Health Effects of Occupational Exposure
to Respirable Crystalline Silica

3.5.1 COPD

3.5.1.1 Definition

COPD describes chronic airflow limitation that is usually irreversible [ATS 1987; Beck-lake 1992; Snider 1989]. COPD includes four interrelated disease processes: chronic bronchitis, emphysema, asthma [Barnhart 1994; Snider 1989], and peripheral airways disease [ATS 1987]. Cigarette smoking is a major cause of COPD, but community air pollution and occupational exposure to dust, particularly among smokers, also contribute to COPD [Becklake 1992].

3.5.1.2 Epidemiologic Studies

Although thousands of studies have been published about occupational exposure to nonorganic dusts and COPD, only 13 studies of 4 cohorts of silica-exposed workers met rigorous methodologic criteria for a review conducted by Oxman et al. [1993]. Three of the cohorts were coal miners and one was South African gold miners. According to Oxman et al. [1993], the studies provided evidence that exposure to gold mine dust is an important cause of COPD, particularly in smokers, and that the risk of COPD appeared to be greater for gold miners than for coal miners.

3.5.2 Asthma

Crystalline silica has not been identified as an occupational asthma inducing agent [Chan-Yeung 1994], and no published epidemiologic studies have specifically investigated whether asthma is related to crystalline silica dust exposure.

3.5.3 Chronic Bronchitis

3.5.3.1 Definition

Chronic bronchitis is clinically defined as the occurrence of chronic or recurrent bronchial hypersecretion (i.e., a productive cough) on most days of the week for at least 3 months of 2 sequential years [ATS 1987, 1995; Barnhart 1994]. The excess mucus secretion should not be related to a disease such as TB [ATS 1987, 1995]. Chronic bronchitis has been associated with both airflow obstruction and abnormalities in gas exchange [Barnhart 1994]. Although the terms industrial bronchitis and occupational bronchitis traditionally refer to chronic bronchitis that is associated with occupational exposure, bronchitic symptoms may also occur after occupational exposures that are acute or that last less than 2 years. An association between reduced ventilatory function and bronchitic symptoms has been reported in studies of workers exposed to coal dust, asbestos, or dust that contained crystalline silica [Barnhart 1994]. However, cigarette smoking is also associated with chronic bronchitis and must be considered when investigating the relationship between occupational exposures and bronchitic symptoms [Barnhart 1994; ATS 1997].

3.5.3.2 Epidemiologic Studies

Statistically significant (P<0.05) relationships independent of smoking were found between exposure to gold mine dust and chronic bronchitis or chronic sputum production in cross-sectional studies of gold miners in South Africa [Wiles and Faure 1977; Cowie and Mabena 1991] and Australia [Holman et al. 1987]. However, no statistically significant relationships independent of smoking were found between exposure and chronic bronchitis or bronchitic symptoms in cross-sectional studies of molybdenum miners [Kreiss et al. 1989b], uranium miners [Samet et al. 1984], taconite miners [Clark et al. 1980], Indian agate grinders and chippers [Rastogi et al. 1991], and a population-based study of South African gold miners [Sluis-Cremer et al. 1967] (Table 16).

Wiles and Hnizdo [1991] studied the relationship between mortality, airflow obstruction, and mucus hypersecretion in 2,065 South African gold miners. They found that after standardization for airways obstruction, mucus hypersecretion was not related to mortality from COPD (54 deaths). However, mucus hypersecretion remained significantly related to mortality from ischemic heart disease and all causes of death, even after adjustment for years of cigarette smoking and particle-years of exposure to gold mine dust [Wiles and Hnizdo 1991].

‡Cumulative exposure, duration of exposure, or intensity of exposure.

A mortality study of workers in dusty trades reported a statistically significant number of deaths from bronchitis when compared with mortality rates for other white males in the United States (P<0.05; 6 deaths observed; 0.8 deaths expected) [Amandus et al. 1991].

