Metal-Induced Lung Disease: Lessons from Japanâ€™s Experience

J Occup Health 2001; 43: 1–23Journal of

Occupational Health

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

Yukinori KUSAKA1, Kazuhiro SATO1, Narufumi SUGANUMA1 and Yutaka HOSODA2

1Department of Environmental Health, School of Medicine, Fukui Medical University and2Institute of Radiation Effects Association

Abstract: Metal-Induced Lung Disease: Lessonsfrom Japan’s Experience: Yukinori KUSAKA, et al.Department of Environmental Health, School ofMedicine, Fukui Medical University—Metals inducingoccupational respiratory diseases, e.g. metal fever,acute and chronic pneumonia, asthma, bronchitis,chronic obstructive lung disease, pulmonary fibrosisand lung cancer are described. The metals mentionedare the following: aluminum, antimony, arsenic, barium,beryllium, cadmium, chromium, cobalt, copper, iron,lithium, manganese, mercury, nickel, platinum, rhodium,rare earth metals, titanium, uranium, vanadium,welding, zinc, zirconium. With respect to these metals,mechanism of the disease, disease statistics, casereports, diagnostic methods, patho-physiology of thedisease, and preventive measures includingoccupational exposure limits are also described.Experience in Japan on these issues is given in detail.(J Occup Health 2001; 43: 1–23)

Key words: Metal, Lung disease, Occupational,Toxicity, Pneumoconiosis, Pneumonia, Bronchitis,Asthma, Lung cancer, Pulmonary fibrosis

Buddha, Jipang and Meiji revolution in Japan

Since ancient times, inorganic mercury has been usedas an amalgam by which mixtures of metals are plated orcoated. The “Nara Daibutsu”, Great Buddha Statue inthe oldest capital city, was plated with gold by usingmercury amalgam and it was reported that, during thisprocess, workers inhaled high levels of mercury fumes,resulting in poisoning.

In the middle of the Edo Era lasting from early in the1600 to the middle of the 1800, gold mines were opened.Refined gold was then exported through China and theNetherlands to Europe, and Japan came to be known forits gold trade and was named Jipang, meaning Golden

Received June 8, 2000; Accepted Oct 13, 2000Correspondence to: Y. Kusaka, Department of EnvironmentalHealth, School of Medicine, Fukui Medical University, 23–3,Shimoaitsuki, Matsuoka-cho, Fukui 910-1193, Japan

Hope Island. Marco Polo, who tried to reach the GoldenHope Island by boat, in fact discovered a sea route fromWest Europe to India.

Pneumoconiosis and associated respiratory failure waswell known among gold miners, and was named “Yoroke”which means severe cardiopulmonary failure. It was saidthat on the Sado Island, which had the biggest gold mine,since miners died young, their wives often remarried to atotal of up to seven husbands.

Japan experienced the Meiji Civil Revolution in 1868followed by an industrial revolution and thenwesternization. In the middle of the 1930, pneumo-coniosis was legally recognized as a compensatabledisease and a prevention code for silicosis was introducedamong miners.

After the Second World War, the Government’s effortswere focused on recognition of and compensation forvarious occupational diseases. The Silicosis Law wastherefore passed in 1960, particularly for miners in copper,iron and coal mines suffering from silicosis andsilicotuberculosis.

In the meantime along with the growth of the Japaneseeconomy cases of occupational lung diseases increased,including pneumoconiosis from agents other than silicaand metal. Asbestosis, for instance, arose in Japan andthere was a need for workers exposed to asbestos to besupervised and compensated. Therefore, along withadvances in knowledge of pneumoconiosis in otherindustries, the Pneumoconiosis Law was passed in 19781).

The pneumoconiosis law

This Law covers asbestosis and other types ofpneumoconiosis such as siderosis and mixed dustpneumoconiosis2).

Under this Law, dusty types of work are listed in whichworkers may develop pneumoconiosis. Some types ofdusty work where exposure to metal aerosols take placehave also been designated under the Pneumoconiosis Law(Table 1).

According to the Law, employers responsible for thesetypes of work should provide employees with periodic

Review

2 J Occup Health, Vol. 43, 2001

health examinations including chest x-rays. ThePneumoconiosis Law has designated its own standardchest x-rays, and its coding system is according to theILO classification scheme3).

It is recommended that once a worker’s chestradiograph is judged by the Local Pneumoconiosis Paneldesignated by the Bureau for Labour Standard, Ministryof Labour, to show pneumoconiotic changes, he or sheshould have a health examination annually. Severe casesof pneumoconiosis associated with large opacities of typeC or with severe pulmonary dysfunction are compensated.Other pulmonary conditions such as tuberculosis andbronchitis secondary to pneumoconiosis are also subjectto compensation for treatment and disability.

Special Ordinance on Specified Hazardous Metals

Apart from the Pneumoconiosis Law, there areregulations to protect against metal-related lung toxicity.Among them the Special Ordinance on SpecifiedHazardous Substances deals with metal-related lungcancer, metal fume fever, airway syndrome includingperforation of the nasal septum, bronchial irritation,bronchial asthma and bronchitis due to exposure to metals(Table 2)4).

According to this Ordinance, workers under thesecircumstances shall be subject to health supervision, andhealth examinations targeting specific respiratorydisorders. At the same time, the working environment inwhich these metals are handled shall be monitored interms of metal levels in general air samples and evaluatedby comparing the levels with administrative limitsdesignated by the government according to the WorkingEnvironment Measurement Law5).

Diagnostic criteria for classification of occupationaldiseases including metal-related lung diseases are opento public scrutiny through governmental codes, andlitigation has taken place over these criteria.

Governmental statistics are only limited to lungdiseases related to metals in terms of exposed populationsize, kinds of industries, and prevalence4): Table 3 showsthe prevalence of these diseases recognized amongcurrently exposed workers. There may be negative casereport bias.

Disease recognition codes under the practice andenforcement ordinance of labour standards lawon metals

With respect to other metals, not covered by the

Table 1. Dusty work where there is exposure to metals causing pneumoconiosis according to thePneumoconiosis 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 operationsinvolving grinding or deflashing of rocks, minerals or metals, or cutting of metal by motive powerwith abrasives (except work listed in the preceding item). Work at a site of operations involvinggrinding or deflashing of rocks, minerals or metals, or cutting of metal by motive power withabrasives 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, rawmaterials having carbon for their principal element (hereinafter referred to as “carbonic rawmaterial”), or aluminium foil, by motive power (except work listed in item 3, 15 or 19). Work listedbelow 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 otherinorganic material. Work at a site of operations involving steaming out of a converter or casting ina metal mold is excluded.

No. 18 Work at a site of operations involving scraping off, scratching up, loading or unloading or puttinginto vessels slag or ash adhering to or accumulating inside a furnace, flue or chimney, etc., or in theprocess of the combustion of pulverized ores or in the process of smelting or melting metals or otherinorganic material.

No. 20 Work of cutting metals by means of melting, arc welding of metals or gouging metals with an arcindoors, in the open air, a pit or inside a tank, vessel, pipes or vehicle, etc. Cutting automatically bymeans of melting, or automatic welding indoors is excluded.

No. 21 Work at a site of metal spraying operations.

3Yukinori KUSAKA, et al.: Metals Known in Japan to Induce Occupational Respiratory Diseases

Pneumoconiosis Law or the Ordinance on SpecifiedHazardous Substances, there are Disease RecognitionCodes under the Practice and Enforcement Ordinance ofthe Labour Standards Law, defining occupationalcausation (Table 4)2). Workers exposed to these metalsare not under health supervision specific to relevantdisorders but, once workers develop the relevant disease,workers or their relatives can claim compensation fordisability and for treatment costs. The Practice Code hasrecently been raised so that employers must informemployees about the state of knowledge of hazardousmetals in their workplace and potential health effects.This can be done by occupational health personnel duringperiodic health checks, mainly for age-related andlifestyle-related diseases, which employers are compelledto provide.

Furthermore, any metals which have not beendesignated by the Pneumoconiosis Law, the Ordinance,

or the Codes can theoretically be subjected to recognitionas causing occupational lung diseases and compensation,if patients or their physicians appeal to the LabourStandard Bureau of the Ministry of Labour. This dependson the physicians’ knowledge of the diseases.

Statistics of recognized metal-related lung diseases

Little has been known of the numbers of cases of metal-related lung diseases legally recognized in Japan. Japan’sMinistry of Labour reported the data accumulated during1977 and 1999: 159 chromium-related lung cancers and75 arsenic-related lung cancers or skin cancers. Therewere no cases with nickel-related lung cancer during 1994and 1999.

Exposure standards in Japan

At the same time the Japan Society for OccupationalHealth (JSOH)6) has recommended occupational exposure

Table 2. Metals causing occupational lung diseases designated by Ordinanceon Prevention of Hazards due to Specified Chemical Substanceswith reference to administrative levels (mg/m3) assigned byWorking Environment Measurement Law

Metal Administrative level (mg/m3)

Alkyl mercury compound 0.01 (as Hg)Arsenic trioxide 0.5Beryllium 0.002 (as Be)Cadmium 0.05Chromic acid and its salts, dichromate 0.1 (as Cr)Vanadium pentoxide 0.03 (as V)Nickel carbonyl NDManganese 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 workercovered (1993)

Number of Number of Number of Rate ofworkplaces workers workers positiveconducting examined with positive findings

examination findings to total

Beryllium 53 913 0 0Alkyl mercury compounds 30 117 2 1.7Cadmium 338 6644 64 1.0Chromic acid 2548 26674 238 0.9Vanadium pentoxide 157 2102 4 0.2Arsenic trioxide 174 2759 20 0.7Mercury 303 3492 92 2.6Nickel carbonyl 7 495 0 0Manganese 776 12958 42 0.3


limits (OELs) for various chemical substances overseveral decades. Recommendations with explanatorydocumentation have been made on the basis of globalscientific knowledge and have been regularly renewedwhenever new data have become available. Table 5shows the metals for which the JSOH has maderecommendations, the OELs with reference to targetorgans including therespiratory systems and to classes ofcarcinogenicity.

Epidemiology of metal-related lung diseases:Overviews of overseas and Japanese literature

For centuries metals have been known to be capableof causing human diseases, including pulmonarydiseases7–14). From a toxicological viewpoint, a metalcan be defined as “an element which under biologicallysignificant conditions may react by losing one or moreelectrons to form cations”15). Thus some of the so-calledmetalloids, e.g. Arsenic (As) and Antimony (Sb), areincluded in the subjects for this review.

Although silicates such as talc, mica, and kaolin areassociated with various cations including aluminum (Al),magnesium (Mg), and iron (Fe), these minerals causing“classical” pneumoconioses, the majority of occupationallung diseases, are excluded.

The present review focuses on human data, rather thanon information obtained from animal or in vitroexperimentation. Information which is available instandard texts12–14) has been taken as such, whereas morerecent acquisitions appearing up to 199716–18) areemphasized and referred to more specifically.

Furthermore, we have reviewed all papers publishedup to 1997 in Japan as well as other countries. The search

for this literature covered the period between 1935 and1997. Sensitizing metals such as beryllium, chromium,nickel, cobalt and hard metal, platinum, rhodium,mercury, zirconium and gold were included in a reviewarticle by one of the authors19). Case reports, reports onepidemiological studies, and reports on the mechanismof metal-related lung diseases have been reviewed by oneof the authors. From them, reports of interest foroccupational chest medicine were included in the presentreview.

AluminiumCross-sectional studies have suggested an increased

prevalence of chronic bronchitis and a loss of ventilatoryfunction, mainly forced vital capacity (FVC), inassociation with chronic exposure to aluminium20, 21).These are apparently independent of the overt forms ofother respiratory diseases seen with some of these metalsin steel or from welding. The underlying mechanism isnot fully clarified.

The causative agent of asthma (“potroom-asthma”) andbronchial hyper-reactivity in aluminium smelters (or otherworkers exposed to aluminium salts)22–26) is not known.The condition is not considered to be due to allergicmechanisms, but rather to an inflammatory response toirritation by fluorides, in view of the close relationshipbetween the levels of fluoride exposure and work-relatedasthmatic symptoms observed27).

A recent report has confirmed the presence ofaluminium potroom asthma by means of a positiveresponse in workplace challenge28, 29).

Aluminium exposure has been suggested to have ledto sarcoid-like lung granulomatosis in a patient who hadapparently not been exposed to beryllium30). These casesconfirm that an occupational exposure (also to silicates,such as talc) should always be considered in cases of“sarcoidosis”.

The recent report by Devuyst et al.30) posed theinteresting question as to whether aluminium-inducedpulmonary fibrosis or “aluminum lung” may present inits early stage as a granulomatous lung disease. The veryexistence of aluminum lung has been the subject ofconsiderable controversy31, 32). Indeed, in view of theextensive industrial use of aluminium, lung disease causedby exposure to this metal has been questionable. Onreviewing past literature, Dinman31) concluded thatfibrosis only occurred: 1) in workers who were heavilyexposed to submicron-sized particles from aluminiumplates lubricated with an easily removed lubricant duringthe production of fireworks and explosives; and 2) inworkers involved in the smelting of bauxite for theproduction of corundum abrasive (Shaver’s disease), butwho were perhaps also exposed to crystalline silica.Nevertheless, isolated cases of alveolar proteinosis33) orfibrosis in aluminium welders or polishers30, 34–36) do not

Table 4. Metals hazardous to the respiratory systemdesignated by the Enforcement Ordinance of LabourStandard Law

Metal Pulmonary disorders

Zinc and other metals Metal Fume FeverZinc chloride NS*Cadmium Emphysema, Airway DiseaseChromium NSInorganic mercury NSSelenium NSNickel carbonyl NSVanadium NSArsenic NSBeryllium NSManganese PneumoniaCobalt NSPlatinum NS

*Not specified.


entirely corroborate this conclusion. The physicalcharacteristics of the aluminium particles, notably theirsurface area, or even their possibly fibrous nature37), havebeen suggested as important determinants of theirbioreactivity and hence fibrogenicity.

