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Eur Respir J REVIEW 1990,3,202-219

Metal and the

B. Nemery

Melal toxicity and the respiralory tract. B. Nemery. Laboratory of Long , Division of Pneu­ ABSTRACT: The type of caused by compounds depends mology and Dept of , K. U. on the nature of the offending agent, Its physicochemical form, the dose, Leuven, Leuven, Belgium. exposure conditions and host factors. The fumes or gaseous forms of several , e.g. (Cd), (Mn), (Hg), carbonyl Correspondence: B. Nernery, Laboratorium , ), Longtoxicologie, Kapucijnenvoer3S, B-3000 Leuven, (NI(C0)4 chloride (ZnCI ), pentoxide (V20 5 may to acute chemical and pulmonary oedema or to acute tracheobron­ Belgium. chitJs. Metal fume , whlc.h may follow the of metal fumes e.g. zinc (Zn), copper (Cu) and many others, is a poorly understood ­ Keywords: Awtetracheobronchitis; bronchial ; ; chronic obstructive lung dis­ like reaction, accompanied by an acute self-limiting neutrophil alveolitls. ease; fibrosing alveolitis; interstitial lung disorder; Chronic may result from occupational exposure to lung ; ; metals; occupational dusts, including probably some metaliic dusts, or from jobs involv­ lung ; . ing the worldng of metal compounds, such as . Exposure to cadmium may lead to emphysema. Bronchial asthma may be caused by complex Received: May 29, 1989; accepted after revision July salts, nickel, or , presumably on the basis of allergic 31, 1989. sensitlzatlon. The cause of asthma In workers Is unknown. It is remarkable that asthma Induced by nickel (NI) or chromium (Cr) Is appar­ ently Infrequent, considering their potency and frequent Involvement as dermal sensltizers. Metallic dusts deposited in the lung may give rise to pulmonary and functional impairment, depending on the fibrogenic potential of the agent and on poorly understood host factors. Inhalation of compounds causes , a pneumoconiosis with little or no fibrosis. Hard metal lung disease Is a fibrosis characterized by desquamative and giant cell Interstitial pneumonitis and Is probably caused by cobalt, since a similar disease has been observed in workers exposed to cobalt in the absence of tungsten carbide. Chronic disease is a fibrosis with sarcoid-like epithelold granulomas and is presumably due to a cell-mediated immune response to berylllum. Such a mechanism may be responsible for the occasionally found In subjects exposed to other metals e.g. aluminium (AI), titanium (TI), rare earths. The proportion of attributable to occupation Is around 15%, with exposure to metals being frequently lncrlmlnated. Underground of e.g. or Iron Is associated with a high incidence of lung cancer, as a result or exposure to radon. At least some forms of , chromium and nickel are well estab­ lished lung in humans. There is also evidence for increased lung cancer mortality in cadmium workers and In lron or steel workers. Eur Respir J., 1990, 3, 202-219.

For centuries metals have been known to be capable of silicon. This review will, therefore, not deal with causing human diseases, including pulmonary disease workers pneumoconiosis, (caused by crystalline [1-8]. Elements may be defined as metals on the basis of free silica or SiOz), -related disease (caused by their physical or chemical properties, but these defini­ some fibrous silicates) or pneumoconioses caused by other tions do not allow a sharp distinction to be made silicates such as , mica, kaolin etc., although silicates between metals and non-metals, because a number of are associated with various cations including aluminium elements, e.g. arsenic (As), (Bi), gennanium (Ge), (Al). magnesium (Mg) or iron (Fe). These "classical" (Sb), (Se) and tellurium (Te), often pneumoconioses constitute the majority of lung diseases called , share properties of both. From a toxi­ due to mineral dusts and they have been extensively cological viewpoint, a metal can be defined as "an studied and reviewed. element which under biologically significant conditions In contrast, lung diseases caused by mineral compounds may react by losing one or more electrons to fonn other than or silicon probably concern fewer cations" [9]. individuals, who often work in small industries with For the purposes of this review we may consider generally poor characterization of exposure. Consequently, that metal-induced lung diseases are those lung disorders lung disorders caused by metals have been less well caused by mineral compounds other than carbon and studied and this may pose problems for occupational AND THE RESPIRATORY TRACT 203

who need to prevent such disorders and for and other metals bind to , a pulmonary physicians who have to diagnose and treat low-molecular weight protein rich in sulphydryl (SH) them. groups. This process also plays a role in the defence The present review focuses on human data, rather than against cadmium, but it eventually to the retention on information obtained from animal or in vitro experi­ and progressive accumulation of cadmium in various mentation. Information which is available in standard texts tissues, including probably the pulmonary [12]. [~8] has been taken as such, whereas more recent 3) The interaction of metals with functional groups on acquisitions are emphasized and referred to more specifi­ macromolecules is an important mechanism for their cally. As usual, studies showing disease have been given toxicity and their carcinogenicity [13, 14]. Thus, several more attention than "negative" studies. This survey will metal react avidly with free SH groups, thereby not consider routes of exposure other than inhalation, possibly inhibiting active centres of enzymes, coenzymes although the may be affected via the by or membrane bound receptors. Direct interaction of metal containing drugs or chemicals, e.g. salts. metals with deoxyribonucleic acid (DNA) is one of the possible mechanisms for metal carcinogenesis (as well as for the chemotherapeutic effects of some metal General toxicity of metals [9] complexes). 4) Another toxicologically relevant consequence of metal People are rarely exposed to the pure metallic form binding to proteins is the possible acquisition of antigen­ (zero ) of metals or metalloids, but more kit¥. Thus platinum, chromium, nickel and cobalt are usually to oxides (or other binary metal compounds, such sensitizers probably by mechanisms similar to those of as sulphides, halides, hydrides, carbides, etc.) or to other reactive organic molecules of low molecular weight multielement compounds, mainly saiLS. Metals, most which may function as haptens. notably transition metals, can also form co-ordination The biological activity and toxicity of some metals is complexes with various e.g. ammonia ~). also greatly influenced by their ability to change their carbon monoxide (CO), cyanogen (CN·), organic nitro­ oxidation state by oxidation (loss of electrons) and gen or sulphur molecules. Some metals may also form reduction (gain of electrons). Transition metals are elec­ organometallic compounds in which the metal is bound tronically stable in more than one oxidation state. As a to the carbon atom of an organic group. The chemical result of this property, transition metals play important form of a metal, also called metal speciation, and the roles in catalysing biological oxidation reactions. Of the resulting physicochemical properties have important con­ transition metals, iron and to a lesser extent copper have sequences in terms of toxicokinetics and biological been extensively studied because of their implication in effects. many pulmonary and non-pulmonary disease processes Thus, the biological availability and absorption of by virtue of their ability to enhance the production of metals will be greatly influenced by their in toxic free-radical species of [10, 11, 15]. In water and lipids, but more importantly by their actual pulmonary toxicology, free-radical , which solubility in biological fluids, which contain a variety of seems always to involve metal catalysis [16, 17], is organic ligands. For instance, the more insoluble the considered to be a mechanism for the effects of hyper­ metal compound deposited in the airways, the more likely oxia [18], paraquat [19], nitrofurantoin [20] and asbestos tliat it will be cleared by the mucociliary escalator. Con­ [22]. However, inhaled metals have so far received rather versely, soluble salts will readily dissociate, thus facili­ less attention in this respect. tating their transport as metal ions into lung cells or into the blood circulation. The strong attraction between metal ions and organic Pulmonary disorders due to metal exposure ligands situated within tissue molecules results in the General remarks binding of the metal to those molecules. This under­ lies a number of the biological effects and toxic actions Before discussing the various lung disorders caused by of metals: metals it is worth emphasizing some important points: 1) Some metals e.g. iron (Fe), copper (Cu), manganese (Mn), cobalt (Co), zinc (Zn), chromium (Cr) are 1. The is not necessarily the only, or essential as coenzymes for many enzymes. Dysfunction the principal, target for the toxicity of metal compounds, in these enzymatic processes may, therefore, result from even when their entry to the body is by inhalation. Thus, deficiency states, but also from overwhelming by very the chronic inhalation of lead, mercury or manganese high doses of the essential metal or through substitution may lead to systemic effects, such as neurological damage, and mimicry of essential ions by inappropriate without leading to serious respiratory damage. Other compounds. metals, such as cadmium, are capable of causing both 2) The transport and accumulation of metals is often the lung and alterations, probably depending in part result of their ability to interact with ligands. Transferrin, upon the route of exposure. It is, therefore, important to ferritin, albumin and ceruloplasmin are the main be aware of possible extra-pulmonary manifestations in transport or storage proteins for Fe and Cu and their metal toxicology. abundance probably constitutes a safeguard against the On the other hand, from a scientific point of view, toxicity of free iron and copper ions [10, 11]. Cadmium non-toxicity in the lung may be toxicologically as 204 B. NEMERY

rele vant as frank toxicity, since the absence of serious the patient's history it is, therefore, not sufficient to fill pulmonary injury by inhaled metallic compounds having in the entry relative to occupation with a single job title significant toxicity for other systems may reveal to either demonstrate or exclude occupational exposure the existence of an effective defence mechanism within to metals. In some cases a more thorough enquiry with the lungs (even if this mechanism is obviously not a plant , an occupational hygienist or toxicolo­ the sole basis for the existence of selective targets for gist will be necessary. toxicity). The pulmonary disorders due to inhaled metallic compounds are quite diverse. Two approaches may be 2. Lung disease found in people who are occupationally adopted to describe them. Either the metals can be listed exposed to metals is not necessarily due to these metals. and their possible pulmonary effects enumerated [33], or The most obvious example is the presence of ­ different disease entities can be grouped and their related lung disease in industrial workers. On the other possible metal etiologies discussed [34). For this review hand, cigarette smoking often obscures, or interferes with, we have chosen the second option, but the main toxicity the possible occupational origin of chronic obstructive of the individual metals is given in a summary form in pulmonary disease or lung cancer in the individual table 1. patient Other examples of mixed exposures to metals and non-metals concern silicosis and asbestos-related lung disease in iron or other metal foundries. In metal smelt· Acute toxic effects: chemical pneumonitis and , ing, cutting or burning, as well as during welding, toxic metal fume fever gases are produced in addition to metal oxides. In these Exposure to high concentrations of the fumes of sev­ instances sulphur dioxide (S0 ), ozone (0 ), or 2 3 eral metals can lead to acute pulmonary manifestations, dioxide (N0 ) and other volatile compounds released from 2 the outcome of which can range from complete recovery the pyrolysis of coating materials or solvents and to death depending on the agent involved. degreasers, rather then the metals themselves, may be responsible for acute or chronic airway or lung disease. Chemical pneumonitis and bronchitis. The most severe Organic compounds are also present in metal industries, form of acute pulmonary damage is chemical pneumo­ e.g. isocyanate asthma has been described by several nitis which classically follows the inhalation of cadmium groups in iron and steel plants, in processes where fumes (7]. Cadmium is present in several areas of synthetic resin binders are used [23-26). metallurgy; from a practical point of view, the important points to be aware of in relation to the risk of cadmium 3. Exposure to metals is not confined to workers involved pneumonitis are: I) that cadmium oxides may be in metal mining or metallurgy. Metal compounds are liberated from the welding or burning of cadmium­ indeed used in almost every sector of industry and even containing alloys [35) or from the smelting of zinc or in agriculture. Thus, cobalt-induced fibrosing alveolitis lead [36], which often contain significant levels of and bronchial asthma have been described in diamond contaminating cadmium; and 2) that exposure to toxic polishers who used cobalt-containing polishing discs [27, levels of cadmium fumes does not necessarily lead to 28]. Dental technicians are at risk of pneumoconiosis immediate respiratory symptoms. Indeed respiratory [29, 30]. Several processes in the electronics industry distress is usually delayed for several hours involve the use of metals or metalloids, e.g. gallium, until severe non-cardiogenic pulmonary oedema germanium, the toxicology of which is often poorly develops [7]. known. Numerous metal compounds are used as The inhalation of other metallic compounds can also pigments in the paint industry, as catalysts in the chemi­ cause acute pulmonary damage. Past literature [7), and cal industry, or as additives in the plastics industry, where recent reports of accidental and non-accidental exposures they have not so far been reported to cause much show that exposure to fumes or dusts containing . However, to give an example of an beryllium, cobalt, manganese, mercury [37, 38], a priori unsuspected use of metals, a case of asthma to nickel carbonyl [Ni(C0)4] [39), and osmium are cobalt was recently diagnosed in a man working in the capable of causing chemical pneumonitis or acute airway animal feed industry, where he was involved in the irritation. Cases of adult respiratory distress syndrome addition of cobalt sulphate to the feed (used for the have recently been reported in military or civilian prevention of cobalt deficiency in cattle) [31] (Dr E. personnel accidentally exposed to smoke bombs which Stevens, personal communication, unpublished). ) liberate zinc chloride (ZnC11 [40, 41). Antimony ) trichloride (SbCi:s) and pentachJoride (SbCl5 [7], ) 4. Significant exposure to metals is not confined to the zirconium tetrachloride (ZrCI4 [7], titanium tetrachlo­ work environment. Hobbies and domestic activities may ride (fiCI.) [42] and uranium bexanuoride (UF~ [43] lead to significant exposure. A classical example of para­ may also lead to inhalation injury (presumably as a result occupational exposure is that of in housewives of damage by the halide ion, rather than by the metal ) and family contacts of beryllium-workers who brought ion). hydride (LiH) and (PH3 have factory-dust to their homes [32). also been reported to cause pulmonary oedema [7). From these introductory considerations we may con­ It is worth mentioning that the inhalation of the clude that the pulmonary physician should always hydride forms of arsenic (arsine, AsH3) or antimony remember that metal exposure is ubiquitous. When taking (stibine, SbH,) can also be lethal as a result of fulminant Table 1. - Summary of pulmonary toxicity of metals

