rhabdomyosarcomas show pronounced
alterations in ultrastructure (Basrur, et al. 1970; Friedmann and
Bird, 1969; Bruni and Rust, 1975) to include mitochondrial ccnfor-
mational changes, accumulation of electron-dense granules, and
elaboration of cristae which have coalesced and formed wavy or
parallel stacks in all cases. Degenerative changes, including dis-
ruption of inner and outer membranes, were sometimes seen. Some of
these changes could also be detected in rat muscle tissue exposed
to nickel subsulfide for relatively brief periods, 24 to 48 hours
(Basrur, et al. 1970). Cultured rat embryo myoblasts exposed to
nickel subsulfide exhibited a variety of organellar changes (Sykes
and Basrur, 1971). At the cell periphery, cytoplasmic: blebs con-
taining clusters of free riboscmes appeared to form and dissociate
C-93
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from the myotube while cellular organelles aggreqated in the cen-
ter. Alterations in the fine structure and alignment of mitochon-
dria caused derangement of the contractile elements. Using scan-
ning electron microscopy, Geissinger, et al. (1973) showed that
chromosomal abnormalities existed in a nickel subsulfide sarcoma
from rat muscle tissue (20 mg intramuscularly). Meoplastic cells
from renal tumors in rats induced by intrarenal administration of
nickel subsulfide are characterized by large swollen mitochondria,
cisternae of rough endoplasmic reticulum, abundant polysomes, lipid
vacuoles, and dense bodies. Nuclei are irregular in shape with
marginal chromatin and prominent nucleolus.
A number of investigators have described the effects of nickel
compounds in cultures of cells. These in vitro correlates of nick-
el's effects ir\ vivo have proved particularly valuable in helping
elucidate the allergenic, immunological, and carcinogenic aspects
of nickel toxicity in man and experimental animals.
Reports have appeared in the literature dealing with the re-
sponse of alveolar macrophages and other components that serve a
protective function in respiratory tract to nickel compounds, wat-
ers, et al. (1975) have studied the toxicity of nickel ion to rab-
bit alveolar macrophages ir\ vitro. At a concentration of about 4
mM nickel, a 50 percent reduction in viable cells occurred, via-
bility being determined by trypan blue exclusion. In a related
study, Graham, et al. (1975) studied the response of rabbit alveo-
lar macrophages to levels of nickel that did not affect their via-
bility. Of various metal ions tested, nickel was the only element
that induced changes in phaqocytic activitv without significant
C-99
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effect on cell life. In a medium containing 1.1 mM nickel ion,
these macrophages had minimal morphological evidence of injury, but
lacked the ability to phagocytize polystyrene latex snheres. In
vitro exposure of rabbit alveolar macrophages to nickel ion at 0.1
mM concentration or greater caused significant inhibition of anti-
body-mediated rosette formation, the extent of inhibition being
concentration-dependent (Hadley, et al. 1977). These results sug-
gested to the authors that antibody-mediated rosette formation may
be useful as a rapid and sensitive screen for metal toxicity.
Transformation of cultured human peripheral lymphocytes as a
sensitive iji vitro screening technique for nickel hypersensitivity
versus the classical patch testing has been studied in a number of
laboratories, and the earlier conflicting studies have been re-
viewed (NAS, 1975). The studies of Hutchinson, et al. (1972), For-
man and Alexander (1972), Millikan, et al. (1973), Gimenez-Cama-
rasa, et al. (1975), and Svejgaard, et al. (1978) have, however,
established the reliability of the technique.
Jacobsen (1977) has investigated the response of cultured epi-
thelium-like cells from human gingiva to nickel inasmuch as the
element appears in dental prosthetic materials. Significant ef-
fects on cell viability are seen at nickel (II) levels down to 0.08
mM. In this study, no correlation was seen between the amount of
serum present and cytotoxicity, suggesting that both complexed and
uncomplexed nickel ion are equally active.
Exposure of rat embryo myoblasts in culture to nickel subsul-
fide dust results in drastic reduction of mitotic index and cell
survival (Sykes and Basrur, 1971). Daniel, et al. (1974) assessed
C-100
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the effect of nickel-serum complexation on cultures of chick myo-
blasts by pre-incubation of nickel dust in serum for up to 30 days
followed by analysis of serum supernatant for nickel content.
Nickel, at a level of 20 ug/1 serum and greater prevents normal
cell differentiation and causes cell degeneration.
Costa, et al. (1978) have used various nickel compounds to
assess the morphological transformations of Syrian hamster cells as
a possible rapid screening technique for carcinogenicity. Using as
an index the loss of contact inhibition, the most pronounced ef-
fects were noted with nickel subsulfide, nickel dust, and nickel
subselenide. These data are consistent with other documented com-
parative effects discussed below in the section dealing with nickel
carcinogenicity.
Rat fat cells, when exposed to divalent nickel at levels of 1
to 6 mM, showed decreased adrenalin- and glucagon-stimulated lip-
olysis, along with increased glucose incorporation into lipids,
possibly mimicking the action of insulin at the cell plasma mem-
brane (Saggerson, et al. 1976).
According to Taubman and Malnick (1975), nickel ion at levels
of 1.0 uM-1.0 mM did not trigger histamine release from rat peri-
toneal mast cells, indicating that the anaphylactoid edema seen in
the rat following nickel (II) injection operates by some mechanism
other than a direct cellular effect.
Synergism and/or Antagonism
There are experimental data that demonstrate that nickel has a
synergistic effect on the carcinogenicites of polycyclic aromatic
hydrocarbons. ^oda (1962) has found that 17 percent of rats re-
C-101
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ceiving intratracheal doses of nickel oxide alonq with 20-methyl-
cholanthrene developed squamous cell carcinomas. Maenza, et al.
(1971) demonstrated a synergistic rather than additive effect in
the latency period reduction (30 percent) of sarcomas when simul-
taneous exposure to benzopyrene and nickel subsulfide was carried
out. As stated elsewhere, the inhibitory activity of nickel on
enzyme systems that mediate the metabolism of agents such as benzo-
pyrene was noted. It is likely, then, that tissue retention of
these organic compounds is prolonged with nickel exposure. Kas-
przak, et al. (1973) observed pathological reactions in lungs of
rats given both nickel subsulfide and benzooyrene that were greater
than was the case for either agent alone.
Nickel and other elements are known to be present in asbestos
and may possibly be a factor in asbestos carcinogenicity. The oer-
tinent literature has been reviewed (Morgan, et al. 1973; N^S,
1975). Little in the way of experimental studies exists to shed
light on any etiological role of nickel in asbestos carcinogeni-
city, however. Cralley (1971) has speculated that asbestos fibers
may serve as a transport mechanism for metals into tissue and that
the presence of chromium and manganese may enhance the carcinogeni-
city of nickel.
Virus-nickel synergism is suggested by the observation of
Treagon and Purst (1970) that ijn vitro suppression of mouse L-cell
interferon synthesis occurs in response to Newcastle Disease virus
with nickel present.
0-102
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Teratogenicity
Little evidence for nickel as a teratogen has been documented.
While Perm (1972) has claimed unspecified malformations in surviv-
ing hamster embryos when mothers were exposed to parenteral nickel
(0.7 to 10.0 mg/kg). Sunderman, et al. (1978) found no teratogenic
effects for either nickel chloride (16 mg/kg) or nickel subsulfide
(80 mg/kg) in rats.
In animals, several studies have demonstrated that nickel
crosses the placental barrier and is lodged in fetal tissue. Whole
body analysis of offspring from rats fed nickel at dietary levels
of 250 to 1,000 ppm and in different chemical form showed nickel at
22 to 30 ppm in those offspring whose mothers were exposed to the
highest level in diet and 12 to 17 ppm for the maternal exposure of
500 ppm (Phatak and Patwardhan, 1950) . Lu and co-workers (1976)
have reported placental transfer of nickel in pregnant mice.
Intraperitoneal administration of a single dose of nickel chloride
(3.5 mg/kg) at day 16 of gestation led to maximal accumulation of
nickel in fetal tissue at eight hours post-exposure, while oeak
levels of nickel in maternal blood and placentae were observed two
hours afterwards. Tn a recent detailed study by Sunderman, et al.
(1978), the uptake of Ni label given intramuscularly to rats was
seen in embryo and embryonic membrane at day eight gestation, the
amount of label being equivalent to that in maternal lungs, adren-
als and ovaries. Furthermore, autoradiograms revealed nickel label
in yolk sacs of placentae one day post injection (day 18 of gesta-
tion) and some passage of label into fetal tissue. On day 19, fetal
urinary bladder had the highest level of label.
C-103
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The data of Phatak and Patwardhan (1950) on litter sizes from
pregnant rats fed nickel in various forms at a level of 1,000 ppm
suggest a reduction in pup numbers at this exposure level. Schroe-
der and Mitchener (1971) followed three generations of rats contin-
uously exposed to nickel in drinking water (5 ppm). Increased num-
bers of runts and enhanced neonatal mortality were seen in each of
three generations, along with a significant reduction in litter
size and a reduced proportion of males in the third generation. In
a similar endeavor, Ambrose, et al. (1976) followed three genera-
tions of rats given nickel in diet at concentrations of 250 to
1,000 ppm. There was increased fetal mortality in the first gener-
ation while body weights were decreased in all generations at
1,000 ppm. Perm (1972) noted that intravenous administration of
nickel acetate (0.7 to 10.0 mg/kg) to pregnant hamsters at day
eight of gestation resulted in increases in the number of resorbed
embryos.
Gametotoxic Effects of Nickel
when nickel sulfate was administered to rats subcutaneously at
a dosing of 2.4 mg Ni/kg, Hoey (1966) observed shrinkage of central
tubules, hyperemia of intertubular capillaries and disintegration
of spermatozoa in testicular tissue 18 hours after a single dose.
Multiple dosing produced disintegration of spermatocytes and soerm-
atids and destruction of Sertoli cells. Such effects were noted to
be reversible. Waltschewa, et al. (1972) noted inhibition of sper-
matogenesis in rats given daily oral doses of nickel sulfate (25
mg/kg) with reduction in the number of basal cells within the tub-
ules and in the number of spermatozoa-containing tubules. Continu-
C-104
-------
ation of the dosing regimen for 120 days resulted in complete
obliteration of fertility in these animals.
No gametotoxic effects have been documented in man.
Carcinogenic!ty
The present status of nickel's role in occupational and exper-
imental carcinogenesis has been the subject of a number of reviews
[International Agency for Research on Cancer (IARC), 1976; NAS,
1975; NIOSH, 1977; Sunderman, 1973, 1976, 1977].
A carcinogenic response to various nickel compounds upon in-
jection has been observed in a number of animal studies (Sunderman,
et al. 1976; Sunderman and Sunderman, 1963; Sunderman and Maenza,
1976; Sunderman, 1973, 1978; Lau, et al. 1972; Stoner, et al. 1976;
IARC, 1976). in nickel refinery workers, an excess risk of nasal
and lung cancers has been demonstrated (IARC, 1976). However,
there is no evidence at present that orally ingested nickel is
tumorigenic.
Experimental Carcinoqenesis
The qualitative and quantitative character of the carcinogenic
effects of nickel as seen in experimental animal models has been
shown to vary with the chemical form of the nickel, the routes of
exposure, the animal model employed (including strain difference
within animal models), and the amounts of the substance employed.
Some of the experimental models of nickel carcinoqenesis which
have evolved out of various laboratories are given in Table 22,
along with the various carcinogenic nickel compounds employed, the
levels of material used and the routes of administration. Resoons-
es are usually at the site of injection, although in the case of
C-105
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TABLE 22
Experimental Models of Nickel Carcinogenesis
O
I
Animal
Rat,- mice
Guinea pig
Kat
Rat
Rat
Rat, mouse
Syr ian
hamster
Rat
Agent
Ni dust
Ni dust
Ni dust
Ni dust
Ni pellet
Ni3S2 or
Ni O dust
Ni S.
