Health Effects of Occupational Exposure
to Respirable Crystalline Silica

3.1 Epidemiologic Considerations in Occupational Respiratory Disease Studies

3.1.1 Study Designs

Epidemiology is the study of patterns of disease occurrence in human populations and the factors that influence those patterns [Lilienfeld and Stolley 1994]. Epidemiology is the primary science used to study silica related diseases in workers. Most epidemiologic studies of silica-exposed workers discussed in this review are cross-sectional studies (i.e., prevalence studies) or retrospective (i.e., historical) cohort studies. Cross-sectional studies measure symptom or disease occurrence in a selected population at one point in time. An example of a cross-sectional study design would be the spirometric testing of lung function in a group of granite shed workers during an annual health survey and comparison with respiratory function in nongranite workers. Cross-sectional studies have two disadvantages:

• Usually only the “survivor” population is examined. Retired, former, or deceased workers are not included, possibly resulting in an underestimate of the disease prevalence.
  
  
• It may be impossible to determine whether exposure preceded the disease if both are measured at the same time.

Construction workers drilling holes in concrete pavement during highway repair. Photograph by Kenneth Linch, NIOSH

Many epidemiologic studies of silica-related diseases are retrospective cohort morbidity or mortality studies. In this approach, the illnesses, deaths, and exposures (surrogate or reconstructed) of an entire cohort (e.g., all workers ever employed in one foundry) are followed forward from a time in the past to a designated time in the future, and the number and causes of deaths that occur in that interval are assessed. Exposures for the followup period may be reconstructed from historical information or a surrogate measure such as duration of employment. The mortality of the cohort is then compared with the mortality of a standard population. For example, Steenland and Brown [1995b] used a retrospective study design to examine the mortality of a cohort of white male underground gold miners employed for at least 1 year between 1940 and 1965. The miners were followed from their first date of mining employment to their date of death or until the end of 1990, whichever came first. Their mortality was then compared with that of the U.S. population or the county where the mine was located. A disadvantage of silicosis mortality studies that use death certificate data is that silicosis cases could be under-ascertained even when contributing causes of death are included, as suggested by a study of silicosis mortality surveillance in the United States [Bang et al. 1995].

3.1.2 Sources of Bias

Three main (but not mutually exclusive) types of bias may affect the results of epidemiologic studies of silica-exposed workers—selection bias, information bias, and confounding [Checkoway 1995]:

Selection bias originates from the method of choosing study subjects. This type of bias is a common criticism of lung cancer studies of compensated silicotics because silicotic workers who sought compensation for their disease may differ from all silicotics in symptoms, radiographic changes, social and psychological factors, and industry [Weill and McDonald 1996; McDonald 1995]. However, Goldsmith [1998] reviewed this question and concluded that lung cancer risk estimates were not higher in compensated silicotics when compared with those of silicotics ascertained from other clinical sources (i.e., hospital or registry data).

Information bias involves misclassification of study subjects by disease or exposure status [Checkoway et al. 1989]. An example of disease (silicosis) misclassification occurred in a study of North Carolina dusty trades workers [Amandus et al. 1991; Rice et al. 1986]: a re-evaluation of the chest X-rays found that 104 of the 370 cases categorized as silicosis were actually International Labour Organization (ILO) category 0 (nonsilicotic) [Amandus et al. 1992]. Sources of exposure assessment errors include instrument error, incorrect imputation of exposure when data are missing, and data extrapolation errors [Checkoway 1995]. Misclassification of exposure may occur in retrospective cohort studies of silicosis when quantitative dust exposure measurements are mathematically converted from particle counts to gravimetric respirable silica equivalents.

Confounding variables are factors that are related to exposure and are also independent risk factors for the disease under study [Checkoway 1995]. Most studies of silica-related diseases controlled for confounding factors such as age and race by study design or data analysis. Confounding from cigarette smoking is an important concern in studies of lung cancer, bronchitis, asthma, emphysema, chronic obstructive pulmonary disease (COPD), and lung function. Confounding of an exposure-disease relationship by cigarette smoking is less likely when an internal comparison group is used e.g., when both groups are from the same plant [Siemiatycki et al. 1988]. (Some studies in this review used external comparison populations.) Most of the lung cancer studies among underground miners did not control for the effects of other carcinogens that may have been present, such as arsenic, radon progeny, and diesel exhaust (see Section 3.4.1).

