Early Detection Methods for Silicosis in Australia and Internationally: A Review of the Literature

Pneumoconiosis, or occupational lung disease, is one of the world’s most prevalent work-related diseases. Silicosis, a type of pneumoconiosis, is caused by inhaling respirable crystalline silica (RCS) dust. Although silicosis can be fatal, it is completely preventable. Hundreds of thousands of workers globally are at risk of being exposed to RCS at the workplace from various activities in many industries. Currently, in Australia and internationally, there are a range of methods used for the respiratory surveillance of workers exposed to RCS. These methods include health and exposure questionnaires, spirometry, chest X-rays, and HRCT. However, these methods predominantly do not detect the disease until it has significantly progressed. For this reason, there is a growing body of research investigating early detection methods for silicosis, particularly biomarkers. This literature review summarises the research to date on early detection methods for silicosis and makes recommendations for future work in this area. Findings from this review conclude that there is a critical need for an early detection method for silicosis, however, further laboratory- and field-based research is required.


Introduction
Silicosis is an incurable, sometimes fatal, but completely preventable lung disease caused by exposure to respirable crystalline silica (RCS). Worldwide, thousands of workers in a range of industries are at risk of developing silicosis. Early detection of silicosis is vital to identify the disease at a pre-clinical stage to allow interventions that improve outcomes for workers, while investigating inadequacies in workplace control practices. Currently, international respiratory surveillance includes health and exposure questionnaires, spirometry, X-rays, and high-resolution computed tomography (HRCT). However, some of these techniques are unable to detect silicosis at an early stage. This review investigates current respiratory surveillance for silicosis and explores potential opportunities for alternative early detection methods, particularly biomarkers and exhaled breath condensate (EBC).
Pneumoconioses are a group of non-malignant parenchymal (interstitial) lung diseases caused by inhaling dust particles [1,2]. Worldwide, one of the most common work-related injuries is pneumoconiosis, specifically caused by exposure to RCS [3]. Indeed, in China, pneumoconiosis is the most prevalent occupational disease [4]. Recent years have seen a resurgence of certain types of pneumoconiosis, particularly in the United States [5] and Australia [6].
The three primary types of pneumoconiosis are asbestosis, coal workers' pneumoconiosis (CWP), and silicosis [6]. Silicosis is a fibrotic lung disease caused by inhaling RCS [7]. For both developed and developing countries, silicosis is a major cause of mortality and morbidity [8]. Silicosis is highly prevalent in low-and middle-income countries, although the true extent is likely underreported due to poor respiratory surveillance [7]. to be scanned every year for their whole career. Regulators have a duty of care not to expose workers to an ongoing, annual dose of radiation, although it may be argued that the level of radiation is incidental, and must be weighed against the opportunity for a more sensitive test that reliably detects disease [19].
Despite efforts to establish and maintain best practices, respiratory surveillance continues to be a disparate process [27]. Standardisation of the process is required in order to protect workers exposed to RCS.
Despite the acknowledgment that improved detection methods other than spirometry, X-ray, and HRCT are needed, knowledge gaps remain around alternatives. Although research has been conducted into EBC and biomarkers as methods for detecting silicosis, these techniques have not been validated, and remain at an investigative stage. In addition, there is inconclusive evidence as to which biomarker(s) most effectively capture silicosis.
The literature review was directed by the following research questions: • What methods are currently used in respiratory surveillance for occupational lung disease? Have they been validated? • What alternative methods exist or are under investigation, and what evidence is there for the effectiveness of these methods?

•
Is there evidence to support conducting a prospective cohort study to test the validity of alternative methods of early detection of silicosis?
The overarching objective of this review is to inform changes to respiratory surveillance with the global goal to reduce the prevalence of silicosis and improve the prognosis of workers who develop silicosis. Although the search did return a large number of studies that investigated treatments, including murine experiments and investigations of DNA, treatments for silicosis are not a focus of this review.

