AMORPHOUS SILICA: A REVIEW OF HEALTH EFFECTS FROM INHALATION EXPOSURE WITH PARTICULAR REFERENCE TO CANCER Joseph K.

McLaughlin, Wong-Ho Chow International Epidemiology Institute, Rockville, Maryland, USA Leonard S. Levy Institute of Occupational Health, University of Birmingham, United Kingdom

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Silicas and silicates are some of the most abundant compounds found naturally in the earth's crust. Excessive exposure to crystalline silicas can cause serious lung disease such as silicosis and has been associated with lung cancer in some studies, but the potential health effects of amorphous silicas (silicon dioxide without crystalline structure) have not been well studied. Results from animal studies of amorphous silicas, unlike those seen with crystalline silicas, have suggested limited and largely reversible cytotoxic and possibly fibrogenic effects associated with some forms, but data on cancer outcomes are scanty and for the most part negative. Epidemiologic investigations to date for any potential cancer risk are not informative because the effects of crystalline and amorphous silicas have not been separated. Any future epidemiologic study should attempt to clarify the health effects of amorphous silicas from those of crystalline silicas, particularly with regard to any potential for carcinogenicity.

Silica, or silicon dioxide (SiO2), is a compound formed by the two most abundant elements on earth, oxygen and silicon. Silica may be "free" (i.e., not chemically combined with other elements) or may be combined with other elements to form silicates (Weill et al., 1994). Silica exists in two major varieties, crystalline and amorphous, both of which may be natural or synthetic. While exposure to crystalline silicas has been associated with a variety of adverse health outcomes, including silicosis and possibly cancer (IARC, 1987; Weill et al., 1 994; McDonald, 1996), the impact of amorphous silicas on human health is uncertain. This review summarizes the limited scientific literature on the health effects of amorphous silicas among humans over the past few decades, with emphasis on the latest evidence and special attention to any potential role in cancer risk. To facilitate the review, the classification of amorphous silicas and industrial exposure to these compounds is briefly described in the next section.
Received 17 July 1996; sent for revision 7 August 1996; accepted 20 August 1996. Address correspondence to Dr. Joseph K. McLaughlin, International Epidemiology Institute, 1550 Research Boulevard, Rockville, Maryland 20850, USA. 553 Journal of Toxicology and Environmental Health, 50553-566,1997 Copyright 1997 Taylor & Francis 0098-4108/97 $12.00 + .00

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CLASSIFICATION OF AMORPHOUS SILICA

Amorphous silica is silicon dioxide without crystalline structure, as defined by x-ray diffraction. Natural amorphous silicas are mostly opaline in character and/or biogenic in origin, that is, as a constituent of living matter (Vigliani & Mottura, 1948; Rabovsky, 1995). Diatomaceous earth (also known as diatomite or kieselguhr) is a rock formed from the sedimentation of prehistoric unicellular algae (diatoms). Crude diatomite is composed mainly of amorphous silica, although varying amounts of crystalline silicas in the form of quartz, tridymite, and cristobalite and other impurities may be present (Vigliani & Mottura, 1948; Weill et al., 1994). Amorphous silicas accumulate naturally in some higher plants such as rice and wheat (Parry & Hodson, 1982; Rabovsky, 1995). Tripolite is another biogenic amorphous silica formed from sedimentation of the skeletons of radiolarii. Commercially used amorphous silicas are often synthetically produced. Synthetic amorphous silicas can be classified into the following types: wet process silicas, pyrogenic or thermal silicas (also known as fumed silicas), vitreous silicas (fused silica, silica glass), and after-treated silicas (chemically modified, surface-coated, or physically treated silicas). There are three types of wet process silicas: colloidal silica (silica sol), precipitated silica, and silica gel. Silica gel, in turn has three variants: silica hydrogel (wet), silica aerogel (dry), and silica xerogel (dry). In addition to these intentionally manufactured products whose quality is continually monitored and controlled, other forms of amorphous silica may be generated as by-products from certain industrial processes in uncontrolled settings. These by-products include fly ashes from power stations, and "silica fume" from metallurgical processes, such as the production of ferrosilicon. The level of purity of the different forms of amorphous silica varies by manufacturing process. It is noteworthy that the forms of some silicas can change with temperature (IARC, 1987). For instance, the silica content in raw diatomaceous earth is primarily amorphous, but calcination at temperatures ranging from 800 to 1100C increases the percentage of crystalline silicas, mainly cristobalite, to 10-20%. When the calcining is done with a flux material, either sodium carbonate or sodium chloride, the crystalline silica content becomes even higher (IARC, 1987; Weill et al., 1994; Rabovsky, 1995). The vitreous silicas are formed by melting crystalline silica and then cooling it quickly; however, a small amount of crystalline silica may remain (Weill et al., 1994). It is therefore important to consider the possibility of concomitant exposure to crystalline silica when assessing the health effects of amorphous silicas, because the biologic effects of silica appear to vary greatly with the proportion of crystalline material, as well as with particle size and shape, surface area and composition,

