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Journal of
J Occup Health 2001; 43: 1–23 Occupational Health
Review
Metal-Induced Lung Disease: Lessons from Japan’s Experience
Yukinori K 1, Kazuhiro S 1, Narufumi S 1 and Yutaka H 2
USAKA ATO UGANUMA OSODA
1Department of Environmental Health, School of Medicine, Fukui Medical University and
2Institute of Radiation Effects Association
Abstract: Metal-Induced Lung Disease: Lessons Hope Island. Marco Polo, who tried to reach the Golden
from Japan’s Experience: Yukinori KUSAKA, et al. Hope Island by boat, in fact discovered a sea route from
Department of Environmental Health, School of West Europe to India.
Medicine, Fukui Medical University—Metals inducing
Pneumoconiosis and associated respiratory failure was
occupational respiratory diseases, e.g. metal fever,
well known among gold miners, and was named “Yoroke”
acute and chronic pneumonia, asthma, bronchitis,
which means severe cardiopulmonary failure. It was said
chronic obstructive lung disease, pulmonary fibrosis
that on the Sado Island, which had the biggest gold mine,
and lung cancer are described. The metals mentioned
since miners died young, their wives often remarried to a
are the following: aluminum, antimony, arsenic, barium,
beryllium, cadmium, chromium, cobalt, copper, iron, total of up to seven husbands.
lithium, manganese, mercury, nickel, platinum, rhodium, Japan experienced the Meiji Civil Revolution in 1868
rare earth metals, titanium, uranium, vanadium, followed by an industrial revolution and then
welding, zinc, zirconium. With respect to these metals, westernization. In the middle of the 1930, pneumo-
mechanism of the disease, disease statistics, case coniosis was legally recognized as a compensatable
reports, diagnostic methods, patho-physiology of the disease and a prevention code for silicosis was introduced
disease, and preventive measures including
among miners.
occupational exposure limits are also described.
After the Second World War, the Government’s efforts
Experience in Japan on these issues is given in detail.
were focused on recognition of and compensation for
(J Occup Health 2001; 43: 1–23)
various occupational diseases. The Silicosis Law was
therefore passed in 1960, particularly for miners in copper,
Key words: Metal, Lung disease, Occupational,
Toxicity, Pneumoconiosis, Pneumonia, Bronchitis, iron and coal mines suffering from silicosis and
Asthma, Lung cancer, Pulmonary fibrosis silicotuberculosis.
In the meantime along with the growth of the Japanese
economy cases of occupational lung diseases increased,
Buddha, Jipang and Meiji revolution in Japan
including pneumoconiosis from agents other than silica
Since ancient times, inorganic mercury has been used and metal. Asbestosis, for instance, arose in Japan and
as an amalgam by which mixtures of metals are plated or there was a need for workers exposed to asbestos to be
coated. The “Nara Daibutsu”, Great Buddha Statue in supervised and compensated. Therefore, along with
the oldest capital city, was plated with gold by using advances in knowledge of pneumoconiosis in other
mercury amalgam and it was reported that, during this industries, the Pneumoconiosis Law was passed in 19781).
process, workers inhaled high levels of mercury fumes,
The pneumoconiosis law
resulting in poisoning.
In the middle of the Edo Era lasting from early in the This Law covers asbestosis and other types of
1600 to the middle of the 1800, gold mines were opened. pneumoconiosis such as siderosis and mixed dust
Refined gold was then exported through China and the pneumoconiosis2).
Netherlands to Europe, and Japan came to be known for Under this Law, dusty types of work are listed in which
its gold trade and was named Jipang, meaning Golden workers may develop pneumoconiosis. Some types of
dusty work where exposure to metal aerosols take place
Received June 8, 2000; Accepted Oct 13, 2000 have also been designated under the Pneumoconiosis Law
Correspondence to: Y. Kusaka, Department of Environmental (Table 1).
Health, School of Medicine, Fukui Medical University, 23–3, According to the Law, employers responsible for these
Shimoaitsuki, Matsuoka-cho, Fukui 910-1193, Japan types of work should provide employees with periodic
2 J Occup Health, Vol. 43, 2001
Table 1. Dusty work where there is exposure to metals causing pneumoconiosis according to the
Pneumoconiosis Law (The following Nos. are as set out in the Law)
Number Work
No. 7 Work at a site of operations involving grinding by spraying abrasives or work at a site of operations
involving grinding or deflashing of rocks, minerals or metals, or cutting of metal by motive power
with abrasives (except work listed in the preceding item). Work at a site of operations involving
grinding or deflashing of rocks, minerals or metals, or cutting of metal by motive power with
abrasives by means of a sprinkler or an oiling system, is excluded.
