Relationship between Occupational Exposure to Respirable Crystalline Silica and Serum Copper Level as an Indicator of Silicosis

A Systematic Review and Meta-analysis

Abstract

Background: 

This systematic review and meta-analysis study evaluates a relationship between occupational exposure to respirable crystalline silica and serum copper (Cu) levels as an indicator for early detection of silicosis.

Materials and Methods: 

A systematic search was conducted, and the quality of results was evaluated in accordance with the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The following databases were searched, including Web of Sciences, Scopus, and PubMed from inception until November 2021. The following keywords were selected for searching in the mentioned databases including, “copper” OR “serum copper” AND “silicosis”. The mean (standard deviation [SD]) of Cu was extracted for both silicosis and non-silicosis subjects. The differences in mean effect size were pooled using the random-effect model. Heterogeneity and publication bias were evaluated using the I² value and Begg's test and Egger's test, respectively.

Results: 

A total of 159 studies were initially found, among which eight studies were included in the meta-analysis. Random-effect meta-analysis of these eight studies showed that silicosis patients had higher copper levels than the non-silicosis group with a pooled standardized mean difference (SMD) of 3.02 (95% confidence interval: 0.25, 5.78); I² = 99.3%, P value < 0.001. The subgroup analysis showed that the corresponding figures in those with mean age >40 years and <40 years were 5.79 (2.06, 9.52) and −0.43 (−4.57, 3.70), respectively. Moreover, no publication bias was found in the analyses.

Conclusions: 

The results of the present study demonstrated that silica exposure may be associated with increasing serum Cu levels.

INTRODUCTION

Silicosis as a progressive, irreversible, and incurable fibrotic pulmonary disease generally occurs due to the inhalation of respirable crystalline silica (RCS) dust in workplaces.[¹] RCS refers to respirable silica dust particles that are smaller than 10 μm. Crystalline silica, as a common mineral found in the earth's crust, is found in sand, stone, concrete, and mortar. Moreover, it is commonly used in the production of a wide range of products in many occupations.[²] Silica has different polymorphs such as quartz, tridymite, cristobalite, coesite, stishovite, and several others. Among them, quartz is the most common form of silica polymorphs.[³⁴] As mentioned earlier, RCS exposure can occur in a wide range of activities and occupations such as construction, drilling, foundries, abrasive and sandblasting excavation, silica flour mixing, sand and clays, and casting, buffing, and molding of dental materials and jewelry.[⁵]

Due to the important adverse health effects of the inhalation of RCS, strict standards have been provided by various organizations such as occupational exposure limits (OELs) for RCS. The current Occupational Safety and Health Administration (OSHA) permissible exposure limit (PEL) for crystalline silica is based on a particle counting formula recommended in the 1970s by the American Conference of Governmental Industrial Hygienists (ACGIH). In 1986, the ACGIH revised the threshold limit value of 0.1 mg/m³ for respirable quartz.[⁵⁶] The National Institute for Occupational Safety and Health (NIOSH) (1998) and the ACGIH (2001) both recommend an occupational exposure limit of 0.05 mg/m³ for RCS. OSHA recognized the need to revise the PEL to reflect current sampling and analytical methods, and the agency determined to address the significant risk of silicosis and other serious diseases associated with silica through a special emphasis program (SEP) on silicosis.[⁶] However, this limit has been gradually reduced over the years to its current adopted value of 0.025 mg/m³ for time-weighted average measurements.[⁷] In recent years, numerous studies have focused on the detection of biomarkers or compounds in body fluids that indicate the level of actual exposure to a determined pollutant or disease. This issue has very important in occupational exposure because it can specifically represent workers’ exposure to a specific pollutant in workplaces. Until now, various biomarkers have been proposed for silica exposure among exposed individuals.[⁸] For instance, in a previous study, the plasma level of malondialdehyde was introduced as a potential biomarker for silicosis.[⁹] Moreover, it has been reported that during the inflammatory process followed by the inhalation of RCS, several compounds are generated by the immune system and then released such as macrophages, neutrophils, lymphocytes, cytokines, chemokines, and cell adhesion molecules.[¹⁰] Therefore, the level of this inflammatory parameter in body fluids can be considered as a potential biomarker for determining RCS-induced toxicity in exposed workers. The gene expression of some related proteins has been also reported as a biomarker in silicosis disease.[¹¹]

Several studies have reported a relationship between serum copper levels and silicosis.[¹²¹³¹⁴] Cu has a fibrogenic role in the primary pathologic changes of silicosis including fibrosis and the proliferation of collagen tissue in the lungs, which raises the possibility of an association between serum Cu levels and silicosis.[¹²] Due to inconsistent results regarding the relationship between serum copper levels and silicosis, the present study aimed to evaluate this association as a systematic review and meta-analysis.

