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Review

Metal-Induced Lung Disease: Lessons from Japan's Experience

Yukinori KUSAKA1, Kazuhiro SATO1, Narufumi SUGANUMA1 and Yutaka HOSODA2

1 Department of , School of Medicine, Fukui Medical University and Institute of Radiation Effects Association 2

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 and associated was occupational respiratory diseases, e.g. metal , well known among miners, and was named "Yoroke" acute and chronic , , , which means severe cardiopulmonary failure. It was said chronic , and lung cancer are described. The metals mentioned that on the Sado Island, which had the biggest gold mine, are the following: aluminum, antimony, , barium, since miners died young, their wives often remarried to a , , , , copper, iron, total of up to seven husbands. lithium,, mercury, , , rhodium, Japan experienced the Meiji Civil Revolution in 1868 rare earth metals, titanium, uranium, , followed by an industrial revolution and then , , 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 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 Key words: Metal, Lung disease, Occupational, therefore passed in 1960, particularly for miners in copper, 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. , 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 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 1978'). process, workers inhaled high levels of mercury fumes, resulting in poisoning. The pneumoconiosis law 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 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 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)

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 scheme'). 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 Law". 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 prevalence": 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 , bronchial irritation, on metals bronchial asthma and bronchitis due to exposure to metals (Table 2)". With respect to other metals, not covered by the Table 2. Metals causing occupational lung diseases designated by Ordinance on Prevention of due to Specified Chemical Substances with reference to administrative levels (mg/m3) assigned by Working Environment Measurement Law

Table 3. Numbers of workers undergoing special medical examinations by type of worker covered (1993)

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 disorders but, once workers develop the relevant disease, Statistics of recognized metal-related lung diseases 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 to provide. Exposure standards in Japan 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 Table 4. Metals hazardous to the 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 article by one of the authors'91. Case reports, reports on epidemiological studies, and reports on the mechanism of metal-related lung diseases have been reviewed by one of the authors. From them, reports of interest for occupational chest medicine were included in the present review.

Aluminium Cross-sectional studies have suggested an increased prevalence of chronic bronchitis and a loss of ventilatory function, mainly forced vital capacity (FVC), in association with chronic exposure to aluminium20' 211. These are apparently independent of the overt forms of other respiratory diseases seen with some of these metals in steel or from welding. The underlying mechanism is not fully clarified. The causative agent of asthma ("potroom-asthma") and bronchial hyper-reactivity in smelters (or other limits (OELs) for various chemical substances over workers exposed to aluminium salts )22-211is 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 challenge2s.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 beryllium"). 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 diseases' 14'. From a toxicological viewpoint, a metal "" . can be defined as "an element which under biologically The recent report by Devuyst et al.") 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 controversy", 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 texts 12-14'has been taken as such, whereas more workers involved in the smelting of bauxite for the recent acquisitions appearing up to 199716-'8) 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 polishers", 11-161do not Table 5. Occupational exposure limits (OEL) and carcinogenicity class designated by Japan Society for Occupational Health of metals hazardous to the respiratory system