2
Ni S
3 2
Dos i ng
Intrapleural/intraosseous:
0.06% suspension
5% suspension
Inhalation .
15 mg 1 m
I.M., 28 mg in serum
I. P., intrathoracic
S mg in saline
S.C. , 2 x 2 nun
I.M. , 20 mg/thigh
I.M. , 5 or 10 mg
single
Inhalation ,
ca 1 mg/m
Response
Sarcomas
Lung anaplastic carcinomas
and adenocar cinemas
Rha bdomyos a r coma s
Mesotheliomas
Sarcomas
Rha bdomyos a r coma s
Sarcomas
Epidermoid carcinomas and
adenocar cinomas (lung)
Reference
Hueper , iyt>t>
Hueper, 195U
Heath and Daniel, x9b4;
Heath and Webb, I*o7
Furst, et al. 197J
Mitchell, et al. J.9bO
Gilman, iyoz
Sunderman, i97V
Ottolengni, et al.
1974
Rat
Rat
Ni3S2
Intrarenal
5 mg/saline or
glycerol
Intratesticular,
O.b-iu mg
Renal adenocarcimomas
Fibrosarcomas and
thabuumyosdi. comas
Jasmin and Riopelle,
1976
Damjanov, et al.
-------
TABLE 22 (continued)
o
1
I-1
o
Animal
Rat
Rat
Mouse
Rat,
hamster
Rat
Agent Dosing Response
Ni(CO)4 Inhalation, Epidermoid and anaplastic
4-80 ppm carcinoma, and adenocar-
cinomas (lung)
Ni(CO)4 I.V., 50 pi/kg Carcinomas and sarcomas
Nickel acetate i.p., 360 mg/kg Lung adenocarcinomas
Nickel- I.M. Sarcomas
ocene
Ni3S2/ I-M" 10 »9/5 "9 Sarcomas
Benzpyrene
Reference
Sunderman, et al. 1959;
Sunderman and Donnelly, I9bb
Lau, et
8 toner ,
Haro, et
Furst
Haenza,
al. 1972
et al. 1976
al. 1968;
and Schlauder, i9/i
et al. 1971
Rat
Rat
Benzpyrene
NiO/
raethyl-
cholanthcene
Intratracheal:
2-5 mg
Intratracheal:
Squamous cell carcinomas
Squamous cell carcinomas
Karsprzak, et al. 1973
Toda,
-------
nickel acetate injection, pulmonary carcinomas were detected in
mice given repeated intraoeritoneal injections (Stoner, et al.
1976). There have been no reports of experimental caroinogenesis
induced by oral or cutaneous exposure.
Nickel metal, in the form of dust or pellets, leads to induc-
tion of malignant sarcomas at the site of dosing in rats, guinea
pigs, and rabbits (Hueper, 1955; Heath and Daniel, 1964y Heath and
Webb, 1967; Mitchell, et al. 1960) , while inhalation of nickel dust
leads to lung anaplastic carcinomas and adenocarcinomas (Hueper,
1958) .
In a study of the carcinogenicities of various metal com-
pounds, Oilman (1962) noted that nickel subsulfide (Ni3S2) was a
potent inducer of rhabdomyosarcomas when given intramuscularly.
Later studies of the carcinogenicity of nickel subsulfide demon-
strated adenocarcinomas in rats given the substance intrarenally
(Jasmin and Riopelle, 1976) , rhabdomyosarcomas, f ibrosaiccomas, and
fibrohistocytomas in rat testicular tissue after intratesticular
dosing (Damjanov, et al. 1978) and lung epidermoid and adenocar-
cinomas in rats inhaling nickel subsulfide (Ottolenghi, et al.
1974) .
Exposure to nickel carbonyl either via inhalation (Sunderman,
et al. 1959; Sunderman and Donnelly, 1965) or intravenously (Lau,
et al. 1972) has been observed to induce pulmonary carcinomas or
carcinomas and sarcomas in organs such as liver and kidney, respec-
tively. As noted above, repeated intraoeritoneal dosing yields
lung carcinomas in mice (Stoner, et al. 1976) when nickel acetate
is used, while nickelocene, an organonickel "sandwich" structure,
C-108
-------
induces sarcomas in rats and hamsters when given intramuscularly
(Haro, et al. 1968; Furst and Schlauder, 1971).
The underlying biochemical mechanisms governing the carcino-
genicities of various nickel compounds have yet to be fully eluci-
dated.
Transport to the site(s) of carcinogenic action is known to
differ among carcinogenic nickel agents. As noted earlier, nickel
carbonyl decomposes extracellularly, and the liberated nickel is
oxidized intracellularly and mobilized. In the case of insoluble
dusts, such as metallic nickel and nickel subsulfide, slow dissolu-
tion from extracellular deposition by extracellular fluid presum-
able occurs.
Nickel dust gradually dissolves when incubated with horse
serum to yield complexes of oxidized nickel with proteins and amino
acids (Weinzierl and Webb, 1972) while ultrafiltrable nickel com-
plexes obtained by adding nickel dust to muscle homogenate in vitro
are similar to those formed when nickel implants slowly dissolved
in muscle (Weinzierl and Webb, 1972). Webb and Weinzierl (1972)
using Ni label have demonstrated that mouse dermal fibroblasts in
culture take up nickel complexes with proteins and other ligands,
and they suggest that myoblasts involved in repair of muscle in-
jured by dust contact take up solubilized nickel and undergo subse-
quent neoplastic transformation.
Singh and Gilman (1973), in a study using double-diffusion
chambers containing nickel subsulfide implanted intraperitoneallv
in rats, observed effects on rhabdomyocytes 2 to 24 davs later,
indicating the intermediacy of a soluble nickel complex, since the
C-109
-------
technique interposes a solution barrier between agent and cellular
surface. Using 63Ni-labeled nickel subsulfide, Sunderman, et al.
(1976), observed that intramuscular administration in rats was fol-
lowed by localization within macrophages and fibroblasts by the end
of the first week. In a related report, Kasprzak and Sunderman
(1977) monitored the relative rates of dissolution of Icibeled nick-
el (63Ni) subsulfide in water, whole rat serum, and rat serum
ultrafiltrate. Dissolution rates were more rapid in seirum or serum
ultrafiltrate and were attended by formation of nickel sulfide and
nickel hydroxide. These authors speculate that subsequent solubi-
lizing of these latter forms ir\ vivo is conceivable owing to the
lower pH existing in lysosomes, nickel particles being observed in
the lysosomes of macrophages from nickel subsulfide-treated rats
(Sunderman, et al. 1976).
Experimental clues as to the ways in which intracellular nick-
el imparts neoplastic transformations include the following:
(1) the intracellular distribution of nickel in nickel-induced
rhabdomyosarcomas is highest in the nucleus (70 to 90 percent),
with roughly half of this amount being in the nucleolus; (2) nickel
is bound to an RNA polymerase-chromatin complex from hepatic cell
nuclei of rats with nickel carbonyl; (3) this complex carries out
diminished RNA synthesis; (4) the fidelity of DNA synthesis is
impaired in various cell types in vitro; (5) addition of nickel ion
to cultures of mouse L-929 cells interferes with interferon synthe-
sis (Treagon and Furst, 1970); and (6) addition of nickel subsul-
v I
fide to cultured embryonic muscle cells inhibits mitotic activity
and causes abnormal mitotic figures (Basrur and Gilman, 1967; Swie-
renga and Basrur, 1968).
0110
-------
The above discussion has focused on nickel compounds used
alone to induce carcinogenic responses. An equally important as-
pect of these effects is the synergistic action of nickel in the
carcinogenicity of other agents, since environmental situations
entail simultaneous exposure to a number of such substances. Ms-
cussion of this area has been presented previously under the Syner-
gism and/or Antagonism section.
Comparative carcinogenicity for various nickel compounds has
been studied and demonstrated in various laboratories (Sunderman
and Maenza, 1976; Jasmin and Riopelle, 1976; nilman, 1962; Payne,
1964). Furthermore, there is a general inverse relationship be-
tween solubility and carcinogenic potential: insoluble nickel
metal, nickel oxide, and nickel subsulfide are carcinogenic, while
most of the nickel salts are noncarcinogens. A few exceptions to
this do exist: nickel acetate, for example, is soluble but also
has carcinogenic character (Table 22). This relationship reflects
mainly the relative speed of clearance of soluble nickel from the
organism by the renal excretion, the time for clearance being
shorter than the induction interval for carcinogenic manifesta-
tions,
Sunderman and Maenza (1976) studied the incidence of sarcomas
in Fischer rats within two years after single intramuscular injec-
tions of four insoluble nickel-containing powders: metallic nick-
el, nickel sulfide, o<-nickel subsulfide and nickel-iron sulfide
matte. Amorphous nickel sulfide had no tumorigenic ootential,
while nickel subsulfide was most active. The relative carcinogeni-
city of nickel-iron sulfide matte was intermediate between nickel
C-lll
-------
subsulfide and metallic nickel powder, suggesting to these authors
that there may also be a previously unrecognized carcinogenic po-
tential in other nickel-sulfur mineral complexes, as well as the
corresponding arsenides, selenides, and tellurides.
Epidemiology
The epidemiological data on the carcinogenicity of nickel is
reported for occupationally exposed nickel refinery workers from a
number of countries. Cancer of the respiratory tract, specifically
the lung and nasal cavities, among nickel refinery workers has been
cited in these reports. The variety of processes for different raw
nickel materials results in the production of different nickel com-
pounds and consequently, workers at specific refineries at differ-
ent work stations are exposed in significantly different ways.
The data have been summarized and reviewed by numerous authors
and, since the evidence is incontrovertible, there has been univer-
sal agreement that nickel refinery workers are at ssignificantly
higher risk for cancer of the lungs and nasal cavity (NAS, 1975;
IARC, 1976; NIOSH, 19.77; Sunderman, 1977). Sunderman (1977), in a
review, points out that in addition to the increased risk for can-
cer of the lungs and nasal cavities, increased risk has been found
for cancer of the larynx in Norwegian refinery workers and for qas-
tric cancer and soft tissue sarcoma in Russian refinery workers.
According to the IARC (1976): "Epidemiological studies con-
clusively demonstrate an excessive risk of cancer of the nasal cav-
ity and lung in workers at nickel refineries. It is likely that
nickel in some form(s) is carcinogenic to man."
C-112
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Summaries of the epidemiological and occupational studies are
given in Tables 23 and 24, respectively.
The nickel compounds which are implicated are insoluble dusts
of nickel subsulfide (Ni3S2) and nickel oxides (NiO and Ni203) the
vapor of nickel carbonyl (Ni(CO)4); and soluble aerosols of nickel
sulfate, nitrate, or chloride (NiS04, NiN03, NiCl2) (Sunderman,
1977).
Inasmuch as respiratory tract cancers have occurred in indus-
trial facilities that are metallurgically diverse in their opera-
tions, carcinogenicity probably resides in several compounds of
nickel (NAS, 1975). This is certainly consistent with the animal
models of carcinogenicity previously described. Furnace workers
appear to have the highest risk in this regard, and freshly formed
hot nickel dusts from some roasting procedures may be especially
carcinogenic.
Table 25 is an earlier tabulation (NAS, 1975) of the numbers
of different types of cancers of the lung and nasal cavities seen
in nickel workers. As of March 1977, Sunderman (1977) had tabulat-
ed 477 cases of lung cancer and 143 cases of cancers of the nose and
perinasal sinuses. Other excess cancer risk categories reported
are laryngeal cancers in Norwegian nickel refinery workers (Peder-
sen, et al. 1973), gastric and soft tissue carcinomas in Russian
nickel refinery employees (Saknyn and Shabynina, 1973) , and the
relatively rare renal cancer in Canadian nickel electrolytic refin-
ery workers (Sunderman, 1977).
