Silicate pneumoconiosis—a literature review

1 Introduction

Despite extensive literature on occupational silicosis and high-level exposure, key gaps remain in understanding the biological significance of chronic, low-dose environmental exposure to crystalline silicates, particularly outside traditional workplace settings. Specifically, the pathological correlates, early tissue responses, and long-term implications of intermittent environmental exposure remain incompletely characterized, and are often underrepresented in conventional exposure-centric frameworks.

This review advances existing literature by integrating ecological, experimental, occupational, and comparative pathology evidence to emphasize early and subclinical pulmonary changes associated with environmental silicate exposure, including silicate-laden macrophages and non-fibrotic lesions. The aims of this review are to (i) synthesize multidisciplinary evidence linking environmental and occupational silicate exposure to respiratory pathology, (ii) highlight mechanistic insights relevant to early disease stages, and (iii) propose the value of animal and tissue-based findings as sentinels for environmental exposure and long-term respiratory risk.

1.1 Pneumoconiosis

Pneumoconiosis refers to pulmonary disease resulting from inhalation and retention of inorganic particulates, with pathological manifestations ranging from non-fibrotic macrophage accumulation to progressive fibrosis (1–4). Pneumoconiosis is identified and typed based on the inhaled material. The materials responsible for pneumoconiosis that have had the most clinical relevance have been those acquired through occupational exposure. Carbon, asbestos, beryllium, talc, and silica are a few examples of these materials which humans can be exposed to in varying degrees while working in particular industries (5).

PM_2.5 refers to fine particulate matter with an aerodynamic diameter of ≤2.5 μm. These particles can penetrate deep into the lungs and reach the alveolar region, making them highly relevant for respiratory health. PM₁₀ includes particles with a diameter of ≤10 μm, which are inhalable but generally deposit in the upper airways and bronchi rather than the alveoli (6).

2 Materials and methods

2.1 Review methodology

We conducted this review as a narrative, integrative synthesis rather than a formal systematic review. As such, study selection prioritized relevance, methodological rigor within study type, biological plausibility, and contribution to understanding environmental vs. occupational exposure contexts. Table 1 highlights representative studies across evidence tiers to illustrate the hierarchy of inference, rather than to provide an exhaustive or systematically graded summary.

Table 1. Comparative evidence from ecological, occupational, and experimental models linking silicate or particulate exposure to respiratory health effects.

Evidence level reflects qualitative assessment of causal inference based on study design, exposure characterization, outcome validity, and control of confounding. “High” indicates experimental or longitudinal cohort evidence with well-defined exposure and direct biological or clinical endpoints. “Moderate” indicates consistent observational or ecological associations with plausible biological mechanisms but inherent limitations in exposure assignment or confounder control.

2.2 Search strategy

A narrative literature search was conducted in PubMed/MEDLINE, Web of Science, and Scopus, covering English-language publications from 1960 to January 2025. Search terms included combinations of silica, silicates, crystalline silica, pneumoconiosis, silicosis, particulate matter (PM2.5/PM10), Saharan dust, volcanic ash, environmental exposure, occupational exposure, animal models, and experimental inhalation. Reference lists of key articles were hand-searched to identify additional relevant studies. Using this approach, approximately 350–400 records were identified, of which roughly 120–140 articles underwent full-text review. Approximately 85 studies were ultimately synthesized and cited, selected to represent key epidemiological, experimental, occupational, and comparative pathology evidence relevant to the aims of this review.

Inclusion and exclusion criteria: Included studies comprised human epidemiological studies (ecological, cross-sectional, cohort), occupational exposure studies, experimental animal models, and relevant in vitro mechanistic studies addressing respiratory effects of silicate or particulate exposure. Studies focusing solely on unrelated dusts, non-respiratory outcomes without mechanistic relevance, non-peer-reviewed reports, or articles lacking exposure characterization were excluded.

2.2 Study selection process

Titles and abstracts were screened for relevance, followed by full-text review of selected articles. Studies were grouped by exposure context (environmental, occupational, experimental) and evidence type. Evidence level was assigned qualitatively based on study design, exposure characterization, outcome validity, and capacity for causal inference, rather than through a formal systematic review scoring tool.

3 Silicate pneumoconiosis

Crystalline silica relevant to human and animal health is primarily encountered as quartz, cristobalite, and tridymite. Silicate represents a salt of any of the silicic acids (17). Silicosis, asbestosis, and anthracosis are the most common forms of pneumoconiotic lung diseases (2). Silicosis is categorized into either acute or classic forms. The acute form, referred to as alveolar silicoproteinosis, is a severe and fatal filling of the alveolar space with proteinaceous fluid that occurs after short but massive exposure to silica dust. Chronic exposure leads to the classic form of silica pneumoconiosis characterized by chronic interstitial reticulonodular disease. The classification system has further subdivided the classic form of silicosis into simple or complicated based on a well-defined vs. confluent radiographic pattern (2).