The discrepancies among the cross-sectional studies of bronchitis in quartz-exposed populations may be attributable to the presence or absence of concurrent exposures among the cohorts that have been studied [Kreiss et al. 1989b]. Particle size is another factor that may have affected the results. The dust in one work environment may have had a higher proportion of particles that were not of respirable size§ compared with dust in another work environment. Larger-sized dust particles may be responsible for large-airways diseases such as chronic bronchitis, whereas respirable dust particles are responsible for lung parenchymal diseases such as silicosis [Morgan 1978]. In addition to physical size, the shape and density of inorganic dust particles also influence where they are deposited in the airways and whether they can be cleared from the airways [Becklake 1985].

§Respirable particles have aerodynamic diameters less than approximately
µ10m.

3.5.4 Abnormalities in Pulmonary Function Tests

3.5.4.1 Definition

Pulmonary function tests measure lung volumes (e.g., vital capacity [VC]), air flow (e.g., expiratory volume in 1 second [FEV₁]), blood gas exchange, and other aspects of lung function [Rosenstock 1994]. Spirometric pulmonary function tests routinely performed are forced vital capacity (FVC), FEV₁, and VC [Parkes 1982]. Lung function tests alone cannot diagnose any particular disease [Parkes 1982]; however, they are an important part ofthe clinical evaluation of workers with occupational lung diseases. Nonoccupational factors (e.g., the subjects age, height, racial group, and smoking habit) as well as the quality and interpretation of the spirometric testing can influence pulmonary function test results [Parkes 1982; Rosenstock 1994; Crapo 1994]. In general, an FEV₁ loss of about 20 to 30 ml/year in nonsmokers or >60 ml/year in smokers [Crapo 1994] may suggest a decline greater than expected. Wagner [1994] suggests further clinical evaluation of workers with a 15% decrease from the baseline percentage of predicted value for FEV₁ or FVC (e.g., from 105% to 90% of the predicted FEV₁).

Loss of FEV₁ has been associated with an increased risk of death from various diseases, including COPD [Crapo 1994; Tockman and Comstock 1989; Anthonisen et al. 1986; Foxman etal. 1986]. Although pulmonary function tests can define and measure respiratory impairment, they are not a diagnostic tool for silicosis or a measure of silica exposure [Wagner 1997], because no single pattern of pulmonary function abnormality is associated with silica exposure or silicosis [Wagner 1997; Weill et al. 1994; ATS 1997].

3.5.4.2 Epidemiologic Studies Quantitative Estimates of Dust-Related Loss of Lung Function

Most epidemiologic studies of pulmonary function and occupational exposure to respirable crystalline silica are cross-sectional studies that do not provide quantitative modeling of cumulative dust exposure. They report occupationally related annual declines in ventilatory function in workers with and without silicosis (i.e., gold and other hard-rock miners, iron ore miners, coal miners, talc miners, slate workers, and kaolin workers). Details of these studies are reported elsewhere [ATS 1997; Becklake 1985, 1992; Eisen et al. 1995; NIOSH 1995a; EPA 1996; Graham et al. 1994].

Thirteen studies with quantitative dust exposure data for four silica exposed cohorts found statistically significant associations between loss of lung function (i.e., FEV₁, FVC) and cumulative respirable dust exposure in coal miners and South African gold miners [Oxman et al. 1993]. The study of gold miners [Hnizdo 1992] estimated that a 50-year old, white South African gold miner (nonsmoker) who was exposed to gold mine dust (containing 0.09 mg/m³ of crystalline silica) at an average respirable concentration of 0.3 mg/m³ for 24 years would lose 236 ml of FEV₁ (95% CI= 134337). This loss is equivalent to about half of the estimated loss of FEV₁ in a typical U. S. male (nonminer) who smoked one pack of cigarettes per day for 30 years (i.e., 552 ml [95% CI=461644]) [Dockery et al. 1988; Hnizdo 1992]. The combined effects of respirable dust exposure and smoking on the loss of FEV₁ were additive [Hnizdo 1992].

