T H E AMEHICAN J O U R N A L OF CLINICAL
PATHOLOGY
Vol. 40, N o . 6, p p . 563-575
December, 1963
C o p y r i g h t © 11)63 b y T h e Williams & Wilkins C o .
Printed in
U.S.A.
STUDIES OF NICKEL CARCINOGENESIS
T H E SUBCELLULAR PAKTITION OF NICKEL IN LUNG AND LIVER FOLLOWING INHALATION OP
NICKEL
CARBONYL
F. WILLIAM SUNDERMAN, J R . , M.D., AND F. WILLIAM SUNDERMAN, M.D., P H . D .
WITH THE TECHNICAL ASSISTANCE OF LURA A. COLEMAN,
B.S.
Division of Metabolic Research, Department of Medicine, Jefferson Medical College,
Philadelphia 7, Pennsylvania
Previous studies from our laboratory have
emphasized the prevalence of cancer of the
lung among industrial workers exposed to
nickel carbonyl, Ni(CO).,.20' 36' 38-40' 42
Nickel carbonyl is a volatile, highly toxic
compound which is formed whenever
reactive nickel comes into contact with
carbon monoxide. Nickel carbonyl is an
intermediate product in the Mond process
for refining nickel ore. Owing to its catalytic
properties, nickel carbonyl also finds application in a wide variety of industrial
operations.
The relation of nickel to pulmonary
carcinogenesis has been studied by numerous
investigators. 1 ' 2 ' "• 8' 9' 12"16' 18' 19' 2l- 23 ' 24 ' 36'
38,40, 42,47 j)0]\s. 9 n a s r e p 0 r t e d that between
the years 1938 and 1956, 35.5 per cent of
nickel workers in Glamorganshire, Wales,
died of cancer of the lung and nose. Recently,
Passey24 has compiled statistical information
on 147 cases of lung cancer among workmen
at the Glamorganshire nickel refineries. The
Ministry of Pensions and National Insurance
of Great Britain has officially recognized
pulmonary cancer as a compensable disease
among workmen exposed to "nickel produced by decomposition of a gaseous
nickel compound." 9 ' 14
Investigations in our laboratory have
Received, July 3,1903; accepted for publication
August 29.
Dr. Sunderman, Jr., is Instructor in Medicine
and a member of the Division of Metabolic Research, Department of Medicine. Dr. Sunderman,
Sr., is Director of Division of Metabolic Research,
and Clinical Professor of Medicine.
This is the fourteenth paper in a series of
studies of nickel poisoning supported by contracts
of Jefferson Medical College with the Atomic
Energy Commission and the Rohm and Haas
Company.
563
demonstrated the induction of metastasizing
pulmonary carcinomas in rats after chronic
inhalation of nickel carbonyl in an atmospheric concentration of 4 parts per million
(p.p.m.) for 30 min. 3 times weekly for 1
year, and also after single massive exposure
to nickel carbonyl in a concentration of 80
p.p.m. for 30 min.3S Further investigations
have demonstrated
that
main-stream
tobacco smoke contains nickel in a mean
concentration of 0.14 p.p.m.42 It has been
estimated that the amount of nickel
inhaled annually by a heavy cigarette
smoker is approximately 3 times that which
is carcinogenic for the rat.
Schroeder and associates33 have observed
that, until recently, nickel was the only
metal in the first transitional group of the
periodic classification which had not been
demonstrated to have specific biologic
activity in vitro or in vivo. Such biologic
activity for nickel was suggested by Wacker
and Vallee,46 who observed that ribonucleic"
acids from diverse biologic sources contain
large concentrations of nickel, as well as
iron, chromium, manganese, lead, copper,
and zinc. These observations were confirmed
by a previous investigation from our
laboratory. 36 Nickel was demonstrated in
purified preparations of ribonucleic acids
(RNA) from normal rat lung and liver and
was not removed from these preparations of
RNA by prolonged dialysis. After exposure
of rats to nickel carbonyl, increases were
observed in the concentrations of nickel in
high-molecular weight RNA from both
lung and liver. These interactions in vivo
between nickel and RNA were attended by
alterations in physical-chemical properties
of the ribonucleic acids.38
As a further step towards the elucidation
564
SUNDERMAN AND SUNDERMAN
of nickel carcinogenesis, an attempt has
been made to determine the subcellular
localization of nickel in lung and liver.