The particulate responsible for the development of silicosis, silica, is silicon dioxide (SiO₂) found in either amorphous or crystalline forms and is one of the most abundant minerals in the Earth's crust (18). The term “crystalline” refers to the orderly arrangement of the silicon and oxygen molecules as opposed to the loosely fixed orientation that is found in the amorphous forms. These authors further discuss that silica, mainly in the crystalline form, can be found throughout nature and in several types of rock such as sandstone and granite. The crystalline forms of silica can also be a component of some industrial processes in which silica is exposed to high temperatures and pressure (19).

Silicosis remains a major global occupational and environmental health problem, with millions of workers estimated to be exposed to respirable crystalline silica worldwide. In parallel, ambient particulate matter (PM2.5) is now recognized as a leading contributor to global respiratory morbidity and mortality, particularly in low- and middle-income regions with high dust, mining, or construction-related exposures. These global trends underscore the relevance of both occupational and environmental silicate exposure pathways discussed in this review.

Measured health outcomes reported in the literature for silicate pneumoconiosis include asthma exacerbations and increased pediatric emergency visits, as well as chronic conditions such as COPD, development of fibrotic lung lesions, and heightened susceptibility to respiratory infections (20–23). These outcomes reflect both acute and long-term effects of silicate dust exposure on pulmonary health.

3.1 Occupational exposure

The crystalline polymorphs of silica most frequently associated with occupational exposure are quartz, cristobalite, and tridymite. Quartz is found abundantly in rock, sand, and soil with 67% of their composition being this particular form, making the sandblasting, construction, and mining industries a significant source of exposure (24). Cristobalite is frequently present in the ceramic, refractory, and diatomaceous earth industries. This is due to the use of very high temperatures within these fields which would facilitate the development of this particular polymorph (25). Tridymite is another of the polymorphs which is produced under conditions of extremely high temperatures. For this reason, tridymite and cristobalite are commonly found within volcanic dust (11, 12).

3.2 Environmental exposure

Environmental studies predominantly rely on ambient monitoring and remote sensing proxies (e.g., PM2.5/PM10 concentrations, visibility indices), whereas occupational studies typically incorporate personal exposure measurements or job-exposure matrices, allowing for more precise dose estimation. It is well accepted in the literature that occupational exposure is not the only source of these polymorphs that could contribute to the development of changes within the pulmonary parenchyma. Environmental exposure not associated with a high-risk occupation has been reported and a database created of non-farming and farming individuals from the state of Idaho in an attempt to correlate the exposure of quartz with increased incidence of chronic obstructive pulmonary disease (COPD) and lung cancer. While the correlation proved unsuccessful, the results did prove that quartz contributed to 10% of PM₁₀ (particulate material measuring between 2.5 and 10 micrometers in diameter) sampled from environmental air with the assertion that this matter was aerated dust from the topsoil (5). Recent reviews highlight that dust-derived particulate matter contributes measurably to respiratory and cardiovascular morbidity, particularly as climate change amplifies dust generation and long-range transport (26).

3.3 Saharan dust

Another source that has been implicated in environmental exposure to silica is the sub-Saharan dust cloud. This “cloud” is an environmental phenomenon of a massively large migrating plume of Saharan sand originating from the Bodélé Depression in the Sahel region of Northern Africa within the country of Chad (27). Eastern Mauritania is also suggested to be implicated as an origin of the dust cloud in a report concerning the time of year at which the dust begins its migration from the African continent. They describe that the trajectory of the dust changes between the winter and summer months. The African dust is transported long distances and has been reported to travel by four main paths. The first is a westward path which extends across the North Atlantic to North and South America. The second is northward, crossing the Mediterranean and spreading across southern Europe. The third path is a northern extension that can reach as far as Scandinavia. The last path takes the sand east through the eastern Mediterranean and throughout the Middle East (28).

The literature abounds with documentation of the substantial output (30%–50%) of the westward path to the entirety of dust which is expelled from Africa every year. The westward dust plume emerges from the western coast of Africa, specifically from the Bodélé Depression and an area encompassing eastern Mauritania, western Mali, and southern Algeria. This plume erupts every 3–4 days, takes 5–7 days to reach the Caribbean island chain, and is not greatly affected by anthropogenic activity; instead being driven mainly by “natural factors and geomorphology” (28). The dynamics of the plume were described in an evaluation of a single plume event in June of 1994. The plume's journey began as a steep ascent of 5,000 m before being expelled over the Atlantic. As the plume traveled from Africa to the Caribbean there was a gradual descent from 5,000 m to 3,200 m and with duration of travel lasting approximately 4.25 days (29). The masses of Saharan dust begin the trans-Atlantic migration through disturbance by strong surface winds which lifts the dust. The subsequent plume is transported by convection across the ocean.