Mixed dust pneumoconiosis is derived from silicateswith low free silica and other mineral content. Mixeddust pneumoconiotic foci are typically stellate lesionswith slight to moderate fibrosis. In histopathological dataobtained in Japan, aluminium-related pulmonary fibrosishas been described as mixed dust pneumoconiosisaccompanied with interstitial pneumonitis38–41).

As stated previously, pulmonary fibrosis related toaluminium and/or aluminium oxides has been designated

as pneumoconiosis by the Pneumoconiosis Law in Japan.It is possible that case reports included individuals withso-called Shaver’s disease whose typical pathologicalfindings were compatible with granulomatous lungdisease, but to date Shaver’s disease has been neitherreported in Japan nor designated as a recognized disease.

AntimonyAntimony trichloride (SbCl

3) and pentachloride

(SbCl5)13) may lead to inhalation injury, presumably as a

result of damage caused by the halide ion, rather than bythe metal ion. It is worth mentioning that the inhalationof the hydride forms of antimony (stibine, SbH

3) can also

be lethal as a result of fulminant haemolysis, which

Table 5. Occupational exposure limits (OEL) and carcinogenicity class designated by Japan Society for Occupational Healthof metals hazardous to the respiratory system

Metal OEL (mg/m3) Target organs or Class ofpulmonary manifestation carcinogenicity

Arsenic trioxide 0.5 (as As) Systemic toxicity 1Beryllium and compounds 0.002 (as Be) Acute berylliosis 2ACadmium and compounds 0.05 (as Cr) Renal disorder 1Chromium 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 1Cobalt and compounds 0.05 (as Co) Pulmonary fibrosis 2B

Pulmonary function impairmentManganese and compounds except for 0.3 (as Mn for respirable fraction) Neurological disease organic compoundsMercury and compounds except for 0.05 (as Hg) Neurological disease alkyl mercury compoundsNickel 1 Lung cancer 2BNickel carbonyl 0.007 Acute pneumoniaSelenium and compounds 0.1 (as Se, inorganic

compounds except SeH2)Silver and compounds 0.01 (as Ag) Skin diseaseVanadium compounds Asthmatic bronchitis Vanadium oxide fume 0.1 Vanadium oxide dust 0.5 Ferrovanadium dust 1Zinc oxide fume 5 Metal feverAlumina, aluminum 0.5 for respirable fraction

2.0 for total portion Pulmonary fibrosisIron oxide 1 for respirable fraction

4 for total portion Pneumoconiosis

Titanium oxide 1 for respirable fraction4 for total portion Pneumoconiosis

Zinc oxide 1 for respirable fraction4 for total portion Pneumoconiosis


sometimes manifests itself initially as dyspnoea42). Thisis not the case for insoluble antimony trioxide.

Antimony is known to cause “benign” pneumo-coniosis43, 44).

ArsenicIt is worth mentioning that the inhalation of the gaseous

hydride forms of arsenic (arsine, AsH3) can also be lethal

due to the mechanism of fulminant hemolysis45, 46).Epidemiological and experimental studies have

established the carcinogenic risk of exposure to inorganicarsenic compounds47–51). In recent years lung cancer, atan odds ratio as high as 15.2, was reported for arsenicexposed populations52). In another study, SMR as highas 3.73 was found in both a case-control study and acohort study made by the same authors53, 54). A recentreview of occupational lung carcinogens has reportedrelative risks of lung cancer due to arsenic with referenceto the number of exposed workers55).

This is also the case for other occupational exposuresto arsenic, such as in the manufacture or spraying ofarsenic pesticides56, 57). By contrast, no excess lung cancerwas noted in the study by Enterline et al.58) for smelterswhose exposures were estimated to be at the currentOSHA level, 10 ug/m3.

In Japan, several areas with arsenic mines and refinerieshave been recognized as environmentally-polluted sitesaccording to Law for Prevention of Public Pollution. Bothworkers and residents have been found there to be victimsof arsenic. It was reported, for example, that the residentsin an area producing the most arsenic in Japan also hadlung cancer highly associated with skin cancer59, 60).

BariumBaritosis, a benign pneumoconiosis, has been

associated with exposure to barium12–14).

BerylliumPast literature13) on accidental and non-accidental

exposures shows that exposure to fumes or dustscontaining beryllium is capable of causing chemicalpneumonitis or acute airway irritation. A cross-sectionalstudy has also suggested an increased prevalence ofchronic bronchitis and loss of ventilatory function, mainlyforced vital capacity (FVC), in association with chronicexposure to beryllium61), although another study did notreach the same conclusion62).

Berylliosis or chronic beryllium disease (CBD) is wellknown for its striking histological and clinicalresemblance to sarcoidosis. The clinical, epidemiologicaland experimental aspects of the disease have recently beenreviewed63–65). Apart from the extraction and primaryrefining industry, beryllium exposure is an occupationalrisk in many sectors of modern industries, such as aircraftand ae rospace , e l ec t ron ic s , compu te r s and

communications, where beryllium may be found in alloys(often with copper) or in ceramics. However, it isimportant to realize that scrap metal refiners66), non-ferrous metal welders, dental technicians, laboratorymaintenance or transport workers may also be exposedto an often unsuspected but significant risk. Contactswith beryllium-workers who brought factory-dust to theirhomes caused a classical para-occupational example ofchronic berylliosis67).

The differential diagnosis between chronic berylliumdisease and other interstitial lung diseases, mainlysarcoidosis, rests essentially on the proof of exposure,which may be difficult to obtain solely on the basis ofoccupational history. The finding of beryllium inbiological samples confirms present (urine) andsometimes past exposure (lung tissue, lymph nodes)68).Specific blast transformation test of lymphocytes (LTT)in response to culture with beryllium appears to be highlyspecific, but not very sensitive in peripheral bloodlymphocytes, although recent data suggest a greatimprovement in sensitivity in lymphocytes frombronchoalveolar lavage69). Saltini et al.70) showed thatmajor histocompatibility complex class II antigens andfunctional interleukin 2 receptors were necessary forCD4+ lung T cells from patients with chronic berylliumdisease to proliferate in vitro in response to stimulationby beryllium.

This and other experimental evidence strongly suggestthat beryllium triggers a cell-mediated immune response,thereby explaining the low incidence and high variationin the time of onset of disease in exposed workers.Moreover, an HLA-DPB1 (HLA-DPB1 glutamate 69)allele was suggested to be closely associated with chronicberyllium disease71).

This marker could be useful in screening for thoseworkers who should be monitored for evidence ofsensitization or disease. However, the chemical andphysical forms of beryllium probably also play a role,and this remains to be clarified.

The Japanese literature on CBD including the firstreport by Izumi et al.72) was reviewed by one of theauthors19).

Compared to other developed countries, Japan hasexperienced fewer cases (n=25) with CBD; five of thesedied from complications of CBD including pulmonaryinfection and pulmonary failure. A reason for the lownumber of cases is believed to be the geneticbackground72). All of these cases dealt with berylliumoxide (BeO) which is said to be less toxic or potent insensitization than beryllium salts.

According to the regulations in Japan as well as theU.S.A., workers handling beryllium alloy containing Beat less than 3% are not subjected to periodic healthexaminations. Moreover, beryllium-copper alloy has beenrecognized as being less potent in initiating CBD than


BeO but in recent reports in Japan, Be-Co alloy with Becontent less than 3% caused CBD in two cases73, 74). Thefindings and test results including blood-Be-LTT for thesecases matched the criteria of the U.S.A. Beryllium CaseRegistry75).

Follow-up studies have revealed that individuals withchronic beryllium disease have a higher incidence of lungcancer than the general population76). A thorough reviewarticle77) has recently been published on the carinogenesisof beryllium, which is now assigned to category 1 byIARC49).

CadmiumCadmium and other metals bind to metallothionein, a

low-molecular weight protein rich in sulphydryl (SH)groups. This process also plays a role in the defenseagainst cadmium, but it eventually leads to the retentionand progressive accumulation of cadmium in varioustissues including probably the lungs78). Cadmium iscapable of causing both lung and kidney changes,probably depending in part on the route of exposure.

The most severe form of acute pulmonary damage ischemical pneumonitis which classically follows theinhalation of cadmium fumes13). Cadmium is present inseveral areas of metallurgy. From a practical viewpoint,it is important to be aware that risks in relation to cadmiumpneumonitis are: 1) that liberation of cadmium oxidesfrom welding, silver brazing, or burning of cadmium-containing alloys79) or from the smelting of lead80), whichoften contain significant levels of cadmium; 2) thatexposure to toxic levels of cadmium fumes does notnecessarily lead to immediate respiratory symptoms.Indeed respiratory distress is usually delayed for severalhours until severe non-cardiogenic pulmonary oedemadevelops13). A follow-up study81) showed that cadmiumchemical pneumonitis leads to pulmonary fibrosis.

For instance in Japan, there have been reported casesof acute interstitial pneumonitis resulting from inhalationof cadmium fumes at high levels82–85). One report81)

contained data on airborne concentrations of a numberof metals generated during welding.

Symptoms suddenly developed several hours afterburning cadmium alloys (Fig. 1), presenting with fever,dry cough, general malaise and so on. One day afteronset, diffuse shadows were seen on chest x-rays (Fig. 2)and lung biopsy specimens revealed interstitialpneumonitis with infiltration of lymphocytes andeosinophils [Personal communications from Professor R.Tokunaga].

Exposure to cadmium also relates to metal fume fever,a malaria-like or influenza-like reaction consisting offever, chills, and malaise, sometimes associated with X-ray abnormalities86).

The as yet controversial issue of whether chroniccadmium fume inhalation leads to pulmonary

emphysema87, 88) has recently been settled by the resultsof a study of a large group (n=101) of workers and ex-workers from a cadmium factory in England89). This studyshowed a clear excess of functional (ventilatory functionand diffusing capacity) and radiological signs ofemphysema in the exposed subjects compared toappropriate controls. Evidence of a causal role forcadmium was strengthened by the existence of a positiveexposure/response relationship with exposure beingestimated from both past hygiene measurements and theinternal (liver) cadmium burden. Moreover, thesignificance of these findings has been borne out by thedemonstration of increased mortality from non-malignant

Fig. 1. A worker melting battery alloy for reusing cadmiumcontained wore only cotton gauze mask. Metal fumeis seen to come out from the furnace.

Fig. 2. His chest radiograph taken one dayafter onset of respiratory symptomsshowed diffuse reticular nodularopacities throughout both lungs.


respiratory disease in cadmium-exposed workers90, 91).The mechanism of cadmium-induced emphysema is stillnot elucidated. Animal studies suggested that fibrosis,rather than alveolar wall destruction, precede thedevelopment of emphysematous lesions92–94).

There are also epidemiological and experimentalindications that cadmium is carcinogenic in the humanlung47–50). Increased mortality from lung cancerattributable to cadmium has been shown in some91, 95, 96),but not all studies of cadmium exposed workers97–99). Arecent review on occupational lung carcinogens hasreported relative risks of lung cancer due to cadmiumwith reference to exposed workers in a number ofindustries55).

ChromiumExposure to chromic acid during chrome-plating leads

to upper airway lesions, particularly nasal septalulceration and perforation, which, in a recent study, wasfound in an astonishing two thirds of subjects exposed tomoderately high peak levels of Cr100).

Chromium is reported to cause asthma in chromiumplating workers, mostly in case reports101, 102). Shirakawaet al.103) demonstrated the existence of a specific IgEantibody to chromium-human serum conjugate in a 50-yr-old male engaged in metal plating.

The assay for the type I immediate reaction incombination with a bronchial provocation test is expectedto clarify the basic mechanism underlying chromium-related lung sensitization.

Simultaneous exposure to sensitizing metals (Ni andCr) takes place in electroplating and the question of across reaction between the two metals or simultaneoussensitization to the metals has been debated104).

Epidemiological and experimental studies have clearlyestablished the carcinogenic risk from exposure tochromium, in some of its chemical forms. A greatlyincreased risk of lung cancer has also been demonstratedfor workers in primary chromate production and in thechromate pigment industry47–51, 55, 105–108).

In Japan lung cancer was observed to occur in asignificantly greater proportion of chromate workers thanin the Japanese general population106, 109).

Ishikawa et al.110) demonstrated that lung cancer fromchromate tends to develop on the bronchial bifurcationsin association with increased deposition at that site.Bronchial dysplasia also occurs at this site, and mucouscells express the p53 oncogene product, often followedby squamous cell lung cancer. This latter finding maysupport the dysplasia-carcinoma sequence theory.

There are several recent studies showing increased lungcancer mortality in welders and platers111–115). Theexposure in these jobs is probably to the carcinogenicform of chromium, i.e. hexavalent chromium116), althougha recent report suggested the potential for insoluble

(trivalent) chromium to cause lung cancer117).Epidemiological studies of the carcinogenic risk ofexposure to chromium during metal plating or duringstainless steel welding have been considered inconclusive.