Exposures and uses• Acute toxicity Airways.. t Lung parenchyma••• Lung cancert••• Extra-pubnonary toxicitytt Coounents

Aluminium Bauxite, cryolite, Potroom asthma, Fibrosis (rare), (), CNS Pubnonary AI electrical engineering, bronchial hyperreactivity, (granulomatous fibrosis], disease rare transport & building industry, (fluorides?, some salts), (alveolar proteinosis) considering packaging, ab111sives COLD extensive use

Antimony Alloys (with Sn, Pb, Cu), Pneumonitis (SbCI,, Benign pneumOCQniosis, Possible Heart Often concomiWll Sb chemical & textile SbCI,), haemolysis (antimoniosis) exposure to As 3: industry, pigments, (SbH,) rrl >-l ceramics, glass > r >-l Arsenic Smelting of Cu, Pb, Metal fume fever, Nasal seplUm Defmite , PNS, C-V system, 0 >< As gold (Au), Zn, Co, haemolysis (AsH,) perforation blood 5 glass, pigments, tanning, >-l -< pesticides, alloys >z tj Barium Alloys, paints, glass, Benign pneumoconiosis, Heart >-l :I: Ba ceramics () rrl ~ Cll Beryllium Alloys (with Cu), Pneumonitis, G111nulomatous fibrosis, Suspect Skin Cell-mediated ~ Be ceramics, electronics, metal fume fever (chronic beryllium immune response, > "'>-l nuclear, space, aircraft, disease, berylliosis) LIT in BAL 0 dental technicians, metal lympbocytes "'-< reclaiming >-l > "'() Cadmium In association with Zn & Pb Pneumonitis, COLD Emphysema, Suspect Kidney Cumula.tive metal >-l Cd alloys, , metal fume fever (fibrosis in animals) (in man & environment) batteries, pigments, plas1ics, welding electrodes & , cigarettes

Chromium Alloys (), Allergic asthma (111re?) Defmite (CrVI) Contact Strong sensitizer Cr , pigments, nasal seprum perfo111tion (frequent) ref111ctory bricks, tanning, welding

Cobalt Alloys, hard metal Pneumonitis, Allergic asthma, Fibrosing alveolitis, Possible Heart, Giant cells in BAL Co (with wq, diamond metal fume fever COLD ("hard metal lung disease", contact dermatitis N 0 polishing, magnets, "cobalt-lung") t.ll pigments, catalystS, animal feed Table 1. 2 tv 0 Exposures and uses• Acute toxicity Airways ..t Lung parenchyma*** Lungcancert*.. Extn-pulmonaJY toxicitytt Ccmments 0\

Ccpper Electrical equipment, Metal fume fever "Vineyard sprayen'lung" Skin Cu .smelters: As, Cu alloys (brass=Cu+Zn, sol bronze=Cu+Sn), pesticides, pigments

Gold JewelleJY, (Pneumonitis wilh Skin Gold refm.ing: Hg Au lherapeutic gold salt therapy)

Iron Mining, Metal fume fever COLD Benign pneumoconiosis, mines Concomitant , Fe steel (siderosis) (radon?), Si02 asbestos, foundries (PAH ?) catalysis of Fentoo reaction (oxygen free radicals) Lanlhanons Pboloengraving, Fibrosis, (ran: earlhs) glass (rare eanh pneumoconiosis, CeriumCe, cerium pneumoconiosis)

Lead Lead smelting, Metal fume fever G-1 tract, CNS, PNS, Contamination Pb alloys, batteries, pigments, kidney, blood withCd, paints, welding, cnvirorunental petrol (alkyllead) concern ?' z Lithium Alloys, ceramics, Pneumonitis (LiH) m ~ u electronics, catalysts m ::0-< Magnesium Alloys Metal fume fever Mg

Manganese Steel, alloys, baoeries, Pneumonitis, COLD CNS Methylcyclopenta- Mn pigments, welding, chemical metal fume fever dienyl manganese industry, meW slags tricarbonyl (MMT) (fertilizer) lung damage in animals

MttCUJY Otlor-alkali industry, Pneumonitis, CNS,Ir.idney, Saturation of air Hg electrical, paints, measuring, metal fume fever contact dermatitis with Hg rapidly pesticides, drugs, dentists, achieved, gold & silver refming envirorunental concern

Nickel Alloys, nickel plating, coins, Metal fume fever, Allergic aslhma Defmite (mainly low Contact dermatitis Slnlng sensitizer Ni batteries, eleci.J'Oilics, pneumonitis [Ni(CO).] (rare) solubility comp.), (frequent) catalysts, cheap jewellery also nasal cancer

Platinum Catalyst, photography. Allergic Contact dermati.tis Anaphylactic Pt jewelleJY, cbemod!erapeutic and asthma following agent (complex halide salts) trealmenl wilh cisplatinum drug Table 1.3

Exposures and uses• Acute toxicity Lung parenchyma*** Lung canoert••• Exua-pubnmary t~icilytt Comments

Osmium Electron microscopy Bronchitis, Os pneumonitis

Selenium Byproduct of Cu Pneumonitis Garlic odour Se refining, alloys, pigments, breath, (also with electronics, rubber, glass tellurium)

Silver Alloys, , Discoloration of ::: m Ag photography,catalys~ skin and mucosae o-j () > jewellery i' o-j 0 Tm plating, alloys, Metal fume Benign pneumoconiosis >< Sn welding fever (starmosis) n =i Usually oonsidered -< TIIAnium Alloys, Pneumonitis (fiQ•) COLD? [granulomatous pneumonitis] > white pigment (fi0 ) to be inert n 3 ~ o-j Probably not directly :I; Tungsten Hard metal (WC+Co+other tn w metals), cutting, drilling, involved in polishing tools hard metal lung disease ~en ~ Uranium Nuclear fuel Pneumonitis (UFJ Defmite Kidney > u cl "'-< Vanadium Steel, alloys, catalys~ Tracheobronchitis, Broncflial hyperreactivity Green tongue, ...., (boilermaker's metallic taste V pigments, > present in fuel ash & bronchitis) "'(") metal slags o-j

Zinc Alloys, brass, Metal fume fever, [Asthma? Contamination Zn galvanizing, pneumonitis (ZnC9 (galvanized steel welding)] withCd pigments, pesticides, Zn~ (smoke bombs)

Zirconium Alloys, nuclear, industry, Pneumonitis (ZrO.) Benign pneumoconiosis Skin granulomas Pulmonary Zr pigments, catalysts, granulomas in abrasives animals

This summary is compiled from general souw:s [3-7] and is intended only for use as a quick reference. Not all species of a metal cause the indicated disorder; the reader is referred to the text and original references for a complete description of exposun: conditions and diseases. Metals not indicated in the table have not been associa.ted with respiratory disease in humans. •: only typical or noteworthy uses are indicated; **: in general, chronic excessive ~sure to mineral dust may lead to industrial bronchitis and possibly chrmic ob5lructive lung disease (COLD): t: high temperature treatments of metals during refinery, smelting, CUtting or welding may Lead to exposure to toxic gases and/orcarcinogenicorganiccompounds: .,. •: undergrolDld mining ofmetal ores may lead to exposure to free silica and/or radon dAughters; tt: only some selected target-organs are indicated, particularly when relevant S to chronic exposure by inhalation. C-V system: cardio-vasrular system: G-I Ullct: gastro-intestinal uact; PNS: peripheral : CNS: central nervous system: LTI: lymphocyte transformation test: BAL: . Diseases in square bradcets [ J concern isolated case reports. 208 B.NEMERY

haemolysis, which may sometimes manifest itself Chronic obstructive lung disease initially ~s dyspnoea. Chemical pneumonitis has often been said not to There is no doubt that the main exogenous cause of lead to sequelae, however, this is certainly not a rule chronic obstructive lung disease and emphysema in the and in several case reports various chronic pulmonary general population is cigarette smoking [58]. However, manifestations, such as fibrosis, bronchial lesions or clinically important airflow limitation occurs in less than airway hyperreactivity were shown to follow the acute 15% of smokers [59]. In our opinion, this concept under­ episode [35, 37, 38, 42-44]. scores two important points with regard to occupational Acute tracheobronchitis with persisting bronchial factors. Firstly, since the basis for the susceptibility to hyperreactivity [45] can be caused by exposure to cigarette smoke is still largely unknown, there is no a