Materials and Methods
The review involved three separate search strategies: a scoping literature review of peer-reviewed articles, a search of the grey literature, and a search of websites and online material. In addition, the research team consulted with leading academics and regulatory professionals in Australia and overseas to gain insights into the current prevalence of silicosis and screening methods.

Scoping Review
The scoping review was conducted according to the PRISMA-ScR framework. PRISMA-ScR is a systematic approach to assist with mapping evidence on a topic and identifying the main concepts, theories, and knowledge gaps relevant to that topic [28,29].
An initial browsing search of the online database MEDLINE was completed to familiarise the researchers with the key search terms. The scoping review search was conducted in the online library databases Scopus, Embase, and CINAHL. Using the keyword search function, search terms were: "silicosis" or "pneumoconiosis" or "black lung" or "respiratory fibrosis" or "dust disease", together with "monitor" or "early detect" or "mass screening" or "screen" (truncation and proximity searching were applied to some terms). The search was limited to articles written in English and published since 2010. Articles were catalogued and screened using the referencing software Endnote and the web-based software platform Covidence, which streamlines the production of reviews. The reference lists of included articles were also searched. The search was conducted in March 2020.

Grey Literature
When searching grey literature, it was necessary to keep the search terms more broad than when searching peer-reviewed journal databases. Google Scholar was searched with the terms "silicosis" and "early detection" and "screening". The records were presented according to relevancy; the first 200 records were screened, and those that were appropriate were included in the review [30]. The Mednar database was searched with the search term "silicosis". The first 200 records were screened, and relevant documents were included in the review. Mednar conducts a comprehensive search across medical societies, the National Institute of Health resources, US government websites, and patents. The OpenTrials database was searched to find clinical trials specifically relating to silicosis and early detection methods.

Websites, Industry, Government, and Regulators
When searching websites, it is optimal to maintain generic and overarching search terms, as the search relies on the website's own search engine. Websites searched included regulatory bodies, industry organisations, and government websites in Australia and internationally.

Results
The findings from the three search methods are synthesised below. The database search for the review returned 1751 articles. After 46 duplicates were removed, the titles and abstracts of 1705 articles were screened for relevance, of which 122 progressed to full-text screening. This final screening process determined that 52 articles were eligible for the final scoping review. Figure 1 shows the screening process for the scoping review. The final 52 articles included in the scoping review are summarised in Table 2.

Grey Literature
When searching grey literature, it was necessary to keep the search terms more broad than when searching peer-reviewed journal databases. Google Scholar was searched with the terms "silicosis" and "early detection" and "screening". The records were presented according to relevancy; the first 200 records were screened, and those that were appropriate were included in the review [30]. The Mednar database was searched with the search term "silicosis". The first 200 records were screened, and relevant documents were included in the review. Mednar conducts a comprehensive search across medical societies, the National Institute of Health resources, US government websites, and patents. The OpenTrials database was searched to find clinical trials specifically relating to silicosis and early detection methods.

Websites, Industry, Government, and Regulators
When searching websites, it is optimal to maintain generic and overarching search terms, as the search relies on the website's own search engine. Websites searched included regulatory bodies, industry organisations, and government websites in Australia and internationally.

Results
The findings from the three search methods are synthesised below. The database search for the review returned 1751 articles. After 46 duplicates were removed, the titles and abstracts of 1705 articles were screened for relevance, of which 122 progressed to fulltext screening. This final screening process determined that 52 articles were eligible for the final scoping review. Figure 1 shows the screening process for the scoping review. The final 52 articles included in the scoping review are summarised in Table 2.

Outcomes Location
Aggarwal [31] Investigate total lactate dehydrogenase (LDH) activity in blood samples as a non-invasive method to measure silica-induced toxicity. First study to estimate LDH activity in blood cells of silica-exposed agate workers and controls. Proposes LDH activity as a diagnostic tool for early silica exposure-induced cytotoxicity.
Cross-sectional Silica-exposed agate workers Blood plasma: LDH activity is higher (~25×) in exposed workers, suggesting that silica exposure may have induced cellular and tissue injuries, with more extracellular LDH enzyme released into blood plasma Alexopoulos et al. [32] Compare cellular profiles of asbestosis-exposed workers using induced sputum (IS) and bronchoalveolar lavage fluid (BALF) to test the usefulness of IS in monitoring workers over an extended period. Validate screening tool for biological

Outcomes Location
Codorean et al. [38] Perform exploratory study on peripheral whole-blood to analyse early effects of exposure in coal fired power plants.