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dissolution characteristics, and compositional variations (Hemenway et al., 1986; Guthrie & Heaney, 1995).
EXPOSURE TO AMORPHOUS SILICA

Human exposure may occur in a variety of environmental and occupational settings, since amorphous silicas are widely used in synthetic resins, plastics, lacquers, vinyl coatings, varnishes, pharmaceuticals, cosmetics, adhesives, paints, and foods (Beskow, 1978; Villota & Hawkes, 1986; Lewinson et al., 1994). A major route of occupational exposure is through inhalation, and potential impairment to pulmonary function has been the main health concern. Skin or eye contact and ingestion also may occur. During diatomite mining and processing, the respirable dust levels vary greatly at different sites and locations within the sites, ranging from 0.14 to 28.2 mg/m3 (IARC, 1987). The crystalline silica content of the airborne dust may range from less than 1 % to as high as 75% depending on the source of the diatomaceous ores and temperature of processing. In addition, farmers may be exposed to biogenic amorphous silicas during harvesting, crop burning, or incineration (Boeniger et al., 1991; Lawson et al., 1995; Rabovsky, 1995). Exposure to synthetic amorphous silicas may occur during the production or bagging of the finished products. In the ferrosilicon industry, amorphous silica fume is created as a by-product of the industrial process. Workers in many other industries, such as glass, ceramics, refractory brick, paper, paint, and rubber, may also be exposed to various forms of amorphous silica when used as fillers, filters, or for other purposes. Amorphous silicas also have gained widespread use in the food and pharmaceutical industries as anticaking agents or carriers (Villota & Hawkes, 1986; Lewinson et al., 1994; Weill et al., 1994). A substantial amount of nonoccupational exposure to amorphous silicas therefore may occur through dietary intake. Moreover, diatomite fragments are present in drinking water worldwide, although the amount of ingestion through this source is unclear (IARC, 1987). Diatomite also has been used as a filler in tobacco sheets. The opaline form may be partly converted to the crystalline cristobalite as it contacts the burning tip (IARC, 1987). Prior to reviewing information on the health effects of human exposure to amorphous silicas, a brief summary of the limited data on experimental studies in short-term tests and animal bioassays is presented.
EXPERIMENTAL STUDIES OF AMORPHOUS SILICA

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The majority of studies that have been conducted on experimental animals have focused on pulmonary effects such as fibrogenicity and

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short-term cytotoxicity rather than carcinogenesis. The few studies that have been reported (IARC, 1987; Lewinson et al., 1994) have been on the whole negative, although many were inadequate in design, description, and even lacked a clear characterization of type of silica used (amorphous or crystalline). In particular, the inhalation route of exposure, the most appropriate, has been evaluated in a few limited studies. A well-conducted study using a food-grade micronized silica up to a concentration of 5% in the diet found no relation to cancer in both mice and rats (Takizawa et al., 1988). Exposure of laboratory animals to amorphous silica by inhalation has mainly been conducted in studies evaluating fibrogenicity and associated pulmonary toxicity. The types of studies, animals and materials used, and endpoints examined have varied. Some studies have reported contradictory findings ranging from no fibrosis to marked fibrosis with associated lymph node fibrosis (Tebbens & Beard, 1957; Klosterkotter, 1956; Groth et al., 1981; Rosenbruch, 1992) and even impaired pulmonary function in rabbits and monkeys (Schepers et al., 1957; Groth et al., 1981). In general, however, the gross pathologic changes seen with crystalline silica inhalation do not occur following amorphous silica exposure. More recently, attention has focused on mechanistic studies comparing amorphous with crystalline silica to explain this difference in pulmonary effects. As an example, in vitro studies with rat alveolar macrophages have shown that compared with crystalline silica, amorphous silicas appear to be more potent activators of eicosanoids (a measure of reactive oxygen species production), which some researchers consider to be an important biochemical mediator in dust-related lung disease (Kuhn & Demers, 1992). Another study (Warshawsky et al., 1994) showed that at equivalent doses, precipitated and fumed amorphous silicas appear equally cytotoxic to rat and hamster alveolar macrophages as crystalline silica, while gelled amorphous silica may be more cytotoxic. However, caution must be taken in the interpretation of such short-term measures of lung cell toxicity as predictors of longer term damage. This is exemplified in studies that have shown that the initial inflammatory damage and even early fibrotic changes seen in rat cells and tissues after inhalational exposure to amorphous silicas are either completely or nearly completely reversible, while those induced by quartz or cristobalite silica are not (Hemenway et al., 1986; Reuzel et al., 1991; Warheit et al., 1991, 1995). The laboratory results taken overall seem to strongly suggest that chronic persistence of cytotoxicity and pathogenicity occurring with crystalline silicas is not seen with amorphous silicas. The reason for the different effects for these two forms of silicas (e.g., solubility, cellsurface chemistry, etc.) is uncertain. Thus, the inconsistency of findings in laboratory studies, particularly the earlier ones, is likely due to sev-