The Saharan dust and its geochemical components have been implicated as a contributor to the topsoil and poor air quality of western locations in the path of its trans-Atlantic movement. The results from the Terra-Moderate Resolution Imaging Spectroradiometer (MODIS) spacecraft which orbits over the Atlantic Ocean were analyzed and showed that the dust not only contributes nutrients to the Amazon basin and ocean biota but significantly deteriorates the air quality in Florida (30). These findings were supported by data which indicated that long range transport dust was chemically confirmed to be a source material for topsoil in the Florida Keys, Bahamas, and Barbados. Based on the present understanding of the seasonal path of the plume and their results, the authors of this particular study concluded that the African dust is a substantial contributor to the soil formation throughout a wide latitudinal range to include the Caribbean Sea and western Atlantic (31).

One of the earliest studies on this topic was to trace dust from an observed dust event on Barbados in June 12, 1967 to a large dust storm covering an area of West Africa on June 7, 1967. The dust events and trans-Atlantic path of the dust plume was confirmed by satellite (ESSA 5) imagery. Following sampling of both the dust on Barbados and the dust from West Africa, it was determined that quartz was the predominant particulate material within the dust and that there were “considerable amounts of layered silicates present” within all samples collected from each source. The authors reported similarities between the composition and air trajectories which proved that the source of the dust event, in Barbados, was from the area of West Africa which includes Mauritania, Mali, and Senegal. This study regarded these countries as the main source of atmospheric dust for that particular region of the North Atlantic. (32).

The characterization and identification of the origin of African dust transported over the Atlantic was further documented in a study acquiring three years of daily mineral dust concentration measurements at Sal Island (Cape Verde) during the dusty season (October to April) and used backward trajectories to compare these samples to dust from three sectors of the Sahara. This was accomplished by evaluating the calcium amount and Si/Al ratio of dust collected from Sal Island, Sahara (north/west and central/south), and Sahel regions (33). The transport of this Saharan dust was studied again through the description of a dust cloud event occurring June 14–23, 1994 with transport of the cloud from the Atlantic Ocean to Guadeloupe and final dispersion in the Caribbean Sea. The average particle size of the dust was noted to be 4 micrometers, falling within the fine particulate category. The authors were able to comprehensively detail the steep ascent of the hot dusty air mass, by strong surface wind speed, to 5,000 m above the surface of the African land mass and its gradual descent to 3,200 m as it is transported, by convection, across the Atlantic to the Caribbean. The total duration of the transport was 4.25 days. The authors work also pointed out the contribution, made by the dust, to the underlying marine layer (visibility measurements) and to the water from rainfall (rain sample analysis) (29).

Further clarification was desired to determine the exact region of the Sahara that was responsible for the most voluminous westward flow of material over the North Atlantic Ocean. The authors reported that dust plumes emerge over the North Atlantic from the coast of Africa every 3–4 days and can last as short as seven days but can persist for up to a month or more with transport to the Caribbean taking an additional 5–7 days. Through analysis of data accrued by the Total Ozone Mapping Spectrometer (TOMS) for 1999, the authors identified the source areas and the trajectories of dust plumes' long-range transport. The specific source areas were the Bodélé depression and the area of eastern Mauritania/western Mali/southern Algeria (28). The Bodélé depression was later determined to be the area of the Sahara that provides the largest volume of mineral dust to the Amazon rain forest (34). The contributions to top soils throughout the western Atlantic islands was further explained by studies indicating that dust from Africa serves as parent material for top soil in the Florida Keys, Bahamas, and Barbados which makes African dust contribution to the topsoil of Caribbean island highly likely (31). It was also determined that the production of these dust plumes from these areas was driven by climate and geomorphological factors, not anthropogenic activities (28).

The chemical constituents of the Saharan dust were determined by a study published in 2003. The authors found that Fe in the form of hematite (Fe₂O₃) is one of the most commonly encountered minerals in the Sahara which is an important point considering the implication of iron's role in the toxigenic nature of silicates documented by other studies discussed later within this review. Iron (Fe) made up 2%–5% of the dust mass fraction of samples within this study, while Al accounted for 8.13% of the mass and Ca (in the form of calcite) was 2%–5% as well. This study also pointed out that there was evidence of anthropogenic pollution within the dust, evidenced by the presence of fine SO42−, NH4+, and NO3− (35).