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 nature", 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 (SbCl3) and pentachloride obtained in Japan, aluminium-related pulmonary fibrosis (SbC15)13)may to inhalation injury, presumably as a has been described as mixed dust pneumoconiosis result of damage caused by the halide ion, rather than by accompanied with interstitial pneumonitis384". the metal ion. It is worth mentioning that the inhalation As stated previously, pulmonary fibrosis related to of the hydride forms of antimony (stibine, SbH3) can also aluminium and/or aluminium oxides has been designated be lethal as a result of fulminant haemolysis, which sometimes manifests itself initially as dyspnoea421. 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 refiners"', non coniosis4sn 441. 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, AsH3) can also be lethal homes caused a classical para-occupational example of due to the mechanism of fulminant hemolysis45• 461. chronic berylliosis671. 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 compounds47-511. 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 population S52). 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 authors 13,541 A recent sometimes past exposure (lung tissue, lymph nodes)"'. 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 workers551 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 pesticides56.571.By contrast, no excess lung cancer bronchoalveolar lavage691. Saltini et al.701 showed that was noted in the study by Enterline et al."' 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 cancer5y.6O1 Moreover, an HLA-DPB 1 (HLA-DPB 1 glutamate 69) allele was suggested to be closely associated with chronic Barium beryllium disease'''. , a benign pneumoconiosis, has been This marker could be useful in screening for those associated with exposure to barium 12 111. 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 literature'-' 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. 12, was reviewed by one of the or acute airway irritation. A cross-sectional authors'91. 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 beryllium611, although another study did not infection and pulmonary failure. A reason for the low reach the same conclusion621. number of cases is believed to be the genetic or chronic beryllium disease (CBD) is well background 72). 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 reviewed63-61 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 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 Registry"'. Follow-up studies have revealed that individuals with chronic beryllium disease have a higher incidence of lung cancer than the general population 76'. A thorough review article 17' 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 to the retention and progressive accumulation of cadmium in various tissues including probably the lungs7"~. 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 which classically follows the inhalation of cadmium fumes'). 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, , or burning of cadmium containing alloys79' or from the smelting of lead"', 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 develops''. A follow-up study"" 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 a of acute interstitial pneumonitis resulting from inhalation fter onset of respiratory symptoms showed diffuse reticular nodular of cadmium fumes at high level S12-151.One report") 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, emphysema", "8)has recently been settled by the results dry , 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 England". 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 -like reaction consisting of exposure/response relationship with exposure being fever, , and malaise, sometimes associated with X estimated from both past hygiene measurements and the ray abnormalities"). 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 in cadmium-exposed workers"', 9". (trivalent) chromium to cause lung cancer'"). 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 welding have been considered inconclusive. development of emphysematous lesions9z-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 some9',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 industries"'. 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 Cr'°° 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•'02'.Shirakawa important roles in catalyzing biological oxidation et al.1031demonstrated 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 oxygen"'-"0). to clarify the basic mechanism underlying chromium In pulmonary toxicology, free-radical oxygen toxicity, related lung sensitization. which seems always to involve metal catalysis 121,1221, 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 asbestos'26) 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 cobalt'2s,'29) for workers in primary chromate production and in the Cobalt cause asthma'3o-'36) with evidence of the chromate pigment industry"-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-'38),suggesting that asthmatic significantly greater proportion of chromate workers than reaction to the metal involves an IgE-mediated response. in the Japanese general population'o6,'09) Among workers exposed to hard metal containing either Ishikawa et al. I" 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. prevalent"'). 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 hypersensitivity'38,'39), 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 platers' 11-1151. 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 chromium' 6),although hard metal workers. a recent report suggested the potential for insoluble Airborne cobalt levels below the current standard limit .