Cross-sectional
Three groups: 10 years; 20 years; control This method is non-invasive and rapid and could be a useful tool in identifying early hazard before it is diagnosed clinically.

Romania
Corradi et al. [39] Review EBC studies that investigate exposure and effect biomarkers in lung disease, particularly toxic metals Exhaled breath biomarkers have been shown to be capable of detecting and monitoring diseases of the respiratory system.

N/A
Cox and Lynch [40] Provide review of recent developments in medical imaging of environmental lunch disease.
Medical imaging is useful in the diagnosis, epidemiological study and management of occupational lung disease. Studies that compare HRCT with film-screen radiography found CT was more sensitive.

N/A
Dinescu et al. [41] Identify correlations between electrocardiographic and echocardiographic changes in patients with silicosis prior to chronic pulmonary heart disease occurring.

Electrocardiograph, echocardiograph
Values of the right heart echocardiographic parameters at the upper limit of normality are early markers for cardiovascular damage in patients with silicosis.

Control: 25
Doganay et al. [3] Assess MDCT findings of silicosis in denim sandblasters and define the role of MDCT in the early detection of silicosis.

Outcomes Location
Greabu et al. [43] Evaluate the relationships between occupational exposure to mine dust and salivary antioxidants, blood uric acid and the possible implications for the causes of diseases caused by exposure.

Cross-sectional
Long-term occupational exposure in non-ferrous metal mines Johnsen et al. [45] Investigate the relationship between dust exposure and annual change in lung function among Norwegian silicon carbide exposed workers using a quantitative job matrix (JEM) regarding total dust First prevalence study in dental prosthetic technicians using HRCT. Pneumoconiosis was detected in 46%, possible because HRCT is able to detect very early changes.

Turkey
Kamaludin et al. [47] Determine biomarker to be used in diagnosis of occupational airways inflammation from occupational inorganic dust exposure.
Larici et al. [48] Highlight the current role of imaging, describe classic as well as uncommon HRCT patterns helpful in guiding diagnosis.
HRCT is the best imaging modality. Imaging plays a role in diagnosis, surveillance, and prediction.

Outcomes Location
Lee et al. [49] Review the roles of previously identified molecules in silicosis-related lung fibrosis from the literature. Miao et al. [55] Conduct proteomic profiling for the early stages of silicosis to investigate the pathophysiology and to identify potential candidate proteins for early diagnosis.
Case-control Dust-exposed workers without silicosis; silicosis patients; Healthy controls 45 N/A 55-64 X-ray, blood sample A number of proteins involved in silicosis development were identified, with a large number of proteins and peptides being dramatically altered during early development. This may contribute to future work to identify potential biomarkers.

China
Nardi et al. [56] Evaluate inflammatory and oxidative stress parameters as potential early biomarkers for RCS exposure.
Case-control CS exposed miners

Outcomes Location
Ophir et al. [58] Screen exposed workers using quantitative biometric monitoring of functional and inflammatory parameters.

Case-control
Artificial stone workers Exposed workers: 68 Male Exposed workers: 48.6 ± 11.4 Questionnaires, PFT, induced sputum Reports first application of XRF technology for quantifying elements in biological samples. PFT were significantly lower for exposed workers. Also IS in exposed workers showed significantly higher neutrophilic inflammation. Particle size in IS of exposed workers was similar to the artificial stone dust. Pelclová et al. [59] Evaluate the potential impact of lung fibrosis on the levels of oxidative stress markers in blood and urine of workers exposed to silica.

