NICKEL
Ambient Water Quality Criteria
Criteria and Standards Division
Office of Water Planning and Standards
U.S. Environmental Protection Agency
Washington, B.C.
-------
CRITERION DOCUMENT
NICKEL
CRITERIA
Aquatic Life
For nickel the criterion to protect freshwater aquatic life
as derived using the Guidelines is "ed-01 'ln(hardness) - 1.02)
as a 24-hour average and the concentration should not exceed
«e(0.47-ln(hardness) + 4.19).. at any time.
The data base for saltwater aquatic life is insufficient to
allow use of the Guidelines. The following recommendation is in-
ferred from toxicity data for freshwater organisms.
For nickel the criterion to protect saltwater aquatic life as
*
derived using procedures other than the Guidelines is 220 ug/1 as
a 24-hour average and the concentration should not exceed 510 ug/1
at any time.
Human Health
For the protection of human health based on the toxic proper-
ties of nickel ingested through water and through contaminated
aquatic organisms, the ambient water criterion is determined to be
133 ug/I/day.
-------
Introduction
Nickel is a bright, silver metal of the iron-cobalt-
nickel triad. It is a hard and malleable metal with a high
tensile strength and is used in electroplating and virtually
all areas of metallurgy. It is a divalent metal, with char-
acteristic divalent metal chemistry, although it does not
readily form chloro-complexes and under environmental condi-
tions would not be expected to form significant amounts
of sulfate complexes. Nickel levels in U.S. drinking waters
are typically less than 10 /ig/1 (Durfor and Becker, 1962) .
In the aquatic environment nickel is acutely toxic
to fishes at concentrations as low as 2,480 jug/1 (Lind,
et al. manuscript). Chronic toxicity to fishes has been
reported at 433 jug/1 (Lind, et al. manuscript). Water quality
also affects nickel toxicity. For instance, Lind, et al.
(manuscript) found the lowest effect level for fathead minnows
to lie between 109 and 433 jug/1 in embryo-larval tests in
water with a hardness of 44 mg/1 as calcium carbonate, while
Pickering (1974) reported a range 380 to 730 jug/1 in a life
cycle test with the same species at a water hardness of
210 mg/1 as calcium carbonate.
The human health criterion is calculated on the basis
of adverse effects seen in rats provided with drinking water
containing 5 ppm nickel. These effects included reduction
of litter size, increased numbers of runts, and increased
neonatal mortality (Schroeder and Mitchener, 1971).
A-l
-------
AQUATIC LIFE TOXICOLOGY*
FRESHWATER ORGANISMS
Introduction
Nickel is a common component of natural freshwaters and can
occur at concentrations less than 1 y.g/1 in areas impacted to a
minimal degree by man. As with other divalent heavy metals, free
nickel (Ni2"1") may participate in various types of aqueous
.chemical reactions such as adsorption, precipitation, complexa-
tion, and bioaccumulation. Since the chemical environment 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, chloride, and carbonate. For example,
chloride is not an important complexing agent, since its concen-
tration would have to be greater than that of typical salt water
to form the nickel chloride complex. Sulfate concentrations
*The reader is referred to the Guidelines for Deriving Water
Quality Criteria for the Protection of Aquatic Life [43 FR 21506
(May 18, 1978) and 43 FR 29028 (July 5, 1978)] in order to better
understand 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 the calcula-
tions for deriving various measures of toxicity as described in
the Guidelines.
B-l
-------
would have to approach about 10 2M concentrations (an unlikely
natural condition) before approximately one-half of the nickel
would be complexed. Although precipitation by carbonate is pos-
sible, this reaction is also relatively unimportant since condi-
tions conducive to its occurrence appear unlikely.
With respect to more reactive substances, complexation by
organic conplexing agents such as aminopolycarboxylic acids is
possible. At present, equilibria with natural substances such as
suspended clays, humic acids, and microorganisms is generally
poorly understood. Therefore, as a first approximation, the most
prevalent form of nickel in toxicity test systems with low concen-
trations of suspended solids and dissolved organic matter is esti-
mated to be the free form, Ni2+.
Acute Toxicity
Adjusted LC50 values for fish (Table 1) ranged from 2,433
ug/1 for the guppy (hardness = 20 mg/1) to 48,881 u.g/1 for the
bluegill (hardness = 42 mg/1). At comparable hardness values
(20-29 mg/1), several of the lowest adjusted LC50 values (5,368,
2,832, 2,504, 2,916, 2,923, 2,433, 2,480, 2,832, and 2,930 ug/D
generally appear to be relatively similar for five different
species of fish: goldfish, fathead minnow, guppy, rock bass, and
bluegill (Pickering and Henderson, 1966, and Lind et al.r manu-
script). At the high end of the hardness scale (360 mg/1), there
are three adjusted LC50 values (23,180, 24,328, 21,649 mg/1) which
also appear relatively close for two species of fish, fathead min-
now and bluegill (Pickering and Henderson, 1966). However, in
some cases, greater variability (15,800, 26,663, 23,898, 7,406
ug/1) was observed at comparable hardness levels (42 mg/1) for
four different species of trout (Willford, 1966).
B-2
-------
The toxicity data in Table 1 indicate that water hardness
significantly influences the acute toxicity of nickel to fish.
Following the Guidelines, an exponential equation describing
the relationship of toxicity to hardness for each species was fit
by least squares regression of the natural logarithms of the
toxicity values and hardness. For nickel, sufficient acute
toxicity data and hardness ranges were available for two fish
species to fit regression equations. The slope of these equations
ranged from 0.86 for the fathead minnow to 0.63 for the bluegill,
with a geometric mean of 0.74.
As a measure of relative species sensitivity to nickel,
logarithmic intercepts were calculated for each species by fitting
the mean slope (0.74) through the geometric mean toxicity value
and hardness for each species. These intercepts varied from 5.41
for rock bass to 7.45 for banded killifish, with an arithmetic
average of 6.28 for all 16 fish species. This variation in
logarithmic intercepts indicates a range of species sensitivity to
nickel of only seven fold. The Final Fish Acute Value is derived
using the geometric mean slope (0.74), the adjusted average
intercept (4.92), and the species sensitivity factor (3.9).
In comparison to the results for fish, acute tests with
invertebrate species (Table 2) generally have a greater range of
adjusted LC50 values at a fixed hardness. The caddisfly exhibited
the highest adjusted value (33,220 ug/1/ Rehwoldt et al., 1973)
and Daphnia magna (Biesinger and Christensen, 1972) gave the
lowest value (432 ug/1). Lind et al. (manuscript) provided the
only data obtained under relatively high hardness conditions (244
mg/1).
B-3
-------
Sufficient data were available for only one invertebrate
species, Daphnia pulicaria, to demonstrate the relationship of
toxicity to hardness, and the resulting slope is 0.47. As a
measure of relative species sensitivity to nickel, logarithmic
intercepts were calculated for each species by fitting the slope
through the geometric mean toxicity value and hardness for each
species. These intercepts ranged from 4.67 for Daphnia magna to
8.57 for the caddisfly with an arithmetic average of 7.23 for all
11 species.
The Final Invertebrate Acute Value is derived using the
geometric mean slope (0.47), the adjusted average intercept
(4.19) and the species sensitivity factor (21). Since this value
is lower than the one for fish, this one becomes the Final Acute
Value.
Chronic Toxicity
A life cycle test (Pickering, 1974) and an embryo-larval test
(Lind et al., manuscript) have been conducted with the fathead
minnow (Table 3) and the chronic values are 527 ug/1, at a
hardness of 210 mg/1, and 109 ug/1/ at a hardness of 44 mg/1,
respectively. These two chronic values for the fathead minnow
give a slope of 1.01 and an intercept of 0.88. Use of the species
sensitivity factor of 6.7 results in a Final Fish Chronic Value
based on a slope of 1.01 and an intercept of -1.02.
Biesinger and Christensen (1972) conducted a life cycle test
with Daphnia magna, which resulted in a chronic value of 53 ug/1
(Table 4) at a hardness of 45 mg/1. Due to the lack of data for
chronic toxicity to invertebrate species, the slope of 1.01 from
the fish chronic data must be assumed. Since daphnids were the
B-4
-------
most sensitive invertebrate species to nickel in acute tests, it
would appear to be inappropriate to use the species sensitivity
factor of 5.1 with the chronic data. Thus the Final Invertebrate
Chronic Value is derived using the slope of 1.01 and an intercept
of 0.13. Since the Final Fish Chronic Value is lower, it becomes
the Final Chronic Value.
Plant Effects
Hutchinson (1973) and Hutchinson and 'Stokes (1975) observed
reduced growth of several algal species at concentrations ranging
from 100 to 700 ug/1 (Table 5). The relationship between these
results and the 24-hour average concentrations derived as the
criterion is not known, since 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 7), the possible effects this may have are
uncertain. The occurrence of slight changes in diversity due to
nickel may or may not be significantly deleterous to ecological
functions and biomass production. It should initiate further
consideration and study since these changes occurred at concen-
trations below the criterion. Since the values in Table 5 are
higher than the chronic data on fish and invertebrate species.,
plant effects are presently not used in determining the criterion.
Residues
The only available 'bioconcentration factors (BCF) are for the
fathead minnow (Lind et al., manuscript) and an alga (Hutchinson
and Stokes, 1975). The BCF for the whole body of the fathead
B-5
-------
minnow was 61 and for the alga the BCF was 9.8 (Table 6). The geo-
metric mean BCF is 24.
Since no maximum permissible tissue concentration is avail-
able, no Residue Limited Toxicant Concentration can be calculated.
B-6
-------
CRITERION FORMULATION
Freshwater-Aquatic Life
Summary of Available Data
All concentrations herein are expressed in terms of nickel.
The concentrations below have been rounded to two significant
figures.
Final Fish Acute Value = e(0.74'ln(hardness) + 4.92)
Final Invertebrate Acute Value = eCO.47-ln(hardness) + 4.19)
Final Acute Value = e(°47'ln(hardness) + 4.19)
Final Fish Chronic Value = ed01*ln(hardness) - 1.02)
Final Invertebrate Chronic Value = e(*01>ln(hardness}+ 0.13)
Final Plant Value = 100 ug/1
Residue Limited Toxicant Concentration = not available
Final Chronic Value = e(!01'ln(hardness) - 1.02)
The maximum concentration of nickel is equal to the Final
Acute Value as given by e(°-47*ln(hardness + 4.19) and the
24-hour average concentration is the Final Chronic Value as given
by e(1-01'ln(hardness) - 1.02). NO important adverse effec
on freshwater organisms have been reported to be caused by concen-
trations lower than the 24-hour average concentration other than
the possible changes in diatom diversity discussed earlier.
The final values can also be expressed as follows:
Final Fish Acute Value = 14,000 ug/1
Final Invertebrate Acute Value = 510 ug/1
Final Acute Value = 510 ug/1
B-7
-------
CRITERION: For nickel, the.criterion to protect freshwater
aquatic life as derived using the Guidelines is "e(l'°l*ln
(hardness) - 1.02)" as a 24-hour average and the concentration
should not exceed "e(° .47-ln(hardness) + 4.19),, at any
time.
B-8
-------
400 .Cr
200.0
CP
(
:z
o
o
LL)
v
g-§
2 £40.0
QJ _
s-
o:
Ld
or
o
X
CVJ
20.0
IO.O
4.0
24-HOUR AVER AGE
NICKEL CONCENTRATION
VS.
HARDNESS
10
20 4O IOO
TOTAL HARDNESS (mg/l)
In scale
200
400
B-9
-------
lOOOOr
400O
^Z
5
O 2OOO
o:
i
UJ
O
LJ
^
O
:z
x
<
g IOOO
C/5
400
200
IOO-
10
MAXIMUM NICKEL CONCENTRATION
VS.
HARDNESS
2O 4O IOO
TOTAL HARDNESS (mg/l)
In scale
200
40O
B-10"
-------
Table 1- Freshwater fish acute values for nickel
Organism
Ar.erican eel,
Anguilla rostrata
American eel.
Anguilla rostrata
Rainbow trout,
Salmo gairdneri
Rainbow trout ,
Salmo gairdneri
Rainbow trout,
Salmo gairdneri
Uj Brown trout,
1 Salmo trutta
1-1 Brook trout.
Salvelinus fontinalis
Lake trout ,
Salvelinus namaycush
Goldfish,
Carassius auratus
Fathead minnow,
Pimephales promelas
Fathead minnow.
Pimephales promelas
Fathead minnow,
Pimephales promelas
Fathead minnow,
Pimephales promelas
Fathead minnow,
Pimephales promelas
Fathead minnow,
bioassay
MeUiou"
c*
S
FT
R
S
S
S
S
S
S
S
FT
FT
S
S
Test
Cone.**
1 >
M
M
U
U
U
U
U
U
U
M
M
M
U
U
Iiaraness
(mq/i as
CaCO,)
53
55
f ».
240
42
42
42
42
20
210
210
210
210
20
20
Time
LC'jO
Adjusted
LC'jU
jtUB ) (uq/l 1 (uy/ij
96
96
96
48
48
48
48
48
96
96
96
96
96
96
96
13,000
13,000
35,500
32.000
35,680
60,210
53.966
16,725
9,820
27,000
32,200
28,000
25,000
5,180
4,580
9,230
9,230
35.500
14,170
15.800
26.663
23.898
7.406
5,368
14,761
22,862
28,000
25,000
2.832
2.504
Kbttrence
Rehwoldt, et al.
1971
Rehwoldt, et al.
1972
Hale. 1977
Brown &
Dalton, 1970
Willford. 1966
Willford. 1966
Willford, 1966
Willford. 1966
Pickering &
Henderson, 1966
Pickering, 1974
Pickering, 1974
Pickering, 1974
Pickering, 1974
Pickering &
Henderson, 1966
Pickering &
Pimephales promelas
Henderson, 1966
-------
Table 1. (Continued)
GO
Organism
Fathead minnow,
Pimeph;i1 es promelas
Fathead minnow,
Pimephales promelas
Fathead minnow,
Pimephales promelas
Fathead minnow,
Pimephales promelas
Fathead minnow,
Pimephales promelas
Fathead minnow,
Pimephales promelas
Fathead minnow,
Pimephales promelas
Fathead minnow,
Pimephales promelas
Fathead minnow,
Pimephales promelas
Fathead minnow,
Pimephales promelas
Carp,
Cyprinus carpio
Carp,
Cyprinus carpio
Channel catfish,
Ictalurus punctatus
Banded killifish,
Fundulus diaphanus
Banded killifish,
Fundulus diaphanus
Guppy ,
bioassay
Meuiod*
i i i « ^^^»
S
S
FT
FT
FT
FT
FT
FT
FT
FT
S
S
S
S
S
S
Test
U
U
M
M
M
M
M
M
M
M
M
M
U
M
M
U
Hardness
(IIUJ/I ob
CaCO,)
3 -
360
360
45
44
29
28
77
89
91
86
53
55
42
53
55
20
Time
96
96
96
96
96
96
96
96
96
96
96
96
48
96
96
96
LC!>U
42,400
44.500
5,209
5.163
2,916
2,923
12.356
17,678
8,617
5,383
10,600
10,400
36.795
46,200
46,100
4,450
Adjusted
LC-jO
23,180
24,328
5,209
5,163
2,916
2,923
12,356
17.678
8.617
5,383
7,526
7.384
16.294
32,802
32,731
2,433
Heterence
Pickering &
Henderson, 1966
Pickering &
Henderson, 1966
Lind, et al. ,
Manuscript
Lind, et al .
Manuscript
Lind, et al .
Manuscript
Lind, et al. ,
Manuscript
Lind, et al .
Manuscript
Lind, et al .
Manuscript
Lind, et al.
Manuscript
Lind, et al.
Manuscript
Rehwoldt, et al
1971
Rehwoldt, et al
1971
Willford, 1966
Rehwoldt, et al
1971
Rehwoldt, et al
1972
Pickering &
Lebistes reticulatus
Henderson, 1966
-------
Table 1. (Continued)
Hardness
Adjusted
Organism
Rock bass,
Ambloplites rupescris
Striped bass,
Roecus saxatilus
Striped bass,
Roecus saxatilus
Pumpkinseed,
Lepomis gibbosus
Pumpkinseed,
Lepomis gibbosus
Bluegill.
03 Lepomis macrochirus
1
£ Bluegill,
Lepomis macrochirus
Bluegill,
Lepomis macrochirus
Bluegill,
Lepomis macrochirus
White perch,
Roecus americanus
White perch,
Roecus americanus
BicusGay
Method *
FT
Test
Cone. **
M
(mq/i c
CaC03)
26
> s Time
itusj
96
LC
iil
2
bO
q/lj
,480
in
2
.480
iMiterenue
Lind, et al .
Manuscript
S
S
S.
S
S
S
S
S
S
S
M
M
M
M
U
U
U
U
M
M
53
55
53
55
20
20
360
42
53
55
96
96
,
96
96
96
96
96
48
96
96
6
6
8
8
5
5
39
110
13
13
.200
.300
,100
.000
.180
,360
,600
,385
,600
,700
4
4
5
5
2
2
21
48
9
9
,402
,473
.751
,680
.832
,930
.649
,881
,656
.727
Rehwoldt ,
1971
Rehwoldt,
1972
Rehwoldt ,
1971
Rehwoldt,
1972
Pickering
. Henderson
Pickering
Henderson
Pickering
Henderson
Willford,
Rehwoldt ,
1971
Rehwoldt ,
1972
et
et
et
et
&
al.
al.
al.
al.
. 1966
&
. 1966
&
. 1966
1966
et
et
al.
al.
* S = static, FT = flow-through
** U = unmeasured, M = measured
Adjusted LC50 vs. hardness:
Fathead minnow: slope = 0.86, intercept = 5.30, r = 0.94, p = 0.01, N = 16
Bluegill: slope = 0.63, intercept = 6.72, r = 0.60, Not significant, N = 4
Geometric mean slope =0.74
Average intercept for 16 fish species = 6.28
Adjusted average intercept = 6.28-ln(3.9) = 4.92
Final Fish Acute Value = e(0-74In(hardness) + 4.92)
-------
Table 2. Freshwater invertebrate acute values for nickel
Organism
3 i
Rotifer,
Philoiiina acuticornus
Rotifer,
Philodina acuticornus
Bristleworm,
Nais sp.
Snail (egg).
Amnicola sp.
Snail (adult),
Amnicola sp.
Cladoceran,
Daphnia hyalina
Cladoceran,
Daphnia magna
Cladoceran,
Daphnia magna
Cladoceran,
Daphnia pulicaria
Cladoceran,
Daphnia pulicaria
Cladoceran,
Daphnia pulicaria
Cladoceran,
Daphnia pulicaria
Cladoceran,
Daphnia pulicaria
Cladoceran,
Daphnia pulicaria
Cladoceran,
Daphnia pulicaria
Bioassay
MetJioa*
R
R
S
S
S
S
S
S
R
R
R
R
R
R
R
Test
Cor.c.**
U
U
M
U
U
U
U
U
M
M
M
M
M
M
M
Hardness
(mq/1 as
CaCO,)
J
25
25
50
50
50
45
45
48
48
44
29
28
28
86
Time
(hr s)
96
96
96
96
96
48
48
48
48
48
48
48
48
48
48
LC b 0
(uq/11
2,900
7,400
14,100
11.400
14,300
1,900
1.120
510
2.182
1.813
1.836
697
1.140
1,034
3,316
Adjusted
LC'.)0
(ucj/il
2,456
6,268
.
15,510
12.540
15,730
1,609
949
432
2,400
1,994
2.020
767
1,254
1,137
3,648
Kuifcrence
Buikema, et al.
1974
Buikema, et al.
1974
Rehwoldt, et al .
1973
Rehwoldt, et al.
1973
Rehwoldt, et al.
1973
Baudouin &
Scoppa, 1974
Biesinger &
Christensen, 1972
Biesinger &
Christensen, 1972
Lind, et al.
Manuscript
Lind, et al .
Manuscript
Lind, et al .
Manuscript
Lind, et al.
Manuscript
Lind, et al.
Manuscript
Lind, et al .
Manuscript
Lind, et al .
Manuscript
-------
Table 2. (Continued)
Organism
Cladoceran,
Daphnia pulicaria
Cladoceran,
Daphnia pulicaria
Cladoceran,
Daphnia pulicaria
Cladoceran,
Daphnia pulicaria
Cladoceran,
Daphnia pulicaria
Cladoceran,
03 Daphnia pulicaria
*" Cladoceran,
1/1 Daphnia pulicaria
Clacoderan,
Daphnia pulicaria
Cladoceran,
Daphnia pulicaria
Cladoceran,
Daphnia pulicaria
Cladoceran,
Daphnia pulicaria
Cladoceran,
Daphnia pulicaria
Copepod,
Cyclops abyssorum
Copepod,
Eudiaptomus padanus
Scud,
Gammarus sp.
Method*
in ^fc ^»^^^»^^
R
.R
R
R
R
R
R
R
R
R
R
R
S
S
S
Test
Cone,**
M
M
M
M
M
. M
M
M
M
M
M
M
U
U
M
Hardness
(imj/i as
CaCO,,)
3
44
94
144
244
94
144
244
84
74
73
100
25
--
--
50
Time
48
48
48
48
i 48
48
48
48
48
48
48
48
48
48
96
LCbO
jug/11
1,901
3,162
3,826
3,304
2,470
2,470
2,409
3,014
2,325
3,414
3.757
2.171
15.000
3.600
13,000
Adjusted
LCliO
4UH/1)
2.091
3.478
4,209
3,634
2,717
2.717
2,650
3,315
2,558
3,755
4.133
2,388
12,705
3,049
14,300
heterence
Lind, et al .
Manuscript
Lind, et al.
Manuscript
Lind, et al .
Manuscript
Lind, et al.
Manuscript
Lind, et al .
Manuscript
Lind, et al .
Manuscript
Lind, et al.
Manuscript
Lind, et al.
Manuscript
Lind, et al.
Manuscript
Lind, et al.
Manuscript
Lind, et al .
Manuscript
Lind, et al.
Manuscript
Baudouin &
Scoppa, 1976
Baudouin &
Scoppa, 1976
Rehwoldt, et
1973
-------
Table 2. (Continued)
03
1
M
Organism
Mayfly,
Epliki.it: rel la subvaria
Stonefly,
Acroneuria lycorias
Damselfly,
(unidentified)
Midge.
Chironomus sp.
Caddisfly,
(unidentified)
Bioassay
Method*
»^^i^^ ^*i^» ^Bw
S
S
S
S
S
Haraness
Test (m.)/i as
Cone.** CaCO,)
J
U 42
U 40
M 50
M 50
M 50
Time
(lirs)
96
96
96
96
96
LCSO
iaa/ii
4.000
33.500
21.200
8,600
30,200
Adjusted
LCbO
Jiia1
3,388
28,374
23.320
9,460
33.220
heterence
Warnick & Bell,
1969
Warnick & Bell,
1969
Rehwoldt, et al .
1973
Rehwoldt, et al .
1973
Rehwoldt, et al .
1973
* S = static, R = renewal
** U = unmeasured, M =
measured
Adjusted LC50 vs. hardness:
Daphnia pulicaria
: slope = 0
.47, intercept = 5.80
. r =
0.72, p = 0
.01. N = 19
Geometric mean slope = 0.47 (only value available)
Average intercept for 11 invertebrate species = 7.23
Adjusted average intercept = 7.23-ln(21) = 4.19
. , . , rn 47'ln(hardness) + 4.19)
Final Invertebrate Acute Value = ev
-------
Table 3. Freshwater fish chronic values for nickel
CO
I
Organism
Fathead minnow,
Pimephales promelas
Fathead minnow,
Pimephales promelas
Chronic Hardness
Limits Value (mq/1 as
Test* (uq/l> (uq/i) CaCO,)
J
LC 380-730 527 210
E-L 109-433 109 44
Reference
Pickering,
Lind, et al
1974
. Manuscript
* LC = life cycle or partial life cycle, E-L = embryo-larval
Adjusted chronic values vs. hardness:
Fathead minnow: slope = 0.01, intercept = 0.88, Not significant, N
Geometric mean slope = 1.01 (only value available)
Average intercept = 0.88 (only value available)
Adjusted average intercept = 0.88-ln(6.7) = -1.02
Final Fish Chronic Value - eU. 01'In(hardness)-1. 02)
Species
Fathead minnow,
Pimephales promelas
Application Factor Values
96-hr LC50 MATC
527
26,458
AF
0.020
Reference
Pickering, 1974
-------
03
I
M
00
Tafcle l\. Freshwater invertebrate chronic values for nickel (Biesinger & Christenscn. 1972)
.
