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Monday, 28 February 2011 22:28

Aetiopathogensis of pneumoconioses

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Pneumoconioses have been recognized as occupational diseases for a long time. Substantial efforts have been directed to research, primary prevention and medical management. But physicians and hygienists report that the problem is still present in both industrialized and industrializing countries (Valiante, Richards and Kinsley 1992; Markowitz 1992). As there is strong evidence that the three main industrial minerals responsible for the pneumoconioses (asbestos, coal and silica) will continue to have some economical importance, thus further entailing possible exposure, it is expected that the problem will continue to be of some magnitude throughout the world, particularly among underserved populations in small industries and small mining operations. Practical difficulties in primary prevention, or insufficient understanding of the mechanisms responsible for the induction and the progression of the disease are all factors which could possibly explain the continuing presence of the problem.

The aetiopathogenesis of pneumoconioses can be defined as the appraisal and understanding of all the phenomena occurring in the lung following the inhalation of fibrogenic dust particles. The expression cascade of events is often found in the literature on the subject. The cascade is a series of events that first exposure and at its farthest extent progresses to the disease in its more severe forms. If we except the rare forms of accelerated silicosis, which can develop after only a few months of exposure, most of the pneumoconioses develop following exposure periods measured in decades rather than years. This is especially true nowadays in workplaces adopting modern standards of prevention. Aetiopathogenesis phenomena should thus be analysed in terms of its long-term dynamics.

In the last 20 years, a large amount of information has become available on the numerous and complex pulmonary reactions involved in interstitial lung fibrosis induced by several agents, including mineral dusts. These reactions were described at the biochemical and cellular level (Richards, Masek and Brown 1991). Contributions were made by not only physicists and experimental pathologists but also by clinicians who used bronchoalveolar lavage extensively as a new pulmonary technique of investigation. These studies pictured aetiopathogenesis as a very complex entity, which can nonetheless be broken down to reveal several facets: (1) the inhalation itself of dust particles and the consequent constitution and significance of the pulmonary burden (exposure-dose-response relationships), (2) the physicochemical characteristics of the fibrogenic particles, (3) biochemical and cellular reactions inducing the fundamental lesions of the pneumoconioses and (4) the determinants of progression and complication. The later facet must not be ignored, since the more severe forms of pneumoconioses are the ones which entail impairment and disability.

A detailed analysis of the aetiopathogenesis of the pneumoconioses is beyond the scope of this article. One would need to distinguish the several types of dust and to go deeply into numerous specialized areas, some of which are still the subject of active research. But interesting general notions emerge from the currently available amount of knowledge on the subject. They will be presented here through the four “facets” previously mentioned and the bibliography will refer the interested reader to more specialized texts. Examples will be essentially given for the three main and most documented pneumoconioses: asbestosis, coal workers’ pneumoconioses (CWP) and silicosis. Possible impacts on prevention will be discussed.

Exposure-Dose-Response Relationships

Pneumoconioses result from the inhalation of certain fibrogenic dust particles. In the physics of aerosols, the term dust has a very precise meaning (Hinds 1982). It refers to airborne particles obtained by mechanical comminution of a parent material in a solid state. Particles generated by other processes should not be called dust. Dust clouds in various industrial settings (e.g., mining, tunnelling, sand blasting and manufacturing) generally contain a mixture of several types of dust. The airborne dust particles do not have a uniform size. They exhibit a size distribution. Size and other physical parameters (density, shape and surface charge) determine the aerodynamic behaviour of the particles and the probability of their penetration and deposition in the several compartments of the respiratory system.

In the field of pneumoconioses, the site compartment of interest is the alveolar compartment. Airborne particles small enough to reach this compartments are referred to as respirable particles. All particles reaching the alveolar compartments are not systematically deposited, some being still present in the exhaled air. The physical mechanisms responsible for deposition are now well understood for isometric particles (Raabe 1984) as well as for fibrous particles (Sébastien 1991). The functions relating the probability of deposition to the physical parameters have been established. Respirable particles and particles deposited in the alveolar compartment have slightly different size characteristics. For non-fibrous particles, size-selective air sampling instruments and direct reading instruments are used to measure mass concentrations of respirable particles. For fibrous particles, the approach is different. The measuring technique is based upon filter collection of “total dust” and counting of fibres under the optical microscope. In this case, the size selection is made by excluding from the count the “non-respirable” fibres with dimensions exceeding predetermined criteria.

Following the deposition of particles on the alveolar surfaces there starts the so-called alveolar clearance process. Chemotactic recruitment of macrophages and phagocytosis constitute its first phases. Several clearance pathways have been described: removal of dust-laden macrophages toward the ciliated airways, interaction with the epithelial cells and transfer of free particles through the alveolar membrane, phagocytosis by interstitial macrophages, sequestration into the interstitial area and transportation to the lymph nodes (Lauweryns and Baert 1977). Clearance pathways have specific kinetics. Not only the exposure regimen, but also the physicochemical characteristics of the deposited particles, trigger the activation of the different pathways responsible for the lung’s retention of such contaminants.

The notion of a retention pattern specific to each type of dust is rather new, but is now sufficiently established to be integrated into aetiopathogenesis schemes. For example, this author has found that after long term exposure to asbestos, fibres will accumulate in the lung if they are of the amphibole type, but will not if they are of the chrysotile type (Sébastien 1991). Short fibres have been shown to be cleared more rapidly than longer ones. Quartz is known to exhibit some lymph tropism and readily penetrates the lymphatic system. Modifying the surface chemistry of quartz particles has been shown to affect alveolar clearance (Hemenway et al. 1994; Dubois et al. 1988). Concomitant exposure to several dust types may also influence alveolar clearance (Davis, Jones and Miller 1991).

During alveolar clearance, dust particles may undergo some chemical and physical changes. Examples of theses changes include coating with ferruginous material, the leaching of some elemental constituents and the adsorption of some biological molecules.

Another notion recently derived from animal experiments is that of “lung overload” (Mermelstein et al. 1994). Rats heavily exposed by inhalation to a variety of insoluble dusts developed similar responses: chronic inflammation, increased numbers of particle-laden macrophages, increased numbers of particles in the interstitium, septal thickening, lipoproteinosis and fibrosis. These findings were not attributed to the reactivity of the dust tested (titanium dioxide, volcanic ash, fly ash, petroleum coke, polyvinyl chloride, toner, carbon black and diesel exhaust particulates), but to an excessive exposure of the lung. It is not known if lung overload must be considered in the case of human exposure to fibrogenic dusts.

Among the clearance pathways, the transfer towards the interstitium would be of particular importance for pneumoconioses. Clearance of particles having undergone sequestration into the interstitium is much less effective than clearance of particles engulfed by macrophages in the alveolar space and removed by ciliated airways (Vincent and Donaldson 1990). In humans, it was found that after long-term exposure to a variety of inorganic airborne contaminants, the storage was much greater in interstitial than alveolar macrophages (Sébastien et al. 1994). The view was also expressed that silica-induced pulmonary fibrosis involves the reaction of particles with interstitial rather than alveolar macrophages (Bowden, Hedgecock and Adamson 1989). Retention is responsible for the “dose”, a measure of the contact between the dust particles and their biological environment. A proper description of the dose would require that one know at each point in time the amount of dust stored in the several lung structures and cells, the physicochemical states of the particles (including the surface states), and the interactions between the particles and the pulmonary cells and fluids. Direct assessment of dose in humans is obviously an impossible task, even if methods were available to measure dust particles in several biological samples of pulmonary origin such as sputum, bronchoalveolar lavage fluid or tissue taken at biopsy or autopsy (Bignon, Sébastien and Bientz 1979). These methods were used for a variety of purposes: to provide information on retention mechanisms, to validate certain exposure information, to study the role of several dust types in pathogenic developments (e.g., amphiboles versus chrysotile exposure in asbestosis or quartz versus coal in CWP) and to assist in diagnosis.

But these direct measurements provide only a snapshot of retention at the time of sampling and do not allow the investigator to reconstitute dose data. New dosimetric models offer interesting perspectives in that regard (Katsnelson et al. 1994; Smith 1991; Vincent and Donaldson 1990). These models aim at assessing dose from exposure information by considering the probability of deposition and the kinetics of the different clearance pathways. Recently there was introduced into these models the interesting notion of “harmfulness delivery” (Vincent and Donaldson 1990). This notion takes into account the specific reactivity of the stored particles, each particle being considered as a source liberating some toxic entities into the pulmonary milieu. In the case of quartz particles for example, it could be hypothesized that some surface sites could be the source of active oxygen species. Models developed along such lines could also be refined to take into account the great interindividual variation generally observed with alveolar clearance. This was experimentally documented with asbestos, “high retainer animals” being at greater risk of developing asbestosis (Bégin and Sébastien 1989).

So far, these models were exclusively used by experimental pathologists. But they could also be useful to epidemiologists (Smith 1991). Most epidemiological studies looking at exposure response relationships relied on “cumulative exposure”, an exposure index obtained by integrating over time the estimated concentrations of airborne dust to which workers had been exposed (product of intensity and duration). The use of cumulative exposure has some limitations. Analyses based on this index implicitly assume that duration and intensity have equivalent effects on risk (Vacek and McDonald 1991).

Maybe the use of these sophisticated dosimetric models could provide some explanation for a common observation in the epidemiology of pneumoconioses: “the considerable between-work force differences” and this phenomenon was clearly observed for asbestosis (Becklake 1991) and for CWP (Attfield and Morring 1992). When relating the prevalence of the disease to the cumulative exposure, great differences—up to 50-fold—in risk were observed between some occupational groups. The geological origin of the coal (coal rank) provided partial explanation for CWP, mining deposits of high rank coal (a coal with high carbon content, like anthracite) yielding greater risk. The phenomenon remains to be explained in the case of asbestosis. Uncertainties on the proper exposure response curve have some bearings—at least theoretically—on the outcome, even at current exposure standards.

More generally, exposure metrics are essential in the process of risk assessment and the establishment of control limits. The use of the new dosimetric models may improve the process of risk assessment for pneumoconioses with the ultimate goal of increasing the degree of protection offered by control limits (Kriebel 1994).

Physicochemical Characteristics of Fibrogenic Dust Particles

A toxicity specific to each type of dust, related to the physicochemical characteristics of the particles (including the more subtle ones such as the surface characteristics), constitutes probably the most important notion to have emerged progressively during the last 20 years. In the very earliest stages of research, no differentiation were made among “mineral dusts”. Then generic categories were introduced: asbestos, coal, artificial inorganic fibres, phyllosilicates and silica. But this classification was found to be not precise enough to account for the variety in observed biological effects. Nowadays a mineralogical classification is used. For example, the several mineralogical types of asbestos are distinguished: serpentine chrysotile, amphibole amosite, amphibole crocidolite and amphibole tremolite. For silica, a distinction is generally made between quartz (by far the most prevalent), other crystalline polymorphs, and amorphous varieties. In the field of coal, high rank and low rank coals should be treated separately, since there is strong evidence that the risk of CWP and especially the risk of progressive massive fibrosis is much greater after exposure to dust produced in high rank coal mines.

But the mineralogical classification has also some limits. There is evidence, both experimental and epidemiological (taking into account “between-workforce differences”), that the intrinsic toxicity of a single mineralogical type of dust can be modulated by acting on the physicochemical characteristics of the particles. This raised the difficult question of the toxicological significance of each of the numerous parameters which can be used to describe a dust particle and a dust cloud. At the single particle level, several parameters can be considered: bulk chemistry, crystalline structure, shape, density, size, surface area, surface chemistry and surface charge. Dealing with dust clouds adds another level of complexity because of the distribution of these parameters (e.g., size distribution and the composition of mixed dust).

