For definition of Groups, see Preamble Evaluation.
Vol.: 68 (1997) (p. 41)
Chem. Abstr. Name: Cristobalite
Chem. Abstr. Name: Quartz
Chem. Abstr. Name: Tripoli
Chem. Abstr. Name: Tridymite
Chem. Abstr. Name: Pyrogenic (fumed) amorphous silica
Chem. Abstr. Name: Precipitated silica; silica gel
Chem. Abstr. Name: Diatomaceous earth (uncalcined)
Chem. Abstr. Name: Vitreous silica
Chem. Abstr. Name: Flux-calcined diatomaceous earth
5.1 Exposure data
Silica (silicon dioxide) occurs in crystalline and amorphous forms. Of the several crystalline polymorphs of silica found in nature, quartz is by far the most common, being abundant in most rock types, notably granites, sandstones, quartzites and in sands and soils. Cristobalite and tridymite are found in volcanic rocks. Because of the wide usage of quartz-containing materials, workers may be exposed to quartz in a large variety of industries and occupations. Respirable quartz levels exceeding 0.1 mg/m3 are most frequently found in metal, non-metal and coal mines and mills; in granite quarrying and processing, crushed stone and related industries; in foundries; in the ceramics industry; in construction and in sandblasting operations. Cristobalite is formed from quartz or any other form of silica at high temperatures (> 1400 oC) and from some amorphous silicas (e.g. diatomaceous earth) at somewhat lower temperatures (800 oC). Cristobalite exposure is notably associated with the use and calcination of diatomaceous earth as well as refractory material installation and repair operations. Few data exist on non-occupational exposures to crystalline silica. It has been estimated that respirable crystalline silica levels in the low mg/m3 range are common in ambient air. Exposure may also occur during the use of a variety of consumer or hobby products.
Amorphous silica is found in nature as biogenic silica and as silica glass of volcanic origin. One form of biogenic silica, diatomaceous earth, originates from the skeletons of diatoms deposited on sea floors and contains small amounts of cristobalite and quartz. After calcination (which significantly increases the cristobalite content), diatomaceous earth is used as a filtration agent, carrier for pesticides, filler in paints and paper and as a refractory or abrasive product in a variety of industries. Occupational exposure to both amorphous and crystalline silica may occur during the production and use of diatomaceous earth. Fibres of amorphous silica are produced by a variety of plants, such as sugar cane and rice, and may be inhaled when released into the air during farming operations.
Large quantities of synthetic amorphous silica are produced as pyrogenic (fumed) silicas and wet process silicas (precipitated silicas and silica gels) which are used, notably, for reinforcing elastomers, for thickening resins, paints and toothpaste, and as free-flow additives. Exposure to synthetic amorphous silica may occur during its production and use. Synthetic amorphous silica may also be ingested as a minor constituent (< 2%) of a variety of food products where it serves as an anti-caking agent, and as an excipient in some pharmaceutical preparations. Silica fume is a form of amorphous silica (with small amounts of crystalline silica) unintentionally released into the air from certain metallurgical processes.
The mechanical, thermal and chemical history of a silica particle determines its surface properties and presence and abundance of various surface functionalities. Surface reactivity varies among silica samples from different sources. Heating converts hydrophilic surfaces into hydrophobic ones. In particular, freshly fractured surfaces are more reactive than aged ones.
5.2 Human carcinogenicity data
The evaluations for both crystalline and amorphous silica pertain to inhalation resulting from workplace exposures. Lung cancer was the primary focus. The Working Group's evaluation of the epidemiological evidence for potential causal relations between silica and cancer risk was focused principally on findings from studies that were least likely to have been distorted by confounding and selection biases. Among these studies, those that addressed exposure-response associations were especially influential in the Working Group's deliberations.
Possible differences in carcinogenic potential among polymorphs of crystalline silica were considered. Some studies were of populations exposed principally to quartz. In only one study (that of United States diatomaceous earth workers) was the exposure predominantly cristobalite. Studies of mixed environments (i.e. ceramics, pottery, refractory brick) could not delineate exposures specifically to quartz or cristobalite. Although there were some indications that cancer risks varied by type of industry and process in a manner suggestive of polymorph-specific hazards, the Working Group could only reach a single evaluation for quartz and cristobalite. Nonetheless, the Working Group did note a reasonable degree of consistency across studies of workers exposed to one or both polymorphs.