Organism
Cladoceran,
Daphnia magna
Test *
LC
Limits
(uq/il
30-95
Chronic
Value
(uq/11
53
Haioness
( mi) / i as
CaC00)
J
45
* LC.= life cycle or partial life cycle
Adjusted chronic values vs. hardness:
No hardness relationship could be derived for any invertebrate species.
Using the slope (1.01) from the fish chronic values, the intercept for D. magna = 0.13 (only species
tested).
Final Invertebrate Chronic Value = e(1'01'^(hardness) + 0.13)
-------
Table 5. Freshwater plant effects for nickel
"I
MD
Organism
Alga,
liiuamyaoroonas
eugamotos
Alga,
Chlorella vulgaris
Alga .
Haematococcus
capensis
Alga,
Scenedesmus
acuminata
Alga.
Scenedesmus
acuminata
'
Concentration
Eftect (uq/1) Reference
Reduced growth 700 Hutchinson, 1973
Reduced growth 500 Hutchinson, 1973
Reduced growth 300 Hutchinson, 1973
Reduced growth 500 Hutchinson & Stokes, 1975
Reduced growth 100 Hutchinson, 1973
Lowest plant value = 100 ng/1
-------
DO
I
K)
O
Table 6. Freshwater residues for nickel
Organiam
Alga.
Scenedestnus acuminata
Fathead minnow,
Pimephales promelas
Bioconcentration Factor
9.8
61
Time
(days)
6
30
weference
Hutchlnson & Stokes, 1975
Lind, et al. Manuscript
Geometric mean bioconcentracion factor for all species = 24
-------
00
ro
Table 7. Other freshwater data for nickel
Organism
Algae.
(mixed population)
Test
Duration gttect
Hardness
(mg/1 as
CaC03)
^53 days Decrease in 87 to 99
diatom diver-
sity; popula-
tion shift to
blue and blue-
green algae
Result
2 to 8.6 Patrick, et al. 1975
Cladoceran,
Daphnia magna
64 hrs Immobilization
<317
Anderson, 1948
-------
SALTWATER ORGANISMS
Introduction
The scientific literature on nickel toxicity to saltwater
organisms is limited. There are no chronic or residue data with
fish or invertebrate species. The fish acute and plant data
represent two species. This limited data base indicates that
nickel is less toxic than such metals as mercury, copper, silver,
and cadmium, and more toxic than chromium, manganese and aluminum.
Acute Toxicity
Data on the acute toxicity of nickel to saltwater fishes is
limited (Table 8). The adjusted values range from 14,586 ug/1 for
the Atlantic silverside to 191,345 ug/1 for the mummichog. A
third fish species, winter flounder (Table 11), has a 96-hour LC50
greater than 33,000 ug/1. The geometric mean of the fish acute
data is 52,830 ug/1 which when divided by the species sensitivity
factor of 3.7 results in a Final Fish Acute Value of 14,000 ug/1.
The invertebrate acute toxicity data base consists of 14
data with a range of adjusted values from 262 ug/1 for larvae of
the hard clam (Calabrese and Nelson, 1974) to 271,040 ug/1 for
adults of the soft-shell clam (Eisler and Hennekey, 1977). The
geometric mean of the invertebrate data is 24,970 ug/1 which when
adjusted for species sensitivity gives a Final Invertebrate Acute
Value of 510 ug/1. This value appears to be protective of 95
percent of the species since only one data point is less than 510
ug/1. Most, of the data on adults of macroinvertebrate species,
the larval molluscan data and the planktonic copepod data indicate
a need to Lest more sensitive species and life history stages.
B-22
-------
Since the Final Invertebrate Acute Value of 5*10 ug/1 is less
than the Final Fish Acute Value, 14,000 ug/1, the Final Acute
Value is 510 ug/1.
Plant Effects
There was a 50 percent inactivation of photosynthesis of the
giant kelp (Clendenning and North, 1959) at a nickel concentration
of 2,000 ug/1 (Table 10). Skaar et al. (1974) observed reduced
growth of the alga, Phaeodactylum tricornutum, at a concentration
of 1,000 ug/1 (Table 10).
Miscellaneous
These data indicate that embryos of the sea urchin are
sensitive co nickel (Timourian and Watchmaker, 1972). Delayed
development occurred at 58 ug/1 but abnormal effects were noted at
580 ug/1 after only twenty hours exposure. At this time, the
delayed development observed at 58 ug/1 does not appear to be
important enough to be the basis for the 24-hour average
concentration criterion.
B-23
-------
CRITERION FORMULATION
Saltwater-Aquatic Life
Summary of Available Data
The concentrations below have been rounded to two significant
figures. All concentrations herein are expressed in terms of
nickel.
Final Fish Acute Value = 14,000 ug/1
Final Invertebrate Acute Value = 510 ug/1
Final Acute Value = 510 ug/1
Final Fish Chronic Value = not available
Final Invertebrate Chronic Value = not available
Final Plant Value = 1,000 ug/1
Residue Limited Toxicant Concentration = not available
Final Chronic Value = 1,000 ug/1
0.44 x Final Acute Value = 220 ug/1
No saltwater criterion can be derived for nickel using the
Guidelines because no Final Chronic Value for either fish or
invertebrate species or a good substitute for either value is
available, and there are insufficient data to estimate a criterion
using other procedures. Results obtained with nickel and
freshwater fish indicate how a criterion may be derived.
An application factor of 0.020 was obtained for nickel with
fathead minnows. Multiplying this value times the Final Acute
Value for saltwater fish results in an estimated Final Chronic
Value for saltwater fish of 0.020 x 14,000 ug/1 = 280 ug/lr which
is higher than 0.44 times the Final Acute Value for saltwater
organisms.
B-24
-------
The maximum concentration is the Final Acute Value of 510
ug/1 and the 24-hour average concentration if 0.44 times the Final
Acute Value. No important adverse effects on saltwater aquatic
organisms have been reported to be caused by concentrations lower
than the 24-hour average concentration.
CRITERION: For nickel the criterion to protect saltwater
aquatic life as derived using procedures other than the Guidelines
is 220 ug/1 as a 24-hour average and the concentration should not
exceed 510 ug/1 at any time.
B-25
-------
Table 8. Marino Eish acute values for nickel
CD
I
i-o
CTl
Adjusted
Bioassay Test Time LC50 LC5U
Mununichog, S U
Fundulus heteroclitus
Atlantic silverside, S U
Menidia menidia
96 350,000 191.345 Eisler & llennekey, 1977
72 29,000 14,586 U.S. EPA. 1973
* S = Static
** U = unmeasured
Geometric mean of adjusted values = 52,830 ug/1
,.
wg/1
-------
Tjbit 9. Marine invertebrate acute values for nickel
bicossay
ri r 1 1 A n i c rn M ^ F 1 fjtl *»
03
1
N)
--J
Sandworm,
Nereis virens
Cockle.
Cardium edule
Cockle,
Cardium edule
Atlantic oyster (larva).
Crassostrea virginica
Hard clam (larva) ,
Mercenaria mercenaria
Soft shell clam,
Mya arenaria
Copepod,
Acartia clausi
Stone crab,
Carcinus maenas
Brown shrimp,
Crangon crangon
Brown shrimp.
Crangon crangon
Crab,
Pagurus longicarpus
Shrimp,
Pandalus montagui
Snail.
Nassarius obsoletus
Starfish,
S
S
S
S
S
S
S
S
S
S
S
S
S
S
Test
CoriC .**
U
U
U
U
U
U
U
U
U
U
U
U
U
U
Time
(tirs)
ili f
96
48
48
48
48
96
96
48
48
48
96
48
96
96
LC50
(UCI/i)
25,
500
330
1
320
2
300
150
100
47
200
72
150
,000
.000
,000
,180
310
.000
,850
,000
,000
,000
,000
.000
.000
,000
Adjusted
LCbO
(Ufl/l)
21,175
182,105
120.189
999
262
271,040
2,414
109.263
54,631
36,421
39.809
72,842
60,984
127.050
ivctfci ence
Eisler & Hennekey.
Portmann,
Portmann.
Calabrese
Calabrese
1974
Eisler &
U.S. EPA,
Portmann,
Portmann,
Portmann,
Eisler &
Portmann,
Eisler &
Eisler &
1968
1972
, et al.
& Nelson,
Hennekey,
1974
1968
1968
1972
Hennekey,
1968
Hennekey,
Hennekey ,
1977
1973
1977
1977
1977
1977
Asterius forbesi
-------
Table 9. (Continued)
Organism
Bioaesay Test
Method Cone.
Adjusted
LC50 LC5U
(uq/11 (ug/1)
Keterence
* S = static
** U = unmeasured
Geometric mean of adjusted values = 24,970 ug/1
DO
I
N)
00
-------
CD
to
Table 10- Marine plant effects for nickel
Oman ism
Ettect
Concentration
(ug/i)
Ret ereii
Giant kelp, 507. inactivation 2.000
Macrocystis pyrifera of photosynthesis
Alga, Reduced growth 1,000
Phceodactylum tricornutum
Clendenning & North, 1959
Skaar, et al. 1974
Lowest Plant Value = 1,000 yg/1
-------
Table 11. Other marine data for nickel
Orgdfiism
Test
Duration
Ettect
Result
juq/l)
Retereijcfc
00
I
u>
o
Winner flounder,
Pseudopleuronectes
americanus
Mummichog,
Fundulus heteroclitus
Sofc-shell clam,
My a arenaria
Sea urchin (embryo),
Lytechinus pictus
Sea urchin (embryo),
Lytechinus pictus
Sea urchin (embryo),
Arbacia punctulata
96 hrs LC50
72 hrs LC50
>33,000 U.S. EPA, 1975a
>50,000 U.S. EPA, 1973
48 hrs LC50 >50,000
20 hrs Delayed development 58
20 hrs Abnormal development 580
U.S. EPA, 1975b
Timourian & Watchmaker,
1972
Timourian & Watchmaker,
1972
42 hrs >507. embryo mortality 17,000 Waterman, 1937
-------
NICKEL
REFERENCES
Anderson, B.C. 1948. The apparent thresholds of toxicity
to Daphnia magna for chlorides of various metals when added
to Lake Erie water. Trans. Am. Fish. Soc. 78: 96.
Baudouin, M.F. , and P. Scoppa. 1974. Acute toxicity of
various metals to freshwater zooplankton. Bull. Environ.
Contam. Toxicol. 12: 745.
Biesinger, K.E., and G.M. Christensen. 1972. Effects of
various metals on survival, growth, reproduction, and metabo-
lism of Daphnia magna. Jour. Fish. Res. Board Can. 29:
1691.
Brown, V.M., and R.A. Dalton. 1970. The acute lethal toxi-
%
city 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 virginica).
Mar. Biol. 18: 162.
B-31
-------
Calabrese, A., and D.A. Nelson. 1974. Inhibition of embry-
onic development of the hard shell clam, Mercenaria mercenaria,
by heavy metals. Bull. Environ. Contain. Toxicol. 2: 92.
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. Berke-
ley, Cal. Proc.
Eisler, R., and R.J. Hennekey. 1977. Acute toxicities
of Cd , Cr +, Hg + , Ni +, and Zn + to estuarine macrofauna.
Arch. Environ. Contam. Toxicol. 6: 315.
Hale, J.G. 1977. Toxicity of metal mining wastes. Bull.
Environ. Contam. Toxicol. 17: 66.
Hutchinson, T.C. 1973. Comparative studies of the toxicity
of heavy metals to phytoplankton and their synergistic inter-
actions. Water Pollut. Res. (Canada) 8: 68.
Hutchinson, T.C., and P.M. Stokes. 1975. Heavy metal toxicity
and algal bioassays. ASTM STP 573, Am. Soc. Test. Mater.
pp. 320-343.
Lind, D., et al. Regional copper-nickel study, Aquatic
Toxicology Study, Minnesota Environmental Quality Board,
State of Minnesota (Manuscript).
B-32
-------
Patrick, R., et al. 1975. The role of trace elements in
management of nuisance growths. U.S. Environ. Prot. Agency,
EPA 660/2-75-008, 250 p.
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 analysis and toxicity-testing in relation to
the marine environment. Helgolander wiss. Meeresunters
17: 247.
'PGTtrncmr,,~~J-.-E 197?- Results of acute toxicity tests with
marine organisms, using a standard method. In M. Russo
(ed.), Marine Pollution and Sea Life. Fishery News Ltd.,
London, England.
Rehwoldt, R., et al. 1971. Acute toxicity of copper, nickel
and zinc ions to some Hudson River fish species. Bull.
Environ. Contain. Toxicol. 6: 445.
Rehwoldt, R., et al. 1972. The effect of increased tempera-
ture upon the acute toxicity of some heavy metal ions.
Bull. Environ. Contain. Toxicol. 8: 91.
B-33
-------
Rehwoldt, R., et al. 1973. The acute toxicity of some
heavy metal ions toward benthic organisms. Bull. Environ.
Contain. Toxicol. 10: 291.
Skaar, H.B., et al. 1974. The uptake of 3N, by the diatom
Phaeodactylum tricornutum. Physiol. Plant. 32: 353.
Timourian, H., and G. Watchmaker. 1972. Ni uptake by sea
urchin embryos and their subsequent development. Jour.
Exp. Zool. 182: 379.
U.S. Environmental Protection Agency, Environmental Research
Laboratory-Narragansett, Rhode Island. Semi-Annual Report.
July-Dec., 1973.
U.S. Environmental Protection Agency, Environmental Research
Laboratory-Narragansett, Rhode Island. Semi-Annual Report.
Jan.-June, 1974.
U.S. Environmental Protection Agency, Environmental Research
Laboratory-Narragansett, Rhode Island. Semi-Annual Report.
Jan.-June, 1975a.
U.S. Environmental Protection Agency, Environmental Research
Laboratory-Narragansett, Rhode Island. Semi-Annual Report.
July-Dec., 1975b.
B-34
-------
Warnick, S.L., and H.L. Bell. 1969. The acute toxicity
of some heavy metals to different species of aquatic insects.
Jour. Water Pollut. Control Fed. 4T: 280.
Waterman, A.J. 1937. Effect of salts on heavy metals on
development of the sea urchin, Arbacia punctulata. Biol.
Bull. 73: 401.
Willford, W.A. 1966. Toxicity of 22 therapeutic compounds
to six fishes. Bur. Sport Fish. Wildl. Resour. Publ. 35,
U.S. Dep. Inter., 10 p.
B-35
-------
Mammalian Toxicology and Human Health Effects
EXPOSURE
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 large and population response.
Some obvious questions about the exposure aspects of nickel are: (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 multimedia contaminant.
Thus, one needs to have a clear understanding of fractional contributions on
total body burden in humans through various routes of exposure before one can
assess the relative significance 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 pathophysiological responses to nickel;
(2) subgroups of the U.S. population that can be identified as being at par-
ticular risk to effects of nickel by virtue of either exposure setting or some
physiological 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.
A discussion of the various effects of nickel on man includes dose-effect
and dose-response relationships and the various parameters that are of utility
in assessing both magnitude of exposure and the extent of response.
C-l
-------
"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
internal 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 optimally or the organism's reserve
capacity to cope with other systemic stresses.
A dose-effect relationship is a quantitative statement of the relationship
between changes in the quantity of an agent and observed gradations of severity
in effect resulting therefrom. Dose-response refers to the frequency with
which a given effect occurs within a population at a defined dose.
Furthermore, Nordberg (1976) has defined the concept of critical 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 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 anthropogenic activity,
and a detailed description of sources and prevalence of nickel in the environ-
ment is given in the comprehensive National Academy of Sciences (NAS) review
(Natl. Acad. Sci. , 1975).
C-2
-------
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 general population exposure assessment.
Similarly, the relative contribution 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 population comes into contact with nickel and to
define the nickel levels therein: ambient air, water, foodstuffs, soil, and
other exposure sources.
Ingestion from Water
The values for nickel levels in 969 U.S. public water supplies for 1969-1970
are presented in Table 1. The survey includes eight metropolitan areas (Natl.
Acad. Sci., 1975). The average value, taken at the consumer tap, was 4.8
ug/1, with only 11 systems of this total exceeding 25 ug/1. The highest level
was in one supply, 75 ug/1.
Since the data in Table 1 do not furnish any measure of the number of
people consuming drinking water of variable nickel content, the,nickel levels
for water supplies of the 10 largest U.S. cities have been listed in Table 2.
This table is based on the data of Durfor and Becker (1964).
C-3
-------
TABLE 1. NICKEL LEVELS IN U.<
WATER, 1969-1970'
DRINKING
Ni concn,
mg/1.
0.000
0.001-0.005
0 ..006-0. 010
0.011-0.015
0.016-0.020
0.021-0.025
0.026-0.030
0.031-0.035
0.036-0.040
0.041-0.045
0.046-0.050
0.051-0.055
0.075
Total
No. of Ni frequency
samples (percent of samples)
543
1,082
640
167
46
14
4
2
1
1
1
1
1
2,503
21.69
43.22
25.57
6.68
1.84
0.56
0.16
0.08
0.04
0.04
0.04
0.04
0.04
100.00
Samples from 969 water systems.
Data from Natl. Acad. Sci. (1975),
TABLE 2. NICKEL LEVELS OF DRINKING WATER
OF 10 LARGEST U.S. CITIES3
City
Nickel level, ug/1
New York City
Chicago
Los Angeles
Philadelphia
Detroit
Houston
Baltimore
Dallas
San Diego
San Antonio
2.3"
7.4C
4.8
13.0°
5.6b
4.5C
4.7C
5.2C
<7.8
Not detected
Tabulation adapted from Natl. Acad. Sci. (1975);
.values for 1962 survey of Durfor and Becker (1964),
In storage.
Post-treatment.
C-4
-------
The values for New York City, Chicago, and Los Angeles do not appear to
be markedly at variance with the value of 4.8 (jg/1. from Table 1.
Ingestion from Food
The route by which most people in the general population receive the
largest portion of daily nickel intake is through foods.
The assessment of average daily nickel intake in food can be done either
by considering the aggregate nickel content of average diets in the population
or by fecal nickel determinations. Although fecal nickel levels would be more
meaningful than diet analysis, given the very small gastrointestinal absorption
of nickel in man, such data have been sparse in the literature in terms of
representative groups of individuals.
Some representative nickel values for various foodstuffs, adapted from
data in the MAS Nickel Report, are given in Table 3. These values have been
obtained by different laboratories using different methods and may be dated in
some cases. Total daily dietary intake values may range up to 900 ug nickel,
depending on the nature of the diet, with average values of 300 to 500 ug daily.
Total daily dietary intake values may range up to 900 ug nickel, depending on
the nature of the diet, with average values of 300 to 500 ug daily (Natl. Acad.
Sci., 1975).
Schroeder et al. (1962) calculated an average oral nickel intake by
American adults of 300 to 600 ug/day, while Louria and co-workers (1972)
arrived at a value of 500 ug/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 ug/day. In a related study, Myron et al.
(1978) determined the nickel content of nine institutional diets in the
U.S. and calculated an average intake of 165 ug/day.
C-5
-------
TABLE 3. NICKEL CONTENT OF VARIOUS CLASSES
OF FOODS IN U.S. DIET3
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
0.54
1.33
0.70
0.47
0.23
0.21
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
Seal lops
Crabmeat, canned
Sardines, canned
Haddock, frozen
Swordfish, frozen
Salmon
Meats
Pork (chops)
Lamb (chops)
Beef (chuck)
Beef (round)
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
Not detected
Not detected
Adapted from Natl. Acad. Sci. (1975).
C-6
-------
Food processing methods apparently add to the nickel levels
already present in foodstuffs via (1) leaching from nickel-con-
taining 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
nickel. Nodiya (1972) reported a fecal excretion average of 258
ug in Russian students. Horak and Sunderman (1973) determined
fecal excretions of nickel in 10 healthy subjects and arrived at
a value of 258 ug/day, identical to the Russian study.
A bioconcentration factor (BCF) relates the concentration of
a chemical in water to the concentration in aquatic organisms.
Since BCFs are not available for the edible portions of all four
major groups of aquatic organisms consumed in the United States,
some have to be estimated. A recent survey on fish and shellfish
consumption in the United States (Cordle, et al. 1978) found that
the average per capita consumption is 18.7 g/day. From the data
on the nineteen major species identified in the survey, the rela-
tive consumption of the four major groups can be calculated.
A mean measured bioconcentration factor of 61 was obtained
for fathead-minnow larvae (Lind, et al. Manuscript) based on
whole body measurements after a 28-day exposure to nickel. The
values were corrected for nickel in the control organisms and
corrected from dry weight to wet weight. Based on data for lead
and cadmium, nickel would probably have a lower BCF for fish and
decapod muscle than for fish whole body, but probably would have
a higher BCF for molluscs.
C-7
-------
Consumption Bioconcentration
Group (Percent) Factor
Freshwater fishes 12 6
Saltwater fishes 61 6
Saltwater molluscs 9 70
Saltwater decapods 18 6
Using the data for consumption and estimated bioconcentration
factors for each of these groups, the weighted average BCF for
nickel is 11 in consumed fish and shellfish.
Inhalation
Perhaps the most comprehensive assessment of ambient air
levels of nickel in the U.S. is that of the National Air Surveil-
lance Network. Tabulation of air nickel levels for the period
1964 through 1969 are contained in the NAS Nickel Report (Nickel.
NAS, 1975) for 231 urban and 47 nonurban localities. More recent
figures are available for the period 1970-1974 (EPA, 1976).
Table 4 tabulates the air nickel averages for urban stations
for the period 1970-1974. For 1974, the most recent entry, the
arithmetic mean level was 9 ng/m3.
Table 5 presents the corresponding values for all nonurban
stations for the same period. Again for 1974, the arithmetic
mean level was 2 ng/m3.
It may be seen from Tables 4 and 5 as well as earlier sur-
veys in the NAS Nickel Report, that there is a clear difference
in urban versus nonurban nickel levels, with urban values being
around three- to four-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 McMu/Llen, 1977).
C-8
-------
TABLE 4. ; URBAN CUMULATIVE FREQUENCY DISTRIBUTIONS
OF AMBIENT AIR NICKEL LEVELS3
Year
1970
1971
1972
1973
1974
No. of ; Percentile
sites Min. . 10 50
797 0.001 0.001 0.001
717 0.001 0.001 0.001
708 0.001 0.001 0.001
559 0.001 0.001 0.001
594 0.001 0.001 0.001
Arithmetic Mean
99
0.127
0.126
0.100
0.133
0.057
(SD)
0.015 (0.028)
0.015 (0.028)
0.011 (0.023)
0.014 (0.037)
i
0.009 (0.029)
Contracted tabulation from U.S. EPA data (1976), Table 4.1.
Values under given percentile indicate the percentage of stations
below air level. Values in ug/m .
TABLE 5. NONURBAN CUMULATIVE FREQUENCY DISTRIBUTIONS
OF AMBIENT AIR NICKEL LEVELS3
Year
1970
1971
1972
1973
1974
No. of Percentile
sites Min. 10 50
124 0.001 0.001 0.001
97 0.001 0.001 0.001
137 0.001 0.001 0.001
100 0.001 0.001 0.001
79 0.001 0.001 0.001
99
0.076
0.046
0.076
0.188
0.020
Arithmetic mean
(SD)
0.005 (0.024)
0.003 (0.011)
0.004 (0.012)
0.011 (0.037)
0.002 (0.004)
Contracted tabulation from U.S. EPA data (1976), Table 4.2.
Values under given percentile indicate the-percentage of stations
below the given air value. Values in ug/m .
C-9
-------
Figure 1 depicts the trend in the 50th percentile at urban sites of annual air
»
nickel averages for the period 1965-1974. Nickel shows a downward trend over
this period, being 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 values.
NickeKis 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 1965-1974
appear to be the major factor in lower air nickel levels, particularly in the
northeastern United States. Sulfur removal from residual oil necessitated by
these regulations indirectly 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.
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.
There is an extensive list of commodities which contain nickel and through
which the general population can be externally exposed. In particular, the
use of stainless steel kitchens, nickel-plated jewelry, and various other
nickel-containing materials has created a widespread problem for nickel-
sensitive individuals.
C-10
-------
01
£
Z
M
u
o
2 ooi
5 \
\
0001
6S it i> M 69 70 71 12 11
YIAB
Figure 1. Trend in the 50th percent!le at urban sites of
average for nickel. From Faoro and McMullen (1977),
C-ll
-------
Other Sources of Exposure
Nickel In Soil
Soil nickel levels are considered in this section chiefly from the aspect
of the influence of soil nickel on man's food chain: plants * animals -> 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 5,000 ppm (Natl. Acad. Sci.,
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, organic 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 phosphate fertilizers or municipal sewage sludge.