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eral factors such as different types of amorphous silica used, the presence of crystalline silica and other fibrogenic minerals, and variation in study design including species and strain used, sample size, dose and dosing schedule, route of administration, duration of observation (including postexposure follow-up), and biological endpoints measured. In addition, coating or modification of the surface of silica aggregates in some commercial products (e.g., from hydrophilic to hydrophobic state) and the presence of trace metals and other minerals may contribute to the variation in cytotoxicity (Lewinson et al., 1994; Weill et al., 1994). Overall, therefore, the limited studies reported to date do not indicate that amorphous silica is carcinogenic. However, it should be noted that the available data are too limited for a firm conclusion; thus the contribution from the animal data is not particularly helpful in the overall evaluation of human risk. With regard to general pulmonary cytotoxicity, it would appear that the persistence of cytotoxic events seen with crystalline silica, culminating in permanent fibrotic changes, is not observed with the amorphous silicas that have been examined. HEALTH EFFECTS OF AMORPHOUS SILICA EXPOSURE ON HUMANS Numerous studies have examined health outcomes among mixed silica-exposed workers, but few studies have evaluated specifically the effects of amorphous silicas (IARC, 1987; McDonald, 1995). We conducted a search of literature since the 1960s on health outcomes associated with exposure to amorphous silicas or diatomaceous earth. Earlier studies were also identified, although some case reports and case series, particularly those published in the 1930s and before, were not included. Studies reported in a foreign language without an English abstract were also excluded. The health effects of amorphous silicas in humans remain unclear, despite efforts to examine this issue for more than half a century (Middleton & Edin, 1936; Gardner, 1938). There have been several case reports of pneumoconiosis or silicosis cases among workers exposed to diatomaceous earth (Smart & Anderson, 1952; Caldwell, 1958; Dutra, 1965; Beskow, 1978; Omura et al., 1978; Brambilla et al., 1980). In one case report, Smart and Anderson (1952) described a diatomite-induced pulmonary lesion that appeared distinct from those associated with quartz exposure. This lesion was later referred to as diatomite pneumoconiosis (Dutra, 1965; Weill et a l . , 1994). Furthermore, inhalation of raw diatomite was associated mainly with simple pulmonary fibrosis with few symptoms, while calcined and flux-calcined diatomite occasionally was linked to a rapidly progressive

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pulmonary fibrosis or granuloma with massive coalescence (Smart & Anderson, 1952; Caldwell, 1958; Dutra, 1965). These observations suggest that cristobalite and tridymite in the calcined diatomite may be the key risk factors, although in another series (Brambilla et al., 1980), less than 1 % of the silica particles within the macrophages in 2 biopsied cases with fibrosis were crystalline. It is noteworthy that of 10 cases of pneumoconiosis originally reported in a ferrosilicon alloy melting plant (Bruce, 1937), the diagnosis was subsequently validated in only 1 patient (Swensson et al., 1971), suggesting that misdiagnosis of silicosis/pneumoconiosis may occur. Given the well-established association between chronic pulmonary fibrosis resulting from heavy exposure to other fibrous mineral dusts, such as asbestos and crystalline silicas, and subsequent development of lung cancer (Brand, 1986; Amandus et al., 1995; McDonald, 1995), it is prudent to review the potential fibrogenic and carcinogenic effects of amorphous silicas on human lung tissue. We have not found any reports that indicate an association between human neoplasms and amorphous silica exposure. Recently, a case of bronchiolitis obliterans was reported in an animal feeder who had been exposed to a large number of agents, including crystalline and amorphous silicas, microorganisms, proteolytic enzymes, and various organic substances, but the specific effect of amorphous silica was not delineated (Spain et al., 1995). Table 1 summarizes epidemiologic studies, including cross-sectional surveys and cohort studies, of health effects among workers that were known to have been exposed to amorphous silicas. In 1932, Legge and Rosencrantz (1932) reviewed x-rays for 108 miners of diatomaceous earth and found pneumoconiosis in most. These miners were exposed mainly to raw diatomite, a form of natural amorphous silica. This finding was not supported, however, by subsequent investigations, which showed no pneumoconiosis among those exposed only to raw diatomite (Cooper & Cralley, 1958; Cooper & Jacobson, 1977). In contrast, exposure to calcined diatomite has been associated with an increased risk of pneumoconiosis (Vigliani & Mottura, 1 948; Cooper & Cralley, 1958; Cooper & Jacobson, 1977; Cooper & Sargent, 1984) and some reduction in pulmonary function (Motley et al., 1956; Motley, 1960). However, none of these studies attempted to separate the effect of crystalline silicas from that of amorphous silicas. Other forms of amorphous silica, including precipitated and pyrogenic silicas, generally have not been linked to silicosis in humans (Volk, 1960; Plunkett & DeWitt, 1962; Wilson et al., 1979; Choudat et al., 1990), although x-ray abnormalities and reduced pulmonary function have been reported among workers exposed to pyrogenic silicas in a metallurgical plant (Vitums et al., 1977). In this study, confounding by other agents, including cristobalite and cigarette smoking, was