The earliest epidemiological investigation of the increased
risk of cancer is that of the nickel refinery workers at Clydach,
r-113
-------
TABLE 23
Epidemiological Studies of Nickel Carcinogenesis
o
1
H~*
M
*>
Agent
Nickel Matte
Concentrated
Feed stock
Nickel dust
and fumes
Unknown
Dosing
Inhalation
Inhalation
Inhalation
Response
Carcinoma
Carcinoma
epidermoid
anaplastic
adena
Precancerous
lesions
Organ/Tissue
Lung Nasal
Lung
Biopsies of
mucosa from
middle turbinate
Industry
Clydach, Males
refinery workers
Falconbr idge
refinery-
Norway
Falconbr idge
refinery-
Norway
Reference
Doll, 1977
Kreyuerg, o.97b
Torjussen and
Solbecy, I97o
Ni pxides, Ni
Alloys, Ni
sulfate and Ni
clilor ide
Inhalation -,
O.J mq Ni/m
Cancer
Lung
Aircraft engine
factory
Bernacki ,
-------
TABLE 24
Occupational Studies of Nickel Carcinogenesis
o
1
Agent
Insoluble dusts
Ni3S2
NiO; Ni.,03
Vapors
Ni(CO)4
Soluble aerosols
NiSO,
Dosing Response
Inhalation Carcinoma
epidemoid
anaplastic
pleomorphic
Organ/Tissue Industry Reference
Lung
69%
27%
0
Nasal Refinery S uncle t man, 1973
45%
12%
31%
Ni(N03)2 or
Ni C12
Ni dusts
Soluble and
insoluble
Ni compounds
plus arsenic
and cobalt dusts
Inhalation
Inhalation Cancer
Inhalation Carcinomas
Sarcoma
Kidney
Lung Nasal
Larynx
Gastric
Soft tissue
Canadian refinery
electrolytic workers
Norwegian
refinery
Russian
refinery
Sunderman, iy77
Pedersen, et al.
1973
SaKnyn and
Shabynina, 197J
-------
TABLE 25
Histopathological Classification of Cancer of the Lung and
Nasal Cavities in Nickel Workers*
o
i
Tumor Classification
Epidermoid carcinoma
(squamous cell)
Anaplastic
(undif ferentiated) carcinoma
Alveolar cell carcinoma
Adenocarcinoma
Columnar cell carcinoma
Spheroidal cell carcinoma
Spindle cell carcinoma
Scirrhus carcinoma
Pleomorphic carcinoma
Reticulum cell carcinoma
TOTALS
Lung
No.
34
13
1
1
0
0
0
0
0
0
49
Cancer
%
69
27
2
2
0
0
0
0
0
0
100
Nasal-Cavity
No.
22
6
0
0
2
1
1
1
15
1
49
Cancer
%
45
12
0
0
4
2
2
2
3i
2
100
*Source: NAS, 1975
-------
Wales, where the Mond refining process had been used since the
opening of the refinery in 1900. The mortality experience of these
workers has been monitored continuously. The systematic retrospec-
tive investigations showed that there were significant changes in
risk for workers beginning employment after 1925, since the refin-
ery had undergone basic changes which resulted in control of pol-
lutants and decrease of exposure by that time.
Doll, et al. (1977) reports on an update of the mortality
experience of the Clydach workers, extending the number of men and
the years at risk back in time for inclusion and extending the
observation time for mortality forward. Tables 26, 27, and 28 show
the data for Clydach which led Doll and his associates to revise
the time of the reduction of the risk of cancers from "bv 1925" to
"until 1930".
The epidemiological studies of cancer of the resoiratorv tract
in nickel refinery workers had not considered the role of smoking.
Kreyberg (1978) reports on a study of the nickel refinery workers
from the Palconbridge refinery near Kristiansand, Norway. The pre-
vious epidemiological studies of this worker peculation had estab-
lished their higher risk for cancer of the lungs and determined
that this elevated risk was limited to workers involved in the
roasting, smelting, and electrolysis processes. This earlier work
did not differentiate the lung cancers histologically, nor did it
take account of smoking behavior. Kreyberg and associates were
able to re-examine the data for the Falconbridge refinerv workers
and determine histological characteristics of lung cartcers, the age
at start of employment, lifetime smoking history, employment histo-
C-117
-------
TABLE 26
Number of Men First Employed at Clydach Nickel Refinery, Wales
at Different Periods and Mortality Observed and Expected From all Causes*
o
00
Year of First
Employment
Before 1910
1910-14
1915-19
1920-24
1925-29
1930-44
All periods
No. of
Men
119
150
105
285
103
205
967
Man-years
of Risk
1,980.0
2,266.5
2,204.0
7,126.5
2,678.0
4,538.5
21,193.5
Number
Observed
117
137
89
209
60
77
689
of Deaths
Expected
102.01
92.84
55.44
146.25
51.91
60.42
508.87
Ratio of Observed
and Expected
Deaths 0/E
1.15
1.48
1.61
1.43
1.16
1.27
1.35
*Source: Doll, et al. 1977
-------
TABLE 27
Mortality by Cause and Year of First Employment, Clydach Nickel Refinery, Hales*
Veac of First
Employment
Before 1910
1910-14
1915-19
1920-24
1925-29
All periods
before 1930
1930-44
No.
Nasal
Observed
14
24
11
7
0 (1)
56 (2)
0
Deaths from
Sinus Cancer
Expected
0.036
0.137
0.025
0.071
0.026
0.195
0.034
Ratio
0/B
389
649
440
99
0
287
0
No. Deaths fro*
Lung Cancer
Observed
24
34
20
50
9
137
8
Expected
2.J89
3.267
3.070
9.642
3.615
21.983
5.463
Ratio
O/E
10.0
10.4
6.5
5.2
2.5
6.2
1.5
No. Deaths from Other
Malignant Neoplasms
Observed
10
10
10
27
7
64
11
Expected
14.637
13.549
8.064
20.902
7.247
64.399
8.786
Ratio
O/E
0.68
0.74
1.24
1.29
0.97
0.99
1.2!>
No. Deaths from
Other Diseases
Observed
69
t>9
4U
12b
44
355
58
Expected
84.95
75.99
44. 2b
115. oJ
41. U2
J61.U7
4o.j.4
Ratio
O/E
O.tti
o.yi
l.UU
l.UU
i.07
U.tftt
i.2i
'Source: Doll, et al. 1977
-------
TABLE 28
Chronological Changes in the Feed Material at Clydach Nickel Refinery, Wales*
o
K>
o
Composition of Nickel Mate
Period
1902-33
1933-64
1964-76
Ni,
percent
40-45
75
75
Cu,
percent
35-40
2-6
2-5
s,
percent
16
23 reducing
to 0.7
0.3
Fe,
percent
1
1
0.7
AS,
ppm
0.3
0.3
0.3-0.1
Se,
ppm
trace
trace
50
Te,
ppm
trace
trace
80
Pb,
ppm
trace
trace
0.2-0.4
*Source: Doll, et al. 1977
-------
ry at Falconbridge, and age at diagnosis. The total number of
cases examined was 44.
The total number of workers over Palconbridge's history from
1927 until 1975 was available. Figure 10 shows the number of work-
ers over this time, those exposed and not exposed, both in perma-
nent and temporary positions, and the number and types of lung can-
cers by years of diagnosis. The gap of cases between 1950 and 1958
became the focus of the study. Employment records led to the sepa-
ration of the 44 cases into two series. Series I includes 18 cases
who started employment between 1927 and 1939 (members of a cohort
observed for 35 to 47 years, and almost complete mortality data)
with a mean age of 28.6 years at start of employment and a range of
19 to 38 years. Series II comprises 26 cases who started employ-
ment in 1946 (from a cohort observed for at most 30 years) with a
mean age at start of employment of 38.3 years and a range of 24 to
55 years.
Tumors were identified as Group I (epidermoid and small cell
anaplastic carcinoma) and Group II (adenocarcinomas and others).
Figure 11 shows the development time for the two tumor groups for
the cases in the two series. The sharp differences for the devel-
opmental time for the two series are striking. The relationshio of
the time of development, year of start of employment and year of
diagnosis is shown in Figure 12.
The age at diagnosis for Group I tumor cases in Series I and II
is shown in Table 29. This table also shows the data for a control
group of cases from the Norwegian general population. There is
remarkable agreement between Series I, II and the controls for mean
age at diagnosis.
C-121
-------
3000
2SOO
GROUP 1 TUMOURS:
EPtOERMOID CARCINOMA
SMALL CELL ANAPLASTIC CARCINOMA
_ GROUP II TUMOURS:
O 2000
O
ui
« 1500
u.
O
cc
UI
a
1000
500
I
D
/
J m
I "
r; \A
NA ₯;^\ -t*A--
1929 35 40
IBla
-------
SEHIES II
O
I
SERIES I
GliOUP I TUMOUI1S
() GROUP II TUMOURS
[] DEVELOPMENT TIME
LESS THAN ONE YEAH
B]
1
0
1
0
«M
1
6
1
6
**)
1
10
i
10
s.
1
15
1
16
« » v
UU)
1
20
1
20
.
1
26
?
1
26
1
30
A
4>
<
1
30
1
36
f
» (
1
36
1
40
)
1
40
DEVELOPMENT TIME IN YEARS
FIGURE 11
Development Time tor Lung Tumors in Series I and Series II workers in a Nickel Refinery
Source: Kreyberg, 1978
-------
40 YEARS
20 YEARS
a
a
/ °
o
?
X;';X;.V';Xv;v>;->>;X;XvXvX'XvX'
.33
.36
j
/
/ {
0 .74
a o 7,
> ooo
.70
la o an o _M
O .66
.64
k 0 .52
O .60
0 .5a c,
.56 /
55 «S^
aa K ^
.50 CT
.46 ^
46 ^^
44 ^
.42' ^
4° J*
.<<* EPtOERMOID CARCINOMA
0*
y O SMALL CELL ANAPLASTIC
J4 <$" CARCINOMA
» J?
.30 & O GROUP II TUMOURS
1927
j j YEARS OF RSDUCSD EXPOSURE
(1939-1946)
FIGURE 12
The scatter of occurrence of lung tumors related to time of
first employment (abscissa) and time of diagnosis of tumor (ordi-
nate)
Source: Kreyoerg, 1978
C-124
-------
TABLE 29
Age at Time of Diagnosis of Group I Tumors
of Workers Exposed to Nickel*
Series
I
II
Kreyoerg (1969)
No. of Cases
15
17
596
Mean
57.6
56.0
58.2
Age, Years
Minimum
40
44
31
Maximum
75
73
75+
*Source: Kreyberg, 1978
0125
-------
The Norwegian experience has shown an increase in the ratio of
Group I/II tumors since 1948-50. Group I tumors are associated
with cigarette smoking, and the proportionate increase of nroup I
cases is generally attributed to increase in cigarette smoking.
The smoking status of the cases is shown in Table 30.
The 32 Group I cases had only three possible nonsmokers, but
four of seven Group II cases were documented nonsmokers. The num-
ber of cases, seven, for Group II is small, but the nonsmoking/
smoking ratio of 4/3 in the counties from which the Falconbridge
workers are drawn is not unusual. The implication is strong that
tobacco carcinogens play a significant role in the development of
Group I cases, as well as the exposure to nickel. Most of the work-
ers started smoking years before being exposed to nickel; thus the
nickel exposure can be relegated, at least temporally, to a secon-
dary role.
