ICANCER RESEARCH 54, 2342-2346,
May 1, 19941
“HotSpots― of Chromium
Accumulation
at Bifurcations
of Chromate
Workers'
Bronchi'
Yuichi Ishikawa,2 Ken Nakagawa, Yukitoshi Satoh, Tomoyuki Kitagawa, Haruo Sugano, Toshio Hirano, and
ELJu Tsuchiya
Department of Pathology, Cancer Institute [Y I., 7'. K., H. S., E. T.J, Department of Chest Surgery, Cancer Institute Hospital [K. N., Y. 5/, 1-37-i Kanii-ikebukuro,Toshima
ka@Tokyo 170, and Hirano Kameido Himawari Clinic fT. H.J, Koto-ku@Tokyo 136, Japan
also in experimental animals which have inhaled radioactive (13, 14)
and inorganic particles, including asbestos fibers (15, 16). Schlesinger
To Investigate the mechanisms underlying respiratory tract carcino
and Lippmann (12) showed in their comprehensive study using hol
genesis in chromate workers, we measured the concentration of chromium
low casts that bronchial bifurcations are the site of enhanced accu
in samplesof tissuesfrom50 bronchialbifUrcationsand otherbronchial
mulation from [email protected] (like cigarette smoke) to particles of
tissue obtained at autopsy, or during surgical procedures, from 9 exchro
mate workers known to be at risk of developing lung cancer. The mean more than 10 @mdiameter. However, since human beings are long
lived and their airway physiology and pathology may be more corn
duration ofexposure was 21 years and the average time between cessation
plex, measurements using human organs/tissues are necessary. Nev
ofexposure
and death/surgery
was 15 years. The area ofthe tissue samples
ertheless, very little information has been published on preferential
was measured by image analysis and the chromium concentration deter
mined by neutron activation analysis. Chromium concentrations
ranged
sites of deposition in human bronchi. Little et aL (17) demonstrated
from 0.04 to 39 X 1O@1o
g4im tissue thickness/mm2and in 80% ofthe cases high concentrations of 210po at bronchial bifurcations in smokers by
the concentrations were greater at bifurcations than in neighboring epi
measurement of a activity. Although the half-life of 210p0 is only 138
thelial tissue. The mean concentration
ratios between bifurcations and
days, continued exposure to cigarette smoke could result in persis
adjacent areas were 1.5 (n = 1) in the trachea, 3.0 (n
9) in the main
tently enhanced levels of this a emitter at specific sites. The induction
bronchi, 3.6 (n = 22) in lobar bronchi, and 10.9 (ii = 3) in subsegmental
period for tumors of the respiratory tract is very long, generally in the
bronchi. Our results demonstrated long-term retention of chromium in
order of several decades, and therefore information concerning the
the bronchial walls of chromate workers and also that chromium concen
long-term exposure to inhaled particles is relevant to elucidating the
trations were higher at airway bifurcations than elsewhere, thus providing
underlying mechanisms which initiate tumor formation at hot spots.
solid evidence for a deposition “hot
spot―
concept.
However, to the best of our knowledge, such information is not
available to date.
INTRODUCTION
In an attempt to extend our understanding of the long-term accu
mulation
of an inhaled carcinogen at specific sites, we chose a
Inhalation of environmental carcinogens is considered to be one of
population of exchromate workers. Chrornate workers are known to
the most important causes of human bronchogenic cancers, particu
be at high risk of developing lung carcinomas (18—21)and, according
larly squamous and small cell carcinomas. Incidences of these types of
to our follow-up of such workers by endoscopy, atypical lesions
tumors are much greater in industrial than in rural areas, in smokers
including carcinomas and dysplasias tend to occur preferentially at
than in nonsmokers, and in underground miners than in the general
bronchial bifurcations. In order to determine concentrations of chro
population (1). The findings thus support a strong relationship be
mium in very small samples of tissue with adequate sensitivity,
tween bronchogenic carcinomas and inhaled carcinogens such as
neutron activation analysis was applied.
cigarette smoke, industrial emissions, mine dusts, and the radioactive
gas radon (1, 2).