Ragaini et al. (1977), in their study of trace metal contaminants of
soil and grasses near a lead-smelting operation in Idaho, found that surface
soil nickel levels are enriched 39-fold in sampling sites in the vicinity of
the smelter.
Contamination of roadside soil with nickel, leading to increased 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 roadside. 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 potatoes grown in test pots
in municipal sludge from Ithaca, N.Y., Furr et al. (1976) observed: (1) at
C-12
-------
first-year harvest, nickel levels in the above food crops were increased
two-to-threefold 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
harvest, the increases seen in the first harvest did not recur, except for
about a twofold increase in onions and tomatoes.
John and Van Laerhoven (1976) determined the effect of applying sludge at
various loading rates on trace metal uptake by romaine lettuce and beets grown
on amended soil with and without liming. Sludge used with unlimed soil signifi-
cantly 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 Smoke
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 individual 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.
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 ug into the blood-
stream. This may be contrasted to the markedly smaller amounts taken in by
inhalation of nickel in ambient air (vide supra).
C-13
-------
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 absorbed. Nickel in particulate matter is absorbed from the
pulmonary 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 insolu-
bility has implications for the carcinogenic character of nickel, as will be
noted below.
Absorption from the gastrointestinal tract of dietary nickel 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 or partition-
ing between erythrocyte and plasma cannot be precisely stated. In any event,
C-14
-------
plasma or serum levels reflect the blood burden. Normal serum nickel values
in man are 2 to 3 pg/1. Albumin is the main macromolecular carrier of nickel
in a number of species, including 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 occurring 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 ingestion via
the diet. Percutaneous absorption is a less significant factor for nickel's
systemic effects but important in the allergenic responses to nickel. Parenteral
administration of nickel is mainly of interest to experimental studies and
particularly helpful in the assessment of the kinetics of nickel transport,
distribution, and excretion in addition to maximizing the physiological parameters
for nickel's effects.
C-15
-------
The amounts of nickel absorbed by organisms are determined not only by
the quantities inhaled or ingested, but also by the chemical and physical
forms of nickel. Other factors, such as host organism nutritional and
physiological status, also play a role, but this has been little studied
outside of investigations directed at an essential role for nickel.
Gastrointestinal intake of nickel by man is surprisingly high, relative
to other toxic elements, which is at least partly accounted 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), Nodija (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 63 Ni in dilute acid solution leads to 3 to 6 percent absorption of
the radio-labeled 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.
Percutaneous absorption of nickel is mainly viewed as important in the
dermatopathological effects of this agent, such as contact dermatitis, and
absorption viewed this way is restricted to the passage of nickel past the
outermost layers of skin deep enough to bind with apoantigenie factors.
Wells (1956) demonstrated that divalent nickel penetrates the skin at
sweat-duct and hair-follicle ostia and binds to keratin. Using cadaver skin,
C-16
-------
Kolpokov (1963) found that nickel (II) accumulated in the malpighian layer,
sweat glands, and walls of blood vessels. Spruitt et al. (1965) have shown
that nickel penetrates to the dentil's.
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 co-workers (1977) 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
absorption data from this study.
Respiratory absorption of various forms of nickel is probably the major
route of nickel entry into man under conditions of occupational exposure. Of
these forms, nickel carbonyl is one that has been found to be toxic.
Nickel carbonyl, Ni(CO)4, is a volatile, colorless liquid (b.p. 43°C),
Armit (1908) judged its relative toxicity to be a hundred fold higher than
that of carbon monoxide. More recently, the threshold limit value (TLV) for a
work day exposure has been set at 50 parts per billion (ppb). In contrast,
the corresponding value for hydrogen cyanide is 10 parts per million (ppm),
200-fold greater (Am. Conf. of Gov. Ind. Hyg., 1971). The presence and
toxicological history of Ni(CO). as a workplace hazard followed closely upon
the development of the Mond process of nickel purification in its processing
(Mond et al., 1890). A detailed discussion of the toxicological aspects of
nickel carbonyl poisoning is included in the NAS Report on Nickel (1975) as
well as a recent review by Sunderman (1977).
C-17
-------
Studies of nickel carbonyl metabolism by Sunderman and co-workers
(Sunderman and Selin, 1968; Sunderman et al., 1968) indicate that pulmonary
absorption is both rapid and extensive, the agent passing the alveolar wall as
Ni(CO). intact. 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 4 days postexposure. 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 particulate matter
deposited in the lung exist. The International Radiological Protection
Commission 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 pulmonary 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) based on a detailed study
of eight coal-fired power plants, found that nickel is one of a number of
elements emitted from these sources that is found in the smallest particles of
escaped fly ash, about 1 to 2 urn mass median aerodynamic diameter (MMAD), this
being a size that penetrates deepest into the pulmonary tract. According to
the approaches of the IRPC model, particles of 1 urn undergo a total deposition
percentage of 63 percent, with 30 percent in the nasopharyngeal tract, 8
C-18
-------
percent in the tracheobronchial part, and 25 percent in the pulmonary compartment.
The clearance rate of deposited participate matter in the IRPC model is based
on chemical homogeneity of the particulates, however, and one can only approximate
such clearance 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 clearance rate by assuming
that particles enriched 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 (clearance) of
about 6 percent, with major clearance calculated as taking place from the pulmonary
compartment, 5 percent.
Wehner and Craig (1972), in their studies of the effect of nickel oxide
aerosols on the golden hamster, observed that inhalation by these animals of
nickel oxide particles in a concentration of 2 to 160 jjg/1 (2 to 160 mg/m ) and
particle size of 1.0 to 2.5 um MMAD led to a deposition of 20 percent of the
total amount inhaled. After 6 days postexposure, 70 percent of the nickel
oxide remained 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 showed no effect on either deposition or
clearance.
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
C-19
-------
levels being determined in particles 0.5 to 1.0 urn in diameter at an air level of
8.4 (jm Ni/m . While the authors did not determine the total nickel deposition
in the lungs of these animals, they observed that essentially no clearance of
the element from the lung had occurred by 24 hours, nor were there elevations
in blood nickel, suggesting negligible absorption. In contrast, Graham et
al., (1978), using nickel chloride aerosol and mice (<3 pm diameter, 110 pg
Ni/m ) found about 75 percent clearance by day 4 postexposure. The rapid
clearance of the nickel halide was probably due to its solubility relative to
the oxide.
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
and co-workers (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 possible that nickel carbonyl constitutes the gaseous fraction (Sunderman
and Sunderman, 1961a), one must assume that the relative absorption of nickel
from cigarette smoke is proportionately greater than from airborne nickel
*
particulates and with heavy smokers may be the main source of inhalatory
nickel absorbed. Individuals smoking two packs of cigarettes daily can inhale
up to 5 mg nickel annually (Natl. Acad. Sci., 1975). By contrast, an individual in
an urban U.S. area having an air level of Ni of 0.025 ug/m (Natl. Acad. Sci.,
1975 for regional average values of airborne nickel) and breathing 20 m daily
would inhale somewhat less than 0.2 mg. The relative significance for absorption
would be even greater (vide supra).
C-20
-------
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 blood burden and exposure status (Natl.
Acad. Sci., 1975). In unexposed individuals, serum nickel values are approximately
0.2-0.3 ug/dl.
Distribution of serum-borne nickel among the various biomolecular components
has been discussed in some detail in a recent review (Natl. Acad. Sci., 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
o^-macroglobulin (nickeloplasmin) in rabbits and in man as a 9.5 S c^-glyco-
protein. Sunderman (1977) has suggested that nickeloplasmin may be a complex
of the a,-glycoprotein with serum or,-macroglobulin.
While the relative amounts of protein-bound nickel in sera of various
species have a considerable range (Hendel and Sunderman, 1972) which reflect
relative binding strengths of albumins, the total nickel levels are markedly
similar, as may be seen in Table 6.
A number of studies of the distribution of nickel in experimental animals
exposed to nickel carbonyl have been described (Natl. Acad. Sci., 1975).
C-21;
-------
TABLE 6. SERUM NICKEL IN HEALTHY ADULTS OF SEVERAL SPECIES3
Nickel concentration,
Species (N)
.From Sunderman et al. (1972a)
Mean (and range)
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)
Main lobster (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 (3.3-3.8)
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)
t-22
-------
Armit (1908) exposed dogs, cats, and rabbits to nickel carbonyl vapor and
was able to measure elevated nickel levels in lung, brain, kidney, and adrenal
glands. Later investigators 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 exposure to
inhaled ( Ni) - nickel carbonyl, viscera contained about half of the total
absorbed label with one-third in musc'ie 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 (Kasprzak 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 tha 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
(Natl. Acad. Sci., 1975).
A number of reports in the literature describe the tissue distribution 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. These data are summarized in Table 7.
C-23
-------
TABLE 7. TISSUE DISTRIBUTION OF NICKEL (II) AFTER PARENTERAL ADMINISTRATION0
Species
Dosage1
Relative distribution of 63Ni
Reference
Mouse
Rat
Guinea pig 6
Rabbit
Rabbit
6.2 rag/kg
(one intraperitoneal
injection)
617
(one intravenous
injection)
1 mg/kg
(subcutaneously
for 5 days)
240 ug/kg
(one intravenous
injection)
4.5 ug/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 duodemun =
liver > whole blood > heart > bone > iris > muscle >
cornea = cerebellum = hypothalamus > medulla
oblongata > spinal cord > retina > lens > vitreous
humor
Wase et al.
(1954)
Smith and
Hackley
(1968)
Clary (1975,
Parker and
Sunderman
1974)
'From Natl. Acad. Sci., 1975.
-------
It can be generally stated that nickel administered this way leads to
highest accumulation in kidney, endocrine glands, lung, and liver. Rela-
tively little nickel is lodged in neural tissue, consistent with the observed
low :neurotoxic potential of divalent nickel salts. Similarly, there is rela-
tively 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 injected Ni 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 3 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.
63
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 had the largest labile pool within 16
hours with two intracellular compartments. Liver, lung, and spleen pools
could also be characterized by two compartments, while bone fit a one-compart-
ment model. Corresponding half-times for the fast and slow components were
several hours and several days, respectively.
C-25
-------
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 nickel in drinking water (5 ppm) over the lifetime
1 of the animals. Phatak and Patwardhan (1950) reported the effects of differ-
ent nickel compounds given orally to rats in terms of tissue accumulation.
Among the three chemical forms of nickel used, i.e., carbonater nickel soaps,
and metallic nickel catalyst, tissue levels were greatest in the groups fed
the.carbonate.. O'Dell and co-workers (1971) fed calves supplemental nickel in
the diet at levels of 62.5, 250, and 1000 ppm. While levels of nickel were
somewhat elevated in pancreas, testis, and bone at 250 ppm, pronounced
increases in these tissues were seen at 1000 ppm. Whanger (1973) exposed
weanling rats to nickel (acetate) in the diet at levels up to 1000 ppm. As
nickel exposure was increased, nickel content of kidney, liver, heart, and
testes was also elevated, with greatest accumulation in the kidneys. Spears,
et al. (1978) observed that lambs given tracer levels of Ni orally with or
without supplemental nickel in diet had £he highest levels of the label in
kidney, the relative levels in kidney, lung and liver being less for the
low-nickel group.
Comparing the above studies suggests that a homeostatic mechanism exists
to regulate low levels of nickel intake, e.g., 5 ppm, but such regulation is
overwhelmed in the face of large levels of nickel challenge.
The blood values for nickel, as shown in Table 8, are limited to those
utilizing atomic absorption spectrometry. The data are taken from the report
C-26
-------
by the National Academy of Sciences (1975) and expanded by the addition 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 reported for the Hdgetveit and
Barton study (1976) is of interest, since the authors report in another
publication (Hrigetveit and Barton, 1977): "These figures today (1977) appear
high. 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 location 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 environments with differing degrees of pollution due to
the absence or presence of nickel refineries is that of McNeely (1972), who
examined normal adults who were not occupationally exposed to nickel in Sudbury,
Ontario, the location of North America's largest 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 ug/dl, while respective
values for Hartford were 0.25 ± 0.09 (range 0.08 to 0.52 ug/dl).
C-27
-------
TABLE 8. "NORMAL" BLOOD NICKEL CONCENTRATIONS
No. of
subjects
o
i
oo
Author
Schaller et al. (1968)
Nomoto and Sunderman (1970)
McNeely et al. (1972)
Pekarek and Hauer (1972)
Nomoto (1971)
Hrfgetveit (1976)
Spruit (1977)
Method
Atomic absorption
Atomic absorption
Atomic absorption
Atomic absorption
Atomic absorption
Atomic absorption
Atomic absorption
Area and sex
Germany
Connecticut
Connecticut
Washington, D.C.
Japan
Norway
Holland
26
40
26
20
23
3
10
Serum (S)
or plasma
(P)
P
S
S
S
S
P
P
Nickel concentration of jjg/dl
Mean (± SO)
2.1
0.26
0.26
1.5 (± 0.5)
0.21 (± 0.11)
0.42
0.16
Range
0.6-3.7
0.11-0.46
0.08-0.52
-
0.2-0.6
-
86 samples, number of subjects not given.
-------
It should also be noted that smoking status of the individuals tested has
not been considered systematically in these reports. The National Academy of
Sciences report (1975) cites several studies which showed "that 10 to 20
percent of the nickel in cigarettes is released in the mainstream 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, 1969; Sunderman,
1968; Stahly, 1973), which has a very high retention in the respiratory tract.
It would seem quite possible that regular smoking of one or more packs of
cigarettes a day would contribute the major fraction of daily inhaled nickel
in the general population.
Data from three studies reporting values of nickel in blood for occupa-
tional ly exposed persons and nonexposed controls show significant differences.
Clausen et al. (1977) report on a study in which atomic absorption spectrometry
was used to determine blood nickel levels in a group of Danish garage 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 p <0.01.
Hdgetveit and Barton (1976) reported on the results of monitoring blood
plasma Ni levels in workers in the Falconbridge nickel refinery. They found
Ni plasma values of 0.74 ug/dl for 701 samples from 305 workers while controls
showed an average value of 0.42 ug/dl in 86 samples. Atomic absorption spectro-
metry was used in the analyses. The plasma levels for workers at different
work stations showed that 179 electrolysis department workers had a mean blood
C-29
-------
nickel concentration of 0.74 ug/dl while 126 roasting-smelting workers averaged
0.60 ug/dl. Workers engaged in electrolysis operations were found to be
exposed to soluble nickel salts in aerosol form while the workers in roasting
-Jsmelting operations were exposed to largely insoluble compounds -in dust
(Hrfgetveit 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 duration, 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 pg/dl at different periods during the work year, but 0.53 ug/dl after the
annual two-week holiday. The controls, patients from the dermatology service
without occupational exposure, showed plasma levels of 0.16 and 0.20 ug/dl for
10 males and 14 females, respectively. These data support the Hdgetveit and
Barton (1976) finding that plasma concentrations reflect current exposure and,
further, provide evidence that there is very quick response to exposure.
The specific effects on blood levels of nickel of smoking, faulty hygiene,
and failure to observe safety regulations among exposed workers have either
not been evaluated or, if evaluated, have not been reported. However, there
is one case study of a recalcitrant worker (Hdgetveit 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 dropped to 3.75 ug/dl and
he was given sick leave for 3 weeks. During this leave, the worker's plasma
nickel level dropped to 1.0 ug/dl. After he returned to work, his nickel
C-30
-------
o
I
u>
ELECTROLYSIS WORKERS
.,0--
r»~-
--0,
o
o «o
ROASTING/SMELTING
WORKERS
1943- 1948- 1953- 1958- 1963- 1968- 1971- AFTER
47 52 57 62 67 70 72 JAN 1.1973
Figure 2. Average plasma nickel levels in employees according to year beginning employment.
From Hogeveit and Barton (1976).
-------
level rose steadily until strict safety enforcement 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 occupationally exposed." The criteria for determining
nonexposure and recruitment and selection of volunteers and other "normals"
are not specified. Several of the studies evaluating urine nickel concentrations
appear in Table 8 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 Figures 3, 4, and 5.
Hrigetveit and Barton (1976) state that they consider urine Ni concentrations
an undesirable monitoring method since only 24-hr, collection totals are
indicative of atmospheric nickel concentrations. The authors point out that ,
24-hr, collections require cooperation by workers and avoiding contamination
during sample collection at work.
Some investigators present both types of sets of values, but not all did,
in fact, collect 24-hour urines. In addition, the calculation of nickel con-
centration relative to creatinine to control for renal function is not employed
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. Equally, there are no data to
assess the association between race, urban-rural residential status, geographical
C-32
-------
30 H
20 J
"r 'OH
£ 5
if 0
-...,
"
8 :fi
0 8 !Ci 0 0 '" 0 '''
T/nii-.'.!uy FncJay i5v'.l,ir
0 o V 0
Figure 3. Urine Ni concentrations in consecutive determinations
of urinary nickel from a healthy, nonallergic
volunteer. Mean Ni content: 2.2 ug Ni/1 urine.
From Spruit and Bongaarts (1977a).
C-&3
-------
4 -!
JLS
j i r.
r?
n
rv
s-
4.'
a. 3J
I
3
- Jl:'i
5 [
I!.
;n
Mir
.---0
6 12
0 6 <: i? 0 6 i? '8
506
Figure 4. Urine Ni concentration of two nonallergic patients
showing influence of toothache and extraction.
From Spruit and Bongaarts (1977a).
C-34
-------
30
I
5
R 10
*i
S
I
J 0
H
Ui'-s
« 0 * 'r 0 » 'li 0 1 '< 0 0 f> '
TlH...-'ioXlU-l/ S^"Hi-'/ '-'.".;j.J wifl2» I'-l-, ^
: u A' ] u / [ a
w«k >«"« ~V<
' o *
1.' .-
' o
.|, '.'
-: o
M, T.'
; a i
.--..'.-.c 2)
-o
Figure 5. Urine Ni concentration in an occupationally exposed,
nonallergic volunteer. Mean value 6.0 |jg Ni/1 urine
and peak values up to 40 ug/1 urine during working
hours. From Spruit and Bongaarts (1977a).
CJ35
-------
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 9 show six findings of remarkable 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 environmental exposures. Table 10
shows the findings for exposed, nonexposed, and control subjects as well as
air concentrations for seven work environments. There is only partial
concordance between atmospheric concentrations and urine values. In view of
Hrfgetveit's findings 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, and that concentrations
of specific compounds might be required to explain associations.
Hdgetveit and Barton (1976) found an average urine nickel concentration
of 8.9 ug/dl for 729 samples from 305 workers, while the value for controls
was 2.1 ug/dl. The data for average urine concentrations 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 temporary 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.
C-361
-------
TABLE 9. NICKEL CONCENTRATIONS IN HUMAN URINE
Q
i
u>
Authors
Sunderman (1965)
Nomoto and Sunderman (1970)
Lehnert et al. (1970)
McNeely et al. (1972)
Hdgetveit (1976)
Spruit (1977)
Mikac-Devfc et al. (1977)
Bernacki et al. (1978)
Ader and Stoeppler (1978)
Method
Atomic absorption
Atomic absorption
Atomic absorption
Atomic absorption
Atomic absorption
Atomic absorption
Atomic absorption
Atomic absorption
Atomic Absorption
Area
Pennsylvania
Connecticut
Germany
Connecticut
Norway
Netherlands
Connecticut
Connecticut
a
No. of
subjects
17
26
15 .
20
a
10
a
19
a
Nickel concentration, ug/dl (ug/day)
Mean
1.8 (19.8)
0.23 (2.4)
(9.3)
0.20 (2.5)
2.1
0.06
0.27
0.27b
0.2
Range
0.4-3.1
0.10-0.52 (1.
(5.7-12.7)
0.07-0.40 (0.
0.3-4.2
a
a
0.04-0.51b
a
0-5.6)
05-6.0)
.Not specified.
Ni:2.5 ± 1.3 ug/g creatine (range 0.7-5.7 ug/g creatine); all samples with specific gravity < 1.012 discarded.
-------
TABLE 10. NICKEL CONCENTRATIONS IN URINE SPECIMENS FROM WORKERS IN TWELVE OCCUPATIONAL GROUPS'
Group
A
B
C
D
E
F
n
w G
00
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 (20M.3F)
9M
7 (6M.1F)
9 (7M.2F)
10 (7M.3F)
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 parts 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
Atmospheric Ni
cone, ug/m
Not measured
Not measured
Not measured
26148
(0.05-129)
1.613.0
(2.1-8.8)
6.0114.3
(0.2-46)
52194
(0.011252)
Not measured
2.412.6
(0.04-6.5)
0.810.9
(0.04-2.1)
Not measured
4891560
(20-2,200)
Urine ug/1.
2.711.6
(0.4-5.1)
3.212.6
(0.3-8.5)
4.212.4
(0.4-7.9)
4.113.2
(0.5-9.5)
5.412.4
(2.1-8.8)
6.314.1C
(1.6-14)
12. 2113. 6C
(1.4-41)
11.7l7.75d
(3.4-25)
17.2i9.8d
(1.4-26)
10.5l8.1d
(1.3-30)
27. 5121. 2e
(3.6-65)
2221226s
(8.6-8.3)
Concn ug/g
creatinine
2.511.3
(0.7-5.7)
2.711.7
(0.6-6.1)
3.211.6
(0.1-5.8)
2.411.4
(0.5-4.7)
3.511.6
(1.7-6.1)
5.616.2
(1.1-17)
7.2l6.8C
(0.7-20)
10.2+6.4d
(7.2-23)
16.0121.9
(1.4-54)
5.9l5.0c
(1.0-20)
19. 0114. 7e
(2.4-47)
12411096
(6.1-287)
aFrom Bernacki et al. (1978).
Mean 1 SD with range in parentheses.
cp < 0.05 vs control subjects in Group A, computed by t test.
p < 0.01 vs control subjects in Group A, computed by t test
Jp < 0.001 vs control subjects in Group A, computed by t tes
-------
CO-,
IKON
(FILTER PRESSES eie)
OAT
Figure 6. Plasma and urine nickel values in two temporary
workers tested every 10 days.
From Hrfgetveit and Barton (1976).
C-39
-------
O
I
*>.
o
I ! LI II I I I I I
10
73
276_!§26j6.162657. 1525 4. 14.24 6. 16 26 5 _AT_
10 11 11 11 12 12 12 1 1 1 2 2 2 3 3 3 4 UAIt
Figure 7. Plasma and urine nickel concentrations in a student volunteer. From H0geveit and Barton (1976).
-------
Spruit and Bongaarts (1977a) found a mean nickel urine concentration of
1.8 |jg/dl for seven occupationally exposed individuals and 0.06 ug/dl for 10
unexposed males. After a two-week vacation period, the mean value for the
exposed workers had gone down to 0.18 |jg/dl.
The same authors report on the urine and plasma concentrations in a
healthy, nonexposed volunteer after ingestion of 5 mg of nickel as a solution
of nickel sulfate. Figure 8 shows these concentrations during the first 8
days after ingestion. Plasma and urine concentrations do not follow the same
pattern of response.
As in the case of plasma and serum concentrations, studies of urine
concentrations in occupationally exposed persons have not reported 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 Htfgetveit 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
C-4I
-------
SOH
40 -I
30-1
jUima
1
h
£
z
6
a I' ' ' :'K u N' ,
':V .; T - .1
* i V
1 1 &» ^.B* ^H^ ^H^ a^
1 ,, . «
;
t » 1
0 17 21 .36 4a 00 72 8-> 95
Titne tfttr Hi contunpdon, ft
Figure 8. Blood plasma and Urinary Ni content of a healthy,
non-allergic 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 yg
Ni/1 urine; mean of 8 plasma determinations during the
first 48 hrs. 13.5 ug Ni/1 plasma.
From Spruit and Bongaarts (1977a).
C-42
-------
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, ineffective
cleaning will yield nickel levels from both internal and external exposure. A
second problem is the sampling from different 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 various laboratories can
be compared and conclusions made regarding the exposure - hair level relationship.