Seventeen cohort and five case-control studies were reported on ore miners potentially exposed to silica dust. The majority of these studies reported an elevated mortality for lung cancer among silica-exposed workers. However, in only a few ore mining studies were confounders such as other known occupational respiratory carcinogens taken into account. In such studies consistent evidence for a silica-lung cancer relationship was not found. Noteworthy instances where a relationship between lung cancer and crystalline silica was not detected include two independent studies of gold miners in South Dakota, United States, a study of miners in one lead and one zinc mine in Sardinia, Italy, and a study of tungsten miners in China. The results of most of the other studies could not be interpreted as an independent effect of silica - workers were concomitantly exposed to either radon, arsenic, or both, and in some cases other known or suspected occupational respiratory carcinogens were present in the work environment (e.g. diesel exhaust, polycyclic aromatic hydrocarbons, cadmium). In a few studies, no information was provided on exposure to radon or arsenic, in spite of the likelihood of these exposures.
Quarries and granite works
Six cohort studies were available for review. These studies provide important information on cancer risks because the workplace environments were generally free of reported exposures to potentially confounding agents (e.g., radon). All studies revealed lung cancer excesses. Direct quantification of silica dust exposure concentrations in relation to lung cancer risk was not conducted in any of these studies, mainly due to sparse occupational hygiene measurement data. However, some studies provided indications of exposure-response associations when surrogate dose data, such as duration of employment and category of exposure, were used. For example, findings for lung cancer include a nearly twofold mortality elevation among long-term granite shed workers in Vermont, United States, an eightfold elevation among sandstone workers in Copenhagen, Denmark, and a relative risk of roughly 3.5 among crushed granite stone workers in the United States with long duration of exposure and time since exposure onset. One study of German slate quarry workers indicated a more prominent relationship between employment duration and lung cancer among workers with silicosis than among workers without silicosis. The Working Group regarded radiographic evidence of silicosis as a marker of high exposure to silica.
Ceramics, pottery, refractory brick and diatomaceous earth industries
In refractory brick and diatomaceous earth plants, the raw materials (amorphous or crystalline silica) are processed at temperatures around 1000 oC with varying degrees of conversion to cristobalite. The results of two cohort studies of refractory brick workers from China and Italy and of one cohort study of diatomaceous earth workers from the USA provided consistent evidence of increased lung cancer with overall relative risks of about 1.5. In the study of refractory brick workers from China, a modest increasing trend of lung cancer was found with radiographic profusion category. A nearly twofold elevated lung cancer risk was found among long-term workers in the Italian study. In the study of United States diatomaceous earth workers, increasing exposure-response gradients were detected for both non-malignant respiratory disease and lung cancer mortality.
In ceramic and pottery manufacturing plants, exposures are mainly to quartz, but where high temperatures are used in ovens, potential exposures to cristobalite may occur. In a cohort study of British pottery workers, lung cancer mortality was slightly elevated; a nested case-control analysis of lung cancer did not show an association with duration of exposure, but indicated a relationship between lung cancer mortality and average and peak exposures in firing and post-firing operations, with relative risks of approximately 2.0. In an Italian case-control study, apart from a fourfold increase in lung cancer in registered silicotics, there was a small increase in lung cancer for subjects without silicosis. In a case-control study from the Netherlands, there was little relationship overall between work in ceramics and lung cancer risk, but there was some suggestion that lung cancer risk was related to cumulative exposure.
There were only three large cohort studies of foundry workers where silica dust or silicosis were considered as risk factors for cancer. One study from Denmark found a slightly elevated risk of lung cancer in silicotics compared with non-silicotics. Two studies, one from the United States and one from China, yielded conflicting results for lung cancer. The Chinese study suggested positive associations of silica with both lung cancer and stomach cancer, although there remained a potential for confounding by exposures to polycyclic aromatic hydrocarbons. The United States study did not demonstrate an association of lung cancer with cumulative silica exposure.