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TABLE 1. Studies of occupational pulmonary diseases in workers exposed to amorphous silica Type of amorphous silica exposure Diatomite Calcined diatomite

First author, year

Type of study Cross-sectional survey Cross-sectional survey

Location of study USA Italy

Industry Diatomite quarry Filter candles

Number of subjects 108 Miners 20 Workers in the turning department 30 Workers 869 Workers

Results Pneumoconiosis in 75% of subjects Silicosis in 65% of subjects

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Legge, 1932 Vigliani, 1948

Motley, 1956 Cooper, 1958

Cross-sectional survey Cross-sectional survey

USA USA

Diatomite Diatomite

Diatomite Crude diatomite Calcined diatomite

1O

Cooper, 1977

Survey/follow-up of 1953-1954 cohort

USA

Diatomite

Crude diatomite Calcined diatomite

428 Workers

Cooper, 1984

Motley, 1960

Survey/follow-up of 1953-1954 cohort Cross-sectional survey

USA

Diatomite

Crude diatomite Calcined diatomite Diatomite

473 Workers

Normal to mild reduction in pulmonary function Pneumoconiosis in 46% of workers exposed to calcined diatomite No pneumoconiosis in workers exposed to crude diatomite only All but 2 of 1 3 long-term (20+ yr) workers with pneumoconiosis were exposed to calcined diatomite Pneumoconiosis incidence decreased with reduced dust level, with nearly all cases employed before 1953 All 11 workers with pneumoconiosis were employed for more than 25 yr Slight to no change in pulmonary function in 78 workers, moderate changes in 14, and severe changes in 6 workers Silicosis was not observed Silicosis was not observed

USA

Diatomite

98 Workers

Volk, 1960 Plunkett, 1962

Cross-sectional survey Cross-sectional survey

Germany USA

Amorphous silica Amorphous silica

Aerosil Hi-Sil, Silene (precipitated amorphous silica)

215 Workers 78 workers

[Table continues on next page)

TABLE 1. Studies of occupational pulmonary diseases in workers exposed to amorphous silica [continued) Type of amorphous silica exposure Silica fumes

First author, year Vitums, 1977

Type of study Cross-sectional survey

Location of study USA

Industry Metallurgical plant

Number of subjects 40 Workers

Results 11 Workers showed x-ray abnormalities Of 3 workers who consented to detailed studies: 2 had biopsies showing pneumoconiosis, 2 had reduced pulmonary functions Pneumoconiosis not found with exposure only to amorphous silica No correlation between annual change of pulmonary functions and cumulative index or duration of exposure Pulmonary symptoms related to smoking Significant excess of respiratory tract cancers Among silicotics, significant excess of all death, respiratory-tract cancer (larynx), cardiovascular diseases, nonmalignant respiratory diseases Chest x-rays and blood gas concentration comparable between the exposed and nonexposed Smoking has greater impact on pulmonary function than amorphous silica exposure Significant excess SMR for all causes, nonmalignant respiratory disease and lung cancer

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Wilson, 1979

Cross-sectional survey

USA

Silica

Precipitated silica

165 Workers

Puntoni, 1988
o

Cohort mortality

Italy

Refractory brick

Not specified (only crystalline silica was measured)

231 Workers

Choudat, 1990

Cross-sectional survey

France

Chemical plant

Precipitated silica dust

41 Exposed workers 90 Control workers

Checkoway, 1993

Cohort mortality

USA

Diatom ite

Crude diatomite Calcined diatomite

Corhay, 1995

Cross-sectional survey

Belgium

Blast furnace

Not specified

2570 Workers (129 were exposed only to amorphous silica) 47 Blast-furnace Higher concentration of amorphous workers silica particles in bronchoalveolar 45 White-collar lavage fluid of blast-furnace workers workers than white-collar workers