Table 11 shows hair nickel values from studies employing atomic absorption
spectrometry techniques. Samples for the Schroedar study were of unspecified
length and were collected from a barbershop. 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 specified. 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, 1-hour soak, repeated rinses in methanol,
C-43
-------
TABLE 11. NICKEL CONCENTRATIONS IN HUMAN HAIR
Authors
Schroeder
and Nason (1969
Eads
and Lambdin (1973)
Nechay
i Spruit
*»
(1973)
(1977)
Method Area
Atomic absorption New Hampshire
Atomic absorption Texas
Atomic absorption Connecticut
Atomic absorption Netherlands
No. and sex
of subjects
79M
25F
19M
21F
20M
10M
14F
Nickel concentration, ppj
Mean Range
0.97
3.69
1.9 0.9-7.2
3.4 0.7-7.5
0.22 0.13-0.51
0.6
1.0
-------
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 report significant differences in
values for men and women. In view of the differences in sample collection,
washing techniques, and details of analytic procedures, it is impossible to
reach conclusions about the nickel content of hair from adults without
occupational exposure.
Chattopradhyay 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 by clipping "close to the head," and the samples
i
were washed sequentially with ether, alcohol, and distilled water, and then
analyzed by nuclear activation techniques. Precision and accuracy for nickel
determination as evaluated by the National Bureau of Standards and Environmental
Protection Agency - NBS standard materials analyses 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 96.8 ± 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)
ppm; 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 metropolitan 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
C-45
-------
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 ppm; for 194 adults, the results
were 0.74 geometric mean, ± 0.27=2.07 geometric SO, range 0.045 to 11.0 ppm.
For nickel, environmental exposure gradients were significantly associated for
children but not for adults.
The role of hair as an excretion tissue for nickel is complicated by the
findings for nickel concentrations in scalp hair and pubic hair of women
studied for maternal-fetal levels of trace elements. Creason et al. (1976)
used dry ashing and emission spectroscopy as the method for nickel concentration
assessment. The mean for 63 samples of scalp hair was 1.7 ug/g and the geometric
mean 1.0 ug/g , while 110 samples of pubic hair showed 0.7 and 0.4 ug/g ,
respectively. The differences in these values are not explained, and the
question of the relative role of scalp hair as an indicator of secretion in
relation to exposure and body burden remains 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 11).
Spruit and Bongaarts (1977b) reported the mean hair nickel concentration
for eight occupationally exposed men as 14.5 ppm. The value for nonexposed
males was reported as 0.6 ppm.
Hair nickel determinations are not usually carried out with industrial
population assessment and such studies appear to restrict themselves to
C-46
-------
evaluation of blood and urine nickel levels, since these are more reflective
of current exposure.
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 generally 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 organs. These
studies can be roughly classed into case studies concerned with specific
diseases or population studies, as discussed below. No j_n vivo studies for
nickel have been reported, though Harvey et al. (1975) performed such a study
using neutron-activation analysis for cadmium.
It is necessary to point out some limitations of the data obtained 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 significantly in their willingness to consent to autopsies not legally
required. It 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 nutritional and
health status. The technical problems of speed, collection of information
retrospectively, and the proportion of dead without living contacts all add to
the difficulty of obtaining reliable 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 cases to
C-47
-------
determine this status may also vary. In the case of investigations of nickel
in tissue from cadavers, there is the problem of the effect of pathology,
stress, or trauma, 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) summarized the findings from the
work by Tipton and her group and concluded that the total nickel content in a
normal man is approximately 10 mg. Table 12 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 spectrometry. Mean values were 0.23 ± 0.06 |jg Ni/g wet
weight for lung tissue and 0.81 ± 0.41 ug net weight for lymph nodes. Numeric
values for concentrations found in liver, kidney, 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. Nickel concentrations for those tissue samples with detectable amounts
were reported. The analytic method of nickel was dry ashing, residue digestion,
and flame atomic absorption spectroscopy. The detection level was not stated,
C-48
-------
TABLE 12. NICKEL CONCENTRATIONS IN KIDNEY AND LIVER, BY GEOGRAPHIC REGION1
o
I
*>
Id
Region
United States
Alaska
Honolulu
Non-U.S. subjects
No. of
samples
161
2
5
146
Kidney
Mean nickel
concentration,
ppm of ash
7
35
4
12.4
Liver
Frequency of
nickel
occurrence, %
27
100
40
58.2
No. of
samples
163
1
5
141
Mean nickel
concentration,
ppm of ash
6
36
4
11.0
Frequency of
nickel
occurrence , %
22
100
40
44.0
Trom Nat. Acad. Sci. (1975).
-------
1.
llr
E
i-t
* »
. n
KMI
r»n
T
i
r*-.
l-t-l
i
3iee«
Noen
Figure 9. Distribution of nickel in human tissues.
From Bernstein (1974).
C-50
-------
but the report of the nickel concentrations in the different tissues indicates
that not all samples showed detectable amounts of nickel. Table 13 shows some
of the nickel concentrations. The total body burden for nickel was calculated
as > 5.7 mg of nickel for a body weight of 55 kg.
The NAS report (1975) contains Sunderman's data (1971) obtained by an
atomic absorption method from material from four autopsies (Table 14).
Nickel concentrations in lung tissue for 15 control subjects in a study
of bituminous coal miners were reported by Sweet (1974). Emission spectros-
copy was employed for nickel analysis. The mean nickel concentration was 0.6
pg/g dry weight.
Creason (1976) reported maternal and fetal tissue levels of nickel. Dry
ashing and emission spectroscopy analysis was employed for nickel determinations.
Placenta! tissue from 160 women yielded an arithmetic mean of 3.4 and a geometric
mean of 2.2 ug/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.
Indraprasit et al. (1974) reported nickel concentrations in tissues
obtained from 220 random autopsies. On the basis of clinical findings the
patient population was divided into three groups. The first group was
classified as "controls" (based on serum creatinine < 1.5 mg percent) and
consisted of 116 patients. The other groups, consisting of 104 patients, were
C-51
-------
TABLE 13. NICKEL CONCENTRATIONS IN JAPANESE HUMAN TISSUES3
Nickel concentration, pg/g wet weight
Organ No. of cases Mean + SD Median Range
Lung 30 0.16 ± 0.094 0.16 0.038-0.44
Liver 27 0.078 ±0.046 0.068 0.028-0.22
Kidney 28 0.098 ±0.070 0.081 0.012-0.30
C-52
-------
TABLE 14. NICKEL CONCENTRATION IN HUMAN TISSUES'
Ul
Nickel concentration, ug/lOOg
Subject no. Sex Age, years Cause of death
1 M 44 Stab wounds
2 F 40 Barbiturate
poisoning
3 M 18 Hanging
4 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
Lung
14.6
12.1
3.3
4.3
8.6
Dry Weight
Liver
2.1
3.2
2.6
4.8
3.2
Heart
2.3
2.4
1.6
3.0
2.3
^Derived from Sunderman et al. (1971).
-------
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
emission 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 1 calendar year. Table 15 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 relationships between
renal failure and nickel concentrations, but it seems worthy of note that
there is a consistent gradient of detectability 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
(Natl. Acad. Sci., 1975), where highest levels of nickel are seen in lung,
with lesser amounts in kidneys, liver, and brain. In a study of coal workers'
penumoconiosis (CWP), nickel content of lung tissue of bituminous coal miners
with CWP showed significantly higher nickel concentrations in lung tissue when
compared to values obtained for nonoccupationally exposed males and females
residing in the area (Sweet et al., 1974). The nickel concentrations for coal
miners with CWP ranged from 5.0 ug/g dry weight to 0.5 ug/g for six groups of
disease severity. The mean for the entire group was 2.5 ug/g dry weight and
the mean value for controls was 0.6 ug/g .
C-54
-------
TABLE 15. NICKEL CONCENTRATIONS IN RENAL CORTEX, LIVER, AND SPLEEN FOR
NORMALS AND PATIENTS WITH ACUTE OR CHRONIC RENAL FAILURE
Kidney
Normal
ARFC
CRFd
Percent
detectability
'27
39
34
Mean
Ni , ppm
dry wt
1.82
1.86
1.82
Liver
Percent
detectability
16
39
43
Spleen
Mean
Ni , ppm
dry wt
1.85
2.14
1.95
Percent
detectability
16
38
40
Mean
Ni , ppm
dry wt
1.72
2.11
1.97
aFrom Indraprasit et al. (1974).
Normal: no acute or chronic renal failure present at time of death.
CARF: acute renal failure present at time of death.
CRF: chronic renal failure present at time of death.
C-55
-------
Metabolism
A number of disease states and other physiological stresses are reported
to alter the movement and tissue distribution of nickel in man as well as
experimental animals. Furthermore, ijn vivo movement of nickel may be
deliberately altered to enhance nickel removal from the organism to minimize
toxicity in cases of excessive 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; Sunderman et al., 1972a;
McNeely et al., 1971), such alterations presently being considered as second-
ary to leukocytosis and leukocytolysis (Sunderman, 1977).
Serum nickel levels are also elevated in acute stroke and extensive burn
injury (McNeely et al., 1971), while reduction is seen in hepatic cirrhosis or
uremia, possibly secondary to hypoalbuminemia.
Palo and Savolainen (1973) report that hepatic nickel was increased
10-fold over normal values in a deceased patient with aspartylglycosaminuria,
a metabolic disorder characterized by reduced activity of aspartyl-p-glucos-
aminidase.
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 during pregnancy (Spoerl and Kirchgessner, 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
C-56
-------
efficient chemotherapeutic agents for use in nickel poisoning. The data have
been reviewed (Natl. Acad. Sci., 1975; Sunderman, 1977) and will only be
summarized in this section.
On the basis of reported clinical experience, sodium diethyldithiocarbamate
f
(dithiocarb) is presently the drug of choice in the management of nickel
carbonyl poisoning, being preferable overall to EDTA salts, 2, 3-dimercapto-
propanol (BAL), and penicillamine. In all cases, the agents work to accelerate
the urinary excretion of absorbed amounts of nickel before extensive tissue
injury can result.
i
There is a growing body of literature that establishes an essential role
for nickel, at least in experimental animals, and the earlier studies have
been reviewed (Natl. Acad. Sci., 1975; Neilsen and Sandstead, 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 specific deficiency-related syndromes
which are prevented or cured by the element alone.
Earlier workers in trace-element nutritional research coulc not demonstrate
any consistent effects of nickel deficiency (Natl. Acad. Sci., 1975; Spears
and Hatfield, 1977) owing in part to the technical difficulties of controlling
nickel intake because of its ubiquity. Later workers have demonstrated adverse
effects of nickel deprivation in various animal models.
Nielsen and Higgs (1971) have shown a nickel-deficiency syndrome in
chicks fed nickel at levels of 40 to 80 ppb (control diet: 3 to 5 ppm) charac-
terized by swollen hock joints, scaly dermatitis of the legs, and fat-depleted
livers. Sunderman et al. (1972b) observed ultrastructural lesions such as
C-57
-------
perimitochondrial dilation 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 decreased growth rate, impaired reproduction, and a rough hair coat
(Anke et al., 1973).
Growth responses to nickel supplementation have also been reported for
rats (Nielsen et al., 1975; Schnegg and Kirchgessner, 1975a; Schroeder 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, 1975).
Effects on reproduction have been documented in rats (Nielsen et al.,
1975) and swine (Anke et al., 1974; Schnegg and Kirchgessner, 1975a), mainly
in terms of increased mortality during 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) demonstrated disturbances in
metabolic parameters in lambs maintained on a low-nickel diet (65 ppb), indosing
intraperitoneally yields lung carcinomas in mice (Stoner et al., 1976) when
nickel acetate 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 nickel deficiency
leads to reduced iron contents in organs and iron deficiency anemia, resulting
from markedly impaired iron absorption.
C-58
-------
Nickel appears to pertain also to other criteria for essentiality (Mertz,
1970): apparent homeostatic control and partial transport by specific
nickel-carrier proteins (see. Metabolism section). Fishbein et al. (1976),
furthermore, have reported that jackbean urease is a natural nickel metalloenzyme,
and it is also possible that rumen bacterial urease may also have a specific
nickel 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. Given the rela-
tively low extent of gastrointestinal absorption (vide supra), fecal levels of
nickel roughly approximate daily dietary intake, 300-500 ug/day in man.
Urinary excretion in man and animals is usually the major clearance route
for absorbed nickel. Normal levels in urine vary considerably in the litera-
ture, and earlier value variance probably reflects methodological limitations.
More recent studies suggest values of 2-4 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 major route of nickel excretion. Hohnadel 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 ug/1 for men and 131 ±
65 ug/1 for women.
C-59
-------
The role of nickel deposition in hair as an excretory mechanism in man
has prompted a number of studies. The use of hair nickel levels in assessing
overall nickel body burdens as well as exposure chronology remains to be
widely accepted. Its utility in epidemiological 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 jjg/g,
S.E.M. = ± 1.06) about fourfold 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 quanti-
tative relationships for the role of hair levels in nickel metabolism.
In experimental animals, urinary excretion is the main clearance route
for nickel compounds introduced parenterally.
Animals exposed to nickel carbonyl by inhalation exhale a part of the
respiratory burden of this agent within 2 to 4 hours while the balance is slowly
degraded j_n vivo to divalent nickel and carbon monoxide, with nickel eventu-
ally undergoing urinary excretion (Sunderman and Selin, 1968; Mikheyev, 1971).
C-60
-------
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 documented for nickel in man and
animals. It is not the purpose of this treatment to assemble a thorough
review of the literature on nickel, 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 proper-
ties; thus, for emphasis, these two areas are discussed 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 toxicant. 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 to serve essentiality and not enough to precipitate adverse effects.
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 reflection 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 functional and structural organization. This
approach of course is an arbitrary, if widely used, device to elaborate the
C-61
-------
range and types of toxicant effects. In reality, the overall response of an
organism to a toxic agent is a complex integration of discretely determined
phenomena. In some cases, it is more appropriate to discuss, subcellular and
cellular effects with the associated systemic effects 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 nontoxic, 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 up to 1000 ppm in diet for
8 weeks had no effect on growth rate (Phatak and Patwardhan, 1952);
similarly, these forms of nickel at 1000 ppm when fed to monkeys for up to 6
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 lethal-ity percentages have been tabulated
(Natl. Acad. Sci. , 1975).
Exposure to nickel by inhalation or parenteral administration as well as
cutaneous contact is of greater significance to the picture 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 contact with carbon monoxide, as in the Mond
C-62
-------
process for purification of nickel (Mond et a!., 1890). The threshold limit
value (TLV) for a work day is 1 part per billion (ppb) (Am. Conf. Gov. Ind.
Hyg., 1971).
A sizable body of literature has developed over the years dealing with
the acute exposure of nickel processing workers to nickel carbonyl by inha-
lation (Natl. Acad. Sci., 1975; Natl. Inst. Occup. Safety Health, 1977;
Sunderman, 1977). Since much of this information is relevant mainly to
occupational medicine rather than general environmental health, it is not
appropriate 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 from the weakness and hyperpnea, the
symptomology strongly resembles 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 epithelium, and formation of fibrinous
intra-alveolar exudate. Roentgenological followup on patients surviving the
acute episode of exposure frequently indicates pulmonary fibrosis.
C-63
-------
The pronounced pulmonary tract lesion formation seen in animals acutely
exposed to nickel carbonyl vapor strongly overlaps that reported for cases of
acute industrial poisoning, and these have been tabulated in Table 16.
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 1 hour of exposure.
There is subsequent proliferation and hyperplasia of bronchial epithelium and
alveolar lining cells. By several days postexposure, severe intra-alveolar
edema with focal hemorrhage and pneumocyte derangement has occurred.
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 industrial exposure. Hyperplasia of bronchiolar
and bronchial epithelium with peribronchial lymphocytic infiltrates was seen.
Port et al. (1975) noted that intratracheal injection of a suspension of
nickel oxide (5 mg, <5 urn) into Syrian hamsters first treated with influenza
A/PR/8 virus 48 hours previously significantly increased mortality versus
controls. Surviving animals at this dosing and lesser doses showed mild to
severe acute interstitial infiltrate of polymorphonuclear cells and macrophages
several weeks later. Additional pathological changes included bronchial
epithelial hyperplasia, focal proliferative pleuritis and adenomatosis.
C-64
-------
TABLE 16. ACUTE PULMONARY EFFECTS OF NICKEL CARBONYL EXPOSURE IN ANIMALS
Animal
Dosing
Effects
Reference
Rabbit
Rat
n
i
Rat
Rat, dog
Rat
Rat
Inhalation
1.4 mg/1. ,
50 min
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
Intraalveolar hemorrhages, edema
and exudate; alveolar cell degen-
eration by days 1-5
At 2-12 hr, capillary congestion
and interstitial edema; at 1-3 hr
days, intraalveolar 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, intraalveolar 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
intraalveolar edema, hemorrhage
sub-pleural consolidation, hyper-
trophy and hyperplasia of alveolar
lining cells
Ultrastructural alterations, includ
ing edema of endothelial cells at
6 hr and massive hypertrophy of
membranes and granular pneumocytes
at 2-6 days
Armit, 1908
Barnes and Denz,
1951
Kincaid et al.,
1953
Sunderman et al.,
1961
Hackett and
Sundermann,
1967
Hackett and
Sundermann,
1969
-------
A number of studies have been directed to the effects of nickel on
endocrine-mediated physiological processes. As noted in the previous section
dealing with nickel metabolism, exposure of animals to nickel especially
parenterally consistently shows marked uptake 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 Vignati, 1973; Freeman and Langs!ow, 1973; Horak and
Sunderman, 1975a,b) observed a rapid, transitory hyperglycemia after parenteral
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 hypophysectomized rats. Injection of nickel
chloride (2 or 4 mg/kg) produced prompt elevations in plasma glucose and
glucagon levels with a return to normal 2 to 4 hours afterwards, suggesting
that hyperglucagonemia may be responsible for the acute hyperglycemic response
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, while concurrent administration of insulin
antagonized the hyperglycemic effect (Horak and Sunderman, 1975b). Kadota and
Kurita (1955) observed 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).
C-66
-------
Human endocrine responses to nickel have been poorly studied, although
Tseretili and Mandzhavidze (1969) found pronounced hyperglycemia 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) thereby decreasing
the release of prolactin from bovine and rat pituitary glands (La Bella et
al., 1973a). Furthermore, intravenous administration of small amounts of
nickel to urethane-anesthetized, chlorpromazine-treated rats produces signficant
depression of serum prolactin without any effect on growth hormone or thyroid-
stimulating hormone, although the iji vitro release of pituitary hormones other
than PIF have been demonstrated for bovine and rat pituitary (La Bella et al.,
1973b).
Dormer et al. (1973) and Dormer and Ashcroft (1974) have studied the j_n
vitro effects of nickel on secretory systems, particularly the release of
amylase, insulin, and growth hormone. Nickel (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 La Bella 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 secretory-granule migration or membrane
fusion and microvilli formation.
Nickel-induced nephropathy in man or animals has not been widely docu-
mented. Acute renal injury with proteinuria and hyaline casts were observed
by Azary (1879) in cats and dogs given nickel nitrate. Pathological lesions
of renal tubules and glomeruli have been seen in rats exposed to nickel carbonyl
C-67
-------
(Kincaid et al., 1953; Sunderman et al., 1961; 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. Ultrastructurally,
the site of the effect within the kidney appears to be glomerular epithelium.
These renal effects were seen to be transitory, 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.
Nickel compounds appear to possess low neurotoxic potential save for
fatal acute exposures to nickel carbonyl (Natl. Acad. Sci., 1975; Natl. Inst.
Occup. Safety Health, 1977).
Neural tissue lesion formation in the latter case is profound, including
diffuse punctate hemorrhages in cerebral, cerebellar, 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
Sunderman, 1978), the erythrogenic effect being apparently unrelated to the
carcinogenicity of the compound (Jasmin and Riopelle, 1976). Morse et al.
(1977) showed that the erythrocytosis is dose-dependent, is not elicited
by intramuscular administration and is associated with marked erythroid hyper-
plasia of bone marrow. Hopfer and Sunderman (1978) observed a marked inhi-
bition of erythroctyosis when manganese dust was co-administered.
Effects of nickel on thyroid function have been noted by Lestrovoi et al.
(1974). Nickel chloride given orally to rats (0.5-5.0 mg/kg/day, 2 to 4 weeks)
C-68
-------
or by inhalation (0.05 to 0.5 mg/m ) 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.
Nickel dermatitis and other dermatological effects of nickel have been
extensively documented in both nickel worker populations and populations at
large (Natl. Acad. Sci., 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 occupational 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 (Natl. Acad. Sci., 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 (Natl.
Acad. Sci., 1975).
Nonoccupational exposure to nickel leading to dermatitis includes nickel-
containing jewelry, coinage, tools, cooking utensils, stainless steel kitchens,
prostheses, and clothing fasteners. Women appear to be particularly at risk
for dermatitis of the hands, which has been attributed to their continuous
contact with many of the nickel-containing commodities noted above (Maiten
and Spruit, 1969).
C-69
-------
Nickel dermatitis in nickel miners, smelters, and refiners and known as
"nickel itch" usually begins as itching or burning papular erythema in the
web of the fingers and spreading to the fingers, wrists, and forearms. Clini-
cally, the condition is usually manifested as a papular or papulovesicular
dermatitis with a tendency 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) secondary: 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 removal of obvious sources of exposure.
A clear relationship between atopic dermatitis and that elicited 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 immunoglobulin
in E (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 sulfate has
-*
been considered significant in connecting nickel and atopic dermatitis (Becker
and O'Brien, 1959). Uehara et al. (1975) have reported that pustular patch
test reactions to 5 percent nickel sulfate were regularly produced in patients
with atopic dermatitis, but only when applied to areas of papulae, erythema,
C-70
-------
lichenification, and minimal trauma; such response seldom occurred on
normal-appearing skin surface. Furthermore, traumatizing the test areas in
control as well as dermatitic subjects furnished positive responses. These
workers suggest that pustular patch testing is primarily a primary irritant
reaction.
Christensen and Mb'ller (1975a) found that of 66 female patients 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
(Christensen and Mbller (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 excre-
tion and the status of dermatitis in their patients, Menne and Thorboe (1976)
have reported elevated urinary nickel levels during flare-ups in the derma-
titis. De Jongh et al. (1978) found limited correlation between plasma nickel
level, urinary excretion of nickel and the clinical activity of the condition
in a patient followed during two periods of 5 and 6 weeks each.
Internal exposures to nickel associated with nickel sensitivity and
arising from prosthesis alloys have been reviewed (Natl. Acad. Sci., 1975; Samitz
and Katz, 1975; Fisher, 1977), and much of these data are summarized in this
section.
C-71
-------
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 urticaria! and eczematous
dermatitis have been attributed to implanted prosthesis with resolution of the
condition after removal of the devices (Natl. Acad. Sci., 1975; Samitz and
Katz, 1975). Apparently, sufficient solubilization 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 interpreting 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 nickel 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 object. The optimal nickel concentration 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 (Natl. Acad. Sci.,
1975).
The induction of nickel sensitivity in human subjects has been claimed
by Haxthausen (1936) and Burckhardt (1935). In their subjects, prior sensi-
tivity was not ruled out. Furthermore, the concentration of the sensitizing
C-72
-------
solution, 25 percent, may easily have induced an irritation response. More
recently, Vandenberg and Epstein (1963) successfully sensitized 9 percent (16
of 172) of their clinical subjects.
One area of controversy with regard to nickel dermatitis involves the
question of hypersensitivity to groups of metals, i.e., cross sensitivity, and
various sides of the issue have been reviewed (Natl. Acad. Sci., 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 individuals 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 (Natl. Acad. Sci., 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 10
patients with nickel contact dermatitis could be elicited with nickel bound to
bovine and human serum albumin or human epidermal protein, but not with nickel
ion alone. Hutchinson et al. (1975) noted nickel binding to lymphocyte surfaces
from both sensitive 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 conditions.
C-73
-------
Nilzen and Wilstrdm (1955) reported the sensitization of guinea pigs to
nickel via repeated topical application of nickel sulfate in detergent solu-
tion. Samitz and Pomerantz (1958), however, have attributed this to local
irritation rather than true allergenic response. Samitz et al. (1975) were
unable to induce sensitization 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 sulfate in
highly sensitive guinea pigs. The reactions to the challenge were statistically
greater than with control animals. Turk and Parker (1977) reported sensiti-
zation to nickel manifested as allergic-type granuloma formation. This required
the use of Freund's complete adjuvant followed by weekly intradermal injections
of 25 ug of the salt after 2 weeks. Delayed hypersensitivity reactions developed
in two of five animals at 5 weeks by use of a split-adjuvant method. Interestingly,
these workers also observed (Parker and Turk, 1978) suppression of the delayed
hypersensitivity when intratracheal intubation of nickel sulfate was also
carried out on these animals.