Two previous groups of investigators11, 44
were unsuccessful in the search for nickel in
subcellular fractions of rat liver. In general,
the procedures used in the present study
were similar to those of the previous investigators, except that larger groups of rats were
studied, and nickel was determined by
means of a sensitive ultraviolet spectropho tome trie method.
METHODS
Solutions and apparatus. Precautions were
taken to prevent metallic contamination of
solutions or apparatus. The metal-free water
which was used throughout the study was
prepared by ion-exchange and distillation
and yielded a specific conductivity of less
than 1 x 10~6 mho. All glassware was
cleaned with hot nitric acid immediately
before use. Analyses were made of sucrose to
ensure that it was not contaminated with
nickel. The titanium probe of the ultrasonic disintegration apparatus was certified
by the manufacturer to be free of nickel.
Investigations in our laboratory verified
that disintegration with this probe did not
lead to contamination with nickel.
Analytical procedures. Nickel was measured by means of an ultraviolet spectrophotometric procedure previously reported
by our laboratory.36 Ribonucleic acid was
measured by means of the Ceriotti orcinol
procedure,7' 46 using as standards purified
samples of RNA from rat lung and liver,
previously prepared in our laboratory.36
Nitrogen was measured by a spectrophotometric procedure involving Kjeldahl
microdigestion and the Berthelot color
reaction.37 Succinic dehydrogenase activity
was determined spectrophotometrically by
the Bonner modification3 of the methylene
blue reduction technic. 5 ' 34 For measurements of dry weight, samples were dried in
vacuo over phosphorus pentoxide for 1 week.
Exposures of rats to nickel carbonyl. The
experimental animals were white male rats
of the Wistar strain weighing 200 to 250 Gm.
Nickel carbonyl was administered to the
rats by inhalation in an exposure chamber,
using a procedure previously described.41
Vol. 40
For acute experiments, groups of 12 rats
were exposed to nickel carbonyl for 60
min. in a concentration of 80 p.p.m. (0.60
nig. Ni(CO) 4 per liter of air). For chronic
experiments, similar groups of rats were
exposed to nickel carbonyl in a concentration
of 4 p.p.m. (0.030 mg. Ni(CO) 4 per liter
of air) for 30 min. 3 times weekly for 1
year. Continuous measurement of the
concentration of nickel carbonyl in the
exposure chamber was performed by a
method previously described.20 Control
groups of rats were placed in the exposure
chamber and treated similarly but were not
exposed to nickel carbonyl. In both acute
and chronic experiments, sacrifice of the
rats was performed by cervical fracture 24
hr. after exposure.
Tissue fractionations. Within 2 min. after
sacrifice of each rat, the portal vein and
inferior vena cava were cannulated and the
lungs and liver were freed of blood by
perfusion with cold 0.25 M sucrose solution.
The lungs and liver were excised and
connective tissue and bronchi were removed
by fine dissection. The tissues were pressed
between blotting papers, weighed, and
dropped for a few seconds onto solid carbon
dioxide. The tissues were sliced into thin
sections and added to 0.25 M sucrose in a
volume of 7 ml. per Gm. of wet weight. The
tissues were subjected to ultrasonic
disintegration for 4 min. at 0 C. with the
use of an ultrasonic disintegration apparatus
which generated a frequency of 20,000 cps
and a current of 2.0 amp. Fibrous tissue and
cellular debris were separated by passing the
homogenate through 5 thicknesses of cheese
cloth. Tissue homogenates from 12 rats were
pooled. The concentration of sucrose in
each pooled homogenate was computed from
measurements of the total volume of the
homogenate and of the volume of 0.25 M
sucrose used in its preparation. Aliquots of
each homogenate were taken for measurements of nickel, nitrogen, ribonucleic acid,
specific gravity, dry weight, and ash weight.