for cobalt were shown to carry increased risk'40' 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 applications 141)it is important to deficiency in cattle 14" (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 cobalt 111-114,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 cobalt"'), 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 carbonate'60' 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-'34,'45-I52)On the basis of reviewing all the Japanese literature on hard metal-related relatively crude animal data"') 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 dusts' 62). 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 exposure 154)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 cobalt' 15,1211.The the carcinogenic substances for which 5 mg/m3 is the term cobalt-lung has therefore been proposed"'). maximum acceptable concentration'64) The mechanism of the pulmonary toxicity of cobalt has not yet been elucidated'43,'56' Unlike the classical Dental technician pneumoconiosis pneumoconioses in which the lung burden of dust seems Dental technicians are at risk of pneumoconiosis'6s,'66) 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 molybdenum 168'.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 affected"'). 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 alginate 169',beryllium, hard-metal and silica hypersensitivity to cobalt may cause the fibrosing may also cause lung disease in these workers165,'66,170,171) alveolitis. Conditions more usually considered to be cell Dr. Nanbu et al. including one of the authors, Kusaka, mediated L571,such as alveolitis'55, 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 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 oxygen"". In pulmonary toxicology, free-radical oxygen technicians pneumoconiosis is compatible with cobalt toxicity, seems always to involve metal catalysis"'''22). 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 fever"z, 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 plants14• "5). The proportion free copper ion18'. 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 cancer registries in Japan 176'.These findings suggested conditions do have associated morbidity and that squamous and small cell carcinoma was prominent complications. Moreover, the view that the symptomatic and appeared to be environmentally related to interstitial fibrosis which is sometimes found in welders bronchogenic carcinomas. (welders' pneumoconiosis), is simply siderosis with Workers engaged in refining copper ores are exposed existing silicosis has recently been challenged on the to arsenic at the same time. The carcinogenicity of arsenic grounds that the pulmonary silicon content in such cases has been clearly established in epidemiological and did not differ from that in control lungs"'). experimental studies"-", "' Thus, the relationship of There are epidemiological and experimental indications arsenic to increased risks of lung cancer in copper that iron, or occupations associated with iron exposure smelting workers is unequivocal. may be carcinogenic for the human lung"-"). Increased risk of cancer and mortality have been definitely shown Iron in epidemiological studies to be associated with exposure Iron is another transition metal involved in catalyzing to steel welding 192,191'. These studies of iron and steel biological redox reactions. Studies on implication of iron foundry workers have consistently shown an increased and copper in many pulmonary disease processes have risk of lung cancer, but this may be due to the emission focused on their ability to enhance the production of toxic of polycyclic aromatic hydrocarbons as pyrolysis products free-radical species of oxygen'"-1101. In pulmonary of organic materials used'94.'95) toxicology, free-radical oxygen toxicity seems always to involve metal catalysis12''122'. Lead Iron is an essential as a coenzyme for many enzymes. Lead is known to be toxic for many organs. Although Transferrin, ferritin, and albumin are the main transport it is absorbed mainly by inhalation into the body, there or storage proteins for iron, and their abundance have been very rare reports on respiratory disorders due probably constitutes a safeguard against the toxicity of to the exposure to lead. Lead miners probably associated free iron"8, 119) with silicosis were shown to accumulate lead in the Occupational exposure to iron occurs during iron lungs 196). A cohort study of lead smelter workers in mining and related operations, during iron refining and Sweden described increased incidence of lung cancer at various stages in steel making. Exposure also occurs among them, with dose-response relationships 1971.The during welding, cutting and abrading of iron-containing carcinogenicity of lead, however, has not been confirmed materials, as well as during the manufacture or use of yet. iron-containing abrasives (such as emery). Studies of the effects of iron exposure on ventilatory function in Lithium groups such as "steel workers""'-' 10)or "metal Lithium hydride (LiH) and phosphine (PH3) have been welders"' 1`9())have been largely negative, inconclusive reported to cause pulmonary oedema' 3). or showing only small effects, despite the generally consistent finding of increases in the prevalence of chronic Manganese bronchitis, as founded by means of questionnaires. Manganese (Mn) is essential as a coenzyme for many Nevertheless, for the methodological reasons alluded to enzymes. Exposure to high concentrations of the fumes above, one should not conclude that there are no specific of manganese can lead to acute pulmonary manifestations, work processes within these broad categories which entail the outcome of which can range from complete recovery a risk of significant obstructive respiratory impairment to death, depending on the agent involved. in susceptible subjects. Past literature'3' on accidental and non-accidental Of the "benign" pneumoconioses the most frequent exposure shows that exposure to fumes or dusts and best studied is siderosis, which is caused by the containing manganese is capable of causing chemical inhalation of iron compounds'2' 1,16'. Siderosis is a "radiological disorder" in that it manifests itself by the pneumonitis or acute airway irritation. Cross-sectional studies have also suggested an presence of small, very radio-dense opacities with increased prevalence of chronic bronchitis and a loss of uniform distribution throughout the lungs, but without ventilatory function, sometimes mainly of