Another characteristic feature of inhalation carcinogenesis is site
MATERIALS AND METHODS
specificity. Most human carcinomas occurring after exposure to in
Subjects. Since 1974, 86 male exchromate workers have been followed up
haled carcinogens appear to originate in central rather than peripheral
by sputum cytology and bronchoscopic examinations. All the subjects worked
regions of lungs. Further, there is evidence among cigarette smokers
at a chromate manufacturing factory situated in Tokyo and which started
that epithelial lesions such as carcinomas, cell atypia, and loss of cilia
operation before World War II. All the workers were exposed to a greater or
are often found at or near bronchial bifurcations (3, 4). To elucidate
lesser degree to chromium compounds, including chromate ore (FeO.Cr203),
the etiology of inhalation carcinogenesis, and to estimate the risk of
sodium chromate (Na2CrO4),and various dichromates (Na2Cr2O7,K2Cr2O7,
exposure to toxic inhalants, it is important to establish the relationship
Cr03). For this study blocks of bronchial tissue from 7 consecutive autopsy
between cancer development and the pattern of deposition of inhaled
cases
were taken
for measurement
of chromium.
In addition,
tissues
from 2
cases
in which
lobectomy
was performed
following
the diagnosis
of lung
toxic agents in human bronchi. In particular, it is crucial to establish
whether there is any preferential concentration at specific sites (“hot tumors were available for measurement. Details of the cases are given in Table
1. Case 2 was the only one who died from a cause other than cancer. However,
spots―)such as bifurcations.
he developed a squamous cell carcinoma arising from the bifurcation of the
Computational modeling of the deposition pattern of inhaled par
main bronchus 2.5 years before his death which was cured by radiation
tides in the respiratory tract has shown that enhanced deposition
therapy. Details of the tumors and a consideration of their relationship to
occurs by physical mechanisms at bifurcations in the conducting
chromate exposure will be described elsewhere.3 From the 9 cases, samples of
airways (5—7).This has been confirmed by using hollow casts of
tissue from 50 bifurcations and from neighboring sites were available for
airways and various types of inhalants including fibers (8—12),and
examination.
ABSTRACT
Tissue Materials.
including
Thecostsof publicationof thisarticleweredefrayedin partby the paymentof page
from the center and the edge of bifurcation ridges and from other regions (i.e.,
charges. This article must therefore be hereby marked advertisement
18 U.S.C. Section 1734 solely to indicate this fact.
1 Supported
partly by the Visiting
Researchers'
Program,
Kyoto University, Osaka, Japan.
2 To whom
requests for reprints
noncancerous
Tissue samples 2—5mm thick and 2—20mm2 in area,
Received 10/19193; accepted 2/23/94.
epithelia
and stromata
as well as cartilage,
were taken
in accordance with
Research Reactor Institute,
3 Y.
Ishikawa,
K.
Nakagawa,
T.
Kitagawa,
H.
Sugano,
T.
Hirano,
and
E. Tsuchiya.
Characteristics of chromate workers' cancers, chromium lung deposition and precancer
should be addressed.
ous lung lesions: an autopsy study, submitted for publication.
2342
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HOT SPOTS OF CHROMIUM
Table1Profile of
examinedCaseReferral
IN BRONCHIAL
BIFURCATIONS
archromate workers ‘
cases
from
cessation@'
panoda
no.SexDerived
fromAge
death/operation―12524MAutopsy6919.314.326Lung
(yr)Exposure
(yr)Period
of
habi(
(pack yr)Cause
(yr)Smoking
(SCLC)23141MAutopsy6322.512.039Heart
infarction33351MAutopsy5217.413.916.5Maxillary
cancer428037MAutopsy65321046Epipharyngeal
cancer53498MAutopsy478.319.05Lung
(AC)63583MAutopsy6728.615.533Lung
(SqCC)73647MAutopsy7124.616.218.5Lung
(SqCC)829571MLobectomy5915.619.761.5Lung
(SqCC)929847MLobectomy7723.816.649Lung
(SqCC)Av.63.321.315.232.7
a Period
of engagement
b Period
between
C Product
d SCLC
of
number
small
in jobs
the date
cell
of
packs
lung
exposed
of retirement
(20
cancer;
to chromate
from
cigarettes)
AC,
the job
per
day
cancer
cancer
cancer
cancer
cancer
cancer
compounds.
and
autopsy/operation.
and
duration
adenocarcinoma;
SqCC,
of
smoking
squamous
(years).
cell
carcinoma.