There are no studies of general populations which relate nickel exposures
or levels in tissues and fluids to physiological, subclinical or clinical
changes. The studies previously cited do not cover properly designed and
executed samples of either total populations or selected population segments
which would permit projection 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 carcinogenesis. The
literature on adverse health effects in relation to nickel exposure by the
C-74
-------
general population is limited to the investigation of nickel dermatitis and
nickel sensitivity, with only occasional reports related to other diseases or
conditions.
Nickel Sensitivity and Contact Dermatitis
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 sig-
nificantly by socio-demographic characteristics. For example, a hairdresser
or manicurist with dermatitis 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 10 cities in the United States. The subjects
were selected from outpatient clinics and the private practices of the 13
participating dermatologists. The specific method of selection was not reported,
and therefore the proportions 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
C-75
-------
sulfate. Table 17 shows the results 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 tested 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 frequent in females. The North American study testing 16 allergens found
that nine other allergens had higher positive reaction 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 subjects. Black males in the North American group
data showed the highest reaction rate to nickel.
Brun (1974) reported on 1000 cases of contact dermatitis from the Uni-
versity 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
reaction 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
C-76
-------
TABLE 17. NORTH AMERICAN CONTACT DERMATITIS GROUP PATCH TEST RESULTS FOR
2.5 PERCENT NICKEL SULFATE IN 10 CITIES3
Subjects
Black
White
All
Total
Females
Males
Total
Females
Males
Total
Females
Males
Positive Reactions
Total No.
79
64
143
612
445
1057
691
509
1200
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
aFrom North American Contact Dermatitis Group (1973).
C-77
-------
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 personal or familial atopy were found for nickel-
sensitive and nonsensitive patients with hand eczema. All cases were ladies'
hairdressers; they showed a positive reaction rate of 40 percent to nickel
sulfate (5 percent) solution.
Both Spruit and Bongaarts (1977b) and Wahlberg (1975) reported that
positive reaction to nickel sulfate occurs at very low dilution 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 positive reaction when the solution was 10 ug Ni /I.
Nickel sensitivity is prevalent among women, and nickel content dermatitis
occurs frequently not only among women but also among men who are exposed.
Nickel is extremely common in the articles and substances found in the home
and in metals used for jewelry, 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
dermatitis seems to vary with the surrounding social factors: male factory
C-78
-------
workers appear not to be handicapped by it (Spruit and Bongaarts, 1977b) and
continue in their work; hairdressers leave their occupation when they develop
dermatitis (Wahlberg 1975).
The impact of nickel dermatitis on the health of the total U.S. popula-
tion cannot be assessed at this time since the prevalence of this condition in
the population is unknown. Also, there are no data on the range of severity
and the consequences, the costs, of the condition.
Sensitivity to Nickel in Prostheses
Stainless steel, chrome, and other metal alloys used in prostheses 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 prostheses reported in the literature as
associated with adverse reactions to their nickel contents: wire suture
materials; metallic mesh for nasal prostheses; heart valves; intrauterine
contraceptive 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
electrolysis and metallic corrosion may have occurred.
Deutman and colleagues (1977) report on metal sensitivity before and
after total hip arthroplasty in 212 cases from their orthopedic service in
Groningen, The Netherlands. They instituted their study because recent
C-79
-------
literature contains reports of reactions to orthopedic implants including
loosening of total joint prostheses. The authors 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. Fourteen 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 solution was employed in the
patch test. (The nickel sulfate solution standard has been changed since the
time of the European work reported in this section on Nickel Contact Dermatitis
above.) The 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 joint replacement and subsequent loosen-
ing and reoperations, and six with stable McKee-Farrar prostheses. Of the
eleven 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 previous 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 postoperative patch-testing
of 66 of the 198 patients without pre-operative 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
included one woman with a negative preoperative patch test but a history of
C-80
-------
eczema from garters who was positive on postoperative patch test. None of the
66, regardless of sensitivity status, had shown pain, loosening of the pros-
thesis, infection, or skin symptoms during the postoperative period of
approximately 2 years. This represents a conversion rate of 6 percent within
up to about 2 years postoperatively. A sensitivity rate of 4.6 percent to
nickel by patch test was found in the 173 patients without previous bone
surgery.
While nickel sensitivity in persons receiving orthopedic implants puts
them at higher risk of complications, this does not represent a health problem
to the population 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 (1961) have described one case of chronic inhalation of nickel
carbonyl at low levels, in which the patient had developed asthma and Lb'ffler's
syndrome.
Adverse pulmonary effects in man due to other nickel compounds, are noted
below and discussed elsewhere in regard to occupational carcinogenicity.
Russian workers (Tatarskaya, 1960; Kucharin, 1970; Sushenko and Rafikova,
1972) have observed chronic rhinitis and nasal sinusitis in workers engaged in
nickel electroplating operations where chronic inahaltion of nickel aerosols
such as of nickel sulfate had occurred. Associated findings commonly en-
countered were anosmia and nasal mucosal injury including nasal septum
perforation. Asthmatic lung disease in nickel plating workers has been
documented by Tolat et al. (1956) and McConnell et al. (1973). Based on
C-81
-------
various animal studies as described elsewhere, inhalation of nickel
particulate matter is likely to play a role in chronic respiratory infections
in nickel workers via effects on the activity of alveolar macrophages.
The role of oral nickel in dermatitic responses has also been demon-
strated by Kaaber et al. (1978), who investigated the effect of a low
nickel diet in patients with chronic nickel dermatitis presenting as hand
eczemas of dyshidrotic morphology. Of 17 subjects in the clinical trial,
nine showed significant improvement during a period of 6 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 margarine, Polish margarine having a rather high nickel content, up
to 0.2 mg Ni/kg.
C-82
-------
IN VITRO AND IN VIVO STUDIES
Subcellular and Cellular Aspects of Nickel Toxici'ty
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 jj\ 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, peptides, and amino acids (Natl. Acad,
Sci., 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.
In the previous section dealing with nickel metabolism, it was noted that
serum albumin is the main carrier protein for macromolecular-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 describing
2J2 vivo and jji vitro effects of various nickel compounds on enzyme systems,
nucleic acid and protein synthesis as well as related effects in experimental
animals. Data obtained j_n vivo are tabulated in Table 18, while _ui vitro
effects are presented in Table 19.
C-83
-------
TABLE 18. IN VIVO BIOCHEMICAL EFFECTS OF NICKEL COMPOUNDS
Compound
Ni (C0)4
Ni(CO)4
Ni(CO)4
o
£ Ni(CO)4
Ni(CO)4
Ni(CO).
Animal
Rat
Rat
Rat
Rat
Rat
Rat
Dosing conditions
I.V. 20 mg/kg
Inhalation
0.20 mg/liter air
I.V. 20 mg/kg
I.V. 20 mg/kg
I.V. 22 mg/kg
I.V. 22 mg/kg
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 pyrrol ase
Inhibition of phenobarbital induc-
tion of hepatic cytochrome
Inhibition of RNA polymerase in
hepatic nuclei
Incorporation of ( C)-orotic acid
into hepatic RNA
Inhibition of RNA synthesis by
Reference
Sunderman, 1967a
Sunderman, 1967b
Sunderman, 1968
Sunderman and
fsfahani, 1968
Beach and Sunder-
man, 1969
Beach and Sunder-
Ni(CO),
Ml(CO),
Rat
Rat
I.V. 22 mg/kg
I.V. 22 mg/kg
hepatic chromatin - RNA polymerase
complex
Inhibition of phenobarbital
induction of aminopyrene
demethylase
Slight inhibition of leucine incor-
poration into liver microsomal
proteins
man, 1970
Sunderman and
Leibman, 1970
Sunderman, 1970
Ni(CO),
Rat
I.V. 22 mg/kg
Elevated liver ATP level
Sunderman, 1971
-------
TABLE 18. (continued)
Compound
NiSO,
NiCl,
NiCl.
Animal
Dosing conditions
Effects
Rat
o
1
00
Ln
Nickel (II)
ion
Young
mouse
Rat
Rat
Rat
I.P. 3 mg/kg
daily, 30-90
days
I.P. 19 mg/kg,
single dose
Oral 225 ppm
long term, water
I.P. 250 mg/kg,
single dose, 3-6
hours before
sacrifice
I.M.
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 phosphorylase
4-fold increase in serum glucose,
hyperlipidemia and insulin resistance
elevated serum triglycerides
ATP-ase activity in brain capillaries
abolished Joo, 1969
Glyceraldehyde-3-phosphate dehydro-
genase inhibited; Glucose-6-
phosphate dehydrogenase elevated
within 6 hr.
Reference
Ni(CO).
^
NiCl?
Rat I.V. 22 mg/kg
Rat S.C. 16 mg/kg
Inhibition of RNA synthesis in liver Witschi, 1972
but not lungs
Reduced liver ALA-synthetase, reduced Maines and Kappas,
1977
Mathur et al.,
1977
Weber and Reid,
1968
Clary and Vignati,
1973
Joo, 1968
Basrur and
Swierenga, 1970
-------
TABLE 19. IN VITRO BIOCHEMICAL EFFECTS OF NICKEL COMPOUNDS
Compound
System
Exposure
Effects
Reference
Ni(II) ion Rat liver microsomes Up to 100 uM Ni
Ni(II) ion Rabbit liver and
lung microsomes
, Ni(II) ion
DNA polymerase from
avian myeloblastosis
virus
Ni(II) ion DNA polymerase from
E^ coli
Ni(II) ion Rat brain synapto-
somes
Ni(II) ion Rat hepatic micro-
somes
Ni(II) ion Cilia of Tetrahymena
pyriformis
Ni(II) ion Sheep alveolar
macrophages
Ni(II) ion Sheep alveolar
macrophages
CO
( Ni) - Rat embryo muscle
Ni0S0 culture
Up to 50 mM Ni
Up to 8 mM Ni
5 mM Ni
Up to 300 pM Ni
5 mM Ni
1 mM Ni
0.5 mM Ni
Activity of benzopyrene
hydroxylase reduced to half
at 0.5 umolar Ni; total
inhibition at 10 umoles
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 uM
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 Foil
1974
Si rover and Loeb
1977
Miyaki et al.,
1977
Prakash et al.,
1973
Federchenko and
Petrun, 1969
Raff and Blum,
1969
Mustafa et al.,
1969
0'Sullivan and
Morrison, 1963
Basrur and
Swierenga, 197
-------
A number of investigators have studied the effects of nickel compounds on
inducible 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 induction of
benzopyrene hydroxylase in lungs and liver (Sunderman, 1967a), the cortisone
induction of hepatic tryptophan pyrrolase (Sunderman, 1967b) the phenobarbital
induction of hepatic cytochrome (Sunderman, 1968), and phenobarbital induction
of aminopyrine demethylase (Sunderman and Leibman, 1970). Nickel carbonyl
inhibition of benzopyrenehydroxylase activity probably reflects reduced enzyme
biosynthesis, since _in vitro exposure to the agent had no effect. Nickel
sulfate, however, at levels greater than 1 mM does inhibit the enzyme vn vitro
o
(Dixon et al., 1970). Since benzopyrene is an active carcinogen, it has been
suggested that a mechanism for at least co-carcinogenicity of nickel relates
to increased retention of the hydrocarbon, particularly in the case of heavy
cigarette smokers (Dixon et al., 1970; Sunderman, 1967a).
Maines and Kappas (1977) have reported effects of nickel (II) injection
on cellular heme metabolism 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 jjj vitro at levels of 12.5 to 250 uM, indicating that direct activation
of preformed enzyme does not occur ijn vivo.
Inhibition of RNA symthesis in the rat, probably via an effect on RNA
polymerase (Sunderman and Esfahani, 1968; Beach and Sunderman, 1969, 1970;
Witschi, 1972) has been demonstrated with nickel carbonyl. Moderate inhi-
bition by this agent of hepatic protein synthesis has also been noted (Sunderman,
1970).
C-87
-------
The inhibition of ATPase by nickel salts i_n vitro and in vivo has been
reported for the enzyme from different sources (Prakash et al., 1973; Federchenko
and Petrun, 1969; Raff and Blum, 1969; Mustafa et al., 1971; Joo, 1968 and
1969). In contrast, Mathur et al. (1977) find that ATPase activity is
elevated in rat testicular tissue for all time points (30, 60, and 90 days)
when rats are given Ni intraperitoneally, 3 mg/kg daily. Sunderman (1971) has
suggested that the inhibition of ATPase and other ATP-requiring enzymes
likely involves binding of divalent nickel to ATP, making it unavailable for
subsequent utilization since it is known that nickel can form a stable complex
with ATP (Sigel et al., 1967).
Jji vitro and _ui vivo studies of nickel subsulfide (Ni;^) on muscle
tissue (Basrur and Swierenga, 1970) revealed impairment of glycolytic enzyme
activity.
Si rover and Loeb (1977) have demonstrated alteration of magnesium-
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 carbonyl inhalation in
the rat led to increases in microsomal and supernatant fractions of lung and
liver homogenates. Webb and co-workers (1972) have found that 70-90 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. Further-
more, nickel binding to RNA and DNA was observed in nuclei of rhabdomyo-
sarcomas from rats given nickel subsulfide intramuscularly (Heath and Webb,
C-88
-------
1967). In mouse dermal fibroblasts grown HI vitro and exposed to various
63
Ni-labeled compounds, Webb and Weinzierl (1972) noted a similar distri-
bution. These data are consistent with the findings of Beach and Sunderman
(1970) that nickel is bound to the RNA polymerase-chromatin complex obtained
from rat liver nuclei after nickel carbonyl exposure. Recently, Jasmin and
Solymoss (1977) have reported that intrarenal administration of nickel sub-
sulfide in the rat led to the highest relative amounts in the nuclear fraction
of kidney homogenate with smaller amounts in mitochondria and microsomes.
Moffitt et al. (1972) observed that alterations in the normal subcellular
distribution of nickel in rat tissue occur with the acute administration of
benzopyrene (8 mg intratracheally). By 3 days postexposure, significant
reductions of nickel content were seen in nucleus, mitochondria, and micro-
somes.
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), ultra-
structural alterations in hepatocytes included nuclear distortion by 24 hours,
dilation of rough endoplasmic reticulum at 1 to 4 days, and cytoplasmic inclusion
bodies at 4 to 6 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
mitochondria! conformational changes, accumulation of electron-dense granules,
and elaboration of cristae which have coalesced and formed wavy or parallel
C-89
-------
stacks in all cases. Degenerative changes, including disruption 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 myo-
blasts exposed to nickel subsulfide exhibited a variety of organellar changes
(Sykes and Basrur, 1971). At the cell periphery, cytoplasmic blebs containing
clusters of free ribosomes appeared to form and dissociate from the myotube
while cellular organelles aggregated in the center. Alterations in the fine
structure and alignment of mitochondria caused derangement of the contractile
elements. Using scanning electron microscopy, Geissinger et al. (1973) showed
that chromosomal abnormalities existed in a nickel subsulfide sarcoma from rat
muscle tissue (20 mg intramuscularly). Neoplastic cells from renal tumors in
rats induced by intrarenal administration of nickel subsulfide are character-
ized 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 juj vitro correlates of nickel's effects rn vivo
have proved particularly valuable in helping elucidate the allergenic, immuno-
logical, and carcinogenic aspects of nickel toxicity in man and experimental
animals.
Reports have appeared in the literature dealing with the response of
alveolar macrophages and other components that serve a protective function in
respiratory tract to nickel compounds. Waters et al. (1975) have studied the
toxicity of nickel ion to rabbit alveolar macrophages i_n vitro. At a concentra-
tion of about 4 mM nickel, a 50 percent reduction in viable cells occurred,
C-90
-------
viability being determined by trypan blue exclusion. In a related study,
Graham et al. (1975) studied the response of rabbit alveolar macrophages to
levels of nickel that did not affect their viability. Of various metal ions
tested, nickel was the only element that induced changes in phagbcytic activity
without significant 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 spheres. lr\ vitro ex-
posure of rabbit alveolar macrophages to nickel ion at 0.1 mM concentration or
greater caused significant inhibition of antibody-mediated rosette formation,
the extent of inhibition being concentration-dependent (Hadley et al., 1977).
These results suggested to the authors that antibody-mediated rosette forma-
tion may be useful as a rapid and sensitive screen for metal toxicity.
Transformation of cultured human peripheral lymphocytes as a sensitive HI
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 reviewed (Natl. Acad. Sci., 1975). The studies
of Hutchinson et al. (1972), Forman and Alexander (1972), Millikan et al.
(1973), Gimenez-Camarasa et al. (1975), and Svejgaard et al. (1978) have,
however, established the reliability of the technique.
Jacobsen (1977) has investigated the response of cultured epithelium-like
cells from human gingiva to nickel inasmuch as the element appears in dental
prosthetic materials. Significant effects 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.
C-9-1
-------
Exposure of rat embryo myoblasts in culture to nickel subsulfide dust
results in drastic reduction of mitotic index and cell survival (Sykes and
Basrur, 1971). Daniel et al. (1974) assessed the effect of nickel-serum
complexation on cultures of chick myoblasts 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 along with 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 frequency of
cell colony pi ling-up/test plate, the most pronounced effects were noted
with nickel subsulfide, nickel dust, and nickel subselenide. These data are
consistent with other documented comparative 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 lipolysis, along with
increased glucose incorporation into lipids, possibly mimicking the action
of insulin at the cell plasma membrane (Saggerson et al., 1976).
According to Taubman and Mai nick (1975), nickel ion at levels of 1.0
uM-1.0 mM did not trigger histamine release from rat peritoneal 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.
Synergisim and/or Antagonism
There are experimental data that demonstrate that nickel has a synergistic
effect on the carcinogenicites of polycyclic aromatic hydrocarbons. Toda
(1962) has found that 17 percent of rats receiving intratracheal doses of
c-92
-------
nickel oxide along with 20-methylcholanthrene developed squamous cell carci-
nomas; 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 benzopyrene was noted. It is likely,
then, that tissue retention of these organic compounds is prolonged with
nickel exposure. Kasprzak et al. (1973) observed pathological reactions in
lungs of rats given both nickel subsulfide and benzopyrene 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 pertinent literature
has been reviewed (Morgan et al., 1973; Natl. Acad. Sci., 1975). Little in
the way of experimental studies exists to shed light on any etiological role
of nickel in asbestos carcinogenicity, 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 carcinogenicity
of nickel.
Virus-nickel synergism is suggested by the observation of Treagon and
Furst (1970) that jji vitro suppression of mouse L-cell interferon synthesis
occurs in response to Newcastle Disease virus with nickel present.
Teratogenicity
Little evidence for nickel as a teratogen has been documented. While
Perm (1972) has claimed unspecified malformations in surviving 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.
C-93
-------
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 1000 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 12-17 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 8 hours
post-exposure, while peak levels of nickel in maternal blood and placentae
were observed 2 hours afterwards. In 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 8 of gestation, the amount of label being
equivalent to that in maternal lungs, adrenals and ovaries. Furthermore,
autoradiograms revealed nickel label in yolk sacs of placentae 1 day post
injection (day 18 of gestation) and some passage of label into fetal tissue.
On day 19, fetal urinary bladder had the highest level of label.
The data of Phatak and Patwardhan (1950) on litter sizes from pregnant
rats fed nickel in various forms at a level of 1000 ppm suggest a reduction in
pup numbers at this exposure level. Schroeder and Mitchener (1971) followed
three generations of rats continuously exposed to nickel in drinking water (5
ppm). Increased numbers 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 generations of rats given
nickel in diet at concentrations of 250 to 1000. There was increased fetal
C-94
-------
mortality in the first generation while body weights were decreased in all
generations at 1000 ppm. Perm (1972) noted that intravenous administration of
nickel acetate (0.7-10.0 rtig/kg) to pregnant hamsters at day 8 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 ing 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 spermatids and destruction of Sertoli cells. Such effects
were noted to be reversible. Von Veltschewa et al. (1972) noted inhibition of
spermatogenesis in rats given daily oral doses of nickel suflate (2-5 mg/kg)
with reduction in the number of basal cells within the tubules and in the
number of spermatozoa-containing tubules. Continuation of the dosing regimen
for 120 days resulted in complete obliteration of fertility in these animals.
No gametotoxic effects have been documented in man.
Carcinogenicity
The present status of nickel's role in occupational and experimental
carcinogenesis has been the subject of a number of reviews (Int. Agency Res.
Cancer, 1976; Nat!. Acad. Sci., 1975; Natl. Inst. Occup. Safety Health, 1977;
Sunderman, 1973, 1976, 1977).
A carcinogenic response to various nickel compounds upon injection has
been observed in a number of animal studies (Sunderman et al., 1975, 1976; 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
tumorigenie.
C-95
-------
Experimental Carcinogenesis
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 differences within animal models), and the amounts of the
substance employed.
Some of the experimental models of nickel carcinogenesis which have
evolved out of various laboratories are given in Table 20, along with the
various carcinogenic nickel compounds employed, the levels of material used
and the routes of administration. Responses are usually at the site of in-
jection, although in the case of nickel acetate injection, pulmonary carcino-
mas were detected in mice given repeated intraperitoneal injections (Stoner
et al., 1976). There have been no reports of experimental carcinogenesis
induced by oral or cutaneous exposure.
Nickel metal, in the form of dust or pellets, leads to induction of
malignant sarcomas at the site of dosing in rates, guinea pigs, and rabbits
(Hueper, 1955; Heath and Daniel, 1964; 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 compounds, Gilman
(1962) noted that nickel subsulfide (Ni^S^) was a potent inducer of rhabdomyo-
scarcomas when given intramuscularly. Later studies of the carcinogenicity of
nickel subsulfide demonstrated adenocarcinomas in rats given the substance
intrarenally (Jasmin and Riopelle, 1976), rhabdomyosarcomas, fibrosarcomas,
and fibrohistocytomas in rat testicular tissue after intratesticular dosing
(Damjanov et al., 1978) and lung epidermoid and adenocarcinomas in rats inhaling
nickel subsulfide (Ottolenghi et al., 1974).
C-96
-------
TABLE 20. EXPERIMENTAL MODELS OF NICKEL CARCINOGENESIS
Animal Agent
Rat, mice Ni dust
Guinea pig Ni dust
Rat Ni dust
o
i
15 Rat Ni dust
Rat Ni pellet
Rat, mouse Ni,S2 or
Rio dust
Syrian NioS^
hamster
Rat Nl3S2
Rat Ni3S?
Rat Ni3S2
Dosing
Intrapleural/intraosseous:
0.06% 5% suspension
suspension
Inhalation 3
15 mg 1 m
I.M. , 28 mg in serum
I/P. , intrathoracic
5 mg in saline
S.C. , 2 x 2 mm
I.M. , 20 mg/thigh
I.M. , 5 or 10 mg,
single
Inhalation -
ca 1 mg/m
Intrarenal
5 nig/saline or
glycerol
Intratesticular,
r\ f i f\
Response
Sarcomas
Lung anaplastic carcinomas
and adenocarcinomas
Rhabdomyosarcomas
Mesotheliomas
Sarcomas
Rhabdomyosarcomas
Sarcomas
Epidermoid carcinomas and
adenocarcinomas (lung)
Renal adenocarcinomas
Fibrosarcomas and
._! L J ._
Reference
Hueper, 1955
Hueper, 1958
Heath and Daniel,
1967; Heath an!
Webb, 1967
Furst et al. , 191
Mitchell et al. ,
1960
Gilman, 1962
Sunder man et al . ,
1977
Ottolenghi et al,
1974
Jasmin and Riopel
1976
Damjanov et al. ,
T mo
-------
TABLE 20 (continued)
o
1
VO
00
Animal
Rat
Rat
Mouse
Rat,
hamster
Rat
Rat
Agent
Ni(CO)4
Ni(CO)4
Ni(0ac)2
Nickel -
ocene
NiV/
Benz-
pyrene
Ni3S2/
Benz-
pyrene
Dosing
Inhalation,
4-80 ppm
I.V., 50 pi/kg
I. P. , 360 mg/kg
I.M.
I.M. , 10 mg/5 mg
Intratracheal:
2-5 mg
Response
Epidermoid and anaplastic
carcinoma, and adenocar-
cinomas (lung)
Carcinomas and sarcomas
Lung adenocarcinomas
Sarcomas
Sarcomas
Squamous cell carcinomas
Reference
Sunderman et al. ,
1959; Sunderman
and Donnelly,
1965
Lau et al. , 1972
Stoner et al. ,
1976
Haro et al. , 1968
Furst and
Schlauder, 1971
Maenza et al. , 19
Karsprzak et al. ,
1968
Rat
NiO/
methyl-
cholanthrene
Intratracheal:
Squamous cell carconimas
Toda, 1962
-------
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, respectively. As noted above, repeated
dosing intraperitoneally yields lung carcinomas in mice (Stoner et al., 1976)
when nickel acetate 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).
