Silicosis, one of the oldest occupational diseases, is a pneumoconiosis caused by the long-term inhalation of inorganic dust with high concentrations ($>$10%) of free crystalline silica (SiO${}_2$). This interstitial lung disease is characterized by inflammation, formation of silicotic nodules, and fibrosis, which are progressive and irreversible [1].

The latency period for silicosis ranges from a few years to several decades, depending on the duration and intensity of exposure to silica dust. In some occupational pulmonary diseases, such as silicosis, mesothelioma, and asbestosis, the diagnosis can be delayed due to the long latency period, leading to unfavorable disease outcomes [2]. Thus, it is important to increase awareness of the disease, impose strict safety guidelines and regulations, and follow them in order to minimize workers’ exposure to silica dust. Apart from prevention measures, the long-term health monitoring of individuals who have been exposed to silica dust is also important for the early identification of any potential health problems.

Awareness of the health problems related to silica dust exposure and a rigorous occupational history are essential tools for an early diagnosis. This is especially important, as an accurate diagnosis might be associated with a better prognosis. The migration of workers globally may result in a lack of adequate health monitoring or failure to account for prior exposure to silica dust.

The International Labour Organization (ILO) and the World Health Organization set a goal in 1995 to eliminate silicosis from workplaces by 2030 through the Global Program to Eliminate Silicosis [3]. This goal cannot be easily reached since new sources of silica dust are identified in new technological processes, and the effectiveness and feasibility of dust control methods and technologies vary in different countries.

Silicon dioxide, also known as silica, is a widespread mineral that makes up part of the structure of the Earth’s crust. It is formed from silicon and oxygen under increased pressure and temperature conditions. There are two forms of silica: crystalline and amorphous. The crystalline form is very aggressive in lung tissue [4]. Occupational exposure to silica can occur in many workplaces or industries such as mining, metallurgical and car manufacturing industries, abrasive materials, glass, porcelain, or the tile industry [5]. In addition, occupational exposure to silica particles has also been identified in the case of new technological processes such as jewelry manufacturing, denim sandblasting or manufacturing, and processing of artificial stones [6, 7, 8], which are associated with accelerated forms of silicosis and the rapid degradation of lung function in young people [9]. The results of a study by Hua et al. [9] identified a possible significant emerging population of young stoneworkers who have severe and irreversible silicosis. The artificial stones have a content of 85–93% silica; thus, processing such stones is currently the major cause of the increase in the number of silicosis cases, especially in Spain, Australia, and Israel [10].

During the early 2000s, artificial stones were introduced in Australia, which were processed by dry-cutting methods [11]. A study conducted in Israel on 68 non-smoking workers handling artificial stone showed that ultrafine particles accumulated in their airways, causing sustained neutrophilic inflammation [12]. Another report from Rose et al. [13] described 18 cases of silicosis in Hispanic stone mill workers from four US states. In 2018, the government of Australia launched in Queensland a screening program for workers in artificial stone factories, which diagnosed 98 individuals with silicosis out of the 799 screened [13]. Furthermore, Quan et al. [14] discovered that patients with silicosis linked to artificial stone processing have a more than 5-fold higher risk of experiencing progression with a significant decline in lung function compared to patients with non-artificial stone-related silicosis.

There are three clinical forms of silicosis: chronic (classic), accelerated, and acute (silicoproteinosis). The chronic form of silicosis is the most common and occurs after 15–20 years of exposure to free crystalline silica dioxide particles. Accelerated silicosis can occur after 5–10 years of exposure to increased concentrations of silica dust, and the acute form usually occurs after very high exposure to silica in a period of a few months to 2 years [15, 16]. Individual susceptibility is an important element that could explain the different reactions to silica exposure observed in workers from the same working environment who are exposed to similar concentrations of silica dust. Genetic and epigenetic components play important roles in individual susceptibility [17].

Several valuable reviews on silicosis have been published in the last several years focusing on certain aspects of silicosis such as epidemiology, pathogenic mechanisms, diagnosis, and treatment [9, 11, 18, 19, 20]. Since there is a great deal of interest in silicosis, new data are constantly emerging. The aim of this paper is to integrate all available data, present the current sources of exposure to silica dust, and provide updated information on risk factors (e.g., socioeconomic status, genetic susceptibility), sex differences, silico-tuberculosis (TB), prognostic markers including 16-kDa Clara cell secretory protein (CC16), antifibrotic treatment, and other therapeutic possibilities with promising results. Additionally, the aim of this paper is to raise awareness of the impact of this preventable disease on public health, and to call for continued action to address this important occupational health issue. It is important to ensure that workers are adequately protected from the harmful effects of silica dust exposure and that the incidence of silicosis is reduced. Even though the link between occupational exposures and respiratory diseases is well known, there is often a lack of recognition and awareness of this association among clinicians and workers, and education is an essential tool to overcome unfortunate outcomes.