The development time of cancer when defined as the interval
between the start of exposure to nickel and time of diagnosis has
been confusing and not useful as a variable, wowever, when devel-
opment time to tobacco use is used, the picture clarifies. In Nor-
way, the starting age for cigarette smokinq is between 13 and 18
years, and the mean age at diagnosis can be explained. The authors
conclude that the developmental time due to nickel alone is ob-
scured and is unknown at present. The presence of more than one
carcinogen makes it difficult if not impossible to determine devel-
opmental time. "The incidence may be increased when weak carcino-
gens are involved without the mean age at diagnosis beinq markedlv
altered" (Kreyberg, 1978).
C-126
-------
TABLE 30
Smoking and Tumor Incidence in Workers
at the Falconbridge Nickel Refinery3
Type of Tumor Smokers Nonsmokers
Series I
Epidermoid carcinoma
Small cell anaplastic carcinoma
Group II tumor
Series II
Epidermoid carcinoma
Small cell anaplastic carcinoma
Adenocarcinoma
10
2
0
13
4
3
3 (?)°
0
2
0
0
2
aSource: Kreyberg, 1978
Smoking history not ascertainable. Allocation as nonsmoxers
is the assumption against the hypothetical relationship.
C-127
-------
The medical department of the Falconbridge refinery monitors
exposed workers by obtaining urine and plasma nickel concentra-
tions, enforces safety precautions such as wearing respirators,
protective clothing, showering, and discourages smoking. In re-
spect to prevention of cancers of the nasal cavity, the workers at
risk are asked to rinse out their noses with the aid of a syringe
and are examined periodically for pathology of the nose and si-
nuses.
Torjussen and Solberg (1976) report on a study of 92 randomly
selected workers from Falconbridqe exposed to nickel compounds and
37 nonexposed workers as control. Biopsies of mucosa from the mid-
dle turbinate were examined for precancerous lesions. All workers
were without known nasal disease. All biopsy samples showed in-
flammatory changes, with more in the exposed than nonexposed group.
The exposed group showed 17 percent atypical epithelial changes,
while no such changes were found in the control group. These
changes were not related to age and smoking habits. These lesions
were considered precancerous.
The cancer risk status in workers exposed to nickel in work-
places other than nickel refineries is not established at this
time. Since the nickel compounds associated with the refining pro-
cesses may also occur in other industries, investigations clearly
should be conducted.
Bernacki, et al. (1978) reports on a pilot study of exposure
to nickel and lung cancer mortality in an aircraft engine factory.
The investigators did not find an increased relative risk for work-
ers exposed to nickel compounds. The atmospheric concentrations
0-128
-------
were low, below 1 mg Ni/m , the Occupational Safety and Health
Administration threshold limit value, and the nickel compounds were
not identified.
While nickel is found in asbestos fibers in varying amounts,
the etiological role of nickel as a co-carcinogen in the presence
of asbestos has not prompted any epidemiological studies of this
association.
r-129
-------
CRITERION FORMULATION
Existing Guidelines and Standards
The threshold limit values (TLV) for a work day exoosure has
been set at 1 ppb (ACGIH, 1978).
Current Levels of Exposure
The route by which most people in the general population re-
ceive the largest portion of daily nickel intake is through food.
Based on the available data from composite diet analysis, between
300 to 600 yg nickel Per day are ingested. Fecal nickel analysis, a
more accurate measure of dietary nickel intake, suggests about 300
yg/day. The highest level of nickel observed in water was 75 ug/1.
Average drinking water levels are about 5 ug/1. A tvpical consump-
tion of 2 liters daily would yield an additional 10 yg of nickel, of
which up to 1 yg would be absorbed.
Special Groups at Risk
Occupational groups such as nickel workers and other workers
handling nickel comprise the individuals at the hicfhest risk.
Women, particularly housewives, are at special risk to nickel-
induced skin disorders because of greater than average contact with
nickel-containing materials. Approximately 47 million individu-
als, comprising the smoking population of the United States, are
potentially at risk for possible co-factor effects of nickel in
adverse effects on the respiratory tract.
Basis for Derivation of Criterion
In arriving at a criterion for nickel, several factors must be
taken into account. There is little evidence for accumulation of
nickel in various tissues. Absorption through the Gastrointestinal
C-130
-------
tract is low. Acute exposure of man to nickel is chiefly of concern
in workplaces. In these situations, inhalation is the main route
of entry and the lung is the critical organ.
The major problem posed by nickel for the U.S. population at
large is nickel hypersensitivity, mainly via contact with many
nickel-containing commodities. Nickel could play a role in alter-
ing defense mechanisms against xenobiotic agents in the respiratory
tract, leading to enhanced risk for respiratory tract infections.
Nickel compounds have been shown to be carcinogenic in humans
and experimental animals. There is no evidence for carcinogenicity
due to the presence of nickel in water. The role of nickel as an
essential element is a confounding factor in any risk estimate.
In order to develop a risk assessment based on toxicological
effects other than carcinogenicity, dose-response data would be
most helpful. However, while the frequency or extent of various
effects of nickel are related to the level or frequency of nickal
exposure in man, the relevant data do not permit any quantitative
estimation for dose-response relationships. The lowest levels of
nickel associated with adverse health effects, therefore, must be
used in establishing a criterion level for nickel in drinkinq
water.
To arrive at a risk estimate for nickel, a modification of the
approach used for nonstochastic effects has been adopted (44 FR
15980).
The studies cited in this document have not demonstrated a no-
cbservable-effeet level (NOEL). Therefore, the study demonstrating
the lowest-observable-adverse-effect level (LOASL) for nickel in
013;
-------
drinking water has been used to arrive at a nonstochastic risk
estimate.
In the study of Schroeder and Mitchner (1971), adverse effects
in rats were demonstrated at a level of 5 mg/1 {5 ppm) in drinking
water. Three generations of rats were continuously exposed to 5
mg/1 (5 ppm) of nickel in drinking water. In each of the genera-
tions, increased numbers of runts and enhanced neonatal mortality
were seen. A significant reduction in litter size and a reduced
proportion of males in the third generation also were observed.
To adapt the LOAEL into an Acceptable Daily Intake (ADI) for
man, the LOAEL is divided by an uncertainty factor of 100, as de-
tailed in a recent National Academy of Science report (NAS, 1977)
and adopted by the U.S. Environmental Protection Agency [44(52) FR
15930j. The choice of this factor is based on scanty long-term or
acute human data, and valid results of long-term feeding studies on
experimental animals, and an absence of evidence for carcinogeni-
city. Furthermore, an additional safety factor of 10 is required
because of the use of the LOAEL according to present methodology.
Using data from Schroeder and Mitchner (1971) , a water quality
criterion can be derived based on the exposure of the rats to nick-
el in both the drinking water (5.0 mg/1) and diet (310 ;jg/kg diet).
Assuming an average body weight of 0.3 kg/rat and an average daily
water consumption of 0.025 liters, the daily dose from water can be
estimated at 0.417 mg/kg (5 mg/1 x 0.025 liters/0.3 kg). Assuming
an .average daily food consumption of 0.025 kg,- the daily dose from
food can be estimated at 0.026 mg/kg (310 jag/kg diet x 0.025
ka 7 0.3 kg;. Thus, the total daily dose can be estimated at 0.443
-------
mg/kg. rising a safety factor of 1000 (100 x 10) , the ADI for a 70
kg man is 0.031 mg (0.443 mg/kg x 70 kg V 1000). The water quality
criterion can be calculated from the following formula:
2 (X) 4- (F x B x X) = ADI
where
X - the ambient water quality criterion in mg Ni/1
F = average amount of fish/shellfish products consumed
assume 0.0065 kg/day '
B = weighted average bioconcentration factor = 47
Solving for X, the criterion is 0.0134 mg/1 (or'13.4 yg/1).
Drinking water contributes 37 percent of the assumed exposure
while eating contaminated fish products accounts for 13 ccrcent.
The criterion level for nickel can alternatively be expressed as
0.101 mg/1, if exposure is assumed to be from the consumption of
fish and shellfish products alone:
X x 0.0065 x 47 = 0.031 mg
X = 0.101 mg/1 (or -^ 100 yg/1) .
C-L33
-------
REFERENCES
Ader, D. and M. Stoeppler. 1977. Radiochemical and methodological
studies on the recovery and analysis of nickel in urine. Jour.
Anal. Toxicol. 1: 252.
Ambrose, A.M., et al. 1976. Long term toxicologic assessment of
nickel in rats and dogs. Jour. Food Sci. Technol. 13: 181.
American Conference of Governmental Industrial Hygienists. 1978.
Threshold limit values for chemical substances and physical agents
in the workroom environment with intended changes for 1978.
Anderson, I., et al. 1978. Analysis for nickel in plasma and urine
by electrothermal atomic absorption soectrometry, with sample ore-
paration by protein precipitation. Clin. Chem. 24: 1198.
Anke, M., et al. 1974. Low Nickel Rations for Growth and Reoroduc-
tion in Pigs. In; W.G. Hoekstra, et al. (e^s.), Trace Element
Metabolism in Animals - 2. University Park Press, Baltimore, Mary-
land, p. 715.
Armit, H.W. 1908. The toxicology of nickel carbonyl. Part II.
Jour. Hygiene. 8: 565.
Ashrof, M. and H.D. Sybers. 1974. Lysis of oancreatic exocrine
cells and other lesions in rats fed nickel .acetate. Am. Jour.
Pathol. 74: 102a.
C-134
-------
Azary, A. 1979. Contribution to the toxico.loqv of the nitrates of
nickel and cobalt. Orv. Hetil. 33: 729.
Barnes, J.M. and F.A. Denz. 1951. The effects of 2,3-dimercaoto-
propanol (BAD on experimental nickel carbonyl poisoning. Br.
Jour. Ind. Med. 8: 117.
Basrur, P.K. and J.P.w. Oilman. 1967. Morphologic and synthetic
response of normal and tumor muscle cultures to nickel sulfide.
Cancer Res. 27: 1168.
Basrur, P.K. and S.H.H. Swierenga. 1970. Enzyme changes in muscle
cells during tumor induction with nickel sulfide. Jour. Cell Biol.
47: 14a.
Basrur, P.K., et al. 1970. Changes in mitochondrial ultrastruc-
ture in nickel sulfide-induced rhabdomyosarcoma. Cancer.
25: 1142.
Beach, D.J. and P.W. Sunderman, Jr. 1969. Nickel carbonyl inhibi-
14
tion of C-orotic acid incorpor;
Soc. Exptl. Biol. Med. 131: 321.
14
tion of C-orotic acid incorporation into rat liver RNA. Proc.
Beach, D.J. and F.W. Sunderman, Jr. 1970. Nickel carbonyl inhibi-
tion of RNA synthesis by a chromatin-RNA polymerase comolex from
hepatic nuclei. Cancer Res. 30: 48.
C-135
-------
Bernacki, E.J., et al. 1978. Urine nickel concentrations in
nickel-exposed workers. Ann. Clin. Lab. Sci. 8: 134.
Bernstein, O.M., et al. 1974. Uptake and Distribution of Airborne
Trace Metals in Man. In: D.D. Hemphill (ed.), Trace Substances in
Environmental Health - VIII. University of Missouri, Columbia,
Missouri, p. 329.
Bertrand, G. and M. Macheboeuf. 1926. Influence du nickel et du
cobalt sur 1'action exercee par 1'insuline chez le lapin. Comp.
Rend. Acad. Sci. 182: 1504. (Fre.)
Bingham, E., et al. 1972. Responses of alveolar raarcrophages to
metals. I. Inhalation of lead and nickel. Arch. Environ. Health.
25: 406.
Brandes, r"J.W. 1934. Nickel carbonyl poisoning. Jour. Am. Meet.