The vast majority of studies on registered silicotics reported excess lung cancer risks, with relative risks ranging from 1.5 to 6.0. Excesses were seen across countries, industries and time periods. A number of studies reported exposure-response gradients, using varying indicators of exposure. Some studies, in particular one from North Carolina (USA) and one from Finland, provide reasonable evidence for an unconfounded association between silicosis and lung cancer risk.
Summary of findings for crystalline silica (quartz and cristobalite)
For the evaluation of crystalline silica, the following studies provided the least confounded examinations of an association between silica exposure and cancer risk: (1) South Dakota, United States, gold miners; (2) Danish stone industry workers; (3) Vermont, United States, granite shed and quarry workers; (4) United States crushed stone industry workers; (5) United States diatomaceous earth industry workers; (6) Chinese refractory brick workers; (7) Italian refractory brick workers; (8) United Kingdom pottery workers; (9) Chinese pottery workers; (10) cohorts of registered silicotics from North Carolina, United States and Finland. Not all of these studies demonstrated excess cancer risks. However, in view of the relatively large number of epidemiological studies that have been undertaken and, given the wide range of populations and exposure circumstances studied, some non-uniformity of results would be expected. In some studies, increasing risk gradients have been observed in relation to dose surrogates - cumulative exposure, duration of exposure or the presence of radiographically defined silicosis - and, in one instance, to peak intensity exposure. For these reasons, the Working Group therefore concluded that overall the epidemiological findings support increased lung cancer risks from inhaled crystalline silica (quartz and cristobalite) resulting from occupational exposure. The observed associations could not be explained by confounding or other biases.
Very little epidemiological evidence was available to the Working Group. No association was detected for mesothelioma with biogenic amorphous silica fibres in the three community-based case-control studies. Separate analyses were not performed for cancer risks among a subset of diatomaceous earth industry workers exposed predominantly to amorphous silica.
5.3 Animal carcinogenicity data
Various forms and preparations of crystalline silica were tested for carcinogenicity by different routes of exposure.
Different specimens of quartz with particle sizes in the respirable range were tested in four experiments in rats by inhalation and in four experiments in rats by intratracheal instillation. In these eight experiments, there were significant increases in the incidence of adenocarcinomas and squamous-cell carcinomas of the lung; marked, dense pulmonary fibrosis was an important part of the biological response.
Pulmonary granulomatous inflammation and slight to moderate fibrosis of the alveolar septa but no pulmonary tumours were observed in hamsters in three experiments using repeated intratracheal instillation of quartz dusts.
No increase in the incidence of lung tumours was seen with one sample of quartz in the strain A mouse lung adenoma assay and with another quartz sample in a limited inhalation study in mice. Silicotic granulomas and lymphoid cuffing around airways but no fibrosis were seen in the lungs of quartz-treated mice.
In several studies in rats using single intrapleural or intraperitoneal injection of suspensions of several types of quartz, thoracic and abdominal malignant lymphomas, primarily of the histiocytic type (MLHT) were found. In rats, intrapleural injection of cristobalite and tridymite with particles in the respirable range resulted in malignant lymphomas, primarily MLHT.
A pronounced positive interactive effect of one sample of quartz and Thorotrast (an a-radiation emitting material) on pulmonary carcinogenesis was observed in one inhalation study in rats. Enhancement of benzo[a]pyrene-induced respiratory tract carcinogenesis by two different samples of quartz was seen in one intratracheal instillation study in hamsters.
In two studies in hamsters given mixtures of quartz and ferric oxide (1 : 1) by intratracheal instillation, no pulmonary tumours were observed.
Diatomaceous earth was tested by oral administration in rats and by subcutaneous and intraperitoneal injection in mice. No increase in the incidence of tumours was found after oral and subcutaneous administration; after intraperitoneal injection, a slightly increased incidence of intra-abdominal lymphosarcomas was reported.
In one test by intrapleural injection of biogenic silica fibres to rats, the silica fibres were not found to influence the tumour response to crocidolite but a small number of pleural mesotheliomas was reported in animals injected with 15,16-dihydro-11-methylcyclopenta[a]phenanthren-17-one followed by administration of the biogenic silica fibres.
A food-grade micronized synthetic amorphous silica was tested by oral administration to mice and rats. No increased incidence of tumours was seen. In one study in rats using intrapleural implantation of two different preparations of synthetic amorphous silica, no increased incidence of tumours was observed.