I
Fig. 1. Pictorial representation of definitions of
the termsusedand samplingsitesfrombronchial
bifurcations, and a photograph of a typical sped
men, 5.58 mm2 in area, taken from the ridge center
of an intermediate trunk bifurcation from Case 5.
Bar, 1 mm (for nomenclature of bifurcations, see
Footnote 4)
Branch A
Ridge center
Branch B
Ridge edge
more central or more peripheral portions near the bifurcation) of each forma
lin-fixed lung (Fig. 1). For the purpose of quality control, samples were taken
in duplicate
from the ridge edges of main bronchial
bifurcations
and adjacent
sites of two cases in a pilot study, resulting in good agreement. Among the 9
@
cases
examined,
there
were
some
in whom
tissues
from
bifurcations
were
used
for other analyses or whose lung lobes had been surgically removed due to
cancers and were not therefore available in totality for study. In the autopsy
cases,
invasion
and/or
metastasis
of cancer
were
main
reasons
why
abundance
systematic
sampling could not be performed.
All tissues were embedded in paraffin. The first section was cut for histol
ogy and morphometry, the following 20 to 100 consecutive sections were cut
serially at 8 @m
each, piled up and double sealed with polyethylene for neutron
irradiation, and the last section, again, was taken for histology and morphom
etry.
Sectioning
was
performed
by one technician
always
using
the context of this study. Comparison of the ratio with the generation of
tracheobronchial branching4 allowed correlation coefficients to be calculated.
Neutron Irradiation. Concentrationsof chromium in all samples were
determined by neutron activation analysis at the Research Reactor Institute of
Kyoto University, with a flux of 2.75 X iO'@n cm2
and irradiation times
of up to 60 mm. This leads to the production of 51Crby reaction of 50Cr(n, -y)
5tCr, where @°Cr
is one of the stable components of natural chromium with an
of about 4%. After a 3-week
wait for decay of short-lived
nuclides,
the activity of 51Cr (half-life, 27.7 days) was measured with a cylindrical
germanium detector of 76-mm diameter. The measurement duration was
sufficient to give statistical uncertainties of 7% or less. Calibration was
effected by dissolving accurately weighed pure chromate compounds for
atomic absorption
and counting.
the same
microtome.
Calculation of Chromium Concentration. The area of each tissue section
excluding cartilage was measured by using a microscopical picture analyzer
for both the first and the last sections. Exclusion of cartilage is reasonable
because it is highly unlikely that the bronchial cartilage contains substantial
amounts of chromium and because the fractional area of cartilage was not
materially different from specimen to specimen. Simultaneously, the lack of
any primary cancer or invasion was confirmed histologically. Following quan
tification of chromium by activation analysis (see below), the concentration in
the specimen was obtained by dividing the amount of chromium by the area of
the tissue and the thickness of the irradiated sample. Using this method, we
earlier successfully determined the concentration of thorium in samples from
Thorotrast patients (22). The ratio of chromium concentrations between the
center of the bifurcation ridge and other portions near the bifurcation was also
calculated. The ratio should indicate the degree of enhancement of chromium
at the ridge center of bronchial bifurcation, because our unpublished data
showed systemic background concentrations of chromium in two cases to be in
the order of 1% or less of pulmonary deposits, and consequently negligible in
RESULTS
The concentrations of chromium at the centers and the edges of
bifurcation ridges and other portions near the bifurcations are listed in
Table 2. The bifurcations examined were classified into four catego
lies in terms of chromium levels at the ridge centers and ridge edges
in comparison with the other portions, as shown in Table 3. The most
striking finding was the higher chromium concentrations at most
(80%) of the bifurcations than at the other portions available for
comparison. Within the ridge of many bifurcations, concentrations at
the centers were higher than at the edges. Whereas the concentrations
were relatively constant in other portions, they varied considerably
4 Notations
for
describing
the
sites
of
bronchial
bifurcations
following
the
inhalation
route are: (1@tracheal bifurcation (main bronchi); 121 main bronchial bifurcations (inter
mediate trunk); [31 intermediate tnmk bifurcation (lobar bronchi); (41 lobar bronchial
bifurcation (segmental bronchi); [51 segmental bronchial bifurcation (subsegmental bron
chi); [6] subsegmental bronchial bifurcations. Numbers in brackets, generation of tracheo
bronchial branching.
