sign in sign up
<<
Home , Pneumoconiosis, Silicosis

Silicosis and Workers' Vincent Castranova and Val Vallyathan Pathology and Physiology Research Branch, Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, West Virginia, USA

Exposure to coal mine dust and/or crystalline silica results in pneumoconiosis with initiation and between 1968 and 1990 there were 13,744 progression of pulmonary . This review presents characteristics of simple and complicated deaths with mention ofsilicosis in the United coal workers' pneumoconiosis (CWP) as well as pathologic indices of acute and chronic by States (16). However, in recent years, the summarizing results of in vitro, animal, and human investigations. These results support four basic annual number of deaths has decreased from mechanisms in the etiology of CWP and silicosis: a) direct cytotoxicity of coal dust or silica, resulting 1,157 in 1968 to 301 in 1988 (16). in cell damage, release of lipases and proteases, and eventual lung scarring; b) activation of Currently, several standards exist for the oxidant production by pulmonary phagocytes, which overwhelms the antioxidant defenses and limitation of airborne levels of respirable crys- leads to lipid peroxidation, protein nitrosation, cell injury, and lung scarring; c) activation of mediator talline silica. The Occupational Safety and release from alveolar and epithelial cells, which leads to recruitment of Health Administration permissible exposure polymorphonuclear leukocytes and macrophages, resulting in the production of proinflammatory limit (PEL) is 100 pg/m3 for an 8-hr work and reactive species and in further lung injury and scarring; o) secretion of growth factors The from alveolar macrophages and epithelial cells, stimulating proliferation and eventual exposure. NIOSH recommended expo- scarring. Results of in vitro and animal studies provide a basis for proposing these mechanisms for sure limit (REL) is 50 pg/m3 for up to 10 the initiation and progression of pneumoconiosis. Data obtained from exposed workers lend hr/day for a 40-hr work week. The American support to these mechanisms. Key words: black lung disease, coal mine dust, crystalline silica, Conference of Governmental Industrial cytokines, lung disease, occupational diseases, occupational exposures, , reactive Hygienists threshold limit value is 100 species. - Environ Health Perspect 1 08(suppl 4):675-684 (2000). pg/m3. In occupations such as rock drilling http.//ehpnetl.niehs.nih.gov/docs/2000/suppl-4/675-684castranova/abstract.html and sandblasting, measured respirable crys- talline silica levels often far exceed such stan- dards. It is likely that the majority of overt exposures occur in small, unregulated indus- Silicosis and coal workers' pneumoconiosis (1-12). This review is an overview of expo- trial settings or in high- occupations (CWP) have long been recognized as signifi- sures, toxicologic and pathologic responses, such as sandblasting, drilling, tunneling, silica cant occupational lung diseases. Silicosis and and possible mechanisms involved in silicosis flour mill operations, and stone grinding. CWP continue to occur in several industrial and CWP. Little exposure-response information is avail- workplaces even though these diseases are pre- able concerning mixed exposures such as sil- ventable by environmental dust control. Silica Exposures ica and metal dust generated during Although significant insights have been gained Silicosis is caused by inhalation of crystalline blasting operations. Therefore, it is uncertain into mechanisms involved in the initiation silica, mostly in occupational settings. It if such occupational exposures require unique and progression ofsilicosis and CWP, it is dif- is most common among workers in underde- exposure limits. ficult to conclude that these accomplishments veloped countries. However, silicosis occurs have totally solved the problem of these occu- frequently even in developed countries, par- Physical and Chemical pational diseases. The knowledge acquired ticularly in certain occupations such as Properties of Silica through research has been most valuable in , sandblasting, surface drilling, stone Silicons make up almost 28% of the earth's determining the cause and pathogenesis of cutting, construction, making, silica crust and are found in combination with these occupational lung diseases. In industrial- flour mill operations, and other occupations many other minerals and metals. Silica can ized countries, exposure-response information in which silica dust exposures occur (1-3). In exist in either a crystalline or amorphous and the relationship among pathologic, radio- addition, environmental exposure to crys- form. The crystalline types of silica (SiO2) logic, and physiologic abnormalities of these talline silica is common because of its abun- include five polymorphs, i.e., , diseases have led to the recommendation and dance in soil. Silica can become airborne in , , coesite, and stishovite implementation of exposure limits. However, arid, windy conditions or during agricultural, (2,8). All these polymorphs are fibrogenic and additional innovative research strategies are urban, and construction activities. Indeed, biologically toxic. In most occupational expo- vital to identify susceptible individuals, diag- lung fibrosis and pulmonary changes associ- sures, quartz is the major type of silica nose these pneumoconioses in the early stages ated with environmental silica and mixed involved. Amorphous silica and are ofdevelopment, and develop treatment strate- dust exposures have been observed in the relatively less fibrogenic than crystalline silica gies. In addition, research is needed to identify offarm animals and humans (13). (8). In the case of a-quartz, as well as the biologic mechanisms involved in unique occu- In 1983 the National Institute for other crystalline polymorphs with the excep- pational settings, for example, sandblasting, Occupational Safety and Health (NIOSH) tion of stishovite, the dioxide (SiO2) rock drilling, or exposure to mixed dusts, estimated that approximately 2.3 million molecules are arranged as a tetrahedral where risk ofdisease is unusually high. workers at 238,000 work sites may be The literature concerning symptoms, clin- exposed to silica dust (14). NIOSH estimates ical manifestations, and mechanisms for initi- that as many as 59,000 workers may be at This article is part of the monograph on Environmental ation and progression of silica-induced lung risk of developing some degree of silicosis, and Occupational Lung Diseases. diseases and CWP is extensive. By intent, this with 250 deaths/year being attributed to silica Address correspondence to V. Castranova, review is meant to be brief and somewhat exposure (15). Approximately 1,500 cases of PPRB/HELD/NIOSH, 1095 Willowdale Rd., MS201 5, Morgantown, WV 26505 USA. Telephone: (304) 285- selective. Readers are directed to other sources silicosis are diagnosed annually in the United 6056. Fax: (304) 285-5938. E-mail: [email protected] if more detailed information is desired States (16). NIOSH also reported that Received 3 August 1999; accepted 6 October 1999.

Environmental Health Perspectives * Vol 108, Supplement 4 * August 2000 675 CASTRANOVA AND VALLYATHAN

(8). In the presence of water, the surface of eosinophilic, with a fine granular appearance Chronic Silicosis silica becomes hydrated to form silanol (Figure 1). Radiographically, chest X rays Inhalation of crystalline silica over prolonged groups (-SiOH). It is believed that the high exhibit a ground-glass appearance with dif- periods promotes the formation of the classic reactivity ofcrystalline silica to biologic mem- fuse lesions in the middle and lower lobes. fibrotic nodules having a typical histologic branes is due to the unique properties ofthese Patients often suffer from labored breathing, appearance of concentric arrangements of col- surface silanol groups. The first theory is that , , weight loss, decreased pul- lagen fibers with central hyalinized zones -SiOH groups are hydrogen donors, whereas monary function, and compromised gas (Figure 2). Typical concentric silicotic lesions most biologic macromolecules contain lone- exchange. They develop and respira- with the whorled fibers of are charac- pair electrons on oxygen or nitrogen that tory failure, often complicated by mycobacte- teristic of silicotic lesions produced in humans serve as hydrogen acceptors. The formation rial infections. It has been proposed that by inhalation of crystalline silica and are mor- of hydrogen bonds would result in strong acute silicosis occurs in workers exposed to phologically distinct from lesions produced by interaction between silica and biologic mem- freshly fractured silica dust and that surface other inorganic occupational exposures (1,12). branes, resulting in possible damage. A sec- Si' and SiO' radicals generated during frac- The nodules show variable degrees ofcalcifica- ond theory is that the surface of silica is turing play an important role in the rapid tion and necrosis. Dust-containing macro- negatively charged. At pH 7.0, 1 in 30 onset ofthis disease (17,18). phages, , and lymphocytes are often -SiOH groups would be negatively charged restricted to the periphery of the nodules. (-SiO-). Negatively charged silica particles Accelerated Silicosis Microscopically, lesions of silicosis, which are would react strongly with scavenger receptors Accelerated silicosis is commonly associated sharply demarcated from the adjoining lung on alveolar macrophages and would activate with heavy exposure as might occur in silica parenchyma, usually range in size from few the generation of reactive oxygen species flour mill operations, sandblasting, and other millimeters to several centimeters in diameter. (ROS) and inflammatory cytokines (9,10). A crushing operations (12,20). It is similar in Nodules are often found predominantly in the third theory is that deavage of the silica crys- many respects to acute silicosis, exhibiting an upper zones of the lungs and in subpleural tal, as would occur in silica flour milling, rock exudative alveolar lipoproteinosis associated areas. In pure silicosis, nodules are free of pig- drilling, and sandblasting, results in the gen- with chronic . In addition, mentation, and polarizing microscopy reveals eration of Si and SiO' radicals on the frac- accelerated silicosis is associated with fibrotic dull birefringent partides, primarily in the cen- ture planes, which can induce oxidant granulomas containing collagen, reticulin, ter of the nodules. Radiographically, rounded damage (9,17,18). Stishovite is another poly- and a large number of silica particles. The opacities are evident initially in the upper lobes morph of pure crystalline silica that is distin- granulomas consist of a large number of ofthe lung. As chronic siicosis progresses, pul- guished by its octahedral structure. Structural mononuclear cells, fibroblasts, and collagen monary function deficits evidenced by differences among these polymorphs are con- fibers with a predisposition for circular orien- decreases in static lung volumes and gas sidered to be important in their biologic reac- tation showing the characteristic of immature exchange become obvious. tivity, i.e., > quartz > tridymite > cristobalite silicotic nodules (12). The alveolar septa are > coesite > stishovite. lined with hypertrophic and hyperplastic Conglomerate Silicosis alveolar type II epithelial cells with increased Conglomerate silicosis results from the coales- Human Pathologic Reactions numbers oflamellar bodies. As with acute sil- cence and agglomeration of several smaller to Crystalline Silica Exposure icosis, accelerated silicosis also is associated Exposure to crystalline silica can result in with an increased morbidity and mortality. adverse pulmonary responses such as acute sili- cosis, accelerated siicosis, chronic siicosis, and conglomerate silicosis (1). In addition, silica exposure may also be associated with systemic and autoimmune diseases such as sderoderma, , systemic erythe- matosis, nephropathy, and proliferative glomerulonephritis (1,12). is a common complication ofsilicosis often seen in severe grades of the disease. A possible associa- tion between siicosis and is being accepted on the basis of evidence for a role of silica exposure in increased lung tumor forma- tion in experimental animals and exposed human populations (19). Acute Silicosis Acute silicosis (silicolipoproteinosis) results from exposure to relatively high levels ofsilica (3,20). It has been reported in occupations such as sandblasting, surface drilling, tunnel- ing, silica flour milling, and making. Morphologically the disease is characterized Figure 2. Chronic silicotic nodule showing characteristic by , interstitial inflamma- features of this lesion. The amorphous center is sur- tion, and the accumulation within the alveoli Figure 1. Acute silicosis showing granular eosinophilic rounded by concentrically organized hyalinized collagen of proteinaceous fluid rich in surfactant in alveolar spaces and interstitial inflammatory fibers. A cellular mantle of inflammatory cells is present (1, 12). The exudate in the alveoli is infiltration. at periphery. Mason's trichrome staining.