The remainder of each homogenate was
subjected to the differential sedimentation
technic of Schneider and Hogeboom 30,32 for
isolation of nuclear, mitochondrial, microsomal, and supernatant fractions. The
nuclear and mitochondrial fractions were
Dec. 1963
NICKEL
565
CARCINOGENESIS
washed once by resuspension in 0.25 M
sucrose (1 ml. per Gm. of tissue) followed
by recentrifugation. The washings of each
fraction were included in subsequent steps
in the fractionation procedure. An International model PR-2 centrifuge was used for
sedimentation of the nuclei, and an International model DB ultracentrifuge was
used for sedimentation of the mitochondrial
and microsomal fractions. Throughout the
procedure, the samples were maintained at
0 to 4 C. Aliquots of each subcellular
fraction were taken for measurements of
nickel, nitrogen, and ribonucleic acid.
In certain experiments, measurements were
also made of the dry weights and succinic
dehydrogenase activities of the subcellular
fractions. Nuclear and mitochondrial fractions were inspected microscopically, and
in certain experiments, mitochondria were
identified by staining with Janus green. All
determinations were related to the dry
weights of the homogenates, corrected for
the content of sucrose. Analytical measurements were performed in triplicate or
quadruplicate, and each experiment was
repeated 2 or 3 times.
It should be noted that the preparation of
subcellular fractions of lung parenchyma is
rendered difficult by the relatively great
proportion of connective tissue in the lung.
Insofar as can be ascertained, the only
previous studies of subcellular partitions of
lung are those reported by Reeves.26 The
tissue press which was used by Reeves26 for
preparation of lung homogenates did not
prove satisfactory in our hands. Preliminary
tests with a variety of all-glass or glassTeflon homogenizers likewise were unsatisfactory. By ultrasonic disintegration,
reproducible homogenates of lung were
obtained,
with
preservation
of
the
morphology of subcellular particles. In order
to separate fibrous tissue, it was necessary
to pass the homogenates through several
thicknesses of cheese cloth. In this process a
significant proportion of the nuclei were
removed from the homogenates. The nuclei
which were subsequently separated from
the homogenates by differential centrifugation were predominantly free of intact cells
and cellular debris, such as are usually
encountered in "nuclear" preparations. 26,44
In order that the subcellular partitions of
lung and liver might be comparable, identical
procedures were used for fractionations of
both tissues.
RESULTS
The recoveries of nickel, nitrogen, and
RNA in the subcellular fractions were
computed by dividing the sums of the concentrations of each of these constituents in
the individual fractions by their respective
concentrations in the total homogenates.
The mean recovery of nickel was 105 ± 1 6
per cent; the mean recovery of nitrogen was
100 ± 6 per cent; and the mean recovery of
RNA was 94 ± 11 per cent.
The percentage distributions of dry
weight, nitrogen, RNA, nickel, and succinic
dehydrogenase in homogenates of liver and
lungs from normal rats are reproduced in
Figure 1 and Table 1. In Figure 1, data for
liver partitions are plotted in the columns
labeled "A" and data for lung partitions are
plotted in the columns labeled " B . " The
height of each column represents 100 per
cent, and the percentage of a constituent
which was present in a given fraction is
indicated by the designated area in the
column. Inspection of Figure 1 reveals
general consistency in the percentage
distributions of dry weight, nitrogen, and
nickel in the subcellular fractions from each
organ. The proportions of RNA in the
microsomal fractions were relatively greater
than the corresponding proportions of dry
weight, nitrogen, or nickel. In the liver, 2
per cent of the nickel was found in the
nuclear fraction, 8 per cent in the mitochondrial fraction, 21 per cent in the microsomes, and 69 per cent in the supernatant.
