NIOSH
HAZARD REVIEW
Health
Effects of Occupational Exposure
to
Respirable Crystalline Silica
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Table
20. Molecular epidemiology studies of biomarkers for carcinogenesis
or silicosis
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Reference
and country
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Study
design and cohort*
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Number
of subjects
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Biologic
marker
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Results
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Comments
|
| Bernard et al. [1994], Belgium |
Belgium quarry workers who had worked <2 yr. Controls were manual workers without silica dust exposure, matched by smoking status, body mass index, and age. | 86
quarry workers and 86 controls |
Serum and sputum Clara cell protein (Clara cell 16) | Decreased concentrations of serum and sputum Clara cell protein in quarry workers (P=0.04) compared with controls. | Controls may have been exposed to silica dust. Short duration of exposure among quarry workers may have limited the analysis. Authors state that serum Clara cell 16 may be marker for toxic effects of silica particles on respiratory epithelium. |
| Borm et al. [1986], Netherlands | Male silicosis patients at a hospital in the Netherlands; exposed to silica for 10–38 yr. Controls were "healthy male, Caucasian blood donors" aged 50–65. | 20
silicosis patients (15 coal miners, 4 ceramics workers, 1 foundry worker); 48 controls |
Blood
and plasma concentrations of hemoglobin, reduced and oxidized glutathione, glutathione peroxidase, and super-oxide dismutase |
Silicosis patients had significantly higher concentrations of red blood cell glutathione (P<0.0001). | Small
number of subjects. Controls were not interviewed for their occupational history, and definition of "healthy" was not reported. Medication administered to patients may have been a confounder. |
| Brandt-Rauf
et al. [1992], Finland |
Prospective
study of compensated pneumoconiosis patients; 91 blood samples were
collected between 1983 and 1987. Cancer cases were identified in the
Finnish Cancer Registry. 4 silicotics had worked as stone workers,
1 as a stone crusher, 2 as miners, and 3 as foundry workers. 3 silicotics with lung cancer were matched by age and smoking habits with 7 controls without cancer. |
46 patients: 36 with asbestosis and 10 with ILO† category >1/1 silicosis | 9 serum oncogene-related proteins or growth factors: growth factor PDGF-B (sis), TGF-β1, ras, fes, myb, int-1, mos, src, myc | 7/15 asbestosis patients had ras (p21) oncogene, but no oncogene-related proteins were found in the 10 silicosis patients. All silicosis patients had PDGF-B (sis) growth factor; only 42% of asbestosis patients had PDGF-B (sis). | Prospective study found that 3 of the 10 silicosis patients developed cancer during the study period (1983–1987). 2 patients had bladder cancer and 1 had lung cancer. PDGF may be a possible marker for development of severe or progressive silicosis. Study results suggest different pathogeneses for silicosis and asbestosis. |
| Calhoun et al. [1986], United States |
Healthy, male, employed granite workers (non-smokers) with no clinical or radiographic evidence of silicosis. Volunteer controls of similar age and smoking history with no history of occupational exposure to dust. All workers and controls had BAL. | 9 workers
and 9 controls |
IgG, IgM, IgA, albumin, and total protein (all were measured in BAL fluid and serum) | No significant differences in mean serum concentrations between workers and controls. Statistically significant differences (i.e., higher concentra-tion) between IgG, IgA, IgM concentrations and lymphocyte counts in lavage fluid of workers compared with controls. | Authors concluded that inhalation of granite dust might initiate and sustain an immune-inflammatory response. |
| Gáliková
[1982], Slovakia |
Miners,
drillers, and tun-nelers, half with silicosis, aged 43–81, exposed 2–30 yr. Control group of healthy blood donors aged 42–82 with no history of exposure to inorganic dusts. |
40 workers and 40 controls | Serum IgG, IgM,and IgA | No
difference in IgM concentration. Significantly elevated average concentration of IgG in workers compared with controls (P<0.001). Significantly elevated average concentration of IgA in workers compared with controls (P<0.05). No significant differences in IgG, IgM, or IgA between silicotic and nonsilicotic workers. |
Method of silicosis diagnosis not reported. |
