From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
Arsenic-Induced
Ultrastructural
By John
R. Feussner,
Bone
Marrow
and Electron-Probe
John
D. Shelburne,
Stephen
A patient
with
severe
arsenic
poisoning
that resulted
in marked
peripheral
blood
and bone marrow
abnormalities,
including
megaloblastic
erythropoiesis
experienced
many of the previously
reported
hematologic complications
of arsenic
poisoning:
leukopenia,
granulocytopenia.
absolute
eosinophilia,
and profound
anemia.
In this
study
we report
an ultrastructural
and
electron-probe
analysis
of the bone marrow. Although
megaloblastic
anemia
associated
with
arsenic
poisoning
has been
described
rarely, the presence
of arsenic in
the local bone marrow
milieu has not been
demonstrated
previously.
The ultrastructural
features
of arsenic-induced
bone
marrow
toxicity
are
similar
to those
described
in other dyserythropoietic
states
and include
marked
nuclear
aberrations
E
ARLY
with
arsenic
solution
with
pernicious
therapy.”3
More
that arsenic
toxicity
can cause
megaloblastic anemia has come
a potential
cause
Although
arsenic
peripheral
we present
toxicity
anemia
recently,
progressive
black
painful
for
Viet
produces
several
in both
of General
of Pathology,
Duke
August
4. 1978;
Supported
in part
by the
Laboratory
Address
Medicine,
© 1979
820
reprint
Durham
by Grune
with
Fowler’s
have suggested
in
to
of hematologic
abnormalities,
a
veteran
legs and inability
Internal
and
REPORT
presented
became
Medicine
University
including
megaloblastosis,
analysis
of the bone marrow.
Medical
to the Durham
to walk
V.A.
Hospital
with
or rise from
a sitting
position.
especially
severe
and Hematology,
Center,
and
2-3
wk
prior
Department
the Durham
complaints
to
presentation.
of Medicine,
Veterans
of
Although
and the
Administration
NC.
Submitted
scopy
sequentially
and others
anemia
effect of
anemia.4 Thus the role of arsenic
therapy
for pernicious
anemia
a variety
his symptoms
months,
Durham,
treated
Westhoff
marrow
abnormalities,
and electron-probe
Nam
sensations
the Divisions
Hospital,
Jay Cohen
erythropoiesis.
CASE
From
Harvey
to megaloblastic
anemia
remains
unproved.
In this report we
with severe
arsenic
poisoning
resulting
in marked
anemia
and
blood and bone
an ultrastructural
a 32-yr-old
Department
and
involving
shape,
chromatin
distribution,
and nuclear
envelope.
Using the technique
of energy-dispersive
x-ray analysis
(electron probe)
we demonstrated
arsenic
in
bone marrow
spicules;
this supports
the
contention
that arsenic can cause megaloblastic anemia.
We suggest
that this technique may be a useful tool in further
studies that attempt
to explore
the mechanism
of arsenic-induced
hematologic
toxicity.
Finally,
we suggest
that
arsenic
has a
direct toxic effect on DNA synthesis
that
results
in marked
disturbances
of nuclear
division.
We recommend
that
the most
appropriate
screening
procedure
to evaluate possible
arsenic
poisoning
is tissue
arsenic
measurements
(hair
and
nails)
rather than 24-hr urinary measurements.
megaloblastic
full circle-from
of megaloblastic
causal
relationship
describe a patient
present
Bredehoeft,
MEDICINAL
USES
of arsenic
included
therapy
for pernicious
Fowler’s
solution.”2
However,
in 1943 Limarzi
found no salutary
in patients
and “liver
W.B.,
Toxicity:
Analysis
accepted
Durham
and by grant
requests
805460
to John
V.A. Hospital,
& Stratton,
December
Veterans
from
R.
Durham,
Inc. ISSN
28, 1978.
Administration
the Environmental
Feussner.
M.D.,
Hospital,
Diagnostic
Protection
Agency.
Ambulatory
Care
Section,
Electron
Micro-
Department
of
NC. 27705.
