Health
Effects of Occupational Exposure
to
Respirable Crystalline Silica
The possible carcinogenicity of crystalline silica dust became a subject of considerable and intense debate in the scientific community in the 1980s, especially after
- publication of new information presented at a 1984 symposium in North Carolina [Goldsmith et al. 1986],
- epidemiologic studies by Westerholm [1980] and Finkelstein et al. [1982], and
- a literature review by Goldsmith et al. [1982] (see McDonald [1989, 1995] and Graham [1998]).
Many epidemiologic studies of cancer mortality and morbidity in silica-exposed occupational groups were published later, but the issue remained unresolved. In October 1996, an IARC expert working group reviewed the published experimental and epidemiologic studies of cancer in animals and workers exposed to respirable crystalline silica. The working group concluded that there is “sufficient evidence in humans for the carcinogenicity of inhaled crystalline silica in the form of quartz or cristobalite from occupational sources” [IARC 1997]. In June 1996, the directors of the ATS adopted an official statement of their Committee of the Scientific Assembly on Environmental and Occupational Health. This statement, prepared at the request of the American Lung Association Occupational Health Expert Advisory Group [ATS 1997], described the adverse health effects of exposure to crystalline silica, including lung cancer. The ATS found the following:
- The available data support the conclusion that silicosis produces increased risk for bronchogenic carcinoma.
- However, less information is available for lung cancer risk among silicotics who never smoked and workers who were exposed to silica but did not have silicosis.
- Whether silica exposure is associated with lung cancer in the absence of silicosis is less clear.
NIOSH concurs with the conclusions of the IARC working group and the ATS. These conclusions agree with NIOSH testimony to OSHA, in which NIOSH recommended that crystalline silica be considered a potentional occupational carcinogen [54 Fed. Reg. 2521 (1989)].
This section, like the IARC review, focuses on lung cancer and discusses the epidemiologic studies that were the least likely to have results affected by confounding and selection biases. In “mixed” environments such as ceramics, pottery, or brick manufacturing, where exposure may be to two or more polymorphs of crystalline silica, epidemiologic studies have usually not identified specific exposures to quartz or cristobalite. Therefore, excess lung cancers that occurred in these environments cannot be associated with exposure to a given polymorph but only with exposure to respirable crystalline silica. The epidemiologic studies of cancer have mainly investigated workers exposed to respirable crystalline silica in
- ore mining,
- quarrying and granite works,
- ceramics, pottery, glass, refractory brick, and diatomaceous earth industries, or
- foundries.
The other major study group was workers with silicosis, usually identified from national or local registries. Studies of workers and silicotics that were not discussed in this document because they failed to meet the least confounded criterion have been criticized for the following reasons [Checkoway 1995; McDonald 1995, 1996; Morgan and Reger 1995; Weill and McDonald 1996; Seaton 1995; Weill et al. 1994; Agius et al. 1992]:
- Inadequate, incomplete, or invalid exposure assessment
- Potential selection and confounding biases in the cohort studies of compensated silicotics
- Inadequate control of confounding from cigarette smoking and from concurrent workplace exposures (e.g., potential exposure to radon progeny, arsenic, or diesel exhaust in ore mines and potential exposure to polycyclic aromatic hydrocarbons in foundries)
- Inability to distinguish differences in fibrogenic and carcinogenic potencies of the various silica polymorphs
- Lack of evidence of an exposure-response relationship
3.4.2 Epidemiologic Studies of Lung Cancer
Following a comprehensive review of the large body of published epidemiologic studies, IARC [1997] found that the following studies provide the least confounded investigations of an association between occupational exposure to crystalline silica and lung cancer:
- U.S. gold miners [Steenland and Brown 1995b]
- Danish stone industry workers [Gunel et al. 1989]
- U.S. granite shed and quarry workers [Costello and Graham 1988]
- U.S. crushed stone industry workers [Costello et al. 1995]
- U.S. diatomaceous earth industry workers [Checkoway et al. 1993, 1996]
- Chinese refractory brick workers [Dong et al. 1995]
- Italian refractory brick workers [Merlo et al. 1991; Puntoni et al. 1988]
- U.K. pottery workers [McDonald et al. 1995,1997; Cherry et al. 1995, 1997; Burgess et al. 1997]
- Chinese pottery workers [McLaughlin et al. 1992]
- Cohorts of registered silicotics from North Carolina [Amandus et al. 1991, 1992] and Finland [Kurppa et al. 1986; Partanen et al. 1994]
Although a few of these studies did not find a statistically significant association between occupational exposure to crystalline silica and lung cancer (Table 15), most of the studies did. Study results are often not uniform when a large number of epidemiologic studies are reviewed and a variety of populations and work environments are studied [IARC 1997]. In addition, IARC noted that the carcinogenicity of quartz or cristobalite “may be dependent on inherent characteristics of the crystalline silica or on external factors affecting its biological activity or distribution of its polymorphs” [IARC 1997].