The African dust cloud has also been implicated as an environmental source of particulate exposure affecting human health. A retrospective ecological study was conducted in 2005 in which the records of pediatric asthma patients from Trinidad were examined for accident and emergency visits due to acute asthmatic events. There has been an increase in prevalence of allergic diseases in the Caribbean over the past 30 years, attributed to the annual arrival of an estimated 20 million tons of dust particles to this area. The particles of dust measured in the PM_2.5 range (particulate diameter measuring <2.5 micrometers) allowing them to more easily reach the lower airways. From May 23, 2001 to May 13, 2002, there were 2,655 asthma related visits recorded to the Accident and Emergency department of the Pediatric Priority Care Facility on the island of Trinidad, with males being overrepresented, although most of these were of children form the East-West Corridor, which is a main urban thorough-fare where traffic and industrialization could have confounded the results (7, 36). A similar retrospective study was conducted by examination of daily attendance data to the asthma clinic of Queen Elizabeth Hospital in Barbados over 1996–1997 (8). There was no statistically significant linkage between increases in asthmatic events hospital admissions and short-term surges in dust concentrations, contradicting Gyan's work published three years earlier. Visibility is an unreliable proxy for determination of day-to-day environmental dust concentrations because this can be confounded by sea-salt and changes to relative humidity. They also commented on the previous size determination of the particulates within the African dust and that their size (below 2.5 micrometers diameter) is defined as respirable and their concentrations would challenge breathable limits set by EPA (Environmental Protection Agency) standards.

The effect of breathable particulates within Saharan dust on the pulmonary health of children was again investigated also in Guadeloupe (9). The authors were able to prove a statistically significant association between particle size between PM₁₀ and PM_2.5 (<2.5 micrometers diameter and >10 micrometer diameter) of African dust and emergency department visits by asthmatic children, ages 5–15, during dust cloud events. This study also reiterated the chemical composition of the Saharan dust being quartz (60%), oxides, and carbonates and supports other studies regarding the association between these substances and the development of bronchial and lung inflammation in experimentally exposed rats, the existence of semi-volatile compounds, capable of bio-accumulation, within the region of Mali (a contributor to the Saharan dust cloud) and proved that these compounds are transported within the cloud as far as the Eastern Caribbean and Cape Verde. The long-term effects of exposure to these compounds is unknown but, due to their intimacy with fine particle size material, make them an additional, if not synergistic, concern for inhaled particulates (37).

Climate-driven increases in the frequency and intensity of desert dust events are expected to expand population-level exposure to mineral particulate matter globally, reinforcing the contemporary relevance of environmentally mediated silicate exposure (38).

3.3.1 Saharan dust, human health implications—key points

West African sources (Bodélé Depression; eastern Mauritania/western Mali/southern Algeria) generate plumes that ascend ∼5,000 m and traverse the Atlantic in ∼4–7 days, depositing mineral dust across the Caribbean and the Americas. Dust composition includes quartz (∼major fraction), layered silicates, and iron oxides (e.g., hematite), with occasional anthropogenic sulfate/nitrate signatures.

• - Respirable fractions (PM_2.5/PM₁₀) penetrate lower airways and are associated with pediatric asthma Emergency Room visits and short-term exacerbations (Caribbean sites).
• - Chemical constituents (quartz; Fe-containing oxides) can amplify oxidative stress via Fenton-like reactions, contributing to airway inflammation.
• - Dust contributes to regional soil formation and air-quality degradation, implying chronic low-level exposure in affected locales.

3.4 Volcanic activity

One of the most frequently cited and examined sources in the literature for environmental silicate contamination in soil or air is volcanic activity. The volcano thought to have the most impact in the Caribbean is Soufriere Hills on the island of Montserrat. Soufriere Hills has been extensively studied and documented as a significant contributor to diminished air quality and soil contamination in Montserrat since it began intermittently erupting in July 1995. The impact of the volcanic ash on the air quality and its subsequent effect on the respiratory health of those living on the island has been evaluated in several publications. The increased occurrence of asthma, exercise induced bronchoconstriction, and general respiratory symptoms in children from the island correlated to respirable ash particle exposure (39). The adult population was also assessed in 1997. Personal exposure was evaluated by cyclone air samples and it was determined that the majority of the 4,500 individuals that had remained on the island since the 1995 eruption had not been exposed to concentrations of volcanic dust sufficiently enough to induce silicosis but did not exclude the development of milder forms of respiratory disturbance. The highest concentrations of the volcanic ash were found on the western and central southern areas of the island which was closest to Soufriere Hills (40). Following the volcanic eruption, most of the population relocated to the north side of island which is rarely downwind of any activity therefore preventing any significant long-term ash exposure. These studies have prompted further research into the components, chemical composition, and possible toxic characteristics of Montserrat ash. Crystalline silica was identified as a very fine particle fraction in the dome-collapse ash and characterized as cristobalite, a silicate. Size, composition, and concentration of remobilized ash proved to be the most influential factors to human exposure risk. The cristobalite from this study contributed to the high concentration of respirable particles and a significant proportion of the fine particle fraction which strengthened the presumption that long term exposure to the dust from Soufriere Hills could be a potential hazard to respiratory health (11, 12).