0006-4971/79/5305-0003$OJ.OO/O
Blood,
Vol. 53.
No. 5 (May),
1979)
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
ARSENIC-INDUCED
Additional
BONE
complaints
a 5-7-kg
weight
he was using
thick
and
tibial
rise from
wide-based.
distribution,
He
Laboratory
neutrophils,
count
rate was I 29 mm/hr.
37 mEq/dl
(54-154
23%
(4-16
ng/ml),
normal.
GOT
phosphatase
will
karyotype.
be
A 24-hr
in a 24-hr
urine
During
collection,
arsenic
skin changes
that
exposure
recent
arsenic
to include
discharge.
The
hematologic
find no environmental
source
and
to explain
Several
bone
of
overnight.
these
marrow
were
Fixation
in a JEOL
IOOB transmission
-
196#{176}C
until
dV
period
Thin
stained
electron
1.7 mg/dl
2.06
on the 34th
a vacuum
torr was obtained.
Following
scanning
electron
microscope
a normal
no arsenic
was present
mg/g
(0.001
mg/g).7’8
resolved.
hospital
Also,
day,
The
paresthesias
to allow
buffer
thus
whereas
suggesting
neurologic
seemed
section.
direct
deficits
improved
Finally,
visualization
Several
3%
was followed
acetate
The
a light
were
and bone marrow
demonstrated
sodium-cacodylate-buffered
uranyl
of 106
mg/dl);
on
we could
exposure.
glass
in the same
temperature.
BUN
lU/liter);
METHODS
over
microscope.
and
(0-1.4
blood
in a following
were
was 3.2
determinations
to hospitalization.
in detail
0.l-M
with
(100-225
and
other
by ethanol
lead citrate
spicules
specimen
carbon
equipped
Si (Li)
dehydration
examined
not
fixed
were
and
at 60 kV
in glutaralde-
by slow warming
the spicules
a Kevex
of spicules.
glutaraldehyde
nitrogen.
The metal
unit and maintained
was freeze-dried
coating,
with
were
were
were placed directly
on a metal stub and snap frozen in liquid
under
liquid
nitrogen
into a Denton
DV-502
freeze-etch
to room
on an ETEC
in
electrolytes
toxicity
painful
capacity
folate
lU/liter
Although
extreme:
total
electrophoresis,
Serum
marrow
The
sedimentation
protein
analysis
count
of 47%
1% basophils.
6. Peripheral
of arsenic
The
AND
tetroxide
sections
were
our patient’s
layered
fixed
in 1% osmium
in Epon.
a 4-hr
gently
promptly
embedding
hyde, but instead
was transferred
was
platelet
Serum
was
Bone
24 pg/liter).
I wk prior
will be presented
of arsenic
zero.
lines developed
footdrop.
152
bilirubin
was
and nails
approximately
variables
glove
differential
Westergren
respectively.
was
total
level
cell,
cell
and
pg/mI).
LDH
chromosome
MATERIALS
Heparinized
(200-900
marrow
Mees
blood
and serum
mEq/dl),
manifestations
wristdrop
patient
slapping,
and
iron and total iron binding
25 and June
levels in hair
ceased
bilateral
without
The
in a stocking
and the
negative,
on May
Bone
resolved,
(3/5)
was unsteady,
102 ism3/red
1.6%,
Serum
13 lU/liter);
ethanol
all gastrointestinal
the hyperkeratotic
progressed
tests were
lead level was zero (less than
hospitalization,
weak
gait
absent
a white
was
lU/liter);
(21-1
later.
were
ejection
and cooperative.
footdrop.
19% eosinophils,
count
pg/mI
(7-40
19) and again
described
urinary
not icteric,
without
His
MCV
with
(246-430
B,2 was 759
(5-1 10 lU/liter);
(May
26%,
mm.,
Coombs
lU/liter
was oriented
(3/5)
was
Although
A soft systolic
and wrists
weak
assistance.