Assoc. 102: 1204.
Brun, R. 1975. Epidemiology of contact dermatitis in Geneva
(1,000 cases). Dermatol. 150: 193. (Fre.)
Bruni, C. and J.N. Rust. 1975. Fine structure of dividing cells
and of nondividing differentiating cells of nickel sulfide-induced
rhabdomyosarcomas. Jour. Natl. Cancer Ins. 54: 6S7.
C-136
-------
Burckhardt, w. 1935. Beitrage zur Ekzemfrage. III. Mitteilung.
Die Rolle der Alkalishadigung der Haut bei der experimentellen.
Sensibilisierung gegen Nickel. Archiv. Dermatol. Syphilis.
173: 262. (Ger.)
Calnan, C.D. 1956. Nickel dermatitis. Br. Jour, nermatol.
68: 229.
Carmichael, J.L. 1953. Nickel carbonyl poisoning. Report of a
case. Arch. Ind. Hyg. Occup. Med. 8: 143.
Caron, G.A. 1964. Nickel sensitivity and atony. Br. Jour. Derma-
tol. 76: 385.
Chattopadhyay, A. and R.E. Jervis. 1974. Hair as an Indicator of
Multielement Exposure of Population Groups. In: o.D. Hemphill
(ed.), Trace Substances in Environmental Health - vin. Ilniversitv
of Missouri, Columbia, Missouri, p. 31.
Chausmer, A.B. 1976. Measurement of exchangeable nickel in the
rat. Nutr. Repts. Int. 14: 323.
Christensen, O.B. and H. Moller. 1975a. Nickel allergy and
eczema. Contact Dermatitis. 1: 129.
C-137
-------
Christensen, O.B. and H. Moller. 1975b. External and internal
exposure to the antigen in the hand eczema of nickel allerqy. Con-
tact Dermatitis. 1: 136.
Clary, J.J. 1975. Nickel chloride-induced metabolic chanqes in
the rat and guinea pig. Toxicol. Appl. Pharmacol. 31: 55.
Clary, J.J. and I. Viganti. 1973. Nickel chloride-induced changes
in glucose metabolism in the rat. Toxicol. Apol. Pharmacol.
25: 467. (Abst. 75)
Clausen, I. and S.C. Rastogi. 1977. Heavy metal pollution among
auto workers. II. Cadmium, chromium, cooper, manganese, and nick-
el. Br. Jour. Ind. Med. 34: 216.
Costa, M., et al. 1978. Morphologic transformation of Svrian ham-
ster fetal cells induced by nickel compounds, ^ed. Proc. 37: 231.
(Abst. 102)
Cralley, L.J. 1971. Electromotive phenomemon in metal and mineral
particulate exposures: Relevance to exposure to asbestos and occur-
rence of cancer. Am. Ind. Hyg. Assoc. Jour. 32: 653.
Creason, J.P., et al. 1975. Trace elements in hair, as related to
exposure in metropolitan New York. Clin. Chem. 21: 603.
C-138
-------
Creason, J.P., et al. 1976. Maternal-fetal Tissue Levels of 16
Trace Elements in 8 Selected Continental United States Communities.
Ir\: D.D. Hemphill (ed.), Trace Substances in Environmental Health -
X. University of Missouri, Columbia, Missouri, p. 53.
D'Alonzo, C.A. and S. Pell. 1963. A study of trace metals in myo-
cardial infarction. Arch. Environ. Health. 6: 381.
Damjanov, I., et al. 1978. Induction of testicular sarcomas in
Fischer rats by intratesticular injection of nickel subsulfide.
Cancer Res. 38: 268.
Daniel, M., et al. 1974. The effect of metal serum complexes on
differentiating muscle in vitro. Br. Jour. EXP. Pathol. 55: 237.
Deutman, R., et al. 1977. Metal sensitivity before and after
total hip arthroplasty. Jour. Bone Joint Surg. 59A: 862.
de Jongh, G.J., et al. 1978. Factors influencing nickel dermati-
tis - I. Contact Dermatitis. 4: 142.
Devereaux, T.R. and J.R. Fouts. 1974. N-oxidation and demethyla-
tion of N,N-dimethylaniline by rabbit liver and luna microso^es.
Effects of age and metals. Chem. Biol. Interaction. 8: 91.
Dixon, J.R., et al. 1970. The role of trace metals in chemical
carcinogenesis: asbestos cancers. Cancer Res. 30: 1068.
C-139
-------
Doll, R., et al. 1977. Cancers of the lung and nasal sinuses in
nickel workers: A reassessment of the period of risk. Br. Jour.
Ind. Med. 34: 102.
Dormer, R.L. and S.J.H. Ashcro^t. 1974. Studies on the role of
calcium ions in the stimulation by adrenaline of amylase release
from rat parotid. Biochem. Jour. 144: 543.
Dormer, R.L., et al. 1973. The effect of nickel on secretory sys-
tems. Studies on the release of amylase, insulin and growth hor-
mone. Biochem. Jour. 140: 135.
nurfor, C.N. and E. Becker. 1964. Public water supplies of the 100
largest cities in the United States, 1962. U.S. Geological Survey
Water Supply Paper No. 1812, U.S. Government Printing Office, Wash-
ington, D.C.
Eads, E.A. and C.E. Lambdin. 1973. A survey of trace metals in
human hair. Environ. Res. 6: 247.
Epstein, S. 1956. Contact dermatitis due to nickel and chromate.
Arch. Dermatol. 73: 236.
Faoro, R.B. and T.B. McMullen. 1977. National trends in trace
metals in ambient air 1965-1974. EPA-450/1-77-003, U.S. Environ.
Prot. Agency, Research Triangle Park, North Carolina.
C-140
-------
Federchenko, O.Y. and L.J. Petru. 1969. Effect of Ni2+ ions on the
dephosphorylation of ATP and formation of amino acylphosohates by
enzymes of rat liver microsomes in the presence of amino acids.
Ukr. Biokhim. Zh. 41: 680.
Perm, V.H. 1972. The Teratogenic Effects of Metals on Mammalian
Embryos. ln: D.H.M. Wollam (ed.), Advances in Teratology. Academ-
ic Press, New York. 5: 51.
Fishbein, W.N., et al. 1976. The first natural nickel metallo-
enzyme: Urease. Fed. Proc. 35: 1680. (Abst.)
Fisher, A.A. 1977. Allergic dermatitis Presumably due to metall
foreign bodies containing nickel or cobalt. Curtis. 19: 285.
1C
Forman, L. and S. Alexander. 1972. Nickel antibodies. Br. Jour.
Dermatol. 87: 320.
Freeman, B.M. and D.R. Langslow. 1973. Responses of plasma glu-
cose, free fatty acids and glucagon to cobalt and nickel chlorides
by gallus domesticus. Comp. Biochem. Physiol. 46A: 427.
Fregert, S. , et al. 1969. Epidemiology of contact dermatitis.
Trans. St. John's Hosp. nerm. Soc. 55: 71.
Friedman, I. and E.S. Bird. 1969. Electron-microscope investiaa-
tion of experimental rhabdomyosarcoma. Jour. Pathol. 97: 375.
C-141
-------
Purr, A.K., et al. 1976. Multi-element absorption by croos grown
on Ithaca sludge-amended soil. Bull. Environ. Contain. Toxicol.
16: 756.
Furst, A. and M.C. Schlauder. 1971. The hamster as a model for
metal carcinogenesis. Proc. West. Pharmacol. Soc. 14: 68.
Furst, A., et al. 1973. Rapid induction of oleural mesotheliomas
in the rat. Proc. West. Pharmacol. Soc. 16: 150.
Geissinger, H.D., et al. 1973. Fast scanning electron microscopic
and light microscopic correlation of oaraffin sections and chromo-
some spreads of nickel-induced tumor. Trans. Am. Micros. Soc.
92: 209.
Ghiringelli, L. and M. Agamennone. 1957. II metabolismo del nick-
el in animali sperimentalmente avvelenati con nickel carbonile.
Med. Lav. 48: 187. (Ttal.)
Gilman, J.P.W. 1962. Metal carcinogenesis. II. A study on the
carcinogenic activity of cobalt, cooper, iron and nickel compounds.
Cancer Res. 22: 158.
Gimenez-Camarasa, J.M., et al. 1975. Lymphocyte transformation
test in allergic contact nickel dermatitis. Br. Jour. Dermatol.
92: 9.
C-142
-------
Gitlitz, P.H., et al. 1975. Aminoaciduria and orote.inuria in rats
after a single intraperitoneal injection of Ni(II). Toxicol. Appl.
Pharmacol. 35: 430.
Graham, J.A., et al. 1975. Effect of trace metals on ohaqocytosis
by alveolar macrophages. Infection Immunity. 11: 1278.
Graham, J.A., et al. 1978. Influence of cadmium, nickel, and
chromium on primary immunity in mice. Environ. Res. 16: 77.
Hackett, R.L. and P.W. Sunderman, Jr. 1967. Acute pathological
reactions to administration of nickel carbonyl. Arch. Environ.
Health. 14: 604.
Hackett, R.L. and F.w. Sunderman, Jr. 1969. Nickel carbonyl.
Effects upon the ultrastructure of heoatic oarenchymal cells.
Arch. Environ. Health. 19: 337.
Hadley, J.G., et al. 1977. Inhibition of antibody-mediated ro-
sette formation by alveolar macrophages: A sensitive assay for
metal toxicity. Jour. Reticuloendothelial Soc. 22: 417.
Haro, R.T., et al. 1968. Studies on the acute toxicity of nickel-
ocene. Proc. West. Pharmacol. Soc. 11: 39.
C-143
-------
Harvey, T.C., et al. 1975. Measurement of liver-cadmium concen-
trations in patients and industrial workers by neutron-activation
analysis. Lancet. 1: 1269.
Haxthausen, H. 1936. Verwandtschaftsreaktonen bei Nickel- und
Kobalt-Allergie der Haut. Archiv. nermatol. Syohilis. 174: 17.
(Ger.)
Heath, J.C. and M.R. naniel. 1964. The oroduction of malignant
tumors by nickel in the rat. Br. Jour. Cancer. 18: 261.
Heath, J.C. and M. Webb. 1967. Content and intracellular distri-
bution of the inducing metal in the primary rhabdomyosarcomata in-
duced in the rat by cobalt, nickel and cadmium. Br. Jour. Cancer.
21: 768.
Hendel, R.C. and F.W. Sunderman, Jr. 1972. Soecies variation in
the proportions of ultra-filtrable and protein-bound serum nickel.
Res. Comm. Chem. Pathol. Pharmacol. 4: 141.
Ho, W. and A. Furst. 1973. Nickel excretion by rats following a
single treatment. Proc. west. Pharmacol. Soc. 16: 245.
Hoey, M.J. 1966. The effects of metallic salts on the histology
and functioning of the rat testes. Jour. Reprod. Fertil. 12: 461.
C-144
-------
Htfgetveit, A.C. and R.T. Barton. 1976. Preventive health program
for nickel workers. Jour. Occup. Med. 18: 805.
H^getveit, A.C. and R.T. Barton. 1977. Monitoring Nickel Exposure
in Refinery Workers. in: S.S. Brown (ed.), Clinical Chemistry and
Chemical Toxicology of Metals. Elsevier Publishing Co., Amsterdam.
p. 265.
Hohnadel, D.C., et al. 1973. Atomic absorption spectrometry of
nickel, copper, zinc, and lead in sweat collected from health sub-
jects during sauna bathing. Clin. Chem. 19: 1288.
Hopfer, S.M. and F.W. Sunderman, Jr. 1978. Manganese inhibition
of nickel subsulfide induction of erythrocytosis in rats. Res.