Eighty percent of 443 children on the island of Montserrat, British West Indies were assessed in 1998 to evaluate the potential effect of ashfalls on the respiratory health of these children following the July 1995 eruption of the Soufriere Hills volcano. The survey results revealed that the respiratory health of the exposed children was affected by long duration exposure to high levels of ambient respirable ash particles. These findings encouraged the need to limit exposure to volcanic ash and ensure appropriate management of respiratory symptoms. As previously highlighted, cristobalite has been documented as the most toxigenic crystalline form of silicates and has also proven to be a constituent of the lava dome of Montserrat. The ash generated by the lava dome of this particular volcano contains 10–24 weight percent crystalline silica, in the form of cristobalite (10, 39).) The findings of this study raised concerns about long-term environmental exposure to ash from lava domes and its impact on human pulmonary health.

In an experimental exposure to assess the toxicity of ash from differing volcanoes, rats were exposed to volcanic ash from Montserrat at average concentrations of approximately 75 mg/m³ for ash and 125 mg/m³. The results showed significant inflammatory and fibrotic changes within the lungs and local lymphatic tissue, at 49 weeks of exposure to cristobalite, insinuating a delayed toxic effect (41). One year later, respirable volcanic ash from Montserrat and its implication on human health was further characterized by the testing of several samples of ejected volcanic material to determine the composition, proportions, and concentrations of the ash and particulates. They identified that ash-fall deposits from Montserrat were extremely rich in respirable particles and, that these particles contain the highest proportion of crystalline silica (cristobalite) with a size of less than or equal to 2 micrometers, classifying them as “fine” particulates and therefore having the ability to affect the lower airways. All these studies, and many more, have contributed to the classification of volcanic ash as an environmental source of exposure to silicates and, with long-term exposure, as a potential respiratory health hazard to humans (11, 12).

3.5 Volcanic ash (Montserrat), human health implications—key points

Soufrière Hills eruptions generate ash rich in fine respirable particles (≤2 μm) with significant cristobalite content (10–24 weight %). Exposure patterns vary with geography and prevailing winds, with documented respiratory effects in children and adults. In Table 1, we summarize a few key studies by design: ecological/retrospective pediatric asthma (Caribbean), cross-sectional occupational cohorts, cohort mortality (diatomaceous earth workers), experimental inhalation in rodents, and in vitro macrophage assays. Ecological and retrospective designs provide valuable population-level associations but are inherently limited by exposure misclassification and residual confounding, particularly in regions affected by multiple co-pollutants. In contrast, cohort and experimental studies allow stronger inference regarding dose–response relationships and biological mechanisms.

• - Fine/cristobalite-rich ash increases risk of bronchial inflammation, exercise-induced bronchoconstriction, and chronic respiratory symptoms.
• - Long-term, low-dose exposures may contribute to early pneumoconiosis without radiographic silicosis, warranting surveillance.

As summarized in Table 1, the strength of evidence varies by study design, with experimental inhalation models and longitudinal occupational cohorts providing the strongest causal inference, while ecological studies offer supportive but inherently associative evidence. This hierarchy is consistent with established environmental health frameworks.

During Saharan dust intrusion events, reported ambient PM10 concentrations in Caribbean regions commonly range from ∼30 to 150 μg/m³, with PM2.5 typically between ∼10 and 50 μg/m³, although extreme events may exceed these levels temporarily. Mineralogical analyses indicate that quartz represents roughly 50%–70% of Saharan dust mass, while the respirable crystalline silica fraction is substantially lower, generally estimated at ≤1%–2% of PM mass (8). For reference, current occupational standards define an 8-hour time-weighted average permissible exposure limit of 50 μg/m³ for respirable crystalline silica; however, these thresholds were developed for occupational settings and are not intended to directly translate to intermittent or mixed-composition environmental exposures (42).