The size of the particles and their surface chemistry were the two parameters most studied to explain the modulation effect. As seen before, retention mechanisms are size related. But size may also modulate the toxicity in situ, as demonstrated by numerous animal and in vitro studies.

In the field of mineral fibres, the size was considered of so much importance that it constituted the basis of a pathogenesis theory. This theory attributed the toxicity of fibrous particles (natural and artificial) to the shape and size of the particles, leaving no role for the chemical composition. In dealing with fibres, size must be broken down into length and diameter. A two-dimensional matrix should be used to report size distributions, the useful ranges being 0.03 to 3.0mm for diameter and 0.3 to 300mm for length (Sébastien 1991). Integrating the results of the numerous studies, Lippman (1988) assigned a toxicity index to several cells of the matrix. There is a general tendency to believe that long and thin fibres are the most dangerous ones. Since the standards currently used in industrial hygiene are based upon the use of the optical microscope, they ignore the thinnest fibres. If assessing the specific toxicity of each cell within the matrix has some academic interest, its practical interest is limited by the fact that each type of fibre is associated with a specific size distribution that is relatively uniform. For compact particles, such as coal and silica, there is unclear evidence about a possible specific role for the different size sub-fractions of the particles deposited in the alveolar region of the lung.

More recent pathogenesis theories in the field of mineral dust imply active chemical sites (or functionalities) present at the surface of the particles. When the particle is “born” by separation from its parent material, some chemical bonds are broken in either a heterolytic or a homolytic way. What occurs during breaking and subsequent recombinations or reactions with ambient air molecules or biological molecules makes up the surface chemistry of the particles. Regarding quartz particles for example, several chemical functionalities of special interest have been described: siloxane bridges, silanol groups, partially ionized groups and silicon-based radicals.

These functionalities can initiate both acid-base and redox reactions. Only recently has attention been drawn to the latter (Dalal, Shi and Vallyathan 1990; Fubini et al. 1990; Pézerat et al. 1989; Kamp et al. 1992; Kennedy et al. 1989; Bronwyn, Razzaboni and Bolsaitis 1990). There is now good evidence that particles with surface-based radicals can produce reactive oxygen species, even in a cellular milieu. It is not certain if all the production of oxygen species should be attributed to the surface-based radicals. It is speculated that these sites may trigger the activation of lung cells (Hemenway et al. 1994). Other sites may be involved in the membranolytic activity of the cytotoxic particles with reactions such as ionic attraction, hydrogen bonding and hydrophobic bonding (Nolan et al. 1981; Heppleston 1991).

Following the recognition of surface chemistry as an important determinant of dust toxicity, several attempts were made to modify the natural surfaces of mineral dust particles to reduce their toxicity, as assessed in experimental models.

Adsorption of aluminium on quartz particles was found to reduce their fibrogenicity and to favour alveolar clearance (Dubois et al. 1988). Treatment with polyvinylpyridine-N-oxide (PVPNO) had also some prophylactic effect (Goldstein and Rendall 1987; Heppleston 1991). Several other modifying processes were used: grinding, thermal treatment, acid etching and adsorption of organic molecules (Wiessner et al. 1990). Freshly fractured quartz particles exhibited the highest surface activity (Kuhn and Demers 1992; Vallyathan et al. 1988). Interestingly enough, every departure from this “fundamental surface” led to a decrease in quartz toxicity (Sébastien 1990). The surface purity of several naturally occurring quartz varieties could be responsible for some observed differences in toxicity (Wallace et al. 1994). Some data support the idea that the amount of uncontaminated quartz surface is an important parameter (Kriegseis, Scharman and Serafin 1987).

The multiplicity of the parameters, together with their distribution in the dust cloud, yields a variety of possible ways to report air concentrations: mass concentration, number concentration, surface area concentration and concentration in various size categories. Thus, numerous indices of exposure can be constructed and the toxicological significance of each has to be assessed. The current standards in occupational hygiene reflect this multiplicity. For asbestos, the standards are based on the numerical concentration of fibrous particles in a certain geometrical size category. For silica and coal, the standards are based on the mass concentration of respirable particles. Some standards have also been developed for exposure to mixtures of particles containing quartz. No standard is based upon surface characteristics.

Biological Mechanisms Inducing the Fundamental Lesions

Pneumoconioses are interstitial fibrous lung diseases, the fibrosis being diffuse or nodular. The fibrotic reaction involves the activation of the lung fibroblast (Goldstein and Fine 1986) and the production and metabolism of the connective tissue components (collagen, elastin and glycosaminoglycans). It is considered to represent a late healing stage after lung injury (Niewoehner and Hoidal 1982). Even if several factors, essentially related to the characteristics of exposure, can modulate the pathological response, it is interesting to note that each type of pneumoconiosis is characterized by what could be called a fundamental lesion. The fibrosing alveolitis around the peripheral airways constitutes the fundamental lesion of asbestos exposure (Bégin et al. 1992). The silicotic nodule is the fundamental lesion of silicosis (Ziskind, Jones and Weil 1976). Simple CWP is composed of dust macules and nodules (Seaton 1983).

The pathogenesis of the pneumoconioses is generally presented as a cascade of events whose sequence runs as follows: alveolar macrophage alveolitis, signalling by inflammatory cell cytokines, oxidative damage, proliferation and activation of fibroblasts and the metabolism of collagen and elastin. Alveolar macrophage alveolitis is a characteristic reaction to retention of fibrosing mineral dust (Rom 1991). The alveolitis is defined by increased numbers of activated alveolar macrophages releasing excessive quantities of mediators including oxidants, chemotaxins, fibroblast growth factors and protease. Chemotaxins attract neutrophils and, together with macrophages, may release oxidants capable of injuring alveolar epithelial cells. Fibroblast growth factors gain access to the interstitium, where they signal fibroblasts to replicate and increase the production of collagen.

The cascade starts at the first encounter of particles deposited in the alveoli. With asbestos for example, the initial lung injury occurs almost immediately after exposure at the alveolar duct bifurcations. After only 1 hour of exposure in animal experiments, there is active uptake of fibres by type I epithelial cells (Brody et al. 1981). Within 48 hours, increased numbers of alveolar macrophages accumulate at sites of deposition. With chronic exposure, this process may lead to peribronchiolar fibrosing alveolitis.

The exact mechanism by which deposited particles produce primary biochemical injury to the alveolar lining, a specific cell, or any of its organelles, is unknown. It may be that extremely rapid and complex biochemical reactions result in free radical formation, lipid peroxidation, or a depletion in some species of vital cell protectant molecule. It has been shown that mineral particles can act as catalytic substrates for hydroxyl and superoxide radical generation (Guilianelli et al. 1993).

At the cellular level, there is slightly more information. After deposition at the alveolar level, the very thin epithelial type I cell is readily damaged (Adamson, Young and Bowden 1988). Macrophages and other inflammatory cells are attracted to the damage site and the inflammatory response is amplified by the release of arachidonic acid metabolites such as prostaglandins and leukotrienes together with exposure of the basement membrane (Holtzman 1991; Kuhn et al. 1990; Engelen et al. 1989). At this stage of primary damage, the lung architecture becomes disorganized, showing an interstitial oedema.

During the chronic inflammatory process, both the surface of the dust particles and the activated inflammatory cells release increased amounts of reactive oxygen species in the lower respiratory tract. The oxidative stress in the lung has some detectable effects on the antioxidant defense system (Heffner and Repine 1989), with expression of antioxidant enzymes like superoxide dismutase, glutathione peroxidases and catalase (Engelen et al. 1990). These factors are located in the lung tissue, the interstitial fluid and the circulating erythrocytes. The profiles of antioxidant enzymes may depend on the type of fibrogenic dust (Janssen et al. 1992). Free radicals are known mediators of tissue injury and disease (Kehrer 1993).

Interstitial fibrosis does result from a repair process. There are numerous theories to explain how the repair process takes place. The macrophage/fibroblast interaction has received the greatest attention. Activated macrophages secrete a network of proinflammatory fibrogenic cytokines: TNF, IL-1, transforming growth factor and platelet-derived growth factor. They also produce fibronectin, a cell surface glycoprotein which acts as a chemical attractant and, under some conditions, as a growth stimulant for mesenchymal cells. Some authors consider that some factors are more important than others. For example, special importance was ascribed to TNF in the pathogenesis of silicosis. In experimental animals, it was shown that collagen deposition after silica instillation in mice was almost completely prevented by anti-TNF antibody (Piguet et al. 1990). The release of platelet-derived growth factor and transforming growth factor was presented as playing an important role in the pathogenesis of asbestosis (Brody 1993).

Unfortunately, many of the macrophage/fibroblast theories tend to ignore the potential balance between the fibrogenic cytokines and their inhibitors (Kelley 1990). In fact, the resulting imbalance between oxidizing and antioxidizing agents, proteases and antiproteases, the arachidonic acid metabolites, elastases and collagenases, as well as the imbalances between the various cytokines and growth factors, would determine the abnormal remodelling of the interstitium component towards the several forms of pneumoconioses (Porcher et al. 1993). In pneumoconioses, the balance is clearly directed towards an overwhelming effect of the damaging cytokine activities.

Because type I cells are incapable of division, after the primary insult, the epithelial barrier is replaced with type II cells (Lesur et al. 1992). There is some indication that if this epithelial repair process is successful and that the regenerating type II cells are not damaged further, the fibrogenesis is not likely to proceed. Under some conditions, the repair by the type II cell is taken to excess, resulting in alveolar proteinosis. This process was clearly demonstrated after silica exposure (Heppleston 1991). To what extent the alterations in epithelial cells influence the fibroblasts is uncertain. Thus, it would seem that fibrogenesis is initiated in areas of extensive epithelial damage, as fibroblasts replicate, then differentiate and produce more collagen, fibronectin and other components of the extracelluar matrix.

There is abundant literature on the biochemistry of the several types of collagen formed in pneumoconioses (Richards, Masek and Brown 1991). The metabolism of such collagen and its stability in the lung are important elements of the fibrogenesis process. The same probably holds for the other components of the damaged connective tissue. The metabolism of collagen and elastin is of particular interest in the healing phase since these proteins are so important to lung structure and function. It has been very nicely shown that alterations in the synthesis of these proteins might determine whether emphysema or fibrosis evolves after lung injury (Niewoehner and Hoidal 1982). In the disease state, mechanisms such as an increase in transglutaminase activity could favour the formation of stable protein masses. In some CWP fibrotic lesions, the protein components account for one-third of the lesion, the rest being dust and calcium phosphate.

Considering only collagen metabolism, several stages of fibrosis are possible, some of which are potentially reversible while others are progressive. There is experimental evidence that unless a critical exposure is exceeded, the early lesions can regress and irreversible fibrosis is an unlikely outcome. In asbestosis for example, several types of lung reactions were described (Bégin, Cantin and Massé 1989): a transient inflammatory reaction without lesion, a low retention reaction with fibrotic scar limited to the distal airways, a high inflammatory reaction sustained by the continuous exposure and the weak clearance of the longest fibres.

It can be concluded from these studies that exposure to fibrotic dust particles is able to trigger several complex biochemical and cellular pathways involved in lung injury and repair. Exposure regimen, physicochemical characteristics of the dust particles, and possibly individual susceptibility factors seem to be the determinants of the fine balance among the several pathways. Physicochemical characteristics will determine the type of the ultimate fundamental lesion. Exposure regimen seems to determine the time course of events. There is some indication that sufficiently low exposure regimens can in most cases limit the lung reaction to non-progressive lesions with no disability or impairment.