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not considered. Indeed, smoking generally appeared to be a stronger determinant of pulmonary symptoms and functions than exposure to amorphous silicas (Wilson et al., 1979; Choudat et al., 1990). In another study (Corhay et al., 1995), a higher concentration of amorphous silica particles, as well as other nonfibrous particles and metals, was found in the macrophages and bronchoalveolar lavage fluid of blast-furnace workers than in a control group of white collar workers from the same plant. These observations underscore the importance of controlling for the confounding effects of other exposures when assessing the health effect of amorphous silicas. Amorphous silicas have been mentioned in two cohort mortality studies (Puntoni et al., 1988; Checkoway et al., 1993). Among 231 workers in a refractory brick plant followed from 1960 to 1979 (Puntoni et al., 1988), significant excess deaths were observed for nonmalignant respiratory diseases and respiratory tract cancers. The excess mortality was particularly pronounced among workers with silicosis in this cohort, including significantly elevated risks for all causes, respiratory tract cancers (larynx in particular), cardiovascular diseases, and nonmalignant respiratory diseases. While the silica used in this plant was a mixture of crystalline alpha quartz and amorphous silicas, only the concentrations of crystalline silica in respirable dust were measured. Mortality was not examined by type of silica or level of exposure, so that any effect of amorphous silicas per se cannot be determined. In another study, significant excess deaths of lung cancer and nonmalignant respiratory diseases were observed in a cohort of 25 70 white male workers from 2 plants in the diatomaceous earth mining and processing industry followed from 1942 to 1987 (Checkoway et al., 1993). A nearly 50% excess of lung cancer deaths occurred only among workers hired before 1960 when the exposure levels were high. However, the lung cancer deaths increased consistently with levels of crystalline silica exposure, as indicated both by duration of employment and a crystalline silica index, a semiquantitative measure of amount and duration of exposure. Again, mortality associated with exposure to amorphous silicas was not assessed, nor was assessment made for subgroups of workers by work areasfor example, the quarry where the exposure presumably was mostly raw diatomite. The authors reported that the number of workers exposed exclusively to amorphous silicas (129) was too small for separate analyses. Nevertheless, the trends in risk with crystalline silica indicate that the 18 excess deaths from lung cancer among the diatomaceous workers could be attributed to high cumulative crystalline silica exposure. We also reviewed the far larger number of studies of cancer occurrence among workers employed in the predominantly crystalline silica-exposed industries, such as the ceramics, glass, and related industries and in foundries and metallurgical industries. Although some

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workers in these industries may be exposed to amorphous silicas (IARC, 1987), no study has attempted to evaluate the role of amorphous silica exposure on cancer risk independent of crystalline silicas or whether concomitant exposure to amorphous silicas modifies the effect of crystalline silicas. Overall, the limited studies on amorphous silicas have revealed minimal effects on human health, despite extensive use in many industries. The silicosis or pneumoconiosis reported among workers in the diatomaceous earth industry appears to be associated mainly with calcined diatomite, which has a high content of crystalline silicas. Occupational exposure to other forms of amorphous silicas generally did not show a silicotic effect, although definitive conclusions cannot be drawn because of limitations in many studies. It therefore may be premature to dismiss the possibility of a permanent adverse pulmonary effect of amorphous silicas, although the laboratory findings generally do not support such an effect. Moreover, there is no evidence to suggest any carcinogenic effect of amorphous silicas among humans, and the animal data on cancer outcomes are scanty. However, given the association between silicosis and lung cancer among workers exposed to crystalline silicas and the potential fibrogenic effect of some amorphous silicas, further examination of the role of amorphous silicas in human carcinogenesis may be warranted. In the next section, limitations of previous human studies are reviewed in the hope that this may serve as a guide for future investigations. LIMITATIONS OF STUDIES ON HEALTH EFFECT OF AMORPHOUS SILICAS IN HUMANS The most severe hindrance to our understanding of the health effects of amorphous silicas in humans is the lack of silica specificity in epidemiological studies. Even in studies of workers who are likely to have substantial exposure to amorphous silicas, the amorphous form of silica is ignored in favor of assessing the crystalline silica levels (Puntoni et al., 1988; Checkoway et al., 1993). The apparent lack of interest in amorphous silicas in part may be due to the perceived safety of these materials and the small number of workers with amorphous silicas as the sole or primary industrial exposure (Checkoway et al., 1993). However, without specific, assessment, the role of amorphous silicas on adverse effects will remain unclear. In a subsequent review of the California diatomaceous earth cohort study, Checkoway (1995) noted a stronger trend in risk with duration of employment than with a crystalline silica index, suggesting that the lung cancer mortality was not accounted for entirely by crystalline silica, and speculated that other components of diatomaceous earth such as amorphous silicas also may be etiologically relevant. The trend with