676 Perspectives * Vol 108, Supplement 4 * August 2000 SILICOSIS AND COAL WORKERS' PNEUMOCONIOSIS nodules. In addition to the enlargement of fibrosis in PMF. In such cases of severe con- Coal Mine Dust Exposures nodules, profusion ofnodular lesions increases glomerate silicosis or PMF, pulmonary hyper- and results in progressive massive fibrosis tension and cor pulmonale are common Coal is a fossil fuel mined throughout the (PMF). Cavitation and extensive destruction features and may become a cause ofdeath. world. The generation of coal mine dust dur- of the lung parenchyma, including bronchi- ing underground is the most sig- oles and blood vessels, are common with Glomerulonepliritis nificant source of coal dust exposure. There PMF. According to the Silicosis and Mild-to-moderate abnormalities in both renal are two basic types of coal mining operations, Disease Committee, a PMF lesion is defined function and structure have been observed in surface mining and underground mining, pro- as a lesion greater than 2 cm in diameter in workers exposed to crystalline silica. ducing distinctively different exposure vari- contrast to the 1-cm or larger radiographic Numerous case reports of severe glomerulo- ables and disease entities. Underground coal size established by the International Labour nephritis with renal failure occurring in per- miners are at greater risk of developing CWP Office (ILO) (1). sons with acute silicosis have been described as than strip or surface miners because of the "silicon nephropathy" (27,28). Immunologic higher dust levels in the underground envi- Silicosis and Tuberculosis abnormalities are often reported as common ronment. In strip or surface mining, generated In the beginning of this century, tuberculosis in these cases and a potential exists for coal dust is diluted by outdoor air. However, reached epidemic proportions in workers immune-mediated renal injury. Direct injury rock-drilling operations associated with sur- with silicosis. The advent of drug therapy and to cells by the microcrystalline silica particles face mining are associated with a greater risk dust control measures has considerably is suspected as a possible cause based on the of developing silicosis. Recent data indicate reduced the prevalence of silicotuberculosis. demonstration of increased numbers of silica that approximately 200,000 workers are However, an increased risk for tuberculosis particles in kidneys of silicotic patients. The employed in the coal mining industry in the has recently been reported in Danish foundry association of silica exposure with focal United States. The and Health workers with advanced silicosis (21). In addi- glomerular disease in several case reports is Administration (MSHA) respirable coal mine tion, tuberculosis is still in great excess in difficult to ignore. dust PEL is 2 mg/m3, while NIOSH has South African gold miners and workers recently lowered its REL to 1 mg/m3 (35). in Wales (22-24). The depressant effect of Bronchogenic Carcinoma Although dust levels are below 2 mg/m3 in crystalline silica on the ability of alveolar Since the first proposed hypothesis by most coal mines, MSHA has noted occasions macrophages to kill the tuberculosis Goldsmith et al. in 1982 indicating a proba- in which the PEL is exceeded. High dust lev- was confirmed in experimen- ble link between exposure to silica and lung els occur more often with long-wall mining tal studies (25). It is believed that silicosis cancer, several epidemiologic and pathologic than with conventional mining. leads to a reduction in cell-mediated immu- studies have either supported or dismissed nity with alterations in lymphocyte subsets such a notion (19,29,30). In 1987, an Physical and Chemical and serum immunoglobulin levels (26). International Agency for Research on Cancer Properties of Coal Microscopically, the silicotic nodules, con- (IARC) working group reviewed all the avail- Although coal is mainly , coal mine comitant with tuberculosis alterations, will able evidence and concluded that there was dust contains hydrogen, oxygen, nitrogen, have laminations and epithelioid cells with a insufficient evidence for the carcinogenicity trace metals, inorganic minerals, and crys- lymphocyte collar. A caseation in the center of crystalline silica in humans (30). These talline silica. Trace metals can include boron, ofthe silicotic nodule is common. conclusions about carcinogenicity of silica in cadmium, copper, nickel, iron, , humans were influenced by five major short- lead, and zinc. Some of these trace elements Rheumatoid Complications comings: inappropriate controls, other occu- can be cytotoxic and carcinogenic in experi- Rheumatoid pneumoconiosis is rare in silico- pational , misclassification of mental models. Common mineral and ele- sis. It is characterized by rapidly developing silicotics, detection bias for silicosis, and mental contaminants are kaolin, , pyrite, large opacities in a size range of 1-5 cm chance of sampling variability (19,30). titanium, calcite, sulfur, sodium, magnesium, located mostly in the periphery of the lungs, However, a recent working group organized and silica. The rank of coal increases from often with only mild silicosis. Rheumatoid by IARC in 1997 concluded that there is peat to lignite, sub-bituminous to bitumi- silicotic complications are often seen in now sufficient evidence for the carcinogenic- nous, and anthracite. As rank increases, the patients with rheumatoid disease or in ity of silica in humans (31-33). Several ratio of carbon to other chemicals and min- patients with a rheumatoid positive factor. studies among the many reviewed by the eral contaminants increases. In general, Macroscopically, the lesions appear to have [ARC working group on the question of sil- anthracite coal mining has been associated dark and light laminating bands with central ica exposure and cancer risk in humans were with higher rates of pneumoconiosis than necrosis. Microscopically, a central zone of negative or equivocal, and carcinogenicity of that found in bituminous miners (36,37). fibrinoid necrosis with silica is surrounded by silica was not detected in all industrial opera- Anthracite coal mine dust contains more sur- palisading histiocytes, neutrophils, lympho- tions. However, nine studies showed exces- face free radicals than bituminous coal, which cytes, and fibroblasts. Small blood vessels in sive risk for lung cancer (19,32). These may explain its higher cytotoxicity and patho- the peripheral zones show clusters of lympho- included refractory brick workers, pottery genicity (38-40). In addition, anthracite has cytes and plasma cells. workers, workers, a higher crystalline silica content than bitumi- foundry workers, workers, and mine nous coal (41). However, experimental evi- Vascular Diseases workers (19,32). It appears that the carcino- dence suggests that silica particles from Chronic is a common cause of death genic property of crystalline silica may be bituminous mines may be coated with clay, in severe acute silicosis. Chronic hypoxia can dependent on its biologic activity, polymor- rendering them less active (41). Respirable bring about pulmonary vascular spasms as a phic nature, or specific industrial processes coal mine dust has a relatively large surface result of the pulmonary disease caused by such as heat treatment and mechanical grind- area due to its small aerodynamic size and severe involvement of lung parenchyma. ing. The relationship between the ability of porous nature. Organic aromatic compounds Morphologic alteration of the vasculature is silica to generate ROS and carcinogenesis has present in the coal atmosphere, such as ben- common as a result of dust accumulation and recently been reviewed (34). zene, methylene, phenol, and phenanthrene,