The effects of bias discussed here can be minimized by applying epidemiologic methods. Description of appropriate methodology is available in epidemiology textbooks.

3.2 Silicosis

3.2.1 Definition

Silicosis most commonly occurs as a diffuse nodular pulmonary fibrosis. This lung disease (which is sometimes asymptomatic [NIOSH 1996b]) is caused by the inhalation and deposition of respirable crystalline silica particles (i.e., particles <10 µm in diameter) [Ziskind et al. 1976; IARC 1987]. According to a report from the U.S. Surgeon General [DHHS 1985], cigarette smoking has no significant causal role in the etiology of silicosis. Probably the most important factor in the development of silicosis is the “dose” of respirable silica-containing dust in the workplace setting that is, the product of the concentration of dust containing respirable silica in workplace air and the percentage of respirable silica in the total dust. Other important factors are

1. the particle size,
   
   
2. the crystalline or noncrystalline nature of the silica,
   
   
3. the duration of the dust exposure, and
   
   
4. the varying time period from first exposure to diagnosis (from several months to more than 30 years) [Banks 1996; Kreiss and Zhen 1996; Hnizdo and Sluis-Cremer 1993; Hnizdo et al. 1993; Steenland and Brown 1995a; ATS 1997].

Experimental evidence supporting the influence of these factors has recently been reviewed [Mossman and Churg 1998; Heppleston 1994]. Many in vitro studies have been conducted to investigate the surface characteristics of crystalline silica particles and their influence on fibrogenic activity [Bolsaitis and Wallace 1996; Fubini 1997, 1998; Castranova et al. 1996; Donaldson and Borm 1998; Erdogdu and Hasirci 1998]. These researchers found that a number of features may be related to silica cytotoxicity. Further research is needed to associate the surface characteristics with occupational exposure situations and health effects [Donaldson and Borm 1998]. Such exposure situations may include work processes that produce freshly fractured silica surfaces [Bolsaitis and Wallace 1996; Vallyathan et al. 1995] or that involve quartz contaminated with trace elements such as iron [Castranova et al. 1997].

A worker may develop one of three types of silicosis, depending on the airborne concentration of respirable crystalline silica:

1. chronic silicosis, which usually occurs after 10 or more years of exposure at relatively low concentrations;
   
   
2. accelerated silicosis, which develops 5 to 10 years after the first exposure; or
   
   
3. acute silicosis, which develops after exposure to high concentrations of respirable crystalline silica and results in symptoms within a period ranging from a few weeks to 5 years after the initial exposure [NIOSH 1996b; Parker and Wagner 1998; Ziskind et al. 1976; Peters 1986].

The symptoms of accelerated silicosis are similar to those of chronic silicosis, but clinical and radiographic progression is rapid. Also, fibrosis may be irregular and more diffuse [Banks 1996; Seaton 1995; Silicosis and Silicate Disease Committee 1988] or not apparent on the chest radiograph [Abraham and Weisenfeld 1997]. Acute silicosis is typically associated with a history of high exposures from tasks that produce small particles of airborne dust with a high silica content, such as sandblasting, rock drilling, or quartz milling [Davis 1996]. The pathologic characteristics of acute silicosis (sometimes referred to as silicoproteinosis) resemble those of alveolar proteinosis [Wagner 1994; Davis 1996]. Pulmonary fibrosis may not be present in acute silicosis [NIOSH 1996b].

Epidemiologic studies of gold miners in South Africa, granite quarry workers in Hong Kong, metal miners in Colorado, and coal miners in Scotland have shown that chronic silicosis may develop or progress even after occupational exposure to silica has been discontinued [Hessel et al. 1988; Hnizdo and Sluis-Cremer 1993; Hnizdo and Murray 1998; Ng et al. 1987; Kreiss and Zhen 1996; Miller et al. 1998]. Therefore, removing a worker from exposure after diagnosis does not guarantee that silicosis or silica-related disease will stop progressing or that an impaired workers condition will stabilize [Parker and Wagner 1998; Weber and Banks 1994; Wagner 1994].

