Table
20. Molecular epidemiology studies of biomarkers for carcinogenesis
or silicosis
|
Reference
and country
|
Study
design and cohort*
|
Number
of subjects
|
Biologic
marker
|
Results
|
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 1038 yr. Controls were "healthy male, Caucasian blood
donors" aged 5065. |
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 (19831987). 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 4381, exposed
230 yr. Control group of healthy blood donors aged 4282
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 1040 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 2040 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 C4A3C4B5 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
558 yr and were aged 3059 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 1,0611,082 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 3050 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 3050. |
32
silicosis patients and
32 controls |
11
HLA antigens (6 on A locus and 5 on B locus) (serum) |
Prevalence
of HLAB8 and HLAB13 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 smokersboth 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 3478, 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 4672 without
silicosis. |
82
patients and 25 controls |
Total
blood lymphocyte count and lymphocyte subsets: OKT3+, OKT4+, OKT8+,
OKIa1+
Serum
IgG, IgM,
IgA, IgD, and IgE
|
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. |