The epidemiology of silicosis is complex and multifactorial and includes several risk factors, such as sex differences, socioeconomic status. The most important risk factors for silicosis include prolonged exposure to silica dust, the duration and intensity of exposure to silica dust, and the shape and size of silica particles. New information on sex differences in silicosis has emerged. Initially, silicosis was considered a disease that predominantly affected males because exposure to silica dust was mostly occupational for men and epidemiological studies have mainly been conducted in heavy male-dominated industries. However, there is an increasing number of women working as dental laboratory technicians, artists, and ceramic technicians, as well as in mining or foundry work, and recent studies have shown that women are also at risk of developing silicosis. A cohort study carried out in the car manufacturing industry in China, which included 2009 subjects (1405 men [70%] and 603 women [30%]), proved that the incidence of silicosis was higher in men and increased with duration of the exposure period [21]. This conclusion was supported by studies carried out in workers in pottery factories [22]. According to Ndlovu [23], the employment of women in gold mining in South Africa has significantly increased, from less than 1% before 2002 to more than 10% in 2013. The development of new technological processes, such as jeans sandblasting or jewelry polishing, can cause silicosis equally in men and women.

Socioeconomic status also plays a role in the development of silicosis. Lack of protective equipment and lack of safety measures in the workplace that might be found in nonregulated countries, are associated with a higher risk of exposure to silica dust. The additional exposure to high levels of air pollution may also lead to an increased risk of developing silicosis [24, 25, 26, 27]. Other factors that may contribute to the epidemiology of silicosis include genetic factors, other co-existing medical conditions, and environmental factors. Individual susceptibility is an important factor that can explain different reactions in workers exposed to silica dust, even though they share the same working environment and are exposed to silica dust in similar concentrations. This is explained by individual genetic factors. According to Zhou et al. [17], susceptibility to silicosis is associated with the presence of single nucleotide polymorphism rs1814521 in long non-coding RNA ADGRG3. Co-existing medical conditions that contribute to developing silicosis are TB or human immunodeficiency virus [4, 16]. As aforementioned, environmental factors such as high levels of air pollution or additional irritants in the air may impact the inhalation and deposition of silica particles in the lungs.

Although efforts have been made to prevent workers from being exposed to silica dust in recent decades, silicosis is still a public health issue with a higher prevalence in developing countries. Even though its incidence has decreased considerably, it is a disease with poor clinical prognosis, which does not yet have an effective treatment. Each year, more than 230 million workers worldwide are exposed to free crystalline silica particles [28], with more than 40.5 million people employed in artisanal and small-scale mining, which involves unmechanized mining methods that result in high exposure to silica dust [29]. In Brazil, exposure to silica dust affects more than 6 million workers daily [30], with the prevalence of silicosis being higher in people aged 60 years and older, followed by adults aged 40–59 years [11]. Similarly, recent literature data suggest that in India, more than 10 million workers are exposed to silica particles [30]. In South Africa, silicosis is a significant public health concern, particularly in the gold mining industry where miners are exposed to high silica dust content (ranging from 9% to 39%). The social conditions associated with mining involve migration and dormitory-style housing [31]. The United States and Europe each have more than 2 million people working with silica [10], whereas in the United Kingdom, about 600,000 workers are considered at risk of illness [7]. In southern Spain, a total of 106 patients were were diagnosed with artificial stone silicosis between 2009 and 2018 [32]. In Romania, there were 29,046 workers exposed to silica dust in 2007, representing 0.98% of all those exposed to occupational hazards [33], with 3066 new cases of silicosis diagnosed between 2007 and 2021 [34]. Statistical data have shown that 4.2% of deaths reported for Chinese workers are caused by exposure to breathable particles of silica [35], with more than 6000 new cases of silicosis reported annually [36]. Globally, the incidence of silicosis is more than 20,000 cases per year [8] and over 12,900 deaths are recorded, with an estimated 0.65 million disability-adjusted life years in 2019 [37].

Inhalation of respirable silica particles leads to formation of mineral deposits in the terminal bronchioles and alveoli and induces pulmonary tissue reactions of the inflammatory type and proliferation of fibroblasts by complex pathogenic mechanisms, causing fibrosis as presented in Fig. 1 [38]. Disease severity and pathogenicity depend on the quantity of inhaled dust and the time of exposure. Under normal conditions, lung epithelial cells can replace damaged cells, due to exposure to silica dust through cell proliferation and differentiation. However, chronic exposure to silica dust can lead to repetitive damage and repair of airway epithelia, resulting in depletion of airway epithelial stem cells in pulmonary silicosis [39].