Medical surveillance and screening always have been part of the strategies for the prevention of pneumoconioses. In that context, the possibility of detecting some early lesions is advantageous. Increased knowledge of pathogenesis paved the way to the development of several biomarkers (Borm 1994) and to the refinement and use of “non-classical” pulmonary investigation techniques such as the measurement of the clearance rate of deposited 99 technetium diethylenetriamine-penta-acetate (99 Tc-DTPA) to assess pulmonary epithelial integrity (O’Brodovich and Coates 1987), and quantitative gallium-67 lung scan to assess inflammatory activity (Bisson, Lamoureux and Bégin 1987).

Several biomarkers were considered in the field of pneumoconioses: sputum macrophages, serum growth factors, serum type III procollagen peptide, red blood cell antioxidants, fibronectin, leucocyte elastase, neutral metalloendopeptidase and elastin peptides in plasma, volatile hydrocarbons in exhaled air and TNF release by peripheral blood monocytes. Biomarkers are conceptually quite interesting, but many more studies are necessary to assess their significance precisely. This validation effort will be quite demanding, since it will require investigators to conduct prospective epidemiological studies. Such an effort was carried out recently for TNF release by peripheral blood monocytes in CWP. TNF was found to be an interesting marker of CWP progression (Borm 1994). Besides the scientific aspects of the significance of biomarkers in the pathogenesis of pneumoconioses, other issues related to the use of biomarkers must be examined carefully (Schulte 1993), namely, opportunities for prevention, impact on occupational medicine and ethical and legal problems.

Progression and Complication of Pneumoconioses

In the early decades of this century, pneumoconiosis was regarded as a disease that disabled the young and killed prematurely. In industrialized countries, it is now generally regarded as no more than a radiological abnormality, without impairment or disability (Sadoul 1983). However, two observations should be set against this optimistic statement. First, even if under limited exposure, pneumoconiosis remains a relatively silent and asymptomatic disease, it should be known that the disease may progress towards more severe and disabling forms. Factors affecting this progression are definitely important to consider as part of the aetiopathogenesis of the condition. Secondly, there is now evidence that some pneumoconioses can affect general health outcome and can be a contributing factor for lung cancer.

The chronic and progressive nature of asbestosis has been documented from the initial subclinical lesion to clinical asbestosis (Bégin, Cantin and Massé 1989). Modern pulmonary investigation techniques (BAL, CT scan, gallium-67 lung uptake) revealed that inflammation and injury was continuous from the time of exposure, through the latent or subclinical phase, to the development of the clinical disease. It has been reported (Bégin et al. 1985) that 75% of subjects who initially had a positive gallium-67 scan but did not have clinical asbestosis at that time, did progress to “full-blown” clinical asbestosis over a four-year period. In both humans and experimental animals, asbestosis may progress after disease recognition and exposure cessation. It is highly probable that exposure history prior to recognition is an important determinant of progression. Some experimental data support the notion of non-progressive asbestosis associated with light induction exposure and exposure cessation at recognition (Sébastien, Dufresne and Bégin 1994). Assuming that the same notion applies to humans, it would be of the first importance to establish precisely the metrics of “light induction exposure”. In spite of all the efforts at screening working populations exposed to asbestos, this information is still lacking.

It is well-known that asbestos exposure can yield to an excessive risk of lung cancer. Even if it is admitted that asbestos is a carcinogen per se, it has long been debated whether the risk of lung cancer among asbestos workers was related to the exposure to asbestos or to the lung fibrosis (Hughes and Weil 1991). This issue is not resolved yet.

Owing to continuous improvement of working conditions in modern mining facilities, nowadays, CWP is a disease affecting essentially retired miners. If simple CWP is a condition without symptoms and without demonstrable effect on lung function, progressive massive fibrosis (PMF) is a much more severe condition, with major structural alterations of the lung, deficits of lung function and reduced life expectancy. Many studies have aimed at identifying the determinants of progression towards PMF (heavy retention of dust in the lung, coal rank, mycobacterial infection or immunological stimulation). A unifying theory was proposed (Vanhee et al. 1994), based upon a continuous and severe alveolar inflammation with activation of the alveolar macrophages and substantial production of reactive oxygen species, chemotactic factors and fibronectin. Other complications of CWP include mycobacterial infection, Caplan’s syndrome and scleroderma. There is no evidence of elevated risk of lung cancer among coal miners.

The chronic form of silicosis follows exposure, measured in decades rather than years, to respirable dust containing generally less than 30% quartz. But in case of uncontrolled exposure to quartz-rich dust (historical exposures with sand blasting, for example), acute and accelerated forms can be found after only several months. Cases of acute and accelerated disease are particularly at risk of complication by tuberculosis (Ziskind, Jones and Weil 1976). Progression may also occur, with the development of large lesions that obliterate lung structure, called either complicated silicosis or PMF.

A few studies examined the progression of silicosis in relation to exposure and yielded diverging results about the relationships between progression and exposure, before and after onset (Hessel et al. 1988). Recently, Infante-Rivard et al. (1991) studied the prognostic factors influencing the survival of compensated silicotic patients. Patients with small opacities alone on their chest radiograph and who did not have dyspnoea, expectoration or abnormal breath sounds had a survival similar to that of the referents. Other patients had a poorer survival. Finally, one should mention the recent concern about silica, silicosis and lung cancer. There is some evidence for and against the proposition that silica per se is carcinogenic (Agius 1992). Silica may synergize potent environmental carcinogens, such as those in tobacco smoke, through a relatively weak promoting effect on carcinogenesis or by impairing their clearance. Moreover, the disease process associated with or leading to silicosis might carry an increased risk of lung cancer.

Nowadays, progression and complication of pneumoconioses could be considered as a key issue for medical management. The use of classical pulmonary investigation techniques has been refined for early recognition of the disease (Bégin et al. 1992), at a stage where pneumoconiosis is limited to its radiological manifestation, without impairment or disability. In the near future, it is probable that a battery of biomarkers will be available to document even earlier stages of the disease. The question of whether a worker diagnosed with pneumoconiosis—or documented to be in its earlier stages—should be allowed to continue with his or her job has puzzled occupational health decision makers for some time. It is a rather difficult question which entails ethical, social and scientific considerations. If an overwhelming scientific literature is available on the induction of pneumoconiosis, the information on progression usable by decision makers is rather sparse and somewhat confusing. A few attempts were made to study the roles of variables such as exposure history, dust retention and medical condition at onset. The relationships between all these variables do complicate the issue. Recommendations are made for health screening and surveillance of workers exposed to mineral dust (Wagner 1996). Programmes are already—or will be—put in place accordingly. Such programmes would definitely benefit from better scientific knowledge on progression, and especially on the relation between exposure and retention characteristics.

Discussion

The information brought by many scientific disciplines to bear upon the aetiopathogenesis of the pneumoconioses is overwhelming. The major difficulty now is to reassemble the scattered elements of the puzzle into unifying mechanistic pathways leading to the fundamental lesions of the pneumoconioses. Without this necessary integration, we would be left with the contrast between a few fundamental lesions, and very numerous biochemical and cellular reactions.

Our knowledge of aetiopathogenesis has so far influenced the practices of occupational hygiene only to a limited extent, in spite of the strong intention of hygienists to operate according to standards having some biological significance. Two main notions were incorporated in their practices: the size selection of respirable dust particles and the dust type dependence of toxicity. The latter yielded some limits specific to each type of dust. The quantitative risk assessment, a necessary step in defining exposure limits, constitutes a complicated exercise for several reasons, such as the variety of possible exposure indices, poor information on past exposure, the difficulty one has with epidemiological models in dealing with multiple indices of exposure and the difficulty in estimating dose from exposure information. The current exposure limits, embodying sometimes considerable uncertainty, are probably low enough to offer good protection. The between-workforce differences observed in exposure-response relationships however, reflect our incomplete control of the phenomenon.

The impact of newer understanding of the cascade of events in the pathogenesis of the pneumoconioses has not modified the traditional approach to workers’ surveillance, but has significantly helped physicians in their capacity of recognizing the disease (pneumoconiosis) early, at a time when the disease has had only a limited impact on lung function. It is indeed subjects at the early stage of disease that should be recognized and withdrawn from further significant exposure if prevention of disability is to be achieved by medical surveillance.

 

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Contents

Preface
Part I. The Body
Blood
Cancer
Cardiovascular System
Digestive System
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Respiratory System
Resources
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Part IV. Tools and Approaches
Part V. Psychosocial and Organizational Factors
Part VI. General Hazards
Part VII. The Environment
Part VIII. Accidents and Safety Management
Part IX. Chemicals
Part X. Industries Based on Biological Resources
Part XI. Industries Based on Natural Resources
Part XII. Chemical Industries
Part XIII. Manufacturing Industries
Part XIV. Textile and Apparel Industries
Part XV. Transport Industries
Part XVI. Construction
Part XVII. Services and Trade
Part XVIII. Guides

Respiratory System Additional Resources

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Respiratory System References

Abramson, MJ, JH Wlodarczyk, NA Saunders, and MJ Hensley. 1989. Does aluminum smelting cause lung disease? Am Rev Respir Dis 139:1042-1057.

Abrons, HL, MR Peterson, WT Sanderson, AL Engelberg, and P Harber. 1988. Symptoms, ventilatory function, and environmental exposures in Portland cement workers. Brit J Ind Med 45:368-375.

Adamson, IYR, L Young, and DH Bowden. 1988. Relationship of alveolar epithelial injury and repair to the indication of pulmonary fibrosis. Am J Pathol 130(2):377-383.

Agius, R. 1992. Is silica carcinogenic? Occup Med 42: 50-52.

Alberts, WM and GA Do Pico. 1996. Reactive airways dysfunction syndrome (review). Chest 109:1618-1626.
Albrecht, WN and CJ Bryant. 1987. Polymer fume fever associated with smoking and use of a mold release spray containing polytetraflouroethylene. J Occup Med 29:817-819.

American Conference of Governmental Industrial Hygienists (ACGIH). 1993. 1993-1994 Threshold Limit Values and Biological Exposure Indices. Cincinnati, Ohio: ACGIH.

American Thoracic Society (ATS). 1987 Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. Am Rev Respir Dis 136:225-244.

—.1995. Standardization of Spirometry: 1994 update. Amer J Resp Crit Care Med 152: 1107-1137.

Antman, K and J Aisner. 1987. Asbestos-Related Malignancy. Orlando: Grune & Stratton.

Antman, KH, FP Li, HI Pass, J Corson, and T Delaney. 1993. Benign and malignant mesothelioma. In Cancer: Principles and Practice of Oncology, edited by VTJ DeVita, S Hellman, and SA Rosenberg. Philadelphia: JB Lippincott.
Asbestos Institute. 1995. Documentation center: Montreal, Canada.

Attfield, MD and K Morring. 1992. An investigation into the relationship between coal workers’ pneumoconiosis and dust exposure in US coal miners. Am Ind Hyg Assoc J 53(8):486-492.

Attfield, MD. 1992. British data on coal miners’ pneumoconiosis and relevance to US conditions. Am J Public Health 82:978-983.

Attfield, MD and RB Althouse. 1992. Surveillance data on US coal miners’ pneumoconiosis, 1970 to 1986. Am J Public Health 82:971-977.

Axmacher, B, O Axelson, T Frödin, R Gotthard, J Hed, L Molin, H Noorlind Brage, and M Ström. 1991. Dust exposure in coeliac disease: A case-referent study. Brit J Ind Med 48:715-717.

Baquet, CR, JW Horm, T Gibbs, and P Greenwald. 1991. Socioeconomic factors and cancer incidence among blacks and whites. J Natl Cancer Inst 83: 551-557.