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duration, however, was only marginally stronger than with the crystalline silica index (RR = 2.88 vs. 2.74), and attributable risk calculations suggest that all the excess of lung cancer (18 deaths) could be associated with crystalline silicas. Given the generally small number of workers with amorphous silicas as the sole exposure, and the difficulty in quantifying exposures to crystalline versus amorphous silicas, it may require studies of large numbers of workers to disentangle effects. Assessment of dose response also would help to delineate the effect of amorphous silicas. An equally important and common limitation of previous studies is the lack of assessment of the confounding effects of cigarette smoking and other industrial agents. In one study that collected information on smoking (Choudat et al., 1990), smokers with amorphous silica exposure had the highest reduction in pulmonary function compared with workers who had either one or none of the exposures. Similarly, exposure to other industrial agents, such as metals in the metallurgical industry, radon in mines, and asbestos in the pottery and related industries, may also confound or modify the effect of amorphous silicas on lung cancer and other pulmonary outcomes. Any risk associated with amorphous silicas therefore cannot be clearly established without proper adjustment for other occupational exposures. Studies of pulmonary function and pathology among amorphous silica workers that rely on nonrandom cross-sectional surveys are prone to bias. For example, workers who have pulmonary symptoms may be more likely to volunteer for examination in such studies. The nonrandom nature of subject selection increases the likelihood of this and other biases and limits the drawing of any etiologic inference. Another issue for consideration is the accuracy of diagnosis of silicosis/pneumoconiosis. A few previous studies (Swensson et al., 1971; Cooper & Jacobson, 1977) have shown that a large proportion of subjects diagnosed with simple pneumoconiosis regressed to normal in subsequent surveys. Since the typical course of silicosis tends to progress, particularly with continuing exposure, this phenomenon suggests that some cases might have been misdiagnosed in the earlier survey (Swensson et al., 1971). This problem may be minimized with well-defined diagnostic criteria and blinded review of x-ray films and pathology records. Finally, the effect of occupational exposure to amorphous silicas other than diatomaceous earth is rarely studied. While experimental studies have suggested that cytotoxicity varies with different forms of amorphous silica (Reuzel et al., 1991; Warshawsky et al., 1994; Warheit et al., 1995), little is known of any differential effects on humans. Although most occupational studies did not observe adverse effects with various forms of amorphous silica, limitations of the studies preclude firm conclusions.

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In summary, the overall evidence from existing studies indicates that amorphous silicas are unlikely to be carcinogenic in humans. However, the limitations in previous studies preclude definitive conclusions. Thus, it is important that future epidemiologic studies focus on workers exclusively or predominantly exposed to amorphous silicas or, when possible, clearly delineate exposures to crystalline versus amorphous silicas in the analysis, to clarify any lingering concerns. Additional laboratory studies also will be helpful to clarify the biologic effects of exposure to uncontaminated amorphous silica. REFERENCES
Amandus, H. E., Shy, C , Castellan, R. M., Blair, A., and Heineman, E. F. 1995. Silicosis and lung cancer among workers in North Carolina dusty trades. Scand. J. Work Environ. Health 21(suppl. 2):81-83. Beskow, R. 1978. Silicosis in diatomaceous earth factory workers in Sweden. Scand. J. Respir. Dis. 59:216-221. Boeniger, M. F,, Fernback, J., Hartle, R., Hawkins, M., and Sinks, T. 1991. Exposure assessment of smoke and biogenic silica fibers during sugar cane harvesting in Hawaii. Appl. Occup. Environ. Hyg. 6:59-66. Brambilla, C , Brambilla, E., Rigaud, D., Perdrix, A., Paramelle, B., and Fourcy, A. 1980. Pneumoconiose aux fumes de silice amorphe: etude minralogique et ultrastructurale de 6 cas. Rev. Franis Mal. Respir. 8:383-391. Brand, K. C. 1986. Fibrotic scar cancer in the light of foreign body tumorigenesis. In Silica, silicosis, and cancer: Controversy in occupational medicine, eds. D. F. Goldsmith, D. M. Winn, and C. M. Shy, pp. 281-286. New York: Praeger. Bruce, T. 1937. The occurrence of silicosis in the manufacture of silicon alloys. J. Ind. Hyg. Toxicol. 19:155-162. Caldwell, D. M. 1958. The coalescent lesion of diatomaceous earth pneumoconiosis. Am. Rev. Tuberc. 77:644-661. Checkoway, H. 1995. Methodological considerations relevant to epidemiology studies of silica and lung cancer. Appl. Occup. Environ. Hyg. 10:1049-1055. Checkoway, H., Heyer, H. J., Demers, P. A., and Breslow, N. E. 1993. Mortality among workers in the diatomaceous earth industry. Br. J. Ind. Med. 50:586-597. Choudat, D., Frisch, C., Barrat, C., Kholti, A. E., and Conso, F. 1990. Occupational exposure to amorphous silica dust and pulmonary function. Br. J. Ind. Med. 47:763-766. Cooper, W. C., and Cralley, L. J. 1958. Pneumoconiosis in Diatomite Mining and Processing. Public Health Service Publication 601. Washington, DC: Government Printing Office. Cooper, W. C., and Jacobson, G. 1977. A 21-year radiographic follow-up of workers in the diatomite industry. J. Occup. Med. 19:563-566. Cooper, W. C , and Sargent, E. N. 1984. A 26-year radiographic follow-up of workers in a diatomite mine and mill. J. Occup. Med. 26:456-460. Corhay, J.-L, Bury, T., Delavignette, J.-P., Baharloo, F., Radermecker, M., Hereng, P., Fransolet, A.-M., Weber, G., and Roelandts, I. 1995. Nonfibrous mineralogical analysis of bronchoalveolar lavage fluid from blast-furnace workers. Arch. Environ. Health 50:312-319. Dutra, F. R. 1965. Diatomaceous earth pneumoconiosis. Arch. Environ. Health 11:613-619. Gardner, L. U. 1938. Etiology of pneumoconiosis. J. Am. Med. Assoc. 111:1925-1936. Groth, D. H., Moorman, W. J., Lynch, D. W., Stettler, L. E., Wagner, W. D., and Hornung, R. W. 1981. Chronic effects of inhaled amorphous silicas in animals. In Health effects of synthetic silica particulates (ASTM STP 732), pp. 118-143. Philadelphia: American Society for Testing and Materials. Guthrie, G. D., Jr., and Heaney, P. J. 1995. Mineralogical characteristics of silica polymorphs in relation to their biological activities. Scand J. Work Environ. Health 21(suppl. 2):5-8.