7% monocytes,
177 mEq/dl
was 74 lU/liter
on admission
morphology
serum
and
His skin was abnormal,
normally.
hands
were
PCV
time were normal.
and
45
g/dl,
the reticulocyte
and indirect
man.
and soles.
patient
to pinprick
3300/cu
lymphocytes,
pain,
On admission,
in his feet.
8.4
count
mm.,
and
was
was 22 lU/liter
performed
cell
The
without
sensation
hemoglobin
mEq/dl)
ng/ml
nor walk
Pain
thromboplastin
were
CPK
position
blood
Direct
and partial
alkaline
The
was diminished
752/cu
was papillated
muscles
abdominal
abuse.
to the palms
and dysdiadochokinesis.
and gastrocnemius
included
was
confined
normal.
areflexic.
white
3% bands,
eosinophil
areas
midepigastric
on his soles and palms.
ill-appearing
were
a sitting
was
data
mm.,
alcohol
a chronically
and abdomen
and proprioception
255,000/cu
protime,
lungs
dysmetria
The anterior
neither
recent
revealed
crampy
skin changes
were pale, and the tongue
The
was bilateral
vomiting,
scaling
and desquamating
membranes
wristdrop.
could
examination
hyperkeratotic
nausea,
he noted
and he disclaimed
physical
was audible.
There
TOXICITY821
anorexia,
recently,
no medications,
the mucous
murmur
included
loss. Most
The admitting
with
MARROW
examined
energy-dispersive
stub
at
over
at 30
x-ray
analyzer.’
RESULTS
The
peripheral
blood
showing
coarse
basophilic
cytes
were
seen,
and
eosinophilia
was present
film suggested
heavy
metal
stippling
and multiple
nucleated
no hypersegmented
neutrophils
despite
leukopenia.
The initial
bone marrow
was striking
marked
hypercellularity
and erythroid
series
demonstrated
typical
megaloblastic
Platelet
in several
hyperplasia.
features
toxicity, with
erythrocytes
forms.
Few macroovalowere
present.
Absolute
morphology
was
normal.
respects.
The biopsy
The erythroid
and
(Fig.
lA).
In addition,
revealed
myeloid
bizarre
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
822
FEUSSNER
El
AL.
A
#{149}.
S
I
C
Fig. 1.
Representative
light micrographs
of Wright-stained
bone marrow
obtained
on admission.
(A) Erythroid
precursors
demonstrating
typical megaloblastic
features, with dissociation of cytoplasmic and nuclear
maturation
and a high nuclear/cytoplasmic
ratio. Megaloblastic
myeloid
precursors
are also present
(X400).
(B) Oil-immersion
views of megaloblastic
erythroid
precursors,
basophilic
stippling,
and bizarre karyorrhexis.
Several
cells are both karyorrhectic
and megaloblastic
(X 1000).
karyorrhexis,
coarse
basophilic
stippling,
present
(Fig.
1 B). Approximately
precursors.
Megakaryocytes
were
tion of their nuclei.
Iron was
results
of serial
bone marrow
listed
in Table
space.
Bone
patient’s
marrow
line of
marrow
of erythroblasts
shape,
chromatin
frequently
spicules
were
of arsenic.
confirmed
distribution,
Figure
examined
exhibited
than
bodies
were
counted
were eosinophil
only by marked
lobulaThe
are
that
microanalysis
of parts
per
of sodium
can
varies
million.
be distinguished
presence
of marked
and nuclear
envelope
The
plasma
membranes
lysosomes
the
control
marrow
counting
in the
analysis
K alpha
of
in
matrix
to demonstrate
arsenic
peak
in the
regions
of the stub lacking
(Fig.
3B). A peak at the L
times.
The sensitivity
of
with different
samples
Most
elements
with
from
cytoplasm
membrane
and vesicles
were
were seen within
the
micelles
by electron-probe
3A demonstrates
the
heterochromatin.
along
the
ferruginous
marrow.
This peak was absent
from
spicules
and from a control
patient’s
arsenic
was also visible
with
longer
energy-dispersive
x-ray
the range
of hundreds
greater
Howell-Jolly
ringed
sideroblasts
were absent.
and other
hematologic
variables
intracytoplasmic
vesicles.