Beaumont, GP. 1991. Reduction in airborne silicon carbide whiskers by process improvements. Appl Occup Environ Hyg 6(7):598-603.

Becklake, MR. 1989. Occupational exposures: Evidence for a causal association with chronic obstructive pulmonary disease. Am Rev Respir Dis. 140: S85-S91.

—. 1991. The epidemiology of asbestosis. In Mineral Fibers and Health, edited by D Liddell and K Miller. Boca Raton: CRC Press.

—. 1992. Occupational exposure and chronic airways disease. Chap. 13 in Environmental and Occupational Medicine. Boston: Little, Brown & Co.

—. 1993. In Asthma in the workplace, edited by IL Bernstein, M Chan-Yeung, J-L Malo and D Bernstein. Marcel Dekker.

—. 1994. Pneumoconioses. Chap. 66 in A Textbook of Respiratory Medicine, edited by JF Murray and J Nadel. Philadelphia: WB Saunders.

Becklake, MR and B Case. 1994. Fibre burden and asbestos-related lung disease: Determinants of dose-response relationships. Am J Resp Critical Care Med 150:1488-1492.

Becklake, MR. et al. 1988. The relationships between acute and chronic airways responses to occupational exposures. In Current Pulmonology. Vol. 9, edited by DH Simmons. Chicago: Year Book Medical Publishers.

Bégin, R, A Cantin, and S Massé. 1989. Recent advances in the pathogenesis and clinical assessment of mineral dust pneumoconioses: Asbestosis, silicosis and coal pneumoconiosis. Eur Resp J 2:988-1001.

Bégin, R and P Sébastien. 1989. Alveolar dust clearance capacity as determinant of individual susceptibility to asbestosis: Experimental oservations. Ann Occup Hyg 33:279-282.

Bégin, R, A Cantin, Y Berthiaume, R Boileau, G Bisson, G Lamoureux, M Rola-Pleszczynski, G Drapeau, S Massé, M Boctor, J Breault, S Péloquin, and D Dalle. 1985. Clinical features to stage alveolitis in asbestos workers. Am J Ind Med 8:521-536.

Bégin, R, G Ostiguy, R Filion, and S Groleau. 1992. Recent advances in the early diagnosis of asbestosis. Sem Roentgenol 27(2):121-139.

Bégin, T, A Dufresne, A Cantin, S Massé, P Sébastien, and G Perrault. 1989. Carborundum pneumoconiosis. Chest 95(4):842-849.

Beijer L, M Carvalheiro, PG Holt, and R Rylander. 1990. Increased blood monocyte procoagulant activity in cotton mill workers. J. Clin Lab Immunol 33:125-127.

Beral, V, P Fraser, M Booth, and L Carpenter. 1987. Epidemiological studies of workers in the nuclear industry. In Radiation and Health: The Biological Effects of Low-Level Exposure to Ionizing Radiation, edited by R Russell Jones and R Southwood. Chichester: Wiley.

Bernstein, IL, M Chan-Yeung, J-L Malo, and D Bernstein. 1993. Asthma in the Workplace. Marcel Dekker.

Berrino F, M Sant, A Verdecchia, R Capocaccia, T Hakulinen, and J Esteve. 1995. Survival of Cancer Patients in Europe: The EUROCARE Study. IARC Scientific Publications, no 132. Lyon: IARC.

Berry, G, CB McKerrow, MKB Molyneux, CE Rossiter, and JBL Tombleson. 1973. A study of the acute and chronic changes in ventilatory capacity of workers in Lancashire Cotton Mills. Br J Ind Med 30:25-36.

Bignon J, (ed.) 1990. Health-related effects of phyllosilicates. NATO ASI series Berlin: Springer-Verlag.

Bignon, J, P Sébastien, and M Bientz. 1979. Review of some factors relevant to the assessment of exposure to asbestos dusts. In The use of Biological Specimens for the Assessment of Human Exposure to Environmental Pollutants, edited by A Berlin, AH Wolf, and Y Hasegawa. Dordrecht: Martinus Nijhoff for the Commission of the European Communities.

Bignon J, J Peto and R Saracci, (eds.) 1989. Non-occupational exposure to mineral fibres. IARC Scientific Publications, no 90. Lyon: IARC.

Bisson, G, G Lamoureux, and R Bégin. 1987. Quantitative gallium 67 lung scan to assess the inflammatory activity in the pneumoconioses. Sem Nuclear Med 17(1):72-80.

Blanc, PD and DA Schwartz. 1994. Acute pulmonary responses to toxic exposures. In Respiratory Medicine, edited by JF Murray and JA Nadel. Philadelphia: WB Saunders.

Blanc, P, H Wong, MS Bernstein, and HA Boushey. 1991. An experimental human model of a metal fume fever. Ann Intern Med 114:930-936.

Blanc, PD, HA Boushey, H Wong, SF Wintermeyer, and MS Bernstein. 1993. Cytokines in metal fume fever. Am Rev Respir Dis 147:134-138.

Blandford, TB, PJ Seamon, R Hughes, M Pattison, and MP Wilderspin. 1975. A case of polytetrafluoroethylene poisoning in cockatiels accompanied by polymer fume fever in the owner. Vet Rec 96:175-178.

Blount, BW. 1990. Two types of metal fume fever: mild vs. serious. Milit Med 155:372-377.

Boffetta, P, R Saracci, A Anderson, PA Bertazzi, Chang-Claude J, G Ferro, AC Fletcher, R Frentzel-Beyme, MJ Gardner, JH Olsen, L Simonato, L Teppo, P Westerholm, P Winter, and C Zocchetti. 1992. Lung cancer mortality among workers in the European production of man-made mineral fibers-a Poisson regression analysis. Scand J Work Environ Health 18:279-286.

Borm, PJA. 1994. Biological markers and occupational lung dsease: Mineral dust-induced respiratory disorders. Exp Lung Res 20:457-470.

Boucher, RC. 1981. Mechanisms of pollutant induced airways toxicity. Clin Chest Med 2:377-392.

Bouige, D. 1990. Dust exposure results in 359 asbestos-using factories from 26 countries. In Seventh International Pneumoconiosis Conference Aug 23-26, 1988. Proceedings Part II. Washington, DC: DHS (NIOSH).

Bouhuys A. 1976. Byssinosis: Scheduled asthma in the textile industry. Lung 154:3-16.

Bowden, DH, C Hedgecock, and IYR Adamson. 1989. Silica-induced pulmonary fibrosis involves the reaction of particles with interstitial rather than alveolar macrophages. J Pathol 158:73-80.

Brigham, KL and B Mayerick. 1986. Endotoxin and Lung injury. Am Rev Respir Dis 133:913-927.

Brody, AR. 1993. Asbestos-induced lung disease. Environ Health Persp 100:21-30.

Brody, AR, LH Hill, BJ Adkins, and RW O’Connor. 1981. Chrysotile asbestos inhalation in rats: Deposition pattern and reaction of alveolar epithelium and pulmonary macrophages. Am Rev Respir Dis 123:670.

Bronwyn, L, L Razzaboni, and P Bolsaitis. 1990. Evidence of an oxidative mechanism for the hemolytic activity of silica particles. Environ Health Persp 87: 337-341.

Brookes, KJA. 1992. World Directory and Handbook of Hard Metal and Hard Materials. London: International Carbide Data.

Brooks, SM and AR Kalica. 1987. Strategies for elucidating the relationship between occupational exposures and chronic air-flow obstruction. Am Rev Respir Dis 135:268-273.

Brooks, SM, MA Weiss, and IL Bernstein. 1985. Reactive airways dysfunction syndrome (RADS). Chest 88:376-384.

Browne, K. 1994. Asbestos-related disorders. Chap. 14 in Occupational Lung Disorders, edited by WR Parkes. Oxford: Butterworth-Heinemann.

Brubaker, RE. 1977. Pulmonary problems associated with the use of polytetrafluoroethylene. J Occup Med 19:693-695.

Bunn, WB, JR Bender, TW Hesterberg, GR Chase, and JL Konzen. 1993. Recent studies of man-made vitreous fibers: Chronic animal inhalation studies. J Occup Med 35(2):101-113.

Burney, MB and S Chinn. 1987. Developing a new questionnaire for measuring the prevalence and distribution of asthma. Chest 91:79S-83S.

Burrell, R and R Rylander. 1981. A critical review of the role of precipitins in hypersensitivity pneumonitis. Eur J Resp Dis 62:332-343.

Bye, E. 1985. Occurrence of airborne silicon carbide fibers during industrial production of silicon carbide. Scand J Work Environ Health 11:111-115.

Cabral-Anderson, LJ, MJ Evans, and G Freeman. 1977. Effects of NO2 on the lungs of aging rats I. Exp Mol Pathol 27:353-365.

Campbell, JM. 1932. Acute symptoms following work with hay. Brit Med J 2:1143-1144.

Carvalheiro MF, Y Peterson, E Rubenowitz, R Rylander. 1995. Bronchial activity and work-related symptoms in farmers. Am J Ind Med 27: 65-74.

Castellan, RM, SA Olenchock, KB Kinsley, and JL Hankinson. 1987. Inhaled endotoxin and decreased spirometric values: An exposure-response relation for cotton dust. New Engl J Med 317:605-610.

Castleman, WL, DL Dungworth, LW Schwartz, and WS Tyler. 1980. Acute repiratory bronchiolitis - An ultrastructural and autoradiographic study of epithelial cell injury and renewal in Rhesus monkeys exposed to ozone. Am J Pathol 98:811-840.

Chan-Yeung, M. 1994. Mechanism of occupational asthma due to Western red cedar. Am J Ind Med 25:13-18.

—. 1995. Assessment of asthma in the workplace. ACCP consensus statement. American College of Chest Physicians. Chest 108:1084-1117.
Chan-Yeung, M and J-L Malo. 1994. Aetiological agents in occupational asthma. Eur Resp J 7:346-371.

Checkoway, H, NJ Heyer, P Demers, and NE Breslow. 1993. Mortality among workers in the diatomaceous earth industry. Brit J Ind Med 50:586-597.

Chiazze, L, DK Watkins, and C Fryar. 1992. A case-control study of malignant and non-malignant respiratory disease among employees of a fibreglass manufacturing facility. Brit J Ind Med 49:326-331.

Churg, A. 1991. Analysis of lung asbestos content. Brit J Ind Med 48:649-652.

Cooper, WC and G Jacobson. 1977. A twenty-one year radiographic follow-up of workers in the diatomite industry. J Occup Med 19:563-566.

Craighead, JE, JL Abraham, A Churg, FH Green, J Kleinerman, PC Pratt, TA Seemayer, V Vallyathan and H Weill. 1982. The pathology of asbestos associated diseases of the lungs and pleural cavities. Diagnostic criteria and proposed grading system. Arch Pathol Lab Med 106: 544-596.

Crystal, RG and JB West. 1991. The Lung. New York: Raven Press.

Cullen, MR, JR Balmes, JM Robins, and GJW Smith. 1981. Lipoid pneumonia caused by oil mist exposure from a steel rolling tandem mill. Am J Ind Med 2: 51-58.

Dalal, NA, X Shi, and V Vallyathan. 1990. Role of free radicals in the mechanisms of hemolysis and lipid peroxidation by silica: Comparative ESR and cytotoxicity studies. J Tox Environ Health 29:307-316.

Das, R and PD Blanc. 1993. Chlorine gas exposure and the lung: A review. Toxicol Ind Health 9:439-455.