vanadium pentoxide (Vz05), a significant risk asso­ priori reason why subjects who are (or would be) ciated with the cleaning of oil tanks ("boilermaker's particularly susceptible to smoking-induced lung and bronchitis") [46, 47]. Exposure to chromic acid during airway disease, will not be equally susceptible to chrome-plating leads to upper airway lesions, particu­ respiratory insults from the occupational environment, larly nasal septal ulceration and perforation, which, in a including metallic compounds which are capable of recent study, was found in an astonishing two thirds causing tissue destruction and . Secondly, of subjects exposed to moderately high peak levels even for environmental substances which would carry a of Cr [48]. risk similar to that of cigarette smoking (i.e. affecting "only" 15% of the exposed subjects) the chances of Metal fume fever. A more benign condition following conclusively demonstrating such a risk are small because exposure to high concentrations of metal fumes, of: i) the relatively small number of subjects exposed; particularly but not exclusively , is metal ii) the complexity of the exposures (in terms of their fume fever [49, 50]. This condition, of which there nature as well as their intensity and duration); iii) the are several synonyms [7). is an influenza-like high prevalence of smoking, particularly in industrial or malaria-like reaction consisting of fever, and populations [60]; and iv) selection factors collectively malaise with relatively mild respiratory symptoms, known as "the healthy worker effect" [61]. and classically little or no X-ray or functional abnormali­ Despite these methodological difficulties, several ties, although this is not always the case [51, 52]. recent studies have shown that occupational factors may The symptoms, often accompanied by a sweet metallic cause not only symptoms of industrial bronchitis, but taste in the mouth, usually begin at home a few hours also loss of ventilatory function, which may be of similar after a heavy exposure to metal oxides, e.g. after magnitude to that associated with cigarette smoking [61]. welding in a confined space, and they then subside spon­ This view, however, is not universally accepted and the taneously. Leucocytosis is present during the acute issue of the real impact of occupational exposures on illness. A recent report of bronchoalveolar lavage ventilatory function is still controversial [62-64]. In findings in a case of zinc fume fever showed marked practice, it remains impossible to determine the contribu­ neutrophil infiltration, and appropriately posed the ques­ tion of occupation in the causation of chronic obstructive tion of how such spectacular inflammatory events lung disease in the individual smoking patient. remain so self-limited [53]. A strange feature of this The mainly longitudinal studies that have led to the syndrome is the occurrence of tolerance: symptoms only conclusion that significant airflow limitation may result appear when exposure takes place after a period of days from dust exposure, have essentially involved coal without exposure and they do no appear on subsequent miners [65-67], grain dust exposed workers [68] or days. workers exposed to poorly defined '\ndustrial dust, fumes The exact pathogenesis of metal fume fever is poorly or gases" [69]. No such studies have been performed understood. In some instances allergic mechanisms may with workers exposed to specific metallic compounds be involved [54], but then metal fume fever may be a and the available information, therefore, mainly stems misnomer or may be superim posed on bronchial asthma from less powerful cross-sectional observations. or hypersensitivity pneumonitis [55). There is a striking The as yet somewhat controversial issue of whether resemblance between metal fume fever and the organic chronic cadmium fume inhalation leads to pulmonary dust toxic syndrome, which occurs after heavy exposure emphysema [70, 71) has recently been senled by the to organic dust contaminated with micro-organisms [56]. results of a study of a large group (n=101) of workers Both syndromes have a similar clinical course with fever, and ex-workers from a cadmium alloy factory in England leucocytosis, acute transient neutrophilic alveolitis [57] [72). This study showed a clear excess of functional and occurrence of tolerance. These similarities indicate (ventilatory function and ) and common pathogenic mechanisms. radiological signs of emphysema in the exposed subjects With appropriate environmental control measures, compared to appropriate controls. The causal role of cases of metal fume fever are fortunately not cadmium was strengthened by the existence of a positive common any more, but the disease has certainly not relationship between effects and dose, with the latter being disappeared and is presumably often overlooked as a estimated both by past hygiene measurements and by the simpleviral . Metal fume fever is said not to internal (liver) cadmium burden. Moreover, the lead to sequelae, but this has not been adequately significance of these findings has been borne out by investigated. the demonstration of an increased mortality from METAL TOXICITY AND THE RESPIRATORY TRACT 209

non-malignant respiratory disease in cadmium-exposed In view of the widespread use of Ni, Cr and Co and workers [73, 74]. The mechanisms for cadmium-induced the occurrence of respiratory exposure in many occupa­ emphysema are not elucidated. Animal studies suggest tional settings, it is remarkable that these metals are so that fibrosis, rather than alveolar wall destruction, rarely incriminated as causing , precede the development of emphysematous lesions particularly when it is realized that they are well known [75-77]. by dermatologists for their potential to cause dermal sen­ Cross-sectional studies have also suggested an increased sitization [128, 129]. Contact dermatitis caused by Cr is prevalence of chronic bronchitis and a loss of ventilatory indeed the most prevalent occupational dermatitis in men, function, sometimes mainly of forced and Ni is the most prevalent contact allergen in women (FVC), associated with chronic exposure to beryllium (probably because of exposure to jewellery), with cobalt­ [78), aluminium [79, 80], cobalt (or hard metal) frequenlly being associated. It should be remem­ [81-83), manganese [84]. or tHanium dioxide (TiOJ bered that epidcmlological investigations conducted after [85], apparently independently from the overt forms of the discovery of a single case of occupational asthma other respiratory diseases seen wilh some of these metals have generally disclosed the existence of many more cases (see below). However, other surveys of workers exposed [130); the relative rarity of respiratory rather then dermal to these compounds do not always reach the same con­ manifestations of metal sensitization may, therefore, result clusions (86-89), possibly because of differences in total in part from underdiagnosis and underreporting. dust, in concomitant exposures, or in population charac­ However, it is unlikely that this is the only explanation; teristics and study designs. differences related to route of exposure and mechanisms Studies of the effect on ventilatory function in groups of sensitization must be involved. Contact dermatitis is such as "steel workers" [58, 90-92) or "metal not an IgE-mediated type of allergy, but a "cellular" welders" (64, 93-101] have been largely negative, allergy [131). It is noteworthy that, at least in the case inconclusive or showing only small effects, despite the of cobalt. a condition more usually considered to be generally consistent finding of increases in the preva­ cell-mediated [132], such as alveolitis [27, 116], and lence of chronic bronchitis, defined by questionnaire. asthma combined with alveolitis [133], has been However, for the methodological reasons alluded to above, described. The apparent absence of correlation between one should not conclude that there are no specific work respiratory and dennal manifestations of occupational processes within these broad categories which entail a allergy to metals is a subject that should merit further risk of significant obstructive respiratory impairment in epidemiological and experimental research. susceptible subjects. It is not known whether the general features of occu­ pational asthma caused by smaii molecular weight Bronchial asthma compounds also apply to metal-induced asthma, but it is fair to assume th3llhis is so. In this case, there is proba­ Several metals are known to be capable of causing bly no relationship between a background of atopy and bronchial asthma [102-105]. The complex halide salts the occurrence of occupational respiratory allergy to of platinum (Pt) provide a unique example of a situation metals [103-105, 134, 135). Cigarette smoking [136] or where a very considerable proportion of exposed exposure to other irritantS such as ozone [137] may well subjects may become sensitized [102). There is good prove to be a more imponant determinant (in interaction evidence for an immunoglobulin E (IgE)-mediated mecha­ with atopy) for the occurrence of asthma in the allergen­ nism in platinum salt asthma [102, 106, 107). However, exposed individual (although the converse seems to hold the determination of Pt-specific by radio­ for occupational asthma due to isocyanates, which is allergosorbent test (RAST) is less sensitive than skin probably not IgE-mediated) [138]. testing in the clinical diagnosis of Pt-hypersensitivity, Another recent concept, which has emerged consis­ possibly because of a frequent increase in total lgE [107). tently from follow-up studies of occupational asthma from Other metals reported to cause asthma, mostly in case various causes, is the need for a rapid and total removal reports, are nickel (108-111), chromium (112, 113) and from exposure of symptomatic people in order to prevent cobalt [28, 87, 114-118). There is evidence for specific permanent asthma [139, 140). It is reasonable to adopt (lgE) formation against protein-conjugates of the same attitude in metal-induced asthma, although the nickel (Ni) [109, 110, 119] and cobalt (Co) (1 18, 120, ubiquity of some of the metals involved may weiJ make 121), thus, suggesting that asthmatic reactions to these total avoidance of exposure very difficult to achieve in metals also result from an IgE-induced response. In a practice. recent report [122) of asthma in subjects welding galva­ nized metal, sensitization to zinc was suggested; however, the possible presence of other metals such as Interstitial lung disorders Co, which can be present in galvanized metal [31], was not addressed. The causative agent of asthma ("potroom­ Metallic dusts deposited in the lungs may give rise to asthma") and bronchial hyperreactivity in aluminium more or less marked pulmonary fibrosis, depending on smelters (or other workers exposed to aluminium salts) the intrinsic properties and amount of the inhaled agent, [126, 127] is not known; the condition is not felt to be as well as on hitherto poorly understood host factors. due to allergic mechanisms, but rather to an inflamma­ The fibrogenic potential of inhaled substances is tory reaction to irritation by fluorides. presumably detcrfl)ined by their ability to interfere with 210 B.NEM ERY

the pulmonary immuno-inflammatory system, either pulmonary fibrosis have been described in various areas directly, e.g. via effects on alveolar , or of the world [81, 88, 11~116, 148-153). On the basis of indirectly, e.g. via injury to epithelial cells. In relatively crude animal data [154) showing little toxicity other words, as in other forms of interstitial lung from the main constituent of hard-metal, i.e. tungsten disease, the fibrotic process is probably dependent on the carbide, the consensus is that tungsten carbide is not the occurrence of alveolitis with an abnormal release of agent responsible for the fibrosis, but that it is more mediators by some cells [140, 141]. It must be recog­ probably due to the binding agent, i.e. cobalt. nized, however, that the exact pathogenic mechanisms of The pneumonitis is often of the desquamative type, lung fibrosis, whether caused by metals or by other agents, and in the subacute forms it appears to be mainly char­ have not been elucidated despite intense research efforts. acterized by the presence of multinucleated giant cells Within the conceptual framework that continued pul­ (to the extent that the proposal was made that giant cell monary injury and/or inflammation ultimately lead to interstitial pneumonitis (GIP) may be pathognomonic for fibrosis, the metal pneumoconioses may be categorized hard-metal exposure) (155]. The aetiological role of cobalt into three broad categories: 1) "benign" pneumoconioses in giant cell interstitial pneumonitis has been strongly with little or no fibrosis, e.g. siderosis; 2) pneumoco­ supported by the observation of several cases of a disease nioses with features of diffuse interstitial pneumonitis identical to hard-metal lung disease in diamond polish­ e.g. hard-metal lung disease; and 3) pneumoconioses with ers, who used polishing discs made with microdiamonds sarcoid-like epitheloid granuloma formation e.g. (not tungsten carbide) cemented with cobalt [27, 156]. berylliosis. The term cobalt-lung has, therefore, been proposed [27]. The mechanisms for the pulmonary toxicity of cobalt 1. Pneumoconioses without fibrosis. Of the "benign" have not yet been discovered [121, 146). Unlike the pneumoconioses the most frequent and best studied is classical pneumoconioses in which the lung burden of siderosis, which is caused by the inhalation of iron dust seems to be the predominant factor in causing the compounds [6, 7, 33]. disease (even if host factors do play a role in these diseases Occupational exposure to iron occurs during iron also), several features of cobalt-lung suggest some form mining and related operations, during iron refining and of hypersensitivity or host idiosyncrasy, perhaps at various stages in steelmaking, during welding, cutting analogous to the situation observed with beryllium (see and abrading of iron-containing materials, as well as below). Indeed for both beryllium and cobalt the dose­ during the manufacture or use of iron-containing abra­ response relationship is not straightforward: on the one sives (such as emery). hand the attack rate of the disease appears to be Siderosis is a "radiological disorder" in that it mani­ determined by the dose of exposure, but on the other fests itself by the presence of small, very radio-dense hand, within similarly exposed workforces only a small opacities with uniform distribution throughout the lungs, minority of sometimes very young subjects, with rela­ but without formation of conglomerates. With cessation tively little cumulative exposure, arc affected (27]. The of exposure the radiographic opacities may gradually known dermal sensitizing potential of cobalt and the disappear. Pure siderosis is not associated with respira­ existence of cobalt-asthma suggest immunological tory symptoms or functional impairment, and does not hypersensitivity to cobalt as causing the fibrosing alveo­ predispose to . However, it is important to litis. However, this is by no means proven, and other realize that exposure to silica or asbestos is not options must be envisaged, such as oxygen free-radical uncommon in many jobs that involve exposure to iron, mediated toxicity resulting from the ability of cobalt to thus giving rise to mixed dust fibrosis or to , promote the Fenton reaction [156]. which do have associated morbidity and complications. In view of the widespread use of cobalt in alloys, Moreover, the view that the symptomatic interstitial magnets, special corrosion resistant steels, pigments, fibrosis, which is sometimes found in welders (welder's plastics and many other applications [31] it is very pneumoconiosis), is simply siderosis with coexisting important to discover the determinants of the toxicity of silicosis has recently been challenged on the grounds this metal, both with regard to the chemical or physical that the pulmonary silicon content of such cases did not form of cobalt compounds that are "intrinsically" harm­ differ from that of control lungs [142]. ful, and the extent to which host or other factors may Other rare "benign" pneumoconioses include those render cobalt toxic. It is indeed remarkable that no lung caused by tin (stannosis), barium (baritosis), antimony fibrosis has been reported in workers involved in the [143, 144] and possibly zirconium [7]. mining or refining of cobalt [157], except perhaps for four cases which arose before World War II in a German 2. Hard-metal lung disease and "cobalt-lung". The con­ factory making cobalt carbonate [158]. dition known as hard-metal lung disease has been the Cobalt does not appear to be implicated, at least not in subject of renewed interest in recent years, particularly the same way as in the previous fibroses, in the causation with regard to the causative role of cobalt [145-147]. of dental technician's pneumoconiosis, which may arise Hard-metal or cemented tungsten carbide (WC) is from excessive exposure to dust produced from the found in tools used for high speed cutting, drilling, grind­ machining of vitallium, an alloy consisting of chromium­ ing or polishing of other metals or hard materials. In a cobalt-molybdenum [159]. Histologically this fibrosis is minority of workers involved in l.he manufacture or utili­ manifested by dense interstitial fibrosis around dust zation of these tools: bronchial asthma and diffuse deposits, without giant cells. Vitallium dust is, however, METAL TOXICITY AND THE RESPIRATORY TRACT 211