forced vital formation of conglomerates. With cessation of exposure capacity (FVC), associated with chronic exposure to the radiographic opacities may gradually disappear. Pure manganese198'. Apparently these conditions arise siderosis is not associated with respiratory symptoms or independently or due to the other overt forms of functional impairment, and does not predispose to respiratory disease seen with some of these metals. tuberculosis. However, it is important to realize that exposure to silica or asbestos is not uncommon in many Mercury jobs that involve exposure to iron, thus giving rise to Past literature '3' and recent reports of accidental and mixed dust fibrosis or to asbestosis, and these two non-accidental environmental exposure show that exposure to fumes or dusts containing mercury199 '021is review on occupational lung carcinogens has reported capable of causing chemical pneumonitis or acute airway relative risks of lung cancer due to metals nickel with irritation. Skin absorption of mercury has been shown to reference to the number of exposed workers for each be involved in the induction of systemic diseases carcinogenic metal"). including pulmonary manifestations"'). The interaction of metals including nickel with functional groups on macromolecules is an important Nickel mechanism for their toxicity and their carcinogenicity216'2"). Past literature]) and a recent report of accidental and Several metal ions react strongly with free SH groups, non-accidental exposure show that exposure to fumes or thereby possibly inhibiting active centres of enzymes, dusts containing, nickel carbonyl [Ni(CO)4]203)is capable coenzymes or membrane bound receptors. Direct of causing chemical pneumonitis or acute airway irritation. interaction of metals with deoxyribonucleic acid (DNA) One of the toxicologically relevant consequences of is one of the possible mechanisms of metal carcinogenesis metal binding to proteins is the possible acquisition of as well as of the chemotherapeutic effects of some metal anitigenicity, i.e. haptenization. As stated above with complexes. respect to hard metal disease, nickel and cobalt, which both belong to element group IV, cause asthma, mediated Platinum by type I allergic reaction of the bronchial tree. Platinum sensitizes probably by mechanisms similar Nickel has been known to cause asthma mostly in case to those of other small reactive organic molecules, i.e. reports201-201)There is evidence of formation of specific haptenisation. (IgE) antibodies to protein-conjugates of nickel (Ni)205' In recent review article S218-221),platinum is clearly 206,2081 , suggesting that asthmatic reaction to these metals shown to cause bronchial asthma. The complex halide also results from an IgE-mediated response. Exposure salts of platinum (Pt) provide a unique example of a to Ni, Cr, or Co takes place in occupational settings such situation in which a very considerable proportion of as hard metal industries and electroplating'o4.'39) Cross exposed subjects may become sensitized 2218j.There is reactivity between the two metals and simultaneous good evidence for an immunoglobulin E (IgE)-mediated sensitization to the metals has been debated. It has also mechanism in platinum salt asthma 2218.222.223). been pointed out that related to Nevertheless, the detection of Pt-specific antibodies by exposure to these metals occurs within the current radioallergosorbent test (RAST) is less sensitive than skin exposure limits'o4.138.'40,161) testing in the clinical diagnosis of Pt-hypersensitivity, New evidence has recently appeared from Japan on possibly because of a frequent increase in total IgE2223). the potential of nickel to provoke eosinophilic Smoking and atopy have been demonstrated to be pneumonia209'. In this case, nickel fumes were inhaled predictors of platinum asthma like cobalt asthma224226). during a training course for welding and after a couple Exposure to other irritants such as ozone may well prove hours the pneumonia confirmed by BAL developed. A to be a more important determinant in interaction with provocation test with nickel sulphate solution caused a atopy in the occurrence of allergic platinum asthma2271. recurrence of the pneumonia. Evidence of a positive Shima et a1.2781reported asthma cases in association provocation test suggests underlying hypersensitivity to with the production of platinum-alloy sensors at Japanese nickel. To date, reports on related factories. to exposure to nickel, compatible with Loeffler's Syndrome in terms of histopathological abnormalities Rare earth metals have been made in a few cases21o-212). Exposure to rare earth metals (or lanthanides), of which Another hypothesis on the role of nickel is in catalyzing cerium is the most abundant element, has also been biological oxidation reactions in the exposed lung. Like associated with interstitial fibrosis in a small number of iron and copper which cause pulmonary disease processes subjects2292331.Rare earth metals are essential compounds by virtue of their ability to enhance the production of of carbon arc lamps used for photoengraving, and the toxic free-radical species of oxygen' 8-120),nickel may majority of cases of this pneumoconiosis have been exert toxicity by the same mechanism. described in photoengravers. Rare earth metals are also Occupational exposure to nickel in nickel smelters and used in the fabrication and polishing of glass. One refineries is also unequivocally associated with an histological report2291 mentions the presence of increase in cancer of the lung and the nasal sinuses2'3.214' granulomatous interstitial alterations, although this is not According to the IARC and a recent study by Andersen mentioned in the other available pathological descriptions et al.2151,all nickel compounds except metallic nickel have of cerium pneumoconiosis2331. been classified as carcinogenic to humans by IARC491. Again the situation in nickel-using industries is less clear, Rhodium but a cancer has not been excluded. A recent Rhodium, belonging to the same element group as platinum, has been assumed to be as potent as platinum There are several recent studies showing increased lung in terms of bronchial and skin sensitization. A report cancer mortality in welders"', 12). Epidemiological from Japan suggested a role of rhodium in the studies of the carcinogenic risk in exposure to chromium sensitization of workers who handled rhodium replacing during stainless steel welding have been considered platinum as a plating agent234). inconclusive.