Comm. Chem. Pathol. Pharmacol. 19: 337.
Horak, E. and P.w. Sunderman, Jr. 1973. Fecal nickel excretion bv
healthy adults. Clin. Chem. 19: 429.
Horak, E. and F.W. Sunderman, Jr. 1975a. Effects of Ni(ll), other
divalent metal ions, and glucagon upon plasma glucose concentra-
tions in normal, adrenalectomized and hvpophysectomized rats. Tox-
icol. Appl. Pharmacol. 32: 316.
Horak, E. and F.W. Sunderman, Jr. 1975b. Effects of Ni(ll) upon
plasma glucagon and glucose in rats. Toxicol. Appl. Pharmacol.
33: 388.
C-145
-------
Hueper, W.C. 1955. Experimental studies in metal canceriqenesis.
IV. Cancer produced by parenterally introduced metallic nickel.
Jour. Natl. Cancer Inst. 16: 55.
Hueper, W.C. 1958. Experimental studies in metal cancerigenesis.
Arch. Pathol. 65: 600.
Hutchinson, P., et al. 1972. The specificity of lymphocyte trans-
formation in vitro by nickel salts in nickel sensitive subjects.
Jour. Invest. Derm. 58: 362.
Hutchinson, F., et al. 1975. Nickel hypersensitivitv. Nickel
binding to amino acids and lymphocytes. Br. Jour. Derm. 93: 557.
Indraprasit, S., et al. 1974. Tissue composition of maior and
trace elements in uremia and hypertension. Jour. Chron. Dis.
27: 135.
International Agency for Research on Cancer. 1976. Nickel and
Nickel Compounds. In; Evaluation of Carcinogenic Risk of Chemicals
to Man (International Agency for Research on Cancer Monographs, 11)
IARC, Lyon, France, p. 111.
International Radiological Protection Commission. 1966. Task
Group on Lung Dynamics for Committee II. Deposition and retention
models for internal dosimetrv of the human resoiratory tract.
Health Physics. 12: 173.
C-146
-------
Jacobsen, N. 1977. Epithelial-like cells in culture derived from
human gingiva: Response to nickel. Scand. Jour. Dent. Res.
85: 567.
Jansen, L.H., et al. 1964. Contact sensitivity to simple chemi-
cals: The role of intermediates in the process of sensitization.
Naturwiss. 51: 387.
Jasmin, G. and J.L. Riopelle. 1976. Renal carcinomas and ervthro-
cytosis in rats following intrarenal injection of nickel subsul-
fide. Lab. Invest. 35: 71.
Jasmin, G. and B. Solymoss. 1977. The topical effects of nickel
subsulfide on renal parenchyma. Adv. Exp. Med. Biol. 91: 69.
John, M.K. and C.J. Van Laerhoven. 1976. Effects of sewage sludge
composition, application rate, and lime regime on plant availabil-
ity of heavy metals. Jour. Environ. Oual. 5: 246.
/
Joo, F. 1968. Effect of inhibition of adenosine triphosohate
activity on the fine structural organization of the brain caoil-
laries. Nature. 219: 1378.
/
Joo, F. 1969. Changes in the molecular organization of the base-
ment membrane after inhibition of adenosine triphosphate activity
in the rat brain capillaries. Cytobiosis. 1: 289.
C-147
-------
Juhlin, L., et al. 1969. Immunoqlobulin E. in dermatoses. Arch.
Dermatol. 100: 12.
Kaaber, K., et al. 1978. Low nickel diet in the treatment of pa-
tients with chronic nickel dermatitis. Br. Jour. Derm., 98: 197.
Kadota, I. and M. Kurita. 1955. Hyperglycemia and islet cell dam-
age caused by nickelous chloride. Metabolism. 4: 337,
Kasprzak, K.S. and F.W. Sunderman, Jr. 1969. The metabolism of
nickel carbonyl C. Toxicol. Appl. Pharmacol. 15: 295.
Kasprzak, K.S. and F.W. Sunderman, Jr. 1977. Mechanisms of dis-
solution of nickel subsulfide in rat serum. Res. Comm. Chem.
Pathol. Pharmacol. 16: 95.
Kasprzak, K.S., et al. 1973. Pathological reactions in rat lungs
following intratracheal injection of nickel subsulfide and 3,4-
benzpyrene. Res. Comm. Chem. Pathol. Pharmacol. 6: 237.
Kincaid, J.F., et al. 1953. Nickel poisoning. I. Experimental
study of the effects of acute and subacute exposure to nickel car-
bonyl. Arch. Ind. Hyg. Occup. Med. 8: 48.
Kolpakov, F.I. 1963. Permeability of skin to nickel compounds.
Arkh. Patol. 25: 38. (Russian with English summary)
C-148
-------
Kreyberg, L. 1978. Lung cancer in workers in a nickel refinery.
Br. Jour. Ind. Med. 35: 109.
Kucharin, G.M. 1970. Occupational disorders of the nose and nasal
sinuses in workers in an electrolytic nickel refining plant. Gig.
Tr. Prof. Zabol. 14: 38. (Rus.)
LaBella, F., et al. 1973a. Prolactin secretion is specifically
inhibited by nickel. Nature. 245: 32
LaBella, F., et al. 1973b. Pituitary hormone releasing or inhib-
iting activity of metal ions present in hypothalmic extracts. Bio-
chem. Biophys. Res. Comm. 52: 786.
Lagerwerff, J.V. and A.W. Specht. 1970. Contamination of roadside
soil and vegetation with cadmium, nickel, lead and zinc. Environ.
Sci. Technol. 4: 583.
Lau, T.J., et al. 1972. The carcinogenicitv of intravenous nickel
carbonyl in rats. Cancer Res. 32: 2253.
Lehnert, G., et al. 1970. Zur Problem der medikamentosen Proohvl-
axe beruflicher Schwermetallintoxikationen mit D-Penicillamin.
Med. Welt. 21: 346. (Ger.)
C-149
-------
Leslie, A.C.D., et al. 1976. Prediction of Health Effect of Pol-
lution Aerosols. In; D.D. Hemohill (ed.), Trace Substances in
Environmental Health - X. University of Missouri, Columbia, Mis-
souri, p. 497.
Lestrovoi, A.P., et al. 1974. Effect of nickel on the iodine fixa-
tion of the thyroid gland when administered oerorally and by inha-
lation. Gig. Sanit. 10: 105.
Louria, D.B., et al. 1972. The human toxictty of certain trace
elements. Ann. Int. Med. 76: 307.
Lu, C.C., et al. 1976. Placental transfer of NiCl2 to fetuses in
mice. Teratology. 14: 245. (Abst.)
Maenza, R.M., et al. 1971. Rapid induction of sarcomas in rats by
combination of nickel sulfide and 3,4-benzyoyrene. Cancer Res.
31: 2067.
Maines, M.D. and A. Kappas. 1976. Studies on the mechanism of
induction of heme oxygenase by cobalt and other metal ions. Bio-
chem. Jour. 154: 125.
Maines, M.D. and A. Kapoas. 1977. Enzymes of heme metabolism in
the kidney. Regulation by trace metals which do not form heme com-
olexes. Jour. Exotl. Med. 146: 1286.
C-150
-------
Malten, K.E. and 0. Spruit. 1969. The relative importance of var-
ious environmental exposures to nickel in causing contact hypersen-
sitivity. Acta Oermatovenereologica. 49: 14.
Marcussen, P.V. 1957. Spread of nickel dermatitis. Dermato-
logica. 115: 596.
Mathur, A.K., et al. 1977a. Effect of nickel sulohate on male
rats. Bull. Environ. Contam. Toxicol. 17: 241.
Mathur, A.K., et al. 1977b. Biochemical and morohological changes
in some organs of rats in nickel intoxication. Arch. Toxicol.
37: 159.
McConnell, L.H., et al. 1973. Asthma caused by nickel sensitiv-
ity. Ann. Int. Med. 78: 888.
McNeely, M.D., et al. 1971. Abnormal concentrations of nickel in
serum in cases of myocardial infarction, stroke, burns, hepatic
cirrhosis, and uremia. Clin. Chem. 17: 1123.
McNeely, M.C., et al. 1972. Measurements of nickel in serum and
urine as indices of environmental exoosure to nickel, Clin. Chem.
18: 992.
, T. and A. Thorboe. 1976. Nickel dermatitis - nickel excre-
tion. Contact Dermatitis. 2: 353.
C-151
-------
Mertz, W. 1970. Some aspects of nutritional trace element re-
search. Fed. Proc. 29: 1482.
Mik^c-Devic, D., et al. 1977. Furildioxime method for nickel
analysis in serum and urine by electrothermal atomic absorption
spectrometry. Clin. Chem. 23: 948.
Mikheyev, M.I. 1971. Distribution and excretion of nickel car-
bonyl. Gig. Tr. Prof. Zabol. 15: 35.
Millikan, L.E., et al. 1973. In vitro studies of contact hyper-
sensitivity: Lymphocyte transformation in nickel sensitivity.
Jour. Invest. Dermatol. 60: 88.
Mitchell, D.F., et al. 1960. Determining the tumorigenicitv of
dental materials. Jour. Dent. Res. 39: 1023.
Miyaki, M., et al. 1977. Effect of metal cations on misincorpora-
tion. Biochem. Biophys. Res. Comm. 77: 854.
Moffitt, A.E., Jr., et al. 1972. The effect of benzpyrene, Pheno-
barbital, and carbon tetrachloride on subcellular metal distribu-
tion and microsomal enzyme activity. Cancer Res. 32: 1149.
Mond, L. , et al. 1890. Action of carbon monoxide on nickel. Jour.
Chem. Soc. 57: 749.
C-152
-------
Morgan, A., et al. 1973. Some observations of the distribution of
trace metals in chrysotile asbestos. Ann. Occup. Hyg. 16: 231.
Morse, E.E., et al. 1977. Dose-response and time-response study
of erythrocytosis in rats after internal injection of nickel sub-
sulfide. Ann. Clin. Lab. Sci. 7: 17.
Murthy, G.D., et al. 1973. Levels of copper, nickel, rubidium,
and strontium in institutional total diets. Environ. Sci. Technol.
7: 1042.
Mustafa, M.G., et al. 1971. Effects of divalent metal ions on
alveolar macrophage membrane adenosine triphosphatase activity.
Jour. Lab. Clin. Med. 77: 563.
Myron, D.R., et al. 1978. Intake of nickel and vanadium bv humans.
A survey of selected diets. Am. Jour. Clin. Nutr. 31: 527.
National Academy of Sciences. 1975. Nickel. National Academy of
Sciences Committee of Medical and Biological Effects of Environ-
mental Pollutants, Washington, D.C.
National Academy of Sciences. 1977. Drinking Water and Health.
Washington, D.C. P. 803.
C-153
-------
National Institute for Occupational Safety and Health. 1977. Cri-
teria for a Recommended Standard: Occupational Exposure to Inorgan-
ic Nickel. Publication No. 77-164. DREW (NIOSH) U.S. Government
Printing Office, Washington, D.C.
Natusch, D.F.S., et al. 1974. Toxic trace elements: Preferential
concentration in respirable particles. Science. 183: 202.
Nechay, M.W. and F.W. Sunderman, Jr. 1973. Measurements of nickel
in hair by atomic absorption spectrometry. Ann. Clin. Lab. Sci.
3: 30.
Nielson, F.H. 1976. Newer trace elements and possible application
in man. Trace Elem. Human Health Disease. 2: 379.
Nielsen, F.H. and D.J. Higgs. 1971. Further Studies Involving a
Nickel Deficiency in Chicks. In; D.D. Hemphill (ed.), Trace Sub-
stances in Environmental Health - IV. University of Missouri,
Columbia, Missouri, p. 241.