Environmental Health Perspectives * Vol 108, Supplement 4 * August 2000 677 CASTRANOVA AND VALLYATHAN can be adsorbed onto the surface ofcoal mine lobes of the lung. The macules range in size immunologic factors (49-53). There is a dust and may affect its biologic activity. from 1 to 6 mm in diameter and are irregular tendency for PMF to progress with or with- in size. Microscopically, macules contain coal out further exposure (49). Progression from Human Pathologic Reactions to Coal dust-laden macrophages with a fine network simple CWP to PMF has been related to Mine Dust of reticulin and some collagen fibers (Figure radiographic severity of disease, to coal mine Inhalation of coal mine dust can lead to the 3). Focal emphysema is a characteristic feature dust exposure level, and to total dust burden. development of several diseases including associated with these macules (43). These PMF lesions have a predilection to occur CWP, , emphysema, Caplan syn- small coal dust- or carbonaceous material- in the upper lobes of the right lung. However, drome, and silicosis (42,43). Coal miners typ- laden pulmonary lesions have not been associ- in advanced cases, lesions are bilateral. ically develop one of two forms of disease ated with pulmonary symptoms. Microscopically, PMF lesions appear as coal patterns-simple CWP or complicated CWP. Increased exposure to coal mine dust dust-laden irregular or round, well-demar- With chronic exposure, the milder form of results in the development of nodular lesions cated fibrotic masses of collagen bundles and CWP may become complicated CWP, with that are firm on palpation in contrast to non- haphazardly laid hyalinized collagen fibers enlargement and profusion of lesions in the palpable macules. They are classified on the intertwined with reticulin (Figure 5). Lesions lung. Black lung is a legal term used to basis of size as micronodules (< 7 mm diame- may also appear as amorphous collagenization include CWP, bronchitis, emphysema, and ter) and macronodules, which range in diam- or clusters of nodules. Necrosis is often associ- silicosis when they are found in association eter from 8 mm to 2 cm (42). They develop ated with central cavitation, and cholesterol with employment history in coal mines. at the bifurcations of respiratory bronchioles are usually present. Vascular degenera- and are commonly seen against a background tive changes associated with bronchial and Coal Workers' Pneumoconiosis of macules, mostly in the upper lungs. pulmonary arteries and lymphatic vessels are The first case report on CWP was by Gregory Nodules contain heavily coal dust-laden common in the lesions. (44) in 1831 in a British coal miner. Initially macrophages interlaced with collagen fibers coal dust was considered innocuous, and oriented in a haphazard manner and may Rheumatoid Pneumoconiosis CWP was thought to be a variant of silicosis have round, irregular, or stellate borders (Caplan Syndrome) due to similarities in chest radiographs. This (Figure 4). The fibrotic stroma is composed In coal miners with circulating rheumatoid hypothesis was disproved by Collins and of mature and immature collagen and retic- factor, rheumatoid pneumoconiosis (Caplan Gilchrist (45). They studied the pathologic ulin. With chronic exposure to coal mine syndrome) can occur (54,55). It is reported to changes in the lungs of coal trimmers exposed dust, nodules may converge and coalesce to be more common in Europe, particularly in to coal that was free ofsilica and showed that produce lesions measuring larger than 2 cm Welsh miners. There is no evidence that coal workers developed pneumoconiosis despite with a fibrous nature. At this stage, the mining predisposes workers to rheumatoid low silica exposure. Gough et al. (46) and disease is called complicated CWP or PMF. arthritis; however, it is often associated with Heppleston (47,48) confirmed these findings severe categories of CWP (56). Macroscopi- and showed that the histologic pulmonary Progressive Massive Fibrosis cally, the nodules are pale yellow and show lesions in coal trimmers were identical to Progressive massive fibrosis is a generic term variable layers of concentric dark bands. The those found in underground coal miners. common in many pneumoconioses, includ- central zone is eosinophilic, granular, and CWP is now clinically and pathologically ing silicosis and CWP. In complicated CWP necrotic, with fragments of nuclear material, distinguished from silicosis. or PMF, lung function is compromised due collagen, and elastin often associated with The spectrum oflung lesions in coal work- to extensive fibrosis and emphysema. cavitation and calcification. Microscopically, ers is wide, and CWP is categorized according Progression of simple CWP to the more the nodules are similar to rheumatoid nod- to the severity of disease (42,43). Simple aggressive form of PMF is thought to be asso- ules, circumscribed, and range in size from CWP is characterized by the formation of ciated with severe cumulative dust exposure, 0.5 to 5 cm in diameter. The periphery of black coal dust macules centered around the concentration of inorganic minerals and sil- the lesion is composed of concentrically respiratory bronchioles, mostly in the upper ica, impaired clearance, infections, and arranged collagen with lymphocyte, plasma

Figure 4. Stellate-shape micronodules developing around respiratory bronchioles. Figure 3. Typical coal macule in the walls of respiratory bronchioles, with focal Greater collagen and fewer coal dust particles are distinguishable compared emphysema surrounding the macule. to macules.

678 Environmental Health Perspectives * Vol 108, Supplement 4 * August 2000 SILICOSIS AND COAL WORKERS' PNEUMOCONIOSIS cells, and macrophages containing coal dust. Relationship between Radiographic miners with simple CWP (small rounded Palisading fibroblasts and plasma cells are a Category and Morphology ofCWP opacities) showed only a small fall in gas characteristic feature ofthese lesions; they are exchange (61). Such a small drop in gas rare in tuberculosis and other infectious Radiographically, simple CWP is classified exchange would not be expected to compro- granulomata (43). according to the number, size, and shape of mise arterial oxygen content even during mild small opacities, which are most prevalent in exercise (62). It was, however, shown that Silicosis in CoalWorkers the upper zones of both lungs. Multiple small lung mechanics are decreased in simple Silicosis in coal miners is rarely an isolated rounded opacities on the chest radiographs are CWP, leading to an increase in residual vol- form of pneumoconiosis and is usually found classified and categorized based on size (i.e., p, ume (63). Focal emphysema associated with in conjunction with simple CWP. Micro- q, or r), shape (i.e., s, t, u), and profusion (i.e., coal macules is thought to be involved in col- scopically, silicotic nodules.appear with the 0, 1, 2, or 3) using standard reference films lapse of small airways. In addition, a condi- typical concentric laminations of mature col- developed by the ILO (59). In simple CWP, tion known as industrial bronchitis is lagen surrounding a hyalinized and partially radiographic opacities range in size from reported in coal miners with and without necrotic or calcified center. The nodule is sur- 0.001 to 1.0 cm, and in complicated CWP radiographic evidence ofCWP (64). rounded by a pigmented zone often contain- they are greater than 1.0 cm in diameter. In complicated CWP, premature death is ing histiocytes in reticulin stroma (Figure 6). Complicated CWP with opacities greater than associated with pulmonary disability. Higher Nodules are found more frequently in the 1.0 cm are defined in terms of their dimen- grades of PMF are associated with severe air- upper lung zones but are also found in sub- sion as A (< 50 mm), B (50 mm plus but not way obstruction, restrictive defects, abnor- pleural and peribronchiolar locations. greater than right upper lung lobe), and C malities in ventilation and perfusion, reduced Polarized light microscopy may reveal numer- (exceeding the size of right upper zone). In diffusing capacity, and low arterial oxygen ous weekly birefringent particles within the general, there is good correlation between pressure (65). These progressive changes nodules and highly birefringent particles in pathologic grading of disease severity and X- eventually lead to the peripheral mantle. With chronic exposure ray category; large opacities showed a better and cor pulmonale (65). to silica, confluence and profusion of lesions correlation with pathologic PMF (59). may occur, resulting in the development of However, moderate-to-severe pathologic Lung Cancer in Coal Miners conglomerate silicosis or PMF. abnormality has to be present before abnor- Lung cancer in coal miners occurs less Prevalence of silicosis in coal miners can mality can be detected radiographically with frequently than in the general population be reliably determined only in autopsy studies certainty. In cases with a radiographic profu- after adjustment for age and smoking because of the inability of chest radiography sion of0/0, moderate numbers ofmacules and (66,67). Epidemiologic studies of British and to distinguish between silicosis and CWP. miconodules were present in pathologic evalu- U.S. coal miners reported a lower risk oflung Furthermore, eggshell calcification indicative ation (59). PMF may be confused in chest cancer for miners compared to that in non- of silicosis in radiographs is often not associ- radiography with carcinoma, tuberculosis, or miners, and there was no apparent influence ated with parenchymal silicosis in autopsy bacterial infectious lesions (59). of mining tenure on the prevalence of lung studies. Pathologic evaluations of 4,115 tumors. There were also no changes in the autopsy cases from the National Coal Respiratory Symptoms ofCWP histopathology of lung cancer cell types in Workers' Autopsy Study from 1972 to 1996 Coal miners with milder forms ofsimple CWP coal miners, a point of view critically evalu- have found 23% of coal miners with pul- usually have no symptoms. Nevertheless, in a ated to assess the relationship of smoking monary silicosis and 58% with lymph node small proportion of coal miners' abnormal (68). The tumors were mostly squamous cell silicosis (57). Certain job categories such as pulmonary function tests, airflow obstruction (30%), adenocarcinoma (27%), and small tunnel drilling, roof bolting, and transporta- and changes in diffusing capacity were cell (26%), again showing no influence of tion are associated with increased risk for observed with macules (pea-size small opaci- mining tenure on the frequency of these cell developing silicosis (58). ties) (60). A 9-year follow-up study of coal types. From these histopathologic studies, it is

Figure 5. Progressive massive fibrosis lesion showing cavitation and distortion of the Figure 6. Silicotic lesion in a coal miner's lung showing characteristic features of sili- bronchiole and blood vessels. Necrosis in the cavity contains coal dust and dust- cotic nodule, such as an amorphous center with concentrically arranged collagen containing macrophages. fibers. Note the nodule is surrounded by coal dust.