3.2.2 Epidemiologic Exposure-Response Models of Silicosis

This section reviews published epidemiologic studies that provide evidence of an exposure-response relationship for crystalline silica and silicosis using cumulative exposure data. Exposure-response models based on cumulative exposure data can predict silicosis risk for a particular silica dust exposure over a period of time. Epidemiologic studies that provided evidence of an exposure-response relationship for silica and silicosis on the basis of other kinds of exposure data (e.g., duration of exposure) have been reviewed elsewhere [EPA 1996; Davis 1996; Hughes 1995; Rice and Stayner 1995; Seaton 1995; Steenland and Brown 1995a; Goldsmith 1994a; WHO 1986].

Table 12 summarizes the published studies that predict the incidence or prevalence of radiographic silicosis based on models of cumulative exposure to respirable crystalline silica. Table 13 presents details about the cohorts, quartz content of the dust, followup periods, and limitations of each study. All of the studies predicted the occurrence of at least one case of radiographic silicosis per 100 workers at cumulative exposures approximately equal to the OSHA and MSHA PELs and the NIOSH REL over a 40- or 45-year working lifetime (see appendix for the PELs and REL). Three studies predicted prevalences of 47% to 95% at the OSHA PEL. Each study followed a cohort of miners for at least three decades from first employment in the industry [Kreiss and Zhen 1996; Hnizdo and Sluis-Cremer 1993; Steenland and Brown 1995a]. Studies of foundry workers [Rosenman et al. 1996], hardrock miners [Muir et al. 1989a,b; Muir 1991], and workers in the diatomaceous earth industry [Hughes et al. 1998] followed workers for less than 30 years (mean) and predicted prevalences of 1% to 3%. The studies presented in Table 12 predicted that approximately 1 to 7 silicosis cases per 100 workers would occur at respirable quartz concentrations of 0.025 mg/m³—half the NIOSH REL of 0.05 mg/m³—with the contingencies and exceptions noted in Table 12. However, that concentration cannot be measured accurately at this time for the reasons given in Section 2.4.

Table 12 does not include a cohort study of 1,416 coal miners exposed to coal dust with quartz concentrations ranging from 0.4% to 29.4% of respirable dust [Miller et al. 1998]. This study predicted pneumoconiosis risks for 47 men with a “profusion of median small opacities” of ILO category >2/1 (i.e., 2/1+), a higher category of radiographic abnormality than reported in the studies listed in Tables 12 and 13. Logistic regression models predicted that the risk of small opacities of 2/1+ at the time of followup examination would be about 5% for miners exposed to a mean respirable quartz concentration of 0.1 mg/m³ and about 2% for miners exposed to a mean respirable quartz concentration of 0.05 mg/m³ for about 15 years [Miller et al. 1998]. The predicted risks increased with cumulative exposure to respirable quartz dust.

A currently unpublished study of 600 retired Vermont granite workers found nodular opacities consistent with silicosis (degrees of profusion not reported in abstract) in 4.7% of 360 radiographs read by three readers [Graham et al. 1998]. The average duration of employment for these workers was 31 years, and the average time from first exposure to radiographic examination was 39 years. Most workers in the cohort were first employed after 1940, when average quartz dust concentrations were below the current OSHA PEL [Graham et al. 1991; Ashe and Bergstrom 1964].

Although the variability in prevalence estimates (i.e., 1% to 90%) cannot be solely attributed to differences in followup periods, chronic silicosis is a progressive disease, and its development after a long latency period and after workers leave employment must be accounted for in epidemiologic studies. A study of autopsied gold miners in South Africa also supports the need for examining workers after a long latency period and after they leave employment [Hnizdo et al. 1993]. Radiologic findings for profusion of rounded opacities (ILO category >1/1) were compared with pathological findings for silicosis in 326 miners with an average of 2.7 years between the radiologic and pathologic examinations. Silicosis was not diagnosed radiographically for at least 61% of the miners with slight to marked silicosis at autopsy. The probability of a false negative reading increased with years of mining and average concentration of respirable dust [Hnizdo et al. 1993]. Experimental studies of rats also reported a lack of complete agreement between histopathologic indicators of silica dust exposure and radiographic readings [Drew and Kutzman 1984a,b].