The underlying biochemical mechanisms governing the carcinogenicities of
various nickel compounds have yet to be fully elucidated.
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 dissolution from extracellular deposition by extracellular
fluid presumably 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 complexes obtained by adding nickel
dust to muscle homogenate jji 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 injured
by dust contact take up solubilized nickel and undergo subsequent neoplastic
transformation.
C-99
-------
Singh and Gilman (1973), in a study using double-diffusion chambers con-
taining nickel subsulfide implanted intraperitoneally in rats, observed effects
on rhabdomyocytes 2 to 24 days later, indicating the intermediacy of a soluble
nickel complex, since the technique interposes a solution barrier between
agent and cellular surface. Using Ni-labeled nickel subsulfide, Sunderman
et al. (1976), observed that intramuscular administration in rats was followed
by localization within macrophages and fibroblasts by the end of the first
week. In a related report, Kasprzak and Sunderman (1977) monitored the
63
relative rates of dissolution of labeled nickel ( Ni) subsulfide in water,
whole rat serum, and rat serum ultrafiltrate. Dissolution rates were more
rapid in serum or serum ultrafiltrate and were attended by formation of nickel
sulfide and nickel hydroxide. These authors speculate that subsequent
solubilizing of these latter forms j_n vivo is conceivable owing to the lower
pH existing in lysosomes, nickel particles being observed in the lysosomes of
o
macrophages from nickel subsulfide-treated rats (Sunderman et al., 1976).
Experimental clues as to the ways in which intracellular nickel imparts
neoplastic formation include the following: (1) The intracellular distribution
of nickel in nickel-induced rhabdomyosarcomas is highest in the nucleus (70-90
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
jjn vitro; (5) addition of nickel ion to cultures of mouse L-929 cells
interferes with interferon synthesis (Treagon and Furst, 1970); and (6) addi-
tion of nickel subsulfide to cultured embryonic muscle cells inhibits mitotic
C-100
-------
activity and causes abnormal mitotic figures (Basrur and Gilman, 1967;
Swierenga and Basrur, 1968).
The above discussion has focused on nickel compounds used alone to induce
carcinogenic responses. An equally important aspect 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. Discussion of this area has been presented previously under the
Synergism 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; Gilman, 1962; Payne, 1964). Furthermore, there is a
general inverse relationship between 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 20). 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
manifestations.
Sunderman and Maenza (1976) studied the incidence of sarcomas in Fischer
rats within 2 years after single intramuscular injections of four insoluble
nickel-containing powders: metallic nickel, nickel sulfide, a-nickel subsulfide
and nickel-iron sulfide matte. Amorphous nickel sulfide had no tumorigenic
potential, while nickel subsulfide was most active. The relative carcinogenicity
of nickel-iron sulfide matte was intermediate between nickel subsulfide and
metallic nickel powder, suggesting to these authors that there may also be a
C-101
-------
previously unrecognized carcinogenic potential 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 compounds and consequently, workers at specific refineries at
different 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 universal agreement that
nickel refinery workers are at significantly higher risk for cancer of the
lungs and nasal cavity (Natl. Acad. Sci., 1975; Int. Agency Res. Cancer, 1976;
Natl. Inst. Occup. Safety Health, 1977; Sunderman, 1977). Sunderman (1977), in
a review, points out that in addition to the significantly high risk for
cancer of the lungs and nasal cavities, increased risk has been found for
cancer of the larynx in Norwegian refinery workers and for gastric cancer and
soft tissue sarcoma in Russian refinery workers.
According to the IARC (1976): "Epidemiological studies conclusively
demonstrate an excessive risk of cancer of the nasal cavity and lung in workers
at nickel refineries. It is likely that nickel in some form(s) is carcinogenic
to man."
Summaries of the cancer risks demonstrated in epidemiological and
occupational studies are given in Tables 21 and 22, respectively.
The nickel compounds which are implicated are insoluble dusts of nickel
subsulfide (Ni^) and nickel oxides (NiO and Ni^O-) the vapor of nickel
c-102
-------
TABLE 21. EPIDEMIOLOGICAL STUDIES OF NICKEL CARCINOGENESIS
Agent
Nickel Matte
Concentrated
Feed stock
Nickel dust
and fumes
Unknown
Ni oxides, Ni
o Alloys, Ni
1 cnlfato anH Mi
Dosing
Inhalation
Inhalation
Inhalation
Inhalation »
>0.3 mg Ni/nT
Response
Carcinoma
Carcinoma
epidermoid
anaplastic
adena
Precancerous
lesions
Cancer
Organ/Tissue
Lung Nasal
Lung
Biopsies of
mucosa from
middle turbinate
Lung
Industry
Clydach, Wales
refinery workers
Falconbridge
refinery-
Norway
Falconbridge
refinery-
Norway
Aircraft engine
factory
Reference
Doll, 1977
Kreyberg,
Torjussen
Solberg,
Bernacki,
1978
and
1976
1978
o
u>
chloride
-------
TABLE 22. OCCUPATIONAL STUDIES OF NICKEL CARCINOGENESIS
o
i
Agent Dosing
Insoluble dusts
Ni-S^ Inhalation
NiO; Ni203
Vapors
Ni(CO)4
Soluble aerosols
NiS04
Ni(NO,)2 or Inhalation
Ni Cl^
Ni dusts Inhalation
Soluble and Inhalation
insoluble
Ni compounds
plus arsenic
and cobalt dusts
Response
Carcinoma
epidemoid
anaplastic
pleomorphic
Cancer
Carcinomas
Sarcoma
Organ/Tissue
Lung Nasal
69% 45%
27% 12%
0 31%
Kidney
Lung Nasal
Larynx
Gastric
Soft tissue
Industry
Refinery
Canadian refinery
electrolytic workers
Norwegian
refinery
Russian
refinery
Reference
Sunderman, 1973
Sunderman, 1977
Pedersen, et al. ,
1973
Saknyn and
Shabynina,
1973
-------
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 industrial facili-
ties that are metal!urgically diverse in their operations, carcinogenicity
probably resides in several compounds of nickel (Natl. Acad. Sci., 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.
In Table 23 is an earlier tabulation (Natl. Acad. Sci., 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 tabulated 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 (Pedersen 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 refinery
workers (Sunderman, 1977).
The earliest epidemiological investigation of the increased risk of
cancer is that of the nickel refinery workers at Clydach, 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 retrospective investigations showed that there were significant
changes in risk for workers beginning employment after 1925, since the refinery
had undergone basic changes which resulted in control of pollutants and decrease
of exposure by that time.
C-105
-------
TABLE 23. HISTOPATHOLOGICAL CLASSIFICATION OF CANCEROF THE LUNG
AND NASAL CAVITIES IN NICKEL WORKERS3
Tumor Classification
Epidermoid carcinoma
(squamous cell)
Anaplastic
(undifferentiated) 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 -Cavi
No.
22
6
0
0
2
1
1
1
15
1
49
ty Cancer
%
45
12
0
0
4
2
2
2
31
2
100
'From Natl. Acad. Sci., 1975.
C-106
-------
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 24, 25, and 26 show the data for Clydach which led Doll and his associates
to revise the time of the reduction of the risk of cancers from "by 1925" to
"until 1930."
The epidemiological studies of cancer of the respiratory 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 Falconbridge refinery
near Kristiansand, Norway. The previous epidemiological studies of this
worker population had established 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 refinery workers and determine histological characteristics
of lung cancers, the age at start of employment of the cases, their lifetime
smoking history employment history at Falconbridge and age at diagnosis. The
total number of cases examined was 44.
The total number of workers over Falconbridge's history from 1927 until
1975 was available. Figure 10 shows the number of workers over this time,
those exposed and not exposed, both in permanent and temporary positions, and
the number and types of lung cancers by years of diagnosis. The gap of cases
between 1950 and 1958 became the focus of the study. Employment records led
to the separation 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
C-107
-------
TABLE 24. NUMBER OF MEN FIRST EMPLOYED AT CLYDACH NICKEL REFINERY, WALES3
AT DIFFERENT PERIODS AND MORTALITY OBSERVED AND EXPECTED FROM ALL CAUSES'
Year of first
employment
Before 1910
1910-14
1915-19
1920-24
1925-29
1930-44
Al 1 periods
No. of
men
119
150
105
285
103
205
967
Man-years
of risk
1,980.0
2,2666.5
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
'From Doll et al. (1977).
C-108
-------
3000
2500
O
uj
O 2000
_i
a.
UJ
Ul
n
i
a.
O
UJ
O.
U.
O
CC
ut
to
5
z
1500
1000
500
GROUP I TUMOURS:
| EPIDERMOID CARCINOMA
S SMALL CELL ANAPLASTIC CARCINOMA
GROUP (I TUMOURS:
D
»/**{A)a
r; \A
<
O
u.
O
oc
UJ
03
Figure 10. Lung cancer cases diagnosed 1929-1975 at Falconbridge. Plots of number of
people employed at Falconbridge nickel refinery (curves) and number of new cases of
lung cancer diagnosed between 1929 and 1975 (histogram): (A) number of people on
the payroll (a = total number, b = those occupationally exposed to nickel); (B) number
of people in established positions (a = total number, b = those occupationally exposed
to nickel). The two cases from 1951 with development time of 1 year or less are not
included. From Kreyberg (1978).
-------
TABLE 25. MORTALITY BY CAUSE AND YEAR OF FIRST EMPLOYMENT, CLYDACH NICKEL REFINERY, WALES3
O
I
No. deaths from .
nasal sinus cancer
Year of first
employment
Before 1910
1910-14
1915-19
1920-24
1925-29
All periods
before 1930
1930-44
Observed
14
24
11
7
0 (1)
56 (2)
0
Expected
0.036
0.137
0.025
0.071
0.026
0.195
0.034
Ratio
0/E
389
649
440
99
0
287
0
No. deaths from
lung cancer
Observed
24
34
20
50
9
137
8
Expected
2.389
3.267
3.070
9.642
3.615
21.983
5.463
0/E
10.0
10.4
6.5
5.2
2.5
6.2
1.5
No. deaths from other
malignant neoplasms
Ratio
Observed
10
10
10
27
7
64
11
Expected
14.637
13.549
8.064
20. 902
7.247
64.399
8.786
Ratio
0/E
0.68
0.74
1.24
1.29
0.97
0.99
1.25
No. deaths from
other diseases
Observed
69
69
48
125
44
355
58
Expected
84.95
75.99
44.28
115.63
41.02
361.87
46.14
Ratio
0/E
0.81
0.91
1.08
1.08
1.07
0.98
1.25
aFrom Doll et al. (1977).
-------
TABLE 26. CHRONOLOGICAL CHANGES IN THE FEED MATERIAL AT CLYOACH NICKEL REFINERY, WALES3
O
I
H
H
H
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
aFron Doll et al. (1977).
-------
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 employment 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 developmental time for the two series are
striking. The relationship 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 27. 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.
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 Group I cases is generally attributed to
increase in cigarette smoking. The smoking status of the cases is shown in
Table 28.
The 32 Group I cases had only three possible nonsmokers, but four of
seven Group II cases were documented nonsmokers. The number 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 workers
C-112
-------
o
I
u>
SERIES II
SERIES!
GROUP I TUMOURS
() GROUP II TUMOURS
[] DEVELOPMENT TIME
LESS THAN ONE YEAR
r:i *) t ~> . s.:J&J .
I
0
1
0
III 1 1
5 10 15 20 25
I I I II
5 10 15 20 25
I I I
30 35 . 40
II I
30 35 40
DEVELOPMENT TIME IN YEARS
Figure 11. Development time for lung tumours in Series I and Series II workers in a
nickel refinery. From Kreyberg (1978).
-------
O
I
40 YEARS
20 YEARS
i
/
1927
D
O
.38
.36
.32
.30
pa o an
/
D O
OOO
DO
.52
.50 tf
.48
.46
.44
.42
.74
.72
.70
.68
.66
.64
.62
.60
58 «£>
EPIDERMOID CARCINOMA
D SMALL CELL ANAPLASTIC
CARCINOMA
O GROUP II TUMOURS
YEARS OF REDUCED 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(ordinate). From Kreyberg (1978).
-------
TABLE 27. AGE AT TIME OF DIAGNOSIS OF GROUP I TUMORS
OF WORKERS EXPOSED TO NICKELa
Series No.
I
II
Kreyberg (1969)
of cases
15
17
596
Mean
57.6
56.0
58.2
Age, years
Minimum
40
44
31
Maximum
75
73
75+
From Kreyberg (1978).
TABLE 28. 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
From Kreyberg (1978).
'Smoking history not ascertainable. Allocation as nonsmokers is the assumption
against the hypothetical relationship.
C-115
-------
started smoking years before being exposed to nickel; thus the nickel exposure
can be relegated, at least temporally, to a secondary 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. However, when development time to tobacco use is used,
the picture clarifies. In Norway, the starting age for cigarette smoking 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 obscured
and is unknown at present, The presence of more than one carcinogen makes it
difficult if not impossible to determine developmental time. "The incidence
may be increased when weak carcinogens are involved without the mean age at
diagnosis being markedly altered" (Kreyberg, 1978).
The medical department of the Falconbridge refinery monitors exposed
workers by obtaining urine and plasma nickel concentrations, enforces safety
precautions such as wearing respirators, protective clothing, showering, and
discourages smoking. In respect 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 sinuses.
Torjussen and Sol berg (1976) report on a study of 92 randomly selected
workers from Falconbridge exposed to nickel compounds and 37 nonexposed workers
as control. Biopsies of mucosa from the middle turbinate were examined for
precancerous lesions. All workers were without known nasal disease. All
biopsy samples showed inflammatory 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.
C-116
-------
The cancer risk status in workers exposed to nickel in workplaces other
than nickel refineries is not established at this time. Since the nickel
compounds associated with the refining processes 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
nou find an increased relative risk for workers exposed to nickel compounds.
The atmospheric concentrations 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.
C-117
-------
CRITERION FORMULATION
Existing Guidelines and Standards
The threshold limit values (TLV) for a work day exposure
has been set at 1 ppb (Am. Conf. Gov. Ind. Hyg. 1971).
Current Levels of Exposure
The route by which most people in the general population
receive the largest portion of daily nickel intake is through
food. Based on the available data from composite diet analysis,
between 300 to 600 jug nickel per day are ingested. Fecal
nickel analysis, a more accurate measure of dietary nickel
intake, suggests about 300 jug/day. The highest level of
nickel observed in water was 75 jjg per liter. Average drinking
water levels are about 5 /ig/1. A typical consumption of
2 liters daily would yield an additional 10 jug of nickel,
or which up to 1 pg would be absorbed.
Special Groups at Risk
Occupational groups such as nickel workers and other
workers handling nickel comprise the individuals at the
highest risk. Women, particularly housewives, are at special
risk to nickel-induced skin disorders. Approximately 47
million individuals, comprising the smoking population of
the United States, are potentially at risk for possible
co-factor effects of nickel in adverse effects on the respira-
tory tract.
Basis for Derivation of Criterion
In arriving at a standard for nickel, several factors
must be taken into account. There is little evidence for
accumulation of nickel in various tissues. Absorption through
C-118
-------
the gastrointestinal tract is minimal. Acute exposure of
man to nickel is chiefly of concern in workplaces where
nickel carbonyl or nickel dust are present at high levels.
In these situations, inhalation is the main route of entry
and the lung is the critical organ although, in some instances
of high exposure, the central nervous system may also be
involved.
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 altering defense mechanisms against xenobiotic
agents in the respiratory tract, leading to enhanced risk
for respiratory tract infections.
While nickel has a possible role as a co-carcinogen
in producing respiratory cancer, as suggested by animal
studies, this remains to be demonstrated. 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 toxico-
logical 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 nickel 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 drinking water.
C-119
-------
To arrive at a risk estimate for nickel/ a modification
of the approach used for non-stochastic effects (Fed. Register
44 (52) :15980, March 15, 1979) has been adopted.
The studies cited in this document have not demonstrated
a no-observable-effect level (NOEL). Therefore, the study
demonstrating the lowest-observable-effect level (LOEL)
for nickel in drinking water has been used to arrive at
a non-stochastic risk estimate.
In the study of Schroder and Mitchner (1971), adverse
effects in rats were demonstrated at a level of 5 mg/1 (5
ppin) 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 generations, 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 LOEL into an Acceptable Daily Intake (ADI)
for man, the LOEL is divided by an uncertainty factor of
100, as detailed in a recent National Academy of Science
report (Drinking Water and Health, pp. 803-04, NAS, 1977)
and adopted by The U.S. Environmental Protection Agency
(Fed. Register 44(52) :15980, March 15, 1979). The choice
of this factor is based on the absence of long-term or acute
human data, scanty results on experimental animals, and
an absence of evidence for carcinogenicity.
If the 5.0 mg/1 level were used in the standard water
quality criteria, the criterion can be determined to be 133 jjg/1.
C-120
-------
5(mg/1) x 25 ml/day/rat = 125
.3(kg/av. rat) ,3
= 416.67 pg
^ 420
dose/day/av. rat
= 4.2 pg (ADI)
4.2 x 70 = 294 pg (ADI for 70 kg/man)
2(X) = {Av. Fish intake)(BCF)(X) = Daily Intake
2(X) + (0.0187)(11)(X) = 294 pg
2.205 X = 294 jug
X = 133 jug/1 (criterion)
2 = amount of water ingested, liters/day
X = Ni concentration, mg/1
0.0187 = amount of fish/shellfish products consumed, kg/day
F = 11 (BCF) mg Ni/kg fish
t 11 (BCF), mg Ni/1 Qf waj
Drinking water contributes 91 percent of the assumed
exposure while eating contaminated fish products accounts
for nine percent. The criterion level for nickel can alterna-
tively be expressed as 1.4 mg/1, if exposure is assumed
to be from the consumption of fish and shellfish products
alone.
X x 0.0187 x 11 = 294 Cwg/1)
X x 0.2057 = 294
X = 1.429 mg
X = 1.4 (mg/1)
C-121
-------
REFERENCES
Ader, D. , and M. Stoeppler. Radiochemical and methodological studies on the
recovery and analysis of nickel in urine. J. Anal. Toxicol. 1:252-260, 1977.
Ambrose, A. M., P. S. Larson, J. R. Borzelleca, and G. R. Hennigar, Jr. Long
term toxicologic assessment of nickel in rats and dogs. J. Food Sci. and
Techno!. 13:181-187, 1976.
American Conference of Governmental Industrial Hygienists. Threshold limit
values for chemical substances and physical agents in the workroom environ-
ment with intended changes for 1978. 94 pp.
Anderson, I., W. Torjussen and H. Zachariasen. Analysis for nickel in plasma
and urine by electrothermal atomic absorption spectrometry, with sample
preparation by protein precipitation. Clin. Chem. 24:1198-1202, 1978.
Anke, M. , M. Grun, G. Ditrich, B. Groppel, and A. Hennig. Low nickel rations
fcr growth and reproduction in pigs. In: Trace Element Metabolism in Animals -
2. W. G. Hoekstra, J. W. Suttie, H. E. Ganther, and W. Mertz (eds.). University
Park Press, Baltimore, MD, 1974. pp. 715-718.
Armit, H. W. The toxicology of nickel carbonyl. Part II. J. Hygiene 8:565-600
1908.
Ashrof, M., and H. D. Sybers. Lysis of pancreatic exocrine cells and other
lesions in rats fed nickel acetate. Am. J. Pathol. 74:102a, 1974.
Azary, A. Contribution to the toxicology of the nitrates of nickel and cobalt.
Orv. Hetil. 33:729-734, 1879.
Barnes, J. M., and F. A. Denz. The effects of 2,3-dimercapto-propanol (BAL)
on experimental nickel carbonyl poisoning. Brit. J. Ind. Med. 8:117-126,
1951.
Basrur, P. K. and S. H. H. Swiergnga. Enzyme changes in muscle cells during
tumor induction with nickel sulfide. J. Cell Biol. 47:14a-15a, 1970.
Basrur, P. K. , A. K. Sykes, and J. P. W. Gilman. Changes in mitochondria!
ultrastructure in nickel sulfide-induced rhabdomyosarcoma. Cancer 25:1142-1152,
1970.
Basrur, P. K., and J. P. W. Gilman. Morphologic and synthetic response of
normal and tumor muscle cultures to nickel sulfide. Cancer Res. 27:1168-1177,
1967.
14
Beach, D. J., and F. W. Sunderman, Jr. Nickel carbonyl inhibition of C-orotic
acid incorporation into rat liver RNA. Proc. Soc. Exptl.' Biol. and Med.
131:321-322, 1969.
Beach, D. J., and F. W. Sunderman, Jr. Nickel carbonyl inhibition of RNA
synthesis by a chromatin-RNA polymerase complex from hepatic nuclei. Cancer
Res. 30:48-50, 1970.
C-122
-------
Bernacki, E. J. , G. E. Parsons, B. R. Roy, M. Mikac-Devic, D. C. Kennedy, and
F. W. Sunderman, Jr. Urine nickel concentrations in nickel-exposed workers.
Ann. Clin. and Lab. Sci. 8:184-189, 1978.
Bernstein, D. M. , T. J. Kneip, M. T. Kleinman, R. Riddick, and M. Eisenbut.
Uptake and distribution of airborne trace metals in man. In: Trace Substances
in Environmental Health - VIII, D. D. Hemphill (ed.)» University of Missouri,
Columbia, MO, 1974, pp. 329-334.
Bertrand, G. , and M. Macheboeuf. Influence du nickel et du cobalt sur 1'action
exercee par 1'insuline chez le lapin. Comp. Rend. Acad. Sci. (Paris)
182:1504-1507, 1926.
Bingham, E. , W. Barkley, M. Zerwas, K. Stemmer, and P. Taylor. Responses of
alveolar marcrophages to metals. I. Inhalation of lead and nickel. Arch.
Environ. Health 25:406-414, 1972.
Brandes, W. W. Nickel carbonyl poisoning. J. Am. Med. Assoc. 102:1204-1206,
1334.
Brun, R. Epidemiology of contact dermatitis in Geneva (1,000 cases). Dermatol.
150:193-199, 1975. (in French)
i, C. , and J. N. Rust. Fine structure of dividing cells and of nondividing
differentiating cells of nickel sulfide - induced rhabdomyosarcomas. J. Natl.
Cancer Ins. 54:687-696, 1975.
Burckhardt, W. Beitrage zur Ekzemfrage. III. Mitteilung. Die Rolle der
A~i kalishadigung der Haut bei der experimentellen Sensibilisierung gegen Nickel.
Archiv. Dermatol. Syphilis 173:262-266, 1935.
Calnan, C. D. Nickel dermatitis. Brit. J. Dermatol. 68:229-236, 1956.
Ccrmichael, J. L. Nickel carbonyl poisoning. Report of a case. Arch. Ind.
Hyg. and Occup. Med. 8:143-148, 1953.
Carmichael, J. L. Nickel carbonyl poisoning. Arch. Ind. Hyg. Occup. Med. 8:
143-148, 1953.
Caron, G. A. Nickel sensitivity and atopy. Brit. J. Dermatol. 76:385-387,
1964.
Chattopadhyay, A. , and Jervis, R. E. Hair as an indicator of multielement
exposure of population groups. In: Trace Substances in Environmental Health -
VIII, D. D. Hemphill (ed.), Columbia, MO, University of Missouri, 1974, pp.
31-38.
Chausmer, A. B. Measurement of exchangeable nickel in the rat. Nutr. Repts.
Int. 14:323-326, 1976.
Christensen, 0. B. , and H. Moller. External and internal exposure to the
antigen in the hand eczema of nickel allergy. Contact Dermatitis 1:136-141,
1975b.
C-123
-------
Christensen, 0. B., and H. Holler. Nickel allergy and hand eczema. Contact
Dermatitis 1:129-135, 1975a.
Clary, J. J. Nickel chloride - induced metabolic changes in the rat and
guinea pig. Toxicol. Appl. Pharmacol. 31:55-65, 1975.
C"!ary, J. J. , and I. Vignati. Nickel chloride - induced changes in glucose
metabolism in the rat. Toxicol. Appl. Pharmacol. 25:467-468, 1973. abstr.
#75. ~
Costa, M., J. Nye, and F. W. Sunderman, Jr. Morphologic transformation of
Syrian hamster fetal cells induced by nickel compounds. Fed. Proc. 37:231,
1978. abstr. #102.
Cralley, L. J. Electromotive phenomenon in metal and mineral particulate
exposures: Relevance to exposure to asbestos and occurrence of cancer. Am.
Ind. Hyg. Assoc. J. 32:653-661, 1971.