In contrast, volcanic ash from dome-collapse eruptions at Soufrière Hills (Montserrat) contains 10–24 wt% crystalline silica (primarily cristobalite) within the sub-10 μm respirable fraction. While ambient environmental concentrations are typically intermittent and lower than chronic occupational exposures, short-term airborne levels during ashfall may approach or transiently exceed occupational exposure limits established for respirable crystalline silica (10–12, 43).

4 Microscopical appearance of silicates depositions in domestic and wild animals

A recent study we conducted in the Caribbean, identified a high prevalence (201 of 259 animals) of pulmonary crystalline material in domestic and wild animals (44). Histologically, the accumulations of heterogenous crystalline particulate material was either free or intracytoplasmic in macrophages (silicate laden macrophages), and most cases did not have any associated inflammatory response or fibrosis, making them early lesions. On SEM/EDXA (Figure 1) the crystalline material appeared composed of silicate aggregates that were 10 µm in diameter or larger. Their composition was found to be a mixture of particles of particles of silicon, oxygen, aluminum, iron, potassium, sodium, and titanium which was consistent with environmental silicates that are typical components of anthracosilicotic dust. The material may be highlighted in basophilic shades in the lung by the acid-fast stain (Figure 2), presumably due to the uptake of the new methylene blue counterstain rather than carbol fuchsin staining of the crystals. On HE slides, the crystals appear polymorphic, with lamellar, acicular, radial, or fibrous morphologies, and measuring usually less than 10 µm in diameter (range 1–20 µm) postfixation and poststaining (Figure 3). They are located multifocally within the lung parenchyma, mostly around larger airways (bronchi and bronchioles) or blood vessels and are partially engulfed by clusters of pulmonary interstitial macrophages (silicate laden macrophages). In some animals like the small Indian mongoose, the silicate crystals may be present in the tracheobronchial lymph nodes (Figure 4), where they may efface the local architecture and may sometimes induce a foreign body response with multinucleated giant cell infiltration.

5 Silica/silicates pathogenicity

The pathogenicity of silica/silicates and their effects on the pulmonary system of many species has been extensively studied incorporating environmental vs. occupational acute and chronic exposure. One of the earliest in vitro studies on these effects showed that experimental exposure to cultures of guinea pig peritoneal macrophages produced impactful results concerning the rapidity of toxicity and the effect of the surface components of separate crystalline forms. Rapidity was related to dose concentration and was highest when the particle: cell ratio equated to every cell being “infected” at the end of the exposure duration. The crystalline form that proved to be the most toxic was tridymite, showing a toxic effect in macrophages of 5 different mammalian species. The authors exposed polymorphonuclear cells to the same concentrations and forms of the silica without showing any subsequent detrimental effect, therefore proving that macrophages were the cells most influenced by silica (45).

Another study, performed to examine the cytotoxic nature of silica on macrophages, was motivated by the lack of information in regard to the fibrogenic effects of silica. This study showed that, through the experimental exposure of silica to mouse peritoneal macrophages, that enclosed silica particles could react with secondary lysosomal membranes, making them permeable, allowing for lytic enzymes and particles to leak into the cytoplasm causing oxidative damage. The induced permeability is made possible by the hydrogen bonding capability of silicic acid with lipid and protein components of these membranes. This study also showed that once the lysosomal membrane was disrupted, macrophage cell death with re-release of the silica into the local environment would occur. The re-released silica proved to have the same cytotoxic capacity when exposed to a fresh culture of macrophages leading to the concept of “in vivo cyclical killing.” The authors suggested that the repeated killing of silica-containing macrophages and the secondary oxidative local tissue damage would, in time, lead to a fibrotic response through the recruitment of fibroblasts and fibrogenesis, all hallmarks of silicosis (46).

Fibrogenesis secondary to the presence of silica in the lungs (pneumoconiosis) was previously described. The results of in vitro, animal, and human investigations around coal workers' pneumoconiosis revealed four main pathogenic mechanisms to explain the etiology of pulmonary fibrotic change in the presence of silica. The results from earlier studies on the effects of silica on components of the innate immune system have raised questions concerning the adaptive immune response and whether it plays a role in the development of silicosis. Some of these scientific mysteries were answered in a study in which immunoglobulin and autoantibody elevations were evaluated in relation to lung changes seen in cases of silicosis (49). It was concluded that there was an increase in humoral immunological factors like rheumatoid factor and anti-nuclear antibody in the studied patients although neither factor's level was associated with any corresponding level of disease nor was there any significant increase in immunoglobulin levels. They speculated that the elevations in the tested humoral components could support B-lymphocyte hyperactivity in silicosis. This could be explained by direct stimulation through interaction between silica particles and the lymphocytes or the enzyme degradation products from disrupted lysosomes due to the presence of phagocytosed silica. This study proved that there was an interplay between both parts of the immune system and motivated the further characterization of the pathogenicity of the silicotic disease process (49).