Environmental Health Perspectives * Vol 108, Supplement 4 * August 2000 679 CASTRANOVA AND VALLYATHAN evident that there are no apparent cellular Direct Cytotoxicity radical production and cytotoxicity both in differences in lung cancer of coal miners who The ability ofsilica or coal dust to cause lipid vitro and in vivo (17,92). smoke and the cigarette-smoking general peroxidation and induce damage to cells or population (68). lung tissue is summarized in Table 1. In vitro Activation ofOxidant Species In contrast to lung cancer, epidemiologic and in vivo damage resulting from silica expo- Production byAlveolar Macrophages studies have revealed a higher-than-normal sure has generally been reported to be more The production ofreactive species (superoxide, incidence of mortality from gastric cancer in severe than with coal dust. hydrogen peroxide, nitric oxide) from alveolar coal miners compared to that in nonminers Christian and Nelson (78) have correlated macrophages has been associated with cell (69-71). A significant relationship between the cytotoxicity of coal dust with the nickel damage and disease (93). Indeed, a relation- cumulative dust exposure and increased mor- content of the mine dust samples. Samples ship has been reported between the level of tality from cancers of the digestive system was from Pennsylvania coal mines had higher oxidant production by pulmonary phagocytes also evident from these studies. It has been nickel content and exhibited greater cytotoxi- and lung damage and severity of pneumoco- suggested that nitrosation of ingested coal dust city than samples from Utah coal mines. This niosis (84,94). Silica- and/or coal dust-induced in the acidic gastric environment could result cytotoxicity was related to the higher rates of oxidant production from alveolar macrophages in the production of carcinogenic products, CWP in Pennsylvania mines than that has been measured directly or by monitoring which may lead to the higher incidence ofgas- reported in Utah. Dalal et al. (39) have found chemiluminescence in cellular, animal, and tric cancer in coal miners (72). In support of radicals on the fracture surfaces of freshly human exposure studies. The data are summa- this hypothesis, it was shown that upon nitro- ground anthracite coal and noted that rized in Table 2. As with direct cytotoxicity, sation of coal dust extracts they become muta- hemolytic activity of this coal dust decreased silica appears to be a more potent stimulant of genic and are able to induce neoplastic as these surface radicals decayed. oxidant production than coal dust. transformation ofmammalian cells (72,73). Nash et al. (87) have suggested that SiOH Freshly fractured silica is a more potent groups on the surface of crystalline silica are stimulant of oxidant species production by Mechanisms of Silica and Coal capable of forming hydrogen bonds with alveolar macrophages than aged silica where Pathogenicity membrane components, resulting in mem- surface radicals had decayed. This greater Interstitial lung disease caused by exposure to brane injury and leakage. Polyvinylpyridine- potency of fresh silica dust has been demon- silica and/or coal dust is the consequence of N-oxide is thought to detoxify silica by acting strated after both in vitro and inhalation expo- damage to lung cells and the resultant lung as a proton acceptor and shielding the SiOH sures of rat alveolar macrophages (86,99). scarring associated with activation of the groups on quartz. Nolan et al. (88) have pro- Similarly, extremely high levels of chemilumi- fibrotic process. The following mechanisms posed that the negative surface charge of the nescence have been reported from a rock have been proposed to characterize this cycle SiO- groups is critical to cytotoxicity. It is driller who was exposed to fresh silica and was ofdamage and scarring (9,10): possible that this negative charge allows silica diagnosed with acute siicosis (97). * Direct cytotoxicity: Chemical features of to interact with scavenger receptors on alveo- silica or coal dust result in reaction with lar macrophages (80,89). Indeed, neutraliza- Stimulation ofInflammatory lung cells, leading to peroxidation of tion of the surface of quartz with aluminum Release membrane lipids and damage to cell salts markedly reduces cytotoxicity (81). As discussed above, silica and, to a lesser membranes. Damaged cells may release The grinding ofsilica results in the gener- extent, coal dust can stimulate oxidant gener- intracellular enzymes, which would cause ation of Si and SiO radicals on the fracture ation. Evidence indicates that oxidant stress further tissue damage, leading to scarring planes (17,90). Upon contact of these surface can activate the nuclear transcription factor or destruction ofalveolar septa. radicals with aqueous solution, hydroxyl radi- NF-icB (100). Data indicate that silica can * Activation ofoxidant generation by alveo- cals are generated (1?). There appears to be a simulate NF-icB binding to DNA (101). lar macrophages: Silica or coal dust stimu- direct relationship between the ability ofsilica Such binding to various gene promoters can lates the generation of ROS from alveolar particles to generate hydroxyl radicals and the result in mRNA production for a variety of macrophages, which overwhelms antioxi- potential to cause lipid peroxidation and inflammatory cytokines. Recent evidence dant defenses of the lung and causes lipid cytotoxicity in vitro (17,91). A similar rela- indicates that silica-induced activation of peroxidation and cell damage. Such dam- tionship has been demonstrated in vivo as another transcription factor, activation pro- age may lead to scarring or destruction of well (18,86). Surface iron plays an important tein-1, also may play an important role in the alveolar septa. role in augmenting silica-induced hydroxyl regulation ofinflammatory cytokines (102). * Stimulation of the secretion of inflamma- tory cytokines and chemokines from Table 1. Direct cytotoxicity of silica or coal mine dust. alveolar macrophages and/or alveolar epithelial cells: These inflammatory medi- Toxic reaction Silica Coal dust Reference ators act as chemoattractants to recruit In vitro studies Lipid peroxidation e- + (74,75) polymorphonuclear leukocytes (PMNs) Hemolysis ++ + (74-76) and macrophages from pulmonary capil- LDH release from alveolar macrophages ++ + (76,77) laries to the air spaces. These cytokines Inhibition of mammalian cell growth NR + (78) also activate pulmonary phagocytic gener- Increased permeability of Tll monolayers ++ NR (79 ation of oxidant species, leading to tissue Apoptosis ++ NR (80) damage and scarring. In vivo studies * Stimulation of secretion of fac- Lipid peroxidation ++ NR (18) fibrogenic Lavage enzyme levels ++ (81,82) tors from alveolar macrophages and/or Lavage protein ++ + (83-85) alveolar epithelial cells: Release of fibro- Lavage red blood cells ++ NR (18,86) genic factors results in induction of fibro- Lavage lactate dehydrogenase ++ NR (83,85) blast proliferation and/or the stimulation Abbreviations and symbols: -, no significant response; +, significant response; ++, greater response than +; NR, response has not ofcollagen synthesis, leading to fibrosis. been reported.