The
granules.
Occasional
secondary
Mitochondria
the presence
abundant,
and
examinations
The majority
of chromatin
was
showed
rhopheocytotic
invaginations
addition
to similar
lined by ferritin-like
cytoplasm.
numerous
1.
Electron
photomicrographs
nuclear
aberrations
involving
(Fig.
2A-D).
normoblasts
and
40% of all myeloid
cells
numerous,
distinguished
one
another
but is usually
in
atomic
numbers
easily,
especially
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
ARSENIC-INDUCED
BONE
MARROW
TOXICITY
823
a
a
.c
a
‘D
u,
a
‘D
.C
‘
‘
‘a
a
c
II
II
‘
Ew..
w.
H
,
ow
‘
a
a
-
0)
C1
>.D
-
(I,
C’)
.
0
U)
a
0)
CO
d
Cl)
a
Co
to
Co
OC”4LC)
CC)
‘-C’)Co
,
:
0
C’)
a
C
r’.l
N
E
d
e
Cl)
CO
g)
C’J
a-.
(DOLt)
C
Lt)C’)CO
LOC’)C4
a
e
8
a
C’)
C’)
(‘)C’)
(O
000LONO
C’)(D
00(05(01))
E
a
C1N
C
(‘4
>
(0
1))’-
COLt)
CoC)’-C)N
(‘.4
c%4c’4
C-4C’)
‘)‘C’)C’)
>
8
-.
aO
.0
E2
LC)(’4
F”.
SN
0),-
br’
a
C’4C’4C’)C1(’4
-
a
I
0
C
0
-
(D
c’400
c
O
I
LO0)(0’
c’.4c’)C’)Lt)
‘
i.
a
0)
C’)LC)
c’.4c’1
1))
101))
C’)(0
10(0
‘-c’.lN’-c’J
(ONNNN
*4-
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
824
FEUSSNER
El
AL.
Fig. 2.
(A) Low-magnification
electron
micrograph
of bone marrow
exhibiting
numerous
abnormal erythroblasts
(X2050).
(B) Serial section
of the “binucleate”
cell seen in section
A. This cell is.
in fact,
not binucleate;
the two lobes of the nucleus are connected by a chromatin
bridge.
One
siderosome
is present in this cell (bottom
right), and ferruginous
micelles are visible in the
mitochondrial
matrix of an adjacent erythroblast
(top right) (X 6900).
(C) Another
erythroblast
present in section
A exhibiting
marked
irregularity
of nuclear
contour;
note the two protrusions
of
euchromatin
above (X 9100).
(D) This erythroblast exhibits a Howell-Jolly body and a mitochondrion
with ferruginous
micelles
in the matrix
space (X 13.900).
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
ARSENIC-INDUCED
Fig.
position
BONE
MARROW
TOXICITY
3.(A)
for
X-ray spectrum
of the freeze-dried
the K alpha
peak of arsenic
seen
and the energy of the x-rays is displayed
ordinate,
the specimen
platinum
support)
(from
the
825
marrow.
The long vertical
line indicates
the correct
below.
The number
of counts
is displayed
on the
on the abscissa.
Two large peaks for copper
(from
are visible at the left. Between
carbon
coating).
(B) X-ray
them and the arsenic peak there is a peak for
spectrum
of a control
region
of the
stub
devoid
of
marrow.
No arsenic peak is seen at the energy that corresponds to the K alpha peak of arsenic. As in
section A. two large peaks for copper are visible at left. The microscope
conditions are identical
in
sections
A and B. including
the
total
the peak of interest
when
elements
(compare
of counts
lies in a region
Figs.
energy-dispersive
number
x-ray
3A
and
(778.000).
of the spectrum
3B).
microanalysis
collected
The
usual
devoid
of peaks
resolution
is approximately
from
other
obtainable
with
150 eV.9
DISCUSSION
Our
patient
manifested
ing-gastrointestinal,
laboratory
confirmation
mg/g
of tissue
potential
lack
all
of the
common
clinical
cutaneous,
of the
and
clinical
neurologic
findings
symptoms
and signs.’7
In addition,
was unquestionable,
given the 2.06
arsenic
level.
of sensitivity
The
of that
negative
test,
urine
suggesting
features
of arsenic
determination
that
poison-
emphasizes
it is an inadequate
the
screening
test
for arsenic
exposure.