Case-control
Various occupations with exposure Asbestos exposed workers: 45 Asbestos exposed workers: 24 male Asbestos exposed workers: 69.6 ± 2.0 Questionnaires, physical examination, X-ray, CT, blood sample, urine sample, lung function, EBC 8-isoprostane appears to be the optimal oxidative stress marker for respiratory disorders. HNE can be used as a marker for pneumoconiosis. Findings support the suggestion that EBC can contribute to a better understanding of the pathogenesis of silicosis.
Czech Republic Silica exposed workers: 37 Silica exposed workers: 36 male Pelclová et al. [60] Measure multiple markers in the EBC, plasma and urine of exposed workers to determine the possible impact of systemic disease, pharmaceuticals and diet on EBC levels.

Case-control
Various occupations with exposure Asbestos exposed workers: 45 Asbestos exposed workers: 24 male Asbestos exposed workers: 69.6 ± 2.0 Questionnaires, physical examination, X-ray, CT, blood sample, urine sample, EBC Findings suggest that for the detection of pneumoconiosis EBC is the most useful compared to plasma and urine.
Czech Republic Silica exposed workers: 37 Silica exposed workers: 36 male  Sener et al. [63] Compare the ability of chest X-ray (ILO classification) and HRCT (ICOERD) to make an early diagnosis of pneumoconiosis.

Outcomes Location
Weissman [68] Provide update on literature relevant to using CT as a tool for preventing occupational respiratory disease.

Review N/A N/A N/A N/A N/A
Although HRCT is more sensitive than X-ray there are insufficient data to determine the effectiveness of HRCT in improving individual outcomes. However, if HRCT is used to screen populations, the ICOERD classification has been shown to be an important tool.

N/A
Xing et al. [69] Compare film-screen radiography and HRCT for the recognition of the profusion of small opacities and to evaluate the role of HRCT in CWP diagnosis.

Outcomes Location
Young et al. [72] Evaluate the use of CAD to diagnose both TB and silicosis in a population with a high burden of both diseases.
Using CAD as a mass screening tool for TB and silicosis shows promise, however current ability to differentiate between the two is limited. The successful use of CAD to streamline the process of detection requires knowledge of the local context.

South Africa
Yu et al. [73] Establish an automated scheme for CAD of pneumoconiosis in X-rays Propose a multi-scale opacity detection approach to detect suspected opacities from X-ray Findings demonstrate the approach to be effective in detecting and recognising silicosis opacity. The approach successfully revealed changes in silicosis pathology and may be adopted as an appropriate tool for automatic silicosis diagnosis.

China
In addition, following the search methods outlined above, there were 19 grey literature sources screened and included in the final review; these are summarised in Table 3. The countries represented by the peer-reviewed literature included in the scoping review are shown in Figure 2.
The worldwide occurrence of silicosis was demonstrated in the spatial distribution of the studies included. This was not necessarily an exhaustive list of all countries that had incidences of silicosis.
Many studies included in this review reported a high incidence of smoking among participants. This confounder makes it difficult to isolate the impacts of silica dust exposure from the damage caused by smoking. It is common practice for cessation of smoking programs to be promoted at screening appointments and to participants in silicosis research studies. The worldwide occurrence of silicosis was demonstrated in the spatial distribution of the studies included. This was not necessarily an exhaustive list of all countries that had incidences of silicosis.
Many studies included in this review reported a high incidence of smoking among participants. This confounder makes it difficult to isolate the impacts of silica dust exposure from the damage caused by smoking. It is common practice for cessation of smoking programs to be promoted at screening appointments and to participants in silicosis research studies.

Clinical Trials
OpenTrials returned 44 entries when we searched for "silicosis" and "pneumoconiosis", however, these trials either had no results available or were testing drugs for treatment. It appears from the search conducted for this review that clinical trials investigating early detection methods for silicosis are rare.