MATERIALS AND METHODS

In the present study, the quality of results was evaluated in accordance with the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).[¹⁵]

Study selection and data extraction

To identify qualified studies published in the desired databases, a systematic search was conducted. For this reason, two authors independently searched the desired databases. The following parameters were considered for reviewing the selected papers, including, country of study, sample size, methods to measure RCS, silicosis status, serum Cu levels, job position, work experience, and RCS exposure level. The following databases were searched, including Web of Sciences, Scopus, and PubMed from inception until November 2021. The following keywords were then selected for searching in the mentioned databases including, “copper” OR “serum copper” AND “silicosis”. Moreover, the reference list of each paper was checked by another author, and related articles were manually searched to identify further acceptable studies. The filters employed were humans and the English language.

Inclusion and exclusion criteria

In the present study, the potential papers from the three desired databases were imported into EndNote software. After importing into the software, duplicate articles were removed using an option in the used software. Then, the title and abstract of the selected paper were reviewed to select the eligible papers. This step was conducted by two authors. Some papers without an available abstract in EndNote were further searched in the related databases to access their full texts. Original papers including cross-sectional, case-control, and cohort studies in the English language were identified and selected for further investigations. Case reports, case series, letters to editors, review articles, animal studies, articles without available full text, and non-relevant conference records were excluded.

Statistical analysis

Because Cu levels were measured in a variety of ways in included studies, the Standardized Mean Difference (SMD) suggested by Cohen (Cohen's d)[¹⁶] was used to compare the difference in mean of Cu levels between silicosis and non-silicosis groups. The pooled results were expressed as the pooled SMDs and 95% confidence intervals (CIs). SMDs of 0.2, 0.5, and 0.8 represent small, medium, and large effect sizes, respectively.[¹⁶] Heterogeneity among included studies was quantified through the Higgins I² value. Substantial heterogeneity was set as I² > 50%.[¹⁷] Random-effect meta-analysis was used to calculate the pooled effect sizes; otherwise, the fixed effect model was applied. Potential publication bias was checked using a funnel plot, Begg and Mazumdar rank correlation test, and Egger's regression test. Statistical significance was set at P < 0.05. All statistical analysis was conducted using STATA package version 11.0 (Stata Corporation, College Station, TX, USA).

RESULTS

Search results

Figure 1 presents the PRISMA flow diagram of the systematic review and meta-analysis selection process. According to the search strategy, 25, 84, and 50 published papers were found in the Web of Sciences, Scopus, and PubMed until November 2021, respectively. After discarding 64 duplicates, a total of 95 articles were screened. Five studies met the eligibility criteria. Three other papers were identified using reviewing the reference list of eligible articles. Finally, 8 articles were selected and included in the meta-analysis.[^{1213181920212223}]

Figure 1: PRISMA flow diagram of the systematic review and meta-analysis selection process

Study characteristics

The characteristics of 8 studies included in the meta-analysis are presented in Table 1. Five studies were from African countries.[^1213192022] It is noteworthy that among the studies from African countries, four studies were from Egypt. The year of publication of the included studies varied from 1981[²¹] to 2016.[¹⁸¹⁹] The total sample size in silicotic and non-silicotic groups was 404 and 546, respectively. There was a high variation in the exposure duration. For example, in one study,[¹²] the mean (SD) of the duration of exposure was 26.8 ± 5.0 years, whereas the duration of exposure in one another study was 5 years.[²¹] The mean age of the study population in 50% of the included studies was less than 40 years. In all included studies, the method ascertainment for Cu was atomic absorption spectroscopy (AAS), except for one study[²⁰] in which the colorimetric assay was used for the determination of serum Cu levels.