In addition, improved exposure assessment methods and data analyses that account for variations and deficiencies in exposure data would improve the risk estimates for silica-exposed workers [Agius et al. 1992; Checkoway 1995]. Although epidemiologic studies that used cumulative exposure estimates represent the best available source of information for characterizing the dose-response relationship in occupational cohorts, peak exposures may predict silicosis risk better than cumulative exposures [Checkoway and Rice 1992]. However, data on peak exposures are rarely available, and data supporting this hypothesis are limited.

3.3 TB and Other Infections

3.3.1 Definition

As silicosis progresses, it may be complicated by severe mycobacterial or fungal infections [NIOSH 1996b; Ziskind et al. 1976; Parkes 1982; Parker 1994]. The most common of these infections, TB, occurs when the macrophages are overwhelmed by silica dust and are unable to kill the infectious organism Mycobacterium tuberculosis [Parker 1994; Ng and Chan 1991; NIOSH 1992a,b; Allison and Hart 1968]. About half of the mycobacterial infections that occur in workers with exposure to silica are caused by M. tuberculosis, and the other half are caused by the nontuberculous mycobacteria (NTM) Mycobacterium kansasii and Mycobacterium avium-intracellulare [Owens et al. 1988; NIOSH 1996b]. Infections in workers with silicosis may also be caused by Nocardia asteroides and Cryptococcus [Ziskind et al. 1976; NIOSH 1996b; Parker 1994; Parker and Wagner 1998]. ATS [1997] recommends that the diagnostic investigation of a patient with silicosis and possible TB include consideration of NTM disease. The ATS also recommends that tuberculin tests be administered to persons with silicosis and to those without silicosis who have at least 25 years of occupational exposure to crystalline silica [ATS 1997].

3.3.2 Epidemiologic Studies

Recent surveillance data indicate that TB rates in the United States are 5 to 10 times higher among racial and ethnic minorities (after adjustment for the effects of age, sex, and country of birth) [Cantwell et al. 1998]. Cantwell et al. [1998] reported that the relative risk of TB increased as socioeconomic status (measured by six indicators) decreased, after adjustment for the effects of age (relative risks ranged from 2.6 to 5.6 in the lowest versus highest quartiles). The number of TB cases among foreign-born persons in the United States increased by 56% during the period 1986 to 1997 [CDC 1998c].

The association between TB and silicosis has been firmly established by the results of epidemiologic studies conducted during this century [Balmes 1990]. This association was supported by a survey of TB deaths among silicotics in the United States for the period 1979 to 1991 [Althouse et al. 1995] and by the results of four recent epidemiologic studies [Goldsmith et al. 1995; Cowie 1994; Sherson and Lander 1990; Kleinschmidt and Churchyard 1997]. Black South African gold miners [Cowie 1994] and Danish foundry workers [Sherson and Lander 1990] with chronic silicosis had threefold and tenfold incidences of TB, respectively, compared with nonsilicotic, non-silica-exposed workers of similar age and race. Goldsmith et al. [1995] compared the mortality of 590 California silicosis claimants with that of U.S. males and found that the TB mortality of the claimants was 50 times that of all U.S. males (standardized mortality ratio [SMR]=56.35; 45 deaths observed, 0.8 expected; 95% confidence interval [CI]=41.10—75.40). A retrospective study of TB among 4,976 miners from the Freegold mines in South Africa reported that the incidence rate ratio for miners with silicosis (ILO category >1/1) was 1.54 (95% CI=1.00—2.37) compared with miners without silicosis (after adjusting for the effects of age, followup period, cumulative service, and occupation) [Kleinschmidt and Churchyard 1997]. The incidence of TB for the oldest age group was 21 times that of the youngest group (incidence rate ratio=21.17; 95% CI=8.60—52.11); and for workers in occupations with high dust exposure (such as drilling), the incidence was twice that of surface and maintenance workers (adjusted incidence rate ratio=2.25; 95% CI=1.49—3.38) [Kleinschmidt and Churchyard 1997].