Nielsen, F.H. and D.A. Ollerich. 1974. Nickel: A new essential
trace element. Fed. Proc. 33: 1767.
Nielsen, F.H. and H.H. Sandstead. 1974. Are nickel, vanadium,
silicon, fluorine, and tin essential for man? A review. Am. Jour.
Clin. Nutr. 27: 515.
C-154
-------
Nielsen, F.H., et al. 1975. Nickel deficiency in rats. Jour.
Nutr. 105(12): 1620.
Nilzen, A. and K. Wilstrom. 1955. The influence of lauryl sul-
phate on the sensitization of guinea pigs to chrome and nickel.
Acta Dermatovnereologica. 35: 292.
Nodiya, P.I. 1972. Cobalt and nickel balance in students of an
occupational technical school. Gig. Sanit. 37: 108.
Nomoto, S. 1971. Evaluation of normal values of serum nickel
among Japanese - isolation of nickel-binding protein. Jap. Jour.
Clin. Path. 19: 200. (Jap.)
Nomoto, S. and F.W. Sunderman, Jr. 1970. Atomic absorption spec-
trometry of nickel in serum, urine, and other biological materials.
Clin. Chem. 16: 477.
Nordberg, G.F. (ed.) 1976. Effects and Dose-response Relation-
ships of Heavy Metals. Elsevier Publishing Co., Amsterdam.
North American Contact Dermatitis Group. 1973. Epidemiology of
contact dermatitis in North America: 1972. Arch. Dermatol.
108: 537.
O'Dell, G.D., et al. 1971. Effect of dietary nickel level on ex-
cretion and nickel content of tissues in male calves. Jour. Anim.
Sci. 32: 767.
C-155
-------
Onkelinx, C. 1977. Whole-body Kinetics of Metal Salts in Rats.
In; S.S. Brown (ed.), Clinical Chemistry and Chemical Toxicology of
Metals. Elsevier Publishing Co., Amsterdam, p. 37.
Onkelinx, C., et al. 1973. Comoartmental analysis of the metabo-
lism of Ni(II) in rats and rabbits. Res. Comm. Chem. Pathol.
Pharmacol. 6: 663.
O'Sullivan, W.J. and J.F. Morrison. 1963. The effect of trace
metal contaminants and EDTA on the velocity of enzyme-catalyzed
reactions. Studies on ATP: creatine phosphotransferase. Biochim.
Biophys. Acta. 77: 142.
Ottolenghi, A.D., et al. 1974. Inhalation studies of nickel sul-
fide in pulmonary carcinogenesis of rats. Jour. Natl. Cancer Inst.
54: 1165.
Palo, J. and H. Savolainen. 1973. Biochemical diaanosis of
aspartylglycosaminuria. Ann. Clin. Res. 5: 156.
Parker, D. and J.L. Turk. 1978. Delay in the development of 'the
allergic response to metals following intratracheal instillation.
Int. Arch. Allergy Appl. Immunol. 57: 289.
Parker, K. and F.W. Sunderman, Jr. 1974. Distribution of Mi in
rabbit tissues following intravenous iniection on "NiCl-. Res.
Commun. Chem. Pathol. Pharmacol. 7: 755.
C-156
-------
Payne, w.w. 1964. Carcinogenicitv of nickel compounds in experi-
mental animals. Proc. Am. Assoc. Cancer Res. 5: 50. (Abst. 197)
Pedersen, E., et al. 1973. Cancer of resoiratory organs among
workers at nickel refinery in Norway. Int. Jour. Cancer. 12: 32.
Pekarek, R.S. and E.G. Hauer. 1972. Direct determination of serum
chromium and nickel by an atomic absorption spectrophotometer with
a heated graphite furnace. Fed. Proc. 31: 700. (Abst. 2730)
Perry, H.M., Jr. and E.P. Perry. 1959. Normal concentrations of
some trace metals in human urine: Changes oroduced by ethylenedia-
metetracetate. Jour. Clin. Invest. 38: 1452.
Phatak, S.S. and V.N. Patwardhan. 1950. Toxicitv of nickel.
Jour. Sci. Ind. Res. 9B: 70.
Phatak, S.S. and V.N. Patwardhan. 1952. Toxicitv of nickel - Ac-
cumulation of nickel in rats fed on nickel-containing diets and its
elimination. Jour. Sci. Ind. Res. 11B: 173.
Port, C.D., et al. 1975. Interaction of nickel oxide and influ-
enza infection in the hamster. Environ. Health Persoect. 10: 268.
(Abst.)
C-157
-------
Prakash, N.J., et al. 1973. Effect of transitional metal ions on
(Na + K ) ATPase activity and the uptake of norepinephrine and
choline by brain synaptosomes. Life Sci. 12: 249.
Raff, E.G. and J.J. Blum. 1969. Some properties of a model assay
for ciliary contractility. Jour. Cell Biol. 42: 331.
Ragaini, R.C., et al. 1977. Environmental trace metal contami-
nation in Kellogg, Idaho, near a lead smelting complex. Environ.
Sci. Technol. 11: 773.
Reno, H.T. 1974. Nickel. In; Minerals Yearbook 1972. Metals,
Minerals and Fuels. U.S. Government Printing Office, Washington,
D.C. 1: 871.
Rudzki, E. and Z. Grzywa. 1977. Exacerbation of nickel dermatitis
by margarine. Contact Dermatitis. 3: 344.
Saggerson, R.D., et al. 1976. Insulin-like actions of nickel and
other transition-metal ions in rat fat cells. Biochem. Jour.
154: 349.
Saknyn, A.V. and N.K. Shabynina. 1973. Epidemiology of malignant
neoplasms in nickel plants. Gig. Tr. Prof. Zabol. 17: 25. (Rus.)
Samitz, M.H. and S.A. Katz. 1975. Nickel dermatitis hazards from
prostheses. Jn vivo and ^Lri vitro solubilization studies. Br.
Jour. Der^atol. 92: 287.
C-158
-------
Samitz, M.H. and H. Pomerantz. 1958. Studies of the effects on the
skin of nickel and chromium salts. Arch. Ind. Health. 18: 473.
Samitz, M.H., et al. 1975. Attempts to induce sensitization in
guinea pigs with nickel complexes. Acta Dermatovener (Stockholm).
55: 475.
Schaller, K.H., et al. 1968. Nickel als Sourenelement im menschi-
lichen Blut. Blut. 17: 155. (Ger.)
Schnegg, A. and M. Kirchgessner. 1975a. The essentiality of nick-
el for the growth of animals. Z. Tierphysiol., Tierernaehr. Fut-
termittelkd. 36: 63.
Schnegg, A. and M. Kirchgessner. 1975b. Veranderungen ^es Hamo-
globigehaltes der Erythrozytenzahl und des Hamatokrits bei Nickel-
mangel. Nutr. Metabol. 19: 268.
Schnegg, A. and M. Kirchgessner. 1976. Zur Absorotion und Verfuq-
barkeit von Eisen bei Nickel-Mangel. Internat. Z. Vit. Ern. For-
schung. 46: 96. (Ger.)
Schroeder, H.A. and M. Mitchener. 1971. Toxic effects of trace
elements on the reproduction of mice and rats. Arch. Environ.
Health. 23: 102.
C-159
-------
Schroeder, H.A. and A.P. Nason. 1969. Trace metals in human hair.
Jour. Invest. Derm. 53: 71.
Schroeder, H.A., et al. 1962. Abnormal trace metals in mannick-
el. Jour. Chronic Dis. 15: 51.
Schroeder, H.A., et al. 1974. Life-term effects of nickel in
rats: Survival, tumors, interactions with trace elements* and tissue
levels. Jour. Nutr. 104: 239.
Sigel, H., et al. 1967. Ternary complexes in solution influence
of 2,2I-bipyridyl on the stability of 1:1 complexes of Co2+, Ni2+,
Cu , and Zn with hydrogen phosphate, adenosine 5 -monophosphate,
and adenosine 5 -triphosphate. Biochim. Biophys. Acta, 148: 655.
Singh, A. and J.P.W. Gilman. 1973. Use of the double diffusion
chamber for an analysis of muscle-nickel sulphide interaction.
Ind. Jour. Med. Res. 61: 704.
Sirover, M.A. and L.A. Loeb, 1977. On the fi^elitv of ^NA replica-
tion. Effect of metal activators during synthesis with avian mye-
loblastosis virus DNA polymerase. Jour. Biol. Chem. 252: 3605.
Smith, J.C. and B. Hackley. 1968. Distribution and excretion of
nickel-63 administered intravenously to rats. Jour. Nutr.
95: 541.
C-160
-------
Spears, J.W. and E.E. Hatfield. 1977. Role of nickel in animal
nutrition. Feedstuffs. 49: 24.
Spears, J.W., et al. 1977. Rumen bacterial urease requirement for
nickel. Jour. Dairy Sci. 60: 1073.
Spears, J.W., et al. 1978. Studies on the role of nickel in the
ruminant. Jour. Nutr. 108: 313.
Spoerl, R. and M. Kirchgessner. 1977. Studies on increased accu-
mulation of iron, zinc, manganese and nickel by the gravid organ-
ism. Z. Tierphysiol, Tierernaehr, and *uttermittelkd. 38: 205.
Spruit, D. and P.J.M. Bongaarts. 1977a. Nickel content of olasma,
urine and hair in contact dermatitis. Dermatologica. 154: 291.
Spruit, D. and P.J.M. Bongaarts. 1977b. Nickel Content of Plasma,
Urine and Hair in Contact Dermatitis. In: S.S. Brown (ed.), Clini-
cal Chemistry and Chemical Toxicology of Metals. Elsevier Publish-
ing Co., Amsterdam, p. 261.
Spruit, D., et al. 1965. The interaction of nickel ions with human
cadaverous dermis. Jour. Invest. Dermatol. 44: 103.
Stahly, E.E. 1973. Some consideration of metal carbonyls in
tobacco smoke. Chem. Ind. London 13: 620.
C-161
-------
Stephan, C.E. 1980. Memorandum to J. Stara. U.S. EPA. July 3.
Stokinger, H.E. 1963. The Metals (excluding lead). In: D.W. Fas-
sett and D.D. Irish (eds.), Industrial Hygiene and Toxicology. 2nd
rev. ed. Interscience, New York. 2: 987.
Stoner, G.D., et al. 1976. Test for carcinogenicity rj metallic
compounds by the pulmonary tumor response in strain A mice. Cancer
Res. 36: 1744.
Sumino, K., et al. 1975. Heavy metals in normal Japanese tissues.
Arch. Environ. Health. 30: 487.
Sunderman, P.W. 1970. Nickel Poisoning. In; F.W. Sunderman and
F.W. Sunderman, Jr. (eds.), Laboratory Diagnosis of Diseases Caused
by Toxic Agents. Warren H. Green, St. Louis, Missouri,, p. 387.
Sunderman, F.W. and A.J. Donnelly. 1965. Studies of nickel car-
cinogenesis metastesizing oulmonary tumors in rats induced by the
inhalation of nickel carbonyl. Am. Jour. Pathol. 46: 1027.
Sunderman, F.W. and F.W. Sunderman, Jr. 1961a. Nickel poisoning.
XI. Implications of nickel as a pulmonary carcinogen in tobacco
smoke. Am. Jour. Clin. Pathol. 35: 203.
/
Sunderman, F.W. and F.W. Sunderman, Jr. 1961b. Loffler's syndrome
associated with nickel sensitivity. Arch. Int. Med. 107: 405.
C-162
-------
Sunderman, F.W., et al. 1957. Nickel poisoning. IV. Chronic ex-
posure of rats to nickel carbonyl; a report after one year of ob-
servation. Arch. Ind. Health. 16: 480.