In the lung, 5 per cent of the nickel was in
the nuclear fraction, 6 per cent in the mitochondrial fraction, 10 per cent in the
microsomes, and 79 per cent in the supernatant. Succinic dehydrogenase, a mitochondrial
enzyme,10' "• 2 8 ' 2 9 , "• 3 5 was
assayed as an index of mitochondrial
disruption. Previous investigators10' "• 2 8 ' 2 9
have reported that 59 to 80 per cent of
succinic dehydrogenase activity is observed
in the mitochondrial
fraction
after
mechanical disruption of rat liver cells. In
the present study, after ultrasonic disruption
Vol
SUNDERMAN AND SUNDERMAN
SUB-CELLULAR PARTITION OF NITROGEN AND RNA IN L U N G PARENCHYMA
FOLLOWING INHALATION OF NICKEL CARBONYL
100NITROGEN _
mg/gm
(DryWt.)
t «
5(J
1 l - l - l A l
I—J—l.,,J,M.
I
I
r*niiii
20-
RNA
mg/gm
A1
m
(Dry Wl.)
-s-rir-*-i—-^a
TOTAL
PARENCHYMA
•
CONTROLS
NUCLEI AND
DEBRIS
MITOCHONDRIA
ACUTE EXPOSURE
MICROSOMES
SUPERNATANT
CHRONIC EXPOSURE
FIG. 3
NICKEL: NITROGEN RATIOS IN FRACTIONS OF L U N G
PARENCHYMA
FOLLOWING INHALATION OF NICKEL CARBONYL
mcgm N i
gmN
2000-
IP
Ii i
1500-
i
1000-
1*1
500-
II
TOTAL
PARENCHYMA
•
CONTROLS
NUCLEI AND
DEBRIS
MITOCHONDRIA
ACUTE EXPOSURE
FIG. 4
11
MICROSOMES
SUPERNATANT
CHRONIC EXPOSURE
Dec. 1968
NICKEL
569
CARCINOGENESIS
nickel in the microsomal and supernatant
fractions were likewise increased, and
significant increases were also observed in
the nuclear and mitochondrial fractions.
The subcellular partitions of nitrogen and
RNA in lungs of control rats and of rats
exposed to nickel carbonyl are illustrated in
Figure 3. No significant alterations were
TABLE 3
R A T I O S OF N I C K E L TO N I T R O G E N AND OF N I C K E L TO RNA IN FRACTIONS OF L U N G PARENCHYMA AFTER
INHALATION OF N I C K E L CARBONYL
Nickel: Nitrogen Ratios*
Fraction
Acute
exposuref
Controls
Nickel: RNA Ratios*
Chronic
exposurej
tig. Ni/Gm. Ar in fraction
Total parenchyma
Nuclei and
debris
Mitochondria
Microsomes
Supernatant
73
(60 to 7C)
107
(137 to 197)
158
(128 to 189)
69
(50 to 81)
08
(04 to 71)
1210
(908 to 1400)
097
(331 to 1060)
838
(054 to 1010)
1270
(1050 to 1490)
1230
(990 to 1460)
Acute
exposuref
Controls
Chronic
exposurej
Hi. Ni/Gm. RNA
718
(590 to 841)
1970
(1560 to 2380)
1540
(1190 to 1880)
743
(519 to 906)
634
(509 to 700)
305
(355 to
267
(260 to
484
(370 to
215
(168 to
400
(304 to
374)
273)
598)
261)
443)
infraction
4080
(3510 to 0260)
1030
(1180 to 2090)
1780
(1090 to 1870)
3390
(2640 to 4120)
5810
(5010 to 6800)
3040
(2810 to 3270)
0380
(5000 to 7000)
3480
(3100 to 3840)
2270
(2130 to 2410)
3050
(2880 to 3210)
* Mean and range of duplicate or triplicate experiments.
f Single exposure to Ni(CO)<, 80 p.p.m. (0.00 mg. per 1. of air) for 00 min.
% Exposures to Ni(CO)4, 4 p.p.m. (0.030 mg. per 1. of air) for 30 min., 3 times weekly for 1 year.
SUB-CELIULAR PARTITION OF NICKEL IN L I V E R PARENCHYMA
FOLLOWING INHALATION OF NICKEL CARBONYL
NICKEL
11
.
megm/gm
(DryWl.)