Some evidence indicates that workers who do not have silicosis but who have had long exposures to silica dust may be at increased risk of developing TB. Two epidemiologic studies reported that, compared with the general population, a threefold incidence of TB cases occurred among 5,424 nonsilicotic, silica-exposed Danish foundry workers employed 25 or more years [Sherson and Lander 1990], and nearly a tenfold incidence occurred among 335 nonsilicotic, black South African gold miners with a median underground employment of 26 years [Cowie 1994].

Westerholm etal. [1986] found 13 cases among 428 silicotic Swedish iron and steel workers and 1 case in a comparison group of 476 Swedish iron and steel workers with normal chest radiographs (level of statistical significance not reported). Both groups had been exposed to silica for at least 5 years.

A study of TB incidence in 2,255 white South African gold miners included 1,296 miners who had an autopsy [Hnizdo and Murray 1998, 1999]. The smoking-adjusted relative risk for TB in miners without silicotic nodules on autopsy examination (n=577) increased slightly with quartiles of cumulative dust exposure (relative risk=1.38 [95% CI=0.33—5.62] for the highest quartile of cumulative exposure). For miners without radiologically diagnosed silicosis (n=1,934), the smoking-adjusted relative risk increased to 4.01 (95% CI=2.04—7.88) in the highest quartile of cumulative dust exposure [Hnizdo and Murray 1998, 1999]. The authors defined radiologic silicosis as ILO category >1/1. TB was diagnosed, on the average, 7.6 years after the end of dust exposure and 6.8 years after the onset of radiological silicosisa result that supports the need for medical surveillance of workers after the end of exposure to silica dust [Hnizdo and Murray 1998]. Miners who developed TB before completing 10 years of underground employment were excluded because they were not allowed to continue working underground after diagnosis.

Corbett et al. [1999] conducted a recent case-control study of TB and pulmonary disease caused by NTM in South African gold miners. These researchers found that radiographic silicosis, focal radiological scarring, and human immunodeficiency virus (HIV) infection were significant risk factors for NTM disease and for TB. Past medical history of TB treatment (odds ratio [OR]=15.1; 95% CI=7.64—29.93) and current employment in a “dusty job” at the mines (OR=2.5; 95% CI=1.46—4.44) were significant risk factors for NTM. ORs for NTM and TB increased with years of employment (range of ORs was 1.0 to 9.4 for NTM and 1.0 to 4.1 for TB). The study included 206 NTM patients and 381 TB patients of known HIV status admitted to a South African hospital. Also included were 180 controls who were HIV-tested surgical or trauma patients admitted to the same hospital during the same period.

Two recent studies about silica exposure and TB used U.S. occupational mortality data to conduct a proportionate mortality study of persons with TB by occupation for 1979 through 1990 [CDC 1995; Chen et al. 1997]. Although the study design did not control for confounding, it identified six occupational groups with potential exposure to silica dust that had age adjusted proportionate mortality ratios (PMRs) for TB that were statistically significant (lower bound of the 95% CI>100) or greater than 200. Table 14 shows significant PMRs by race for construction occupations, mining machine operators, grinding and polishing machine operators, furnace and kiln operators, laborers, and mixing and blending machine operators [CDC 1995].

Chen et al. [1997] conducted a case-control study (8,740 cases; 83,338 controls) with U.S. National Occupational Mortality Surveillance (NOMS) data for 1983-1992. The study controlled for confounding from age, sex, race, socioeconomic status, potential exposure to active TB, and the presence of silicosis and other pneumoconioses. The potential for silica exposure was based on data from NOES [NIOSH 1988] and the National Occupational Health Survey of Mining (NOHSM) [NIOSH 1996c]. This potential was categorized as “high”, “intermediate”, or “low or no.” The study found that decedents with high potential for exposure to silica and no documentation of silicosis on the death certificate had a 30% greater odds of mortality from respiratory TB than decedents with no potential exposure to silica after adjustment by logistic regression for the possible confounders mentioned earlier (OR=1.3; 95% CI=1.14—1.48). The results also suggest an exposure-response relationship between silica exposure (in the absence of silicosis) and death from respiratory tuberculosis [Chen et al. 1997].