Fig. 1.

Schematic representation of the pathogenetic mechanisms of silicosis.

Lung tissue reactions result from the joint action of several mechanisms, such as the direct cytotoxic effects of silica particles on macrophages, activation of the surface of receptors of the macrophages, rupture of lysosomes, production of free radicals, activation of inflammasomes, production of cytokines and growth factors, and cellular apoptosis, which finally lead to fibrosis [19]. Most of the studies investigating the pathogenesis of silicosis have focused on the roles of alveolar macrophages and alveolar epithelial cells, which secrete pro-inflammatory and profibrotic mediators secondary to exposure to silica [40].

Alveolar macrophages, alveolar epithelial cells, and fibroblasts are involved in the complex pathogenesis of silicosis. Alveolar macrophages are the first cells to react against inhaled silica particles, as they are found in the alveolar surfactant. They have a protective role as they recognize, phagocytose, and degrade the silica dust. During this process, alveolar macrophages can undergo disintegration, necrosis, and apoptosis. The apoptosis of alveolar macrophages leads to pulmonary fibrosis. In addition, apoptotic alveolar macrophages release a significant amount of inflammatory factors, increasing inflammation [41, 42]. Alveolar epithelial cells are also affected by silica exposure. One study showed that silica exposure increases the permeability of alveolar epithelial cells [43]. Another study identified the activation of autophagy in alveolar epithelial cells and concluded that blockage of autophagic flux in alveolar epithelial cells is crucial in silica-induced pulmonary fibrosis [44]. Fibroblast activation and myofibroblast differentiation are also part of the pathogenetic mechanism of pulmonary fibrosis in silicosis. Following exposure to silica dust, fibroblasts are activated and differentiate into myofibroblasts, secreting substantial amounts of extracellular matrix (ECM) proteins. According to Li et al. [45], silicosis is associated with the deposition of excessive ECM produced by activated fibroblasts.

As aforementioned, silica particles can activate alveolar macrophages and also directly damage epithelial cells, which leads to the release of a large number of profibrotic factors (e.g., tumor transformation and growth factor beta [TGF-$\beta$], platelet-derived growth factor [PDGF]). These factors facilitate the activation and proliferation of lung fibroblasts causing, in turn, further secretion of the ECM and leading to pulmonary fibrosis [46]. According to Qi et al. [47], the process of fibroblast transdifferentiation into myofibroblasts, as well as their plasticity and phenotypic transition, are of particular importance in the progression of fibrosis. Silica particles from the breathable fraction are recognized by alveolar macrophages and phagocytosed, triggering an inflammatory response. The inflammatory response includes the production of reactive oxygen species and reactive nitrogen species, cytokines, nuclear transcription activation factors (nuclear factor kappa B and activator protein 1), mediators that recruit and activate inflammatory cells, and caspase-1, which stimulates the growth factor of fibroblasts responsible for the proliferation of fibroblasts [48]. The mediators and cytokines that contribute to inflammation and pulmonary fibrosis are tumor necrosis factor alpha (TNF-$\alpha$), TGF-$\beta$, interferon gamma (IFN-g), PDGF, proinflammatory interleukins (interleukin 1 beta [IL-1$\beta$], IL-2, IL-6, IL-8, IL-12), and fibronectin. Inflammasomes are large macromolecular signaling complexes that control the proteolytic activation of two highly proinflammatory IL-1 family cytokines: IL-1$\beta$ and IL-18 [49]. The NACHT, LRR and PYD domains-containing protein 3 (NALP3) inflammasome is of special interest, because it is a complex intracellular structure that is considered a sensor of cellular stress involved in inflammatory reactions. Furthermore, activation of the NALP3 inflammasome by silica plays an important role in both inflammation and fibrosis [50], stimulating T cells to express IL-10, cytotoxic T-lymphocyte antigen 4, and TGF-$\beta$ [51].

Oxidative stress induces cellular apoptosis. During apoptosis, the cells release chemotactic factors that recruit new inflammatory cells, thereby increasing inflammation. In addition, following phagocytosis, macrophages release silica particles back to the lung parenchyma, where they are phagocytosed by other macrophages, perpetuating the vicious cycle of tissue destruction [30]. The increased production of profibrotic substances and the role of cytokines in differentiation into fibroblasts, cause excessive accumulation of collagen and fibronectin fibers, leading to the formation of silicotic nodules, tissue fibrosis, and the reduction of gaseous exchange surfaces [4, 40]. The process of pulmonary fibrosis is irreversible and the impairment of lung function is progressive and continues even after the cessation of exposure to silica dust affecting all areas of the respiratory system, including lung parenchyma and central and small airways [52].