Davis, JMG, AD Jones, and BG Miller. 1991. Experimental studies in rats on the effects of asbestos inhalation couples with the inhalation of titanium dioxide or quartz. Int J Exp Pathol 72:501-525.

Deng, JF, T Sinks, L Elliot, D Smith, M Singal, and L Fine. 1991. Characterisation of respiratory health and exposures at a sintered permanent magnet manufacturer. Brit J Ind Med 48:609-615.

de Viottis, JM. 1555. Magnus Opus. Historia de gentibus septentrionalibus. In Aedibus Birgittae. Rome.

Di Luzio, NR. 1985. Update on immunomodulating activities of glucans. Springer Semin Immunopathol 8:387-400.

Doll, R and J Peto. 1985. Effects on health of exposure to asbestos. London, Health and Safety Commission London: Her Majesty’s Stationery Office.

—. 1987. In Asbestos-Related Malignancy, edited by K Antman and J Aisner. Orlando, Fla: Grune & Stratton.

Donelly, SC and MX Fitzgerald. 1990. Reactive airways dysfunction syndrome (RADS) due to acute chlorine exposure. Int J Med Sci 159:275-277.

Donham, K, P Haglind, Y Peterson, and R Rylander. 1989. Environmental and health studies of farm workers in Swedish swine confinement buildings. Brit J Ind Med 46:31-37.

Do Pico, GA. 1992. Hazardous exposure and lung disease among farm workers. Clin Chest Med 13: 311-328.

Dubois, F, R Bégin, A Cantin, S Massé, M Martel, G Bilodeau, A Dufresne, G Perrault, and P Sébastien. 1988. Aluminum inhalation reduces silicosis in a sheep model. Am Rev Respir Dis 137:1172-1179.

Dunn, AJ. 1992. Endotoxin-induced activation of cerebral catecholamine and serotonin metabolism: Comparison with Interleukin.1. J Pharmacol Exp Therapeut 261:964-969.

Dutton, CB, MJ Pigeon, PM Renzi, PJ Feustel, RE Dutton, and GD Renzi. 1993. Lung function in workers refining phosphorus rock to obtain elementary phosphorus. J Occup Med 35:1028-1033.

Ellenhorn, MJ and DG Barceloux. 1988. Medical Toxicology. New York: Elsevier.
Emmanuel, DA, JJ Marx, and B Ault. 1975. Pulmonary mycotoxicosis. Chest 67:293-297.

—. 1989. Organic dust toxic syndrome (pulmonary mycotoxicosis) - A review of the experience in central Wisconsin. In Principles of Health and Safety in Agriculture, edited by JA Dosman and DW Cockcroft. Boca Raton: CRC Press.

Engelen, JJM, PJA Borm, M Van Sprundel, and L Leenaerts. 1990. Blood anti-oxidant parameters at different stages in coal worker’s pneumoconiosis. Environ Health Persp 84:165-172.

Englen, MD, SM Taylor, WW Laegreid, HD Liggit, RM Silflow, RG Breeze, and RW Leid. 1989. Stimulation of arachidonic acid metabolism in silica-exposed alveolar macrophages. Exp Lung Res 15: 511-526.

Environmental Protection Agency (EPA). 1987. Ambient Air Monitoring reference and equivalent methods. Federal Register 52:24727 (July l, 1987).

Ernst and Zejda. 1991. In Mineral Fibers and Health, edited by D Liddell and K Miller. Boca Raton: CRC Press.

European Standardization Committee (CEN). 1991. Size Fraction Definitions for Measurements of Airborne Particles in the Workplace. Report No. EN 481. Luxembourg: CEN.

Evans, MJ, LJ Cabral-Anderson, and G Freeman. 1977. Effects of NO2 on the lungs of aging rats II. Exp Mol Pathol 27:366-376.

Fogelmark, B, H Goto, K Yuasa, B Marchat, and R Rylander. 1992. Acute pulmonary toxicity of inhaled (13)-B-D-glucan and endotoxin. Agents Actions 35:50-56.

Fraser, RG, JAP Paré, PD Paré, and RS Fraser. 1990. Diagnosis of Diseases of the Chest. Vol. III. Philadelphia: WB Saunders.

Fubini, B, E Giamello, M Volante, and V Bolis. 1990. Chemical functionalities at the silica surface determining its reactivity when inhaled. Formation and reactivity of surface radicals. Toxicol Ind Health 6(6):571-598.

Gibbs, AE, FD Pooley, and DM Griffith. 1992. Talc pneumoconiosis: A pathologic and mineralogic study. Hum Pathol 23(12):1344-1354.

Gibbs, G, F Valic, and K Browne. 1994. Health risk associated with chrysotile asbestos. A report of a workshop held in Jersey, Channel Islands. Ann Occup Hyg 38:399-638.

Gibbs, WE. 1924. Clouds and Smokes. New York: Blakiston.

Ginsburg, CM, MG Kris, and JG Armstrong. 1993. Non-small cell lung cancer. In Cancer: Principles & Practice of Oncology, edited by VTJ DeVita, S Hellman, and SA Rosenberg. Philadelphia: JB Lippincott.

Goldfrank, LR, NE Flomenbaum, N Lewin, and MA Howland. 1990. Goldfrank’s Toxicologic Emergencies. Norwalk, Conn.: Appleton & Lange.
Goldstein, B and RE Rendall. 1987. The prophylactic use of polyvinylpyridine-N-oxide (PVNO) in baboons exposed to quartz dust. Environmental Research 42:469-481.

Goldstein, RH and A Fine. 1986. Fibrotic reactions in the lung: The activation of the lung fibroblast. Exp Lung Res 11:245-261.
Gordon, RE, D Solano, and J Kleinerman. 1986. Tight junction alterations of respiratory epithelia following long term NO2 exposure and recovery. Exp Lung Res 11:179-193.

Gordon, T, LC Chen, JT Fine, and RB Schlesinger. 1992. Pulmonary effects of inhaled zinc oxide in human subjects, guinea pigs, rats, and rabbits. Am Ind Hyg Assoc J 53:503-509.

Graham, D. 1994. Noxious gases and fumes. In Textbook of Pulmonary Diseases, edited by GL Baum and E Wolinsky. Boston: Little, Brown & Co.

Green, JM, RM Gonzalez, N Sonbolian, and P Renkopf. 1992. The resistance to carbon dioxide laser ignition of a new endotracheal tube. J Clin Anesthesiaol 4:89-92.

Guilianelli, C, A Baeza-Squiban, E Boisvieux-Ulrich, O Houcine, R Zalma, C Guennou, H Pezerat, and F MaraNo. 1993. Effect of mineral particles containing iron on primary cultures of rabbit tracheal epithelial cells: Possible implication of oxidative stress. Environ Health Persp 101(5):436-442.

Gun, RT, Janckewicz, A Esterman, D Roder, R Antic, RD McEvoy, and A Thornton. 1983. Byssinosis: A cross-sectional study in an Australian textile factory. J Soc Occup Med 33:119-125.

Haglind P and R Rylander. Exposure to cotton dust in an experimental cardroom. Br J Ind Med 10: 340-345.

Hanoa, R. 1983. Graphite pneumoconiosis. A review of etiologic and epidemiologic aspects. Scand J Work Environ Health 9:303-314.

Harber, P, M Schenker, and J Balmes. 1996. Occupational and Environmental Respiratory Disease. St. Louis: Mosby.

Health Effects Institute - Asbestos Research. 1991. Asbestos in Public and Commercial Buildings: A Literature Review and Synthesis of Current Knowledge. Cambridge, Mass.: Health Effects Institute.

Heffner, JE and JE Repine. 1989. Pulmonary strategies of antioxidant defense. Am Rev Respir Dis 140: 531-554.

Hemenway, D, A Absher, B Fubini, L Trombley, P Vacek, M Volante, and A Cabenago. 1994. Surface functionalities are related to biological response and transport of crystalline silica. Ann Occup Hyg 38 Suppl. 1:447-454.

Henson, PM and RC Murphy. 1989. Mediators of the Inflammatory Process. New York: Elsevier.

Heppleston, AG. 1991. Minerals, fibrosis and the Lung. Environ Health Persp 94:149-168.

Herbert, A, M Carvalheiro, E Rubenowiz, B Bake, and R Rylander. 1992. Reduction of alveolar-capillary diffusion after inhalation of endotoxin in normal subjects. Chest 102:1095-1098.

Hessel, PA, GK Sluis-Cremer, E Hnizdo, MH Faure, RG Thomas, and FJ Wiles. 1988. Progression of silicosis in relation to silica dust exposure. Am Occup Hyg 32 Suppl. 1:689-696.

Higginson, J, CS Muir, and N Muñoz. 1992. Human cancer: Epidemiology and environmental causes. In Cambridge Monographs on Cancer Research. Cambridge: Cambridge Univ. Press.

Hinds, WC. 1982. Aerosol Technology: Properties, Behavior, and Measurement of Airborne Particles. New York: John Wiley.

Hoffman, RE, K Rosenman, F Watt, et al. 1990. Occupational disease surveillance: Occupational asthma. Morb Mortal Weekly Rep 39:119-123.

Hogg, JC. 1981. Bronchial mucosal permeability and its relationship to airways hyperreactivity. J Allergy Clin immunol 67:421-425.

Holgate, ST, R Beasley, and OP Twentyman. 1987. The pathogenesis and significance of bronchial hyperresponsiveness in airways disease. Clin Sci 73:561-572.

Holtzman, MJ. 1991. Arachidonic acid metabolism. Implications of biological chemistry for lung function and disease. Am Rev Respir Dis 143:188-203.

Hughes, JM and H Weil. 1991. Asbestosis as a precursor of asbestos related lung cancer: Results of a prospective mortality study. Brit J Ind Med 48: 229-233.

Hussain, MH, JA Dick, and YS Kaplan. 1980. Rare earth pneumoconiosis. J Soc Occup Med 30:15-19.

Ihde, DC, HI Pass, and EJ Glatstein. 1993. Small cell lung cancer. In Cancer: Principles and Practice of Oncology, edited by VTJ DeVita, S Hellman, and SA Rosenberg. Philadelphia: JB Lippincott.

Infante-Rivard, C, B Armstrong, P Ernst, M Peticlerc, L-G Cloutier, and G Thériault. 1991. Descriptive study of prognostic factors influencing survival of compensated silicotic patients. Am Rev Respir Dis 144:1070-1074.

International Agency for Research on Cancer (IARC). 1971-1994. Monographs on the Evaluation of Carcinogenic Risks to Humans. Vol. 1-58. Lyon: IARC.

—. 1987. Monographs on the Evaluation of Carcinogenic Risks to Humans, Overall Evaluations of Carcinogenicity: An Updating of IARC
Monographs. Vol. 1-42. Lyon: IARC. (Supplement 7.)

—. 1988. Man-made mineral fibres and radon. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, No. 43. Lyon: IARC.

—. 1988. Radon. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, No. 43. Lyon: IARC.

—. 1989a. Diesel and gasoline engine exhausts and some nitroarenes. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, No. 46. Lyon: IARC.

—. 1989b. Non-occupational exposure to mineral fibres. IARC Scientific Publications, No. 90. Lyon: IARC.

—. 1989c. Some organic solvents, resin monomers and related compounds, pigments and occupational exposure in paint manufacture and painting. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, No. 47. Lyon: IARC.

—. 1990a. Chromium and chromium compounds. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, No. 49. Lyon: IARC.

—. 1990b. Chromium, nickel, and welding. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, No. 49. Lyon: IARC.

—. 1990c. Nickel and nickel compounds. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, No. 49. Lyon: IARC.

—. 1991a. Chlorinated drinking-water; Chlorination by-products; Some other halogenated compounds; Cobalt and cobalt compounds. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, No. 52. Lyon: IARC.