No. 8 Work at a site of operations involving cutting, crushing or screening of minerals and others, raw
materials having carbon for their principal element (hereinafter referred to as “carbonic raw
material”), or aluminium foil, by motive power (except work listed in item 3, 15 or 19). Work listed
below is excluded.
No. 10 Work at a site of operations involving packing of pulverized aluminum or titanium oxide into bags.
No. 17 Work at a site of operations involving supplying a blast furnace with soil, sand, ores, or minerals,
reducing of them, steaming or casting in the process of smelting or melting metals or other
inorganic material. Work at a site of operations involving steaming out of a converter or casting in
a metal mold is excluded.
No. 18 Work at a site of operations involving scraping off, scratching up, loading or unloading or putting
into vessels slag or ash adhering to or accumulating inside a furnace, flue or chimney, etc., or in the
process of the combustion of pulverized ores or in the process of smelting or melting metals or other
inorganic material.
No. 20 Work of cutting metals by means of melting, arc welding of metals or gouging metals with an arc
indoors, in the open air, a pit or inside a tank, vessel, pipes or vehicle, etc. Cutting automatically by
means of melting, or automatic welding indoors is excluded.
No. 21 Work at a site of metal spraying operations.
health examinations including chest x-rays. The According to this Ordinance, workers under these
Pneumoconiosis Law has designated its own standard circumstances shall be subject to health supervision, and
chest x-rays, and its coding system is according to the health examinations targeting specific respiratory
ILO classification scheme3). disorders. At the same time, the working environment in
It is recommended that once a worker’s chest which these metals are handled shall be monitored in
radiograph is judged by the Local Pneumoconiosis Panel terms of metal levels in general air samples and evaluated
designated by the Bureau for Labour Standard, Ministry by comparing the levels with administrative limits
of Labour, to show pneumoconiotic changes, he or she designated by the government according to the Working
should have a health examination annually. Severe cases Environment Measurement Law5).
of pneumoconiosis associated with large opacities of type Diagnostic criteria for classification of occupational
C or with severe pulmonary dysfunction are compensated. diseases including metal-related lung diseases are open
Other pulmonary conditions such as tuberculosis and to public scrutiny through governmental codes, and
bronchitis secondary to pneumoconiosis are also subject litigation has taken place over these criteria.
to compensation for treatment and disability. Governmental statistics are only limited to lung
diseases related to metals in terms of exposed population
Special Ordinance on Specified Hazardous Metals
size, kinds of industries, and prevalence4): Table 3 shows
Apart from the Pneumoconiosis Law, there are the prevalence of these diseases recognized among
regulations to protect against metal-related lung toxicity. currently exposed workers. There may be negative case
Among them the Special Ordinance on Specified report bias.
Hazardous Substances deals with metal-related lung
Disease recognition codes under the practice and
cancer, metal fume fever, airway syndrome including
enforcement ordinance of labour standards law
perforation of the nasal septum, bronchial irritation,
on metals
bronchial asthma and bronchitis due to exposure to metals
(Table 2)4). With respect to other metals, not covered by the
Yukinori KUSAKA, et al.: Metals Known in Japan to Induce Occupational Respiratory Diseases 3
Table 2. Metals causing occupational lung diseases designated by Ordinance
on Prevention of Hazards due to Specified Chemical Substances
with reference to administrative levels (mg/m3) assigned by
Working Environment Measurement Law
Metal Administrative level (mg/m3)
Alkyl mercury compound 0.01 (as Hg)
Arsenic trioxide 0.5
Beryllium 0.002 (as Be)
Cadmium 0.05
Chromic acid and its salts, dichromate 0.1 (as Cr)
Vanadium pentoxide 0.03 (as V)
Nickel carbonyl ND
Manganese 2.5 (as Mn)
Mercury and its inorganic compounds 0.05 (as Hg)
*Not determined.
Table 3. Numbers of workers undergoing special medical examinations by type of worker
covered (1993)
Number of Number of Number of Rate of
workplaces workers workers positive
conducting examined with positive findings
examination findings to total
Beryllium 53 913 0 0
Alkyl mercury compounds 30 117 2 1.7
Cadmium 338 6644 64 1.0
Chromic acid 2548 26674 238 0.9
Vanadium pentoxide 157 2102 4 0.2
Arsenic trioxide 174 2759 20 0.7
Mercury 303 3492 92 2.6
Nickel carbonyl 7 495 0 0
Manganese 776 12958 42 0.3
Pneumoconiosis Law or the Ordinance on Specified or the Codes can theoretically be subjected to recognition
Hazardous Substances, there are Disease Recognition as causing occupational lung diseases and compensation,
Codes under the Practice and Enforcement Ordinance of if patients or their physicians appeal to the Labour
the Labour Standards Law, defining occupational Standard Bureau of the Ministry of Labour. This depends
causation (Table 4)2). Workers exposed to these metals on the physicians’ knowledge of the diseases.