CobaltCobalt (Co) is an essential metal in many coenzymes

and enzymes. Dysfunction in enzymatic processes, e.g.megalocytic anemia, may, therefore, result from Codeficiency. However, high doses of the essential metalmay cause substitution and mimicry as inappropriatecompounds.

Another toxicologically relevant consequence of cobaltbinding to proteins is the acquisition of anitigenicity, sothat cobalt sensitizes probably by mechanisms similar tothose of other reactive low molecular weight moleculesand metals which may function as haptens.

The biological activity and toxicity of some metals isalso greatly influenced by their ability to change theirredox state by loss or gain of electrons. Transition metalsare electronically stable in more than one oxidation state.As a result of this property, transition metals playimportant roles in catalyzing biological oxidationreactions. Of the transition metals, iron and, to a lesserextent, copper have been extensively studied because oftheir implication in many pulmonary and non-pulmonarydisease processes by virtue of their ability to enhance theproduction of toxic free-radical species of oxygen118–120).In pulmonary toxicology, free-radical oxygen toxicity,which seems always to involve metal catalysis121, 122), isconsidered to be a mechanism for the effects ofhyperoxia123), paraquat124), nitrofurantin125) and asbestos126).Cobalt performs all of these activities, and cobaltaccumulated in the lungs enhances hyperoxia by thismechanism127).

Cross-sectional studies have suggested an increasedprevalence of chronic bronchitis and a loss of ventilatoryfunction associated with chronic exposure to cobalt128, 129).

Cobalt cause asthma130–136) with evidence of theformation of specific (IgE) antibodies to protein-conjugates of cobalt (Co)136–138), suggesting that asthmaticreaction to the metal involves an IgE-mediated response.Among workers exposed to hard metal containing eithercobalt or nickel as a binding matrix, cobalt-inducedbronchial asthma and nickel-induced asthma areprevalent138). Immunological mechanisms includeimmedia te type ( IgE-media ted) and ce l lu larhypersensitivity138, 139), and questions relating to the crossreactivity between the two metals versus simultaneoussensitization to the metals has been debated. In additionto sensitization to cobalt, atopy reflected in positiveantibodies to common environmental antigens has beenshown to be an independent risk factor for asthma amonghard metal workers.

Airborne cobalt levels below the current standard limit


for cobalt were shown to carry increased risk140).A case of asthmatic sensitization to cobalt was recently

diagnosed in a man working in the animal feed industry.This individual was involved in the addition of cobaltsulphate to the feed used for the prevention of cobaltdeficiency in cattle141) (Dr. E. Stevens, personalcommunication, unpublished).

The condition known as hard-metal lung disease hasbeen the subject of renewed interest in recent years,particularly with regard to the causative role ofcobalt142–144). Hard-metal or cemented tungsten carbide(WC) is found in tools used for high-speed cutting,drilling, grinding and polishing of other metals or hardmaterials. In a minority of workers involved in themanufacture or utilization of these tools, bronchial asthmaand diffuse pulmonary fibrosis have been reported invarious parts of the world132–134, 145–152). On the basis ofrelatively crude animal data153) showing little toxicity fromthe main constituent of hard-metal, i.e. tungsten carbide,the consensus is that tungsten carbide is not the agentresponsible for the fibrosis, but that it is more probablydue to the binding agent, i.e. cobalt.

The pneumonitis is often of the desquamative type,and in the subacute forms it appears to be mainlycharacterized by the presence of multinucleated giantcells. Indeed it has been proposed that giant cellinterstitial pneumonitis (GIP) may be pathognomonic forhard-metal exposure154). The aetiological role of cobaltin giant cell interstitial pneumonitis has been stronglysupported by the observation of several cases of a diseaseidentical to hard metal lung disease in diamond polishers,who used polishing discs made with cobalt155, 127). Theterm cobalt-lung has therefore been proposed155).

The mechanism of the pulmonary toxicity of cobalthas not yet been elucidated143, 156). Unlike the classicalpneumoconioses in which the lung burden of dust seemsto be the predominant factor in causing the disease (evenif host factors do also play a role in these diseases), severalfeatures of cobalt-lung suggest some form ofhypersensitivity or host idiosyncrasy, perhaps analogousto the situation observed with beryllium. Indeed for bothberyllium and cobalt the dose-response relationship isnot straightforward: on the one hand, the attack rate ofthe disease appears to be determined by the extent ofexposure, but on the other hand, within similarly exposedworkforces only a small minority of sometimes veryyoung subjects, with relatively little cumulative exposure,are affected155). The known dermal sensitizing potentialof cobalt and the existence of cobalt-asthma suggest thathypersensitivity to cobalt may cause the fibrosingalveolitis. Conditions more usually considered to be cell-mediated157), such as alveolitis155, 134), and asthmacombined with alveolitis158), have been reported.However, this is by no means proven, and other optionsmust be considered, such as oxygen free-radical mediated

toxicity resulting from the ability of cobalt to promotethe Fenton reaction127).

In view of the widespread use of cobalt in alloys,magnets, special corrosion resistant steels, pigments,plastics and many other applications141) it is important todiscover the determinants of the toxicity of this metal.Both the chemical and physical forms of cobaltcompounds that are “intrinsically” harmful, and the extentto which host or other factors may render cobalt toxicrequire investigation. It is indeed remarkable that no lungfibrosis has been reported in workers involved in themining or refining of cobalt159), with the exception of fourcases seen before World War II in a Germany factorymaking cobalt carbonate160).

Japan is now the third largest producer of hard metaltools in the world. An article by one of the authors161),reviewing all the Japanese literature on hard metal-relatedbroncho-pulmonary diseases, demonstrated theprevalence of hard metal asthma to be 5.3%.

Apart from interstitial pulmonary fibrosis probablysecondary to interstitial pneumonitis, cases of mixed-dustpneumoconiosis have been demonstrated to be due to amixture of tungsten carbide dusts and grinding wheeldusts162).

This finding is consistent with a report fromSwitzerland where imported hard metal tools are groundfor reuse163).

There are also epidemiological and experimentalindications that cobalt may be carcinogenic in the humanlung47–50). Cobalt is a 2A carcinogen according to theIARC criteria49). In Germany, cobalt is listed as one ofthe carcinogenic substances for which 5 mg/m3 is themaximum acceptable concentration164).

Dental technician pneumoconiosisDental technicians are at risk of pneumoconiosis165, 166),

as shown in Fig. 3. Intensive monitoring data on airbornedusts at dental technology workplaces have beendescribed by Fukuzawa167): some toxic metals includingcobalt, chromium, and nickel, and mineral dusts includingasbestos and silicates were shown to be present. Somedental pneumoconiosis may arise from excessiveexposure to dust produced from the machining ofvitallium, an alloy consisting of chromium-cobalt-molybdenum168). Histologically this fibrosis is manifestedby dense interstitial fibrosis around dust deposits, withoutgiant cells. Vitallium dust is, however, not the sole dustto which dental technicians may be exposed, and otheragents such as alginate169), beryllium, hard-metal and silicamay also cause lung disease in these workers165, 166, 170, 171).

Dr. Nanbu et al. including one of the authors, Kusaka,reported a technician who presented with interstitialpneumonitis of giant cell type (GIP) (Histopathologicalfindings not shown, HRCT images shown in Fig. 4). Thiscase showed a positive lymphocyte stimulation test with


cobalt (stimulation index, SI; 4.1) (Fig. 5), while the samelymphocytes from the peripheral blood reacted positivelyto purified protein derivative of tuberculin (SI 7.4) [Dr.Nanbu and Dr. Kusaka, personal communication]. Thisevidence might raise the possibility that some dentaltechnicians pneumoconiosis is compatible with cobaltlung which has been designated as interstitial pneumonitisfor diamond polishers using cobalt discs155).

CopperCopper (Cu) is also an essential metal for coenzymes

and enzymes. The transport and accumulation of copperis often the result of its ability to interact with ligandssuch albumin, and ceruloplasmin whose abundanceprobably constitutes a safeguard against the toxicity offree copper ion118).

Copper is a transition metal which plays an important

role in catalyzing biological oxidation reactions. Copperhas been studied because of its implication in manypulmonary disease processes by virtue of its ability toenhance the production of toxic free-radical species ofoxygen118). In pulmonary toxicology, free-radical oxygentoxicity, seems always to involve metal catalysis121, 122).However, inhaled metals have so far received rather littleattention in this connection.

A more benign condition following exposure to highconcentrations of copper fume is metal fume fever172, 173).This condition is described more precisely in the sectionon zinc.

In Japan increased mortality from lung cancer has beenreported from a cohort study associated with a net casecontrol study at copper finery plants174, 175). The proportionof Kreyberg group I among these cases with lung cancerwas significantly larger than that in the population-based

Fig. 3. A dental technician grinding implant materialsincluding metals. Local dust ventilation utility isseen beside him.

Fig. 4. A High Resolution Computed Tomography (HRCT)picture compatible with interstitial fibrous thickeningaccompanied with honeycombing from a dentaltechnician having diffuse shadows on chest x-rays.

Fig. 5. Positive lymphocyte proliferation with cobalt antigen in a pneumoconiotic dentaltechnician.


cancer registries in Japan176). These findings suggestedthat squamous and small cell carcinoma was prominentand appeared to be environmentally related tobronchogenic carcinomas.

Workers engaged in refining copper ores are exposedto arsenic at the same time. The carcinogenicity of arsenichas been clearly established in epidemiological andexperimental studies47–51, 55). Thus, the relationship ofarsenic to increased risks of lung cancer in coppersmelting workers is unequivocal.

IronIron is another transition metal involved in catalyzing

biological redox reactions. Studies on implication of ironand copper in many pulmonary disease processes havefocused on their ability to enhance the production of toxicfree-radical species of oxygen118–120). In pulmonarytoxicology, free-radical oxygen toxicity seems always toinvolve metal catalysis121, 122).

Iron is an essential as a coenzyme for many enzymes.Transferrin, ferritin, and albumin are the main transportor storage proteins for iron, and their abundanceprobably constitutes a safeguard against the toxicity offree iron118, 119).

Occupational exposure to iron occurs during ironmining and related operations, during iron refining andat various stages in steel making. Exposure also occursduring welding, cutting and abrading of iron-containingmaterials, as well as during the manufacture or use ofiron-containing abrasives (such as emery). Studies ofthe effects of iron exposure on ventilatory function ingroups such as “steel workers”177–180) or “metalwelders”181–190) have been largely negative, inconclusiveor showing only small effects, despite the generallyconsistent finding of increases in the prevalence of chronicbronchitis, as founded by means of questionnaires.Nevertheless, for the methodological reasons alluded toabove, one should not conclude that there are no specificwork processes within these broad categories which entaila risk of significant obstructive respiratory impairmentin susceptible subjects.

Of the “benign” pneumoconioses the most frequentand best studied is siderosis, which is caused by theinhalation of iron compounds12, 13, 16). Siderosis is a“radiological disorder” in that it manifests itself by thepresence of small, very radio-dense opacities withuniform distribution throughout the lungs, but withoutformation of conglomerates. With cessation of exposurethe radiographic opacities may gradually disappear. Puresiderosis is not associated with respiratory symptoms orfunctional impairment, and does not predispose totuberculosis. However, it is important to realize thatexposure to silica or asbestos is not uncommon in manyjobs that involve exposure to iron, thus giving rise tomixed dust fibrosis or to asbestosis, and these two

condit ions do have associated morbidity andcomplications. Moreover, the view that the symptomaticinterstitial fibrosis which is sometimes found in welders(welders’ pneumoconiosis), is simply siderosis withexisting silicosis has recently been challenged on thegrounds that the pulmonary silicon content in such casesdid not differ from that in control lungs191).

There are epidemiological and experimental indicationsthat iron, or occupations associated with iron exposuremay be carcinogenic for the human lung47–50). Increasedrisk of cancer and mortality have been definitely shownin epidemiological studies to be associated with exposureto steel welding192, 193). These studies of iron and steelfoundry workers have consistently shown an increasedrisk of lung cancer, but this may be due to the emissionof polycyclic aromatic hydrocarbons as pyrolysis productsof organic materials used194, 195).

LeadLead is known to be toxic for many organs. Although

it is absorbed mainly by inhalation into the body, therehave been very rare reports on respiratory disorders dueto the exposure to lead. Lead miners probably associatedwith silicosis were shown to accumulate lead in thelungs196). A cohort study of lead smelter workers inSweden described increased incidence of lung canceramong them, with dose-response relationships197). Thecarcinogenicity of lead, however, has not been confirmedyet.

LithiumLithium hydride (LiH) and phosphine (PH

3) have been

reported to cause pulmonary oedema13).

ManganeseManganese (Mn) is essential as a coenzyme for many

enzymes. Exposure to high concentrations of the fumesof manganese can lead to acute pulmonary manifestations,the outcome of which can range from complete recoveryto death, depending on the agent involved.

Past literature13) on accidental and non-accidentalexposure shows that exposure to fumes or dustscontaining manganese is capable of causing chemicalpneumonitis or acute airway irritation.

Cross-sectional studies have also suggested anincreased prevalence of chronic bronchitis and a loss ofventilatory function, sometimes mainly of forced vitalcapacity (FVC), associated with chronic exposure tomanganese198). Apparently these conditions ariseindependently or due to the other overt forms ofrespiratory disease seen with some of these metals.