6
.
ii
•I
2-
^ita
TOTAL
PARENCHYMA
•
CONTROLS
NUCLEI AND
DEBRIS
MITOCHONDRIA
ACUTE EXPOSURE
FIG. 5
r+
n
MICROSOMES
SUPERNATANT
| | | | CHRONIC EXPOSURE
570
Vol. J,0
SUNDERMAN AND SUNDEBMAN
observed in the total content or in the
percentage distribution of nitrogen or RNA
after exposures to nickel carbonyl. It may
be noted from Figure 4 and Table 3 that in
control rats the ratios of nickel to nitrogen
were greater in the nuclear and mitochondrial fractions than in the microsomal
and supernatant fractions. After acute
exposure, the greatest increases in the
ratios of nickel to nitrogen were observed in
TABLE 4
SUBCELLULAR P A R T I T I O N OK N I C K E L IN L I V E R PARENCHYMA AFTER INHALATION OK N I C K E L CARBONYL
Percentage Distribution of Nickel*
Fraction
Acute
exposure!
Absolute Distribution of Nickel*
Controls
100
100
5.0
(4.7 to 5.4)
8.9
(0.8 to 11.1)
32.0
(21.0 to 42.9)
54.1
(45.0 to 02.5)
2.2
(0.6 to 2.8)
8.1
(3.8 to 12.4)
21.7
(20.3 to 23.1)
68.0
(01.7 to 74.3)
3.82
(2.89 to 4.97)
0.080
(0.00 to 0.20)
0.32
(0.21 to 0.58)
0.80
(0.08 to 0.86)
2.63
(2.00 to 3.32)
Chronic
exposure!
tig. NiJGm. of total parenchyma (dry wt.)
percentage of total
Total paren100
chyma
Nuclei and
2.2
(0.2 to 4.2)
debris
Mitochon8.2
dria
(0.0 to 11.7)
Microsomes
20.8
(17.3 to 23.0)
Supernatant
08.8
(00.8 to 70.5)
Acute
exposure*
Chronic
exposure!
Controls
7.45
(7.11 to 7.78)
0.37
(0.33 to 0.42)
0.60
(0.48 to 0.86)
2.38
(1.64 to 3.06)
4.03
(3.24 to 4.S6)
7.90
(G.2S to 9.50)
0.17
(0.15 to 0.18)
0.64
(0.30 to 0.78)
1.72
(1.45 to 1.93)
5.37
(3.39 to 7.08)
* Mean and range of duplicate or triplicate experiments.
f Single exposure to Ni(CO).i, 80 p.p.m., (0.60 mg. per 1. of air) for 00 min.
| Exposures to Ni(CO)4, 4 p.p.m., (0.030 mg. per 1. of air) for 30 min., 3 times weekly for 1 year.
SUB-CELLULAR PARTITION OF NITROGEN AND RNA IN L I V E R PARENCHYMA
F0LIOWING INHALATION OF NICKEL CARBONYL
300-
200-
NITROGEN.
mg/gm
(DryWt.) 100-
40RNA
mg/gm
(Diy Wt.)
*
*
•
20-
nl
TOTAL
PARENCHYMA
•
CONTROLS
NUCLEI AND
DEBRIS
MITOCHONDRIA
ACUTE EXPOSURE
FIG. 6
MICROSOMES
If
III
SUPERNATANT
CHRONIC EXPOSURE
Dec. 1963
571
NICKEL CARCINOGENESIS
the microsomes and supernatant. After
chronic exposure, the greatest increases in
the ratios of nickel to nitrogen were observed
in the nuclear and mitochondrial fractions,
Essentially the same relations were observed
iii the ratios of nickel to RNA (Table 3).