are not under health supervision specific to relevant
Statistics of recognized metal-related lung diseases
disorders but, once workers develop the relevant disease,
workers or their relatives can claim compensation for Little has been known of the numbers of cases of metal-
disability and for treatment costs. The Practice Code has related lung diseases legally recognized in Japan. Japan’s
recently been raised so that employers must inform Ministry of Labour reported the data accumulated during
employees about the state of knowledge of hazardous 1977 and 1999: 159 chromium-related lung cancers and
metals in their workplace and potential health effects. 75 arsenic-related lung cancers or skin cancers. There
This can be done by occupational health personnel during were no cases with nickel-related lung cancer during 1994
periodic health checks, mainly for age-related and and 1999.
lifestyle-related diseases, which employers are compelled
Exposure standards in Japan
to provide.
Furthermore, any metals which have not been At the same time the Japan Society for Occupational
designated by the Pneumoconiosis Law, the Ordinance, Health (JSOH)6) has recommended occupational exposure
4 J Occup Health, Vol. 43, 2001
Table 4. Metals hazardous to the respiratory system for this literature covered the period between 1935 and
designated by the Enforcement Ordinance of Labour 1997. Sensitizing metals such as beryllium, chromium,
Standard Law nickel, cobalt and hard metal, platinum, rhodium,
mercury, zirconium and gold were included in a review
Metal Pulmonary disorders
article by one of the authors19). Case reports, reports on
Zinc and other metals Metal Fume Fever epidemiological studies, and reports on the mechanism
Zinc chloride NS* of metal-related lung diseases have been reviewed by one
Cadmium Emphysema, Airway Disease of the authors. From them, reports of interest for
Chromium NS occupational chest medicine were included in the present
Inorganic mercury NS review.
Selenium NS
Nickel carbonyl NS Aluminium
Vanadium NS Cross-sectional studies have suggested an increased
Arsenic NS prevalence of chronic bronchitis and a loss of ventilatory
Beryllium NS function, mainly forced vital capacity (FVC), in
Manganese Pneumonia association with chronic exposure to aluminium20, 21).
Cobalt NS These are apparently independent of the overt forms of
Platinum NS other respiratory diseases seen with some of these metals
in steel or from welding. The underlying mechanism is
*Not specified.
not fully clarified.
The causative agent of asthma (“potroom-asthma”) and
bronchial hyper-reactivity in aluminium smelters (or other
limits (OELs) for various chemical substances over workers exposed to aluminium salts)22–26) is not known.
several decades. Recommendations with explanatory The condition is not considered to be due to allergic
documentation have been made on the basis of global mechanisms, but rather to an inflammatory response to
scientific knowledge and have been regularly renewed irritation by fluorides, in view of the close relationship
whenever new data have become available. Table 5 between the levels of fluoride exposure and work-related
shows the metals for which the JSOH has made asthmatic symptoms observed27).
recommendations, the OELs with reference to target A recent report has confirmed the presence of
organs including therespiratory systems and to classes of aluminium potroom asthma by means of a positive
carcinogenicity. response in workplace challenge28, 29).
Aluminium exposure has been suggested to have led
Epidemiology of metal-related lung diseases:
to sarcoid-like lung granulomatosis in a patient who had
Overviews of overseas and Japanese literature
apparently not been exposed to beryllium30). These cases
For centuries metals have been known to be capable confirm that an occupational exposure (also to silicates,
of causing human diseases, including pulmonary such as talc) should always be considered in cases of
diseases7–14). From a toxicological viewpoint, a metal “sarcoidosis”.
can be defined as “an element which under biologically The recent report by Devuyst et al.30) posed the
significant conditions may react by losing one or more interesting question as to whether aluminium-induced
electrons to form cations”15). Thus some of the so-called pulmonary fibrosis or “aluminum lung” may present in
metalloids, e.g. Arsenic (As) and Antimony (Sb), are its early stage as a granulomatous lung disease. The very
included in the subjects for this review. existence of aluminum lung has been the subject of
Although silicates such as talc, mica, and kaolin are considerable controversy31, 32). Indeed, in view of the
associated with various cations including aluminum (Al), extensive industrial use of aluminium, lung disease caused
magnesium (Mg), and iron (Fe), these minerals causing by exposure to this metal has been questionable. On
“classical” pneumoconioses, the majority of occupational reviewing past literature, Dinman31) concluded that
lung diseases, are excluded. fibrosis only occurred: 1) in workers who were heavily
The present review focuses on human data, rather than exposed to submicron-sized particles from aluminium
on information obtained from animal or in vitro plates lubricated with an easily removed lubricant during
experimentation. Information which is available in the production of fireworks and explosives; and 2) in
standard texts12–14) has been taken as such, whereas more workers involved in the smelting of bauxite for the
recent acquisitions appearing up to 199716–18) are production of corundum abrasive (Shaver’s disease), but
emphasized and referred to more specifically. who were perhaps also exposed to crystalline silica.