not the sole dust to which dental technicians may be components of carbon arc lamps used for photoengrav­ exposed, and other agents such as alginate [160), ing, and the majority of cases of this pneumoconiosis beryllium, hard-metal and silica may also cause lung have been described in photoengravers. Rare earths are disease in these workers [29, 30, 161, 162]. also used in the fabrication and polishing of glass. One histological report [1711 mentions the presence of gran­ 3. Interstitial lung disease with granuloma formation. ulomatous interstitial alterations, although this is not Berylliosis or chronic beryllium disease is well known mentioned in the other available pathological descrip­ for its striking histological and clinical resemblance to tions of cerium-pneumoconiosis [175]. . The clinical, epidemiological and experimen­ The authors of a recent report [1701 posed the interest­ tal aspects of the disease have recently been reviewed ing question as to whether aluminium-induced (163-165]. Apart from the extraction and primary pulmonary fibrosis or "aluminium-lung" may present in refining industry, beryllium exposure is an occupational its early stage as a granulomatous lung disease. The very risk in many sectors of modem technological industries, existence of aluminium-lung has been the subject of such as aircraft and aerospace, electronics, computers considerable controversy [176, 177]. Indeed, in view of and communications, where beryllium may be found in the extensive industrial use of aluminium, lung disease alloys (often with copper) or in ceramics. However, it is caused by exposure to this metal is very uncommon. On important to realize that scrap metal refiners [ 166]. reviewing past literature, DINMAN [176] concluded that non-ferrous metal welders, dental technicians, laboratory fibrosis only occurred: 1) in workers who were heavily maintenance or transport workers may also be exposed exposed to submicron-sized aluminium plates lubricated to an often unsuspected, but significant, risk. with an easily removed lubricant during the production The differential diagnosis between chronic beryllium of fireworks and explosives; and 2) in workers involved disease and other interstitial lung disease, mainly sar­ in the smelting of bauxite for the production of corun­ coidosis, rests essentially on the proof of exposure, which dum abrasive (Shaver's disease), but who were perhaps may be difficult to obtain solely on the basis of the also exposed to crystalline silica. However, isolated cases occupational history. The finding of beryllium in bio­ of alveolar proteinosis [178) or fibrosis in aluminium logical samples confirms ongoing (urine) and sometimes welders or polishers [170, 179-181] do not entirely past exposure (lung tissue, lymph nodes). Specific blast corroborate this conclusion. The physical characteristics transformation test of lymphocytes (LTI') in response to of the aluminium particles, notably their surface area, or culture with beryllium appears to be highly specific, but even their possibly fibrous nature [182], have been not very sensitive in peripheral blood lymphocytes, suggested as important determinants of their bioreactiv­ alLhough recent data suggest a great improvement in sen­ ity and hence fibrogenicity. sitivity in lymphocytes from the bronchoalveolar lavage Although the synthetic abrasive silicon carbide (SiC) [167]. or carborundum is not a metallic compound - in contrast to some other abrasives, such as corundum (A1p ) or This and other experimental evidence strongly suggest 3 that beryllium triggers a cell-mediated immune response, emery (corundum with iron oxides) - it is worth men­ thereby explaining the low incidence and high variability tioning that respiratory disease, including pneumoconiosis in time of onset of disease in exposed workers. However, with fibrosis, has been associated with exposure to SiC, the chemical and physical forms of beryllium probably during its manufacture or use [183-185]. also play a role, which remains to be clarified. It is possible that beryllium is not the sole metal Lung cancer involved in causing sarcoid-like lung disease. Zirconium may cause granulomas in human skin, but Several metallic compounds are proven lung carcino­ has not been associated with granulomatous or fibrotic gens in humans; they include radioactive metals (and lung disease in man [168]. Titanium, otherwise consid­ their decay products) and non-radioactive metals ered as virtually non-toxic, has been suggested as an [186-189]. aetiological agent in a case of granulomatous lung dis­ The increased incidence of lung cancer observed in ease on the basis of the presence of metallic uranium miners has been causally linked with the containing titanium in the lung granulomas and of a inhalation of radon daughters [190]. However, the positive blood L TI to titanium chloride, and not to the underground mining of other compounds may also be other metals tested, including beryllium [169]. On the associated with significant exposure to radioactivity, if basis of similar reasoning, aluminium exposure has there is insufficient ventilation of the radon which leaks also been suggested to have led to sarcoid-like lung from igneous rocks [191]. This factor has been impli­ granulomatosis in a patient who had apparently not cated in the higher incidence of lung cancer seen in been exposed to beryllium [170]. These cases confirm various groups of mineworkers, such as Swedish iron ore that an occupational exposure (also to silicates, such miners [192], although it does not seem play a role in the as talc) should always be considered in cases of similarly increased lung cancer incidence of French iron "sarcoidosis". ore miners [193]. The role of domestic radon gas expo­ Exposure to rare earth metals (or lanthanides), of sure in the .causation of bronchial cancer is the subject of which cerium is the most abundant element, has also intense research [194]. been associated with interstitial fibrosis in a small number Epidemiological and experimental studies have clearly of subjects [171-175]. Rare earths are essential established the carcinogenic risk of exposure to arsenic, 212 B.NEMERY

chrome and nickel, at least to some of their chemical Conclusions and perspectives forms [186-189, 195]. Thus, the relationship of arsenic to increased lung cancer risk in copper smelting This review attempts to show that the toxic effects of workers is unequivocal. This is also the case for metallic compounds may be manifested in almost any other occupational exposures to arsenic, such as the form of pulmonary disease. The most important step manufacture or spraying of arsenical pesticides [196-197]. towards uncovering a possible occupational or A greatly increased risk of lung cancer has also been environmental cause for an illness in the individual patient demonstrated for workers in the primary chromate is a careful and complete history taking. Inquiring about production and in the chromate pigment industry present and past jobs and understanding the patient's [186-189, 198-201]. Epidemiological studies of the occupational history generally require a good knowledge carcinogenic risk of exposure to chromium during of existing or past work practices. To link this with metal plating or during stainless steel welding possible pulmonary disorders, it is essential for the have been considered inconclusive. However, the practising physician to possess, and frequently consult. exposure in these jobs is to the carcinogenic form of standard textbooks on and to chromium, i.e. , and there are complement this with some awareness of the relevant several recent studies showing an increased lung cancer contemporary literature. However, the recognition of mortality in welders or platers [202-206]. Occupational occupational disease may in addition sometimes require exposure to nickel in nickel smelters and refineries is an alertness for "strange" occurrences and some degree also unequivocally associated with an increase in of scepticism against "idiopathic" or "intrinsic" origins. cancer of the lung and the nasal sinuses [207-208]. Again This attitude must always be backed by elementary the situation in nickel-using industries is less clear, but a scientific principles of toxicology and epidemiology. cancer has not been excluded. Obviously further clinical, radiological, functional, There are also epidemiological or experimental pathological and other investigations will usually be indications that antimony, beryllium, cadmium, cobalt needed to characterize the disease and its progression. and iron, or occupations associated with these metals are Various immunological assays may be helpful for evalu­ carcinogenic for the human lung [186-189]. Thus, stud­ ating immunologically mediated lung disease, including ies of iron and steel foundry workers have consistently that caused by metals, although these tests are generally found an increased risk of lung cancer, but this may be still to be regarded "as adjuncts to clinical diagnosis, and due to the emission of polycyclic aromatic hydrocarbons not as independent proof of causation or of diagnosis" as pyrolysis products of organic materials used [209, 210]. (225]. When hypersensitivity is suspected, bronchial An increased mortality from lung cancer attributable to challenge testing may be justified [226]. cadmium has also been shown in some [74, 211, 212], Bronchoalveolar lavage (BAL) is increasingly used, but not all [213-215], recent studies of cadmium mainly in the assessment of interstitial lung diseases [227]. exposed workers. B~GIN [228] has recently advocated the use of this Clearly the study of occupational exposures in the technique in the pneumoconioses in order to eliminate causation of lung cancer is hampered by the effect of other causes of lung disease, to document mineral dust cigarette smoking, which has been found to act in any exposure, to support other clinical information, and to fashion from less than additive to multiplicative with investigate the biological mechanisms of these diseases. occupational exposure, depending on the agent, but also With regard to metal toxicity, no systematic studies have on characteristics of the study population [19 1, 216]. Since as yet appeared concerning the profile of inflammatory there are no indications that specific histological types of cells in BAL, although case reports have mentioned the lung cancer are associated with any specific used of this technique. Besides the proportions of environmental (217-219], it is not possible to inflammatory cell types, other features may be of attribute a particular lung cancer to a particular possible diagnostic value, such as the presence of multi­ aetiology. nucleated giant cells. The latter were found in BAL from Various studies have shown that the proportion of lung subjects with cobalt-related fibrosing alveolilis (27]. cancer attributable to occupation is far from negligible, Analysis of mediators of inflammation and fibrosis [229], being around 15%, but possibly up to 47%, in some cellular subtypes and responsiveness of lymphocytes to populations [205, 206, 220-224]. in vitro challenge [167] are all potentially useful. The In all of these studies, most of the incriminated expo­ toxic effects of metallic compounds on pulmonary alveo­ sures are related to asbestos, underground mining, and lar macrophages are also being investigated, but so far metals or metal industries. It is therefore worthwhile, macrophages from laboratory animals have mainly been even in the individual patient with lung cancer, to used. thoroughly search the past occupational history for expo­ Documentation of exposure to metals may be obtained sure to carcinogens rather than to limit the aetiological from the analysis of metal concentrations in blood or "investigation" to cigarette smoking. Not only can this urine taken for biological monitoring [230]. In addition, have implication in terms of compensation, where legis· elemental analysis may be carried out on BAL, on biopsy lation provides for such compensation, but it may also tissue or on autopsy material. Both macroanalytical (or help to discover or further strengthen the role of hitherto bulk) and microMalytical techniques may be applied unproven carcinogenic exposures, particularly when [231-233]. The former are destructive techniques which clusters of are found. allow the detection, quantitation and/or characterization METAL TOXICITY AND THE RESPIRATORY TRACT 213