680 Environmental Health Perspectives * Vol 108, Supplement 4 * August 2000 SILICOSIS AND COAL WORKERS' PNEUMOCONIOSIS

Excessive and prolonged inflammation of This recruitment of phagocytic cells into to stimulate oxidant production by these the lung has been associated with the develop- the alveolar spaces is in response to the particle- phagocytes. This would increase the oxidant ment of pulmonary disease. In studies of silica induced production of chemotactic cytokines burden in the lung, overwhelm antioxidant exposure of rats, the recruitment of PMNs and chemokines by alveolar macrophages and defenses, and cause lung injury and scarring. from the pulmonary capillaries to the alveolar alveolar type II epithelial cells (106). A list of Indeed, activation of ROS production by airspaces is a hallmark of the initiation and inflammatory cytokines and chemokines pro- PMNs has been demonstrated in response to progression of silica-induced lung disease duced in response to silica or coal dust exposure PAF, TNF-a, and IL-1 (107,119). (83,85,86,103). As with cytotoxic responses, is given in Table 3. Leukotriene B4, platelet- the degree of pulmonary inflammation is activating factor (PAF), and interleukin (IL)-1 Stimulation ofFibrogenic Factor related to the ability of the silica particles to are chemotaxins for PMNs and in the case of Release generate radicals, i.e., freshly fractured silica IL-1 lymphocytes as well (6). Tumor necrosis A number of cytokines produced by alveolar exhibits more surface radicals and causes more factor alpha (TNF-a) may not be a direct macrophages have regulatory effects on PMN recruitment than aged silica (18,86). chemoattractant factor; however, it is a potent fibroblast growth and/or collagen synthesis. PMN recruitment has also been demonstrated stimulant of chemokines, such as When the balance between fibrotic and anti- as a hallmark ofacute silicosis in humans (97). inflammatory protein (MIP-1 or MIP-2) and fibrotic mediators shifts, pulmonary fibrosis Exposure ofanimals to coal dust also results in cytokine-induced neutrophil chemoattractant can develop. IL-1 (120), TNF-a (121), inflammation characterized as an increase in (118). Indeed, the importance ofTNF-a in the platelet-derived growth factor (PDGF) (122), the number ofmacrophages and PMNs in the inflammatory reaction to silica has been fibronectin (123), alveolar macrophage- alveolar space (82,104). In general the magni- emphasized by the fact that a) PMN recruit- derived growth factor (123), and type 1 tude ofthe inflammatory response to coal dust ment exhibits a direct, linear relationship to insulinlike growth factor (124) have been exposure is smaller than that to silica (84) and TNF-a production in silica-exposed rats (119); reported to increase fibroblast proliferation. is less dominated by PMN recruitment (104). and b) treatment of silica-exposed rats with PDGF and fibronectin are competence fac- An increased number of alveolar macrophages anti-TNF-a dramatically attenuates PMN tors, whereas alveolar macrophage-derived have also been reported in coal miners, with recruitment (118). growth factor is a progression factor for pro- the number of lavagable macrophages increas- Once PMNs are recruited into the alveo- liferation of fibroblasts. IL-1 has also been ing with the severity ofCWP (105). lar spaces, several inflammatory cytokines act described as a direct stimulant of collagen production (125). TNF-ct is not only a direct Table 2. Silica or coal dust-induced activation of oxidant release from alveolar macrophages. proliferative agent for fibroblasts but also stimulates the secretion of PDGF in vitro Response Silica Coal dust Reference (126). A critical role ofTNF-a in pulmonary In vitro studies fibrosis is demonstrated by the fact that anti- Superoxide anion ++ NR (95) Hydrogen peroxide ++ NR (95) TNF-ax significantly decreased silica-induced Chemiluminescence ++ NR (95) pulmonary fibrosis in a mouse model (127). In vivo animal studies In contrast, IL-6 exhibits antifibrotic activ- Hydrogen peroxide ++ NR (95) ity (128). Prostaglandin E2 and transforming Chemiluminescence ++ + (82,86,95) growth factor beta (TGF-P) exhibit a depres- Nitric oxide ++ + (84,86,96) sive effect on cell growth (122,124). However, Human studies-patients with silicosis or CWP Superoxide anion ++ + (94,98) under certain conditions, TGF-P can stimu- Hydrogen peroxide ++ NR (98) late collagen synthesis in vitro (129). Chemiluminescence ++ + (96,97) The effects of silica or coal dust exposure Nitric oxide + + (96) on alveolar macrophage production of Abbreviations and symbols: +, significant response; ++, greater response than +; NR, response has not been reported. cytokines that regulate fibrogenesis are listed in Table 4. Although exposure has been reported Table 3. Silica or coal dust-induced stimulation of cytokine and chemokine secretion from lung cells. to stimulate both fibrogenic and antifibrogenic Response Silica Coal dust Reference factors, it appears the balance shifts toward fibrotic stimuli. For example, TNF-a, type 1 In vitro studies Platelet-activating factor ++ + (107) insulinlike growth factor, and PDGF all Leukotriene B4 ++ + (105) increase as simple CWP progresses to PMF. Prostaglandin E2 NR + (109) Thromboxane A2 NR + (109) Data Gaps and Unresolved TNF-ca ++ + (108,110) Issues in Silicosis IIL-1 ++ + (111( * Controversy over the relationship IL-6 NR + (11a) In vivo animal studies between crystalline silica exposure and the Leukotriene B4 + + (112,113) development of lung cancer still exists. Prostaglandin E2 + NR (112) Further evidence from both experimental Thromboxane A2 NR + (113) animal studies and human investigations TNF-a ++ NR (114) is desirable. IL-1 + NR (114) * Why does silica induce lung tumors in rat Macrophage inflammatory protein ++ NR (106) models but not in mice or hamsters? What Human studies-patients with silicosis or CWP TNF-a NR + (115) is the mechanistic reason for this difference? IL-1 NR + (115) * In rats, silica-induced lung tumors have Monocyte chemoattractant peptide-1 NR + (115) been associated with a particle overload. Is IL-6 NR + (117 silica overload a prerequisite for the neo- Abbreviations and symbols: +, significant response; ++, greater response than +; NR, response has not been reported. plastic response in humans?

Environmental Health Perspectives * Vol 108, Supplement 4 * August 2000 681 CASTRANOVA AND VALLYATHAN

Table 4. Silica or coal dust-induced stimulation of fibrogenic factor secretion from lung cells Comprehensive Toxicology-Toxicology of the , Vol 8 (Roth RA, ed). New York:Elsevier Press, 1997; Response Silica Coal dust Reference 373-391. In vitro studies 7. Jones W, Ma JYC, Castranova V, Ma JKH. Dust particles: occu- TNF- a ++ + (108,110) pational considerations. In: Handbook of Hazardous Materials. IL-1 ++ New York:Academic Press, 1993;213-222. + (111) 8. Mandel G, Mandel N. The structure of crystalline SiO2. In: Silica Prostaglandin E2 NR + (l09) and Silica-induced Lung Diseases (Castranova V, Vallyathan V, [L-6 NR + (110) Wallace WE, eds). Boca Raton:CRC Press, 1996;63-78. In vivo animal studies 9. Castranova V. Particulates and the airways: basic biological TNF-a ++ NR (114) mechanisms of pulmonary pathogenicity. AppI Occup Environ IL-1 + NR (114) Hyg 13:613-616 (1998). Fibronectin + NR (114) 10. Lapp NL, Castranova V. How silicosis and coal workers' pneu- TGF-,B + NR (130) moconiosis develop-a cellular assessment. Occup Med: State + of the Art Rev 8:35-56 (1993). Prostaglandin E2 NR 112) 11. Schins RPF, Borm PJA. Mechanisms and mediators in coal dust Human studies-patients with silicosis or CWP induced toxicity: a review. Ann Occup Hyg 43:7-33 (1998). TNF-a NR + (115) 12. Green FHY, Vallyathan V. Pathologic responses to inhaled silica. IL-1 NR + (115) In:Silica and Silica-induced Lung Diseases (Castranova V, Fibronectin + + (98) Vallyathan V, Wallace WE, eds). Boca Raton, FL:CRC Press, Alveolar macrophage-derived growth factor + + (98) 1996;39-59. Platelet-derived growth factor NR + (124) 13. Sherwin RP, Bowman ML, Abraham JL. Silicate pneumoconio- Type insulinlike growth factor NR + sis in farm workers. Lab Invest 40: 576-582 (1979). (124) 14. Sanderson WT. US population at risk to occupational respira- TGF-P NR + ( 124) tory diseases. In: Occupational Respiratory Diseases. NIOSH [l-6 NR + (117) Publ 86-102 (Merchant JA, Boehlecke BA, Taylor G, Pickett- Abbreviations and symbols: +, significant response; ++, greater response than +; NR, response has not been reported. Harner M, eds). Cincinnati, OH:National Institute for Occupational Safety and Health, 1986;739-759. 15. Roznowski E. Silica update: National Conference to Eliminate * Lung carcinomas in silica-exposed rats * Can silicosis be treated or its progression Silicosis-Construction. AppI Occup Environ Hyg 12:581-583 tend to be mostly in peripheral airways inhibited? (1997). and adenocarcinomas/bronchoalveolar 16. NIOSH. Work-Related Lung Disease Surveillance Report. NIOSH Data Gaps and Unresolved Publ 94-120. Cincinnati, OH:National Institute for Occupational carcinomas are the frequent cell types. Is Health and Safety, 1994. there a predilection in humans for similar Issues in CWP 17. Vallyathan V, Shi X, Dalal NS, lrr W, Castranova V. Generation tumors? * Controversy over the relationship of free radicals from freshly fractured silica dust: potential role in acute silica-induced lung injury. Am Rev Respir Dis 138: * Dose-response relationships between between the extent of exposure to crys- 1213-1219(1988). tumor incidence and exposure to crys- talline silica or silicates and the develop- 18. Vallyathan V, Castranova V, Pack D, Leonard S, Shumaker, talline silica is required in both animal ment of lung lesions such as nodules or Hubbs AF, Shoemaker DA, Ramsey DM, Pretty JR, McLaurin JL, et al. Freshly fractured quartz inhalation leads to enhanced lung models and human studies. PMF is unresolved. injury and inflammation. Am J Crit Care Med 152:1003-1009 * Is silicosis in the lymph nodes associated * Is impaired clearance or dust overload a (1995). with excess lung cancer? Does this impede requirement for the progression of simple 19. McDonald JC. Silica and cancer. In: Silica and Silica-induced Lung Diseases (Castranova V, Vallyathan V, Wallace WE, eds). the clearance of other carcinogens from CWP to PMF? Boca Raton, FL:CRC Press, 1996;383-396. the lung and provide an increased resi- * Is an oxidant burden (particle derived 20. Banks DE. Clinical features of silicosis. In: Silica and Silica- dence time? If so, what evidence is avail- and/or inflammation derived) an intrinsic Induced Lung Diseases (Castranova V, Vallyathan V, Wallace WE, eds). Boca Raton, FL:CRC Press, 1996;23-37. able to support DNA damage or increased mechanism involved in the development 21. Sherson D, Lander F. Morbidity of pulmonary tuberculosis frequency ofmutations? ofCWP? among silicotic and nonsilicotic foundry workers in Denmark. J * Is pulmonary fibrosis a prerequisite for * Why do coal miners have a lower than Occup Med 32:110-113 (1990). silica-induced lung cancer in humans? normal risk of lung cancer? Does coal 22. Cowie RL. The epidemiology of tuberculosis in gold miners with silicosis. Am J Respir Crit Care Med 150:1460-1462 (1994). * Is an oxidant burden (particle derived dust inhibit the metabolic activation of 23. Cowie Rl. The five stages of pulmonary tuberculosis and the and/or inflammation derived) an intrinsic chemicals to carcinogens? South African gold miner. S Afr Med J 76:566-567 (1989). mechanism involved in triggering silica- * What is the true incidence of lung cancer 24. Glover JR, Bevan C, Cotes JE, Elwood PC, Hodges NG, Kell RL, Lowe CR, McDermott M, Oldham PD. Effects of exposure to induced tumors? in never-smoker coal miners? Is there a slate dust in North Wales. Br J lnd Med 37:152-162 (1980). * Is crystalline silica a direct-acting carcino- dose response? 25. Policard A, Gernez-Rieux C, Tacquet A, Martin JC, Devulder B, gen or cocarcinogen? Is it an initiator or LeBouffant L. Influence of pulmonary dust load on the develop- ment of experimental infection by mycobacteria Kansasie. promoter? REFERENCES AND NOTES Nature 216:177-178 (1967). * Why do different strains of mice exhibit 26. Watanabe S, Shirakami A, Takeichi T, Ohara T, Saito S. different susceptibilities to silica-induced 1. Craighead JE, Kleinerman J, Abraham JL, Gibbs AR, Green FHY, Alterations in lymphocyte subsets and serum immunoglobulin Harley RA, Ruettner JR, Vallyathan NV, Juliano EB. Diseases levels in patients with silicosis. J Clin Lab Immunol. 23:45-51 fibrosis? What are the mechanistic differ- associated with exposure to silica and non-fibrous silicate min- 11987). ences involved? erals. Arch Pathol Lab Med 112:673-720 (1998). 27. Saldana LF, Rose VJ, Gonick HC. Silicon nephropathy. Am J * Since freshly fractured silica is more cyto- 2. Castranova V, Vallyathan V, Wallace WE, eds. Silica and Silica- Med 59:95-103 (1975). toxic and inflammatory than aged silica, Induced Lung Diseases. Boca Raton, FL:CRC Press, 1996. 28. Hauglustaine D, Van Damme, B Daenes P, Michielsen P. Silicon 3. Peters JM. Silicosis. In: Occupational Respiratory Diseases. nephropathy: a possible . Nephron 26: does this necessitate a lower exposure NIOSH Publ 86-102 (Merchant JA, Boehlecke BA, Taylor G, 219-224 (1980). standard in occupations that generate Pickett-Harner M, eds). Cincinnati, OH:National Institute for 29. Goldsmith DF, Winn DM, Shy CM. Epidemiologic studies of sili- freshly fractured silica dust? How much Occupational Health and Safety, 1986;219-237. cotics and dusty trades workers. In: Silica, Silicosis and Cancer: 4. Merchant JA, Taylor G, Hodous TK. Coal workers' pneumoco- Controversy in , Cancer Research lower should the standard be? niosis and exposure to other carbonaceous dusts. In: Monographs, Vol 2. New York:Praeger Scientific, 1986; * What is the toxicity of Occupational Respiratory Diseases. NIOSH Publ 86-102, 311-357. substitutes in relationship to silica? Do (Merchant JA, Boehlecke BA, Taylor G, Pickett-Harner M, eds). 30. IARC. IARC Monograph on the Evaluation of the Carcinogenic Cincinnati, OH:National Institute for Occupational Safety and Risk of Chemicals to Humans. Silica and Some Silicates, Vol 42. safe substitutes exist? Health, 1986;329-384. Lyon:lnternational Agency for Research on Cancer, 1987. * Can biomarkers be developed to identify 5 Castranova V, Ducatman BS. Coal dust. In: Comprehensive 31. IARC. IARC Monograph on the Evaluation of the Carcinogenic adverse reactions to silica before disease Toxicology-Toxicology of the Respiratory System, Vol 8 (Roth Risk of Chemicals to Humans. Silica, Some Silicates, Coal Dust RA, ed). New York:Elsevier Press, 1997;361-372. and Para-aramid Fibrils. Vol 68. Lyon:lnternational Agency for becomes irreversible? 6. Driscoll KE, Guthrie GD. Crystalline silica and silicosis. In: Research on Cancer, 1997.