| Gualde et al. [1977], France | Caucasian silicosis patients (radiographic diagnosis) who had a silica-related occupation for 10–40 yr (38 gold, wolfram, and uranium miners; 35 porcelain workers; 2 quarry workers). "Normal and healthy" Caucasian controls plus second control group of porcelain workers employed 20–40 yr but with no clinical or radiographic signs of silicosis. | 75 patients, 160 controls in first group, and 46 in control group of porcelain workers | 27
HLA antigens (serum) |
Prevalence of B7 antigen was significantly less (P<0.05 before correction for multiple comparisons of tested antigens) than in healthy or silica-exposed controls. No other significant differences found between silicotics and controls. | Small number of controls may have resulted in low statistical power to detect any differences after correction for multiple comparisons. Authors sug-gested that presence of B7 antigen may be related to resistance to development of silicosis. (See also Sluis-Cremer and Maier [1984] later in table.) |
| Honda et al. [1993], Japan | Japanese silicosis patients who had been sandblasters and who had radiographic evidence of silicosis. Controls were "healthy unrelated Japanese." | 46 patients, 315 controls for HLA typing, and 94, 127, 100, or 128 controls for other analyses | HLA-DQ alleles, RFLP patterns, and IGLV gene extracted from peripheral gran-ulocytes (medium not reported) | Some
HLA-DQ alleles were more frequent in silicosis patients (P<0.05). RFLP pattern of C4A3–C4B5 allotype and IGLV more frequent in silicosis patients (P<0.05). |
Source
and occupational history of control group not reported. Definition
of "healthy" not reported. Potential confounders of exposure
and immunological outcomes not reported.
Authors suggested that their findings indicate that a gene for silicosis may be near the HLA-B locus. Validation of these findings is needed. |
| Husgafvel-Pursiainen
et al. [1997], Finland |
Finnish white males with lung cancer (see comments). | 5 patients
with silicosis and 16 patients with asbestosis |
Mutation of p53 gene and serum elevation of p53 protein (serum samples were not available for the silicosis patients) | Two of the five silicosis patients had lung tumors with DNA mutations of the p53 gene. | Subjects
for study were drawn from cohort studied by Brandt-Rauf et al. [1992]
(described earlier).
The results of the serum tests do not support use of p53 assay by itself as a screening tool for lung cancer because only 36% of cancer cases tested positive for the mutant protein. The authors state that it may be a useful biomarker if combined with serum assays for altered oncoproteins as in the study by Brandt-Rauf [1992]. |
| Karnik et al. [1990], India | Male
slate pencil workers. Controls with no history of occupational exposure to dust or silica. |
130
silica-exposed workers: 80 with ILO category 1, 2, or 3 silicosis and 50 controls |
Serum IgG, IgM, and IgA | Higher concentrations (P<0.05) of IgG, IgM, and IgA in silicotic workers compared with controls. | Results may have been confounded by bacterial infections in some workers. Authors stated that an increase in immunoglobulin concentrations was not a marker for severity of silicosis. |
| Koskinen et al. [1983], Finland | Finnish male silicosis pa-tients (ILO category >1/1) who had been exposed to silica dust >10 yr. Non-silicotic controls matched by age (±5 yr), duration of silica exposure (± 5 yr), and work environment. Additional control group of healthy Finnish blood donors. | 27
patients; 27 non-silicotic, silica-exposed controls; and 900 blood donor controls |
Serum HLA antigens | Higher
prevalence of HLA-Aw19 in silicotics compared with non-silicotic,
silica-exposed controls (P=0.02). Higher prevalence of HLA-Aw19
in unexposed blood donor group than in silica- exposed controls (P=0.04). |
Authors state HLA-Aw19 may be marker for silicosis progression in Finnish population, but larger study groups are needed. |
| Kreiss et al. [1989a], United States | Silicotic residents from hardrock mining town in Colorado who had mined for 5–58 yr and were aged 30–59 when diagnosed with ILO category >1/0 silicosis. Published antigen prevalences of North American whites and international whites used for comparison. | 49 silicotics, 1,029 North American controls, and 1,061–1,082 international controls | HLA-A, HLA-B, HLA-DR, and HLA-DQ antigens (blood) | Significantly higher prevalence of A29 and B44 in silicotics compared with two control groups (P<0.05 after correction for number of antigens tested). | Population-based
study design.