Epidemiologic studies of Vermont granite workers provided quantitative predictions of FEV₁ loss based on cumulative past exposure to granite dust. As shown in Table 17, the predicted FEV₁ loss for Vermont granite workers is 3 to 4 ml per mg/m³ Ayear for cumulative exposure to granite dust and 2.9 ml per mg/m³Ayear for cumulative exposure to quartz dust. This estimate represents a loss of about 6.5 ml of FEV₁ for a working lifetime (i.e., 45 years) of exposure to crystalline silica at the current NIOSH REL of 0.05 mg/m³. However, the findings of Theriault et al. [1974b] were based on measurements that may have been inaccurate. In 1979, Graham etal. [1981] administered pulmonary function testing to about 73% (n=712) of the workers tested in 1974 and found small annual increases in FEV₁. These researchers concluded that technical deficiencies in the previous studies led to exaggerated and erroneous estimates of loss. The significance of predicted losses can be compared with the annual estimated FEV₁ decline for a nonminer who smokes one pack of cigarettes per day (10 ml/year) [Xu et al. 1992] or with the approximate annual FEV₁ decrease in men over age 25 (25 to 30 ml/year) [Burrows 1986].

A cross-sectional study of 389 male residents of a U.S. hardrock mining community also predicted FEV₁ loss [Kreiss et al. 1989b]. Multiple regression analyses found a significant difference (P#0.05) in the mean FEV₁ for nonsmokers with dust exposure (96% of predicted FEV₁) compared with that of nonsmokers without occupational dust exposure (101% of predicted FEV₁) [Kreiss et al. 1989b].

3.5.5 Emphysema

3.5.5.1 Definition

Emphysema is the abnormal enlargement of the air spaces distal to the terminal bronchiole with destructive changes in the alveolar walls [ATS 1987]. Obvious fibrosis is not present [ATS 1987, 1995; Barnhart 1994; Becklake 1992], although small emphysematous spaces are frequently seen radiographically around the edges of large silicotic masses [Weill et al. 1994]. The diagnosis of emphysema is defined by pathologic criteria, and more recently by the presence of avascular spaces on computed tomographic (CT) scans of the lung [Barnhart 1994; Hayhurst et al. 1984]. Clinical signs include hyperinflation on chest radiographs, increased total lung capacity, reduced FEV₁, reduced diffusing capacity for carbon monoxide (DLCO) [Barnhart 1994], and weight loss [Stulbarg and Zimmerman 1996]. Emphysema is caused mainly by destruction of the lung parenchyma from excess proteolytic enzymes. One cause of excess proteolytic enzymes and the premature development of emphysema is the rare homozygous deficiency of the protein "1 antitrypsin [Laurell and Eriksson 1963; Stulbarg and Zimmerman 1996]. Excess proteolytic enzymes can also occur when there is excessive recruitment of polymorphonuclear leukocytes (e.g., from damage caused by cigarette smoke) [Stulbarg and Zimmerman 1996].

Emphysema is classified microscopically by type based on the distribution of enlarged airspaces and destruction. The main types of emphysema include centriacinar, focal, centrilobular, panacinar, distal acinar, and irregular (scar) [Barnhart 1994; Parkes 1994]. Focal and centrilobular emphysema are the types frequently associated with environmental and occupational exposures. Focal emphysema is associated with exposure to coal dust, and centrilobular emphysema is commonly found in the upper lobes of the lungs of cigarette smokers and others exposed to chronic irritants [Barnhart 1994]. However, findings from a study of postmortem lung examinations showed that panacinar or centriacinar were the predominant types of emphysema found in the lungs of white South African gold miners [Hnizdo et al. 1991].

3.5.5.2 Epidemiologic Studies

Studies of emphysema in silica-exposed workers (excluding coal miners) show conflicting results: it is not clear whether silica exposure is associated with emphysema in all exposed workers or mainly in silica exposed workers who smoke. In these studies, researchers have investigated cohorts of South African gold miners, usually by combining historical data about occupational exposures and smoking with postmortem examination of the lungs. (Attending physicians in South Africa who know or suspect that their deceased patient was a miner are legally required to remove the cardiorespiratory organs and send them to the Medical Bureau for Occupational Diseases if permission is granted by the next-of-kin [Goldstein and Webster 1976]).