5.4 Other relevant data
Crystalline silica deposited in the lungs causes epithelial and macrophage injury and activation. Crystalline silica translocates to the interstitium and the regional lymph nodes. Crystalline silica results in inflammatory cell recruitment in a dose-dependent manner. Neutrophil recruitment is florid in rats exposed to high concentrations of quartz; marked, persistent inflammation occurs accompanied by proliferative responses of the epithelium and interstitial cells. In humans, a large fraction of crystalline silica persists in the lungs, culminating in the development of chronic silicosis, emphysema, obstructive airways disease and lymph node fibrosis in some studies. In-vitro studies have shown that crystalline silica can stimulate release of cytokines and growth factors from macrophages and epithelial cells; evidence exists that these events occur in vivo and contribute to disease. Crystalline silica stimulates release of reactive oxygen and nitrogen intermediates from a variety of cell types in vitro. Oxidative stress is detectable in the lungs of rats following exposure to quartz.
Much less is known about the acute lung responses to inhaled crystalline silica in humans. Subjects with silicosis show an inflammatory response characterized by increased macrophages and lymphocytes but minimal increases in neutrophil numbers.
Only one human study was available on subjects exposed to dust containing crystalline silica, with no indication of the level of exposure; it showed an increase in the levels of sister chromatid exchange and chromosomal aberrations in peripheral blood lymphocytes.
Most cellular genotoxicity assays with crystalline silica have been performed with quartz samples. Some studies gave positive results, but most were negative. Some quartz samples induced micronuclei in Syrian hamster embryo cells, Chinese hamster lung V79 cells and human embryonic lung Hel 299 cells, but not chromosomal aberrations in the same cell types. Two quartz samples induced morphological transformation in Syrian hamster embryo cells in vitro and 5 quartz samples induced transformation in BALB/c-3T3 cells. While quartz did not induce micronuclei in mice in vivo, epithelial cells from the lungs of rats intratracheally exposed to quartz showed hprt gene mutations. Inflammatory cells from the quartz-exposed rat lungs caused mutations in epithelial cells in vitro. Direct treatment of epithelial cells in vitro with quartz did not cause hprt mutation.
Tridymite was tested in only one study, where it induced sister chromatid exchange in co-cultures of human lymphocytes and monocytes.
Increasing in-vitro and in-vivo evidence suggests that the rat lung tumour response to crystalline silica exposure is a result of marked and persistent inflammation and epithelial proliferation. Other pathways such as a role for crystalline silica surface-generated oxidants or a direct genotoxic effect are not ruled out; however, at present, there is no convincing evidence for these alternative pathways.
Amorphous silicas have been studied less than crystalline silicas. They are generally less toxic than crystalline silica and are cleared more rapidly from the lung.
Biogenic silica fibres induced ornithine decarboxylase activity of epidermal cells in mice following topical application. No data were available to the Working Group on the genotoxicity of other amorphous silica particles.
There is sufficient evidence in humans for the carcinogenicity of inhaled crystalline silica in the form of quartz or cristobalite from occupational sources
There is inadequate evidence in humans for the carcinogenicity of amorphous silica.
There is sufficient evidence in experimental animals for the carcinogenicity of quartz and cristobalite.
There is limited evidence in experimental animals for the carcinogenicity of tridymite.
There is inadequate evidence in experimental animals for the carcinogenicity of uncalcined diatomaceous earth.
There is inadequate evidence in experimental animals for the carcinogenicity of synthetic amorphous silica.
In making the overall evaluation, the Working Group noted that carcinogenicity in humans was not detected in all industrial circumstances studied. Carcinogenicity may be dependent on inherent characteristics of the crystalline silica or on external factors affecting its biological activity or distribution of its polymorphs.
Crystalline silica inhaled in the form of quartz or cristobalite from occupational sources is carcinogenic to humans (Group 1).
Amorphous silica is not classifiable as to its carcinogenicity to humans (Group 3).
For definition of the italicized terms, see Preamble Evaluation.
Previous evaluation: Suppl. 7 (1987) (p. 341)
Synonyms for crystalline silica
See Also: Toxicological Abbreviations