The subcellular partitions of nickel in
liver parenchyma are presented in Figure 5
NICKEL: NITROGEN RATIOS IN FRACTIONS OF L I V E R PARENCHYMA
FOLLOWING INHALATION OF NICKEL CARBONYL
mcgm N i
gm N
100-1
75-
H
II
|1
50-
|l
25-
*
TOTAL
PARENCHYMA
•
NUCLEI AND
DEBRIS
•
CONTROLS
MITOCHONDRIA
MICROSOMES
ACUTE EXPOSURE
SUPERNATANT
CHRONIC EXPOSURE
FIG. 7
TABLE 5
R A T I O S OF NICKEL, TO N I T R O G E N AND OF N I C K E L TO RNA IN FRACTIONS OF L I V E R PARENCHYMA AFTER
INHALATION OF N I C K E L CARBONVL
Nickel:RNA Ratios
Nickel :Nitrogen Ratios*
Fraction
Acute
exposuref
Controls
tig. Ni/Gm. N
Total parenchyma
(13
Nuclei and debris
(44
Mitochondria
(13
Microsomes
(8
Supernatant
(16
17
to
50
to
23
to
13
to
18
to
21)
(28
5G)
(33
32)
(23
10)
(25
21)
(25
32
to
53
to
33
to
31
to
28
to
Chronic
exposure!
fig. iYi/Gm.
infraction
3G)
(24
72)
(43
50)
(10
38)
(19
34)
(27
Acute
exposuref
Controls
42
to
40
to
21
to
24
to
03
to
58)
48)
25)
30)
09)
103
(154 to
400
(321 to
350
(111 to
82
(09 to
254
(178 to
172)
598)
590)
90)
330)
Chronic
exposure!
RiVA infra tion
247
(229 to
550
(215 to
550
(262 to
14S
(123 to
290
(245 to
265)
S95)
S3S)
174)
334)
353
(222 to
41S
(331 t o
213
(IIS to
160
(146 to
577
(305 to
* Mean and range of duplicate or triplicate experiments.
t Single exposure to Ni(CO)4, 80 p.p.m. (0.00 mg. per 1. of air) for 60 min.
% Exposures to Ni(CO).i, 4 p.p.m. (0.030 mg. per 1. of air) for 30 min., 3 times weekly for 1 year.
4S4)
454)
30S)
174)
S4S)
572
Vol. 40
STJNDERMAN AND SUNDERMAN
and Table 4. The nickel content of liver
parenchyma of control rats averaged 3.8 Mgper Gm. After acute and chronic exposures
to nickel carbonyl, the nickel content
increased to 7.5 and 7.9 Mg- per Gm.,
respectively (p < 0.01). These increases
were principally attributable to localization
of nickel in the microsomal and supernatant fractions.
As illustrated in Figure 6, the subcellular
partitions of nitrogen and RNA in liver
parenchyma were not significantly altered
after acute or chronic exposures to nickel
carbonyl. In Figure 7 and Table 5 are given
the ratios of nickel to nitrogen, in each of the
subcellular fractions of liver. After both
acute and chronic exposures, significant
increases were observed in the ratios of
nickel to nitrogen in the microsomal and
supernatant fractions. Essentially the same
relations were observed in the ratios of nickel
to RNA (Table 5).
DISCUSSION
Although a number of investigators have
studied the subcellular distribution of trace
metals, 4 ' u ' 2 2 ' 2 6 -"' 4 3 - 4 4 a search of the
literature has not revealed previous determinations of the subcellular distribution of
nickel. In Table 6 the ratios of nickel to
nitrogen obtained in the present study are
contrasted with the corresponding ratios of
other trace metals, compiled from the
literature. In Table 7, these data have
been computed so that direct comparisons
may be made of the distributions of the
various metals relative to the nitrogen
content of the fractions. Inspection of
Table 7 indicates that the ratios of calcium,
magnesium, and molybdenum to nitrogen
are greatest in the mitochondrial fraction.
The ratios of iron, zinc, and copper to
nitrogen are greatest in the supernatant
fraction, and the ratio of chromium to
nitrogen is greatest in the nuclear fraction.