Of the five studies presented in Table 18, one found that a significant relationship (P<0.05) independent of smoking and silicosis existed between gold mine dust exposure** and emphysema [Becklake et al. 1987]. Two studies found no relationship between emphysema and years of mining [Chatgidakis 1963; Cowie et al. 1993]. A study of emphysema type in 1,553 miners with autopsy examinations found that centriacinar emphysema was more common in smokers, whereas panacinar emphysema was more common in nonsmokers; exposure to gold mine dust was related to both types. A miner who had worked 20 years in high-dust occupations was 3.5 times more likely (95% CI= 1.76.6) to have emphysema (i.e., an emphysema score $30%) at autopsy than a miner who did not have a dusty occupation. However, the authors stated that this result was likely to be true of smoking miners only because there were only four nonsmokers with an emphysema score between 30% and 40% [Hnizdo et al. 1991]. Later, a study of 242 miners who were lifelong nonsmokers found that the severity of emphysema at autopsy was not related to most recent lung function measurements or to years of gold mining, cumulative dust exposure, or parenchymal silicosis after adjustment for age at death [Hnizdo et al. 1994]. All of the studies but two [Becklake et al. 1987; Hnizdo et al. 1994] found that the presence of emphysema was significantly associated with silicosis.

3.5.6 Nonmalignant Respiratory Disease (NMRD) Mortality

Epidemiologic studies of silica-exposed workers [Checkoway et al. 1993, 1997; Chen et al. 1992; Cherry et al. 1998; Brown et al. 1986; Costello and Graham 1988; Costello et al. 1995;

**The number of shifts worked in mining occupations with high dust exposure.

Costello 1983; Steenland and Brown 1995b; Steenland and Beaumont 1986; Thomas and Stewart 1987; Thomas 1990] and silicotics [Goldsmith et al. 1995; Brown et al. 1997; Rosenman et al. 1995] found significant increases in mortality from NMRD, a broad category that can include silicosis and other pneumoconioses, chronic bronchitis, emphysema, asthma, and other related respiratory conditions.

The studies of U.S. gold miners [Steenland and Brown 1995b], U.S. diatomaceous earth workers [Checkoway et al. 1993, 1997], silicotic men in Sweden and Denmark [Brown et al. 1997] and parts of the United States [Rosen-man et al. 1995], and U.S. pottery workers [Thomas and Stewart 1987] reported mortality ratios (SMRs or PMRs) for some categories of NMRD. However, the other studies either did not report SMRs for categories of NMRD or did not separate silicosis deaths from other categories of NMRD, thus limiting any conclusion about the association of silica exposure with death from a specific COPD based on death certificate data.

Some studies have reported exposure-response trends for NMRD and silica exposure. The study of diatomaceous earth workers found a statistically significant exposure-response trend for cumulative exposure to respirable crystalline silica and NMRD mortality after adjustment for the effects of age, calendar year, duration of followup, and ethnicity (rate ratio=5.35 in the highest exposure stratum [$5.0 mg/m³@year]; 95% CI=2.2312.80; 15-year exposure lag) [Checkoway et al. 1997]. Other studies found exposure-response trends for NMRD mortality and duration of employment [Costello et al. 1995; Thomas and Stewart 1987], years since first exposure [Thomas and Stewart 1987], or qualitative categories of silica exposure (none, low, and high) [Thomas and Stewart 1987].