Furthermore, we have reviewed all papers published Nevertheless, isolated cases of alveolar proteinosis33) or
up to 1997 in Japan as well as other countries. The search fibrosis in aluminium welders or polishers30, 34–36) do not
Yukinori KUSAKA, et al.: Metals Known in Japan to Induce Occupational Respiratory Diseases 5
Table 5. Occupational exposure limits (OEL) and carcinogenicity class designated by Japan Society for Occupational Health
of metals hazardous to the respiratory system
Metal OEL (mg/m3) Target organs or Class of
pulmonary manifestation carcinogenicity
Arsenic trioxide 0.5 (as As) Systemic toxicity 1
Beryllium and compounds 0.002 (as Be) Acute berylliosis 2A
Cadmium and compounds 0.05 (as Cr) Renal disorder 1
Chromium and compounds
Chromium metal 0.5 (as Cr) Nasal disorder
Chromium (III) compounds 0.5 Nasal disorder
Chromium (VI) compounds 0.05 Lung cancer 1
Certain Chromium (VI) compounds 0.01 Lung cancer 1
Cobalt and compounds 0.05 (as Co) Pulmonary fibrosis 2B
Pulmonary function impairment
Manganese and compounds except for 0.3 (as Mn for respirable fraction) Neurological disease
organic compounds
Mercury and compounds except for 0.05 (as Hg) Neurological disease
alkyl mercury compounds
Nickel 1 Lung cancer 2B
Nickel carbonyl 0.007 Acute pneumonia
Selenium and compounds 0.1 (as Se, inorganic
compounds except SeH)
2
Silver and compounds 0.01 (as Ag) Skin disease
Vanadium compounds Asthmatic bronchitis
Vanadium oxide fume 0.1
Vanadium oxide dust 0.5
Ferrovanadium dust 1
Zinc oxide fume 5 Metal fever
Alumina, aluminum 0.5 for respirable fraction
2.0 for total portion Pulmonary fibrosis
Iron oxide 1 for respirable fraction
4 for total portion Pneumoconiosis
Titanium oxide 1 for respirable fraction
4 for total portion Pneumoconiosis
Zinc oxide 1 for respirable fraction
4 for total portion Pneumoconiosis
entirely corroborate this conclusion. The physical as pneumoconiosis by the Pneumoconiosis Law in Japan.
characteristics of the aluminium particles, notably their It is possible that case reports included individuals with
surface area, or even their possibly fibrous nature37), have so-called Shaver’s disease whose typical pathological
been suggested as important determinants of their findings were compatible with granulomatous lung
bioreactivity and hence fibrogenicity. disease, but to date Shaver’s disease has been neither
Mixed dust pneumoconiosis is derived from silicates reported in Japan nor designated as a recognized disease.
with low free silica and other mineral content. Mixed
dust pneumoconiotic foci are typically stellate lesions Antimony
with slight to moderate fibrosis. In histopathological data Antimony trichloride (SbCl ) and pentachloride
3
obtained in Japan, aluminium-related pulmonary fibrosis (SbCl)13) may lead to inhalation injury, presumably as a
5
has been described as mixed dust pneumoconiosis result of damage caused by the halide ion, rather than by
accompanied with interstitial pneumonitis38–41). the metal ion. It is worth mentioning that the inhalation
As stated previously, pulmonary fibrosis related to of the hydride forms of antimony (stibine, SbH) can also
3
aluminium and/or aluminium oxides has been designated be lethal as a result of fulminant haemolysis, which
6 J Occup Health, Vol. 43, 2001
sometimes manifests itself initially as dyspnoea42). This communications, where beryllium may be found in alloys
is not the case for insoluble antimony trioxide. (often with copper) or in ceramics. However, it is
Antimony is known to cause “benign” pneumo- important to realize that scrap metal refiners66), non-
coniosis43, 44). ferrous metal welders, dental technicians, laboratory
maintenance or transport workers may also be exposed
Arsenic to an often unsuspected but significant risk. Contacts
It is worth mentioning that the inhalation of the gaseous with beryllium-workers who brought factory-dust to their
hydride forms of arsenic (arsine, AsH) can also be lethal homes caused a classical para-occupational example of
3
due to the mechanism of fulminant hemolysis45, 46). chronic berylliosis67).