Titanium Zinc Titanium tetrachloride (TiC14)235)may lead to inhalation Zinc (Zn) is an essential metal in coenzymes and injury presumably as a result of damage caused by the enzymes. Deficiency states may therefore cause problems halide ion, rather than by the metal ion. but also high doses of the essential metal caused by Cross-sectional studies have suggested an increased substitution and mimicry of essential ions by prevalence of chronic bronchitis and a loss of ventilatory inappropriate compounds. function associated with chronic exposure to titanium Cases of adult respiratory distress syndrome have dioxide236.237) recently been reported in military and civilian personnel Titanium, otherwise considered as virtually non-toxic, accidentally exposed to smoke bombs which liberate zinc has been suggested as an aetiological agent in a case of chloride (ZnC12)244,245) granulomatous lung disease. This was based on the A more benign condition after exposure to high presence of metallic particulates containing titanium in concentrations of metal fumes such as those of copper, lung granulomas and of a positive blood LTT to titanium manganese, zinc, and cadmium, is metal fume fever172.173) chloride, and not to other metals tested, including Among these metals, zinc is the best known causative agent beryllium238'_ for metal fumes because of wide application in various Similar histological findings including granulomatous industries. This condition, of which there are several abnormalities, slight focal fibrosis, alveolar septal symptoms"), is an influenza-like or malaria-like reaction thickening, and interstitial infiltration with lymphocytes, consisting of fever, chills and malaise with relatively mild were reported in one Japanese case with occupational respiratory symptoms, and classically little or no X-ray or exposure to organic titanium (tetra-butyl-titanium). The functional abnormalities, although this is not always the element analysis with electron x-ray dispersive analysis case 2411.The symptoms, often accompanied by a sweet detected the presence of organic titanium compound in a metallic taste in the mouth, usually begin at home a few fibrotic lung239'. hours after a heavy exposure to metal oxides, e.g. after welding in a confined space, and they then subside Uranium spontaneously. Leucocytosis is present during the acute Uranium hexafluoride (UF6)240)may also cause stages of the illness. A recent report of bronchoalveolar pulmonary injury after inhalation possibly as a result lavage findings in a case of zinc fume fever showed marked of damage caused by the halide ion, rather than by the neutrophil infiltration, and appropriately posed the question metal ion. of how such spectacular inflammatory events remain so self-limited 247).A strange feature of this syndrome is the Vanadium occurrence of tolerance: symptoms only appear when Acute tracheobronchitis with persisting bronchial exposure takes place after a period of days without hyper-reactivity241) can be caused by exposure to exposure and they do not appear on subsequent days. vanadium pentoxide (V,O5),a significant risk associated The exact pathogenesis of metal fume fever is poorly with the cleaning of oil tanks ("boilermaker's understood. In some instances allergic mechanisms may bronchitis" )212,243). be involved 248),but then metal fume fever may be a misnomer or it may be superimposed on bronchial asthma Welding or hypersensitivity pneumonitis2491. There is a striking Chronic obstructive lung disease may result from resemblance between metal fume fever and the organic welding. Studies of the effect on ventilatory function in dust toxic syndrome, which occurs after heavy exposure groups such as metal welders"'-191) have been largely to organic dust contaminated with micro-organisms250j negative, inconclusive or showing only small effects, Both syndromes have a similar clinical course with fever, despite the generally consistent finding of an increase in leucocytosis, acute transient neutrophilic alveolitis251Iand the prevalence of chronic bronchitis, defined by a occurrence of tolerance. Their similarities indicate questionnaire. However, for the methodological reasons common pathogenic mechanisms. alluded to above, one should not conclude that there are With appropriate environmental control measure, cases no specific work processes within these broad categories of metal fume fever are fortunately not common any more, which entail a risk of significant obstructive respiratory but the disease has certainly not disappeared and is impairment in susceptible subjects. presumably often overlooked as a simple viral infection. Table 6. Occupational respiratory diseases related to inhalation of metals