3.6 Autoimmune and Chronic Renal Diseases

In this century, many published case reports have described various autoimmune disorders in workers or patients who were occupationally exposed to crystalline silica [Bramwell 1914; Erasmus 1957; Jones et al. 1976; Mehlhorn 1984; Mehlhorn et al. 1990a; de Bandt et al. 1991; Yanez Diaz et al. 1992; Pelmear et al. 1992; Caux et al. 1991; Cointrel et al. 1997; Yamamoto et al. 1994; Guseva 1991; Ebihara 1982; Agarwal et al. 1987; Koeger et al. 1991, 1992, 1995; Anandan et al. 1995; Sanchez Roman et al. 1993; Aoki et al. 1988; Fukata et al. 1983, 1987; Muramatsu et al. 1989; Masuda 1981; Tokumaru et al. 1990; Perez Perez et al. 1986; Bernardini and Iannaccone 1982; Siebels et al. 1995; Suratt et al. 1977; Meyniel et al. 1981; Hatron et al. 1982; Masson et al. 1997; zoran et al. 1997; Haustein 1998; Cledes et al. 1982; Mehlhorn and Gerlach 1990]. The most frequently reported autoimmune diseases were sclero-derma, systemic lupus erythematosus (lupus), rheumatoid arthritis, autoimmune hemolytic anemia [Muramatsu et al. 1989], and derma-tomyositis or dermatopolymyositis [Robbins 1974; Koeger et al. 1991]. Case reports have also described health effects such as the following that may be related to the immunologic abnormalities in patients with silicosis: chronic renal disease [Saita and Zavaglia 1951; Bolton et al. 1981; Giles et al. 1978; Pouthier et al. 1991; Neyer et al. 1994; Dracon et al. 1990; Sherson and Jorgensen 1989; Rispal et al. 1991; Osorio et al. 1987; Bonnin et al. 1987; Arnalich et al. 1989; Wilke et al. 1996; Banks et al. 1983; Hauglustaine et al. 1980; Slavin et al. 1985], ataxic sensory neuropathy [Toku-maru et al. 1990], chronic thyroiditis [Masuda 1981], hyperthyroidism (Graves disease) [Koeger etal. 1996], monoclonal gammopathy [Fukata et al. 1983, 1987; Aoki et al. 1988], and poly-arteritis nodosa [Arnalich et al. 1989].

In addition to these case reports, 13 post-1985 epidemiologic studies reported statistically significant numbers of excess cases or deaths from known autoimmune diseases or immunologic disorders (scleroderma, systemic lupus erythematosus, rheumatoid arthritis, and sarcoidosis), chronic renal disease, and subclinical renal changes (Table 19). Epidemiologic studies found statistically significant associations between occupational exposure to crystalline silica dust and several renal diseases or effects, including end-stage renal disease morbidity [Steenland et al. 1990], morbidity from end-stage renal disease caused by glomerulonephritis [Calvert et al. 1997], chronic renal disease mortality [Steenland and Brown 1995b], Wegeners granulomatosis (systemic vasculitis often accompanied by glomerulonephritis) [Nuyts et al. 1995], and subclinical renal changes [Hotz etal. 1995; Boujemaa et al. 1994; Ng et al. 1992a, 1993].

The pathogenesis of glomerulonephritis and other renal effects in silica exposed workers is not clear. Some case reports provide evidence of an immunologic injury by immune complex formation, and other reports point to a direct toxic effect of silica [Calvert et al. 1997; Calvert and Steenland 1997; Kallenberg 1995; Wilke et al. 1996; Wilke 1997]. The immunologic aspects of renal disease are reviewed in Ambrus and Sridhar [1997].

The cellular mechanism that leads from silica exposure to autoimmune diseases is not known [Otsuki et al. 1998]. One theory is that when respirable silica particles are encapsulated by macrophages, fibrogenic proteins and growth factors are generated, and ultimately the immune system is activated [Haustein and Anderegg 1998; Ziegler and Haustein 1992; Haustein et al. 1992]. Immune activation by respirable crystalline silica may be linked to scleroderma, rheumatoid arthritis, polyarthritis, mixed connective tissue disease, systemic lupus erythematosus, Sjgrens syndrome, polymyositis, and fibrositis [Ziegler and Haustein 1992; Haustein et al. 1990; Otsuki et al. 1998]. A possible mechanism for development of scleroderma is a direct local effect of nonrespirable quartz particles that have penetrated the skin of workers [Green and Vallyathan 1996], as observed in skin samples from deceased scleroderma patients [Mehl-horn et al. 1990b].