Some of the least confounded studies reported that lung cancer risk tended to increase with
- cumulative exposure to respirable silica [i.e., Checkoway et al. 1993, 1996],
- duration of exposure [i.e., Merlo et al. 1991; Partanen et al. 1994; Costello and Graham 1988; Costello et al. 1995; Dong et al. 1995],
- peak intensity of exposure [Burgess et al. 1997; Cherry et al. 1997; McDonald et al. 1997],
- the presence of radiographically defined silicosis [Amandus et al. 1992; Dong et al.1995], and
- length of followup time from date of silicosis diagnosis [Partanen et al. 1994] (see Table 15).
These observed associations, including the exposure-response associations, are unlikely to be explained by confounding or other biases. Thus overall, the epidemiologic studies support increased lung cancer risks from occupational exposure to inhaled crystalline silica (i.e., quartz and cristobalite) [IARC 1997].
3.4.2.1 Updated or New Studies Since the IARC Review
Two studies discussed in this section have recently been updated: Checkoway et al. [1997, 1999] updated their previous mortality studies of diatomaceous earth workers [Checkoway et al. 1993, 1996] by including deaths after 1987 and through 1994, and by analyzing lung cancer risk among workers with radiographic silicosis. Lung cancer mortality risk was highest in the highest category of cumulative exposure to respirable crystalline silica (rate ratio with no exposure lag period=2.11; 95% CI=1.07—4.1; rate ratio for 15-year exposure lag period=1.05; 95% CI=0.99—1.11). The rate ratios were adjusted for the effects of age, calendar year, duration of followup, and ethnicity. Among workers with radiological silicosis (ILO category >1/0 or large opacity; n=81), the lung cancer SMR was 1.57 (95% CI= 0.43—4.03) [Checkoway et al. 1999]. For workers without silicosis (ILO category <1/0), the SMR was 1.19 (95% CI=0.87—1.57). The SMRs were adjusted for age and calendar year and were based on the expected number of deaths for white U.S. males. For the nonsilicotic workers, a statistically significant, positive dose-response relationship (P=0.02) was observed between SMRs for lung cancer and category of cumulative respirable silica exposure. The SMRs ranged from 1.05 in the lowest exposure category (<0.5 mg/m3·year, 13 deaths, 95% CI=0.56—1.79) to 2.40 in the highest exposure category (>5.0 mg/m3·year; 12 deaths, 95% CI=1.24—4.20). For the 81 workers with radiographic silicosis, an SMR >1.0 was observed only in the highest exposure category (i.e., >5.0 mg/m3·year) (4 deaths observed; SMR=2.94; 95% CI=0.80—7.53). These results suggest that silicosis may not be a necessary condition for silica-related lung cancer. However, radiographic surveillance of this cohort did not extend beyond the dates of employment termination, and autopsies were not routinely conducted [Checkoway et al. 1999].
Cherry et al. [1998] finalized the preliminary results of a nested case control study of 52 lung cancer deaths in 5,115 pottery workers (see Burgess et al. [1997], Cherry et al. [1997], and McDonald et al. [1997] in Table 15). After adjustment for smoking and inclusion of a 20-, 10-, or 0 year lag period, mean respirable silica concentration (i.e., estimated daily 8-hr TWA airborne concentrations in µg/m3) was associated with lung cancer (P<0.008 for each lag period):
However, exposure duration and cumulative silica dust exposure were not significantly associated with lung cancer mortality, regardless of lag time [Cherry et al. 1998]. The presence of small, parenchymal radiographic opacities (ILO category >1/0) was not related to lung cancer mortality before adjustment for smoking (P=0.78) or after adjustment for smoking and mean silica concentration (P=0.68). The authors concluded “that crystalline silica may well be a human carcinogen” [Cherry et al. 1998].