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HEALTH EFFECTS OF AMORPHOUS SILICA INHALATION

565

Hemenway, D. R., Absher, M., Landesman, M., Trombley, L., and Emerson, R. J. 1986. Differential lung response following silicon dioxide polymorph aerosol exposure. In Silica, silicosis, and cancer: Controversy in occupational medicine, eds. D. F. Goldsmith, D. M. Winn, and C. M. Shy, pp. 105-116. New York: Praeger. IARC. 1987. Silica and some silicates. Monogr. Eval. Carcinogen. Risk Chem. Hum. 42:39-143. Klosterktter, V. W. 1965 Gewerbehygienisch-toxikologische Untersuchungen mit hydrophoben amorphen Kieselsuren. I. Aerosil-R 972. Arch. Hyg. Bakteriol. 149:1-24. Kuhn, D. C , and Demers, L. M. 1992. Influence of mineral dust surface chemistry on eicosanoid production by the alveolar macrophage. J. Toxicol. Environ. Health 35:39-50. Lawson, R. J., Schenker, M. B., McCurdy, S. A., Jenkins, B., Lischak, L. A., John, W., and Scales, D. 1995. Exposure to amorphous silica fibers and other paniculate matter during rice farming operations. Appl. Occup. Environ. Hyg. 10:677-684. Legge, R. T., and Rosencrantz, E. 1932. Observations and studies on silicosis by diatomaceous silica. Am. J. Public Health 32:1055-1060. Lewinson, J., Mayr, W., and Wagner, H. 1994. Characterization and toxicological behavior of synthetic amorphous hydrophobic silica. Regul. Toxicol. Pharmacol. 20:37-57. McDonald, C. 1995. Silica, silicosis, and lung cancer: an epidemiological update. Appl. Occup. Environ. Hyg. 10:1056-1063. McDonald, J. C. 1996. Silica and lung cancer. In Silica and silica-induced lung diseases, eds. V. Castranova, V. Vallyathan, and W. E. Wallace, pp. 383-406. New York: CRC Press. Middleton, E. L , and Edin, M. D. 1936. Industrial pulmonary disease due to the inhalation of dust: with special reference to silicosis. Lancet 2:59-64. Motley, H. L. 1960. Pulmonary function studies in diatomaceous earth workers. 2. A cross-section survey of 98 workers on the job. Ind. Med. Surg. 29:370-378. Motley, H. L., Smart, R. H., and Valero, A. 1956. Pulmonary function studies in diatomaceous earth workers. AMA Arch. Ind. Health 13:265-274. Omura, T., Nakagawa, H., Yamamoto, S., Kato, T., Honda, R., and Nogawa, K. 1978. Respiratory function abnormalities in workers exposed to diatomaceous earth dust. Jpn. J. Ind. Health 20:254-260. Parry, D. W., and Hodson, M. J. 1982. Silica distribution in the caryopsis and inflorescence bracts of foxtail millet [Setartia italica (L.) Beauv.] and its possible significance in carcinogenesis. Ann. Bot. 49:531-540. Plunkett, E. R., and DeWitt, B. J. 1962. Occupational exposure to Hi-Sil and Silene. Arch. Environ. Health 5:469-472. Puntoni, R., Goldsmith, D. F., Valerio, F., Vercelli, M., Bonassi, S., Giorgio, F. D., Ceppi, M., Stagnaro, E., Filiberti, R., Santi, L., and Merlo, F. 1988. A cohort study of workers employed in a refractory brick plant. Tumori 74:27-33. Rabovsky, J. 1995. Biogenic amorphous silica. Scand. J. Work Environ. Health 21(suppl. 2):108-110. Reuzel, P. G. J., Bruijntjes, J. P., Feron, V. J., and Woutersen, R. A. 1991. Subchronic inhalation toxicity of amorphous silicas and quartz dust in rats. Food. Chem. Toxicol. 29:341-354. Rosenbruch, M. 1992. Inhalation of amorphous silica: morphological and morphometric evaluation of lung associated lymph nodes in rats. Exp. Toxicol. Pathol. 44:10-14. Schepers, G. W. H., Delahant, A. B., Schmidt, J. G., VonWecheln, J. C , Greedon, F. T., and Clark, R. W. 1957. The biological action of Degussa submicron amorphous silica dust (Dow Corning silica). Ill. Inhalation studies on rabbits. AMA Arch. Ind. Health 16:280-301. Smart, R. H., and Anderson, W. M. 1952. Pneumoconiosis due to diatomaceous earth: Clinical and x-ray aspects. Ind. Med. Surg. 21:509-518. Spain, B. A., Cummings, O., and Garcia, J. G. N. 1995. Bronchiolitis obliterans in an animal feed worker. Am. J. Ind. Med. 28:437-443. Swensson, A., Kvarnstrom, K., Bruce, T., Edling, N. P. G., and Glmme, J. 1971 Pneumoconiosis in ferrosilicon workersA follow-up study. J. Occup. Med. 13:427-432. Takizawa, Y., Hirasawa, F., Noritomi, E., Aida, M., Tsunoda, H., and Uesugi, S. 1988. Oral ingestion of Syloid to mice and rats and its chronic toxicity and carcinogenicity. Acta Med. Biol. 36:27-56.