Epidemiological and experimental studies have The differential diagnosis between chronic beryllium
established the carcinogenic risk of exposure to inorganic disease and other interstitial lung diseases, mainly
arsenic compounds47–51). In recent years lung cancer, at sarcoidosis, rests essentially on the proof of exposure,
an odds ratio as high as 15.2, was reported for arsenic which may be difficult to obtain solely on the basis of
exposed populations52). In another study, SMR as high occupational history. The finding of beryllium in
as 3.73 was found in both a case-control study and a biological samples confirms present (urine) and
cohort study made by the same authors53, 54). A recent sometimes past exposure (lung tissue, lymph nodes)68).
review of occupational lung carcinogens has reported Specific blast transformation test of lymphocytes (LTT)
relative risks of lung cancer due to arsenic with reference in response to culture with beryllium appears to be highly
to the number of exposed workers55). specific, but not very sensitive in peripheral blood
This is also the case for other occupational exposures lymphocytes, although recent data suggest a great
to arsenic, such as in the manufacture or spraying of improvement in sensitivity in lymphocytes from
arsenic pesticides56, 57). By contrast, no excess lung cancer bronchoalveolar lavage69). Saltini et al.70) showed that
was noted in the study by Enterline et al.58) for smelters major histocompatibility complex class II antigens and
whose exposures were estimated to be at the current functional interleukin 2 receptors were necessary for
OSHA level, 10 ug/m3. CD4+ lung T cells from patients with chronic beryllium
In Japan, several areas with arsenic mines and refineries disease to proliferate in vitro in response to stimulation
have been recognized as environmentally-polluted sites by beryllium.
according to Law for Prevention of Public Pollution. Both This and other experimental evidence strongly suggest
workers and residents have been found there to be victims that beryllium triggers a cell-mediated immune response,
of arsenic. It was reported, for example, that the residents thereby explaining the low incidence and high variation
in an area producing the most arsenic in Japan also had in the time of onset of disease in exposed workers.
lung cancer highly associated with skin cancer59, 60). Moreover, an HLA-DPB1 (HLA-DPB1 glutamate 69)
allele was suggested to be closely associated with chronic
Barium beryllium disease71).
Baritosis, a benign pneumoconiosis, has been This marker could be useful in screening for those
associated with exposure to barium12–14). workers who should be monitored for evidence of
sensitization or disease. However, the chemical and
Beryllium physical forms of beryllium probably also play a role,
Past literature13) on accidental and non-accidental and this remains to be clarified.
exposures shows that exposure to fumes or dusts The Japanese literature on CBD including the first
containing beryllium is capable of causing chemical report by Izumi et al.72) was reviewed by one of the
pneumonitis or acute airway irritation. A cross-sectional authors19).
study has also suggested an increased prevalence of Compared to other developed countries, Japan has
chronic bronchitis and loss of ventilatory function, mainly experienced fewer cases (n=25) with CBD; five of these
forced vital capacity (FVC), in association with chronic died from complications of CBD including pulmonary
exposure to beryllium61), although another study did not infection and pulmonary failure. A reason for the low
reach the same conclusion62). number of cases is believed to be the genetic
Berylliosis or chronic beryllium disease (CBD) is well background72). All of these cases dealt with beryllium
known for its striking histological and clinical oxide (BeO) which is said to be less toxic or potent in
resemblance to sarcoidosis. The clinical, epidemiological sensitization than beryllium salts.
and experimental aspects of the disease have recently been According to the regulations in Japan as well as the
reviewed63–65). Apart from the extraction and primary U.S.A., workers handling beryllium alloy containing Be
refining industry, beryllium exposure is an occupational at less than 3% are not subjected to periodic health
risk in many sectors of modern industries, such as aircraft examinations. Moreover, beryllium-copper alloy has been
and aerospace, electronics, computers and recognized as being less potent in initiating CBD than
Yukinori KUSAKA, et al.: Metals Known in Japan to Induce Occupational Respiratory Diseases 7
BeO but in recent reports in Japan, Be-Co alloy with Be
content less than 3% caused CBD in two cases73, 74). The
findings and test results including blood-Be-LTT for these
cases matched the criteria of the U.S.A. Beryllium Case
Registry75).
Follow-up studies have revealed that individuals with
chronic beryllium disease have a higher incidence of lung
cancer than the general population76). A thorough review
article77) has recently been published on the carinogenesis
of beryllium, which is now assigned to category 1 by
IARC49).
Cadmium
Cadmium and other metals bind to metallothionein, a Fig. 1. A worker melting battery alloy for reusing cadmium
low-molecular weight protein rich in sulphydryl (SH) contained wore only cotton gauze mask. Metal fume
groups. This process also plays a role in the defense is seen to come out from the furnace.
against cadmium, but it eventually leads to the retention
and progressive accumulation of cadmium in various
tissues including probably the lungs78). Cadmium is
capable of causing both lung and kidney changes,
probably depending in part on the route of exposure.