Metal fume fever is said to not lead to suquelae, but this Carcinogenicity of metals is defined according to IARC has not been adequately investigated. criteria49) In recent reports252.253)of asthma in subjects welding Diagnosis, treatment and prevention galvanized metal, sensitization to zinc was suggested; -Research perspectives but the possible presence of other metals such as Co, which can be present in galvanized metal141),was not Diagnosis of metal-related occupational pulmonary investigated. Another suggestion of hypersensitivity to diseases, as with other occupational diseases, is dependent zinc is from a recent report on hypersensitivity on the level of knowledge of the physician who first sees pneumonitis in a smelter exposed to zinc fumes254).These the patient. Knowledge leads to recognition. Careful reports still show a lack of a specific allergic mechanism inquiry into occupational history is the first step in making in zinc mediated lung injury. a correct diagnosis. Respiratory symptoms are not pathognomonic for the Zirconium metal-related pulmonary diseases. As stated above, metal Zirconium tetrachloride (ZrCl4)13) may lead to fume fever is easily overlooked because it is so much inhalation injury, presumably as a result of damage caused like influenza or the . The presence of work by the halide ion rather than by the metal ion. Zirconium related asthmatic symptoms is a guide to diagnosis. may cause granulomas in human skin, but has not been However, their absence does not necessarily deny associated with granulomatous or fibrotic lung disease occupational origin, because failure to remove relevant in human subjects255> workers with occupational hypersensitivity from the work leads to persistent and fixed bronchial obstruction. Summary Pulmonary image techniques are again not specific to The metals causing occupational respiratory diseases each disease entity. Histopathological diagnosis of are listed in Table 6 with reference to disease entities. autopsy and biopsy is useful for interstitial lung diseases .