Thiers and Vallee44 found the greatest ratio
of manganese to nitrogen to occur in the
nuclei, whereas Edwards and associates11
reported the greatest ratio of manganese to
nitrogen in the mitochondria. The studies of
Maynard and Cotzias,22 using radioactive
manganese,
support
the view
that
manganese is localized primarily in the
mitochondria. In the present investigations, the greatest ratios of nickel to nitrogen
were observed in the nuclear fractions of
lung and liver. Of the metals listed in Table
7, only chromium and nickel are known to
have carcinogenic properties. 14 ' 19,24 It may
be noteworthy, therefore, that the greatest
ratios of these metals to nitrogen in tissues
TABLE 0
SUBCELLULAR D I S T R I B U T I O N OP M E T A L S IN T I S S U E S OF N O R M A L R A T S *
Tissue
Liver
Metal
Reference N o .
Total
Nuclei
Mitochondria
Microsomes
Supernatant
Cil
44
44
11
44
11
44
11
44
11
44
11
11
This article
This article
0.99
8.5
0.015
1.4
3.3
0.78
1.05
0.26
0.25
O.0G9
0.037
0.0036
0.017
0.073
1.3
8.4
0.011
1.3
2.G
1.1
0.77
0.086
0.25
0.13
0.029
0.0041
0.050
0.167
2.7
10.3
0.025
2.1
1.7
0.35
0.42
0.16
0.19
0.099
0.067
0.0029
0.023
0.160
1.4
9.9
0.0050
3.3
3.6
1.4
0.05
0.12
0.061
0.048
0.032
0.0020
0.013
0.009
0.50
5.3
0.019
4.0
5.0
1.7
2.0
0.56
0.39
0.020
0.0072
0.0040
0.01S
0.06S
Mg
Mo
Fe
Zn
Cu
Mn
Lung
!
Cr
Ni
Ni
Mg. of metal in fraction
Gm. of nitrogen in fraction
Dec. 1968
573
NICKEL CARCINOGENESIS
TABLE 7
SUBCELLULAR D I S T R I B U T I O N O F M E T A L S I N T I S S U E S O F N O R M A L R A T S * !
Tissue
Metal
Liver
Ca
Mg
Mo
Fe
Zn
Cu
Mn
Lung
Cr
Ni
Ni
Reference No.
Nuclei
Mitochondria
Microsomes
Supernatant
44
44
11
44
11
44
11
44
11
44
11
11
This article
This article
1.31
0.99
0.73
0.93
0.73
1.41
0.73
0.38
1.00
1.86
0.78
1.14
2.94
2.28
2.73
1.21
1.67
1.50
0.48
0.45
0.40
0.62
0.76
1.44
1.81
0.81
1.35
2.21
1.42
1.16
0.33
2.36
1.01
1.80
0.62
0.46
0.24
0.70
0.S6
0.72
0.76
0.95
0.51
0.62
1.27
2.86
1.41
2.18
1.90
2.15
1.56
0.29
0.19
1.11
1.06
0.93
* Mg. of metal per Gm. of nitrogen in fraction
Mg. of metal per Gm. of nitrogen in total
f The highest value for each element is indicated by italics.
of normal rats are found in the nuclear
fractions.
SUMMARY
Measurements were made of the subcellular partitions of nickel in the lungs and
livers of normal rats and of rats exposed to
inhalation of carcinogenic levels of nickel
carbonyl. In normal rats nickel was located
principally in the microsomal and supernatant fractions of the lung and liver.
After acute as well as chronic exposures to
nickel carbonyl, increases in nickel occurred
predominantly in the microsomal and
supernatant fractions of lung and liver.
After chronic exposure to nickel carbonyl,
increased amounts of nickel were also
observed in nuclear and mitochondrial
fractions of the lung.
SUMMAItIO IN INTERLINGUA
Esseva facite mesurationes del partitiones
subcellular de nickel in le pulmones e hepates
de rattos normal e de rattos exponite al
inhalation de nivellos carcinogenic de carbonyl de nickel. In rattos normal, le nickel
esseva locate primarimente in le fractiones
microsomal e supernatante del pulmon e del
hepate.
Post acute e etiam chronic expositiones a
carbonyl de nickel, augmentos de nickel
occurreva primarimente in le fractiones
microsomal e supernatante del pulmon e del
hepate. Post exposition chronic a carbonyl
de nickel, augmentate quantitates de nickel
esseva etiam observate in le fractiones
nucleari e mitochondrial del pulmon.
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