of crystalline structure of inorganic elements. The latter vant to their carcinogenicity. Environ Perspect, 1981, techniques allow in situ analysis of individual cells and 40, 27-34. particles. Several microanalytical techniques exist [231], 14. Jennette KW. - The role of metals in carcinogenesis: but the one which has been most widely applied, mainly biochemistry and metabolism. Environ Health Perspect, 1981, 40, 233--252. in silicosis and asbestos-related lung disease, is that based 15. Slater TF. - Free-radical mechanisms in tissue injury. on the analysis of X-rays emitted from elements Biochem J, 1984, 222, 1-15. following their bombardment with electrons: energy 16. Aust SD, Morehouse LA, Thomas CE. - Role of metals dispersive X-ray analysis (EDXA). This analysis may be in oxygen radical reactions. J Free Rad Bioi Med, 1985, coupled to scanning or transmission electron microscopy. 1, 3-25. One of the disadvantages of this technique in the field of 17. Halliwell B, Gutteridge JMC. - Free radicals and pulmonary metal-toxicity, is that it does not allow the antioxidant protection: mechanisms and significance in toxicity detection of beryllium. The latter metal can, however, be and disease. Humczn Toxicol, 1988, 7, 7-13. detected by electron energy loss spectrometry (EELS) 18. Freeman BA, Crapo ID. - Hyperoxia increases oxygen (234] and laser microprobe mass analysis (LAMMA) radical production in rat lungs and lung mitochondria. J Biol Chem, 1981, 256, 10986-10992. [235]. 19. Smith LL.- Mechanism of paraquat toxicity in lung and A potential danger of indiscriminate use of these its relevance to treatment. Humczn Toxicol, 1987, 6, 31-36. techniques is that the finding of metallic elements in 20. Martin WJ. - Nitrofurantoin: evidence for the oxidant certain disease states may be unduly associated with a injury of lung parenchyma! cells. Am Rev Respir Dis, 1983, causative role of these elements [236]. Only properly 127, 482-486. conducted studies, including experimental studies, will 21. Cooper JAD, White DA, Matthay RA. - Drug-induced prevent such erroneous conclusions being drawn, although pulmonary disease. Part 1: Cytotoxic drugs. Am Rev Respir case reports will continue to be helpful in suggesting Dis, 1986, 133, 321-340. possible associations and stimulating further research. 22. Goodlick LA, Kane AB. - Role of reactive oxygen metabolites in crocidolite asbestos toxicity to mouse macrophages. Cancer Res, 1986, 46, 5558-5566. Acknowkdgements: The author !hanks Prof. M. 23. Zammit-Tabona M, Sherkin M, Kijek K, Chan H, Demedts, Prof. D. Lahaye, Dr H. Veulemans and Dr Chan-Yeung M. - Asthma caused by dipheny lmethane C. Lewis for critical reading ofthe manuscript, and G. Croes, I. Dekeye and M. Hugaerts for typing it. diisocyanate in foundry workers. Am Rev Respir Dis, 1983, 128, 226-230. 24. Venables KM, Dally MB, Burge PS, Pickering CAC, References Newman-Taylor AJ. -Occupational asthma in a steel coating plant. Br J lnd Med, 1985, 42, 517-524. 1. Sakula A. - Ramazzini's de Morbis Artificum and occu­ 25. Johnson A, Chan-Yeung M, Maclean L, Atkins E, pational lung disease. Br J Dis Chest, 1983, 77, 349-361. Dybuncio A, Cheng F, Enarson 0 . -Respiratory abnormalities 2. Bisetti AA. - Bemardino Ramazzini and occupational lung among workers in an iron and steel foundry. Br J lnd Med, medicine. Ann NY Acad Sci, 1988, 534, 1029-1037. 1985, 42, 94-100. 3. Friberg L, Nordberg GF, Vouk VB, (eds). -In: Handbook 26. Low I, Mitchell C. - Respiratory disease in foundry work­ on the toxicology of metals. Vol I and Vol 11. 2nd Edn. ers. Br J lnd Med, 1985, 42, 101-115. Elsevier, North-Holland, 1986. 27. Demedts M, Gheysens B, Nagels J, Verbeken E, Lauweryns 4. Lauwerys RR. - In: Toxicologie industrielle et intoxica­ J, Van Den Eeckhout A, Lahaye D, Gysel~n A.- Cobalt lung tions professionnelles. 2nd Edn. Masson, Paris, 1982, p. 462. in diamond polishers. Am Rev Respir Dis, 1984, 130, 130-135. 5. Hammond PB, Beliles RP. - Metals. In: Casarett and 28. Gheysens B, Auwerx J, V an Den Eeckhout A, Demedts Doull's toxicology. The basic science of . 2nd Edn. J. M. - Cobalt-induced bronchial asthma in diamond polishers. Doull, C.D. Klaassen and M.O. Amdur eds, MacMillan, New Chest, 1985, 88, 740-744. York, 1980, pp. 409-467. 29. Anonymous. - Lung disease in dental laboratory 6. Rom WN, (ed.). - In: Environmental and occupational technicians. Lancet, 1985, i, 1200-1201. medicine. Little, Brown and Co., Boston, 1983, p.1015. 30. Rom WN, Lockey JE, Jeffrey LS, Lee JS, Kirnball AG, 7. Parkes WR. - In: Occupational lung disorders. 2nd Edn, Bang KM, Leaman H, Johns RE Jr, Perrota D, Gibbons HL. - Butterworths, London, 1982, p. 529. Pneumoconiosis and exposure of dental laboratory technicians. 8. Morgan WKC, Seaton A. - In: Occupational lung Am J , 1984, 74, 1252-1257. diseases. Saunders, Philadelphia, 1975, p. 391. 31. Donaldson JD, Clark SJ, Grimes SM.- Cobalt in chemi­ 9. Vouk V.- General chemistry of metals. Chp 2.1n: Hand­ cals. (The monograph series). Cobalt Development Institute book on the toxicology of metals. Vol. I. General aspects. L. Slough, UK, 1986. Friberg, G.F. Nordberg and V.B. Vouk eds, Elsevier, North­ 32. Knishkowy B, Baker EL. -Transmission of occupational Holland, 1986, pp. 15-35. disease to family contacts. Am J lnd Med, 1986, 9, 543-550. 10. Halliwell B, Gutteridge JMC. - Oxygen toxicity, oxygen 33. Brooks SM. - Lung disorders resulting from the inhala­ radicals, transition metals and disease. Biochem J, 1984, tion of metals. C/in Chest Med, 1981, 2, 235-254. 219, 1-14. 34. Anonymous. - Metals and the lung. Lancet, 1984, ii, 11. Halliwell B, Gutteridge JMC. - Oxygen free radicals and 903--904. iron in relation to biology and medicine: some problems and 35. Barnhart S, Rosenstock L. - Cadmium chemical co.tcepts. Arch Biochem Biophys, 1986, 246, 501-514. pneumonitis. Chest, 1984, 86, 789-791. 12. Hart BA. -Cellular and biochemical response of the rat 36. Taylor A, Jackson MA, Burston J, Lee HA. - lung to repeated inhalation of cadmium. Toxicol Appl with cadmium fumes after smelting lead. Br Med J, 1984, 288, Pharmacol, 1986, 82, 281-291. 1270-1271. 13. Martell AE. - Chemistry and metabolism of metals rele- 37. Liles R, Miller A, Lerman Y.- Acute 214 B.NEMERY

with severe chronic pulmonary manifestations. Chest, 1985, year study of early chronic obstructive lung disease in working 88, 306-309. men in London. Oxford University Press, 1976, p. 272. 38. Levin M, Jacob J, Polos PG.- Acute mercury poisoning 60. Covey LS, Wynder EL. - Smoking habits and and mercurial pneumonitis from gold ore purification. Chest, occupational status. J Occup Med, 1981, 23, 537-542. 1988, 94, 554-556. 61. Becklake MR. - Chronic airflow limitation: its 39. Zhicheng S. - Acute nickel carbonyl poisoning: a report relationship to work in dusty occupations. Chest, 1985, 88, of 179 cases. Br J lnd Med, 1986, 43, 422-424. 608-ti17. 40. Matarese SL, Matthews JI.- Zinc chloride (smoke bomb) 62. Barnhart S. - Occupational bronchitis: a marker for irri­ inhalational lung injury. Chest, 1988, 89, 308-309. tant exposure. Semin Respir Med, 1986, 7, 249-256. 41. Hjortsjil E, Qvist J, Bud MI, Thomsen JL, Andersen JB, 63. Morgan WKC. - On dust, disability, and death. Am Rev Wiberg-Jorgensen F, Jensen NK, Jones R, Reid LM, Zapol Respir Dis, 1986, 134, 639-641. WM.- ARDS after accidental inhalation of zinc chloride smoke. 64. Department of Health and Social Security. - Bronchitis !nJensive Care Med, 1988, 14, 17-24. and emphysema. HMSO, London, 1988. 42. Park T, Di Benedetto R, Morgan K, Colmers R, Sherman 65. Soutar CA. - Update on lung disease in coalminers E. - Diffuse endobronchial polyposis following a titanium (Editorial). Br J lnd Med, 1987, 44, 145-148. tetrachloride inhalation injury. Am Rev Respir Dis, 1984, 130, 66. Marine WM, Gurr D, Jacobsen M. - Clinically important 315-317. respiratory effects of dust exposure and smoking in British 43. Brooks SM, Weiss MA, Bemstein IL. - Reactive coal-miners. Am Rev Respir Dis, 1988, 137, 106-112. airways dysfunction syndrome (RADS). Persistent asthma syn­ 67. Nemery B, Veriter C, Brasseur L, Frans A. - Impairment drome after high level irritant exposures. Chest, 1985, 88, of ventilatory function and pulmonary in non­ 376-384. smoking coalminers. Lancet, 1987, ii, 1427-1430. 44. Townshend RM. - Acute cadmium pneumonitis: a 17 year 68. Enarson DA, Vedal S, Chan-Yeung M.- Rapid decline in follow-up. Br J lnd Med, 1982, 39, 411-412. FEV, in grain handlers: relation to level of dust exposure. Am 45. Musk AW, Tees JG. - Asthma caused by occupational Rev Respir Dis, 1985, 132, 814-817. exposure to vanadium compounds. Med J Aust, 1982, 1, 69. Kauffmann F. Drouet D. Lellouch J, Brille D. - 183-184. Occupational exposure and 12-year spirometric changes among 46. Lees REM. - Changes in lung function after exposure to Paris area workers. Br J lnd Med, 1982, 39, 221-232. vanadium compounds in fuel oil ash. Br J lnd Med, 1980, 37, 70. Bemard A, Lauwerys R. - Effects of cadmium exposure 253-256. in humans. In: Cadmium. Handbook of Experimental Pharma­ 47. Levy BS, Hoffman L, Gottsegen S. - Boilermakers cology, Vol80. E.C. Foulkes ed., Springer Verlag, Berlin, 1986, bronchitis. Respiratory tract irritation associated with vanadium pp. 135-177. pentoxide exposure during oil-to-coal conversion of a power 71. Edling C, Elinder CG, Randma E. - Lung function in plant J Occup Med, 1984, 26, 567-570. workers using cadmium containing solders. Br J lnd Med, 1986, 48. Lindberg E, Hedenstierna G. - Chrome plating: 43, 657-662. symptoms, findings in the upper airways, and effects on lung 72. Davison AG, Newman Taylor AJ, Darbyshire J, Chetlle function. Arch Environ Health, 1983, 38, 367-374. DR, Gutherie CJG, O'Malley D, Mason HJ, Payers PM, 49. Mueller EJ, Seger DL. -Metal fume fever: a review. J Venables KM, Pickering CAC, Franklin D, Scott MC, Holden Emerg Med, 1985, 2, 271-274. H, Wright AL, Gompertz D. - Cadmium fume inhalation and 50. Armstrong CW, Moore LW, Hackler RL, Miller GB Jr, emphysema. Lancet, 1988, i, 663- 667. Stroube RB. - An outbreak of metal fume fever. Diagnostic 73. Armstrong BG, Kazantzis G. - Prostatic cancer and chronic use of urinary copper and zinc determinations. J Occup Med, respiratory and renal disease in British cadmium workers: a 1983, 25, 886-888. case control study. Br J lnd Med, 1985, 42, 540-545. 51. Brown JJ. - Zinc fume fever. Br J Radio/, 1988, 61, 74. Kazantzis G, Lam TH, Sullivan KR. - Mortality of 327-329. cadmium-exposed workers. Scand J Work Environ Heallh, 1988, 52. Johnson JS, Kilbum KH.- Cadmium induced metal fume 14, 220-223. fever: results of inhalation challenge. Am J Jnd Med, 1983, 4, 75. Niewoehner DE, Hoidal JR. - Lung fibrosis and emphy­ 533-540. sema: divergent responses to a common injury. Science, 1982, 53. Vogelmeier C, Konig G, Bencze K, Fruhmann G. - 217, 359-360. Pulmonary involvement in zinc fume fever. Chest, 1987, 92, 76. Martin FM, Witschi HP. - Cadmium-induced lung injury: 946-948. cell kinetics and long-term effects. Toxicol Appl Pharmacol, 54. Farrell FJ. - Angioedcma and urticaria as acute and late 1985, 80, 215-227. phase reactions to zinc fume exposure, with associated 77. Snider GL, Lucey EC, Faris B, Jung-Legg Y, Stone PJ, metal fume fever-like symptoms. Am J lnd Med, 1987, 12, Franzblau C. - Cadmium chloride-induced airspace enlarge­ 331-337. ment with interstitial pulmonary fibrosis is not associated with 55. Kawane H, Soejirna R, Umeki S, Niki Y, Malo JL. - the destruction of lung elastin. Implications for the pathogene­ Metal fume fever and asthma (letters). Chest, 1988, 93, sis of human emphysema. Am Rev Respir Dis, 1988, 137, 1116-1117. 918-923. 56. May JJ, Stallones L, Darrow D, Pratt DS. - Organic dust 78. Kriebel D, Sprince NL, Eisen EA, Greaves IA, Fcldman toxicity (pulmonary mycotoxicosis) associated with silo HA, Greene RE. - Beryllium exposure and pulmonary func­ unloading. , 1986, 41, 919-923. tion. A cross-sectional study of beryllium workers. Br J /nd 57. Lecours R, Laviolette M, Cormier Y.- Bronchoalveolar Med, 1988, 45, 167-173. lavage in pulmonary mycotoxicosis (organic dust toxic 79. Chan-YeungM, Wong R, Maclean L, Tan F, Schulzer M, syndrome). Thorax, 1986, 41, 924-926. Enarson D, Martin A, Dennis R, Grzybowski S. - 58. Elmes PC. - Relative importance of cigarette smoking in Epidemiologic health study of workers in an aluminium smelter occupational lung disease. Br J /nd Med, 1981, 38, 1-13. in British Columbia. Am Rev Respir Dis, 1983, 127, 465-469. 59. Fletchcr Ch, Peto R, Tinker C, Speizer FP. - In: The 80. Townsend MC, Enterline PE, Sussman NB, Bonney TB, natural history of chronic bronchitis and emphysema. An eight Rippcy LL. - Pulmonary function in relation to total dust METAL TOXICITY AND THE RESPIRATORY TRACT 215