—. 1991b. Occupational exposures in spraying and application of insecticides and some pesticides. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, No. 53. Lyon: IARC.

—. 1992. Occupational exposures to mists and vapours from sulfuric acid, other strong inorganic acids and other industrial chemicals. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, No. 54. Lyon: IARC.

—. 1994a. Beryllium and beryllium compounds. IARC Monographs on the Evaluationof Carcinogenic Risks to Humans, No. 58. Lyon: IARC.

—. 1994b. Beryllium, cadmium and cadmium compounds, mercury and the glass industry. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, No. 58. Lyon: IARC.

—. 1995. Survival of cancer patients in Europe: The EUROCARE study. IARC Scientific Publications, No.132. Lyon: IARC.

International Commission on Radiological Protection (ICRP). 1994. Human Respiratory Tract Model for Radiological Protection. Publication No. 66. ICRP.

International Labour Office (ILO). 1980. Guidelines for the use of ILO international classification of radiographs of pneumoconioses. Occupational Safety and Health Series, No. 22. Geneva: ILO.

—. 1985. Sixth International Report on the Prevention and Suppression of Dust in Mining, Tunnelling and Quarrying 1973-1977. Occupational Safety and Health Series, No.48. Geneva: ILO.

International Organization for Standardization (ISO). 1991. Air Quality - Particle Size Fraction Definitions for Health-Related Sampling. Geneva: ISO.

Janssen, YMW, JP Marsh, MP Absher, D Hemenway, PM Vacek, KO Leslie, PJA Borm, and BT Mossman. 1992. Expression of antioxidant enzymes in rat lungs after inhalation of asbestos or silica. J Biol Chem 267(15):10625-10630.

Jaurand, MC, J Bignon, and P Brochard. 1993. The mesothelioma cell and mesothelioma. Past, present and future. International Conference, Paris, Sept. 20 to Oct. 2, 1991. Eur Resp Rev 3(11):237.

Jederlinic, PJ, JL Abraham, A Churg, JS Himmelstein, GR Epler, and EA Gaensler. 1990. Pulmonary fibrosis in aluminium oxide workers. Am Rev Respir Dis 142:1179-1184.

Johnson, NF, MD Hoover, DG Thomassen, YS Cheng, A Dalley, and AL Brooks. 1992. In vitro activity of silicon carbide whiskers in comparison to other industrial fibers using four cell culture systems. Am J Ind Med 21:807-823.

Jones, HD, TR Jones, and WH Lyle. 1982. Carbon fibre: Results of a survey of process workers and their environment in a factory producing continuous filament. Am Occup Hyg 26:861-868.

Jones, RN, JE Diem, HW Glindmeyer, V Dharmarajan, YY Hammad, J Carr, and H Weill. 1979. Mill effect and dose-response relationships in byssinosis. Br J Ind Med 36:305-313.

Kamp, DW, P Graceffa, WA Prior, and A Weitzman. 1992. The role of free radicals in asbestos-induced diseases. Free Radical Bio Med 12:293-315.

Karjalainen, A, PJ Karhonen, K Lalu, A Pentilla, E Vanhala, P Kygornen, and A Tossavainen. 1994. Pleural plaques and exposure to mineral fibres in a male urban necropsy population. Occup Environ Med 51:456-460.

Kass, I, N Zamel, CA Dobry, and M Holzer. 1972. Bronchiectasis following ammonia burns of the respiratory tract. Chest 62:282-285.

Katsnelson, BA, LK Konyscheva, YEN Sharapova, and LI Privalova. 1994. Prediction of the comparative intensity of pneumoconiotic changes caused by chronic inhalation exposure to dusts of different cytotoxicity by means of a mathematical model. Occup Environ Med 51:173-180.

Keenan, KP, JW Combs, and EM McDowell. 1982. Regeneration of hamster tracheal epithelium after mechanical injury I, II, III. Virchows Archiv 41:193-252.

Keenan, KP, TS Wilson, and EM McDowell. 1983. Regeneration of hamster tracheal epithelium after mechanical injury IV. Virchows Archiv 41:213-240.
Kehrer, JP. 1993. Free radicals as mediators of tissue injury and disease. Crit Rev Toxicol 23:21-48.

Keimig, DG, RM Castellan, GJ Kullman, and KB Kinsley. 1987. Respiratory health status of gilsonite workers. Am J Ind Med 11:287-296.

Kelley, J. 1990. Cytokines of the Lung. Am Rev Respir Dis 141:765-788.

Kennedy, TP, R Dodson, NV Rao, H Ky, C Hopkins, M Baser, E Tolley, and JR Hoidal. 1989. Dusts causing pneumoconiosis generate OH and product hemolysis by acting as fenton catalysts. Arch Biochem Biophys 269(1):359-364.

Kilburn, KH and RH Warshaw. 1992. Irregular opacities in the lung, occupational asthma, and airways dysfunction in aluminum workers. Am J Ind Med 21:845-853.

Kokkarinen, J, H Tuikainen, and EO Terho. 1992. Severe farmer’s lung following a workplace challenge. Scand J Work Environ Health 18:327-328.

Kongerud, J, J Boe, V Soyseth, A Naalsund, and P Magnus. 1994. Aluminium pot room asthma: The Norwegian experience. Eur Resp J 7:165-172.

Korn, RJ, DW Dockery, and FE Speizer. 1987. Occupational exposure and chronic respiratory symptoms. Am Rev Respir Dis 136:298-304.

Kriebel, D. 1994. The dosimetric model in occupational and environmental epidemiology. Occup Hyg 1:55-68.

Kriegseis, W, A Scharmann, and J Serafin. 1987. Investigations of surface properties of silica dusts with regard to their cytotoxicity. Ann Occup Hyg 31(4A):417-427.

Kuhn, DC and LM Demers. 1992. Influence of mineral dust surface chemistry on eicosanoid production by the alveolar macrophage. J Tox Environ Health 35: 39-50.

Kuhn, DC, CF Stanley, N El-Ayouby, and LM Demers. 1990. Effect of in vivo coal dust exposure on arachidonic acid metabolism in the rat alveolar macrophage. J Tox Environ Health 29:157-168.

Kunkel, SL, SW Chensue, RM Strieter, JP Lynch, and DG Remick. 1989. Cellular and molecular aspects of granulomatous inflammation. Am J Respir Cell Mol Biol 1:439-447.

Kuntz, WD and CP McCord. 1974. Polymer fume fever. J Occup Med 16:480-482.

Lapin, CA, DK Craig, MG Valerio, JB McCandless, and R Bogoroch. 1991. A subchronic inhalation toxicity study in rats exposed to silicon carbide whiskers. Fund Appl Toxicol 16:128-146.

Larsson, K, P Malmberg, A Eklund, L Belin, and E Blaschke. 1988. Exposure to microorganisms, airway inflammatory changes and immune reactions in asymptomatic dairy farmers. Int Arch Allergy Imm 87:127-133.

Lauweryns, JM and JH Baert. 1977. Alveolar clearance and the role of the pulmonary lymphatics. Am Rev Respir Dis 115:625-683.

Leach, J. 1863. Surat cotton, as it bodily affects operatives in cotton mills. Lancet II:648.

Lecours, R, M Laviolette, and Y Cormier. 1986. Bronchoalveolar lavage in pulmonary mycotoxicosis (organic dust toxic syndrome). Thorax 41:924-926.

Lee, KP, DP Kelly, FO O’Neal, JC Stadler, and GL Kennedy. 1988. Lung response to ultrafine kevlar aramid synthetic fibrils following 2-year inhalation exposure in rats. Fund Appl Toxicol 11:1-20.

Lemasters, G, J Lockey, C Rice, R McKay, K Hansen, J Lu, L Levin, and P Gartside. 1994. Radiographic changes among workers manufacturing refractory ceramic fiber and products. Ann Occup Hyg 38 Suppl 1:745-751.

Lesur, O, A Cantin, AK Transwell, B Melloni, J-F Beaulieu, and R Bégin. 1992. Silica exposure induces cytotoxicity and proliferative activity of type II. Exp Lung Res 18:173-190.

Liddell, D and K Millers (eds.). 1991. Mineral fibers and health. Florida, Boca Raton: CRC Press.
Lippman, M. 1988. Asbestos exposure indices. Environmental Research 46:86-92.

—. 1994. Deposition and retention of inhaled fibres: Effects on incidence of lung cancer and mesothelioma. Occup Environ Med 5: 793-798.

Lockey, J and E James. 1995. Man-made fibers and nonasbestos fibrous silicates. Chap. 21 in Occupational and Environmental Respiratory Diseases, edited by P Harber, MB Schenker, and JR Balmes. St.Louis: Mosby.

Luce, D, P Brochard, P Quénel, C Salomon-Nekiriai, P Goldberg, MA Billon-Galland, and M Goldberg. 1994. Malignant pleural mesothelioma associated with exposure to tremolite. Lancet 344:1777.

Malo, J-L, A Cartier, J L’Archeveque, H Ghezzo, F Lagier, C Trudeau, and J Dolovich. 1990. Prevalence of occupational asthma and immunological sensitization to psyllium among health personnel in chronic care hospitals. Am Rev Respir Dis 142:373-376.

Malo, J-L, H Ghezzo, J L’Archeveque, F Lagier, B Perrin, and A Cartier. 1991. Is the clinical history a satisfactory means of diagnosing occupational asthma? Am Rev Respir Dis 143:528-532.

Man, SFP and WC Hulbert. 1988. Airway repair and adaptation to inhalation injury. In Pathophysiology and Treatment of Inhalation Injuries, edited by J Locke. New York: Marcel Dekker.

Markowitz, S. 1992. Primary prevention of occupational lung disease: A view from the United States. Israel J Med Sci 28:513-519.

Marsh, GM, PE Enterline, RA Stone, and VL Henderson. 1990. Mortality among a cohort of US man-made mineral fiber workers: 1985 follow-up. J Occup Med 32:594-604.

Martin, TR, SW Meyer, and DR Luchtel. 1989. An evaluation of the toxicity of carbon fiber composites for lung cells in vitro and in vivo. Environmental Research 49:246-261.

May, JJ, L Stallones, and D Darrow. 1989. A study of dust generated during silo opening and its physiologic effect on workers. In Principles of Health and Safety in Agriculture, edited by JA Dosman and DW Cockcroft. Boca Raton: CRC Press.

McDermott, M, C Bevan, JE Cotes, MM Bevan, and PD Oldham. 1978. Respiratory function in slateworkers. B Eur Physiopathol Resp 14:54.

McDonald, JC. 1995. Health implications of environmental exposure to asbestos. Environ Health Persp 106: 544-96.

McDonald, JC and AD McDonald. 1987. Epidemiology of malignant mesothelioma. In Asbestos-Related Malignancy, edited by K Antman and J Aisner. Orlando, Fla: Grune & Stratton.

—. 1991. Epidemiology of mesothelioma. In Mineral Fibres and Health. Boca Raton: CRC Press.

—. 1993. Mesothelioma: Is there a background? In The Mesothelioma Cell and Mesothelioma: Past, Present and Future, edited by MC Jaurand, J Bignon, and P Brochard.

—. 1995. Chrysotile, tremolite, and mesothelioma. Science 267:775-776.

McDonald, JC, B Armstrong, B Case, D Doell, WTE McCaughey, AD McDonald, and P Sébastien. 1989. Mesothelioma and asbestos fibre type. Evidence from lung tissue analyses. Cancer 63:1544-1547.