The most severe form of acute pulmonary damage is
chemical pneumonitis which classically follows the
inhalation of cadmium fumes13). Cadmium is present in
several areas of metallurgy. From a practical viewpoint,
it is important to be aware that risks in relation to cadmium
pneumonitis are: 1) that liberation of cadmium oxides
from welding, silver brazing, or burning of cadmium-
containing alloys79) or from the smelting of lead80), which
often contain significant levels of cadmium; 2) that
exposure to toxic levels of cadmium fumes does not
necessarily lead to immediate respiratory symptoms.
Indeed respiratory distress is usually delayed for several
hours until severe non-cardiogenic pulmonary oedema
develops13). A follow-up study81) showed that cadmium
chemical pneumonitis leads to pulmonary fibrosis.
For instance in Japan, there have been reported cases Fig. 2. His chest radiograph taken one day
of acute interstitial pneumonitis resulting from inhalation after onset of respiratory symptoms
showed diffuse reticular nodular
of cadmium fumes at high levels82–85). One report81)
opacities throughout both lungs.
contained data on airborne concentrations of a number
of metals generated during welding.
Symptoms suddenly developed several hours after
burning cadmium alloys (Fig. 1), presenting with fever, emphysema87, 88) has recently been settled by the results
dry cough, general malaise and so on. One day after of a study of a large group (n=101) of workers and ex-
onset, diffuse shadows were seen on chest x-rays (Fig. 2) workers from a cadmium factory in England89). This study
and lung biopsy specimens revealed interstitial showed a clear excess of functional (ventilatory function
pneumonitis with infiltration of lymphocytes and and diffusing capacity) and radiological signs of
eosinophils [Personal communications from Professor R. emphysema in the exposed subjects compared to
Tokunaga]. appropriate controls. Evidence of a causal role for
Exposure to cadmium also relates to metal fume fever, cadmium was strengthened by the existence of a positive
a malaria-like or influenza-like reaction consisting of exposure/response relationship with exposure being
fever, chills, and malaise, sometimes associated with X- estimated from both past hygiene measurements and the
ray abnormalities86). internal (liver) cadmium burden. Moreover, the
The as yet controversial issue of whether chronic significance of these findings has been borne out by the
cadmium fume inhalation leads to pulmonary demonstration of increased mortality from non-malignant
8 J Occup Health, Vol. 43, 2001
respiratory disease in cadmium-exposed workers90, 91). (trivalent) chromium to cause lung cancer117).
The mechanism of cadmium-induced emphysema is still Epidemiological studies of the carcinogenic risk of
not elucidated. Animal studies suggested that fibrosis, exposure to chromium during metal plating or during
rather than alveolar wall destruction, precede the stainless steel welding have been considered inconclusive.
development of emphysematous lesions92–94).
There are also epidemiological and experimental Cobalt
indications that cadmium is carcinogenic in the human Cobalt (Co) is an essential metal in many coenzymes
lung47–50). Increased mortality from lung cancer and enzymes. Dysfunction in enzymatic processes, e.g.
attributable to cadmium has been shown in some91, 95, 96), megalocytic anemia, may, therefore, result from Co
but not all studies of cadmium exposed workers97–99). A deficiency. However, high doses of the essential metal
recent review on occupational lung carcinogens has may cause substitution and mimicry as inappropriate
reported relative risks of lung cancer due to cadmium compounds.
with reference to exposed workers in a number of Another toxicologically relevant consequence of cobalt
industries55). binding to proteins is the acquisition of anitigenicity, so
that cobalt sensitizes probably by mechanisms similar to
Chromium those of other reactive low molecular weight molecules
Exposure to chromic acid during chrome-plating leads and metals which may function as haptens.
to upper airway lesions, particularly nasal septal The biological activity and toxicity of some metals is
ulceration and perforation, which, in a recent study, was also greatly influenced by their ability to change their
found in an astonishing two thirds of subjects exposed to redox state by loss or gain of electrons. Transition metals
moderately high peak levels of Cr100). are electronically stable in more than one oxidation state.