MercuryPast literature13) and recent reports of accidental and

non-accidental environmental exposure show that


exposure to fumes or dusts containing mercury199–202) iscapable of causing chemical pneumonitis or acute airwayirritation. Skin absorption of mercury has been shown tobe involved in the induction of systemic diseasesincluding pulmonary manifestations202).

NickelPast literature13) and a recent report of accidental and

non-accidental exposure show that exposure to fumes ordusts containing, nickel carbonyl [Ni(CO)

4]203) is capable

of causing chemical pneumonitis or acute airway irritation.One of the toxicologically relevant consequences of

metal binding to proteins is the possible acquisition ofanitigenicity, i.e. haptenization. As stated above withrespect to hard metal disease, nickel and cobalt, whichboth belong to element group IV, cause asthma, mediatedby type I allergic reaction of the bronchial tree.

Nickel has been known to cause asthma mostly in casereports204–208). There is evidence of formation of specific(IgE) antibodies to protein-conjugates of nickel (Ni)205,

206, 208), suggesting that asthmatic reaction to these metalsalso results from an IgE-mediated response. Exposureto Ni, Cr, or Co takes place in occupational settings suchas hard metal industries and electroplating104, 139). Crossreactivity between the two metals and simultaneoussensitization to the metals has been debated. It has alsobeen pointed out that occupational asthma related toexposure to these metals occurs within the currentexposure limits104, 138, 140, 161).

New evidence has recently appeared from Japan onthe potential of nickel to provoke eosinophilicpneumonia209). In this case, nickel fumes were inhaledduring a training course for welding and after a couplehours the pneumonia confirmed by BAL developed. Aprovocation test with nickel sulphate solution caused arecurrence of the pneumonia. Evidence of a positiveprovocation test suggests underlying hypersensitivity tonickel. To date, reports on eosinophilic pneumonia relatedto exposure to nickel, compatible with Loeffler’sSyndrome in terms of histopathological abnormalitieshave been made in a few cases210–212).

Another hypothesis on the role of nickel is in catalyzingbiological oxidation reactions in the exposed lung. Likeiron and copper which cause pulmonary disease processesby virtue of their ability to enhance the production oftoxic free-radical species of oxygen118–120), nickel mayexert toxicity by the same mechanism.

Occupational exposure to nickel in nickel smelters andrefineries is also unequivocally associated with anincrease in cancer of the lung and the nasal sinuses213, 214).According to the IARC and a recent study by Andersenet al.215), all nickel compounds except metallic nickel havebeen classified as carcinogenic to humans by IARC49).Again the situation in nickel-using industries is less clear,but a cancer hazard has not been excluded. A recent

review on occupational lung carcinogens has reportedrelative risks of lung cancer due to metals nickel withreference to the number of exposed workers for eachcarcinogenic metal55).

The interaction of metals including nickel withfunctional groups on macromolecules is an importantmechanism for their toxicity and their carcinogenicity216, 217).Several metal ions react strongly with free SH groups,thereby possibly inhibiting active centres of enzymes,coenzymes or membrane bound receptors. Directinteraction of metals with deoxyribonucleic acid (DNA)is one of the possible mechanisms of metal carcinogenesisas well as of the chemotherapeutic effects of some metalcomplexes.

PlatinumPlatinum sensitizes probably by mechanisms similar

to those of other small reactive organic molecules, i.e.haptenisation.

In recent review articles218–221), platinum is clearlyshown to cause bronchial asthma. The complex halidesalts of platinum (Pt) provide a unique example of asituation in which a very considerable proportion ofexposed subjects may become sensitized218). There isgood evidence for an immunoglobulin E (IgE)-mediatedmechanism in plat inum sal t asthma 218, 222, 223).Nevertheless, the detection of Pt-specific antibodies byradioallergosorbent test (RAST) is less sensitive than skintesting in the clinical diagnosis of Pt-hypersensitivity,possibly because of a frequent increase in total IgE223).Smoking and atopy have been demonstrated to bepredictors of platinum asthma like cobalt asthma224–226).

Exposure to other irritants such as ozone may well proveto be a more important determinant in interaction withatopy in the occurrence of allergic platinum asthma227).

Shima et al.228) reported asthma cases in associationwith the production of platinum-alloy sensors at Japanesefactories.

Rare earth metalsExposure to rare earth metals (or lanthanides), of which

cerium is the most abundant element, has also beenassociated with interstitial fibrosis in a small number ofsubjects229–233). Rare earth metals are essential compoundsof carbon arc lamps used for photoengraving, and themajority of cases of this pneumoconiosis have beendescribed in photoengravers. Rare earth metals are alsoused in the fabrication and polishing of glass. Onehistological report229) mentions the presence ofgranulomatous interstitial alterations, although this is notmentioned in the other available pathological descriptionsof cerium-pneumoconiosis233).

RhodiumRhodium, belonging to the same element group as


platinum, has been assumed to be as potent as platinumin terms of bronchial and skin sensitization. A reportfrom Japan suggested a role of rhodium in thesensitization of workers who handled rhodium replacingplatinum as a plating agent234).

TitaniumTitanium tetrachloride (TiCl

4)235) may lead to inhalation

injury presumably as a result of damage caused by thehalide ion, rather than by the metal ion.

Cross-sectional studies have suggested an increasedprevalence of chronic bronchitis and a loss of ventilatoryfunction associated with chronic exposure to titaniumdioxide236, 237).

Titanium, otherwise considered as virtually non-toxic,has been suggested as an aetiological agent in a case ofgranulomatous lung disease. This was based on thepresence of metallic particulates containing titanium inlung granulomas and of a positive blood LTT to titaniumchloride, and not to other metals tested, includingberyllium238).

Similar histological findings including granulomatousabnormalities, slight focal fibrosis, alveolar septalthickening, and interstitial infiltration with lymphocytes,were reported in one Japanese case with occupationalexposure to organic titanium (tetra-butyl-titanium). Theelement analysis with electron x-ray dispersive analysisdetected the presence of organic titanium compound in afibrotic lung239).

UraniumUranium hexafluoride (UF

6)240) may also cause

pulmonary injury after inhalation possibly as a resultof damage caused by the halide ion, rather than by themetal ion.

VanadiumAcute tracheobronchitis with persisting bronchial

hyper-reactivity241) can be caused by exposure tovanadium pentoxide (V

2O

5), a significant risk associated

with the cleaning of oil tanks (“boilermaker ’sbronchitis”)242, 243).

WeldingChronic obstructive lung disease may result from

welding. Studies of the effect on ventilatory function ingroups such as metal welders181–190) have been largelynegative, inconclusive or showing only small effects,despite the generally consistent finding of an increase inthe prevalence of chronic bronchitis, defined by aquestionnaire. However, for the methodological reasonsalluded to above, one should not conclude that there areno specific work processes within these broad categorieswhich entail a risk of significant obstructive respiratoryimpairment in susceptible subjects.

There are several recent studies showing increased lungcancer mortality in welders111, 112). Epidemiologicalstudies of the carcinogenic risk in exposure to chromiumduring stainless steel welding have been consideredinconclusive.

ZincZinc (Zn) is an essential metal in coenzymes and

enzymes. Deficiency states may therefore cause problemsbut also high doses of the essential metal caused bysubstitution and mimicry of essential ions byinappropriate compounds.

Cases of adult respiratory distress syndrome haverecently been reported in military and civilian personnelaccidentally exposed to smoke bombs which liberate zincchloride (ZnCl

2)244, 245).

A more benign condition after exposure to highconcentrations of metal fumes such as those of copper,manganese, zinc, and cadmium, is metal fume fever172, 173).Among these metals, zinc is the best known causative agentfor metal fumes because of wide application in variousindustries. This condition, of which there are severalsymptoms13), is an influenza-like or malaria-like reactionconsisting of fever, chills and malaise with relatively mildrespiratory symptoms, and classically little or no X-ray orfunctional abnormalities, although this is not always thecase246). The symptoms, often accompanied by a sweetmetallic taste in the mouth, usually begin at home a fewhours after a heavy exposure to metal oxides, e.g. afterwelding in a confined space, and they then subsidespontaneously. Leucocytosis is present during the acutestages of the illness. A recent report of bronchoalveolarlavage findings in a case of zinc fume fever showed markedneutrophil infiltration, and appropriately posed the questionof how such spectacular inflammatory events remain soself-limited247). A strange feature of this syndrome is theoccurrence of tolerance: symptoms only appear whenexposure takes place after a period of days withoutexposure and they do not appear on subsequent days.

The exact pathogenesis of metal fume fever is poorlyunderstood. In some instances allergic mechanisms maybe involved248), but then metal fume fever may be amisnomer or it may be superimposed on bronchial asthmaor hypersensitivity pneumonitis249). There is a strikingresemblance between metal fume fever and the organicdust toxic syndrome, which occurs after heavy exposureto organic dust contaminated with micro-organisms250).Both syndromes have a similar clinical course with fever,leucocytosis, acute transient neutrophilic alveolitis251) andoccurrence of tolerance. Their similarities indicatecommon pathogenic mechanisms.

With appropriate environmental control measure, casesof metal fume fever are fortunately not common any more,but the disease has certainly not disappeared and ispresumably often overlooked as a simple viral infection.


Metal fume fever is said to not lead to suquelae, but thishas not been adequately investigated.

In recent reports252, 253) of asthma in subjects weldinggalvanized metal, sensitization to zinc was suggested;but the possible presence of other metals such as Co,which can be present in galvanized metal141), was notinvestigated. Another suggestion of hypersensitivity tozinc is from a recent report on hypersensitivitypneumonitis in a smelter exposed to zinc fumes254). Thesereports still show a lack of a specific allergic mechanismin zinc mediated lung injury.

ZirconiumZirconium tetrachloride (ZrCl

4)13) may lead to

inhalation injury, presumably as a result of damage causedby the halide ion rather than by the metal ion. Zirconiummay cause granulomas in human skin, but has not beenassociated with granulomatous or fibrotic lung diseasein human subjects255).

SummaryThe metals causing occupational respiratory diseases

are listed in Table 6 with reference to disease entities.

Carcinogenicity of metals is defined according to IARCcriteria49).

Diagnosis, treatment and prevention—Research perspectives—

Diagnosis of metal-related occupational pulmonarydiseases, as with other occupational diseases, is dependenton the level of knowledge of the physician who first seesthe patient. Knowledge leads to recognition. Carefulinquiry into occupational history is the first step in makinga correct diagnosis.

Respiratory symptoms are not pathognomonic for themetal-related pulmonary diseases. As stated above, metalfume fever is easily overlooked because it is so muchlike influenza or the common cold. The presence of work-related asthmatic symptoms is a guide to diagnosis.However, their absence does not necessarily denyoccupational origin, because failure to remove relevantworkers with occupational hypersensitivity from the workleads to persistent and fixed bronchial obstruction.

Pulmonary image techniques are again not specific toeach disease entity. Histopathological diagnosis ofautopsy and biopsy is useful for interstitial lung diseases

Table 6. Occupational respiratory diseases related to inhalation of metals

Metal Respiratory disease

Aluminium (Al) Asthma, Granulomatous fibrosis (Shaver’s disease)Antimony (Sb) Acute pneumonitis, PneumoconiosisArsenic (As) Lung cancer, Acute pneumonitis (AsH3)Barium (Ba) PneumoconiosisBeryllium (Be) Acute pneumonitis, Chronic beryllium disease, Lung cancerCadmium (Cd) Acute pneumonitis, Metal fume fever, Emphysema, Lung cancerChromium (Cr) Nasal septal perforation, Asthma, Lung cancerCobalt (Co) Chronic bronchitis, Asthma, Interstitial pneumonitis (Hard-metal

lung disease, Cobalt lung)Copper (Cu) Metal fume feverIron (Fe) Pneumoconiosis (Siderosis)Lead (Pb) Lung cancer?Lithium (Li) Pulmonary oedema (LiH)Manganese (Mn) Metal fume fever, Acute pneumonitisMercury (Hg) Acute pneumonitisNickel (Ni) Asthma, Eosinophilic pneumonia, Lung cancer

Acute pneumonitis {Ni2(CO4)}Platinum (Pt) AsthmaRare earth metal (Cerium, etc.) PneumoconiosisRhodium (Rh) AsthmaTitanium (Ti) Chronic bronchitis, Granulomatous lung diseaseUranium (U) Acute pneumonitisVanadium (V) TracheobronchitisZinc (Zn) Respiratory disease syndrome (ZnCl2), Metal fume fever, Asthma,

Hypersensitivity pneumonitisZirconium (Zr) Acute pneumonitis


related to metals, such as granulomatous lung disease, ifelemental or metal analysis of the lung samples isavailable. Giant cell interstitial pneumonitis ispathognomonic for hard metal lung or cobalt lung.Allergoimmunological tests such as lymphocytetransformation test with metal antigens and specificantibodies are of high specificity, but of less sensitivity,although these test are generally still to be regarded “asadjuncts to clinical diagnosis, and not as independentproof of causation or of diagnosis”256). Whenhypersensitivity is suspected, bronchial challenge testingmay be justified257). Bronchoalveolar lavage can containmore lymphocytes responding to metal antigens thanperipheral lymphocytes. Bronchoalveolar lavage (BAL)is increasingly used, mainly in the assessment ofinterstitial lung disease258). Begin259) has recentlyadvocated the use of this technique for pneumoconiosisin order to eliminate other causes of lung disease, todocument mineral dust exposure, to support other clinicalinformation, and to investigate the biological mechanismsof these diseases. The latter were found in BAL fromsubjects with cobalt-related fibrosing alveolitis155).Analysis of mediators of inflammation and fibrosis260),cellular subtypes and responsiveness of lymphocytes toin vitro challenge69) are all potentially useful. The toxiceffects of metallic compounds on pulmonary alveolarmacrophages are also being investigated, but so farmacrophages from laboratory animals have mainly beenused.