Discussion
This review was guided by the overarching aim to inform changes in respiratory surveillance with the global goal to reduce the prevalence of silicosis and improve the prognosis of workers who develop silicosis. Some articles included in the scoping review focus more broadly on pneumoconiosis in general or other types of pneumoconiosis, such as CWP. The methods investigated in these articles are pertinent to respiratory surveillance for silicosis. Different surveillance methods were identified, including spirometry, imaging, and HRCT, and these are discussed in more detail below.

Spirometry
Spirometry is a type of pulmonary function test. Spirometry is currently used for diagnosing the risk of damage, identifying lung disease, monitoring workers exposed to particulate matter, and to evaluate therapeutic interventions [35]. Although spirometry has been used as the first-choice method to evaluate pulmonary alterations in workers exposed to particulate matter, spirometry has limited sensitivity when detecting abnormalities before extensive damage occurs [35]. In addition, there are different standards for

Clinical Trials
OpenTrials returned 44 entries when we searched for "silicosis" and "pneumoconiosis", however, these trials either had no results available or were testing drugs for treatment. It appears from the search conducted for this review that clinical trials investigating early detection methods for silicosis are rare.

Discussion
This review was guided by the overarching aim to inform changes in respiratory surveillance with the global goal to reduce the prevalence of silicosis and improve the prognosis of workers who develop silicosis. Some articles included in the scoping review focus more broadly on pneumoconiosis in general or other types of pneumoconiosis, such as CWP. The methods investigated in these articles are pertinent to respiratory surveillance for silicosis. Different surveillance methods were identified, including spirometry, imaging, and HRCT, and these are discussed in more detail below.

Spirometry
Spirometry is a type of pulmonary function test. Spirometry is currently used for diagnosing the risk of damage, identifying lung disease, monitoring workers exposed to particulate matter, and to evaluate therapeutic interventions [35]. Although spirometry has been used as the first-choice method to evaluate pulmonary alterations in workers exposed to particulate matter, spirometry has limited sensitivity when detecting abnormalities before extensive damage occurs [35]. In addition, there are different standards for the procedure itself, for example, in Australia, the test must be performed for coal mine workers by practitioners with a particular qualification [77], but this is not required in other occupations.
Spirometry, or some form of pulmonary function test, was used in many of the studies in the scoping review. In these investigations, spirometry was always accompanied by health and exposure questionnaires and, in most cases, by additional surveillance methods, such as chest X-ray or HRCT [20,45,61,62,66]. Spirometry can contribute to the diagnosis and monitoring of pneumoconiosis, and specifically, Trakultaweesuk et al. [66] found that spirometry, using a mean decline in FEV 1 of 272.0 ± 155.5, was a good parameter for the respiratory surveillance of silica-exposed workers. It is important to note that spirometry and questionnaires alone are not able to diagnose the difference between silicosis and COPD. Despite the widespread use of spirometry, the practical implications and inconsistencies in performing the test must be considered [77].