• (a) Macrophage cytotoxicity. Phagocytosed silica damages alveolar macrophages, inducing release of proteases and inflammatory mediators (e.g., TNF-α, IL-1β), initiating local tissue injury (47).
• (b) Oxidative stress and reactive oxygen species (ROS). Surface radicals on freshly fractured silica and iron-contaminated particles catalyze ROS generation (OH•), driving lipid peroxidation, protein nitrosation, DNA damage, and mucin gene induction (1).
• (c) Lysosomal membrane permeabilization and apoptosis. Silicic acid interactions with lysosomal membranes increase permeability, leading to enzyme leakage, mitochondrial depolarization, caspase activation, apoptosis, and cyclical re-release of particles (48).
• (d) Fibrogenic pathways and immune dysregulation. Growth factor signaling and persistent inflammation recruit fibroblasts and drive collagen deposition; adaptive immune alterations (e.g., B-cell hyperactivity; T-cell unresponsiveness) link silica exposure with autoimmunity and infection susceptibility (1, 47, 48).

The characterization of the pathogenicity of silicotic lung disease was attempted by examining the kinetics of the rat bronchoalveolar (BAL) leukocyte response during experimental exposure to equal masses of respirable materials, including quartz, asbestos, and a non-pathogenic titanium dioxide. BAL samples were assessed for levels and concentrations of cellular contents, macrophage activation, free total protein, lactate dehydrogenase, and N-acetyl-B-D-glucosamidase at varying intervals of exposure time with the rats being euthanized and their lungs examined by histopathology at these same intervals. The BAL results showed a definitive difference in the response between the inhaled materials. Quartz elicited the most significant reaction with not only a 5 fold increase in macrophages but also substantial neutrophil recruitment while asbestos had marginal macrophage involvement with no involvement from neutrophils which the authors attributed to the documented clearance mechanism by multinucleate giant cells (MNGCs) for asbestos. The results of this study provided a unique perspective by using inhalation exposure as opposed to instillation (15).

The specific cell populations implicated in the development of silicosis and the resident pulmonary cells most affected were reviewed in a study that described, even at low intensity exposure, reversible inflammatory lesions, neutrophils, T-lymphocytes and mast cell accumulation in BAL and/or interstitial regions of the lungs. Early fibrogenesis develops as a result of injury to the type I pneumocyte with consequent hyperplasia and hypertrophy of type II pneumocytes. This proliferation of epithelial cells is a crucial step in the reparative process but can become overwhelmed in chronic silica exposure leading to fibrogenesis and carcinogenesis (25, 50, 51).

The persistent inflammatory response induced by silica in animal models has been linked to the propagation of cell injury and apoptosis with reactive oxygen species mediating these events. Silica has been reported to directly increase TNF (tumor necrosis factor) gene transcription and production in pulmonary macrophages through up regulation of the TNF promoter. This was further elucidated in studies which characterized the inflammatory cytokines most commonly associated with the production of silica-induced free radicals: TNF-a, IL-1B, and IL-8. The “receptor theory”, thought to be responsible for silica's pro-inflammatory and fibrotic potential, was examined and highlighted TLR-4, expressed on the surface of pulmonary macrophages, and discussed that this receptor had been shown to induce MARCO (a scavenger receptor) in animal models. Reports from other publications involving the in-vitro and in-vivo exposure of silica in animal models has shown that ICAM-1 (an adhesion protein) was unregulated in alveolar macrophages even though ICAM has not been previously implicated in silica uptake (25, 51).

The characterization and mechanisms of silica toxicity were further elucidated in a study focused on the electrical charge of silica particles and how that might affect its toxicity with an emphasis on the death of macrophages which releases the phagocytosed particles and the formation of collagen; both considered significant steps in the development of lung fibrosis (52). Bagchi determined that respirable particles of silica carried high levels of positive charge and that low humidity increases the magnitude of that charge. He also correlated and concluded, through the experimental incubation of these particles with mouse alveolar macrophages, that the release of collagenases and the subsequent activation of fibroblasts to lay down new collagen was a combined effect of the positive charge on the surface of the silica particles and the electron rich protein components of the macrophages (52).