Documentation of exposure to metals may be obtainedfrom the analysis of metal concentrations in blood, urine,or hair taken for biological monitoring261), although failureto detect the relevant metal in biological samples is notnecessarily a denial of relevance. For instance, cobalt isexcreted very rapidly in the urine after being absorbedthrough inhalation262).

In addition, elemental analysis may be carried out onBAL, on biopsy tissue or on autopsy material. Bothmacro-analytical (or bulk) and microanalytical techniquesmay be applied263–265). One of the disadvantages of thistechnique in the field of pulmonary metal-toxicity is thatit does not allow the detection of beryllium. This lattermetal can, however, be detected by electron energy lossspectrometry (EELS)266) and laser microprobe massanalysis (LAMMA)267). A potential danger in theindiscriminate use of these techniques is that the findingof metallic elements in certain disease states may beunduly associated with a causative role for theseelements268). Only properly conducted studies, includingexperimental studies, will prevent such erroneousconclusions being drawn, although case reports willcontinue to be helpful in suggesting possible associationsand stimulating further research.

Treatment of metal-related lung diseases is not specific,but a combination of infusion of steroid hormone with

oxygen inhalation is sometimes crucial for acute chemicalpneumonitis due to cadmium, beryllium and so on269).Treatment of chronic beryl l ium disease withcorticosteroid hormone has been shown to be effective270).Chelating agents such as sodium diethyldithiocarbamatefor nickel carbonyl pneumonitis are recommended271).Desensitization with platinum failed in a platinum asthmacase272).

Prevention of metal-related lung diseases can beattained as for other occupational lung diseases. Metalshazardous to the respiratory system should be notified toemployers and employees through the MSDS sheet.Exposure to these metals, and to what extent, should benotified at workplaces. The regulations contribute toenforcing these actions by employers and industries.Exposure standards developed on the basis ofepidemiological studies, if present, are appropriateindicators for comparison to keep working environmentssafe. If exposure exceeds certain levels, technologicalintervention and personal protection are necessary. Healthexaminations associated with biological monitoring forindividuals are obligatory for some metals in Japan.Educating employees about the health effects of toxicmetals, for effective preventive measures, are crucial.

Epidemiological studies and case studies adopting basicscientific techniques have revealed some factors relevantto the onset of metal-related pulmonary diseases: atopy,genetic background, smoking, malnutrition, and so on.Knowledge of these issues should be considered whenrecruiting workers to aid in risk assessment.

Another recent concept, which has emergedconsistently from follow-up studies of occupationalasthma from various causes, is the need for rapid andtotal removal of symptomatic people from exposure inorder to prevent permanent asthma273, 274). It is reasonableto adopt the same attitude in metal-induced asthma,although the ubiquity of some of the metals involved maywell make total avoidance of exposure very difficult toachieve in practice.

It is necessary to develop diagnostic methods specificto each metal. Experimental studies can generateevidence for chemical forms of metals exerting toxicitywhich can make a contribution to monitoring anddiagnosis. Experimental research also helps in developingpharmaceutical agents. Protective agents and physiologycan also be clarified by means of such experiments.Further epidemiological studies are needed to determineoccupational exposure limits for many of the toxic metalswhich are still lacking or poorly understood.

Acknowledgment: The authors sincerely thank EmeritusPrinciple Y. Sera, National Kinki Central Hospital, ProfessorR. Tokunaga, Department of Environmental Health, KansaiMedical University, Dr. S. Nanbu, Department of InternalMedicine, Kanazawa Medical University, and Dr. Koichi


Ochi, the former Chief, Department of Chest Medicine,Osaka Prefectural Hospital, for providing us valuable data.

References1) Nakamura M, Chiyotani K, Takishima, T. Pulmonary

dysfunction in pneumoconiosis. Tokyo: MaruzenPlanning Network Co. Ltd., 1991.

2) Japan Industrial Safety and Health Association.Industrial safety and health law and related legislationof Japan. Tokyo: Japan Industrial Safety and HealthAssociation, 1991.

3) Kusaka Y, Morimoto K. A pilot study to evaluateJapanese standard radiographs of pneumoconiosis(1982) according to the ILO 1980 InternationalClassification of Radiographs of Pneumoconioses.Ann Occup Hyg 1992; 36: 425–431.

4) Labour Standards Bureau, Ministry of Labour.General guidebook on industrial health. Tokyo: JapanIndustrial Safety and Health Association, 1994.

5) Industrial Health Division, Industrial Safety andHealth Department, Labour Standard Bureau,Ministry of Labour. Working environmentmeasurement system in Japan. Tokyo: JapanAssociation for Working Environment Measurement,1986.

6) Committee for the recommendation of occupationalexposure limits. Recommendation of occupationalexposure limits. J Occup Health 1997; 39: 247–260.

7) Sakula A. Ramazzini’s de Morbis Artificum andoccupational lung disease. Br J Dis Chest 1983; 77:349–361.

8) Bisetti AA. Bermadino Ramazzini and occupationallung medicine. Ann NY Acad Sci 1988; 534: 1029–1037.

9) Friberg L, Nordberg GF, Vouk VB. Handbook on thetoxicology of metals. Vol I and Vol II. 2nd ed. North-Holland: Elsevier, 1986.

10) Lauwerys RR. Toxicologie Industr ie l le e tintoxications professionnelles. 2nd ed, Paris: Masson,1982.

11) Hammond PB, Beliles RP. Metals. In: Doull J,Klassen CD, Amdur MO, eds. MacMillan, Casarettand Doull’s toxicology. The basic science of poisons.2nd ed, New York: MacMillan, 1980: 409–467.

12) Rom WN. Environmental and occupational medicine.Boston: Little Brown and Co., 1998.

13) Parkes WR. Occupational lung disorders. 3rd ed.,London: Butterworths, 1994.

14) Morgan WKC, Seaton A. Occupational lung diseases.3rd ed., Philadelphia: Saunders, 1995.

15) Vouk V. General chemistry of metals. Chp 2. In:Friberg L, Norberg GF, Vouk VB, eds. Handbook onthe toxicology of metals. Vol. I. General aspects,North-Holland: Elsevier, 1986: 15–35.

16) Brooks SM. Lung disorders resulting from theinhalation of metals. Clin Chest Med 1981; 2: 253–254.

17) Anonymous. Metals and the lung. Lancet 1984; ii:903–904.

18) Nemery B. Metal toxicity and the respiratory tract.

Eur Respir J 1990; 3: 202–219.19) Kusaka Y. Occupational diseases caused by exposure

to sensitizing metals. Jpn J Ind Health 1993; 35: 75–87.

20) Chan-Yeung M, Wong R, Maclean L, et al.Epidemiologic health study of workers in analuminium smelter in British Columbia. Am RevRespir Dis 1983; 127: 465–469.

21) Townsend MC, Enterline PE, Sussman NB, BonneyTB, Rippey LL. Pulmonary function in relation tototal dust exposure at a bauxite refinery andaluminium-based chemical products plant. Am RevRespir Dis 1985; 132: 1174–1180.

22) Field GB. Pulmonary function in aluminum smelters.Thorax 1984; 39: 743–751.

23) Saric M, Godnic-Cvar J, Gomzi M, Stilinovic L. Therole of atopy in potroom workers’ asthma. Am J IndMed 1986; 9: 239–242.

24) Wergeland E, Lund E, Waage JE. Respiratorydysfunction after potroom asthma. Am J Ind Med1987 11: 627–636.

25) Simonsson BG, Sjoberg A, Rolf C, Haege-AronsonB. Acute long-term airway hyperreactivity inaluminium-salt exposed workers with nocturnalasthma. Eur J Respir Dis 1985; 66: 105–118.

26) Hjortsberg U, Nise G, Orbaek P, Soos-Petersen U,Arborelius M Jr. Bronchial asthma due to exposureto potassium aluminum tetrafluoride (Letter). ScandJ Work Environ Health 1986; 12: 223.

27) Kongerud J, Boe J, Soyseth V, Naalsund A, MagnusP. Aluminum potroom asthma: the Norwegianexperience. Eur Respir J 1994; 7: 165–172.

28) Desjardins A, Bergeron J-P, Ghezzo H, Cartier A,Malo J-L. Aluminum potroom asthma confirmed bymonitoring of forced expiratory volume in onesecond. Am J Respir Crit Care Med 1994; 15: 1714–1717.

29) Soyseth V, Kongerud, Boe J. Increased variability inbronchial responsiveness in aluminium potroomworkers with work-related asthma-like symptoms. JOccup Environ Med 1996; 38: 66–69.

30) Devuyst P, Dumortier P, Schandene L, Estenne M,Verhest A, Yernaul t JC. Sarcoidl ike lunggranulomatosis induced by aluminium dust. Am RevRespir Dis 1987; 135: 493–497.

31) Dinman BD. Aluminium in the lung: the pyropowdercorundum. J Occup Med 1987; 29: 869–876.

32) Dinman BD. Alumina-related pulmonary disease. JOccup Med 1988; 30: 328–335.

33) Miller RR, Churg AM, Hutcheon M, Lam S.Pulmonary alveolar proteinosis and aluminumexposure. Am Rev Respir Dis 1984; 130: 312–314.

34) Vallyathan V, Bergeron WN, Robichaux PA,Craighead JE. Pulmonary fibrosis in an aluminumarc welder. Chest 1982; 81: 372–374.

35) Herbert A, Sterling G, Abraham J, Corrin B.Desquamative interstitial pneumonia in an aluminumwelder. Human Pathol 1982; 13: 694–699.

36) De Vuyst P, Dumortier P, Rickaert F, Van de WeyerR, Lenclud C, Yermault JC. Occupational lung


fibrosis in an aluminium polisher. Eur J Respir Dis1986; 68: 131–140.

37) Gilks B, Churg A. Aluminum-induced pulmonaryfibrosis: do fibers play a role? Am Rev Respir Dis1987; 136: 176–179.

38) Sunami K, Yamadori I, Kishimoto T, Ozaki S,Kawabata Y. Unilateral mixed-dust pneumoconiosiswith aluminum deposition associated with interstitialpneumonia. Jpn J Thoracic Dis 1997; 35: 189–195.

39) Konishiike J, Tanaka M, Hashimoto T, Kan K,Yokoyama K, Sera Y. A clinical study on seven caseswith aluminium (alumina) lung. Jpn J Chest Dis 1980;39: 195–204.

40) Toki J, Tateiwa J, Maeda R. Elemental analysis ofthe intrapulmonary deposits in the reported autopsycase of aluminum dust lung using electron probe X-ray microanalysis. Kansai Med J 1984; 36(suppl):102–116.

41) Ueda M, Mizoi Y, Maki Z, Maeda R, Takada R. Acase of aluminium dust lung. Kobe J Med Science1958; 4: 91–99.

42) Renes LE. Antimony poisoning in industry. Arch IndHyg 1953; 7: 99–108.

43) Daguenel J, Gaucher P, Dumortier L, et al.Antimoniose pulmonaire. Arch Mal Prof, 1979; 40:110–112.

44) Potkonjal V, Pavlovich M. Antimoniosis: a particularform of pneumoconiosis. I. Etiology, clinical and X-ray findings. Int Arch Occup Environ Health 1983;51: 199–207.

45) Pinto S, McGill CM. Arsenic trioxide exposure inindustry. Ind Med Sug 1953; 22: 281–287.

46) Pinto S, Petronella SJ, Johns DR, et al. Arsinepoisoning: A study of 13 cases. Arch Ind Hyg OccupMed 1950; 1: 437–451.

47) Doll R. Problems of epidemiological evidence.Environ Health Perspect 1981; 40: 11–20.

48) Cone JE. Occupational lung cancer. State of the ArtRev Occup Med 1987; 2: 273–295.

49) International Agency for Research on Cancer (IARC).IARC Monographs on the evaluation of carcinogenicr i sks to humans . Overa l l eva lua t ions o fcarcinogenicity: an updating of IARC MonographsVolumes 1 to 69. Lyon: IARC, 1997.

50) Norseth T. Metal carcinogenesis. Ann NY Acad Sci1988; 534: 377–386.

51) Peters JM, Thomas D, Falk H, Oberdorster G, SmithTJ. Contribution of metals to respiratory cancer.Environ Health Perspect 1986; 70: 71–83.

52) Taylor P, Qiao Y, Schatzkin A, et al. Relation ofarsenic exposure to lung cancer among tin miners inYunnan Province, China. Br J Ind Med 1989; 46; 881–886.

53) Jarup L, Pershagen G, Wall S. Cumulative arsenicexposure and lung cancer in smelter workers: A dose-response study. Am J Ind Med 1989; 15: 31–41.

54) Jarup L, Pershagen G. Arsenic exposure, smoking,and lung cancer in smelter workers-A case controlstudy. Am J Epidemiol 1991; 134: 545–551.

55) Steenland K, Loomis D, Shy C., Simonsen N. Review

of occupational lung carcinogens. Am J Ind Med1996; 29: 474–490.