related to metals, such as granulomatous lung disease, if oxygen inhalation is sometimes crucial for acute chemical elemental or metal analysis of the lung samples is pneumonitis due to cadmium, beryllium and so on"". available. Giant cell interstitial pneumonitis is Treatment of chronic beryllium disease with pathognomonic for hard metal lung or cobalt lung. corticosteroid hormone has been shown to be effective270). Allergoimmunological tests such as lymphocyte Chelating agents such as sodium diethyldithiocarbamate transformation test with metal antigens and specific for nickel carbonyl pneumonitis are recommended"". antibodies are of high specificity, but of less sensitivity, Desensitization with platinum failed in a platinum asthma although these test are generally still to be regarded "as case272) adjuncts to clinical diagnosis, and not as independent Prevention of metal-related lung diseases can be proof of causation or of diagnosis'"256>. When attained as for other occupational lung diseases. Metals hypersensitivity is suspected, bronchial challenge testing hazardous to the respiratory system should be notified to may be justified 257).Bronchoalveolar lavage can contain employers and employees through the MSDS sheet. more lymphocytes responding to metal antigens than Exposure to these metals, and to what extent, should be peripheral lymphocytes. Bronchoalveolar lavage (BAL) notified at workplaces. The regulations contribute to is increasingly used, mainly in the assessment of enforcing these actions by employers and industries. interstitial lung disease"'). Begin259)has recently Exposure standards developed on the basis of advocated the use of this technique for pneumoconiosis epidemiological studies, if present, are appropriate in order to eliminate other causes of lung disease, to indicators for comparison to keep working environments document mineral dust exposure, to support other clinical safe. If exposure exceeds certain levels, technological information, and to investigate the biological mechanisms intervention and personal protection are necessary. Health of these diseases. The latter were found in BAL from examinations associated with biological monitoring for subjects with cobalt-related fibrosing alveolitis'55> individuals are obligatory for some metals in Japan. Analysis of mediators of inflammation and fibrosis260, Educating employees about the health effects of toxic cellular subtypes and responsiveness of lymphocytes to metals, for effective preventive measures, are crucial. in vitro challenge 69)are all potentially useful. The toxic Epidemiological studies and case studies adopting basic effects of metallic compounds on pulmonary alveolar scientific techniques have revealed some factors relevant macrophages are also being investigated, but so far to the onset of metal-related pulmonary diseases: atopy, macrophages from laboratory animals have mainly been genetic background, smoking, malnutrition, and so on. used. Knowledge of these issues should be considered when Documentation of exposure to metals may be obtained recruiting workers to aid in . from the analysis of metal concentrations in blood, urine, Another recent concept, which has emerged or hair taken for biological monitoring261U,although failure consistently from follow-up studies of occupational to detect the relevant metal in biological samples is not asthma from various causes, is the need for rapid and necessarily a denial of relevance. For instance, cobalt is total removal of symptomatic people from exposure in excreted very rapidly in the urine after being absorbed order to prevent permanent asthma273. 274). It is reasonable through inhalation262>. to adopt the same attitude in metal-induced asthma, In addition, elemental analysis may be carried out on although the ubiquity of some of the metals involved may BAL, on biopsy tissue or on autopsy material. Both well make total avoidance of exposure very difficult to macro-analytical (or bulk) and microanalytical techniques achieve in practice. may be applied226s-265'.One of the disadvantages of this It is necessary to develop diagnostic methods specific technique in the field of pulmonary metal-toxicity is that to each metal. Experimental studies can generate it does not allow the detection of beryllium. This latter evidence for chemical forms of metals exerting toxicity metal can, however, be detected by electron energy loss which can make a contribution to monitoring and spectrometry (EELS )166)and laser microprobe mass diagnosis. Experimental research also helps in developing analysis (LAMMA)267). A potential danger in the pharmaceutical agents. Protective agents and physiology indiscriminate use of these techniques is that the finding can also be clarified by means of such experiments. of metallic elements in certain disease states may be Further epidemiological studies are needed to determine unduly associated with a causative role for these occupational exposure limits for many of the toxic metals elements268'.Only properly conducted studies, including which are still lacking or poorly understood. experimental studies, will prevent such erroneous conclusions being drawn, although case reports will Acknowledgment: The authors sincerely thank Emeritus continue to be helpful in suggesting possible associations Principle Y. Sera, National Kinki Central Hospital, Professor and stimulating further research. R. Tokunaga, Department of Environmental Health, Kansai Treatment of metal-related lung diseases is not specific, Medical University, Dr. S. 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