The pathogenesis of silicosis may also be associated with an immunological mechanism, an idea supported by the identification of serum immunoglobulins, anti-DNA, and antinuclear factor antibodies in the serum of patients with silicosis [51]. After inhalation, the silica particles that are deposited in the lung tissue or lymph nodes can modulate the activity of immune cells such as natural killer cells, B cells, regulatory T cells, CD4 T helper cells, and cytotoxic T lymphocytes, thereby influencing immune tolerance. A study by Tomokuni et al. [53] reported that soluble Fas levels (a molecule that inhibits Fas-mediated apoptosis of responder T lymphocytes) were significantly higher in silicosis patients than in healthy volunteers. Additional studies are needed to clarify the cellular and molecular pathogenetic mechanisms of silicosis. These could also be useful for the prevention of immune diseases associated with silicosis (e.g., rheumatoid arthritis, systemic lupus erythematosus, scleroderma, and vasculitis) [54].

Silicosis is a disease with progressive evolution to respiratory failure, the main cause of death. In 1997, the International Agency for Research on Cancer introduced crystalline free silica into group 1 of carcinogens. There is strong and consistent evidence of a dose-response relationship between silica exposure and the risk of lung cancer [55]. The prognosis of the disease can be severe, especially when silicosis is associated with comorbidities such as pulmonary TB, autoimmune diseases, fungal or bacterial infections, pulmonary cancer, chronic obstructive pulmonary disease (COPD), or kidney disease [4, 16].

Since there is a long time between silica exposure and the pulmonary tissue reactions becoming radiologically visible, biomarkers that can be found in the initial stages of silicosis would be particularly useful for the screening or health evaluation of workers with occupational exposure to free silica particles. The serum level of the following inflammatory mediators could be a prognostic biomarker in silica-exposed workers: IL-6, IL2R, IL-1b, IL-8, TNF-$\alpha$, TGF-$\beta$1, alpha-1 antitrypsin, C-reactive protein, lactate dehydrogenase, and ferritin [56]. Plasma determination of CC16, a protein present in bronchoalveolar secretions, is reportedly used for the periodic screening of workers exposed to silica dust for the early detection of silicosis [57]. A study conducted by the Indian Council of Medical Research-National Institute of Occupational Health (Ammedabad, India) showed that CC16 levels between 6 and 9 ng/mL indicate the early stages of silicosis [58]. Still, chest X-ray (CXR) and computed tomography (CT) scan are required to confirm the diagnosis. However, other lung conditions such as asthma or COPD can also cause a decrease in CC16 [57]. There are studies claiming the usefulness of CC16; however, it is a nonspecific marker and may not be that useful due to its nonspecificity.

Several researchers have shown increased serum levels of angiotensin convertase in pulmonary granulomatous diseases such as silicosis and sarcoidosis. Increased serum values of copper and ceruloplasmin can be associated with pathological changes, such as fibrosis and the proliferation of collagen tissue in the silicotic lung [51]. Furthermore, studies have shown a correlation between an increase in the neutrophil/lymphocyte ratio and the radiological evolution from simple silicosis to massive progressive fibrosis, given that no other factors that influence the pulmonary inflammatory process are associated such as smoking or other acute or chronic respiratory diseases [59, 60]. However, none of these factors is conclusively a specific biomarker with clinical application or the potential for early diagnosis in silicosis. Thus, further research on the pathogenic and biological mechanisms of the disease is needed.

Pulmonary TB is one of the most common comorbidities associated with silicosis, with an increased incidence in less developed countries. Silico-TB is active TB superimposed on silicosis. The relative risk of patients with silicosis developing pulmonary TB is estimated to be 2.8 [61]. Approximately one-quarter of patients with silicosis and coal workers’ pneumoconiosis, commonly affected by peripheral lymph node calcification known as “eggshell calcification”, have silico-TB [62]. The risk of TB increases with the severity of silicosis, and exposure to silica dust increases the risk of TB even without silicosis [18].

The diagnosis of silico-TB is often difficult, especially in the early stages of disease when clinical manifestations may not be indicative and radiological changes may be indistinguishable from those due to pre-existing silicosis. The suspicion of silico-TB should be raised when there are radiological findings of the rapid appearance of new opacities and pleural effusion or excavations. Generally, active disease is difficult to detect clinically in patients with silicosis [61]. Silicosis can be a contributing factor of TB mortality due to diagnostic confusion and consequent delayed TB treatment [36].