682 Environmental Health Perspectives * Vol 108, Supplement 4 * August 2000 SILICOSIS AND COAL WORKERS' PNEUMOCONIOSIS

32. Cherry NM, Burgess GL, Turner S, McDonald JC. Crystalline sil- 56. Benedek TG, Zawadzki ZA, Medsger TA, Jr. Serum immunoglob- 83. Driscoll KE, Lindenschmidt RC, Maurer JK, Perkins L, Perkins M, ica and risk of lung cancer in the . Occup Environ Med ulins, rheumatoid factor and pneumoconiosis in coal miners with Higgins J. Pulmonary response to inhaled silica or titanium 55:779-785(1998). rheumatoid arthritis. Arthritis Rheum 19: 731-736 (1976). dioxide. Toxicol AppI Pharmacol 111:201-210 (1991). 33. Weill H, McDonald JC. Exposure to crystalline silica and risk of 57. Green FHY, Althouse R, Parker J, Kahn J, Weber K, Vallyathan 84. Blackford JA, Jones W, Dey RD, Castranova V. Comparison of lung cancer: the epidemiological evidence. Thorax 51:97-102 V. Trends in the prevalence of coal workers' pneumoconiosis in inducible nitric oxide synthase gene expression and lung inflam- (1996). US autopsied coal miners. In: Advances in the Prevention of mation following intratracheal instillation of silica, coal, car- 34. Shi X, Castranova V, Halliwell B, Vallyathan V. Reactive oxygen Occupational Respiratory Diseases (Chiyotani K, Hosoda Y, bonyl iron or titanium dioxide in rats. J Toxicol Environ Health species and silica-induced carcinogenesis. J Toxicol Environ Aizawa, eds). New York:Elsevier Science, 1998;145-148. 51:203-218 (1997). Health 1:181-197 (1998). 58. Green FHY, Althouse R, Weber KC. Prevalence of silicosis at 85. Warheit DB, Carakostas MC, Harsky MA, Hansen JF. 35. Kuempel ED, Althouse RB, Attfield MD, Bartley DL, Brower PL, death in underground coal miners. Am J Ind Med 16:805-816 Development of a short-term inhalation bioassay to assess pul- Castranova V, Chan HS, Coffey CC, Dames BL, Doak CB, et al. (1989). monary toxicity of inhaled particles: comparisons of pulmonary NIOSH Criteria for a Recommended Standard: Occupational 59. Vallyathan V, Brower PS, Green FHY, Attfield MD. Radiographic responses to carbonyl iron and silica. Toxicol AppI Pharmacol Exposure to Respirable Coal Mine Dust. NIOSH Publ 95-106. and pathologic correlation of coal workers' pneumoconiosis. 107:350-368 (1991). Cincinnati, OH:National Institute for Occupational Safety and Am J Respir Crit Care Med 154:741-748 (1996). 86. Castranova V, Pailes WH, Dalal NS, Miles PR, Bowman L, Health, 1995. 60. Seaton A, Lapp NL, Morgan WKC. The relationship of pul- Vallyathan V, Pack D, Weber KC, Hubbs A, Schwegler-Berry D, 36. Ortmeyer CE, Baier EJ, Crawford GM, Jr. Life expectancy of monary impairment in simple coal workers' pneumoconiosis to et al. Enhanced pulmonary response to the inhalation of freshly Pennsylvania coal miners compensated for disability. Arch type of radiographic opacity. Br J Ind Med 29:50-55(1972). fractured silica as compared to aged dust exposure. AppI Occup Environ Health 27:227-230 (1973). 61. Musk AW, Cotes JE, Bevan C, Campbell MJ. Relationship Environ Hyg 11:937-941 (1996). 37. Bennett JG, Dick JA, Kaplan YS, Shand PA, Shennan DH, between type of simple coal workers' pneumoconiosis and lung 87. Nash T, Allison AC, Harington JS. Physico-chemical properties Thomas DJ, Washington JS. The relationship between coal function. A nine year follow-up study of subjects with small of silica in relation to its toxicity. Nature (London) 210:259-261 rank and the prevalence of pneumoconiosis. Br J Ind Med rounded opacities. Br J Ind Med 38:313-320 (1981). (1966). 36:206-210 (1979). 62. Lapp NL, Seaton A. Pulmonary function. In: Pulmonary 88. Nolan RP, Langer AM, Harington JS, Oster G, Selikoff IJ. Quartz 38. Dalal NS, Newman J, Pack D, Leonard S, Vallyathan V. Hydroxyl Reactions to Coal Dust (Key MM, Kerr LE, Bundy M, eds). New hemolysis as related to its surface functionalities. Environ Res radical generation by coal mine dust: possible implication to York:Academic Press, 1971153-177. 26:503-520 (1981). coal workers' pneumoconiosis (CWP). Free Radic Biol Med 18: 63. Legg SJ, Cotes JE, Bevan C. Lung mechanics in relation to radi- 89. Kobzik L. Lung macrophage uptake of unopsonized environmen- 11-20(1995). ographis category of coal workers' simple pneumoconiosis. Br J tal particles. Role of scavenger-type receptors. J Immunol 39. Dalal NS, Jafari B, Vallyathan V, Green FHY. Cytotoxicity and Ind Med 40:20-33 (1983). 155:367-376 (1995). spectroscopic investigations of organic-free radicals in fresh 64. Morgan WKC. Industrial bronchitis. Br J Ind Med 35:285-291 90. Fubini B. The surface chemistry of crushed quartz dust in rela- and stale coal dust. In: Proceedings 7th International (1978). tion to its pathogenicity. Org Chem Acta 138:193-197 (1987). Pneumoconiosis Conference, Part 2, 23-26 August 1988, 65. Lapp NL, Parker JE. Coal workers' pneumoconiosis. Occup Lung 91. Dalal NS, Shi X, Vallyathan V. Role of free radicals in the mech- Pittsburgh, Pennsylvania. NIOSH Publ 90-108. Cincinnati, OH: Dis 13:243-252 (1992). anisms of hemolysis and lipid peroxidation by silica: compara- National Institute for Occupational Safety and Health, 1990; 66. Meijers JMM, Swaen GMH, Slangen JJM, Vliet KV, Sturmans tive ESR and cytotoxicity studies. J Toxicol Environ Health 1470-1477. F. Long-term mortality in miners with coal workers' pneumoco- 29:307-316 (1990). 40. Dalal NW, Jafari B, Petersen M, Green FHY, Vallyathan V. niosis in the Netherlands: a pilot study. Am J Ind Med 19: 92. Castranova V, Vallyathan V, Ramsey RM, McLaurin JL, Pack D, Presence of stable coal radicals in autopsied coal miners' lungs 43-50 (1991). Leonard S, Barger MW, Ma JYC, Dalal NS, Teass A. and its possible correlation to coal workers' pneumoconiosis. 67. Kuempel ED, Stayner LT, Attfield MD, Buncher CR. Exposure- Augmentation of pulmonary reactions to quartz inhalation by Arch Environ Health 46:366-372 (1991). response analysis of mortality among coal miners in the United trace amounts of iron-containing particles. Environ Health 41. Wallace WE, Harrison JC, Grayson RL, Keane MJ, Bolsaitis P, States. Am J Ind Med 28:167-184 (1995). Perspect 104(suppl 105):1319-1324 (1997). Kennedy RD, Wearden AD, Attfield MD. Aluminosilicate surface 68. Vallyathan V, Green FHY, Rodman NF, Boyd DB, Althouse R. 93. Weiss SJ, Lo Buglio AF. Biology of disease: phagocyte-gener- contamination of respirable quartz particles from coal mine Lung carcinoma by histologic type in coal miners. Arch Path Lab ated oxygen metabolites and cellular injury. Lab Invest 47:5-18 dusts and from clay works dusts. Ann Occup Hyg 38:439-445 Med 109: 419-423 (1985). (1982). (1994). 