McDonald, JC, FDK Lidell, A Dufresne, and AD McDonald. 1993. The 1891-1920 birth cohort of Quebec chrystotile miners and millers: mortality 1976-1988. Brit J Ind Med 50:1073-1081.

McMillan, DD and GN Boyd. 1982. The role of antioxidants and diet in the prevention or treatment of oxygen-induced lung microvascular injury. Ann NY Acad Sci 384:535-543.

Medical Research Council. 1960. Standardized questionnaire on respiratory symptoms. Brit Med J 2:1665.

Mekky, S, SA Roach, and RSF Schilling. 1967. Byssinosis among winders in the industry. Br J Ind Med 24:123-132.

Merchant JA, JC Lumsden, KH Kilburn, WM O’Fallon, JR Ujda, VH Germino, and JD Hamilton. 1973. Dose response studies in cotton textile workers. J Occup Med 15:222-230.

Meredith, SK and JC McDonald. 1994. Work-related respiratory disease in the United Kingdom, 1989-1992. Occup Environ Med 44:183-189.

Meredith, S and H Nordman. 1996. Occupational asthma: Measures of frequency of four countries. Thorax 51:435-440.

Mermelstein, R, RW Lilpper, PE Morrow, and H Muhle. 1994. Lung overload, dosimetry of lung fibrosis and their implications to the respiratory dust standard. Ann Occup Hyg 38 Suppl. 1:313-322.

Merriman, EA. 1989. Safe use of Kevlar aramid fiber in composites. Appl Ind Hyg Special Issue (December):34-36.

Meurman, LO, E Pukkala, and M Hakama. 1994. Incidence of cancer among anthophyllite asbestos miners in Finland. Occup Environ Med 51:421-425.

Michael, O, R Ginanni, J Duchateau, F Vertongen, B LeBon, and R Sergysels. 1991. Domestic endotoxin exposure and clinical severity of asthma. Clin Exp Allergy 21:441-448.

Michel, O, J Duchateau, G Plat, B Cantinieaux, A Hotimsky, J Gerain and R Sergysels. 1995. Blood inflammatory response to inhaled endotoxin in normal subjects. Clin Exp Allergy 25:73-79.

Morey, P, JJ Fischer, and R Rylander. 1983. Gram-negative bacteria on cotton with particular reference to climatic conditions. Am Ind Hyg Assoc J 44: 100-104.

National Academy of Sciences. 1988. Health risks of radon and other internally deposited alpha-emitters. Washington, DC: National Academy of Sciences.

—. 1990. Health effects of exposure to low levels of ionizing radiation. Washington, DC: National Academy of Sciences.

National Asthma Education Program (NAEP). 1991. Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma. Bethesda, Md: National Institutes of Health (NIH).

Nemery, B. 1990. Metal toxicity and the respiratory tract. Eur Resp J 3:202-219.

Newman, LS, K Kreiss, T King, S Seay, and PA Campbell. 1989. Pathologic and immunologic alterations in early stages of beryllium disease. Reexamination of disease definition and natural history. Am Rev Respir Dis 139:1479-1486.

Nicholson, WJ. 1991. In Health Effects Institute-Asbestos Research: Asbestos in Public and Commercial Buildings. Cambrige, Mass: Health Effects Institute-Asbestos Research.

Niewoehner, DE and JR Hoidal. 1982. Lung Fibrosis and Emphysema: Divergent responses to a common injury. Science 217:359-360.

Nolan, RP, AM Langer, JS Harrington, G Oster, and IJ Selikoff. 1981. Quartz hemolysis as related to its surface functionalities. Environ Res 26:503-520.

Oakes, D, R Douglas, K Knight, M Wusteman, and JC McDonald. 1982. Respiratory effects of prolonged exposure to gypsum dust. Ann Occup Hyg 2:833-840.

O’Brodovich, H and G Coates. 1987. Pulmonary Clearance of 99mTc-DTPA: A noninvasive assessment of epithelial integrity. Lung 16:1-16.

Parkes, RW. 1994. Occupational Lung Disorders. London: Butterworth-Heinemann.

Parkin, DM, P Pisani, and J Ferlay. 1993. Estimates of the worldwide incidence of eighteen major cancers in 1985. Int J Cancer 54:594-606.

Pepys, J and PA Jenkins. 1963. Farmer’s lung: Thermophilic actinomycetes as a source of “farmer’s lung hay” antigen. Lancet 2:607-611.

Pepys, J, RW Riddell, KM Citron, and YM Clayton. 1962. Precipitins against extracts of hay and molds in the serum of patients with farmer’s lung, aspergillosis, asthma and sarcoidosis. Thorax 17:366-374.

Pernis, B, EC Vigliani, C Cavagna, and M Finulli. 1961. The role of bacterial endotoxins in occupational diseases caused by inhaling vegetable dusts. Brit J Ind Med 18:120-129.

Petsonk, EL, E Storey, PE Becker, CA Davidson, K Kennedy, and V Vallyathan. 1988. Pneumoconiosis in carbon electrode workers. J Occup Med 30: 887-891.

Pézerat, H, R Zalma, J Guignard, and MC Jaurand. 1989. Production of oxygen radicals by the reduction of oxygen arising from the surface activity of mineral fibres. In Non-occupational exposure to mineral fibres, edited by J Bignon, J Peto, and R Saracci. IARC Scientific Publications, no.90. Lyon: IARC.

Piguet, PF, AM Collart, GE Gruaeu, AP Sappino, and P Vassalli. 1990. Requirement of tumour necrosis factor for development of silica-induced pulmonary fibrosis. Nature 344:245-247.

Porcher, JM, C Lafuma, R El Nabout, MP Jacob, P Sébastien, PJA Borm, S Hannons, and G Auburtin. 1993. Biological markers as indicators of exposure and pneumoconiotic risk: Prospective study. Int Arch Occup Environ Health 65:S209-S213.

Prausnitz, C. 1936. Investigations on respiratory dust disease in operatives in cotton industry. Medical Research Council Special Report Series, No. 212. London: His Majesty’s Stationery Office.

Preston, DL, H Kato, KJ Kopecky, and S Fujita. 1986. Life Span Study Report 10, Part 1. Cancer Mortality Among A-Bomb Survivors in Hiroshima and Nagasaki, 1950-1982. Technical Report. RERF TR.

Quanjer, PH, GJ Tammeling, JE Cotes, OF Pedersen, R Peslin and J-C Vernault. 1993. Lung volumes and forced ventilatory flows. Report of Working Party, Standardization of Lung Function Tests, European Community for Steel and Coal. Official Statement of the European Respiratory Society. Eur Resp J 6(suppl 16): 5-40.

Raabe, OG. 1984. Deposition and clearance of inhaled particles. In Occupational Lung Disease, edited by BL Gee, WKC Morgan, and GM Brooks. New York: Raven Press.

Ramazzini, B. 1713. De Moribis Artificium Diatriba (Diseases of Workers). In Allergy Proc 1990, 11:51-55.

Rask-Andersen A. 1988. Pulmonary reactions to inhalation of mould dust in farmers with special reference to fever and allergic alveolitis. Acta Universitatis Upsalienses. Dissertations from the Faculty of Medicine 168. Uppsala.

Richards, RJ, LC Masek, and RFR Brown. 1991. Biochemical and Cellular Mechanisms of Pulmonary Fibrosis. Toxicol Pathol 19(4):526
-539.

Richerson, HB. 1983. Hypersensitivity pneumonitis – pathology and pathogenesis. Clin Rev Allergy 1: 469-486.

—. 1990. Unifying concepts underlying the effects of organic dust exposures. Am J Ind Med 17:139-142.

—. 1994. Hypersensitivity pneumonitis. In Organic Dusts - Exposure, Effects, and Prevention, edited by R Rylander and RR Jacobs. Chicago: Lewis Publishing.

Richerson, HB, IL Bernstein, JN Fink, GW Hunninghake, HS Novey, CE Reed, JE Salvaggio, MR Schuyler, HJ Schwartz, and DJ Stechschulte. 1989. Guidelines for the clinical evaluation of hypersensitivity pneumonitis. J Allergy Clin immunol 84:839-844.

Rom, WN. 1991. Relationship of inflammatory cell cytokines to disease severity in individuals with occupational inorganic dust exposure. Am J Ind Med 19:15-27.

—. 1992a. Environmental and Occupational Medicine. Boston: Little, Brown & Co.

—. 1992b. Hairspray-induced lung disease. In Environmental and Occupational Medicine, edited by WN Rom. Boston: Little, Brown & Co.

Rom, WN, JS Lee, and BF Craft. 1981. Occupational and environmental health problems of the developing oil shale industry: A review. Am J Ind Med 2: 247-260.

Rose, CS. 1992. Inhalation fevers. In Environmental and Occupational Medicine, edited by WN Rom. Boston: Little, Brown & Co.

Rylander R. 1987. The role of endotoxin for reactions after exposure to cotton dust. Am J Ind Med 12: 687-697.

Rylander, R, B Bake, J-J Fischer and IM Helander 1989. Pulmonary function and symptoms after inhalation of endotoxin. Am Rev Resp Dis 140:981-986.

Rylander R and R Bergström 1993. Bronchial reactivity among cotton workers in relation to dust and endotoxin exposure. Ann Occup Hyg 37:57-63.

Rylander, R, KJ Donham, and Y Peterson. 1986. Health effects of organic dusts in the farm environment. Am J Ind Med 10:193-340.

Rylander, R and P Haglind. 1986. Exposure of cotton workers in an experimental cardroom with reference to airborne endotoxins. Environ Health Persp 66:83-86.

Rylander R, P Haglind, M Lundholm 1985. Endotoxin in cotton dust and respiratory function decrement among cotton workers. Am Rev Respir Dis 131:209-213.

Rylander, R and PG Holt. 1997. Modulation of immune response to inhaled allergen by co-exposure to the microbial cell wall components (13)-B-D-glucan and endotoxin. Manuscript.

Rylander, R and RR Jacobs. 1994. Organic Dusts: Exposure, Effects, and Prevention. Chicago: Lewis Publishing.

—. 1997. Environmental endotoxin – A criteria document. J Occup Environ Health 3: 51-548.

Rylander, R and Y Peterson. 1990. Organic dusts and lung disease. Am J Ind Med 17:1148.

—. 1994. Causative agents for organic dust related disease. Am J Ind Med 25:1-147.

Rylander, R, Y Peterson, and KJ Donham. 1990. Questionnaire evaluating organic dust exposure. Am J Ind Med 17:121-126.

Rylander, R, RSF Schilling, CAC Pickering, GB Rooke, AN Dempsey, and RR Jacobs. 1987. Effects after acute and chronic exposure to cotton dust - The Manchester criteria. Brit J Ind Med 44:557-579.

Sabbioni, E, R Pietra, and P Gaglione. 1982. Long term occupational risk of rare-earth pneumoconiosis. Sci Total Environ 26:19-32.

Sadoul, P. 1983. Pneumoconiosis in Europe yesterday, today and tomorrow. Eur J Resp Dis 64 Suppl. 126:177-182.

Scansetti, G, G Piolatto, and GC Botta. 1992. Airborne fibrous and non-fibrous particles in a silicon carbide manufacturing plant. Ann Occup Hyg 36(2):145-153.

Schantz, SP, LB Harrison, and WK Hong. 1993. Tumours of the nasal cavity and paranasal sinuses, nasopharynx, oral cavity,and oropharynx. In Cancer: Principles & Practice of Oncology, edited by VTJ DeVita, S Hellman, and SA Rosenberg. Philadelphia: JB Lippincott.

Schilling, RSF. 1956. Byssinosis in cotton and other textile workers. Lancet 2:261-265.