A29 is a component of Aw19 (see Koskinen et al. [1983] above). |
| Pevnitskiy
et al. [1978], Russia |
Male
Russian patients aged 30–50 with "Stage I" silicosis
who had been employed >10 yr in occupations with exposure to quartz dust (i.e., casting shop cleaners, sandblasters, and molders). Controls were "clinically healthy" Russian male blood donors aged 30–50. |
32
silicosis patients and 32 controls |
11 HLA antigens (6 on A locus and 5 on B locus) (serum) | Prevalence of HLA–B8 and HLA–B13 in silicotics was twice the prevalence in the control group (P value not reported). | Occupational history of control group not reported. Definition of "healthy" not reported. Definition of "Stage I" silicosis not reported. Small number of subjects and controls. |
| Sluis-Cremer and Maier [1984], South Africa | White South African gold miners who had been exposed to at least 20 "low-dust" years. Control group of Caucasian nonminers. | 101 miners (45 silicotics of category >1/0 and 56 nonsilicotics) and 279 controls | 29
HLA antigens (medium not reported) |
Significantly fewer sili-cotics had B40 antigen compared with both silica-exposed and non-exposed comparison groups (P=0.02). | Source of control group not reported. No significant difference was found in the prevalence of B7, which does not agree with the findings of Gualde et al. [1977] (discussed earlier). |
| Sobti and Bhardwaj [1991], India | Male sandstone-crushing workers. Control group of local university teachers and students. | 50 workers and 25 controls | Blood: SCE and CA | Higher proportion of SCE and CA in silica-exposed workers compared with controls (2.72% versus 1.28%; P<0.01). More SCEs (P<0.01) in smokers—both silica-exposed and nonexposed. | Dust contained 50%–60% crystalline silica, 14%–16% aluminum oxide, and 4%–5% iron oxide. Possible effect of socioeconomic differences between workers and control group not accounted for. No statistical test for correlation between duration of exposure and levels of SCE and CA. Silica exposure concentrations not reported. |
| Watanabe et al. [1987], Japan | Males aged 34–78, hospitalized with ILO category >2 silicosis and employed as tunnel workers or metal miners for a mean duration of 23.8 yr. "Normal" male controls aged 46–72 without silicosis. | 82 patients and 25 controls | Total
blood lymphocyte count and lymphocyte subsets: OKT3+, OKT4+, OKT8+,
OKIa–1+
Serum
IgG, IgM, |
Silicosis patients with low lymphocyte counts (<1,500 µl) had significantly increased IgG and IgA levels compared with controls (P<0.001). Decreased number of circulating T-cells in patients. | Source
and occupational history of control group not reported. Definition
of "normal" controls not reported. Potential confounders
of exposure and immunological outcomes not reported.
Need further study of relationship of silicosis with serum immunoglobulin levels and lymphocytes. |
| *Studies
were cross-sectional unless otherwise indicated. †Abbreviations: BAL = bronchoalveolar lavage; CA = chromosomal aberrations; HLA = human leukocyte antigen; Ig = immunoglobulin; IGLV = immunoglobulin lambda variable chain; ILO = International Labour Organization; PDGF = platelet-derived growth factor; RFLP = restriction fragment length polymorphism; SCE = sister chromatid exchange; TGF = transforming growth factor. |
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