Other studies published since the IARC review also investigated exposure-response associations for lung cancer and exposure to crystalline silica. Rafnsson and Gunnarsdóttir [1997] reported that the incidence of lung cancer cases among 1,346 diatomaceous earth workers in Iceland was not statistically significant for workers who had 9 years before start of followup and who were employed >5 years (standardized incidence ratio [SIR] based on 3 cases observed=2.70; 95% CI=0.56—7.90) or employed <5 years (SIR based on 2 cases observed=1.19; 95% CI=0.14—4.30).
de Klerk and Musk [1998] conducted a cohort study of 2,297 surface and underground gold miners in western Australia who participated in surveys of respiratory symptoms, smoking habits, and lung function in 1961, 1974, and 1975. Eighty-nine percent of the cohort was traced to the end of 1993 for trachea, bronchus, and lung cancer mortality and incidence of compensated silicosis (i.e., compensation awarded by the Pneumoconiosis Medical Board). A nested case-control analysis of the 138 lung cancer deaths found that lung cancer mortality was related to log total cumulative silica dust exposure after adjustment for smoking (cigarette, pipe, or cigar) and for the presence of bronchitis at survey (relative rate=1.31; 95% CI=1.01—1.70). However, the effect of cumulative silica dust exposure on lung cancer mortality was not significant after adjustment for smoking, bronchitis, and compensation for silicosis (relative rate=1.20; 95% CI=0.92—1.56). Other silica exposure variables (i.e., duration of underground or surface employment and intensity of underground or surface exposure) were not significantly related to lung cancer mortality (P>0.15) after adjustment for smoking and bronchitis. Cigarette smoking (relative rate=32.5; 95% CI=4.4—241.2 for >25 cigarettes smoked per day), incidence of a compensation award for silicosis after lung cancer diagnosis (relative rate=1.59; 95% CI=1.10—2.28), and presence of bronchitis at survey (relative rate=1.60; 95% CI=1.09—2.33) were significantly related to lung cancer mortality [de Klerk and Musk 1998]. The results of this study do not support a relationship between lung cancer and silica exposure in the absence of silicosis (i.e., a compensation award for silicosis after lung cancer diagnosis). However, controlling for silicosis compensation and bronchitis may have masked a silica effect because both are markers of silica exposure.
Hnizdo et al. [1997] conducted a nested case-control study of lung cancer deaths in a cohort of 2,260 white South African underground gold miners. (A lung cancer mortality cohort study had been conducted earlier [Hnizdo and Sluis-Cremer 1991]). The mineral content of the rock in the gold mines was mostly quartz (70%-90%), silicates (10%-30%), pyrite (1%-4%), and heavy minerals with grains of gold and uranium-bearing minerals (2%-4%). Seventy-eight miners who died from lung cancer (69 of the 78 had a necropsy) during 1970-1986 were matched by year of birth with 386 control subjects from the same cohort [Hnizdo et al. 1997]. Conditional logistic regression models were used to analyze the relationship of lung cancer mortality with cigarette smoking (pack-years), cumulative “dust” exposure (mg/m3·year), years of underground mining, incidence of radiographic silicosis (ILO category >1/1 diagnosed up to 3 years before death of a matched case), and uranium production or uranium grade of the ore in the gold mine. Radon progeny measurements in the gold mines were not available.
Lung cancer mortality was associated with cigarette smoking, cumulative dust exposure (lag time was 20 years from death), duration of underground mining (lag time was 20 years from death), and silicosis. The best-fitting model predicted relative risks of 2.45 (95% CI= 1.2—5.2) for silicosis and the following relative risks for various pack-years of smoking:
The authors stated that variables representing uranium mining were not significantly related to lung cancer mortality (modeling results for these variables were not presented) [Hnizdo et al. 1997]. The authors proposed three explanations for their results:
- Miners with high dust exposure who develop silicosis have increased lung cancer risk.
- High silica dust exposure concentrations are important in the pathogenesis of lung cancer, and silicosis is coincidental.
- High silica dust exposure concentrations are a surrogate measure of exposure to radon progeny [Hnizdo et al. 1997].
3.4.2.2 Lung Cancer Meta-Analyses
Meta-analysis and other systematic literature review methods are useful tools for summarizing exposure risk estimates from a large amount of information [Mulrow 1994]. Meta-analyses or summary reviews of epidemiologic studies of silicotics with lung cancer have been conducted by investigators in the United States [Steenland and Stayner 1997; Smith et al. 1995] and Japan [Tsuda et al. 1997]. IARC is performing a pooled analysis of epidemiologic data from several cohorts to investigate lung cancer risks in nonsilicotic workers.