exposure at a bauxite refinery and alumina-based chemical 99. Stem RM, Berlin A, Fletcher A, Hemminki K, Jarvisalo J, products plant. Am Rev Respir Dis, 1985, 132, 1174-1180. Peto J. - International conference on health and 81. Sprince NI.., Chamberlin RI, Hales CA. Weber AL. Kazemi biological effects of welding fumes and gases. Summary report. H.- Respiratory disease in tungsten carbide production workers. lnt Arch Occup Environ Health, 1986, 57, 237- 246. Chest, 1984, 86, 549-557. 100. Lockey JE, Schenker MB. - Current issues in 82. Kusaka Y, Ichikawa Y, Shirakawa T, Goto S.- Effect of occupational lung disease. (Symposium). Am Rev Respir Dis, hard metal dust on ventilatory function. Br J lnd Med, 1986, 1988, 138, 1047-1049. 43, 486-489. 101. Sjogren B.- Effects of gases and particles in welding and 83. Nemery B, Roosels D, Lahaye D, Casier P, Demedts M. soldering. In: Occupational medicine. Principles and practical - Cross-sectional survey of lung function and assessment of applications (2nd Edn). C. Zenz ed., Year Book Medical Pub!., cobalt exposure in diamond polishers (abstract). Am Rev Respir Chicago-London, 1988, pp. 1053-1060. Dis, 1988, 137 (2), 96. 102. Pepys J. - Occupational asthma: an overview. J Occup 84. Roels H, Lauwerys R, Genet P, Sarhan MJ, de Pays M, Med, 1982, 24, 534-538. Hanotiau I, Buchet JP. -Epidemiological survey among work­ 103. Davies RJ, Blainey AD. - Occupational asthma: classifi­ ers exposed to manganese: effects on lung, central nervous cation and clinical aspects. SeminRespir Med, 1984, 5, 229-239. system, and some biological indices. Am J Jnd Med, 1988, 11, 104. Chan-Yeung M, LamS. - Occupational asthma. Am Rev 307-327. Respir Dis, 1986, 133, 686-703. 85. Garabrant DH, Fine U, Oliver C, Bemstein L, Peters JM. 105. Moller DR, Baughman R, Murlas C, Brooks SM. - New - Abnormalities of pulmonary function and directions in occupational asthma caused by small molecular among titanium metal production workers. Scand J Work weight compounds. Semin Respir Med, 1987, 7, 225-239. Environ Health, 1987, 13, 47-51. 106. Biagini RE, Bemstein IL, Gallagher JS. Moorman WJ, 86. Cotes JE, Gi!son JC, McKerrow CB, Oldham PD. - A Brooks S, Garm PH. - The diversity of reaginic immune long-term follow-up of workers exposed to beryllium. Br J lnd responses to platinum and palladium metallic salts. J Allergy Med, 1983, 40, 13-21. Clin Jmmunol, 1985, 76, 794-802. 87. Roto P. - Asthma. symptoms 9f chronic bronchitis and 107. Murdoch RD. Pepys J, Hughes EG. - IgE antibody ventilatory capacity among cobalt and zinc production workers. responses to platinum group metals: a large scale refinery sur­ Scand J Work Environ Health, 1980, 6 (Suppl. 1), 49. vey. Br J lnd Med, 1986, 43, 37-43. 88. Sprince NL, Oliver LC, Eisen EA, Greene RE, 108. Block GY, Yeung M.- Aslhma induced by nickel. JAm Chamberlin RI. - Cobalt exposure and lung disease in tung­ Med Assoc, 1982, 247, 1600-1602. sten carbide workers: a cross-sectional study of current workers. 109. Malo J, Cartier A, Doepner M. Nieboer E, Evans S, Am Rev Respir Dis, 1988, 138, 1220-1226. Dolovich J. - Occupational asthma caused by nickel sulfate. J 89. Chen JL, Fayerweather WE. - Epidemiologic study of Allergy Clin Jmmunol, 1982, 69, 55-59. workers exposed to titanium dioxide. J Occup Med, 1988, 30, 110. Novey HS, Habib M, Wells ID. - Asthma and JgE anti­ 937-942. bodies induced by chromium and nickel salts. J Allergy Clin 90. Deutsche Forschungsgemeinschaft (H. Valentin and U. lmmunol, 1983, 72, 407-412. Srnidt). - Research report: chronic bronchitis and occupational 111. Davies JE. -Occupational asthma caused by nickel salts. dust exposure. Harald Boldt Verlag KG, Boppard, 1978. J Soc Occup Med, 1986, 36, 29-31. 91. Nemery B, Moavero NE, Mawet M, Kivits A, Brasseur L, 112. Keskinen H, Kalliomaki PL, Alanko K. - Occupational Stanescu D. - Etude de la symptomatologic et de la fonction asthma due to stainless steel welding fumes. Clin Allergy, 1980, pulmonaire chez des sidcrugistes. Rev biSt Hyg Mines (Has­ 10, 151-159. selt), 1981, 36, 198- 218. 113. Moller DR, Brooks SM, Bemstein DI, Cassedy K, Enrione 92. Nemery B, V an Leemputten R, Goemaere E, V eriter C, M, Bemstein IL. - Delayed anaphylactoid reaction in a Brasseur L. - Lung function measurements over 21 days shift­ worker exposed to chromium. J Allergy Clin lmmunol, 1986, work in steelworkers from a strandcasting department. Br J Jnd 77, 45-46. Med, 1985, 42, 601--611. 114. Scherrer M, Maillard JM. - Hartmetall-Pneumopalhien. 93. OxMj H, Bake B, Wedel H, Wilhelmsen L. - Effects of Schweiz Med Wschr, 1982, 112, 198-207. electric arc welding on ventilatory lung function. Arch Environ 115. Hartmarm A, Wuthrich B, Bolognini G. - Berufsbcdingte Health, 1979, 34, 211- 217. Lungenkrankheiten bei der Hartmetallproduktion 94. Akbarkhanzadeh F. - Long-term effects of welding fumes und-bcarbeitung. Ein allergisches Geschehen? Schweiz Med upon respiratory symptoms and pulmonary function. J Occup Wschr, 1982, 112, 1137-1141. Med, 1980, 22, 337-341. 116. Davison AG, Haslam PL, Corrin B, Couus H, Dewar A, 95. Keimig DG, Pomrehn PR, Burmeister LF. - Respiratory Riding WD, Studdy PR, Newman Taylor AJ. -Interstitial lung symptoms and pulmonary function in welders of mild steel: a disease and asthma in hard-metal workers: bronchoalveolar cross-sectional study. Am J lnd Med, 1983, 4, 489-499. lavage, ultrastructural, and analytical findings and results of 96. Mur JM, Cavelier C, Meyer-Bisch C, Pham QT. Masset bronchial provocation tests. Thorax, 1983, 38, 119-128. JC. - Etude de la fonction pulmonaire de soudeurs a !'arc. 117. Kusaka Y, Yokoyama K, Sera Y, Yamamoto S, Sone S, Resultats d'une enquete dans une entreprise de construction de Kyono H. Shirakawa T, Goto S. - Respiratory diseases in hard vehicules industriels. , 1983, 44, 50-57. metal workers: an study in a factory. Br 97. Mur JM, Teculescu D, Pham QT, Gaertner M, Massin N. J lnd Med, 1986, 43, 474-485. Meyer-Bisch C, Moulin JJ, Diebold F. Pierre F. Mcuroy­ 118. Shirakawa T, Kusaka Y. Fujimura N, Goto S, Kato M, Poncelet B. Muller J. - Lung function and clinical findings in Heki S, Morimoto K. - Occupational asthma from cobalt a cross-sectional study of arc welders. An epidemiological study. sensitivity in workers exposed to hard metal dust. Chest, 1989, lnt Arch Occup Environ Health, 1985, 57, 1- 17. 95. 29- 37. 98. Sjogren B, Ulfvarson U. - Respiratory symptoms and 119. Dolovich J, Evans SL, Niebocr E.- Occupational asthma pulmonary function among welders working wilh aluminium, from nickel sensitivity: I. Human serum albumin in the anti­ stainless steel and railroad tracks. Scand J Work Environ Health, genic determinant. Br J lnd Med, 1984, 41, 51-55. 1985, 11, 27-32. 120. Shirakawa T, Kusaka Y, Fujimura N, Goto S, Morimoto 216 B. NEMERY