Sunderman, F.W., et al. 1959. Nickel poisoning. IX. Carcinogene-
sis in rats exposed to nickel carbonyl. Arch. Ind. Health.
20: 36.
Sunderman, P.W., et al. 1961. Nickel poisoning. XII. Metabolic
and pathologic changes in acute pneumonitis from nickel carbonyl.
Am. Jour. Clin. Pathol. 36: 477.
Sunderman, P.W., Jr. 1965. Measurement of nickel in biological
materials by atomic absorption spectrometry. Am. Jour. Clin.
Pathol. 44: 182.
Sunderman, F.W., Jr. 1967a. Inhibition of induction of benzpyrene
hydroxylase by nickel carbonyl. Cancer Res. 27: 950.
Sunderman, F.W., Jr. 1967b. Nickel carbonyl inhibition of corti-
sone induction of hepatic tryptophan pyrrolase. Cancer Res.
27: 1595.
Sunderman, F.W., Jr. 1968. Nickel carbonyl inhibition of pheno-
barbital induction of hepatic cytochrome P-450. Cancer Res.
28: 465.
C-163
-------
Sunderman, F.W., Jr. 1970. Effect of nickel carbonyl upon incor-
14
poration of C-leucine into hepatic microsomal proteins. Res.
Comm. Chem. Pathol. Pharmacol. 1: 161.
Sunderman, F.W., Jr. 1971. Effect of nickel carbonyl upon hepatic
concentrations of adenosine triphosphate. Res. Comm. Chem.
Pathol. Pharmacol. 2: 545.
Sunderman, F.W., Jr. 1973. The current status of nickel carcino-
genesis. Ann. Clin. Lab. Sci. 3: 156.
Sunderman, F.W., Jr. 1976. A review of the carcinoqenicities of
nickel, chromium and arsenic compounds in man and animals. Preven-
tive Med. 5: 279.
Sunderman, F.W., Jr. 1977. The Metabolism and Toxicology of Nick-
el. In; S.S. Brown (ed.), Clinical Chemistry and Chemical Toxico-
logy of Metals. Elsevier Publishing Co., Amsterdam, o. 231.
Sunderman, F.W., Jr. 1978. Carcinogenic effects of metals. Fed.
Proc. 37: 40.
Sunderman, F.W., Jr. and M. Esfahani-. 1968. Nickel carbonyl inhi-
bition of RNA polymerase activity in hepatic nuclei. Cancer Res.
28: 2565.
C-164
-------
Sunderman, F.w. , Jr. and K.C. Leibman. 1970. Nickel carbonvl in-
hibition of induction of aminopyrine demethylase activity in liver
and lung. Cancer Res. 30: 1645.
Sunderman, F.W., Jr. and R.M. Maenza. 1976. Comoarisons of car-
cinogenicities of nickel compounds in rats. Res. Comm. Chem.
Pathol. Pharmacol. 14: 319.
Sunderman, F.W. f Jr. and C.E. Selin. 1968. The metabolism of
nickel-63 carbonyl. Toxicol. Appl. Pharmacol. 12: 207.
Sunderman, F.w. , Jr. and F.W. Sunderman. 1963. Studies of oulmo-
nary carcinogenesis: The sub-cellular partition of nickel and the
binding of nickel by ribonucleic acids. Fed. Proc. 22: 427.
(Abst. 1592)
Sunderman, F.w., Jr. et al. 1968. Gas chromatograohy of nickel
carbonyl in blood and breath. Arch. Environ. Health. 16: 836.
Sunderman, F.w., Jr. et al. 1971. Nickel Metabolism in
Infarction. II. Measurements of Nickel in Human Tissues. In: o.D.
Hemphill (ed.), Trace Substances in Environmental Health -r?. uni-
versity of Missouri, Columbia, Missouri. p. 352.
Sunderman, F.W., Jr. et al. 1972a. Nickel metabolism in Health
and disease. Ann. N.Y. Acad. Sci. 199: 300.
C-165
-------
Sunderman, F.W., Jr. et al. 1972b. Nickel deprivation in chicks.
Jour. Nutr. 102: 259.
Sunderman, F.W.f Jr. et al. 1976. Effects of manganese on carcin-
ogenicity and metabolism of nickel subsulfide. Cancer Res.
36: 1790.
Sunderman, F.W., Jr. et al. 1978. Embryotoxicity and fetal toxi-
city of nickel in rats. Toxicol. Appl. Pharmacol. 43: 381.
Sushenko, O.V. and K.E. Rafikova. 1972. Questions of work hygiene
in hydrometallurgy of copper, nickel and cobalt in a sulfide ore.
Gig. Tr. Prof. Zabol. 16: 42.
Svejgaard, E., et al. 1978. Lymphocyte transformation induced bv
nickel sulphate: An ir\ vitro study of subjects with and without a
positive nickel patch test. Acta Dermatovener (Stockholm).
58: 245.
Sweet, O.V., et al. 1974. The relationship of total dust, free
silica, and trace metal concentrations to the occupational respira-
tory disease of bituminous coal miners. Am. Ind. Hyq. Assoc.
Jour. 35: 479.
Swierenga, S.H.H. and P.K. Basrur. 1968. Effect of nickel on cul-
tured rat embryo muscle cells. Lab. Invest. 19: 663.
0-166
-------
Sykes, A.K. and P.K. Basrur. 1971. Ultrastructural changes in
cultured rat embryo myoblasts exposed to nickel sulfide. in vitro.
6: 377. (Abst. 22)
Szadkowski, o., et al. 1969. Zur okologischen Bedeutunq des
Schwermetallgehaltes von Zigaretten. Arch. Hyg. Bakteriol.
153: 1. (Ger.)
Szadkowski, D., et al. 1970. Serum elektrolyte und elecktrisch-
mechanische Herzaction under chronisher industrieller Hitzeblas-
tung. Arztl. Porsch. 23: 271. (Ger.)
Tatarskaya, A.A. 1960. Occupational diseases of upper respiratory
tract in persons employed in electrolytic nickel refining depart-
ments. Gig. Tr. Prof. Zabol. 6: 35.
Taubman, S.B. and J.w. Malnick. 1975. Inability of Ni++ and Co+4>
to release histamine from rat peritoneal mast cells. Res. Comm.
Chem. Pathol. Pharmacol. 10: 383.
Tedeschi, R.E. and F.w. Sunderman. 1957. Nickel poisoninq. v.
The metabolism of nickel under normal conditions and after exposure
to nickel carbonyl. Arch. Ind. Health. 16; 486.
Thompson, R.f et al. 1974. The metabolism of benzo(a)pyrene in
rat liver microsomes: The effect of asbestos-associated metal ions
and pH. Res. 7: 149.
C-167
-------
Thulin, H. 1976. The leukocyte migration test in nickel contact
dermatitis. Acta Dermatovener (Stockholm). 56: 377.
Toda, M. 1962. Experimental studies of occupational lung cancer.
Bull. Tokyo Med. Dent. Univ. 9: 440.
Tolot, F., et al. 1956. Asthmatic forms of luna disease in workers
exposed to chromium, nickel and aniline inhalation. Arch. Mol.
Prof. Med. Tran. Secur. Soc. 18: 288.
Torjussen, W. and L.A. Solberg. 1976. Histological findings in
the nasal mucosa of nickel workers. Acta Otolaryngol. R2: 266.
Treagan, L. and A. Furst. 1970. Inhibition of interferon synthe-
sis in mammalian cell cultures after nickel treatment. Res. Comm.
Chem. Pathol. Pharmacol. 1: 395.
Tseretili, M.N. and R.P. Mandzhavidze. 1969. Clinical observa-
tions of acute nickel carbonyl poisoning. Gig. Tr. Prof. Zabol.
13: 46.
Turk, J.L. and D. Parker. 1977. Sensitization with Cr, Ni, and Zr
salts and allergic type granuloma formation in the guinea pig.
Jour. Invest. Dermatol. 68: 341.
Uehara, M., et al. 1975. Pustular patch test reactions in atopic
Dermatitis. Arch. Dermatol. Ill: 1154.
C-168
-------
U.S. EPA. 1976. Air Quality Data for Metals 1970 through 1974 from
the National Air Surveillance Network. EPA-600/4-76-041, U.S.
Environ. Prot. Agency, Research Triangle Park, North Carolina.
U.S. EPA. 1980a. Seafood consumption data analysis. Stanford
Research Institute International, Menlo Park, California. Final
report, Task 11. Contract No. 68-01-3887.
U.S. EPA. 1980b. Unpublished laboratory data. Env. Res. Lab.,
Narragansett, Rhode Island.
Vandenberg, J.J. and W.L. Epstein. 1963. Experimental nickel con-
tact sensitization in man. Jour. Invest. Dermatol. 41: 413.
Vuopala, U., et al. 1970. Nickel carbonyl poisoning. Report of 25
cases. Ann. Clin. Res. 2: 214.
Wahlberg, J.E. 1975. Nickel allergy and atopy in hairdressers.
Contact Dermatitis. 1: 161.
Wahlberg, J.E. 1976. Sensitization and testing of guinea nios
with nickel sulfate. Dermatologica. 152: 321.
Wahlberg, J.E. and E. Skog. 1971. Nickel allergy and atony.
Threshold of nickel sensitivity and immunoglobulin E detestation.
Br. Jour. Oermatol. 85: 97.
C-169
-------
Waltschewa, V.W., et al. 1972. Hodenveranderungen bei weissen
Ratten durch chronische Verabreichung von Nickel sulfat. (Testicu-
lar changes due to long-term administration of nickel sulohate in
rats.) Exp. Pathol. 6: 116. (Ger. with Engl. abst.)
Wase, A.W., et al. 1954. The metabolism of nickel. I. Spatial and
temporal distribution of Ni in the mouse. Arch. Biochem. Bio-
phys. 51: 1.
Waters, M.D., et al. 1975. Toxicity of metallic chlorides and
oxides for rabbit alveolar macroohages rn vitro. Environ. Health
Perspect. 10: 267. (Abst.)
Watt, T.L. and R.R. Baumann. 1968. Nickel earlobe dermatitis.
Arch. Dermatol. 98: 155.
Webb, M. and S.M. Weinzierl. 1972. Uptake of Ni from its com-
plexes with proteins and other ligands by mouse dermal fibroblasts
ui vitro. Br. Jour. Cancer. 26: 292.
Webb, M., et al. 1972. Intranuclear distribution of the inducing
metal in primary rhabdomyosarcomata induced in the rat by nickel,
cobalt and cadmium. Br. Jour. Cancer. 26: 274.
Weber, C.W. and B.L. Reid. 1968. Nickel toxicity in growing
chicks. Jour. Nutr. 95: 612.
C-170
-------
Wehner, A.P. and O.K. Craig. 1972. Toxicology of inhaled NiO and
CoO in Syrian golden hamsters. Am. Ind. Hyg. Assoc. Jour.
33: 147.
Wehner, A.P., et al. 1975. Chronic inhalation of nickel oxide and
cigarette smoke by hamsters. Am. Ind. Hyg. Assoc. Jour. 36: 801.
Weinzierl, S.M. and M. Webb. 1972. Interaction of carcinogenic
metals with tissue and body fluids. Br. Jour. Cancer. 26: 279.
Wells, G.C. 1956. Effects of nickel on the skin. Br. Jour. Der-
matol. 68: 237.
Whanger, P.O. 1973. Effects of dietary nickel on enzyme activi-
ties and mineral content in rats. Toxicol. Appl. Pharmacol.
25: 323.
Wilson, H.T.H. 1956. Nickel dermatitis. Practitioner. 177: 303.
Witschi, H. 1972. A comparative study of i.n vivo RNA and protein
synthesis in rat liver and lung. Cancer Res. 32: 1686.
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