In addition to the studies summarized in Table 19, there may be other epidemiologic data sets that have not been analyzed by methods that would detect a possible association between occupational exposure to crystalline silica and autoimmune diseases [Steenland and Goldsmith 1995]. Further clinical and immunologic studies are needed to characterize the relationship between occupational exposure to crystalline silica and autoimmune diseases.

3.7 Other Health Effects

Extrapulmonary deposits of silica have been reported. A review of the literature [Slavin et al. 1985] indicates that silica particles may be transported from the lungs and tracheobronchial lymph nodes to the spleen, liver, kidneys [Osorio et al. 1987], bone marrow, and extra- thoracic lymph nodes as a result of

1. formation of silicotic lesions in pulmonary veins,
   
   
2. erosion of silicotic hilar nodules into pulmonary veins, and
   
   
3. rupture of silicotic nodules into the lymphatic system.

Roperto et al. [1995] reported two cases of extrapulmonary silicosis in two water buffaloes that lived on a farm near a quartz quarry. Silicotic lesions were observed in the mesenteric lymph nodes, tonsils, and spleen. In humans with occupational exposure to silica, peritoneal silicosis has been misdiagnosed as pancreatic carcinoma [Tschopp et al. 1992] or abdominal malignancy [Miranda et al. 1996].

Intravenous injections of silica into the tail veins of rats have resulted in large liver granulomas and hepatic silicosis [Kanta et al. 1986]. In workers exposed to crystalline silica, hepatic changes [Liu et al. 1991], hepatic or hepatosplenic silicosis [Clementsen et al. 1986; Oswald et al. 1995], and hepatocellular carcinoma [Clementsen et al. 1986] have been identified. Two studies reported a significantly higher proportion (P<0.05) of symptomatic hepatic porphyria (a chronic metabolic disease) in silica exposed workers compared with control groups having no history of occupational silica exposure [Okrouhllik and Hyke 1983; Zoubek and Kordac 1986]. However, the effect of silica on porphyrin synthesis and metabolism is not clear. In one study, alcohol consumption (quantity not specified) may have been a confounder [Okrouhllik and Hyke 1983].

Mowry et al. [1991] reported a case of a cutaneous silica granuloma in a 57-year-old stonemason. Silica granulomas are firm, nontender dermal or subcutaneous nodules that usually appear at least several years (mean=10 years) after the exposure to silica. They may appear as a result of occupational exposure or trauma [Kuchemann and Holm 1979; Murphy et al. 1997] and are usually treated by excision. The mechanism that causes the silica crystals in the tissue to form a granuloma is unknown.

Cor pulmonale (enlargement of the right ventricle of the heart because of structural or functional abnormalities of the lungs) may occur as a complication of silicosis [Green and Vallyathan 1996] and other pneumoconioses [Kusiak et al. 1993a]. This condition is usually preceded by pulmonary arterial hypertension. An epidemiologic case-control study of 732 white South African autopsied gold miners reported a statistically significant association (P<0.05) of cor pulmonale with extensive and slight silicosis [Murray et al. 1993].

Pulmonary alveolar proteinosis is a rare respiratory disease identified by an accumulation of phospholipid material in the alveoli [McCunney and Godefroi 1989]. Cases of this disease were identified in a U.S. cement truck driver [McCunney and Godefroi 1989], a U.S. sandblaster [Abraham and McEuen 1986], and a French ceramics worker [Roeslin et al. 1980]. Each worker had been potentially exposed to crystalline silica.

Skin absorption of crystalline and amorphous silica particles from soil, and subsequent obstructive lymphopathies related to the fibrogenic effects of the particles may be related to the development of nonfilarial tropical elephantiasis (podoconiosis) in the lower legs of residents of East Africa and certain volcanic areas [Frommel et al. 1993; Fyfe and Price 1985; Price and Henderson 1981].

Silica dust exposure may be associated with abrasion-related deterioration of dental health. Petersen and Henmar [1988] reported a 100% prevalence of dental abrasion in a group of 33 Danish granite workers. The authors recommended that dust concentrations be reduced, that workers wear face guards, and that dental abrasion from occupational dust exposure be considered an occupational disease.