K. - The existence of specific antibodies to cobalt in hard 144. Potkonjak V, Pavlovich M. - Antimoniosis: a particular metal asthma. Clin Allergy, 1988, 18, 451-460. form of pneumoconiosis.!. Etiology, clinical and X-ray fmdings. 121. Demedts M, Ceuppens JL. - Respiratory diseases from Int Arch Occup Environ Health, 1983, 51, 199-207. hard metal or cobalt exposure. Solving the enigma. (Editorial). 145. National Institute of Occupational Safety and Health Chest, 1989, 95, 2-3. (NIOSH). - Criteria for controlling occupational exposure to 122. Malo JL, Carrier A. - Occupational asthma due to fumes cobalt. U.S. Department of health and human services. Publn of galvanized metal. Chest, 1987, 92, 375-377. no. 82-107, CDC-NIOSH, 1981. 123. Field OB. - Pulmonary function in aluminum smelters. 146. Cullen MR.- Respiratory diseases from hard metal expo­ Thorax, 1984, 39, 743-751. sures. A continuing enigma. Chest, 1984, 86, 513-514. 124. Saric M. Oodnic-Cvar J, Oomzi M. Stilinovic L. - The 147. Balmes JR.- Respiratory effects of hard-metal dust expo­ role of atopy in potroom workers' asthma. Am J Ind Med, sure. State of the Art Rev Occup Med, 1987, 2, 327-344. 1986, 9, 239-242. 148. Sjtigren I, Hillerdal 0, Andersson A, Zetterstrtim 0 . - 125. Wergeland E. Lund E, Waage JE.- Respiratory dysfunc­ Hard metal lung disease: importance of cobalt in coolants. tion after potroom asthma. Am J Ind Med, 1987, 11, 627-636. Thorax, 1980, 35, 653-659. 126. Sirnonsson BO, Sjtiberg A, Rolf C, Haeger-Aronson B.­ 149. Meyer D, Stoecke1 C, Oeist T, Le Bouffant L, Roegel E. Acute and long-term airway hyperreactivity in aluminium-salt - A propos de trois nouveaux cas de fibrose pulmonaire chez exposed workers with nocturnal asthma. Eur J Respir Dis, 1985, des affuteurs d'outils renforces en carbure de tungstcne. 66, 105-118. Poumon-Coeur, 1981, 37, 165-175. 127. Hjortsberg U, Nise 0 , 0rbaek P, S~es-Petersen U, 150. Hartung M, Valentin H. - Lungenfibrose durch Arborelius M Jr. - Bronchial asthma due to exposure to potas­ Hartmetallstliube. Zbl Bald Hyg I Abt Orig B, 1983, 177, sium aluminum tetrafluoride. (Letter). Scand J Work Environ 237-250. Health, 1986, 12, 223. 151. Hartung M. - Lungenfibrosen bei Hartmetallschleifem. 128. Doorns-Ooossens A, Ceuterick A, Vanmaele N, Degreef Bedeutung der Cobalteinwirkung. Schriftanreihe des Hauptver­ N. - Follow-up study of patients with contact dermatitis caused bandes der gewerblichen Berufsgenossenschaften C.Y. Sankt by chromates, nickel, and cobalt. Dermatologica, 1980, 166, Augustin, 1986. 249-260. 152. Anttila S, Sutinen S, Paananen M, Kreus KE, Sivonen SJ, 129. Fisher AA. - Dermatitis and discoloration from metals. Orekula A, Alapieti T. - Hard-metal lung disease: a clinical, In: Contact Dermatitis. 3rd Edn. Lea & Febiger, Philadelphia, histological, ultrastructural and X-ray microanalytical study. Eur 1986, pp. 710-744. J Respir Dis, 1986, 69, 83-94. 130. Burge PS. - Problems in the diagnosis of occupational 153. Rizzato 0, Locicero 0, Barberis M, Torre M, Pietra R, asthma. Br J Dis Chest, 1987, 81, 105-115. Sabbioni E. - Trace of metal exposure in hard metal lung 131. Breatnach SM, Katz SI. - Cell-mediated immunity in disease. Chest, 1986, 90, 101-106. cutaneous disease. Hum Pathol, 1986, 17, 161- 167. 154. Schepers OWH. - The biological action of particulate 132. Daniele RP. - Cell-mediated immunity in pulmonary cobalt metal, tantalum oxide, cobalt oxide, tungsten metal, disease. Hum Pathol, 1986, 17, 154-160. tungsten carbide and carbon, tungsten carbide and cobalt. Am 133. Van Cutsem EJ, Ceuppens JL, Lacquet LM, Demedts M. Arch Ind Health, 1955, 12, 121-146. - Combined asthma and alveolitis induced by cobalt in a dia­ 155. Abraham JL. - Lung pathology in 22 cases of giant mond polisher. Eur J Respir Dis, 1987, 70, 54-61. cell interstitial pneumonia (GIP) suggests GIP is pathognomonic 134. Terr AI. - The atopic worker. Clin Rev Allergy, 1986, 4, of cobalt (hard metal) disease. (Abstract). Chest, 1987, 91, 267-288. 312. 135. Venablcs KM. - Epidemiology and the prevention of 156. Nemery B, Nagels J, Verbeken E, Dinsdale D, Demedts occupational asthma. Br J Ind Med, 1987, 44, 73-75. M. - Rapidly fatal progression of cobalt-lung in a diamond 136. Venables KM, Topping MD, Howe W, Luczynska CM, polisher. Possible involvement of an oxygen free-radical mecha­ Hawkins R, Newman Taylor AJ. -Interaction of smoking and nism. Am Rev Respir Dis, 1990, in press. atopy in producing specific IgE antibody against a hapten protein 157. Morgan LO. - A study into the health and mortality of conjugate. Br Med J, 1985, 290, 201-204. men exposed to cobalt and oxides. J Soc Occup Med, 1983, 33, 137. Biagini RE, Moorman WJ, Lewis TR, Berstein IL.- Ozone 181-186. enhancement of platinum asthma in a primate model. Am Rev 158. Rein! W, Schnellbacher F, Rahm G. - Lungenfibrosen Respir Dis, 1986, 134, 719-725. und entzUndliche Lungenerkrankungen nach Einwirkung von 138. Mapp CE, Boschetto P, Dal Vecchio L. Maestrelli P, Fabbri Kobaltkontaktmasse. Zbl Arbeitsmed, 1979, 12, 318-325. LM. - Occupational asthma due to isocyanates. Eur Respir J, 159. De Vuyst P, Van de Weyer R, Decostcr A, Marchandise 1988, 1, 273-279. FX, Dumortier P, Ketelbant P, Jedwab J, Yemault JC. - Dental 139. Chan-Yeung M. - Occupational asthma update. Chest, technician's pneumoconiosis. A report of two cases. Am Rev 1988, 93, 407-411. Respir Dis, 1986, 133, 316-320. 140. Crystal RO, Oadek JE, Ferrans VJ, Fulmer JD, Line BR, 160. Loewen OM, Weiner D, McMahon J.- Pneumoconiosis Hunninghake OW. -Interstitial lung disease: current concepts in an elderly dentist. Chest, 1988, 93, 1312-1313. of pathogenesis, staging and therapy. Am J Med, 1981, 70, 161. Caries P, Fabre J, Pujol M, Duprcz A, Bollinelli R. - 542-568. Pneumoconioses complexes chez lcs prothCsistes dentaircs. 141. Snider OL. - Interstitial pulmonary fibrosis - which cell Poumon Coeur, 1978, 34, 189-192. is the culprit. Am Rev Respir Dis, 1983, 127, 535- 539. 162. Morgenroth K, Kronenberger H, Tuengerthal S, Schneider 142. Funahashi A, Schluetcr DP, Pintar K, Bemis EL, M, Meyer-Sydow J, Reimann H, Kroid1 RF, Amthor M. - Siegesmund KA. - Welders' pneumoconiosis: tissue elemental Histologische Lungenbefunde bei Pneumokoniosen von microanalysis by energy dispersive X-ray analysis. Br J Ind Zahntechnikem. Prax Klin PneufTU)/, 1981, 35, 670-673. Med, 1988, 45, 14-18. 163. Eisenbud M, Lisson J.- Epidemiological aspects of beryl­ 143. Daguenel J, Oaucher P, Dumortier L, Oeraut C, lium-induced non malignant lung disease: a 30 year update. J Moignetau C, Ligot J, Boiteau HL, Ouichet J, Leseac'h C. - Occup Med, 1983, 25, 196-202. Antimoniose pulmonaire. Arch Mal Prof. 1979, 40, 110-112. 164. Cullen MR, Cherniack MO, Kominsky JR. - Chronic METAL TOXICITY AND THE RESPIRATORY TRACT 217

beryl Hum disease in the United States. Semin Respir Med, 1987, 186. Doll R. - Problems of epidemiological evidence. 7, 203-209. Environ Health Perspect, 1981, 40, 11-20. 165. Kriebel D, Brain ID, Sprince NL, Kazemi H. - The 187. Cone JE. - Occupational lung cancer. State of the Art pulmonary toxicity of beryllium. Am Rev Respir Dis, 1988, Rev Occup Med, 1987, 2, 273-295. 137, 464-473. 188. International Agency for Research on Cancer (IARC). - 166. Cullen MR, Kominsky JR, Rossman MD, Cherniack MG, IARC Monographs on the evaluation of carcinogenic risks to Rankin JA, Balmes JR, Kern JA, Daniele RP, Palmer L, Naegel humans. Overall evaluations of carcinogenicity: an updating of GP. -Chronic beryllium disease in a precious metal refmery. IARC Monographs Volumes 1 to 42. Supplement 7 IARC, Clinical epidemiologic and immunologic evidence for continu­ Lyon, 1987. ing risk from exposure to low level beryllium fume. Am Rev 189. Norseth T. - Metal carcinogenesis. Ann NY Acad Sci, Respir Dis, 1987, 135, 201-208. 1988, 534, 377-386. 167. Rossman MD, Kern JA, Elias JA, Cullen MR, Epstein PE, 190. Samet JM, Kutvirt DM, Waxweiler RJ, Key CR.- Ura­ Preuss OP, Markham TN, Daniele RP. -Proliferative response nium mining and lung cancer in Navajo men. N Engl J Med, ofbronchoalveolar lymphocytes to beryllium. A test for chronic 1984, 310, 1481-1484. beryllium disease. Ann Intern Med, 1988, 108, 687-693. 191. Archer VE.- Lung cancer risks of underground miners: 168. Hadji Michael OC, Brubaker RE. - Evaluation of an cohort and case-control studies. Yale J Bioi Med, 1988, 61, occupational respiratory exposure to a zirconium-containing 183-194. dust. J Occup Med, 1986, 23, 543- 547. 192. Radford EP, Renard StC KG. - Lung cancer in Swedish 169. Redline S, Barna BP, Tomashefski JF Jr, Abraham JL. - iron miners exposed to low doses of radon daughters. N Engl Granulomatous disease associated with pulmonary deposition J Med, 1984, 310, 1485-1494. of titanium. Br J Jnd Med, 1986, 43, 652-656. 193. Mur JM, Meyer-Bisch C, Pham QT, Massin N, Moulin JJ, 170. Devuyst P, Dumonier P, Schandene L, Estcnne M, Verhest Cavelier C, Sadoul P. - Risk of lung cancer among iron ore A, Yernault JC.- Sarcoidlike lung granulomatosis induced by miners: a proportional mortality study of 1,075 deceased miners aluminium dust. Am Rev Respir Dis, 1987, 135, 493-497. in Lorraine, France. J Occup Med, 1987, 29, 762-768. 171.Husain MH, Dick JA, Kaplan YS. - Rare-earth 194. Samet JM, Marbury MC, Spengler JD.- Health effects pneumoconiosis. J Soc Occup Med, 1980, 30, 15-19. and sources of indoor . Part 2. Am Rev Respir Dis, 172. Sinico M, Le Bouffant L, Paillas J, Fabre M, Trincard 1988, 137, 221-242. MD. - Pneumoconiose due au cerium. Documents 195. Peters JM, Thomas D, Falk H. Oberdorster G, Smith TJ. anatomopathologiques. Arch Mal Prof. 1982, 43, 249-252. - Contribution of metals to respiratory cancer. Environ Health 173. Vocaturo 0 , Colombo F, Zanoni M, Rodi F, Sabbioni E, Perspect, 1986, 70, 71-83. Pietra R. - Human exposure to . Rare earth pneu­ 196. Lee-Feldstein A. - Cumulative exposure to arsenic and its moconiosis in occupational workers. Chest, 1983, 83, 780-783. relationship to respiratory cancer among copper smelter 174. Sulotto F, Romano C, Berra A, Botta GC, Rubino GF, employees. J Occup Med, 1986, 28, 296-302. Sabbioni E, Pietra R. - Rare-eanh pneumoconiosis: a new case. 197. Sobel W, Bond GO, Baldwin CL, Ducommun DJ.- An Am J lnd Med, 1986, 9, 567-575. update of respiratory cancer and occupational exposure to 175. Vogt P, Spycher MA, Rtittner JR. - Pncumokoniose arsenicals. Am J lnd Med, 1988, 13, 263-270. durch "seltene Erden" (Cer-Pneumokoniose). Schweiz Med 198. Norseth T. - The carcinogenicity of chromium and its Wschr, 1986, 116, 1303-1308. salts. Br J lnd Med, 1986, 43, 649-651. 176. Dinman BD. - Aluminum in the lung: the pyropowder 199. Satoh K, Fukuza Y, Torii K, Katsuno N.- Epidemiologi­ conundrum. J Occup Med, 1987, 29, 869-876. cal study of workers engaged in the manufacture of chromium 177. Dinman BD. - Alumina-related pulmonary disease. J compounds. J Occup Med, 1982, 23, 835-838. Occup Med, 1988, 30, 328-335. 200. LangArd S, Vigander T. - Occurrence of lung cancer in 178. Miller RR, Churg AM, Hutcheon M, LamS.- Pulmonary workers producing chromium pigments. Br J lnd Med, 1983, 4, alveolar proteinosis and aluminum dust exposure. Am Rev Respir 71- 74. Dis, 1984, 130, 312-314. 201. Davies JM. - Lung cancer mortality among workers 179. Vallyathan V, Bergeron WN, Robichaux PA, Craighead making lead chromate and pigments at three JE. - Pulmonary fibrosis in an aluminum arc welder. Chest, English factories. Br J lnd Med, 1984, 41, 158-169. 1982, 81, 372- 374. 202. Beaumont JJ, Weiss NS.- Lung cancer among welders. 180. Herbert A, Sterling G, Abraham J, Corrin B. - J Occup Med, 1981, 23, 839-844. Desquamative interstitial pneumonia in an aluminum welder. 203. Becker N, Claude J, Frentzel-Beyme R. - Cancer of arc Human Pathol, 1982, 13, 69~99 . welders exposed to fumes containing chromium and nickel. 181. De Vuyst P, Dumortier P, Rickaert F, Van de Weyer R, Scand J Work Environ Health, 1985, 11, 75-82. Lenclud C, Yernault JC. - Occupational lung fibrosis in an 204. Sorahan T, Burges DCL, Waterhouse JAH.- A mortality aluminium polisher. Eur J Respir Dis, 1986, 68, 131- 140. study of nickeVchromium platers. Br J lnd Med, 1987, 44, 182. Gilks B, Churg A.- Aluminum-induced pulmonary fibro­ 250-258. sis: do fibers play a role? Am Rev Respir Dis, 1987, 136, 205. Lerchen ML, Wiggins CL, Samct JM. - Lung cancer and 176-179. occupation in New Mexico. JNCf, 1987, 79, 639-645. 183. Wegman DH, Eisen EA. - Causes of death among em­ 206. Ronco G, Ciccone G, Mirabclli D. Troia B, Vineis P.­ ployees of a synthetic abrasive product manufacturing company. Occupation and lung cancer in two industrialized areas of J Occup Med, 1981, 23, 748-754. Northern Italy. lnJ J Cancer, 1988, 41. 354-358. 184. Peters JM, Smith TJ, Bernstein L, Wright WE, Hammond 207. Orandjean P, Anderson 0, Nielsen GD. - Carcinogen­ SK. - Pulmonary effects of exposures in silicon carbide icily of occupational nickel exposures: an evaluation of the manufacturing. Br J lnd Med, 1984, 41, 109- 115. epidemiological evidence. Am J lnd Med. 1988, 13, 193-210. 185. Funahashi A, Schlueter DP, Pintar K, Siegesmund KA, 208. Kaldor J, Peto J, Easton D, Doll R, Herrnon C, Morgan L. Mandel GS, Mandel NS. - Pneumoconiosis in workers ex­ - Models for respiratory cancer in nickel refinery workers. posed to silicon carbide. Am Rev Respir Dis, 1984, 129, JNCI 1986, 77, 841-848. 635-640. 209. Fletcher AC, Ades A. - Lung cancer mortality in a 218 METAL TOXICITY AND THE RESPIRATORY TRACT