56) Lee-Feldstein A. Cumulative exposure to arsenic andits relationship to respiratory cancer among coppersmelter employees. J Occup Med 1986; 28: 296–302.

57) Sobel W, Bond GG, Baldwin CL, Ducommun DJ.An update of respiratory cancer and occupationalexposure to arsenicals. Am J Ind Med 1988; 13: 263–270.

58) Enterline P, Marsh G, Esmen N, Henderson V,Callahan C, Paik M. Some effects of cigarettesmoking, arsenic, and SO

2 on mortality among US

copper smelter workers. J Occup Med 1987; 29: 831–838.

59) Okazaki M, Idemori M, Ogata K, et al. Skinmanifestations of 144 patients with chronic arsenicpoisoning in the Toroku Area, Miyazaki. West Jpn JSkin Dis 1989; 51: 920–926.

60) Iki Y, Kawatsu T, Matsuda K, Machino H, Kubo K.Cutaneous and pulmonary cancers associated withBowen’s disease. Am Acta Dermatol 1982; 6: 26–31.

61) Kriebel D, Sprince NL, Eisen EA, Greaves IA,Feldman HA, Greene RE. Beryllium exposure andpulmonary function. A cross-sectional study ofberyllium workers. Br J Ind Med 1988; 45: 167–173.

62) Cotes JE, Gilson JC, McKerrow CB, Oldham PD. Along-term follow-up of workers exposed to beryllium.Br J Ind Med 1983; 40: 13–21.

63) Eisenbud M, Lisson J. Epidemiological aspects ofberyllium-induced non-malignant lung disease: a 30year update. J Occup Med 1983; 25: 196–202.

64) Cullen MR, Cherniack MG, Kominsky JR. Chronicberyllium disease in the United States. Seminar RespirMed 1987; 7: 203–209.

65) Kriebel D, Brain JD, Sprince NL, Kazemi H. Thepulmonary toxicity of beryllium. Am Rev Respir Dis1988; 137: 464–473.

66) Cullen MR, Kominsky JR, Rossman MD, et al.Chronic beryllium disease in a precious metalrefinery. Clinical epidemiological and immunologicalevidence for continuing risk from exposure to lowlevel beryllium fume. Am Rev Respir Dis 1987; 135:201–208.

67) Knishikowy B, Baker EL. Transmission ofoccupational disease to family contacts. Am J Ind Med1986; 9: 543–550.

68) Shima S. Immunotoxicity of sensitized metal-A thirtyeight-year study on the beryllium poisoning. Jpn JHyg 1994; 49: 89–104.

69) Rossman MD, Kern JA, Elias JA, et al. Proliferativeresponse of bronchoalveolar lymphocytes toberyllium. A test for chronic beryllium disease. AnnIntern Med 1988; 108: 687–693.

70) Saltini C, Winestock K, Kirby M, Pinkston P, CrystalRG. Maintenance of alveolitis in patients with chronicberyllium disease by beryllium disease by beryllium-specific helper T cells. N Engl J Med 1989; 320:1103–1109.

71) Richeldi L, Sorrentino R, Saltini C. HLA-DPB1glutamate 69: a genetic marker of beryllium disease.


Science 1993; 262: 242–243.72) Izumi T, Kobara Y, Inui S, Tokunaga R, Orita Y,

Kitano N, Jones Williams W. The first seven cases ofchronic beryllium disease in ceramic factory workersin Japan. Ann New York Acad Sci 1976; 278: 636–653.

73) Hasejima N, Kobayashi H, Takezawa S, Yamato K,Kadoyama C, Kawano Y. Chronic beryllium diseaseafter exposure to low-beryllium-content copper. JpnJ Thoracic Dis 1995; 33: 1105–1110.

74) Suzuki M, Ochi T, Kimura K, et al. Chronic berylliumlung disease due to low beryllium content alloys. JpnJ Chest Dis 1987; 46: 138–143.

75) Kazemi H. Beryllium disease. In: Last JM ed.Preventive Medicine and Public Health. New York:Moxcy-Rosenan Appleton Century Craft, 1980.

76) Steenland K, Ward E. Lung cancer incidence amongpatients with beryllium disease: a cohort mortalitystudy. J Nat Cancer Inst 1991; 83: 1380–1385.

77) Meyer KC. Beryllium and lung disease. Chest 1994;106: 942–946.

78) Hart BA. Cellular and biochemical response of therat lung to repeated inhalation of cadmium. ToxicolAppl Pharmacol 1986; 82: 281–291.

79) Barnhart S, Rosenstock L. Cadmium chemicalpneumonitis. Chest 1984; 86: 789–791.

80) Taylor A, Jackson MA, Burston J, Lee HA. Poisoningwith cadmium fumes after smelting lead. Br Med J1984; 288: 1270–1271.

81) Townshend RM. Acute cadmium pneumonitis: a 17year follow-up. Br J Ind Med 1982; 39: 411–412.

82) Hara N, Homma K, Koshi S. Metallic fume generatedin the welding using silver solder. Ind Health 1968;6: 134–139.

83) Yamamoto Y, Ueda M, Kikuchi H, Hattori H, HiraokaY. An acute fatal occupational cadmium poisoningby inhalation. Z Rechtsmed 1983; 91: 139–143.

84) Inoue S, Suzumura Y, Takahashi K. A case ofinterstitial pneumonitis caused by inhalation ofcadmium fumes. Jpn J Thoracic Dis 1994; 32: 861–866.

85) Hamada H, Sakatani M. A case with acute interstitialpneumonitis caused by metal fumes. J Jpn SociBronchol 1997; 19: 67–70.

86) Johnson JS, Kilburn KH. Cadmium induced metalfume fever: results of inhalation challenge. Am J IndMed 1983; 4: 533–540.

87) Bernard A, Lauwerys R. Effects of cadmium exposurein humans. In: E.C. Foulkes, ed., Cadmium.Handbook of experimental pharmacology, vol. 80,Berlin: Springer Verlag, 1986: 135–177.

88) Edling C, Elinder CG, Randma E. Lung function inworkers using cadmium containing solders Br J IndMed 1986; 43: 657–662.

89) Davison AG, Newman Taylor AJ, Darbyshire J, et al.Cadmium fume inhalation and emphysema. Lancet1988; I: 663–667.

90) Armstrong BG, Kazantzis G. Prostatic cancer andchronic respiratory and renal disease in Britishcadmium workers: a case control study. Br J Ind Med

1985; 42: 540–545.91) Kazantzis G, Lam TH, Sullivan KR. Mortality of

cadmium-exposed workers. Scand J Work EnvironHealth 1988; 14: 220–223.

92) Niewoehner DE, Hoidal JR. Lung fibrosis andemphysema: divergent responses to a common injury.Science 1982; 217: 359–360.

93) Martin FM, Witschi HP. Cadmium-induced lunginjury: cell kinetics and long-term effects. ToxicolAppl Pharmacol 1985; 80: 215–227.

94) Snider GL, Lucey EC, Faris B, Jung-Legg Y, StonePJ, Franzblau C. Cadmium chloride-induced airspaceenlargement with interstitial pulmonary fibrosis is notassociated with the destruction of lung elastin.Implication for the pathogenesis of humanemphysema. Am Rev Respir Dis 1988; 137: 918–923.

95) Elinder CG, Kjellstrom T, Hogstedt C, Anderson K,Span G. Cancer mortality of cadmium workers. Br JInd Med 1985; 42: 651–655.

96) Thun MT, Schnorr TM, Smith AB, Halperin WE,Lemen RA. Mortality among a cohort of US cadmiumproduction workers. An update. J National CancerInstitute 1985; 74: 325–333.

97) Sorahan T. Mortality from lung cancer among a cohortof nickel cadmium battery workers: 1946–1984. Br JInd Med 1987; 44: 803–809.

98) Ades AE, Kazantzis G. Lung cancer in a non-ferroussmelters: the role of cadmium. Br J Ind Med 1988;45: 435–442.

99) Oberdorster G. Airborne cadmium and carcinogenesisof the respiratory tract. Scand J Work Environ Health1986; 12: 523–527.

100) Lindberg E, Hedenstierna G. Chrome plating:symptom, findings in the upper airways, and effectson lung function. Arch Environ Health 1983; 38: 367–374.

101) Keskinen H, Kalliomaki PL, Alanko K. Occupationalasthma due to stainless steel fumes. Clin Allergy1980; 10: 151–159.

102) Moller DR, Brooks SM, Bernstein DI, Cassedy K,Enrione M, Bernstein IL. Delayed anaphylactoidreaction in a worker exposed to chromium. J AllergyClin Immunol 1986; 77: 45–46.

103) Shirakawa T, Morimoto K. Brief reversiblebronchospasm resulting from bichromate exposure.Arch Environ Health 1996; 51: 221–226.

104) Bright P, Burge PS, O’Hickey SP, Gannon PFG,Robertson AS, Boran A. Occupational asthma due tochrome and nickel electroplating. Thorax 1997; 52:28–32.

105) Norseth T. The carcinogenicity of chromium and itssalts. Br J Ind Med 1986; 43: 649–651.

106) Satoh K, Fukuzawa Y, Torii K, Katsuno N.Epidemiological study of workers engaged in themanufacture of chromium compounds. J Occup Med1982; 23: 835–838.

107) Langard S, Vigander T. Occurrence of lung cancer inworkers producing chromium pigments. Br J Ind Med1983; 4: 71–74.


108) Davies JM. Lung cancer mortality among workersmaking lead chromate and zinc chromate pigmentsat three English factories. Br J Ind Med 1984; 41:158–169.

109) Ohsaki Y, Abe S, Kimura K, Tsuneta Y, Mikami H,Murao M. Lung cancer in Japanese chromate workers.Thorax 1978; 33: 372–374.

110) Ishikawa Y, Nakagawa K, Satoh Y, Kitagawa T,Sugano H, Hirano T, Tsuchiya E. “Hot spots” ofchromium accumulation at bifurcations of chromateworkers. Cancer Res 1994; 54: 2342–2346.

111) Beaumont JJ, Weiss NS. Lung cancer among welders.J Occup Med 1981; 23: 839–844.

112) Becker N, Claude J, Frentzel-Beyme R. Cancer ofarc welders exposed to fumes containing chromiumand nickel. Scand J Work Environ Health 1985; 11:75–82.

113) Sorahan T, Burges DCL, Waterhouse JAH. Amortality study of nickel/chromium platers. Br J IndMed 1987; 44: 250–258.

114) Lerchen ML, Wiggins CL, Samet JM. Lung cancerand occupational in New Mexico. J National CancerInstitute 1987; 79: 639–645.

115) Ronco G, Ciccone G, Mirabelli D, Troia B, Vineis P.Occupation and lung cancer in two industrializedareas of Northern Italy. Int J Cancer 1988; 41: 354–358.

116) Abe S, Ohsaki Y, Kimura K, Tsuneta Y, Mikami H,Murao M. Chromate lung cancer with specialreference to its cell type and relation to themanufacturing process. Cancer 1982; 49: 783–787.

117) Mancuso TF. Chromium as an industrial carcinogen:Part I. Am J Ind Med 1997; 31: 129–139.

118) Halliwell B, Gutteridge JMC. Oxygen toxicity,oxygen radicals, transition metals and disease.Biochem J 1984; 219: 1–4.

119) Halliwell B, Gutteridge JMC. Oxygen free radicalsand iron in relation to biology and medicine: someproblems and concepts. Arch Biochem Biophys 1986;246: 501–514.

120) Slater TF. Free-radical mechanisms in tissue injury.Biochem J 1984; 222: 1–15.

121) Aust SD, Morehouse LA, Thomas CE. Role of metalsin oxygen radical reactions. J Free Rad Biol Med1985; 1: 3–25.

122) Halliwell B, Gutteridge JMC. Free radicals andantioxidant protection: mechanisms and significancein toxicity and disease. Human Toxicol 1988; 7: 7–13.

123) Freeman BA, Crapo JD. Hyperoxia increases oxygenradical production in rat lungs and lung mitochondria.J Biol Chem 1981; 256: 10986–10992.

124) Smith LL. Mechanism of paraquat toxicity in lungand its relevance to treatment. Human Toxicol 1987;6: 31–36.

125) Martin WJ. Nitrofurantoin: evidence for the oxidantinjury of lung parenchymal cells. Am Rev Respir Dis1983; 127: 482–486.

126) Goodlick LA, Kane AB. Role of reactive oxygenmetabolites in crocidolite asbestos toxicity to mouse

macrophages. Cancer Res 1986; 46: 5558–5566.127) Nemery B, Nagels J, Verbeken E, Dinsdale D,

Demedts M. Rapidly fatal progression of cobalt-lungin a diamond polisher. Am Rev Respir Dis 1990; 141:1373–1378.

128) Kusaka Y, Ichikawa Y, Shirakawa T, Goto S. Effectof hard metal dust on ventilatory function. Br J IndMed 1986; 43; 486–489.

129) Nemery B, Roosels D, Lahaye D, Casier P, DemedtsM. Cross-sectional survey of lung function andassessment of cobalt exposure in diamond polishers(abstract). Am Rev Respir Dis 1988; 137: 96.

130) Roto P. Asthma, symptoms of chronic bronchitis andventilatory capacity among cobalt and zinc productionworkers. Scand J Work Environ Health 1980; 6 (suppl.1).