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HOT SPOTS OF CHROMIUMIN BRONCHIALBIFURCATIONS
Table2 pardonsnear
Concentrationsof chromiumat the centersof bifurcationridges(RC),theedgesof bifurcationridges(RE),and at other(i.e.,morecentraland moreperipheral)
the bifurcations (Other) of exchromate
exposureaTracheal
workers' bronch4 measured by using neutron activation analysis, at 22 years on average after cessation of
SegmentalCase
Main
OtherLeft
RC
RE
Other
Lobar
RC
RE
Other
RC
RE
—
—
1.7
2.6
0.8
2.2
4.4
1.8
1.3
2.0
Other
0.2
12.3
0.70.4
3.9
0.8
1.9
1.88.0
1.0
2.63.8
1.48.4
1.414.4
2.614.6
1.4
4.3
3.1
4.0
4.1
RC
RE
9.2
5.8
lung and
trachea1
0.42
0.73
1.1
3.34
6.5
2.76
0.2
1.1
2.1
1.12.2
3.4
1.32.3
1.8
2.6
4.8
1.6
2.8
4.5
1.87
0.6
0.4
0.4
13.4
6.4
1.1
3.3
1.91.5
1.34.2
1.1
7.4
1.0
9.2
1.18
4.7
2.23.0
2.9Main
Intermediate
OtherRight
Case
1.9
RC
RE
1.2
2.2
1.6
Lobar
Other
RC
RE
Other
1.2
1.9
0.4
4.6
0.4
2.3
2.0
1.1
0.8
0.8
—0.04
1.2
0.7
1.2
—
RC
RE
Segmental
Other
Subsegmental
RC
RE
Other
RC
RE
lung1
0.52
1.24
—5
3.9
23
18.0
12.3
4.9
2.5
2.1
1.912.6
3.7
8.0
0.5
3.1
14.7
2.5
3.9
9.7
0.7
1.90.6
3.4
33
1.6
1.7
14.2
16.5
0.6
0.838.5
1.9
4.2
—6
0.2
1.1
0.3
1.1
1.9
1.01.5
3.0
6.7
6.4
5.7
—
—
1.07
2.4
1.52.2
1.8
2.3
0.99
1.1
1.9
1.5a
7.8
Unit of chromium
concentration
is X 10b0
@p@m
tissue
thickness/mn12.
Blank
or — means
from site to site at the centers of bifurcation ridges (Table 2). This was
particularly
the case
in more
peripheral
regions,
where
very
high
values were found almost exclusively at the ridge centers.
In portions other than the centers of bifurcation ridges, chromium
levels were generally higher in the peripheral than in the central
bronchi in both lungs. Those at the trachea and tracheal bifurcations
were the lowest, in agreement with the scarcity of cancers arising at
these sites.
Mean chromium concentration ratios between portions at ridge
centers and at other portions for each generation of tracheobronchial
branching, calculated from Table 2, are shown in Fig. 2. For this
purpose we propose the term “accumulationratios at ridge centers.―In
all the generations of tracheobronchial branching from tracheal to
subsegmental bifurcations, the mean accumulation ratios were more
than 1. Interestingly, the mean accumulation ratios increased with
generation of tracheobronchial branching, although the high values of
Table3 Classificationof bronchialbifurcationsofexchromateworkersin termsof
chromium concentrations
at the ridge centers (RC) and ridge edges (RE) relative to
thosein the otherportions(other)―
not available.
Tracheal,
Main,
etc., designate
bifurcation
sites.
See Footnote
4.