Schilling, RSF, JPW Hughes, I Dingwall-Fordyce, and JC Gilson. 1955. An epidemiological study of byssinosis among Lancashire cotton workers. Brit J Ind Med 12:217-227.

Schulte, PA. 1993. Use of biological markers in occupational health research and practice. J Tox Environ Health 40:359-366.

Schuyler, M, C Cook, M Listrom, and C Fengolio-Preiser. 1988. Blast cells transfer experimental hypersensitivity pneumonitis in guinea pigs. Am Rev Respir Dis 137:1449-1455.

Schwartz DA, KJ Donham, SA Olenchock, WJ Popendorf, D Scott Van Fossen, LJ Burmeister and JA Merchant. 1995. Determinants of longitudinal changes in spirometric function among swine confinement operators and farmers. Am J Respir Crit Care Med 151: 47-53.

Science of the total environment. 1994. Cobalt and Hard Metal Disease 150(Special issue):1-273.

Scuderi, P. 1990. Differential effects of copper and zinc on human peripheral blood monocyte cytokine secretion. Cell Immunol 265:2128-2133.
Seaton, A. 1983. Coal and the lung. Thorax 38:241-243.

Seaton, J, D Lamb, W Rhind Brown, G Sclare, and WG Middleton. 1981. Pneumoconiosis of shale miners. Thorax 36:412-418.

Sébastien, P. 1990. Les mystères de la nocivité du quartz. In Conférence Thématique. 23 Congrès International De La Médecine Du Travail Montréal: Commission international de la Médecine du travail.

—. 1991. Pulmonary Deposition and Clearance of Airborne Mineral Fibers. In Mineral Fibers and Health, edited by D Liddell and K Miller. Boca Raton: CRC Press.

Sébastien, P, A Dufresne, and R Bégin. 1994. Asbestos fibre retention and the outcome of asbestosis with or without exposure cessation. Ann Occup Hyg 38 Suppl. 1:675-682.

Sébastien, P, B Chamak, A Gaudichet, JF Bernaudin, MC Pinchon, and J Bignon. 1994. Comparative study by analytical transmission electron microscopy of particles in alveolar and interstitial human lung macrophages. Ann Occup Hyg 38 Suppl. 1:243-250.

Seidman, H and IJ Selikoff. 1990. Decline in death rates among asbestos insulation workers 1967-1986 associated with diminution of work exposure to asbestos. Annals of the New York Academy of Sciences 609:300-318.

Selikoff, IJ and J Churg. 1965. The biological effects of asbestos. Ann NY Acad Sci 132:1-766.

Selikoff, IJ and DHK Lee. 1978. Asbestos and Disease. New York: Academic Press.

Sessions, RB, LB Harrison, and VT Hong. 1993. Tumours of the larynx, and hypopharynx. In Cancer: Principles and Practice of Oncology, edited by VTJ DeVita, S Hellman, and SA Rosenberg. Philadelphia: JB Lippincott.

Shannon, HS, E Jamieson, JA Julian, and DCF Muir. 1990. Mortality of glass filament (textile) workers. Brit J Ind Med 47:533-536.

Sheppard, D. 1988. Chemical agents. In Respiratory Medicine, edited by JF Murray and JA Nadel. Philadelphia: WB Saunders.

Shimizu, Y, H Kato, WJ Schull, DL Preston, S Fujita, and DA Pierce. 1987. Life span study report 11, Part 1. Comparison of Risk Coefficients for Site-Specific Cancer Mortality based on the DS86 and T65DR Shielded Kerma and Organ Doses. Technical Report. RERF TR 12-87.

Shusterman, DJ. 1993. Polymer fume fever and other flourocarbon pyrolysis related syndromes. Occup Med: State Art Rev 8:519-531.

Sigsgaard T, OF Pedersen, S Juul and S Gravesen. Respiratory disorders and atopy in cotton wool and other textile mill workers in Denmark. Am J Ind Med 1992;22:163-184.

Simonato, L, AC Fletcher, and JW Cherrie. 1987. The International Agency for Research on Cancer historical cohort study of MMMF production workers in seven European countries: Extension of the follow-up. Ann Occup Hyg 31:603-623.

Skinner, HCW, M Roos, and C Frondel. 1988. Asbestos and Other Fibrous Minerals. New York: Oxford Univ. Press.

Skornik, WA. 1988. Inhalation toxicity of metal particles and vapors. In Pathophysiology and Treatment of Inhalation Injuries, edited by J Locke. New York: Marcel Dekker.

Smith, PG and R Doll. 1982. Mortality among patients with ankylosing sponchylitis after a single treatment course with X-rays. Brit Med J 284:449-460.

Smith, TJ. 1991. Pharmacokinetic models in the development of exposure indicators in epidemiology. Ann Occup Hyg 35(5):543-560.

Snella, M-C and R Rylander. 1982. Lung cell reactions after inhalation of bacterial lipopolysaccharides. Eur J Resp Dis 63:550-557.

Stanton, MF, M Layard, A Tegeris, E Miller, M May, E Morgan, and A Smith. 1981. Relation of particle dimension to carcinogenicity in amphibole asbestoses and other fibrous minerals. J Natl Cancer Inst 67:965-975.

Stephens, RJ, MF Sloan, MJ Evans, and G Freeman. 1974. Alveolar type I cell response to exposure to 0.5 ppm 03 for short periods. Exp Mol Pathol 20:11-23.

Stille, WT and IR Tabershaw. 1982. The mortality experience of upstate New York talc workers. J Occup Med 24:480-484.

Strom, E and O Alexandersen. 1990. Pulmonary damage caused by ski waxing. Tidsskrift for Den Norske Laegeforening 110:3614-3616.

Sulotto, F, C Romano, and A Berra. 1986. Rare earth pneumoconiosis: A new case. Am J Ind Med 9: 567-575.

Trice, MF. 1940. Card-room fever. Textile World 90:68.

Tyler, WS, NK Tyler, and JA Last. 1988. Comparison of daily and seasonal exposures of young monkeys to ozone. Toxicology 50:131-144.

Ulfvarson, U and M Dahlqvist. 1994. Pulmonary function in workers exposed to diesel exhaust. In Encyclopedia of Environmental Control Technology New Jersey: Gulf Publishing.

US Department of Health and Human Services. 1987. Report on cancer risks associated with the ingestion of asbestos. Environ Health Persp 72:253-266.

US Department of Health and Human Services (USDHHS). 1994. Work-Related Lung Disease Surveillance Report. Washington, DC: Public Health Services, Center for Disease Control and Prevention.

Vacek, PM and JC McDonald. 1991. Risk assessment using exposure intensivity: An application to vermiculite mining. Brit J Ind Med 48:543-547.

Valiante, DJ, TB Richards, and KB Kinsley. 1992. Silicosis surveillance in New Jersey: Targeting workplaces using occupational disease and exposure surveillance data. Am J Ind Med 21:517-526.

Vallyathan, NV and JE Craighead. 1981. Pulmonary pathology in workers exposed to nonasbestiform talc. Hum Pathol 12:28-35.

Vallyathan, V, X Shi, NS Dalal, W Irr, and V Castranova. 1988. Generation of free radicals from freshly fractured silica dust. Potential role in acute silica-induced lung injury. Am Rev Respir Dis 138:1213-1219.

Vanhee, D, P Gosset, B Wallaert, C Voisin, and AB Tonnel. 1994. Mechanisms of fibrosis in coal workers’ pneumoconiosis. Increased production of platelet-derived growth factor, insulin-like growth factor type I, and transforming growth-factor beta and relationship to disease severity. Am J Resp Critical Care Med 150(4):1049-1055.

Vaughan, GL, J Jordan, and S Karr. 1991. The toxicity, in vitro, of silicon carbide whiskers. Environmental Research 56:57-67.
Vincent, JH and K Donaldson. 1990. A dosimetric approach for relating the biological response of the lung to the accumulation of inhaled mineral dust. Brit J Ind Med 47:302-307.

Vocaturo, KG, F Colombo, and M Zanoni. 1983. Human exposure to heavy metals. Rare earth pneumoconiosis in occupational workers. Chest 83:780-783.

Wagner, GR. 1996. Health Screening and Surveillance of Mineral Dust Exposed Workers. Recommendation for the ILO Workers Group. Geneva: WHO.

Wagner, JC. 1994. The discovery of the association between blue asbestos and mesotheliomas and the aftermath. Brit J Ind Med 48:399-403.

Wallace, WE, JC Harrison, RC Grayson, MJ Keane, P Bolsaitis, RD Kennedy, AQ Wearden, and MD Attfield. 1994. Aluminosilicate surface contamination of respirable quartz particles from coal mine dusts and from clay works dust. Ann Occup Hyg 38 Suppl. 1:439-445.

Warheit, DB, KA Kellar, and MA Hartsky. 1992. Pulmonary cellular effects in rats following aerosol exposures to ultrafine Kevlar aramid fibrils: Evidence for biodegradability of inhaled fibrils. Toxicol Appl Pharmacol 116:225-239.

Waring, PM and RJ Watling. 1990. Rare deposits in a deceased movie projectionist. A new case of rare earth pneumoconiosis? Med J Austral 153:726-730.

Wegman, DH and JM Peters. 1974. Polymer fume fever and cigarette smoking. Ann Intern Med 81:55-57.

Wegman, DH, JM Peters, MG Boundy, and TJ Smith. 1982. Evaluation of respiratory effects in miners and millers exposed to talc free of asbestos and silica. Brit J Ind Med 39:233-238.

Wells, RE, RF Slocombe, and AL Trapp. 1982. Acute toxicosis of budgerigars (Melopsittacus undulatus) caused by pyrolysis products from heated polytetrafluoroethylene: Clinical study. Am J Vet Res 43:1238-1248.

Wergeland, E, A Andersen, and A Baerheim. 1990. Morbidity and mortality in talc-exposed workers. Am J Ind Med 17:505-513.

White, DW and JE Burke. 1955. The Metal Beryllium. Cleveland, Ohio: American Society for Metals.

Wiessner, JH, NS Mandel, PG Sohnle, A Hasegawa, and GS Mandel. 1990. The effect of chemical modification of quartz surfaces on particulate-induces pulmonary inflammation and fibrosis in the mouse. Am Rev Respir Dis 141:11-116.

Williams, N, W Atkinson, and AS Patchefsky. 1974. Polymer fume fever: Not so benign. J Occup Med 19:693-695.

Wong, O, D Foliart, and LS Trent. 1991. A case-control study of lung cancer in a cohort of workers potentially exposed to slag wool fibres. Brit J Ind Med 48:818-824.

Woolcock, AJ. 1989. Epidemiology of Chronic airways disease. Chest 96 (Suppl): 302-306S.

World Health Organization (WHO) and International Agency for Research on Cancer (IARC). 1982. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Lyon: IARC.

World Health Organization (WHO) and Office of Occupational Health. 1989. Occupational Exposure Limit for Asbestos. Geneva: WHO.


Wright, JL, P Cagle, A Shurg, TV Colby, and J Myers. 1992. Diseases of the small airways. Am Rev Respir Dis 146:240-262.

Yan, CY, CC Huang, IC Chang, CH Lee, JT Tsai, and YC Ko. 1993. Pulmonary function and respiratory symptoms of portland cement workers in southern Taiwan. Kaohsiung J Med Sci 9:186-192.

Zajda, EP. 1991. Pleural and airway disease associated with mineral fibers. In Mineral Fibers and
Health, edited by D Liddell and K Miller. Boca Raton: CRC Press.

Ziskind, M, RN Jones, and H Weill. 1976. Silicosis. Am Rev Respir Dis 113:643-665.