69. Miller BG, Jacobsen M. Dust exposure, pneumoconiosis and 94. Wallaert B, Lassalle P, Fortin F, Aerts C, Bart F, Fourheir E, 42. Kleinerman J, Green FHY, Harley R, Lapp NL, Laqueur W, Naeye mortality of coal miners. Br J Ind Med 42: 723-733 (1985). Voisin C. Superoxide anion generation by alveolar inflammatory RL, Pratt P, Taylor G, Wyatt J. Pathology Standards for Coal 70. Rockette H. Mortality among Coal Miners Covered by UMWA cells in simple pneumoconiosis and in progressive massive Workers' Pneumoconiosis: Report of the Pneumoconiosis Health and Retirement Funds. NIOSH Publ 77-155. Cincinnati, fibrosis of non-smoking coal workers. Am Rev Respir Dis Committee of the College of American Pathologists to the OH:National Institute for Occupational Safety and Health, 1977. 141:129-133 (1990). National Institute for Occupational Safety and Health. Arch 71. Ames RG, Gamble JF. Lung cancer, stomach cancer and smok- 95. Castranova V. Generation of oxygen radicals and mechanisms Pathol Lab Med 103:375-431 (1978). ing status among coal miners. Scand J Work Environ Health 9: of injury prevention. Environ Health Perspect 102(suppl 10): 43. Green FHY, Vallyathan V. Coal workers' pneumoconiosis and 443-448 (1983). 65-68(1994). pneumoconiosis due to other carbonaceous dusts. In: Pathology 72. Wu ZL, Chen JK, Ong T, Mathews EJ, Whong WZ. Induction of 96. Castranova V, Huffman LJ, Judy DJ, Bylander JE, Lapp LN, of Occupational Lung Disease. 2nd ed (Churg A, Green FHY, morphological transformation by coal-dust extract in BALB/3T3 Weber SL, Blackford JA, Dey RD. Enhancement of nitric oxide eds). Philadelphia:Williams and Wilkins, 1998;129-208. A31-1-13 cell line. Mutat Res 242:225- 230 (1990). production by pulmonary cells following silica exposure. Environ 44. Gregory JC. Case of particular black infiltration of the whole 73. Whong WZ, Long R, Ames RG, Ong TM. Role of nitrosation in Health Perspect 106(suppl 15):1165-1169 (1998). lungs resembling melanosis. Edinburgh Med Surg 36:389-394 the mutagenic activity of coal dust: a postulation for gastric car- 97. Goodman GB, Kaplan PD, Stachura I, Castranova V, Pailes WH, (1831). cinogenesis in coal miners. Environ Res 32:298-304 (1983). Lapp NL. Acute silicosis responding to corticosteroid therapy. 45. Collins EL, Gilchrist JC. Effects of dust upon coal trimmers. J 74. Vallyathan V. Generation of oxygen radicals by minerals and its Chest 101:366-370 (1992). lnd Hyg Toxicol 10:101-109(1928). correlation to cytotoxicity. Environ Health Perspect 102(suppl 98. Rom WM, Bitterman PB, Rennard Si, Cantin A, Crystal RG. 46. Gough J. Pneumoconiosis of coal trimmers. J Pathol Bacteriol 10): 111-115 (1994). Characterization of lower inflammation of non- 51:227-285 (1940). 75. Singh SV, Rahman 0. Interrelationships between hemolysis and smoking individuals with interstitial lung disease associated 47. Heppleston AG. The essential lesion of pneumoconiosis in lipid peroxidation of human erythrocytes induced by silicic acid with chronic inhalation of inorganic dusts. Am Rev Respir Dis Welsh workers. J Pathol Bacteriol 59:453-460 (1947). and silicate dusts. J AppI Toxicol 7:91-96 (1987). 136:1429-1434 (1987). 48. Heppleston AG. The pathogenesis of simple pneumoconiosis in 76. Vallyathan V, Schwegler D, Reasor M, Stettler L, Green FHY. 99. Castranova V, Dalal NS, Vallyathan V. Role of surface free radi- coal workers. J Pathol Bacteriol 67:51-63 (1954). Comparative in vitro cytotoxicity and relative pathogenicity of cals in the pathogenicity of silica. In: Silica and Silica-induced 49. Shennan DH, Washington JS, Thomas DJ, Dick DJ, Kaplan YS, mineral dusts. Ann Occup Hyg 32:279-289 (1988). Lung Disease (Castranova V, Vallyathan V, Wallace WE, eds). Bennett JG. Factors predisposing to the development of PMF in 77. Amadis Z, Timiar T. Studies on the effect of quartz, bentonite Boca Raton, FL:CRC Press, 1996;91-105. coal miners. Br J Ind Med 38:321-326 (1981). and coal dust mixtures on macrophages in vitro. Br J Exp Pathol 100. Shi X, Dong Z, Huang C, Ma W, Liu K, Ye J, Chen F, Leonard SS, 50. Douglas AN, Robertoson A, Chapman JS, Ruckley VA. Dust 59:411-419 (1978). Ding M, Castranova V, et al. The role of hydroxyl radical as a exposure, dust recovered from lung and associated pathology in 78. Christian RT, Nelson JB. Coal: response of cultured mammalian messenger in the activation of nuclear transcription factor NF- a group of British coal miners. Br J Ind Med 43:795-801 (1986). cells corresponds to prevalence of coal workers' pneumoconio- KB. Mol Cell Biochem 194:63-70 (1999). 51. Jacobsen M, Maclaren WM. Unusual pulmonary observations sis. Environ Res 15:232-241 (1978). 101. Chen F, Lu Y, Demers LM, Rojanasakul Y, Shi X, Vallyathan V, and exposure to coal mine dust: a case control study. Ann 79. Merchant RK, Peterson MW, Hunninghake GW. Silica directly Castranova V. Role of hydroxyl radical in silica-induced NF-KcB Occup Hyg 26:753-765 (1982). increases permeability of alveolar epithelial cells. J AppI activation in macrophages. Ann Clin Lab Sci 28:1-13 (1998). 52. Wagner JC, McMoemick JN. Immunological investigations of Physiol 68:1354-1359 (1990). 102. Ding M, Shi X, Dong Z, Lu YJ, Castranova V, Vallyathan V. coal workers' pneumoconiosis. J R Coil (London) 2: 80. lyer R, Hamilton RF, Li L, Holian A. Silica-induced apoptosis Freshly fractured crystalline silica induces activator protein-1 49-56 (1967). mediated via scavenger receptor in human alveolar activation through Erks and p38 mitogen-activated protein 53. James WRL. The relationship of tuberculosis to the develop- macrophages. Toxicol AppI Pharmacol 141:84-92 (1996). kinase. J Biol Chem 274:30611-30616 (1999). ment of massive pneumoconiosis in coal workers. Br J Tuberc 81. Brown GM, Donaldson K, Brown DM. Bronchoalveolar leuko- 103. Bowden DH, Adamson IYR. The role of cell injury and the con- 48:89-101 (1954). cyte response in experimental silicosis: modulation by a soluble tinuing inflammatory response in the generation of silicotic pul- 54. Caplan A. Certain unusual radiological appearances in chest of aluminum compound. Toxicol AppI Pharmacol 101:95-105 monary fibrosis. J Pathol 144:149-161)1984). coal miners suffering from rheumatoid arthritis. Thorax 8: (1989). 104. Bowden DH, Adamson IYR. Adaptive responses of the pul- 29-37 (1953). 82. Castranova V, Bowman L Reasor MR, Lewis T, Tucker J, Miles monary macrophagic system to carbon in kinetic studies. Lab 55. Gough J, Rivers E, Seal RME. Pathological studies of modified PR. The response of rat alveolar macrophages to chronic inhala- Invest 38:422-429 (1978). pneumoconiosis in coal miners with rheumatoid arthritis tion of coal dust and/or diesel exhaust. Environ Res 36:405-419 105. Takemura T, Rum WM, Ferrans VJ, Crystal RG. Morphologic (Caplan's syndrome). Thorax 10:9-18 (1955). (1985). characterization of alveolar macrophages from subjects with