Chromium is reported to cause asthma in chromium As a result of this property, transition metals play
plating workers, mostly in case reports101, 102). Shirakawa important roles in catalyzing biological oxidation
et al.103) demonstrated the existence of a specific IgE reactions. Of the transition metals, iron and, to a lesser
antibody to chromium-human serum conjugate in a 50- extent, copper have been extensively studied because of
yr-old male engaged in metal plating. their implication in many pulmonary and non-pulmonary
The assay for the type I immediate reaction in disease processes by virtue of their ability to enhance the
combination with a bronchial provocation test is expected production of toxic free-radical species of oxygen118–120).
to clarify the basic mechanism underlying chromium- In pulmonary toxicology, free-radical oxygen toxicity,
related lung sensitization. which seems always to involve metal catalysis121, 122), is
Simultaneous exposure to sensitizing metals (Ni and considered to be a mechanism for the effects of
Cr) takes place in electroplating and the question of a hyperoxia123), paraquat124), nitrofurantin125) and asbestos126).
cross reaction between the two metals or simultaneous Cobalt performs all of these activities, and cobalt
sensitization to the metals has been debated104). accumulated in the lungs enhances hyperoxia by this
Epidemiological and experimental studies have clearly mechanism127).
established the carcinogenic risk from exposure to Cross-sectional studies have suggested an increased
chromium, in some of its chemical forms. A greatly prevalence of chronic bronchitis and a loss of ventilatory
increased risk of lung cancer has also been demonstrated function associated with chronic exposure to cobalt128, 129).
for workers in primary chromate production and in the Cobalt cause asthma130–136) with evidence of the
chromate pigment industry47–51, 55, 105–108). formation of specific (IgE) antibodies to protein-
In Japan lung cancer was observed to occur in a conjugates of cobalt (Co)136–138), suggesting that asthmatic
significantly greater proportion of chromate workers than reaction to the metal involves an IgE-mediated response.
in the Japanese general population106, 109). Among workers exposed to hard metal containing either
Ishikawa et al.110) demonstrated that lung cancer from cobalt or nickel as a binding matrix, cobalt-induced
chromate tends to develop on the bronchial bifurcations bronchial asthma and nickel-induced asthma are
in association with increased deposition at that site. prevalent138). Immunological mechanisms include
Bronchial dysplasia also occurs at this site, and mucous immediate type (IgE-mediated) and cellular
cells express the p53 oncogene product, often followed hypersensitivity138, 139), and questions relating to the cross
by squamous cell lung cancer. This latter finding may reactivity between the two metals versus simultaneous
support the dysplasia-carcinoma sequence theory. sensitization to the metals has been debated. In addition
There are several recent studies showing increased lung to sensitization to cobalt, atopy reflected in positive
cancer mortality in welders and platers111–115). The antibodies to common environmental antigens has been
exposure in these jobs is probably to the carcinogenic shown to be an independent risk factor for asthma among
form of chromium, i.e. hexavalent chromium116), although hard metal workers.
a recent report suggested the potential for insoluble Airborne cobalt levels below the current standard limit
Yukinori KUSAKA, et al.: Metals Known in Japan to Induce Occupational Respiratory Diseases 9
for cobalt were shown to carry increased risk140). toxicity resulting from the ability of cobalt to promote
A case of asthmatic sensitization to cobalt was recently the Fenton reaction127).
diagnosed in a man working in the animal feed industry. In view of the widespread use of cobalt in alloys,
This individual was involved in the addition of cobalt magnets, special corrosion resistant steels, pigments,
sulphate to the feed used for the prevention of cobalt plastics and many other applications141) it is important to
deficiency in cattle141) (Dr. E. Stevens, personal discover the determinants of the toxicity of this metal.
communication, unpublished). Both the chemical and physical forms of cobalt
The condition known as hard-metal lung disease has compounds that are “intrinsically” harmful, and the extent
been the subject of renewed interest in recent years, to which host or other factors may render cobalt toxic
particularly with regard to the causative role of require investigation. It is indeed remarkable that no lung
cobalt142–144). Hard-metal or cemented tungsten carbide fibrosis has been reported in workers involved in the
(WC) is found in tools used for high-speed cutting, mining or refining of cobalt159), with the exception of four
drilling, grinding and polishing of other metals or hard cases seen before World War II in a Germany factory
materials. In a minority of workers involved in the making cobalt carbonate160).
manufacture or utilization of these tools, bronchial asthma Japan is now the third largest producer of hard metal
and diffuse pulmonary fibrosis have been reported in tools in the world. An article by one of the authors161),
various parts of the world132–134, 145–152). On the basis of reviewing all the Japanese literature on hard metal-related
relatively crude animal data153) showing little toxicity from broncho-pulmonary diseases, demonstrated the
the main constituent of hard-metal, i.e. tungsten carbide, prevalence of hard metal asthma to be 5.3%.
the consensus is that tungsten carbide is not the agent Apart from interstitial pulmonary fibrosis probably
responsible for the fibrosis, but that it is more probably secondary to interstitial pneumonitis, cases of mixed-dust
due to the binding agent, i.e. cobalt. pneumoconiosis have been demonstrated to be due to a
The pneumonitis is often of the desquamative type, mixture of tungsten carbide dusts and grinding wheel
and in the subacute forms it appears to be mainly dusts162).