131) Gheysens B, Auwerx J, Van Den Eeckhout A,Demedts M. Cobalt-induced bronchial asthma indiamond polishers. Chest 1985; 88: 740–774.

132) Scherrer M, Maillard JM. Hartmetall-Pneumopathien.Schweitz Med Wschr 1982; 112: 198–207.

133) Har tmann A , Wuth r i ch B , Bo logn in i G .Berufsbedingte Lungenkrankheiten bei derHartmetallproduktion und-bearbeitung. Einallergische Geschehen? Schweitz Med Wschr 1982;112: 1137–1141.

134) Davison AG, Haslam PL, Corrin B, et al. Interstitiallung disease and asthma in hard metal workers:bronchoalveolar lavage, ultrastructural, and analyticalfindings and results of bronchial provocation tests.Thorax 1983; 38: 119–128.

135) Kusaka Y, Yokoyama K, Sera Y, et al. Respiratorydiseases in hard metal workers: an occupationalhygiene study in a factory. Br J Ind Med 1986; 43:474–485.

136) Shirakawa T, Kusaka Y, Fujimura N, Goto S, KatoM, Heki S, Morimoto K. Occupational asthma fromcobalt sensitivity in workers exposed to hard metaldust. Chest 1989; 95: 29–37.

137) Shirakawa T, Kusaka Y, Fujimura N, Goto S,Morimoto K. The existence of specific antibodies tocobalt in hard metal asthma. Clin Allergy 1988; 18:451–460.

138) Kusaka Y. Cobalt and nickel induced hard metalasthma. In: Chang LW. ed. Toxicology of Metals.Boca Raton: Lewis Publishers, 1996: 461–468.

139) Shirakawa T, Kusaka Y, Morimoto K. Specific IgEantibodies to nickel in workers with known reactivityto cobalt. Clin Exp Allergy 1992; 22: 213–218.

140) Kusaka Y, Kumagai S, Goto S. Epidemiological studyof hard metal asthma. Occup Environ Med 1996; 53:188–193.

141) Donaldson JD, Clark SJ, Grimes SM. Cobalt inchemicals. (The monographic series). Slough: CobaltDevelopment Institute, 1986.

142) National Institute of Occupational Safety and Health(NIOSH). Criteria for controlling occupationalexposure to cobalt. U.S. Department of health andhuman services. Publish No. 82–107, Cincinatti:CDC-NIOSH, 1981.


143) Cullen MR. Respiratory diseases from hard metalexposures. A continuing enigma. Chest 1984; 86:513–514.

144) Balmes JR. Respiratory effects of hard-metal dustexposure. State of the Art Rev Occup Med 1987; 2:327–344.

145) Sprince NL, Chamberlin RI, Hales CA, Weber AL,Kazemi H. Respiratory disease in tungsten carbideproduction workers. Chest 1984; 86: 549–557.

146) Sprince NL, Oliver LC, Eisen EA, Greene RE,Chamberlin RI. Cobalt exposure and lung disease intungsten carbide workers: a cross-sectional study ofcurrent workers. Am Rev Respir Dis 1988; 138: 1220–1226.

147) Sjogren I, Hillerdal G, Andersson A, Zetterstrom O.Hard metal lung disease: importance of cobalt incoolants. Thorax 1980; 35: 653–659.

148) Meyer D, Stoeckel C, Geist T, Le Bouffant L, RoegelE. A propos de trois nouveaux cas de fibrosepulmonaire chez des affuteurs d’outils renforces encarbure de tungstene. Poumon-Coeur 1981; 37: 165–175.

149) Hartung M, Valentin H. Lungenfibrose durchHartmetallstaube. Zbl Bakt Hyg I Abt Orig B 1983;177: 237–250.

150) Hartung M. Lungenfibrosen bei Hartmetallscheifern.Bedeutung der Cobalteinwirkung. Sankt Augustin:Schriftanreihe des Hauptverbanders der gewerblichenBerufsgenossenschaften C.V., 1986.

151) Anttila S, Sutinen S, Paananen M, Kreus KE, SivonenSJ, Grekula A, Alapieti T. Hard-metal lung disease: aclinical, histological, ultrastructural and X-raymicroanalysis study. Eur J Respir Dis 1986; 69: 83–94.

152) Rizzato G, Locicero G, Barberis M, Torre M, PietraR, Sabbioni E. Trace of metal exposure in hard metallung disease. Chest 1986; 90: 101–106.

153) Schepers GWH. The biological action of particulatecobalt metal, tantalum oxide, cobalt oxide, tungstenmetal, tungsten carbide and carbon, tungsten carbideand cobalt. Am Arch Ind Health 1955; 12: 121–146.

154) Abraham JL. Lung pathology in 22 cases of giantcell interstitial pneumonia (GIP) is pathognomonicof cobalt (hard metal) disease. (Abstract). Chest 1987;91: 312.

155) Demedts M, Gheysens B, Nagels J, et al. Cobalt lungin diamond polishers. Am Rev Respir Dis 1984; 130:130–135.

156) Demedts M, Ceuppens JL. Respiratory diseases fromhard metal or cobalt exposure. Solving the enigma(Editorial). Chest 1899; 95: 2–3.

157) Daniele RP. Cell-mediated immunity in pulmonarydisease. Hum Pathol 1986; 17: 154–160.

158) Van Cutsem EJ, Ceuppens JL, Lacquet LM, DemedtsM. Combined asthma and alveolitis induced by cobaltin a diamond polishers. Eur J Respir Dis 1987; 70:54–61.

159) Morgan LG. A study into the health and mortality ofmen exposed to cobalt and oxides. J Soc Occup Med1983; 33: 181–186.

160) Reinl W, Schnellbacher F, Rahm G. Lungenfibrosenund entzundliche Lungenerkrankungen nachEinwirkung von Kobaltkontaktmasse. Zbl Arbeitsmed1979; 12: 318–325.

161) Kusaka Y, Goto S. Is there a threshold limit presentfor cobalt? A lesson from hard metal disease in Japan.In: Chiyotani K, Hosoda Y., Aizawa, K. eds. Advancesin the Prevention of Occupational RespiratoryDiseases. Amsterdam: Elsevier Science, 1998: 388–392.

162) Kusaka Y, Yokoyama K, Sera Y, et al. Respiratorydiseases in hard metal workers: an occupationalhygiene study in a factory. Br J Ind Med 1986; 43:474–485.

163) Ruttner JR, Spycher MA, Stolkin I. Inorganicparticulates in pneumoconiotic lungs of hard metalgrinders. Br J Ind Med 1987; 44: 657–660.

164) Deutsche Forschungsgemainschaft. Maximumconcentrations at the workplace and biologicaltolerance values for working materials 1989.Weinheim: VCH, 1989: 77.

165) Anonymous. Lung disease in dental laboratorytechnicians. Lancet 1985; I: 1200–1201.

166) Rom WN, Lockey JE , Je ff rey LS, e t a l .Pneumoconiosis and exposure of dental laboratorytechnicians. Am J Public Health 1984; 74: 1252–1257.

167) Fukuzawa Y. Study on scattered dust from thepolishing of cast framework of denture from theviewpoint of industrial hygiene. J Dental Health 1987;37: 225–243.

168) De Vuyst P, Van de Weyer R, Decoster A, et al. Dentaltechnician’s pneumoconiosis. A report of two cases.Am Rev Respir Dis 1986; 133: 316–320.

169) Loewen GM, Weiner D, McMahon J. Pneumoconiosisin an elderly dentist. Chest 1988; 93: 1312–1313.

170) Carles P, Fabre J, Pujol M, Duprez A, Bollinelli R.Pneumoconioses complexes chez les prothesistsdentaires. Poumon Coeur, 1978; 34: 189–192.

171) Morgenroth K, Kronenberger H, Tuengerthal S, eta l . H i s t o l o g i s c h e L u n g e n b e f u n d e b e iPneumokoniosen von Zahntechnikern. Prax KlinPneumol 1981; 35: 670–673.

172) Mueller EJ, Seger DL. Metal fume fever: a review. JEmerg Med 1985; 2: 271–274.

173) Armstrong CW, Moore LW, Hacker RL, Miller GBJr, Stroube RB. An outbreak of metal fume fever.Diagnostic use of urinary copper and zincdeterminations. J Occup Med 1983; 25: 886–888.

174) Kuratune M, Tokudome S, Shirakusa T, et al.Occupational lung cancer among copper smelters. IntJ Cancer 1974; 13: 552–558.

175) Tokudome S, Kuratsune M. A cohort study onmortality from cancer and other causes amongworkers at a metal refinery. Int J Cancer 1976; 17:310–317.

176) Tokudome S, Haratake J, Horie A, et al. Histologictypes of lung cancers among male Japanese coppersmelter workers. Am J Ind Med 1988; 14: 137–143.

177) Elmes PC. Relative importance of cigarette smokingin occupational lung disease. Br J Ind Med, 1981;


38: 1–13.178) Deutsche Froschungsgemeinschft (H. Valentin and U.

Smidt). Research report: chronic bronchitis andoccupational dust exposure. Boppard: Harald BoldtVerlag KG, 1978.

179) Nemery B, Moavero NE, Mawet M, Kivits A,Brasseur L, Stanescu D. Etude de la symptomatologieet de la fonction pulmonaire chez des siderugistes.Rev Inst Hyg Mines (Hasselt) 1981; 36: 198–218.

180) Nemery B, Van Leemputten R, Goemaere E, VeriterC, Brasseur L. Lung function measurements over21days shiftwork in steelworkers from a strandcastingdepartment. Br J Ind Med 1985; 42: 601–611.

181) Department of Health and Social Security. Bronchitisand emphysema. London: HMSO, 1988.

182) Oxhoj H, Bake B, Wedel H, Wilhelmsen L. Effectsof electric arc welding on ventilatory lung function.Arch Environ Health 1979; 34: 211–217.

183) Akbarkhanzadeh F. Long-term effects of weldingfumes upon respiratory symptoms and pulmonaryfunction. J Occup Med 1980; 22: 337–341.

184) Keimig DG, Pomrehn PR, Burmeister LF. Respiratorysymptoms and pulmonary function in welders of mildsteel: a cross-sectional study. Am J Ind Med 1983; 4:489–499.

185) Mur JM, Cavelier C, Meyer-Bisch C, Pham QT,Masset JC. Etude de la fonction pulmonaire desoudeurs a l’arc. Resultats d’une enquete dans uneentreprise de construction de vehicules industriels.Respiration 1983; 44: 50–57.

186) Mur JM, Teculescu D, Pham QT, et al. Lung functionand clinical findings in a cross-sectional study of arcwelders. An epidemiological study. Int Arch OccupEnviron Health 1985; 57: 1–17.

187) Sjogren B, Ulfvarson U. Respiratory symptoms andpulmonary function among welders working withaluminium, stainless steel and railroad tracks. ScandJ Work Environ Health 1985; 11: 27–32.

188) Stem RM, Berlin A, Fletcher A, Hemminki K,Jarvisalo J, Peto J. International conference on healthhazards and biological effects of welding fumes andgasses. Summary report. Int Arch Occup EnvironHealth 1986; 57: 237–246.

189) Lockey JE, Schenker MB. Current issues inoccupational lung disease (Symposium). Am RevRespir Dis 1988; 138: 1047–1049.

190) Sjogren B. Effects of gases and particles in weldingand soldering. In: Zenz C, ed. Occupational medicine.Principles and practical applications. 2nd ed. Chicago-London: Year Book Medical Publ., 1988: 1053–1060.

191) Funahashi A, Schlueter DP, Pintak K, Bemis EL,Siegesmund KA. Welders’ pneumoconiosis: tissueelemental microanalysis by energy dispersive X-rayanalysis. Br J Ind Med 1988; 45: 14–18.

192) Moulin JJ. A meta-analysis of epidemiological studiesof lung cancer in welders. Scand J work EnvironHealth 1997; 23: 104–113.

193) Sjogren B, Hansen KS, Kjuus H, Persson P-G.Exposure to stainless steel welding fumes and lungcancer: a meta-analysis. Occup Environ Med 1994;

51: 335–336.194) Fletcher AC, Ades A. Lung cancer mortality in a

cohort of English foundry workers. Scand J WorkEnviron Health 1984; 10: 7–16.

195) Silverstein M, Maizlich N, Park R, Silverstein B,Brodsky L, Mirer F. Mortality among ferrous foundryworkers. Am J Ind Med 1986; 10: 27–43.

196) Masjedi M-R, Estineh N, Bahadori M, Alavi M,Sprince NL. Pulmonary complications in lead miners.Chest 1989; 96: 18–21.

197) Lundstrom N-G, Nordberg G, Englyst V, et al.Cumulative lead exposure in relation to mortality andlung cancer morbidity in a cohort of primary smelterworkers. Scand J Work Environ Health 1997; 23: 24–30.

198) Roels H, Lauwerys R, Genet P, et al. Epidemiologicalsurvey among workers exposed to manganese: effectson lung, central nervous system, and some biologicalindices. Am J Ind Med 1988; 11: 307–327.

199) Liles R, Miller A, Lerman Y. Acute mercury poisoningwith severe chronic pulmonary manifestations. Chest1985; 88: 306–309.

200) Levin M, Jacob J, Polos PG. Acute mercury poisoningand mercurial pneumonitis from gold ore purification.Chest 1988; 94: 554–556.