Creason, J. P., D. Svendsgaard, J. Bumgarner, C. Pinkerton, and T. Hinners.
Maternal-fetal tissue levels of 16 trace elements in 8 selected continental
United States communities. In: Trace Substances in Environmental Health - X,
0. D. Hemphill (ed.), Columbia, MO., University of Missouri, 1976, pp. 53-62.
Creason, J. P., T. A. Hinners, J. E. Bumgarner, and C. Pinkerton. Trace
elements in hair, as related to exposure in metropolitan New York. Clin.
Chem. 21:603-612, 1975.
D'Alonzo, C. A., and S. Pell. A study of trace metals in myocardial infarction.
Arch. Environ. Health 6:381-385, 1963.
Damjanov, I., F. W. Sunderman, Jr., J. M. Mitchell, and P. R. Allpass. Induction
of testicular sarcomas in Fischer rats by intratesticular injection of nickel
subsulfide. Cancer Res. 38:268-276, 1978.
Daniel, M. , M. Edwards, and M. Webb. The effect of metal serum complexes on
differentiating muscle in vitro. Brit. J. Exp. Pathol. 55:237-244, 1974.
Deutman, R., T. J. Mulder, R. Brian, and J. P. Nater. Metal sensitivity
before and after total hip arthroplasty. J. Bone Joint Surg. 59A:862-865.Date
de Jongh, G. J., D. Spruit, P. J. M. Bongaarts, and P. Duller. Factors influencing
nickel dermatitis. I. Contact Dermatitis 4:142-148, 1978.
Devereaux, T. R., and J. R. Fouts. N-oxidation and demethylation of N,
N-dimethylaniline by rabbit liver and lung microsomes. Effects of age and
metals. Chem. Biol. Interactions 8:91-105, 1974.
Dixon, J. R., D. B. Lowe, D. E. Richards, L. J. Cralley, and H. E. Stokinger.
The role of trace metals in chemical carcinogenesis: asbestos cancers.
Cancer Res. 30:1068-1074, 1970.
C-124
-------
Doll, R., J. D. Mathews, and L. G. Morgan. Cancers of the lung and nasal
sinuses in nickel workers: A reassessment of the period of risk. Brit. J.
Ind. Med. 34:102-105, 1977.
Dormer, R. L., A. L. Kerbey, M. McPherson, S. Manley, S. J. H. Ashcroft, J. G.
Schofield, and P. J. Randle. The effect of nickel on secretory systems.
Studies on the release of amylase, insulin and growth hormone. Biochem. J.
140:135-142, 1973.
Dormer, R. L., and S. J. H. Ashcroft. Studies on the role of calcium ions in
the stimulation by adrenaline of amylase release from rat parotid. Biochem.
J. 144:543-550, 1974.
Durfor, C. N., and E. Becker. Public Water Supplies of the 100 Largest Cities
in the United States, 1962. U.S. Geological Survey Water Supply Paper No.
1812, Washington, DC, U.S. Government Printing Office, 1964.
Eads, E. A., and C. E. Lambdin. A survey of trace metals in human hair.
Environ. Res. 6:247-252, 1973.
Epstein, S. Contact dermatitis due to nickel and chromate. Arch. Dermatol.
73:236-255, 1956.
Faorp, R. B., and T. B. McMullen. National Trends in Trace Metals in Ambient
Air 1965-1974. EPA-450/1-77-003, U.S. Environment Protection Agency, Research
Triangle Park, NC, February 1977.
2+
Federchenko, 0. Y., and L. J. Petrum. Effect of Ni ions on the dephosphory-
lation of ATP and formation of ami no acylphosphates by enzymes of rat liver
microsomes in the presence of amino acids. Ukr. Biokhim. Zh. 41:680-685,
1969.
Ferm, V. H. The teratogenic effects of metals on mammalian embryos. In:
Advances in Teratology, Vol. 5. D. H. M. Wollam (ed.). Academic Press, New
York, 1972. pp 51-75.
Fishbein, W. N., M. J. Smith, K. Nagarajan, and W. Scurzi. The first natural
nickel metalloenzyme: Urease. Fed. Proc. 35:1680, 1976. abstr.
Fisher, A. A. Allergic dermatitis presumably due to metallic foreign bodies
containing nickel or cobalt. Curtis 19:285-286, 288, 290, 294-295, 1977.
Forman, L., and S. Alexander. Nickel antibodies. Brit. J. Dermatol. 87:
320-326. 1972.
Freeman, B. M., and D. R. Langslow. Responses of plasma glucose, free fatty
acids and glucagon to cobalt and nickel chlorides by Gall us domesticus. Comp.
Biochem. Physio!. 46A:427-436, 1973.
Fregert, S., N. Jharth, B. Magnusson, H.-J. Bandmann, C. D. Calnan, E. Cronin,
K. Malten, C. L. Menghini, V. Pirila, and D. A. Wilkenson. Epidemiology of
contact dermatitis. Trans. St. Johns Hosp. Derm. Soc. 55:71-75, 1969.
C-125
-------
Friedman, I. , and E. S. Bird. Electron-microscope investigation of experi-
mental rhabdomyosarcoma. J. Pathol. 97:375-382, 1969.
Furr, A. K. , W. C. Kelly, C. A. Bache, W. H. Gutenmann, and D. J. Lisk.
Multi-element absorption by crops grown on Ithaca sludge-amended soil. Bull.
Environ. Contam. Toxicol. 16:756-763, 1976.
Furst, A., and M. C. Schlauder. The hamster as a model for metal carcinogenesis.
Proc. West. Pharmacol. Socl. 14:68-71, 1971.
Furst, A. , D. M. Cassetta, and D. P. Sasmore. Rapid induction of pleural
mesotheliomas in the rat. Proc. West. Pharmacol. Soc. 16:150-153, 1973.
Geissinger, H. D., P. K. Basrur, and S. Yamashiro. Fast scanning electron
microscopic and light microscopic correlation of paraffin sections and chromosome
spreads of nickel-induced tumor. Trans. Am. Micros. Soc. 92:209-217, 1973.
Ghiringelli, L. , and M. Agamennone. II metabolismo del nickel in animali
sperimentalmente avvelenati con nickel carbonile. Med. Lav. 48:187-194, 1957.
Ir Italian.
Gilman, J. P. W. Metal carcinogenesis. II. A study on the carcinogenic
activity of cobalt, copper, iron and nickel compounds. Cancer Res. 22:158-162,
1S62.
Gimenez-Camarasa, J. M. , P. Garcia-Calderon, J. Asensio, and J. M. deMoragas.
Lymphocyte transformation test in allergic contact nickel dermatitis. Brit.
J. Dermatol. 92:9-15, 1975.
Gitlitz, P. H. , F. W. Sunderman, Jr., and P. J. Goldblatt. Aminoaciduria and
proteinuria in rats after a single intraperitoneal injection of Ni(II).
Toxico. Appl. Pharmacol. 35:430-440, 1975.
Graham, J. A., D. E. Gardner, M. D. Waters, and D. L. Coffin. Effect of trace
metals on phagocytosis by alveolar macrophages. Infection and Immunity 11:1278-1283,
1975.
Graham, J. A., F. J. Miller, M. J. Daniels, E. A. Payne, and D. E. Gardner.
Influence of cadmium, nickel, and chromium on primary immunity in mice.
Environ. Res. 16:77-87, 1978.
Hackett, R. L., and F. W. Sunderman, Jr. Acute pathological reactions to
administration of nickel carbonyl. Arch. Environ. Health 14:604-613, 1967.
Hackett, R. L., and F. W. Sunderman, Jr. Acute pathological reactions to
administration of nickel carbonyl. Arch. Environ. Health 14:604-613, 1967.
Hackett, R. L., and F. W. Sunderman, Jr. Nickel carbonyl. Effects upon the
ultrastructure of hepatic parenchyma! cells. Arch. Environ. Health 19:337-343,
1959.
C-126
-------
Hadley, J. G., D. E. Gardner, D. L. Coffin, and 0. B. Menzel. Inhibition of
antibody-mediated rosette formation by alveolar macrophages: A sensitive
assay for metal toxicity. J. Reticuloendothelial Soc. 22:417-425, 1977.
Haro, R. T., A. Furst, and H. Falk. Studies on the acute toxicity of nickel-
ocene. Proc. West. Pharmacol. Soc. 11:39-45, 1968.
Harvey, T. C., J. S. McLellan, B. J. Thomas, and J. H. Fremlin. Measurement
of liver-cadmium concentrations in patients and industrial workers by neutron-
activation analysis. Lancet 1:1269-1272, (June 7, 1975).
Haxthausen, H. Verwandtschaftsreaktonen bei Nickel - und Kobalt-Allergie der
Haut. Archiv. Dermatol. Syphilis 174:17-21, 1936.
Heath, J. C., and M. R. Daniel The production of malignant tumours by nickel
in the rat. Brit. J. Cancer 18:261-264, 1964.
Heath, J. C., and M. Webb. Content and intracellular distribution of the
inducing metal in the primary rhabdomyosarcomata induced in the rat by cobalt,
nickel and cadmium. Brit. J. Cancer 21:768-779, 1967.
Hendel, R. C., and F. W. Sunderman, Jr. Species variation in the proportions
of ultra-filtrable and protein-bound serum nickel. Res. Comm. Chem. Pathol.
Pharmacol. 4:141-146, 1972.
Ho, W., and A. Furst. Nickel excretion by rats following a single treatment.
Proc. West. Pharmacol. Soc. 16:245-248, 1973.
Hrfgetveit, A. C., and R. T. Barton. Monitoring nickel exposure in refinery
workers. In: Clinical Chemistry and Chemical Toxicology of Metals. S. S.
Brown (ed.), Amsterdam, Elsevier, 1977, pp. 265-268.
Htfgetveit, A. C., and R. T. Barton. Preventive health program for nickel
workers. J. Occup. Med. 18:805-808, 1976.
Hoey, M. J. The effects of metallic salts on the histology and functioning of
the rat testes. J. Reprod. Fertil. 12:461-471, 1966.
Hohnadel, D. C., F. W. Sunderman, Jr., M. W. Nechay, and M. D. McNeely.
Atomic absorption spectrometry of nickel, copper, zinc, and lead in sweat
collected from health subjects during sauna bathing. Clin. Chem. 19:1288-1292,
1973.
Hopfer, S. M., and F. W. Sunderman, Jr. Manganese inhibition of nickel sub-
sulfide induction of erythrocytosis in rats. Res. Comm. Chem. Pathol. Pharmacol.
19:337-345, 1978.
Horak, E., and F. W. Sunderman, Jr. Effects of Ni(II), other divalent metal
ions, and glucagon upon plasma glucose concentrations in normal, adrenalectomized
and hypophysectomized rats. Toxicol. Appl. Pharmacol. 32:316-329, 1975a.
-------
Horak, E. , and F. W. Sunderman, Jr. Effects of Ni(II) upon plasma glucagon
c:nd glucose in rats. Toxicol. App7. Pharmacol. 33:388-391, 1975b.
horak, E., and F. W. Sunderman, Jr. Fecal nickel excretion by healthy adults.
Clin. Chem. 29:429-439, 1973.
Horak, E., and F. W. Sunderman, Jr. Fecal nickel excretion by healthy adults.
Clin. Chem. 19:429-430, 1973.
Hueper, W. C. Experimental studies in metal cancerigenesis. IV. Cancer
produced by parenterally introduced metallic nickel. J. Natl. Cancer Inst.
15:55-67, 1955.
Hueper, W. C. Experimental studies in metal cancerigenesis. Arch. Pathol.
£5:600-607, 1958.
Hutchinson, F., E. J. Raffle, and T. M. MacLeod. The specificity of lymphocyte
transformation ui vitro by nickel salts in nickel sensitive subjects. J.
Invest. Derm. 58:362-365, 1972.
Hutchinson, F., T. M. MacLeod, and E. J. Raffle. Nickel hypersensitivity.
Nickel binding to amino acids and lymphocytes. Brit. J. Derm. 93:557-561,
1975.
Indraprasit, S., G. V. Alexander, and H. C. Gonick. Tissue composition of
major and trace elements in uremia and hypertension. J. Chron. Dis. 27:
135-161, 1974.
International Agency for Research on Cancer. Nickel and nickel compounds.
_Ir: Evaluation of Carcinogenic Risk of Chemicals to Man (International Agency
fcr Research on Cancer Monographs, 11) IRAC, Lyon, 1976, p. 111.
International Agency for Research on Cancer. Nickel and Nickel Compounds.
International Agency for Research on Cancer, Vol. 2, Lyon, 1976, pp. 75-112.
International Radiological Protection Commission. Task Group on Lung Dynamics
for Committee II. Deposition and retention models for internal dosimetry of
the human respiratory tract. Health Physics 12:173-207, 1966.
Jacobsen, N. Epithelial-like cells in culture derived from human gingiva:
Response to nickel. Scand. J. Dent. Res. 85:567-574, 1977.
Jansen, L..H., L. Berrens, and J. van Delden. Contact sensitivity to simple
chemicals: The role of intermediates in the process of sensitization. Naturwiss.
51:387-388, 1964.
Jasmin, G., and B. Solymoss. The topical effects of nickel subsulfide on
renal parenchyma. Adv. Exp. Med. Biol. 91:69-83, 1977.
Jasmin, G. , and J. L. Riopelle. Renal carcinomas and erythrocytosis in rats
following intrarenal injection of nickel subsulfide. Lab. Invest. 35:71-78,
1976.
C-128
-------
John, M. K., and C. J. Van Laerhoven. Effects of sewage sludge composition,
application rate, and lime regime on plant availability of heavy metals. J.
Environ. Qua!. 5:246-251, 1976.
JDO, F. Changes in the molecular organization of the basement membrane after
inhibition of adenosine triphosphate activity in the rat brain capillaries.
Cytobiosis 1:289-301, 1969.
Jod, F. Effect of inhibition of adenosine triphosphate activity on the fine
structural organization of the brain capillaries. Nature 219:1378-1379.
1968.
Jordan, W. P., Jr., and J. Dvorak. Leukocyte migration inhibition assay (LIF)
in nickel contact dermatitis. Arch. Dermatol. 112:1741-1744, 1976.
Juhlin, U, G. 0. Johansson, H. Bennich, C. Hogman, and N. Thyresson. Immunoglobulin
E. in dermatoses. Arch. Dermatol. 100:12-16, 1969.
Kaaber, K., N. K. Veien, and J. C. Tjell. Low nickel diet in the treatment of
patients with chronic nickel dermatitis. Brit. J. Derm. 98:197-201, 1978.
Kadota, I., and M. Kurita. Hyperglycemia and islet cell damage caused by
nickelous chloride. Metabolism 4:337-342, 1955.
14
Kasprzak, K. S. , and F. W. Sunderman, Jr. The metabolism of nickel carbonyl- C.
Toxicol. Appl. Pharmacol. 15:295-303, 1969.
14
Kasprzak, K. S. , and F. W. Sunderman, Jr. The metabolism of nickel carbonyl- C.
Toxicol. Appl. Pharmacol. 15:295-303, 1969.
Kasprzak, K. S., L. Marchow, and J. Breborowicz. Pathological reactions in
rat lungs following intratracheal injection of nickel subsulfide and 3,4-
benzpyrene. Res. Comm. Chem. Pathol. Pharmacol. 6:237-245, 1973.
Kasprzak, K. S., and F. W. Sunderman, Jr. Mechanisms of dissolution of nickel
subsulfide in rat serum. Res. Comm. Chem. Pathol. Pharmacol. 16:95-108, 1977.
Keenan, R. G., J. V. Crable, A. W. Smallwood, and J. R. Carlberg. Chemical
composition of the coal miner's lung. Am. Ind. Hyg. Assoc. J. 32:392-397,
1971.
Kincaid, J. F., J. S. Strong, and F. W. Sunderman. Nickel poisoning. I.
Experimental study of the effects of acute and subacute exposure to nickel
carbonyl. Arch. Ind. Hyg. Occup. Med. 8:48-60, 1953.
Kolpakov, F. I. Permeability of ski'n to nickel compounds. Arkh. Patol.
25(6):38-45, 1963. Russian with English summary.
Kreyberg, L. Lung cancer in workers in a nickel refinery. Brit. J. Ind. Med.
35:109-116, 1978.
C-129
-------
Kucharin, G. M. Occupational disorders of the nose and nasal sinuses in workers
in an electrolytic nickel refining plant. Gig. Tr. Prof. Zabol. 14:38-40,
1970. In Russian.
LaBella, F., R. Dular, P. Lemon, S. Vivian, and G. Queen. Prolactin secretion
is specifically inhibited by nickel. Nature 245:33-332, 1973a.
LaBella, F., R. Dular, S. Vivian, and G. Queen. Pituitary hormone releasing
or inhibiting activity of metal ions present in hypothalmic extracts. Biochem.
Biophys. Res. Comm. 52:786-792, 1973b.
Lagerwerff, J. V., and A. W. Specht. Contamination of roadside soil and
vegetation with cadmium, nickel, lead and zinc. Environ. Sci. Technol. 4:
583-586, 1970.
Lau, T. J., R. L. Hackett, and F. W. Sunderman, Jr. The carcinogenicity of
intravenous nickel carbonyl in rats. Cancer Res. 32:2253-2258, 1972.
Lehnert, G. , R. Eschstruth, D. Szadkowski, and K. H. Schaller. Zur Problem
der medikamentosen Prophylaxe beruflicher Schwermetallintoxikationen mit
D-Penicillamin. Med. Welt 21:346-353, 1970.
Leslie, A. C. D., J. W. Winchester, F. W. Leysierffer, and M. S. Ahlberg,
Prediction of health effect of pollution aerosols. In: Trace Substances in
Environmental Health - X. D. D. Hemphill (ed.), University of Missouri,
Columbia, MO, 1976, pp 497-504.
Lestrovoi, A. P., A. I. Itskova, and I. N. Eliseev. Effect of nickel on the
iodine fixation of the thyroid gland when administered perorally and by inhalation.
Gig. Sanit. 10:105-106, 1974.
Lcuria, D. B., M. M. Joselow, and A. A. Browder. The human toxicity of certain
trace elements. Ann. Int. Med. 76:307-319, 1972.
Lo, C. C. , N. Matsumoto, and S. lijima. Placental transfer of NiC^ to fetuses
in mice. Teratology 14:245, 1976. abstr.
Maenza, R. M., A. M. Pradhan, and F. W. Sunderman, Jr. Rapid induction of
sarcomas in rats by combination of nickel sulfide and 3,4-benzypyrene. Cancer
Res. 31:2067-2071, 1971.
Maines, M. D., and A. Kappas. Enzymes of heme metabolism in the kidney.
Regulation by trace metals which do not form heme complexes. J. Exptl. Med.
146:1286-1293, 1977.
Maines, M. D., and A. Kappas. Studies on the mechanism of induction of heme
oxygenase by cobalt and other metal ions. Biochem. J. 154:125-131, 1976.
Malten, K. E. , and D. Spruit. The relative importance of various environmental
exposures to nickel in causing contact hypersensitivity. Acta Dermato-
venereologica 49:14-19, 1969.
C-130
-------
Marcussen, P. V. Spread of nickel dermatitis. Dermatologica 115:596-607,
1957.
Mathur, A. K., K. K. Datta, S. K. Tandon, and T. S. S. Dikshith. Effect of
nickel sulphate on male rats. Bull. Environ. Contain. Toxicol. 17:241-247,
1977a.
Mathur, A. K., S. V. Chandra, J. Behari, and S. K. Tandon. Biochemical and
morphological changes in some organs of rats in nickel intoxication. Arch.
Toxicol. 37:159-164, 1977a.
McConnell, L. H., J. N. Fink, D. P. Schlueter, and M. G. Schmidt. Asthma
caused by nickel sensitivity. Ann. Int. Med. 78:888-890, 1973.
McNeely, M. C., M. W. Nechay, and F. W. Sunderman, Jr. Measurements of nickel
in serum and urine as indices of environmental exposure to nickel. Clin.
Chem. 18:992-995, 1972.
McNeely, M. D., F. W. Sunderman, Jr. , M. W. Nechay, and H. Levine. Abnormal
concentrations of nickel in serum in cases of myocardial infarction, stroke,
burns, hepatic cirrhosis, and uremia. Clin. Chem. 117:1123-1128, 1971.
McNeely, M. D., F. W. Sunderman, Jr., M. W. Nechay, and H. Levine. Abnormal
concentrations of nickel in serum in cases of myocardial infarction, stroke,
burns, heptic cirrhosis, and uremia. Clin. Chem. 17:1123-1128, 1971.
McNeely, M. D., M. W. Nechay, and F. W. Sunderman, Jr. Measurements of nickel
in serum and urine as indices of environmental exposure to nickel. Clin.
Chem. 18:992-995, 1972.
McNeely, M. D., M. W. Nechay, and F. W. Sunderman, Jr. Measurements of nickel
in serum and urine as indices of environmental exposure to nickel. Clin.
Chem. 18:992-995, 1972.
Menne, T., and A. Thorboe. Nickel dermatitis - nickel excretion. Contact
Dermatitis 2:353-354, 1976.
Mertz, W. Some aspects of nutritional trace element research. Fed. Proc.
29:1482-1488, 1970.
Mikac-Devic, D. , F. W. Sunderman, Jr., and S. Nomoto. Furildioxime method for
nickel analysis in serum and urine by electrothermal atomic absorption spectro-
metry. Clin. Chem. 23:948-956, 1977.
Mikheyev, M. I. Distribution and excretion of nickel carbonyl. Gig. Tr.
Prof. Zabol. 15:35-38, 1971.
Millikan, L. E., F. Conway, and J. E. Foote. In vitro studies of contact
hypersensitivity: Lymphocyte transformation in nickel sensitivity. J. Invest.
Dermatol. 60:88-90, 1973.
C-131
-------
Mitchell, 0. F., G. B. Shankwalker, and S. Shazer. Determining the tumor-
igenicity of dental materials. J. Dent. Res. 39:1023-1028, 1960.
Miyaki, M., I. Murata, M. Osabe, and T. Ono. Effect of metal cations on
nisincorporation. Biochem. Biophys. Res. Comm. 77;854-860, 1977.
Moffitt, A. E., Jr., J. R. Dixon, F. C. Phipps, and H. E. Stokinger. The
effect of benzpyrene, phenobarbital, and carbon tetrachloride on subcellular
metal distribution and microsomal enzyme activity. Cancer Res. 32:1148-1153,
1972.
Mond, L. , C. Langer, and F. Quincke. Action of carbon monoxide on nickel. J.
Chem. Soc. 57:749-753, 1890.
Morgan, A., A. E. Lally, and A. Holmes. Some observations of the distribution
of trace metals in chrysotile asbestos. Ann. Occup. Hyg. 16:231-240, 1973.
Morse, E. E., T. Y. Lee, R. F. Reiss, and F. W. Sunderman, Jr. Dose-response
and time-response study of erythrocytosis in rats after internal injection of
nickel subsulfide. Ann. Clin. Lab. Sci. 7:17-24, 1977.
Murthy, G. D., U. S. Rhea, and J. T. Peeler. Levels of copper, nickel, rubidium,
and strontium in institutional total diets. Environ. Sci. Techno!. 7:1042-1045,
1973.
Mustafa, M. G., C. E. Cross, R. J. Munn, and J. A. Hardie. Effects of divalent
mstal ions on alveolar macrophage membrane adenosine triphosphatase activity.
J. Lab. Clin. Med. 77:563-571, 1971.
Myron, D. R. , T. J. Zimmerman, T. R. Shuler, L. M. Klevay, D. E. Lee, and F.
H. Nielsen. Intake of nickel and vanadium by humans. A survey of selected
diets. Am. J. Clin. Nutr. 31:527-531, 1978.
National Academy of Sciences. Nickel. National Academy of Sciences Committee
of Medical and Biological Effects of Environmental Pollutants. Washington,
DC, 1975.
National Academy of Sciences. Drinking Water and Health, 1977. pp. 803-804.
National Clearing House for Smoking and Health. National Center for Health
Statistics, Atlanta, GA., 1975.
National Institute for Occupational Safety and Health. Criteria for a
Recommended Standard: Occupational Exposure to Inorganic Nickel. Publication
No. 77-164. DHEW (NIOSH) U.S. Government Printing Office, Washington, DC,
1977.
National Institute for Occupational Safety and Health. Criteria for a Recommended
Standard: Occupational Exposure to Inorganic Nickel. Publication No. 77-164.
DHEW (NIOSH) Washington, DC, U.S. Government Printing Office, 1977.