Table 1: Characteristics of included studies in meta-analysis

Meta-analysis

Random effects meta-analysis of eight studies showed that silicosis patients had higher copper level than that in the non-silicosis group with a pooled SMD of 3.02 (95% CI: 0.25, 5.78); I² = 99.3%, P value < 0.001 [Figure 2]. The funnel plot was symmetric [Figure 3], and the P values for Begg's Test and Egger's test were 0.80 and 0.88, respectively, indicating no evidence of publication bias. In the subgroup analysis according to the mean age of the study population, the random-effect meta-analysis revealed that SMD (95% CI) was 5.79 [2.06, 9.52] among those with a mean age of higher than 40 years, whereas the corresponding figure was − 0.43 (−4.57, 3.70) among those who were younger than 40 years. The I² value for these two analyses was more than 90% [figure not shown]. The results showed no difference in the copper serum level in silicosis and non-silicosis groups when the analysis was restricted to five studies from African countries (pooled SMD of 1.33; 95% CI: −2.60, 5.27; I² = 99.4%, P value < 0.001) [Figure not shown].

Figure 2: Meta-analysis of SMD of copper serum levels between silicosis and non-silicosis groups

Figure 3: Funnel plot for evaluating potential publication bias for SMDs

DISCUSSION

Due to conflicting results regarding the relationship between silicosis and serum copper levels, this meta-analysis aimed to compare the serum levels of Cu between silicotic and non-silicotic subjects. Our results showed that the difference in the mean of Cu between silicotic and non-silicotic subjects was statistically significant as the mean of Cu in silicotic patients was 3.02 units higher than that in the non-silicotic subjects. The difference can reach 5.79 units when the analysis is restricted to subjects with a mean age of higher than 40 years.

This result is consistent with the findings of the previous studies.[²⁴] For instance, in a previous study, a higher level of urinary Cu in silica-exposed workers with a 10-year work experience was significantly higher than that in the non-exposed group.[¹³] Cu has a fibrogenic property, and hence, due to the primary pathologic changes in silicosis patients including fibrosis and proliferation of collagen tissue in the lungs, increasing the levels of serum Cu can be attributed to the fibrotic involvement of lung tissue. Various studies have reported higher levels of serum Cu in silicotics; however, the mechanism is still not well understood.[¹²] About 90–95% of the total amount of Cu in blood serum is attributed to bound protein, mostly with α2–globulin (Cp).[²⁵²⁶] Therefore, it is significantly higher than that in non-exposed workers.[²⁷] Similar findings were also reported regarding the increased urinary excretion of Cu in silica-exposed workers.[¹³²⁸] In this regard, in a previous study on the influence of exposure to RCS on urinary excretion of some parameters, it was found that the Cu urinary level was significantly increased among the RCS-exposed workers compared to a non-exposed group, and a significant relationship was reported between urinary levels of Cu and the structural urinary parameters, glomerular and proximal tubular functional parameters, and work experience.[¹³] Also, Ahmed et al. (2013)[²⁸] demonstrated a significant increase in the urinary excretion of amino acids and Cu in silica-exposed workers compared to a non-exposed group.

Consistent with our findings, in a previous study, the role of chronic inflammation in the homeostasis of lung trace element biometals, including copper (Cu), zinc (Zn), and selenium (Se), in the transgenic mice tissues was investigated.[²⁹] Proper homeostasis of trace elements such as Cu, Zn, and Se plays key roles in normal physiology, and an imbalance in the level of these elements can result in severe pathologies in mammals. In the mentioned study, Zn and Se levels did not show a decrease during acute severe inflammation in the lungs or other tissues in our chronic-inflammation mouse model. However, the Cu level showed a significant decrease in the lung tissue with Cu being the main component of antioxidant enzymes.[²⁹]

Our study has several limitations that should be considered. First, our meta-analysis should be generalized with caution because no studies have been included in the analysis from most parts of the world. Second, over 90% heterogeneity among the included studies can increase the degree of uncertainty in the results. Third; the results should be presented according to different variables, for example, duration of exposure and job type using further subgroup analysis; however, it was not possible due to a limited number of studies in each subgroup and lack of available data. Fourth, the selection bias in identifying eligible articles can potentially threaten the validity of the results.

CONCLUSION

Our meta-analysis demonstrated significant differences in the mean serum level of Cu between silicotic and non-silicotic subjects, especially among subjects who are older. This analysis emphasizes that Cu can be considered as a marker for the early detection of silicosis. Further large-scale prospective studies are recommended to identify the relationship between serum Cu levels and silicosis.

Ethical consideration

Due to the nature of this study as a meta-analysis and systematic review, there are no ethical considerations in it.

Financial support and sponsorship

This research was supported by the Hamadan University of Medical Sciences. No funding was received for this research.

Conflicts of interest

There are no conflicts of interest.

Acknowledgments

The authors would like to thank the Hamadan University of Medical Sciences for supporting this research. (Grant No. 140011129274, Ethical Code:IR.UMSHA.REC.1400.869).