Our patient also experienced
many
of the previously reported hematologic
complications
of arsenic
poisoning
(Table
2). The bone marrow
exhibited the
marked
red blood cell nuclear
karyorrhexis
classically
described
in arsenic
intoxication
and
not seen
the hereditary
to this
degree
multinuclearity
in conditions
syndromes.3”8
Table
Toxic
2.
Hematologic
other
than
heavy
Megaloblastic
Effects
metal
intoxication
erythropoiesis
has
of Arsenic
Manifestaion
References
Anemia
Uncertain
cause
6, 12-15,
Aplasia
11-13,
Megaloblastic-normal
Megaloblastic-low
Leukopenia
(usually
B,2, folic acid
folic acid
accompanied
17
16
4
5
by granulocytopenia)
1, 4-6,
10-
Eosinophilia
6, 10,
Thrombocytopenia
5, 6, 10-13.
17
17
16
or
been
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
826
FEUSSNER
described
referred
only
twice
previously
to occasional
the vitamin
B,2 level was
range.
Waxman
and
levels
of 0-3
arsenic
forms”
in
“megaloblastoid
ng/ml,
normal,
as measured
intoxication,4’5
although
Kyle6
also
in one of his patients.
In our patient,
by radioassay,
a level of 3.2 ng/ml.
Moreover,
resolution
of the megaloblastic
changes
or
megaloblastic
specific
anemia
ultrastructural
represent
serial
anemia
folic
bone
within
shapes,
and
that abnormalities
directly
referred
our
patient
poisoning.
description
of arsenic-induced
bone
nuclear
envelope
primary
site
several
anomalies
of nuclear
to a defective
of the
many
marrow
to
features
of
et al.22 Several
aberration
of
ours demonstrated
bridges,
irregular
Frisch
suggested
and multinuclearity
noted
close proximity
also
noting
that
the
is the
ER,
thus
the
of injury
findings
in arsenic
poisoning.
This could
so characteristic
of this disease.
Previous
reports
have
not demonstrated
environment,
probably
because
of technical
the experience
of others25
suggested
that
could
be undertaken
demonstration
the contention
report
suggests
using
the
technique
arsenic
limitations.
examination
the
technique
may
be useful
explain
the
in the local
bone
marrow
Our own experience23’24
and
of bone
marrow
spicules
of energy-dispersive
of arsenic within the bone marrow
that arsenic
causes
the observed
that
have
ER
he postulated
that this function
might
be performed
by the nuclear
envelope,
exposing
it to toxic agents.
If this postulate
were proved,
it could also identify
as the site
microscopic
erythroblasts
may be
of the
little
nuclear
envelope
light and electron
Since
have
abnormalities
membrane.
(ER),
reactions.
Our
no dietary
appears
patient
and
chromatin
nuclear
reticulum
detoxification
despite
ultrastructural
by Frisch
the marked
shape,
impaired
mitoses,
nuclear
envelope.
He
to the endoplasmic
for
deficiency.
determinations
3 wk,
therapy.
Thus,
directly
by arsenic
nuclear
shape
and nuclear
envelope.
Both Frisch’s
binucleated
and multinucleated
cells,
internuclear
acid
marrow
replacement
produced
has not been
reported
previously.
However,
unique
dyserythropoiesis
in aplastic
anemia
have been described
of these
features
were present
in our patient,
including
nuclear
AL.
whereas
the folate
level was in the indeterminate
and others20’2’
have suggested
that
only folate
patient
had
documented
An
ET
x-ray
analysis.
Our
by this method
adds credence
to
bone marrow
abnormalities.