201) Rowens B, Guerrero-Betancourt D, Gottlieb CA,Boyes RJ. Respiratory failure and death followingacute inhalation of mercury vapor. A clinical andhistopathologic perspective. Chest 1991; 99: 185–190.

202) Koizumi A, Aoki T, Tsukada M, Naruse M, Saitoh N.Mercury, not sulfur dioxide, poisoning as cause ofsmelter disease in industrial plants producing sulfuricacid. Lancet 1994; 343; 1411–1412.

203) Zicheng S. Acute nickel carbonyl poisoning: a reportof 197 cases. Br J Ind Med 1986; 43: 422–424.

204) Block GY, Yeung M. Asthma induced by nickel. JAm Med Assoc 1982; 247: 1600–1602.

205) Malo J, Cartier A, Doepner M, Nieboer E, Evans S,Dolovich J. Occupational asthma caused by nickelsulfate. J Allergy Clin Immunol 1982; 69: 55–59.

206) Novey HS, Habib M, Wells ID. Asthma and IgEantibodies induced by chromium and nickel salts. JAllergy Clin Immunol 1983; 72: 407–412.

207) Davies JE. Occupational asthma caused by nickelsalts. J Soc Occup Med 1986; 36: 29–31.

208) Dolovich J, Evans SL, Nieboer E. Occupationalasthma from nickel sensitivity: I. Human serumalbumin in the antigenic determinant. Br J Ind Med1984; 41: 51–55.

209) Toyoshima M, Sato A, Taniguchi M, et al. A case ofeosinophilic pneumonia caused by inhalation of nickeldusts. Jpn J Thoracic Dis 1994; 32: 480–484.

210) Arvidsson H, Bogg A. Transitory pulmonaryinfiltrations-loeffler’s syndrome- in acute generalizeddermatitis. Acta Dermato-Venereol 1959; 39: 30–34.

211) Sunderman FW, Jr Sunderman FW. Loffler ’ssyndrome associated with nickel sensitivity. Arch IntMed 1961; 107: 405–408.

212) Gray J. Loeffler’s syndrome following ingestion of a


coin. Canada Med Assoc J 1982; 127: 999–1000.213) Grand j ean P, Ande r son O , N ie l s en GD.

Carcinogenicity of occupational nickel exposures: anevaluation of the epidemiological evidence. Am J IndMed 1988; 13: 193–210.

214) Kaldor J, Peto J, Easton D, Doll R, Hermon C,Morgan L. Models for respiratory cancer in nickelrefinery workers. J National Cancer Institute, 1986;77: 841–848.

215) Andersen A, Berge SR, Norseth ET. Exposure tonickel compounds and smoking in relation toincidence of lung cancer and nasal cancer amongnickel refinery workers. Occup Environ Med 1996;53: 708–713.

216) Martell AE. Chemistry and metabolism of metalsrelevant to their carcinogenicity. Environ HealthPerspect 1981; 40: 27–34.

217) Jennette KW. The role of metals in carcinogenesis:biochemistry and metabolism. Environ HealthPerspect 1981; 40: 233–252.

218) Pepys J. Occupational asthma: an overview. J OccupMed 1982; 24: 534–538.

219) Davies RJ, Blainey AD. Occupational asthma:classification and clinical aspects. Seminar RespirMed 1984; 5: 229–239.

220) Chan-Yeung M, Lam S. Occupational asthma. AmRev Respir Dis 1986; 133: 686–703.

221) Moller DR, Baughman R, Murlas C, Brooks SM. Newdirections in occupational asthma caused by smallmolecular weight compounds. Seminar Respir Med1987; 7: 225–239.

222) Biagini RE, Bernstein IL, Gallagher JS, MoormanWJ, Brooks S, Gann PH. The diversity of reaginicimmune response to platinum and palladium metallicsalts. J Allergy Clin Immunol 1985; 76: 794–802.

223) Murdoch RD, Pepys J, HughesEG. IgE antibodyresponses to platinum group metals: a large scalerefinery survey. Br J Ind Med 1986; 43: 37–43.

224) Venables KM, Topping MD, Howe W, LuczynskaCM, Hawkins R, Newman Taylor AJ. Interaction ofsmoking and atopy in producing specific IgE antibodyagainst a hapten protein conjugate. Br J Ind Med1985; 290: 201–204.

225) Venables KM, Dally MB, Nunn AJ, et al. Smokingand occupational allergy in workers in a platinumrefinery. Br Med J 1989; 299: 939–942.

226) Calverley AE, Rees D, Dowdeswell RJ, Linnett PJ,Kielkowski D. Platinum salt sensitivity in refineryworkers: incidence and effects of smoking andexposure. Occup Environ Med 1995; 52: 661–666.

227) Biagini RE, Moorman WJ, Lewis TR, Bernstein IL.Ozone enhancement of platinum asthma in a primatemodel. Am Rev Respir Dis 1986; 134: 719–725.

228) Shima S, Yoshida T, Tachikawa S, et al. Bronchialasthma due to inhaled chloroplatinate. Jpn J IndHealth 1984; 26: 500–509.

229) Husain MH, Dick JA, Kaplan YS. Rare-earthpneumoconiosis. J Soc Occup Med 1980; 30: 15–19.

230) Sinico M, Le Bouffant L, Pailas J, Fabre M, TrincardMD. Pneumoconiose de au cerium. Documents

anatomopathologiques. Arch Mal Prof 1982; 43: 249–252.

231) Vocaturo G, Colombo F, Zanoni M, Rodi F, SabbioniE, Pietra R. Human exposure to heavy metals. Rareearth pneumoconiosis in occupational workers. Chest1983; 83: 780–783.

232) Suloto F, Romano C, Berra A, et al. Rare earthpneumoconiosis: a new case. Am J Ind Med 1986; 9:567–575.

233) Vogt P, Spycher MA, Ruttner JR. Pneumokoniosedurch “seltene Erden” (Cer-Pneumokoniose).Shcweiz Med Wschr 1986; 116: 1303–1308.

234) Imai T, Nakayama H. Occupational dermatitiscomplicated with bronchial symptoms due to allergywith rhodium. Clin Dermatol 1982; 24: 1033–1041.

235) Park T, Di Benedetto R, Morgan K, Colmers R,Sherman E. Diffuse endothelial polyposis followinga titanium tetrachloride inhalation injury. Am RevRespir Dis 1984; 130: 315–317.

236) Garabrant DH, Fine LJ, Oliver C, Bernstein L, PetersJM. Abnormalities of pulmonary function and pleuraldisease among titanium metal production workers.Scand J Work Environ Health 1987; 13: 47–51.

237) Chen JL, Fayerweather WE. Epidemiologic study ofworkers exposed to titanium dioxide. J Occup Med1988; 30: 937–942.

238) Redline S, Barna BP, Tomashefski JF Jr, AbrahamJL. Granulomatous disease associated with pulmonarydeposition of titanium. Br J Ind Med 1986; 43: 652–656.

239) Tajima G, Tanizima S, Isoyama G, et al. A case oftitanium pneumoconiosis. Jpn J Chest Dis 1976; 35:302–308.

240) Brooks SM, Weiss MA, Bernstein IL. Reactiveairways dysfunction syndrome (RADS). Persistentasthma syndrome after high level irritant exposures.Chest 1985; 88: 376–384.

241) Musk AW, Tees JG. Asthma caused by occupationalexposure to vanadium compounds. Med J Aust 1982;1: 183–184.

242) Lees REM. Changes in lung function after exposureto vanadium compounds in fuel oil ash. Br J Ind Med1980; 37: 253–256.

243) Levy BS, Hoffman L, Gottsegen S. Boilermakersbronchitis. Respiratory tract irritation associated withvanadium pentoxide exposure during oil-to-coalconversion of a power plant. J Occup Med 1984; 26:567–570.

244) Matarese SL, Matthews JI. Zinc chloride (smokebomb) inhalation lung injury. Chest 1988; 89: 308–309.

245) Hjorts ΦE, Qvist J, Bud MI, et al. ARDS afteraccidental inhalation of zinc chloride smoke.Intensive Care Med 1988; 14: 17–24.

246) Brown JJ. Zinc fume fever. Br J Radiol 1988; 61:327–329.

247) Vogemeier C, Konig G, Bencze K, Fruhmann G.Pulmonary involvement in zinc fume fever. Chest1987; 92: 946–948.

248) Farrell FJ. Angioedema and urticaria as acute and late


phase reactions to zinc fume exposure, with associatedmetal fume fever-like symptoms. Am J Ind Med 1987;12: 331–337.

249) Kawane H, Soejima R, Umeki S, Niki Y, Malo JL.Metal fume fever and asthma (letters). Chest 1988;93: 1116–1117.

250) May JJ, Stallones L, Darrow D, Pratt DS. Organicdust toxicity (pulmonary mycotoxicosis) associatedwith silo unloading. Thorax 1986; 41: 919–923.

251) Lecours R, Laviolette M, Comier Y. Bronchoalveolarlavage in pulmonary mycotoxicosis (organic dusttoxic syndrome). Thorax 1986; 41: 924–926.

252) Malo JL, Cartier A. Occupational asthma due to fumesof galvanized metal. Chest 1989; 92: 375–377.

253) Malo J-L, Cartier A, Dolovich J. Occupational asthmadue to zinc. Eur Respir J 1993; 6: 447–450.

254) Ameille J, Brechot JM, Brochard P, Capron F, DoreMF. Occupational hypersensitivity pneumonitis in asmelter exposed to zinc fumes. Chest 1992; 101: 862–863.

255) Hadji Michael OC, Brubaker RE. Evaluation of anoccupational respiratory exposure to a zirconiumcontaining dust. J Occup Med 1986; 23: 543–547.

256) Newman L, Storey E, Kreiss K. Immunologicevaluation of occupational lung disease. State of theArt Rev Occup Med 1987; 2: 345–372.

257) Newman Taylor AJ, Davies RJ. Inhalation challengetesting. In: H.Weil H, Turner-Warwick M, eds.Occupational lung diseases. Lung Biology in Healthand Disease. Vol. 18, Basel: Dekker, 1981: 143–167.

258) Reynolds HY. Bronchoalveolar lavage (State of theart). Am Rev Respir Dis 1987; 135: 250–263.

259) Begin RO. Bronchoalveolar lavage in thepneumoconioses. Who needs it? Chest 1988; 94: 454.

260) Rom WN, Bitterman PB, Rennard SI, Cantin A,Crystal RG. Characterization of the lower respiratorytract inflammation of non-smoking individuals withinterstitial lung disease associated with chronicinhalation of inorganic dust. Am Rev Respir Dis 1987;136: 1429–1434.

261) Lauwerys RR. Biological monitoring of metals: anoverview. In: Fishbein L, Furst A, Mehlman MA. eds.Genotoxic and carcinogenic metals: environmentaland occupational occurrence and exposure. Vol. XIin Advances in Modern Environmental Toxicology.Portmas: Princeton Scientific Publ., 1987: 265–278.

262) Ichikawa Y, Kusaka Y, Goto S. Biological monitoring

of cobalt exposure, based on cobalt concentrations inblood and urine. Int Arch Occup Environ Health 1985;55: 269–276.

263) Abraham JL. Recent advances in pneumoconiosis:the pathologist’s role in etiologic diagnosis. In:Thurlbeck WM, Abell MR, eds., The Lung. Structure,Function, and Disease. Baltimore: Williams &Wilkins, 1978: 96–137.

264) Roggli VL, Ingram P, Linton RW, Gutknecht WF,Mastin P, Shelburne JD. New technique for imagingand analyzing lung tissue. Environ Health Perspect1984; 56: 163–183.

265) Joohnson NF, Haslam Pl, Dewar A, Newman TaylorAJ, Turner-Warwick M. Identification of inorganicdust Particles in bronchoalveolar lavage macrophagesby energy dispersive X-ray microanalysis. ArchEnviron Health 1986; 41: 133–144.

266) Dinsdale D, Bourdillon AJ. The ulrastructurallocalization of beryllium in biological samples byelectron energy-loss spectrometry. Exp Mol Pathol1982; 36: 396–402.

267) Jones Williams W, Kelland D. New aid for diagnosingchronic beryllium disease (CBD): laser ion massanalysis (LIMA). J Clin Pathol 1986; 39: 900–901.

268) Langer AM. Mineral dust and Pulmonary lesions:etiological link or epiphenomenon. Am J Ind Med1984; 6: 169–171.

269) Van Ordstrand HS, Hughes R, De Nardi JM, CarmodyMG. Beryllium poisoning. J Am Med Assoc 1945;129: 1084–1090.

270) Repscher LH. Treatment and prognosis. In: RossmanMD, O.P. Preuss OP, Powers MB, eds. Beryllium.Baltimore: Williams and Wilkins, 1991: 177–182.

271) Sunderman FW Jr. The extended therapeutic role ofdithiocarbamate (sodium diethyldithiocarbamate)from nickel poisoning to AIDS. Ann Clin Lab Sci1992; 22: 245–248.

272) Levene GM, Calnan CD. Platinum sensitivitytreatment by specific hyposensitization. Clin Allergy1971; 1: 75–82.

273) Chan-Yeung M. Occupational asthma update. Chest1988; 93: 407–411.

274) Crystal RG, Gadek JE, Ferrans VJ, Fulmer JD, LineBR, Hunninghake GW. Interstitial lung disease:current concepts of pathogenesis, staging and therapy.Am J Med 1981; 70: 542–568.

Metal-Induced Lung Disease: Lessons from Japanâ€™s Experience

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