Imaging
Respiratory surveillance routinely incorporates imaging, including chest radiography (X-ray) and/or HRCT. Globally, it is typical for chest X-rays to be assessed according to the International Labour Organisation (ILO) Classification System [78]. In addition, many jurisdictions have the requirement for an NIOSH B Reader to assess the chest X-ray, a certification granted to physicians who demonstrate proficiency in the classification of chest X-rays for pneumoconioses using the ILO Classification System [15].
It has been identified that chest X-rays are failing to reliably detect occupational lung disease [19,79]. For example, in a cohort of workers from Queensland, 43% had chest X-rays classified as normal using the ILO Classification System, however, the disease was visible on HRCT [19]. Non-occupational lung disease is now diagnosed using CT, and it is recommended that HRCT also replace chest X-ray for the diagnosis of occupational lung disease due to CT's higher sensitivity to detect early disease and greater accuracy in characterising patterns of disease [19,80,81]. The Royal Australian and New Zealand College of Radiologists [19] strongly recommend CT as the primary imaging modality to be used for respiratory surveillance in exposed workers. This recommendation is supported by Kahraman et al. [46], and the references therein.
Specifically, HRCT has an enhanced capacity to detect pneumoconiosis compared to chest X-ray due to the increased sensitivity provided by the finer spatial resolution and 3D nature of HRCT [6]. While Larici et al. [48] concluded that HRCT is the optimal modality of imaging,Şener et al. [63] resolved that, although HRCT had a higher rate of detection in the early stages, the cost, radiation exposure, accessibility, and lack of ability to evaluate pulmonary functions did not support the introduction of routine use in this setting.
In some jurisdictions, in this case Korea, analog radiography persists as the standard for respiratory surveillance. Lee and Choi [50] concluded that soft images from a flat-panel detector of digital radiography provide more accurate and reliable results in pneumoconiosis classification and diagnosis than analog radiographs, and concluded that, in the circumstance where HRCT is not available, digital radiograph is preferred. Conflictingly, [69] found digital and analog radiography to be equivalent.
There is a body of work that investigates the automatic classification of chest Xrays [57,64,72,73,75,76]. In some locations, there is a lack of expertise in the diagnosis of occupational lung disease, and it appears that these technologies have the capacity to assist by automatically detecting abnormalities in chest X-rays.
As stated previously, detection in the early stages of silicosis has challenges. McBean et al. [6] described radiologists as being at the frontline in occupational lung screening and that they must be aware of the imaging spectrum.

Biomarkers
There is a growing body of epidemiological research that focuses on validating biomarkers by assessing their ability to indicate exposure, effect, disease, or susceptibility [82]. When used in health surveillance, biomarkers can be indicators of hazard, exposure, disease, and population risk [83]. The overarching goal of using biomarkers is to provide insight into the pathogenesis of silicosis and the biological mechanisms that underpin its progression. This review identified a number of studies that aimed to validate particular biomarkers as indicators of silicosis [4,36,37,42,49,61,67]. The grey literature search returned several Chinese articles about biomarkers that could not be accessed.
Thakkar et al. [84] identified that existing studies that consider biomarkers have been conducted with cross-sectional methods within a group population over a short time period. These findings give statistical and probabilistic results in terms of an individual subject. However, what is needed is an observation of biomarkers over time, i.e., a longitudinal cohort study is essential. A study of this design would have prognostic value and contribute to workers adopting preventive strategies, while also reducing individual cases of silicosis [84].
Many studies test for biomarkers of oxidative stress, an imbalance in the body between the production of free radicals and the antioxidant defense [65]. Oxidative stress can lead to damage in biological tissue as a result of an imbalance between oxidants and antioxidants [82]. Metals found in mine dust have the potential to induce oxidative stress, which can cause harmful effects to the human body [43]. The ability of a chemical to exert biological effects dictates the capacity to generate oxidative stress [43]. Oxidative stress has been identified as strongly related to the severity of silicosis [12]. However, the parameters of oxidative stress that represent silicosis remain invalidated.
There are many avenues of biomarkers that require further investigation. It has been identified that, in the search for biomarkers for pneumoconiosis, there is a need to investigate biomarkers that play important roles in screening, diagnosis [74], and disease progression [85]. In addition, Schulte [83] notes the need to justify the cost and difficulty in obtaining samples. Pandey and Agarwal [85] emphasise the need for a cohort and longitudinal study of the potential biomarkers in vulnerable groups.
A large number of biomarkers with the potential to detect lung disease were investigated in the literature summarised in this review, including (but not limited to): Club/Clara cell protein 16 (CC16) [21]; serum HO-1 [61]; IL6 [53]; TNFα, IL6, and IL8 [47]; and Npnt [49]. It was not possible to determine a single biomarker with the most potential. Indeed, the need for research to identify biomarkers that provide insight into the pathogenesis of silicosis and the biological mechanisms that underpin its progression was abundantly clear.