This
in further
studies
that
explore
the mechanism
of arsenic-induced
hematologic
toxicity.
In an effort to explain the cytotoxic
and mutagenic
effects
of arsenic,
studied the effects of inorganic arsenic on DNA
synthesis
in human
attempt
to
Petres
et al.
lymphocyte
cultures.26
They demonstrated
a direct
toxic effect of arsenic
on DNA
synthesis
in
human
lymphocytes
that resulted
in marked
disturbances
of nuclear
division
even
in the presence
of relatively
low doses of arsenic.
Both 3H-thymidine
labeling
index
and
The
mitotic
index
were considerably
types of nuclear
changes
described
the changes
together
with
seen in the red cell
our
direct
reduced
in the presence
in these in vitro studies
precursors
demonstration
in the
of
suggests
that arsenic
might
act in an analogous
megaloblastosis
and karyorrhexis.
Finally,
it does not seem
prudent
to evaluate
anemia
for
should
raise
hair arsenic
bone
arsenic
marrow
in
the
manner
all
arsenic
poisoning.
However,
any suggestion
this diagnostic
possibility,
and appropriate
levels)
to evaluate
arsenic
poisoning
should
of sodium
are quite
of our
bone
patient.
marrow
in vivo
patients
arsenate.
similar
to
with
of nuclear
studies
(nail
be performed.
This,
milieu,
to produce
the
megaloblastic
karyorrhexis
and/or
pubic
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
ARSENIC-INDUCED
BONE
MARROW
grateful
to Dr.
827
TOXICITY
ACKNOWLEDGMENT
The
authors
samples.
are
We appreciate
the skilled
his help
with
the microprobe
Fennel,
Mike
Hale,
Joseph
Moore,
assistance
study,
as well
and Jessie Calder.
who
collected
of Dr. Peter
as the technical
We thank
the
Ingram
initial
assistance
Cynthia
blood
of the Research
L. Dix
of Dr.
and
Joachim
for excellent
bone
Triangle
marrow
Institute
and
Sommer,
secretarial
Walter
assistance.
REFERENCES
1. Osler
W:
Medicine
1892,
2.
(ed.
pp 696,
1). New
York,
D Appleton
GR,
Limarzi
Lee
RK:
206:339,
1943
The
DD,
6.
intoxication
RA,
of hair
and
poisoning.
8.
Lancet
Hematologic
N EngI
to lead
or
J Med
bone
in acute
and
J 1:251,
1942
SH:
RP:
The
arsenic.
The
lead
46 persons
9.
Beaman
1965
273:18,
chronic
of
ciety
for
arsenic
10.
Lawson
GB,
Arsenic
poisoning.
II.
purpura
99:1557,
13.
AB:
85:24,
Toxic
Catanach
and
Ann
and
anemia
Intern
Med
FP,
following
Wilson
The
blood
the
R:
arsphenamines.
Dodd
K,
Williamson
SJ:
marrow.
Severe
JAMA
bone
marrow
Dis Child
RY:
Granulocytic
following
35:1032,
1928
the
aplasia
use of arsenic.
erythroid
C: Measurement
folic
of
acid-binding
Blood
acid
2).
Lewis
of
42:281,
New
SM,
Clin
D:
Shelburne
JD,
Chloride.
Hawkins
of
Incubation
lIT
1976,
P:
of
Scanning
HK,
Lysosomal
Microscopy,
Ingram
vol
1.
p 485
Ultrastructure
Rabbit
with
Alveolar
Soluble
Electron
Research
The
aplastic
1975
Institute,
Microanalysis
after
in
P,
Electron
Research
RW
Blakiston,
Sherman
Ingram
in
Rundles
York,
Mapping
Scanning
2. Chicago,
bind-
deficiency,
AJ,
29:545,
JD,
X-Ray
lIT
Folate
folate.
dyserythropoiesis
Br J Haematol
MD:
M:
for
E, Erslev
(ed
B,
X-Ray
Man-
Microscopy,
Institute,
1977,
p
137
JAMA
granulo-
25. Horowitz
P. Aronson
M, Grodzins
L, Ladd
Ryan
J, Merriam
0, Lechene
C: Elemental
analysis
90:663,
proton
26.