C-132
-------
National Institute for Occupational Safety and Health. Criteria for a Recommended
Standard: Occupational Exposure to Inorganic Nickel. Publication No. 77-164.
DHEW (NIOSH) Washington, DC, U.S. Government Printing Office, 1977.
Natusch, 0. F. S., J. R. Wallace, and C. A. Evans, Jr. Toxic trace elements:
Preferential concentration in respirable particles. Science 183:202-204.
1974.
Nechay, M. W. , and F. W. Sunderman, Jr. Measurements of nickel in hair by
atomic absorption spectrometry. Ann. Clin. Lab. Sci. 3:30-35, 1973.
Nachay, M. W., and F. W. Sunderman, Jr. Measurements of nickel in hair by
atomic absorption spectrometry. Ann. Clin. Lab. Sci. 3-:30-35, 1973.
Nielsen, F. H., and D. A. Ollerich. Nickel: A new essential trace element.
Fed. Proc. 33:1767-1772, 1974.
Nielsen, F. H., and D. J. Higgs. Further studies involving a nickel deficiency
in chicks. In: Trace Substances in Environmental Health - IV, D. D. Hemphill
(ed.). University of Missouri, Columbia, MO, 1971, p. 241-246.
Nielsen, F. H., and D. J. Higgs. Further studies involving a nickel deficiency
in chicks. In: Trace Substances in Environmental Health - IV, D. D. Hemphill
(ed.), Columbia, MO., University of Missouri, 1971, pp. 241-246.
Nielsen, F. W., and H. H. Sandstead. Are nickel, vanadium, silicon, fluorine,
and tin essential for man? A review. Am. J. Clin. Nutr. 27:515-520, 1974.
N;elson, F. H. Newer trace elements and possible application in man. Trace
El em. Human Health and Disease 2:379-399, 1976.
Nilzen, A., and K. Wilstrom. The influence of lauryl sulphate on the sensi-
tization of guinea pigs to chrome and nickel. Acta Dermatovnereologica 35:292-299,
1955.
Nodiya, P. I. Cobalt and nickel balance in students of an occupational technical
school. Gig. Sanit. 37:108-109, 1972.
Nodiya, P. I. Cobalt and nickel balance in students of an occupational technical
school. Gig. Sanit. 37:108-109, 1972.
Nomoto, S., and F. W. Sunderman, Jr. Atomic absorption spectrometry of nickel
in serum, urine, and other biological materials. Clin. Chem. 16:477-485,
1970.
Nomoto, S. Evaluation of normal values of serum nickel among Japanese -
isolation of nickel-binding protein. Jap. J. Clin. Path. 19(Suppl.):200-201,
1971. (in Japanese)
Nordberg, G. F. (ed.). Effects and Dose-Response Relationships of Heavy
Metals. Amsterdam, Elsevier, 1976.
c-133
-------
North American Contact Dermatitis Group. Epidemiology of contact dermatitis
in North America: 1972. Arch. Dermatol. 108:537-540, 1973.
O'Dell, G. D., W. J. Miller, S. L. Moore, W. A. King, J. C. Ellers, and H.
Juracek. Effect of dietary nickel level on excretion and nickel content of
tissues in male calves. J. Anim. Sci. 32:767-773, 1971.
Onkelinx, C. Whole-body kinetics of metal salts in rats. In: Clinical Chemistry
and Chemical Toxicology of Metals. S. S. Brown (ed.), Elsevier, Amsterdam,
1977, p. 37-40.
Onkelinx, C. , J. Becker, and F. W. Sunderman, Jr. Compartmental analysis of
the metabolism of Ni(II) in rats and rabbits. Res. Comm. Chem. Pathol.
Pharmacol. 6:663-676, 1973.
O'Sullivan, W. J., and J. F. Morrison. The effect of trace metal contaminants
and EDTA on the velocity of enzyme-catalyzed reactions. Studies on ATP:
creatine phosphotransferase. Biochimica et Biophysica Acta 77:142-144, 1963.
Ottolenghi, A. D., J. K. Haseman, W. W. Payne, H. L. Falk, and H. N. MacFarland.
Inhalation studies of nickel sulfide in pulmonary carcinogenesis of rats. J.
Natl. Cancer Inst. 54:1165-1172, 1974.
Palo, J. , and H. Savolainen. Biochemical diagnosis of aspartylglycosaminuria.
Ann. Clin. Res. 5:156-162, 1973.
Parker, D., and J. L. Turk. Delay in the development of the allergic response
to metals following intratracheal instillation. Int. Arch. Allergy Appl.
Immunol. 57:289-293, 1978.
Parker, K., and F. W. Sunderman, Jrg3 Distribution of Ni in rabbit tissues
following intravenous injection of NiCl9. Res. Commun. Chem. Pathol. Pharmacol.
7:755-762, 1974. *
Payne, W. W. Carcinogenicity of nickel compounds in experimental animals.
Proc. Am. Assoc. Cancer Res. 5:50, 1964. abstr. #197
Pedersen, E., A. C. Htfgetveit, and A. Andersen. Cancer of respiratory organs
among workers at a nickel refinery in Norway. Int. J. Cancer 12:32-41, 1973.
Pekarek, R. S., and E. C. Hauer. Direct determination of serum chromium and
nickel by an atomic absorption spectrophotometer with a heated graphite furnace.
Fed. Proc. 31:700, 1972 (abstr. #2730).
Perry, H. M., Jr., and E. F. Perry. Normal concentrations of some trace
metals in human urine: Changes produced by ethylenediametetracetate. J.
Clin. Invest. 38:1452-1463, 1959.
Phatak, S. S. and V. N. Patwardhan. Toxicity of Nickel - Accumulation of
nickel in rats fed on nickel-containing diets and its elimination. J. Sci.
Ind. Res. 118:173-176, 1952.
C-134
-------
Phatak, S. S. , and V. N. Patwardhan. Toxicity of nickel. J. Sci. Ind. Res.
9Ei: 70-76, 1950.
Port, C. D., J. D. Fenters, R. Ehrlich, D. L. Coffin, and D. Gardner. Inter-
action of nickel oxide and influenza infection in the hamster. Environ.
Health Perspect. 10:268, 1975. Abstr.
Prakash, N.+J., ^. Fontana, and R. I. Henkin. Effect of transitional metal
ions on (Na + K ) ATPase activity and the uptake of norepinephrine and choline
by brain synaptosomes. Life Sci. 12:249-259, 1973.
Raff, E. C., and J. J. Blum. Some properties of a model assay for ciliary
contractility. J. Cell Biol. 42:831-834, 1969.
Ragaini, R. C. , H. R. Ralston, and N. Roberts. Environmental trace metal
contamination in Kellogg, Idaho, near a lead smelting complex. Environ. Sci.'
Technol. 11:773-781, 1977.
Reno, H. T. Nickel. In: Minerals Yearbook 1972 Vol. I. Metals, Minerals
and Fuels. Washington, DC, U.S. Government Printing Office, 1974, pp. 871-879.
Rudzki, E. and Z. Grzywa. Exacerbation of nickel dermatitis by margarine.
Contact Dermatitis 3:344, 1977.
Saggerson, E. D., S. R. Sooranna, and C. J. Evans. Insulin-like actions of
nickel and other transition-metal ions in rat fat-cells. Biochem. J. 154:349-357,
1276.
Saknyn, A. V., and N. K. Shabynina. Epidemiology of malignant neoplasms in
nickel plants. Gig. Tr. Prof. Zabol. 17:25-29, 1973. In Russian.
Samitz, M. H., and H. Pomerantz. Studies of the effects on the skin of nickel
and chromium salts. Arch. Ind. Health 18:473-479, 1958.
Samitz, M. H., and S. A. Katz. Nickel dermatitis hazards from prostheses. ^n
vivo and in vitro solubil ization studies. Brit. J. Dermatol. 92:287-290,
1975.
Samitz, M. H., S. A. Katz, D. M. Schneiner, and J. E. Lewis. Attempts to
induce sensitization in guinea pigs with nickel complexes. Acta Dermatovener
(Stockholm) 55:475-480, 1975.
Schnegg, A., and M. Kirchgessner. The essentiality of nickel for the growth
of animals. Z. Tierphysiol., Tierernaehr. Futtermittelkd. 36:63-74, 1975a.
Schnegg, A., and M. Kirchgessner. Veranderungen des Hamoglobigehaltes der
Erythrozytenzahl und des Hamatokrits bei Nickelmangel. Nutr. Metabol. 19:268-278,
1975b.
Schnegg, A. , and M. Kirchgessner. Zur Absorption und Verfiigbarkeit von Eisen
bei Nickel-Mangel. Internat. Z. Vit. Ern. Forschung 46:96-99, 1976.
C-135
-------
S'lhroeder, H. A. , and A. P. Nason. Trace metals in human hair. J. Invest.
Dcjrmatol. 53:71-78, 1969.
Schroeder, H. A., and A. P. Nason. Trace metals in human hair. J. Invest.
Derm. 53:71-78, 1969.
Schroeder, H. A. , and M. Mitchener. Toxic effects of trace elements on the
reproduction of mice and rats. Arch. Environ. Health 23:102-106, 1971.
Schroeder, H. A., J. J. Balassa, and I. H. Tipton. Abnormal trace metals in
mannickel. J. Chronic Dis. 15:51-65, 1962.
Schroeder, H. A., M. Mitchener, and A. P. Nason. Life-term effects of nickel
in rats: Survival, tumors, interactions with trace elements and tissue levels.
J. Nutr. 104:239-243, 1974.
Sigel, H. , K. Becker, and D. B. McCormick. Ternary complexes in solytion_+
Influence ofo2.,2 -bipyridyl on the stability of l:l,complexes of Co , Ni ,
Cy , and Zn with hydrogen phosphate, adenosine 5 -monophosphate, and adenosine
5 -triphosphate. Biochim. Biophys. Acta 148:655-664, 1967.
Singh, A., and J. P. W. Gilman. Use of the double diffusion chamber for an
analysis of muscle-nickel sulphide interaction. Indian J. Med. Res. 61:704-707,
1S73.
Sirover, M. A., and L. A. Loeb. On the fidelity of DNA replication. Effect
of metal activators during synthesis with avian myeloblastosis virus DNA
pclymerase. J. Biol. Chem. 252:3605-3610, 1977.
Smith, J. C., and B. Hackley. Distribution and excretion of nickel-63 administered
intravenously to rats. J. Nutr. 95:541-546, 1968.
Sorenson, J. R. J., T. E. Kober, and H. G. Petering. The concentration of Cd,
Cu, Fe, Ni, Pb, and Zn in bituminous coals from mines with differing incidences
of coal workers' pneumoconioses. Am. Ind. Hyg. J. 35:93-98, 1974.
Spears, J. W., and E. E. Hatfield. Role of nickel in animal nutrition. Feedstuffs
49:24-28, 1977.
Spears, J. W., C. J. Smith, and E. E. Hatfield. Rumen bacterial urease requirement
for nickel. J. Dairy Sci. 60:1073-1076, 1977.
Spears, J. W., E. E. Hatfield, R. M. Forbes, and S. E. Koenig. Studies on the
role of nickel in the ruminant. J. Nutr. 108:313-320, 1978.
Spoerl, R., and M. Kirchgessner. Studies on increased accumulation of iron,
zinc, manganese and nickel by the gravid organism. Z. Tierphysiol, Tierernaehr,
and Futtermittelkd. 38:205-210, 1977.
Spruit, D., and P. J. M. Bongaarts. Nickel content of plasma, urine and hair
in contact dermatitis. Dermatologica 154:291-300, 1977a.
C-136
-------
Spruit, D., and P. J. M. Bongaarts. Nickel content of plasma, urine and hair
i
-------
Sunderman, F. W., J. F. Kincaid, A. J. Donnelly, and B. West. Nickel poisoning.
IV. Chronic exposure of rats to nickel carbonyl; a report after one year of
observation. Arch. Ind. Health 16:480-485, 1957.
Sunderman, F. W., Jr. A review of the carcinogenicities of nickel, chromium
and arsenic compounds in man and animals. Preventive Med. 5:279-294, 1976.
Sunderman, F. W., Jr. A review of the carcinogenicities of nickel, chromium
and arsenic compounds in man and animals. Preventive Med. 5:279-294, 1976.
Sunderman, F. W., Jr. Carcinogenic effects of metals. Fed. Proc. 37:40-46,
1978.
14
Sunderman, F. W., Jr. Effect of nickel carbonyl upon incorporation of C-
leucine into hepatic microsomal proteins. Res. Comm. Chem. Pathol. Pharmacol.
1:161-168, 1970.
Sunderman, F. W., Jr. Effect of nickel carbonyl upon hepatic concentrations
of adenosine triphosphate. Res. Comm. Chem. Pathol. Pharmacol. 2:545-551,
1971.
Sunderman, F. W., Jr. Inhibition of induction of benzpyrene hydroxylase by
nickel carbonyl. Cancer Res. 27:950-955, 1967a.
Sunderman, F. W., Jr. Measurement of nickel in biological materials by atomic
absorption spectrometry. Am. J. Clin. Pathol. 44:182-188, 1965.
Sunderman, F. W., Jr. Nickel carbonyl inhibition of phenobarbital induction
of hepatic cytochrome P-450. Cancer Res. 28:465-470, 1968.
Sunderman, F. W., Jr. The current status of nickel carcinogenesis. Ann.
Clin. Lab. Sci. 3:156-180, 1973.
Sunderman, F. W., Jr. The metabolism and toxicology of nickel. In: Clinical
Chemistry and Chemical Toxicology of Metals. S. S. Brown (ed.). Elsevier,
Amsterdam, 1977. pp. 231-259.
Sunderman, F. W., Jr. The metabolism and toxicology of nickel. In: Clinical
Chemistry and Chemical Toxicology of Metals. S. S. Brown (ed.), Amsterdam,
Elsevier, 1977, pp. 231-259.
Sunderman, F. W., Jr. Nickel carbonyl inhibition of cortisone induction of
hepatic tryptophan pyrrolase. Cancer Res. 27:1595-1599, 1967b.
Sunderman, F. W., Jr., and C. E. Selin. The metabolism of nickel-63 carbonyl.
Toxicol. Appl. Pharmacol. 12:207-218, 1968.
Sunderman, F. W., Jr., and K. C. Leibman. Nickel carbonyl inhibition of
induction of aminopyrine demethylase activity in liver and lung. Cancer Res.
30:1645-1650, 1970.
C-138
-------
Sunderman, F. W., Jr., and M. Esfahani. Nickel carbonyl inhibition of RNA
polymerase activity in hepatic nuclei. Cancer Res. 28:2565-2567, 1968.
Sunderman, F. W. , Jr., and R. M. Maenza. Comparisons of carcinogenicities of
nickel compounds in rats. Res. Comm. Chem. Pathol. Pharmacol. 14:319-330,
1976.
Sunderman, F. W., Jr. , and Sunderman, F. W. Studies of pulmonary carcinogenesis:
The sub-cellular partition of nickel and the binding of nickel by ribonucleic
acids. Fed. Proc. 22:427, 1963. abstr. #1592.
Sunderman, F. W., Jr., K. S. Kasprzak, T. J. Lau, P. P. Minghetti, R. M.
Maenza, N. Becker, C. Onkelinx, and P. J. Goldblatt. Effects of manganese on
carcinogenicity and metabolism of nickel subsulfide. Cancer Res. 36:1790-1800,
1976.
Sunderman, F. W. , Jr., M. I. Deesy, and M. D. McNeely. Nickel metabolism in
health and disease. Ann. N. Y. Acad. Sci. 199:300-312, 1972a.
Sunderman, F. W., Jr., N. 0. Roszel, and R. J. Clark. Gas chromatography of
m'ckel carbonyl in blood and breath. Arch. Environ. Health. 16:836-843, 1968.
Sunderman, F. W., Jr., N. 0. Roszel, and R. J. Clark. Gas chromatography of
nickel carbonyl in blood and breath. Arch. Environ. Health 16:836-843, 1968.
Sunderman, F. W., Jr., S. K. Shen, J. M. Mitchell, P. R. Allpass, and I.
Damjanov. Embryotoxicity and fetal.toxicity of nickel in rats. Toxicol. Appl.
Pharmacol. 43:381-390, 1978.
Sunderman, F. W., Jr., S. Nomoto, and M. Nechay. Nickel metabolism in myocardial
infarction II. Measurements of nickel in human tissues. In: Trace Substances
in Environmental Health - IV, 0. D. Hemphill (ed.), Columbia, MO., University
of Missouri, 1971, pp. 352-356.
Sunderman, F. W., Jr., S. Nomoto, R. Morang, M. W. Nechay, C. N. Burke, and S.
W. Nielsen. Nickel deprivation in chicks. J. Nutr. 102:259-268, 1972b.
Sushenko, 0. V., and K. E. Rafikova. Questions of work hygiene in hydro-
metallurgy of copper, nickel and cobalt in a sulfide ore. Gig. Tr. Prof.
Zabol. 16:42-45, 1972.
Svejgaard, E., N. Morling, A. Svejgaard, and N. K. Veien. Lymphocyte trans-
formation induced by nickel sulphate: An j_n vitro study of subjects with and
without a positive nickel patch test. Acta Oermatovener (Stockholm) 58:245-250,
1978.
Sweet, D. V., W. E. Grouse, J. V. Crable, J. R. Carlberg, and W. S. Lainhart.
The relationship of total dust, free silica, and trace metal concentrations to
the occupational respiratory disease of bituminous coal miners. Am. Ind. Hyg.
Assoc. J. 35:479-488, 1974.
C-139
-------
Swierenga, S. H. H., and P. K. Basrur. Effect of nickel on cultured rat
enbryo muscle cells. Lab. Invest. 19:663-674, 1968.
Sykes, A. K., and P. K. Basrur. Ultrastructural changes in cultured rat
enbryo myoblasts exposed to nickel sulfide. In Vitro 6:377. 1971. abstr. #22.
S;:adkowski, D. , G. Kohler, and G. Lehnert. Serum elektrolyte und elecktrisch-
mechanische Herzaction under chronisher industrieller Hitzeblastung. Arztl.
Forsch. 23:271-284, 1970.
Szadkowski, D. , H. Schultze, K. H. Schaller, and G. Lehnert. Zur okologischen
Bedeutung des Schwermetallgehaltes von Zigaretten. Archiv. Hyg. Bakteriol.
153:1-8, 1969.
Szadkowski, D., H. Schultze, K.-H. Schaller, and G. Lehnert. Zur okologischen
Bedeutung des Schwermetallgehaltes von Zigaretten. Arch. Hyg. Bakteriol.
153:1-8, 1969.
Tatarskaya, A. A. Occupational diseases of upper respiratory tract in persons
employed in electrolytic nickel refining departments. Gig. Tr. Prof. Zabol.
6:35-38, 1960.
++ ++
Taubman, S. B., and J. W. Mai nick. Inability of Ni and Co to release
histamine from rat peritoneal mast cells. Res. Comm. Chem. Pathol. Pharmacol.
10:383-386, 1975.
Tedeschi, R. E., and F. W. Sunderman. Nickel poisoning. V. The metabolism
of nickel under normal conditions and after exposure to nickel carbonyl. Arch.
Ind. Health 16:486-488, 1957.
Thomson, R. , I. Webster, and T. A. Kilroe-Smith. The metabolism of benzo(a)-
pyrene in rat liver microsomes: The effect of asbestos-associated metal ions
and pH. Res. 7:149-157, 1974.
Thulin, H. The leukocyte migration test in nickel contact dermatitis. Acta
Dermatovener (Stockholm) 56:377-380, 1976.
Toda, M. Experimental studies of occupational lung cancer. Bull. Tokyo Med.
Dent. Univ. 9:440-441, 1962.
Tolot, F. , P. Broden, and G. Neulat. Asthmatic forms of lung disease in
workers exposed to chromium, nickel and aniline inhalation. Arch. Mol. Prof.
Med. Tran. Secur. Soc. 18:288-293, 1956.
Torjussen, W., and L. A. Solberg. Histological findings in the nasal mucosa
of nickel workers. Acta Otolaryngol. 82:266-267, 1976.
Treagan, L., and A. Furst. Inhibition of interferon synthesis in mammalian
cell cultures after nickel treatment. Res. Comm. Chem. Pathol. Pharmacol.
1:395-401, 1970.
C-140
-------
T.'.eretili, M. N. , and R. P. Mandzhavidze. Clinical observations of acute
n-.ckel carbonyl poisoning. Gig. Tr. Prof. Zabol. 13:46-47, 1969.
Turk, J. L., and D. Parker. Sensitization with Cr, Ni, and Zr salts and
a'lergic type granuloma formation in the guinea pig. J. Invest. Dermatol.
68:341-345, 1977.
U.S. Environmental Protection Agency. Air Quality Data for Metals 1970 through
IS'74 from the National Air Surveillance Network. EPA-600/4-76-041, U.S.
Environmental Protection Agency, Research Triangle Park, NC, August 1976.
Uehara, M., C. Takahashi, and S. Ofuji. Pustular patch test reactions in
atopic dermatitis. Arch. Dermatol. 111:1154-1157, 1975.
Vandenberg, J. J., and W. L. Epstein. Experimental nickel contact
sensitization in man. J. Invest. Dermatol. 41:413-416, 1963.
von Schaller, K. H., A. Kuhner, and G. Lehnert. Nickel als Spurenelement im
menschlichen Blut. Blut 17:155-160, 1968.
Vuopala, U., E. Huhti, J. Takkunen, and M. Huikko. Nickel carbonyl poisoning.
Report of 25 cases. Ann. Clin. Res. 2:214-222, 1970.
Wahlberg, J. E. Nickel allergy and atopy in hairdressers. Contact Dermatitis
1:161-165, 1975.
Wahlberg, J. E. Sensitization and testing of guinea pigs with nickel sulfate.
Dermatologica 152:321-330, 1976.
Wahlberg, J. E., and E. Skog. Nickel allergy and atopy. Threshold of nickel
sensitivity and immunoglobulin E determination. Brit. J. Dermatol. 85:97-104,
1971.
Waltschewa, V. W. , M. Slatewa, and I. Michailow. Hodenveranderungen bei
weissen Ratten durch chronische Verabreichung von Nickel sulfat. (Testicular
changes due to long-term administration of nickel sulphate in rats.) Exp.
Pathol. 6:116-120, 1972. In German with Engl. abstr.
Wase, A. W., D. M. Goss, and M. J. Boydg, The metabolism of nickel. I.
Spatial and temporal distribution of Ni in the mpuse. Arch. Biochem.
Biophys. 51:1-4, 1954.
Waters, M. D., D. E. Gardner, and D. L. Coffin. Toxicity of metallic chlorides
and oxides for rabbit alveolar macrophages j_n vitro. Environ. Health Perspect.
10:267-268, 1975. abstr.
Watt, T. L., and R. R. Baumann. Nickel earlobe dermatitis. Arch. Dermatol.
98:155-158, 1968.
fi "} o+
Webb, M., and S. M. Weinzierl. Uptake of Ni from its complexes with
proteins and other ligands by mouse dermal fibroblasts j_n vitro. Brit. J.
Cancer 26:292-298, 1972.
C-141
-------
Wubb, M. , J. C. Heath, and T. Hopkins. Intranuclear distribution of the
inducing metal in primary rhabdomyosarcomata induced in the rat by nickel,
cobalt and cadmium. Brit. J. Cancer 26:274-278, 1972.
Wuber, C. W., and B. L. Reid. Nickel toxicity in growing chicks. J. Nutr.
9!j: 612-616, 1968.
Wuhner, A. P., and D. K. Craig. Toxicology of inhaled NiO and CoO in Syrian
golden hamsters. Am. Industrial Hyg. Assoc. J. 33:147-155, 1972.
Winner, A. P., R. H. Busch, R. J. Olson, and D. K. Craig. Chronic inhalation
of nickel oxide and cigarette smoke by hamsters. Am. Ind. Hyg. Assoc. J.
36:801-809, 1975.
Weinzierl, S. M., and M. Webb. Interaction of carcinogenic metals with tissue
and body fluids. Brit. J. Cancer 26:279-291, 1972.
Wells, G. C. Effects of nickel on the skin. Brit. J. Dermatol. 68:237-242,
1956.
Whanger, P. D. Effects of dietary nickel on enzyme activities and mineral
content in rats. Toxicol. Appl. Pharmacol. 25:323-331, 1973.
Wilson, H. T. H. Nickel dermatitis. The Practitioner 177:303-308, 1956.
WHschi, H. A comparative study of iji vivo RNA and protein synthesis in rat
liver and lung. Cancer Res. 32:1686-1694, 1972.
C-142
------- |