cohort of English foundry workers. Scarui J Work Environ in Modem . L. Fishbein, A. Furst Health, 1984, 10, 7-16. and M.A. Mehlman eds, Princeton Scientific Pub!., 1987, pp. 210. Silverstein M, Maizlich N, Park R, Silverstein B, Brodsky 265-278. L, Mirer F. - Mortality among ferrous foundry workers. Am J 231. Abraham JL. - Recent advances in pneumoconiosis: the lrui Med, 1986, 10, 27-43. pathologist's role in etiologic diagnosis. In: The lung. Struc­ 211. Elinder CG, Kjcllstrom T, Hogstedt C, Anderson K, Span ture, function and disease. W.M. Thurlbeck and M.R. Abell G. - Cancer mortality of cadmium workers. Br J lrui Med, eds, Williarns & Wilkins, Baltimore, 1978, pp. 96-137. 1985, 42, 651--655. 232. Roggli VL, Ingram P, Linton RW, Gutknecht WF, Mastin 212. Thun MT. Schnorr TM, Smith AB, Halperin WE, Lemen P, Shelbume JD.- New techniques for irnaging and analy2.ing RA. - Mortality among a cohort of US cadmium production lung tissue. Environ Health Perspect, 1984, 56, 163-183. workers. An update. JNCI, 1985, 74, 325-333. 233. Johnson NF, Haslarn PL, Dewar A, Newman Taylor AJ, 213. Sorahan T.- Mortality from hmg cancer among a cohort Turner-Warwick M. - Identification of inorganic dust particles of nickel cadmium battery workers: 1946-1984. Br J lrui Med, in bronchoalveolar lavage macrophages by energy dispersive 1987, 44, 803--809. X-ray microanalysis. Arch Environ Health, 1986, 41, 133-144. 214. Ades AE, Kazantzis G. - Lung cancer in a non-ferrous 234. Dinsdale D, Bourdillon AJ. -The ultrastructural localisa­ smelter: the role of cadmium. Br J bui Med, 1988, 45, 435-442. tion of beryllium in biological samples by electron energy-loss 215. Oberdorster G. - Airborne cadmium and carcinogenesis spectrometry. Exp Mol Pathol, 1982, 36, 396-402. of the respiratory tract. Scarui J Work Environ Health., 1986, 235. Jones Williarns W, Kelland D.- New aid for diagnosing 12, 523-527. chronic beryllium disease (CBD): laser ion mass analysis 216. Steenland K, Thun M. - Interaction between tobacco (LIMA). J Clin Pathol, 1986, 39, 900-901. smoking and occupational exposures in the causation of lung 236. Langer AM. -Mineral dust and pulmonary lesions: etiol­ cancer. J Occup Med, 1986, 28, 110--118. ogicallink or epiphenomenon. Am J lrui Med, 1984, 6, 169-171. 217. Ives JC, Buffler PA, Greenberg SD. - Environmental associations and histopathologic patterns of carcinoma of the lung: the challenge and dilenuna in epidemiologic studies. Am Rev Respir Dis, 1983, 128, 195-209. 218. Pcrshagen G, Bergman F, Klominek J, Damber L, WallS. Toxicite des metaux et appareil respiratoire. B. Nemery. - Histological types of lung cancer among smelter workers RESUME: Le type d'affection pulmonaire caus~ par les com­ exposed to arsenic. Br J Jrui Med, 1987, 44, 454-458. pos~s m~talliques d~pend de la nature de !'agent inhal~, de sa 219. Tokudome S, Haratake J, Horie A, EraS, Fujii H, Kawachi forme physico-chirnique, de la dose, des conditions d'exposi­ J, Miyamoto Y, Suko S, Tokunaga M, Tsuji K, Ik.eda M. - tion. et de facteurs lies al'hote. Les fum~s ou formes gazeuses diff~rents m~taux , ZnC~. Histologic types of lung cancers among male Japanese copper de (par exemple Cd, Mn. Hg, Ni (C0)4 smelter workers. Am J lrui Med, 1988, 14, 137-143. V2 0~) peuvent entrainer une pneumonic chimique aigue, avec 220. Doll R, Peto R. - The causes of cancer: quantitative oedcme pulmonaire ou de la trachCo-bronchite aigue. La ficvre estimates of avoidable risks of cancer in the US today. JNCI, des fumces de metaux, qui peut r~sulter de !'inhalation de fumes 1981, 66, 1191-1308. m~talliques, par exemple Zn. Cu et beaucoup d'autres, est une 221. Kjuus H, Langhd S, Skjaerven R. - A case-referent study r~action pseudo- grippale encore mal comprise et accompagnee of lung cancer, occupational exposures and smoking. m. d'une alveolite aigue a neutrophiles autolimitative, Des Etiologic fraction of occupational exposures. Scarui J Work pneumopathies chroniques obstructives peuvent rcsulter de !'ex­ Environ Health, 1986, 12, 210--215. position professionnelle aux poussieres de mineraux, et proba­ 222. Kvale G, Bjelke E, Heuch I. - Occupational exposure blement de certaines poussieres de mctaux, ou encore de and lung cancer risk. 1nl J Cancer, 1986, 37, 185-193. travaux comportant la manipulation de composes metalliques 223. Darnber LA, Larsson LG. - Occupation and male lung conune par exemple lors du soudage. L'exposition au cadmium cancer: a case-control study in northern Sweden. Br J lrui Med, est capable d'entramer de l'emphyseme. L'astlune bronchique 1987, 44, 446-453. peut etre provoqu~ par des sels complexes de platine, ·Je nickel, 224. Simonato L, Vineis P, Fletcher AC. - Estimates of the le chrome ou le cobalt, sans doute sur la base d'une sensibili­ proportion of lung cancer attributable to occupational exposure. sation allergique. La cause de l'asthme chez lcs travailleurs de Carcinogenesis, 1988, 9, 1159-1165. !'aluminium n'est pas connue. 11 est remarquable que l'asthme 225. Newman L, Storey E, Kreiss K. - Inununologic evalu­ induit par le Ni ou le Cr soit apparenunent peu fr~quent, si l'on ation of occupation lung disease. State of the Art Rev Occup considcre !cur puissance en tant que scnsibilisateurs cutan~s. Med, 1987, 2, 345--372. Les poussieres de m~taux peuvent donner lieu a une fibrose 226. Newman Taylor AJ, Davies RJ. - Inhalation challenge pulmonaire plus ou moins marqu~e. et a des troubles fonction­ testing. In: Occupational lung diseases. Lung Biology in Health nels scion le fibrogene potentiel fibrog~n de !'agent et de fac­ and Disease. Vol. 18. H. Weill and M. Tumer-Warwick eds, teurs de l' bote encore mal compris. L'inhalation de composes Dekker, New York, Base!, 1981, pp. 143- 167. de fer provoque de la sidcrose, une pneumoconiose qui ne pro­ 227. Reynolds HY. - Bronchoalveolar lavage (State of the voque que peu ou pas de fibrose. La pneumopathie des m~taux art). Am Rev Respir Dis, 1987, 135, 250--263. durs est une fibrose caracterisee par une pneumonic intersti­ 228. B~gin RO. - Bronchoalveolar lavage in the pneumoco­ tielle desquamative et a cellules g~antes, et. est probablcment nioses. Who needs it? Chest, 1988, 94, 454. due au cobalt, puisqu'une pathologie sirnilaire a ~Le observ~e 229. Rom WN, Bitterman PB. Rennard SI, Cantin A, Crystal chez les travailleurs exposes au cobalt en !'absence de carbure RG. - Characterization of the lower respiratory tract inflam­ de tungstcne. La berylliose est une fibrose avec granulomes mation of non-smoking individuals with interstitial lung ~pithelioides semblable a la sarcoldose et est probablement due disease associated with chronic inhalation of inorganic dust. a une r~ponse irnmunitaire de type cellulaire a l'egard du Mryl­ Am Rev Respir Dis, 1987, 136, 1429-1434. lium. Un mecanisme similaire pourrait etre responsable de la 230. Lauwerys RR. - Biological monitoring of metals: an fibrose pulmonaire, rencontroo occasionnellcmcnt chez les sujets overview./n: Genotoxic and carcinogenic metals: environmental exposes a d'autres metaux (AI, Ti, terres rares). La proportion and occupational occurrence and exposure. Yol XI in Advances des cancers pulmonaires d'origine professionnclle, est de l'ordre B. NEMERY 219 de 15%, et !'exposition ~ des m6taux est fr6quemment pulmonaires bien d6montr6s chez l'homme. n existe egalement incriminu. Le travail au fond de la mime d'uranium ou de fer, une augmentation de la mortali~ par cancer du poumon chez est associ6 ~ une incidence 6ley6e de cancer du poumon. par les travailleurs du cadmium et chez les travailleurs du fer et de suite de !'exposition au radon. Au moins certaines fonnes l'acier. d'arsenic, de chrome et de nickel, sont des carcinogenes Eur Respir J., 1990, 3, 202-219.