Weelihan
Familial
by
1956
1951
serum
Folic
Shelburne
ganese
1928
14.
254:401,
DaCosta
Beutler
Macrophages
W,
of the bone
FH:
RW,
1976
Hematology
24.
aplastic
Syph
caused
J Med
radioassay
WS:
WJ,
Chicago,
1925
SP,
5:569,
Waters
granulocytopenia,
with
J
Willett
radioassay.
and
Beck
23.
GS:
systemic
Am
6:1274,
and
Rothenberg
proteins
anaemia.
1932
aplasia
3H-PGA
vol
McCarthy
dyscrasias
by
ultrastructure
So-
Sci
1973
56:1953,
1932
12.
protein
Williams
Philadelphia,
WP,
arsphenamines.
5:1238,
levels
Haematol
Beam
The
JB,
S, Schreiber
folate
1977, p 343
22. Frisch
American
func-
Med
poisoning
neuropathy
von Hofe
Waxman
(eds):
Electron
Pfeiffer
Blood
serum
20.
content
HJ:
of arsenic
N Engl
JA,
Inclusions.
Jackson
hemorrhagica
following
cytic
JA:
Materials.
JAMA
Loveman
Wolff
exposure
Rep
506,
and
p 29
intoxication.
21.
Health
Isasi
Testing
1972,
arsenic
ing
arsenical
no known
Publication
ASTM,
A,
Peripheral
1965
content
J
(BAL).
HM:
19.
in
aspects
arsenic
and
with
Public
DR.
Magnuson
cases
Taylor
18.
1941
Microanalysis.
H,
of 227
Heyman
Majoor
1:784,
Smith
from
A,
marrow
Am
1946
17.
A:
deficiency
Pease
EG,
Webster
of urines
Eagle
30:420,
Sci
bone
1930
multinuclearity.
Kunst
Depressed
arsphenamines.
2,3-dimercaptopropanol
Barnes
Folic-acid
GL:
Med
DL:
the
treatment
and
of megaloblastic
poisoning.
Br Med
from
16.
perni-
(Fowler’s
J
RJ,
1975
JHM,
intoxication.
7. Young
Am
PHM:
arsenic
arsenic
tion
1, 1917
of arsenic
as a cause
Schillings
Kyle
J 177:76
Samaha
anemia.
Blood 45:241,
5. Van
Tongeren
chronic
Surg
effect
of
transfusion
erythropoiesis.
Westhoff
CLH,
1 5. Farley
of
and Co.
Treatment
by
Med
LR:
on
Arsenic
Practice
179:214,
Boston
solution)
4.
and
anemia-especially
splenectomy.
3.
Principles
701-703
Minot
cious
The
of
biological
microprobe.
Petres
J, Berger
of the
ischen
Arsens
Am
licher
Lymphocyten
Forsch
242:343,
J
specimens
Science
auf
1972
A: Zum
die
in
194:1162,
Einflusz
DNA-Synthese
in
vitro.
Arch
air
with
1976
anorganmenschDermatol
a
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
1979 53: 820-827
Arsenic-induced bone marrow toxicity: ultrastructural and electron- probe
analysis
JR Feussner, JD Shelburne, S Bredehoeft and HJ Cohen
Updated information and services can be found at:
http://www.bloodjournal.org/content/53/5/820.full.html
Articles on similar topics can be found in the following Blood collections
Information about reproducing this article in parts or in its entirety may be found online at:
http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests
Information about ordering reprints may be found online at:
http://www.bloodjournal.org/site/misc/rights.xhtml#reprints
Information about subscriptions and ASH membership may be found online at:
http://www.bloodjournal.org/site/subscriptions/index.xhtml
Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of
Hematology, 2021 L St, NW, Suite 900, Washington DC 20036.
Copyright 2011 by The American Society of Hematology; all rights reserved.