Exhaled Biomarkers
Exhaled breath condensate (EBC) can be used to assess the respiratory health of pneumotoxic-exposed workers, as it quantifies lung tissue dose and the consequent pulmonary effects [39]. EBC is obtained by collecting exhaled cooled breath, which is analysed for volatile and non-volatile macromolecules [86]. The range of biomarkers that have been explored when investigating pneumoconiosis, including oxidative stress and inflammatoryderived biomarkers, suggests that EBC analysis may contribute to understanding the pathogenesis of the airways of exposed workers [39]. EBC analysis, as a method of studying pulmonary biomarkers of exposure, effect, and susceptibility in the workplace, proves to be one of the most promising methods currently available [39]. In particular, due to its non-invasive collection method, it is highly suitable to be applied in field studies and longitudinal assessments [39].
Although not commonly used, findings support the suggestion that EBC can contribute to an improved understanding of the pathogenesis of silicosis [59,60]. Indeed, when compared to plasma and urine, markers in EBC appeared to be the most useful method for detecting pneumoconiosis [60]. Leese et al. [87] demonstrated that crystalline silica particles can be detected in the EBC of exposed workers, however, there were limitations due to the volume of the sample produced.
The measurement of exhaled NO and volatile organic compounds is considered to be an inexpensive, safe, and easy-to-perform test that can be used to assess peripheral lung inflammation, and could potentially play a role in the diagnosis and follow-up of fibrosing lung disorders [62,71]. However, further research is needed that includes follow-up testing and investigating different levels of exposure [62].
EBC is non-invasive and highly accurate, making it an attractive option for the early detection of silicosis. Again, there is a growing body of research investigating a number of EBC options, and the need for further study is acknowledged [62,71,87]. Indeed, Corradi et al. [39] recognised the substantial limitations that currently exist, preventing its use as a routine method of screening in the workplace. Specifically, they identified the need for further development in the area of standardising EBC collection, data reporting, and validation of biomarkers.

Summary of Methods
This review identified the need to standandarise the process of respiratory surveillance. In addition, X-ray was determined as not sufficient in detecting silicosis, while spirometry is subject to the skill and experience of the practitioner. HRCT is recognised as the optimal method, however, it is not always available. EBC and biomarkers hold promise, although, at this stage, they are not validated and remain at an investigational stage.
The strengths of this review include the search being conducted beyond peer-reviewed literature to include grey literature and supporting regulatory documentation, as well as the scoping review following the systematic PRISMA-ScR framework. However, it should be noted there are some limitations, such as including only papers published in English, and the fact that only those published since 2010 were included.
Based on the findings presented here, a number of recommendations were formulated. Firstly, there is a need for further lab-and field-based studies that monitor a range of biomarkers to successfully identify one or more biomarkers that conclusively provide insight into the pathogenesis of silicosis and the biological mechanisms that underpin its progression. Second, any future empirical studies that attempt to validate the use of biomarkers or EBC as an early detection method for silicosis must also include standard surveillance methods as a point of comparison, i.e., spirometry, X-ray, and HRCT. Lastly, future empirical studies should include a diversity of participants to allow examination of a range of scenarios, for example, diagnosed silicosis patients at different stages of the disease, exposed workers (with no previous diagnosis of silicosis, COPD, TB, fibrosis, etc.) with a varying number of years of occupational exposure, and healthy unexposed controls with no previous diagnosis of silicosis, COPD, TB, fibrosis, etc.

Conclusions
Silicosis is a debilitating and sometimes fatal disease, yet it is totally preventable. Caused by exposure to RCS, hundreds of thousands of workers worldwide are at risk of developing silicosis. The global prevalence of silicosis (and other pneumoconioses) warrants further investigation into methods for detection in the early stage of the disease. While spirometry, X-ray, and HRCT can play important roles in respiratory surveillance, there is opportunity for new methods, such as biomarkers and EBC, to become routine methods of surveillance. Any future effort to research into early detection methods for respiratory surveillance should focus on providing insight into the pathogenesis of silicosis and the biological mechanisms that underpin its progression. These efforts should include longitudinal analysis of at-risk populations.  Data Availability Statement: Not applicable.

Conflicts of Interest:
The authors declare no conflict of interest.