8.4 (n = 4) and 10.9 (n
3) were largely due to two particularly high
ratios of 25.4 (14.20/0.56) and 25.2 (38.54/1.53), respectively, both of
which were from Case 9. Using all the ratios (n
44) from both sides
of the lungs of all the cases, the correlation coefficient (R) regarding
the accumulation ratio and branching generation was calculated to be
significantly positive, at 0.06 < R < 0.58 (P < 0.05).
DISCUSSION
The present investigations revealed 80% of bifurcations to show
higher concentrations of chromium at ridges than in other nearby
portions. Furthermore, all mean accumulation ratios at ridge centers
proved to be more than 1, with values increasing significantly with
increasing generations of bronchial branching. These fmdings imply
that the bifurcation ridges, and in particular the ridge centers, are hot
spots of persisting chromium deposits even more than 10 years after
cessation of exposure. The present study thus produced solid evidence
for the deposition hot spot concept for long-term retention.
There are two main aspects, physical and pathophysiological,
which might be responsible for formation of deposition hot spots at
Relative chromium
No. of bifurcations
bifurcations. Physically, there are four ways in which solid particles
concentration
are deposited in the lung, sedimentation, inertial impaction, intercep
categories
Left lung and trachea
Right lung —Total (%) tion, and diffusion (23). Among these, the former two are of primary
1. RC > RE > other
15
7
22 (50)
importance in the enhanced deposition at bronchial bifurcations of the
2. RE > RC > other
7
6
13(30)
3. RC > other or RE > other
1
3
4 (9)
chromate workers because the other two may concern particles of
4. Other> RCandother> RE
1
4
5(11)
irregular shape and very small particles. In fact, microscopic mea
Total
24
20
44(100)
surements in lung tissues obtained at autopsy showed that most of the
a Other, more central and/or more peripheral
portions of the bronchi (see Fig. 1).
chromate particles were 1—3 @min diameter (24), and the shape was
2344
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@
@
@&\@
@.
HOT SPOTS OF CHROMIUM
IN BRONCHIAL
4.'@'
BIFURCATIONS
12
10
Cl)
0
8
0
Fig.2. Meanratiosof chromiumconcentrations
between the ridge centers of bifurcations and other
portions (mean accumulation ratios) for each gen
eration of bronchial branching. Note that all the
mean accumulation ratios are more than 1 and that
the ratio increases with increasing generation of
tracheobronchial branching. L, left R., rigjst bif,
E
6
0
0
C
4
bifurcation; br, bronchus or bronchial; Intern,. tr.,
intermediate trunk; Seg., segmental; n, no. of bifur
cations available for calculation of the accumulation
ratio.
2
H@'Th
1
0
@
@
@%.I@\
@\
@,%@c,.
@
\,,@
‘V.
‘a,.
@€\
,@.7
@\
@\
\@ @$@.
‘@.
approximatelyspherical.(Actualassessmentof particlesize distribu must carry considerable amount of chromium compounds deposited in
tion in the workplaceis nowimpossiblebecausethe factoryin which alveolar regions, which retain mainly particles with diameter of more
the workerswereemployedterminatedproductionof chromiumcorn than [email protected] and less than 4 @am(28), comparable with typical
pounds in 1975.) Considering
the size and shape of particles and
airway generationsof interest (main to subsegmentalbronchi), the
inertial impaction and sedimentation may be chiefly responsible for
the enhanced deposition in the workers' bronchi (23).
However, the results obtained by this approach should be inter
preted in the light of physiological considerations, where possible,
using animal models for example, because deposited particles are
largely cleared by mucodiiary streaming. It is known that the ciliary
streaming of mucus and the lymphatic flow tend to slow down and
stagnate around the bifurcation (14, 25). The other factors to facilitate
the formation of augmenteddepositionare related to pathologyin
human beings. Prolonged exposure to toxic inhalants such as tobacco
smoke causes loss of cilia and/or squamousmetaplasiawhich occur
preferentiallyat or near bifurcations.This would further delay the
mucociiary removaland henceacceleratethe formationof hot spots.
chromate particles (24). In other words, the fact that at the more
peripheral bifurcations the more enhanced deposition was evident
may imply that the primary mechanism of forming hot spots at
bifurcations is the stagnation of mucus flow at the sites. Further, it is
very interesting that the distribution of chromium is comparable with
that of bronchial cancer which is known to arise most frequently from
segmental bronchi, not from more central bronchi (3). In this study we
successfully examined up to subsegmental bifurcations, but could not
analyze more peripheral bifurcations by using the same method be
cause of their very small dimensions.