Steenland and Stayner [1997] and IARC [1997] found that the majority of studies of silicotics reported statistically significant excess lung cancer risks across different countries, industries, and time periods while controlling for the effects of cigarette smoking [Steenland and Stayner 1997; IARC 1997]. Exposure-response gradients were also observed. The summary relative risk was 2.3 (95% CI=2.2—2.6) for 19 cohort and case-control studies of silicotics—excluding studies of miners and foundry workers because of potential exposure to other carcinogens, and omitting autopsy studies and proportionate mortality studies because of possible selection biases [Steenland and Stayner 1997]. Fifteen of the 19 studies directly or indirectly controlled for the effects of smoking. The summary relative risk of 16 cohort* and case-control studies of silica exposed workers was 1.3 (95% CI= 1.2—1.4)—a moderate and statistically significant relative risk estimate [Steenland and Stayner 1997]. Eight of the 16 studies controlled for the effects of smoking, either directly or indirectly.
*Cohort size ranged from 969 to 6,266 workers.
Another meta-analysis of 23 lung cancer studies of silicotics (including 14 of the studies analyzed by Steenland and Stayner [1997]) reported a pooled risk estimate of 2.2 (95% CI= 2.1—2.4) [Smith et al. 1995]. The statistically significant pooled risk estimates from both meta-analyses strongly support an association between silicosis and lung cancer. The increased risk of lung cancer for silicotics is also supported by the following [IARC 1997]:
- The magnitude of the risk estimates (i.e., most studies reported risks greater than 2.0 for silicotics after adjusting for the effects of cigarette smoking—compared with exposed nonsilicotics or the general population)
- The observation of exposure-response gradients with various indicators of exposure
- Consistent findings of excess risk in different countries, industries, and time periods
- Two studies that provided reasonable evidence for an unconfounded association (i.e., Amandus et al. [1991, 1992, 1995] and Partanen et al. [1994], an update of Kurppa et al. [1986])
Tsuda et al. [1997] conducted a lung cancer meta-analysis of pneumoconiosis or silicosis studies (excluding asbestosis). Lung cancer risk estimates were pooled from 32 mortality studies published from 1980 to 1994. The estimated rate ratios were similar to those reported by Steenland and Stayner [1997] and Smith et al. [1995]:
All studies (32†) Cohort studies only (25 of 32) Case-control studies (5 of 32)
†Two of the studies are proportionate mortality studies for which rate ratios were not reported.
Mortality studies of workers have reported statistically significant excesses of deaths from stomach or gastric cancer in iron ore miners [St. Clair Renard 1984; Lawler et al. 1985; Mur et al. 1987], Canadian gold miners [Muller et al. 1983; Shannon et al. 1987; Miller et al. 1987; Kusiak et al. 1993b], lead and zinc miners [Belli et al. 1989], brick production workers [Katsnelson and Mokronosova 1979], foundry and other metal workers [Neuberger and Kundi 1990], jewelry workers [Hayes et al. 1993; Dubrow and Gute 1987; Sparks and Wegman 1980], farmers (reviewed by Blair and Zahm [1991]), and farm workers [Stubbs etal. 1984] (reviewed by Zahm and Blair [1993]). A recent case-control study of 250 male hospital patients in Canada found a statistically significant excess of pathologically confirmed stomach cancer among the 25 patients who reported a history of “substantial” occupational exposure to crystalline silica compared with 2,822 controls (OR=1.7; 95% CI=1.1—2.7 after adjusting for the effects of age, birthplace, education, and cigarette smoking) [Parent et al. 1998]. However, in a review of epidemiologic studies of gastric cancer and dusty occupations, Cocco et al. [1996] noted that because most studies did not adjust for the effects of confounding factors or assess a dose-response relationship, evidence was insufficient to conclude that silica is a gastric carcinogen.
For workers who may have been exposed to crystalline silica, there have been infrequent reports of statistically significant excesses of deaths or cases of other cancers such as nasopharyngeal or pharyngeal cancer [Chen et al. 1992; Carta et al. 1991], salivary gland cancer [Zheng et al. 1996], liver cancer [Chen et al. 1992; Hua et al. 1992], bone cancer [Forastiere et al. 1989; Steenland and Beaumont 1986], pancreatic cancer [Kauppinen etal. 1995], skin cancer [Partanen et al. 1994; Rafnsson and Gunnarsdóttir 1997], esophageal cancer [Pan et al. 1999; Xu et al. 1996; Belli et al. 1989], cancers of the digestive system [Decoufle and Wood 1979], intestinal or peritoneal cancer [Amandus et al. 1991; Goldsmith et al. 1995; Costello et al. 1995], lymphopoietic or hematopoietic cancers [Redmond et al. 1981; Silverstein et al. 1986; Steenland and Brown 1995b], brain cancer [Rafnsson and Gunnarsdóttir 1997], and bladder cancer [Bravo et al. 1987]. Again, an association has not been established between these cancers and exposure to crystalline silica.
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