Environmental Health Perspectives * Vol 108, Supplement 4 * August 2000 683 CASTRANOVA AND VALLYATHAN

occupational exposure to inorganic particles. Am Rev Respir Dis 113. Kuhn DC, Stanley CF, El-Ayouby N, Demers LM. Effect of in vivo 122. Reist RH, Bryner K, Wearden P, Blackford J, Vranak, Castranova 140:674-685(1989). coal dust exposure on arachiodonic acid metabolism in the rat V, Dey R. Development of a bioassay for pulmonary cell produc- 106. Driscoll KE, Hassenbein DC, Carter JM, Poynter J, Asquith TN, macrophage. J Toxicol Environ Health 29:157-168 (1990). tion of fibrogenic factors. Toxicol Meth 1:53-65 (1991). Grant RA, Whitten J, Purdon MP, Takigiku R. Macrophage 114. Driscoll KE, Lundenschmidt RC, Maurer JK, Higgins JM, Ridder 123. Bitterman PB, Wewers MD, Rennard SI, Adelberg S, Crystal RG. inflammatory proteins 1 and 2 expression by rat alveolar G. Pulmonary response to silica or titanium dioxide: inflamma- Modulation of alveolar macrophage-derived fibroblast prolifera- macrophages, fibroblasts, and epithelial cells in rat lung after tory cells, aJveolar macrophage-derived cytokines and tion by alternative macrophage mediators. J Clin Invest mineral dust exposure. Am J Respir Cell Mol Biol 8:311-318 histopathology. Am J Respir Cell Mol Biol 2:381-390 (1990). 77:770-701 (1986). (1993). 115. Lassalle P, Gosset P, Aerts C, Fournier E, Lafitte JJ, Degreef 124. Vanhee D, Gosset P, Wallaert B, Voisin C, Tonnel AB. 107. Kang JH, VanDyke K, Pailes WH, Castranova V. Potential role of JM, Wallaert B, Tonnel AB, Vorsin C. Abnormal section of inter- Mechanisms of fibrosis in coal workers' pneumoconiosis: platelet-activating factor in development of occupational lung leukin-1 and tumor necrosis factor by alveolar macrophages in increased production of platelet-derived growth factor, insulin- disease: action as an activator or potentiator of pulmonary coal workers' pneumoconiosis and progressive massive fibross. like growth factor type 1, and transforming growth factor P and phagocytes. Chap 23. In: Proceedings of Respiratory Dust in the Exp Lung Res 16:73-80 (1990). relationship to disease severity. Am J Crit Care Med Mineral Industries, 20-21 March 1991, Pittsburgh, 116. Boitelle A, Gosset P, Vanhe D, Wallaert B, Tonnel AV. MCP-1 in 150:1049-1055 (1994). Pennsylvania. Littleton, CO:Society of Mining, Metallurgy and from patients with coal workers pneu- 125. Goldring MB, Krane SM. Modulation of collagen synthesis in Exploration, 1991;171-178. moconiosis. Am J Respir Crit Care Med 151:A517 (1995). human chondrocyte cultures by interleukin-1. J Bone Min Res 108. Driscoll KE, Higgins JM, Leytart MJ, Crosby LL. Differential 117. Vanhee D, Gosset P, Marquette CH, Wallaert B, Lafitte JJ, 1(suppl 1):56-59 (1986). effects of mineral dusts on the in vitro activation of alveolar Gosselin B, Voisin C, Tonnel AB. Secretion and mRNA expres- 126. Hajjar KA, Hajjar DP, Silverstein RZ, Nachman RL. Tumor necro- macrophage eicosanoid and cytokine release. Toxicol In Vitro sion of TNF and IL-6 in alveolar macrophages and in lungs of sis factor-induced release of platelet-derived growth factor 4:284-288 (1990). pneumoconiotic patients. Am Rev Respir Dis 147:906A (1993). from endothelial cells. J Exp Med 166:235-241 (1987). 109. Kuhn DC, Demers LM. Influence of mineral dust surface chem- 118. Driscoll KE, Hassenbein DG, Carter JM, Kunkel SL, Quinlan TR, 127. Piquet PF, Collart MA, Grau GE, Sappino AP, Vassal P. istry on eicosanoid production by the alveolar macrophage. J Mossman BT. TNFa and increased chemokine expression in rat Requirement for tumor necrosis factor for development of sil- Toxicol Environ Health 35:39-50 (1992). lung after particle exposure. Toxicol Lett 82/83:483-489 (1995). ica-induced pulmonary fibrosis. Nature 344:245-251 (1990). 110. Gosset P, Lassalle P, Vanhe D, Wallaert B, Aerts C, Voisin C, 119. Driscoll KE. The role of interleukin-1 and tumor necrosis factor 128. Kelley J. State-of-the-art: cytokines of the lung. Am Rev Respir Tonnel AB, Production of tumor necrosis factor a and inter- a in the lung's response to silica. In: Silica and Silica-induced Dis 141:765-781 (1990). leukin-6 by human alveolar macrophages exposed in vitro to Lung Disease (Castranova V, Vallyathan V, Wallace WE, eds). 129. Dean DC, Newby RF, Bourgeois S. Regulation of fibronectin coal mine dust. Am J Respir Cell Mol Biol 5:431-436 (1991). Boca Raton, FLCRC Press, 1996;163-184. biosynthesis by dexamethasone, transforming growth factor 3 111. Kang JH, Lewis DM, Castranova V, Rojanasakul Y, Banks DE, 120. Prostlethwaite AE, Lachman LB, Kang AH. Induction of fibrob- and cAMP in human cell lines. J Cell Biol 106:2159-2170 Ma JYC, Ma JKH. Inhibitory action of tetrandrine on last proliferation by interleukin-1 derived from human monocyte (1988). macrophage production of interleukin-1 (IL-1 )-like activity and leukemia cells. Arthritis Rheum 27:995-1001 (1984). 130. Williams AO, Flanders KC, Saffiotti U. Immunohistochemical thymocyte proliferation. Exp Lung Biol 18:719-733 (1992). 121. Vilcek J, Palombella VJ, Henriksen-DeStefano D, Swenson C, localization of transforming growth factor-5 in rats with experi- 112. Henderson RF, Harkema JR, Hotchkiss JA, Boehme DS. Effect Feinman R, Hirai M, Tsujimoto M. Fibroblast growth enhancing mental silicosis, alveolar type 11 hyperplasia and lung cancer. of blood leukocyte depletion on the inflammatory response of activity of tumor necrosis factor and its relationship to other Am J Pathol 142:1831-1840 (1993). the lung to quartz. Toxicol AppI Pharmacol 109:127-136 (1991). polypeptide growth factors. J Exp Med 163:632-643 (1986).

684 Environmental Health Perspectives * Vol 108, Supplement 4 * August 2000