Chemical forms may be crucial for metal carcinogenesis. As is well
known, 6-valence chromium is more harmful than 3-valence forms.
However, actual measurements showed that most of the chromium
deposited in pulmonary tissues was 3-valence like Cr203 (29). We
agree with Dr. T. Sano, a pioneer of occupational disease pathology in
Additionally, we should consider the question as to whether chro
mium sticks to bronchial tissues for more than 10 years or whether
steady removal of chromium from alveolar regions is responsible for
the enhanced concentration in bronchial bifurcations. If the former
possibilityis true, most of the chromium detected in bronchial tissues
Japan, who insistedthat 6-valencechromiumis so strong an irritant
must be deposited in bronchial stroma rather than in epithelium,
occur at bronchial
considering
exchromateworkers.3Hence,the resultsof this studywould indicate
that cell renewal
of the epithelium
is estimated
to be an
order of 1 year or less for adults of the age range reported (26, 27). On
the other hand, the latter possibility will imply that most of the
chromium measured is localized to the epithelium. Further study on
finer topographical determination of chromium within the bronchial
tissue may answer the question.
Another finding requiring discussion is the fact that higher en
hancement was evident in the more peripheral bifurcations. This may
be a clue to a question on how the deposition hot spots are formed,
because one of the main causes of hot spot formation is the stagnation
of mucusstreamat the bifurcationsmentionedabove.The mucusflow
that it can cause severe inflammation and subsequently is reduced
to 3-valence, which can be in an insoluble form and could cause
cancer (24).
It is known that carcinomas and atypical lesions preferentially
bifurcations
in smokers
(4). This is also the case for
a direct relationship between the concentration of chromium and
neoplasia. Additionally, it should be noted that the chromium con
centrations at ridge edges were not found to be low. In fact, among the
44 bifurcations where the values at the ridge center, ridge edge, and
another portion were available, 13 (30%) showed the highest level at
the edge (Table 3, Category 2).
Cigarettesmokingmay be a factor in the inductionof carcinomas
in the bronchi of the population of exchromate workers used in this
study. Actually, most of the cases were smokers with an average pack
year of 32.7 (Table 1 and its footnotes). However, an epidemiological
2345
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HOT SPOTS OF CHROMIUMIN BRONCHIALBIFURCATIONS
study of the same population of exchromate workers suggested that
the exposure to chromium compounds played the main role in causing
cancer development (20). Summarizing briefly, the lung cancer mor
bidity rate for the exchromate workers with 9 years or more of
exposure was 21.6 times higher than that for the general population.
The mortality rate of lung cancer for nonchromate smokers, adjusted
to the exchromate worker population by age of starting smoking and
by number of cigarettes per day, is generally 3—4.7times higher than
for nonsmokers in Japan. Unless cigarette smoking had an extraordi
narily synergistic effect on cancer induction, or supermultiplicative
synergism with chromium inhalation, we can therefore conclude that
the chromium exposure was primarily responsible, always bearing in
mind that there is a minor difference between morbidity and mortality.
ACKNOWLEDGMENTS
We wish to thank Professor T. Tamai and J. Takada of the Research Reactor
Institute, Kyoto University, for collaboration in the neutron irradiation; Dr. A.
Morgan, AEA Biomedical Research, Harwell Laboratory, for useful comments
and assistance in preparation of the text; and K. Hiura and K. Yokokawa,
Department of Pathology, the Cancer Institute, for technical assistance. Y. I. is
grateful to Professor Emeritus S. Hatakeyama for his encouragement.
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Lung
''Hot Spots'' of Chromium Accumulation at Bifurcations of
Chromate Workers' Bronchi
Yuichi Ishikawa, Ken Nakagawa, Yukitoshi Satoh, et al.
Cancer Res 1994;54:2342-2346.
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