According to Rupani’s study [37], which included 138 patients with silico-TB and 2610 patients with TB without silicosis, patients with silico-TB were 2.3 times more likely to have unfavorable TB treatment outcomes compared to patients with TB without silicosis, perhaps due to impairment of macrophage function by silica dust and/or poor drug penetration into fibrotic nodules [61]. Furthermore, Rupani suggested undertaking collaborative TB-silicosis activities to improve the outcomes of silico-TB treatment [37].

The fatality rate among patients treated for TB is three times higher in patients with silicosis than in those with non-silicosis due to difficulties in diagnosis, impaired lung function, or reduced effectiveness of tuberculostatic treatment due to pre-existing pulmonary fibrosis [36].

CXR and high-resolution CT (HRCT) are the main tools used for diagnosis. The diagnosis of silicosis typically involves the use of three international criteria: a history of silica exposure that is sufficient to cause the disease, the presence of chest radiograph features consistent with silicosis, and the absence of other illnesses that mimic silicosis.

Currently, there is no effective treatment for silicosis, and prevention is the only tool to decrease the risk of disease. Numerous experimental studies and several clinical studies have focused on several therapeutic options that could slow down the progression of silicosis such as antifibrotic drugs, cell therapies, antibiotics, and immunomodulatory agents. However, the small number of patients with silicosis is a big obstacle to attaining an adequate sample size for clinical trials. Table 1 summarizes the treatment options (in use or under investigation).

There are currently no ways to eliminate silicosis and no drug treatments available to stop the progression of fibrosis or improve the disease. Thus, it is necessary to implement effective safety measures to prevent the disease. Accordingly, prevention strategies are being sought worldwide. In 2019, a collaborative statement was released by the American Thoracic Society and European Respiratory Society, asking for more stringent occupational exposure limits regarding silica dust. In addition, the statement highlighted the need for enhanced clinical recognition and increased public awareness of the role of occupational factors in the development of various nonmalignant respiratory diseases including silicosis [98].

Primary prevention methods aim to reduce or eliminate exposure to silica dust by implementing proper ventilation using dust collectors, wetting techniques, and substituting materials that do not contain quartz. Secondary prevention methods such as respiratory protection and medical monitoring aim to limit exposure and detect the disease early. It is important for employers to provide appropriate training and education to workers on the hazards of silica dust and the proper use of personal protective equipment. Considering the latency period for silica, it is essential to monitor individuals who have been exposed to silica dust, even after exposure has ceased, to detect any potential health problems early. In addition, a rigorous occupational history is the key factor for an early, accurate diagnosis that might be associated with a better prognosis.

CXR and spirometry are the primary methods used to monitor the respiratory health of workers exposed to silicon dust. Once an individual is diagnosed with silicosis, that person should be immediately removed from further exposure to silica [20]. Early detection and removal from further exposure to silica are critical measures to prevent the progression of silicosis and reduce the risk of developing other respiratory diseases such as TB. Implementing prevention measures can effectively reduce exposure to silica dust and prevent silicosis in the workplace (Table 2).

Silicosis is a progressive and incurable disease. Although efforts have been made to prevent workers from being exposed to silica dust in recent decades, silicosis is still a public health issue with a higher prevalence in developing countries, and new data regarding various aspects of this disease are constantly emerging. Currently, there is no treatment for silicosis and prevention remains the most effective way to decrease the risk of developing the disease. There are ongoing studies investigating potential treatments for silicosis including antifibrotic, cellular, and immunomodulatory therapies; however, further research should be done to show the clinical safety and efficacy of such treatments in adequately powered studies. In parallel with research aiming for the development or identification of an effective treatment for silicosis, efforts should be made to develop effective prevention strategies adapted to the current sources of silica dust exposure.

All authors (CMH, MC, ILG and IG) have contributed to the conception and design of the manuscript. CMH has been involved in drafting the manuscript and all authors (CMH, MC, ILG and IG) have been involved in revising it critically for important intellectual content. All authors (CMH, MC, ILG and IG) contributed to editorial changes in the manuscript. All authors (CMH, MC, ILG and IG) have participated sufficiently in the work to take public responsibility for appropriate portions of the content and agreed to be accountable for all aspects of the work in ensuring that questions related to its accuracy or integrity. All authors (CMH, MC, ILG and IG) read and approved the final manuscript.

Not applicable.

Publication of this paper was supported by the University of Medicine and Pharmacy Carol Davila, through the institutional program Publish not Perish.

This research received no external funding.

The authors declare no conflict of interest.