characterized by the presence of multinucleated giant This finding is consistent with a report from
cells. Indeed it has been proposed that giant cell Switzerland where imported hard metal tools are ground
interstitial pneumonitis (GIP) may be pathognomonic for for reuse163).
hard-metal exposure154). The aetiological role of cobalt There are also epidemiological and experimental
in giant cell interstitial pneumonitis has been strongly indications that cobalt may be carcinogenic in the human
supported by the observation of several cases of a disease lung47–50). Cobalt is a 2A carcinogen according to the
identical to hard metal lung disease in diamond polishers, IARC criteria49). In Germany, cobalt is listed as one of
who used polishing discs made with cobalt155, 127). The the carcinogenic substances for which 5 mg/m3 is the
term cobalt-lung has therefore been proposed155). maximum acceptable concentration164).
The mechanism of the pulmonary toxicity of cobalt
has not yet been elucidated143, 156). Unlike the classical Dental technician pneumoconiosis
pneumoconioses in which the lung burden of dust seems Dental technicians are at risk of pneumoconiosis165, 166),
to be the predominant factor in causing the disease (even as shown in Fig. 3. Intensive monitoring data on airborne
if host factors do also play a role in these diseases), several dusts at dental technology workplaces have been
features of cobalt-lung suggest some form of described by Fukuzawa167): some toxic metals including
hypersensitivity or host idiosyncrasy, perhaps analogous cobalt, chromium, and nickel, and mineral dusts including
to the situation observed with beryllium. Indeed for both asbestos and silicates were shown to be present. Some
beryllium and cobalt the dose-response relationship is dental pneumoconiosis may arise from excessive
not straightforward: on the one hand, the attack rate of exposure to dust produced from the machining of
the disease appears to be determined by the extent of vitallium, an alloy consisting of chromium-cobalt-
exposure, but on the other hand, within similarly exposed molybdenum168). Histologically this fibrosis is manifested
workforces only a small minority of sometimes very by dense interstitial fibrosis around dust deposits, without
young subjects, with relatively little cumulative exposure, giant cells. Vitallium dust is, however, not the sole dust
are affected155). The known dermal sensitizing potential to which dental technicians may be exposed, and other
of cobalt and the existence of cobalt-asthma suggest that agents such as alginate169), beryllium, hard-metal and silica
hypersensitivity to cobalt may cause the fibrosing may also cause lung disease in these workers165, 166, 170, 171).
alveolitis. Conditions more usually considered to be cell- Dr. Nanbu et al. including one of the authors, Kusaka,
mediated157), such as alveolitis155, 134), and asthma reported a technician who presented with interstitial
combined with alveolitis158), have been reported. pneumonitis of giant cell type (GIP) (Histopathological
However, this is by no means proven, and other options findings not shown, HRCT images shown in Fig. 4). This
must be considered, such as oxygen free-radical mediated case showed a positive lymphocyte stimulation test with
10 J Occup Health, Vol. 43, 2001
Fig. 3. A dental technician grinding implant materials Fig. 4. A High Resolution Computed Tomography (HRCT)
including metals. Local dust ventilation utility is picture compatible with interstitial fibrous thickening
seen beside him. accompanied with honeycombing from a dental
technician having diffuse shadows on chest x-rays.
Fig. 5. Positive lymphocyte proliferation with cobalt antigen in a pneumoconiotic dental
technician.
cobalt (stimulation index, SI; 4.1) (Fig. 5), while the same role in catalyzing biological oxidation reactions. Copper
lymphocytes from the peripheral blood reacted positively has been studied because of its implication in many
to purified protein derivative of tuberculin (SI 7.4) [Dr. pulmonary disease processes by virtue of its ability to
Nanbu and Dr. Kusaka, personal communication]. This enhance the production of toxic free-radical species of
evidence might raise the possibility that some dental oxygen118). In pulmonary toxicology, free-radical oxygen
technicians pneumoconiosis is compatible with cobalt toxicity, seems always to involve metal catalysis121, 122).
lung which has been designated as interstitial pneumonitis However, inhaled metals have so far received rather little
for diamond polishers using cobalt discs155). attention in this connection.
A more benign condition following exposure to high
Copper concentrations of copper fume is metal fume fever172, 173).
Copper (Cu) is also an essential metal for coenzymes This condition is described more precisely in the section
and enzymes. The transport and accumulation of copper on zinc.
is often the result of its ability to interact with ligands In Japan increased mortality from lung cancer has been
such albumin, and ceruloplasmin whose abundance reported from a cohort study associated with a net case
probably constitutes a safeguard against the toxicity of control study at copper finery plants174, 175). The proportion
free copper ion118). of Kreyberg group I among these cases with lung cancer
Copper is a transition metal which plays an important was significantly larger than that in the population-based