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566

j . K. M C L A U G H L I N ET A L .

Downloaded by [Korea University] at 00:27 14 February 2013

Tebbens, B. D., and Beard, R. R. 1957. Experiments on diatomaceous earth pneumoconiosis. Arch. Ind. Health 16:55-63. Vigliani, E. C., and Mottura, G. 1948. Diatomaceous earth silicosis. Br. J. Ind. Med. 5:148-160. Villota, R., and Hawkes, J. G. 1986. Food applications and the toxicological and nutritional implications of amorphous silicon dioxide. Crit. Rev. Food Sci. Nutr. 23:289-321. Vitums, V. C., Edwards, M. J., Niles, N. R., Borman, J. O., and Lowry, R. D. 1977. Pulmonary fibrosis from amorphous silica dust, a product of silica vapor. Arch. Environ. Health 32:62-68. Volk, H. 1960. The health of workers in a plant making highly dispersed silica. Arch. Environ. Health 1:125-128. Warheit, D. B., Carakostas, M. C., Kelly, D. P., and Hartsky, M. A. 1991. Four-week inhalation toxicity study with Ludox colloidal silica in rats: Pulmonary cellular responses. Fundam. Appl. Toxicol. 16:590-601. Warheit, D. B., McHugh, T. A., and Hartsky, M. A. 1995. Differential pulmonary responses in rats inhaling crystalline, colloidal or amorphous silica dusts. Scand. J. Work Environ. Health 21(suppl. 2):19-21. Warshawsky, D., Reilman, R., Cheu, J., Radike, M., and Rice, C. 1994. Influence of particle dose on the cytotoxicity of hamster and rat pulmonary alveolar macrophage in vitro. J. Toxicol. Environ. Health 42:407-421. Weill, H., Jones, R. N., and Parkes, W. R. 1994. Silicosis and related diseases. In Occupational lung disorders, 3rd ed., ed. W. R. Parkes, pp. 285-339, 841-844. Oxford: ButterworthHeinemann. Wilson, R. K., Stevens, P. M., Lovejoy, H. B., Bell, Z. G., and Richie, R. C. 1979. Effects of chronic amorphous silica exposure on sequential pulmonary function. J. Occup. Med. 21:399-402.