The surface characteristics of silica and their contribution to its toxicity was examined in an attempt to determine if freshly fractured silica was as toxic and irritant in vivo as compared to the results of a previously published in vitro study. Alpha-Quartz was milled and then a portion stored so that freshly fractured and aged silica could be administered to Fischer rats through inhalation. The surface reactivity of the fresh and aged silica was verified by electron spin resonance spectroscopy and based on the presence and concentration of surface radicals. The results were assessed 1–3 days following the initial inhalation exposure and were obtained by BAL and necropsy acquired histopathology samples of the lungs. The aged silica induced an inflammatory response characterized by increased number of total cells, RBCs, WBCs, and lymphocytes as well as lavage protein and phospholipid levels. The freshly fractured silica induced a much more dramatic increase in the BAL results as compared to the aged silica, as well as the activation of alveolar macrophages to produce nitric oxide synthetase. The histopathologic changes were mild and followed the same trend, proving that the inhalation of freshly fractured silica particles leads to a greater toxic and inflammatory effect on pulmonary tissue than aged silica (16, 51).

The evaluation of surface characteristics of commonly inhaled particulates, and their impact on the fibrogenicity and role in apoptosis found that freshly fractured silica had an increased pathogenicity due to the presumed increased redox potential of its highly reactive “fresh” surface with elements such as hydrogen, oxygen, carbon, and nitrogen [3]. The authors reported that the crushing of silica produces radicals (Si, SiO) on surface cleavage planes which react with water and produce hydroxyl radicals (OH). The role of freshly fractured silica in apoptosis has been discussed and reviewed; leading to the conclusion that failed digestion of phagocytosed silica by the alveolar macrophage (AM) leads to caspase activation and apoptosis. A study, conducted using murine macrophage cells exposed to silica and using fluorescent markers to assess lysosomal permeability, showed that lysosomal leakage preceded mitochondrial depolarization and caspase 3 and 9 activation (25).

There have also been studies which comment on the relationship between the increasing weight of retained silica and the pathologic grade of silicosis. Heavier and larger particulate matter are not transported as far into the lower airway and lead to a more intense local inflammatory reaction which increases the pathologic grade of nodular silicosis. While soluble and lighter particulate material can be disseminated throughout the lung parenchyma causing a widespread inflammatory response potentially leading to a higher pathologic grade of silicosis (lipoproteinosis). The development of silicosis can be offset by the presence or absence of other mineral substances inhaled along with silica. If there is concomitant exposure to relatively nonfibrogenic dust of the same weight as the inhaled silica, there is usually only a mild development of silicosis; this phenomenon reflects silica's ability to absorb constituents of other dusts onto its surface therefore decreasing its toxicity (25, 53).

From an environmental health perspective, these findings support the use of animals as sentinel indicators of chronic environmental silicate exposure, rather than as direct predictors of human disease burden. The high prevalence of silicate-laden macrophages and early non-fibrotic lesions in domestic and wild animals reflects sustained ambient exposure in shared environments and provides biological evidence of exposure that complements physicochemical monitoring. Such tissue-based indicators may therefore inform environmental biomonitoring, hypothesis generation, and risk stratification, particularly in regions affected by chronic dust or ash exposure, while not replacing population-based human risk assessment (2, 3, 44, 54, 55).

The presence of silica can catalyze the production of reactive oxygen species (ROS) and induce hydrogen peroxide and superoxide to interact with endogenous iron via a Fenton-like reaction to form hydroxyl ions. This iron-contaminated silica is believed to be more cytotoxic due to its heightened ability to produce significant amounts of hydroxyl radicals. Silica-derived ROS (hydroxyl ions) have been shown to cause direct DNA damage and apoptosis in vitro as well as in vivo lung damage. The interplay between these oxide-inducing events contributes significant support to the cascades of inflammation and fibrogenesis and the role of the oxidizing substances can be substantiated by using anti-oxidants and antibodies to TNF (tumor necrosis factor) in successful attempts to inhibit fibrotic lung disease in animal models. Silica has also been implicated in T-cell unresponsiveness and mitogenicity within draining pulmonary lymph nodes which could explain compromise of regional pulmonary defenses leading to regional immunosuppression and reportedly increasing risk and incidence of mycobacterial infection in cases of silicosis. The mechanism of silica's mitogenicity was illustrated by exposure of a non-transformed alveolar type II epithelial cell line to alpha-quartz and n-silica. The results confirmed persistent dose related increases in phosphorylation JNKs (Jun-NH2-terminal amino kinases) and AP-1 (activator protein-1) gene expression, DNA synthesis via oxidative stress, and increased expression of proto-oncogenes. These findings could implicate silica, mechanistically, as a nongenotoxic tumor promoter in lung tissue (25, 51, 56, 57).

Recent outbreaks of accelerated silicosis associated with artificial stone fabrication underscore the pathogenic potential of high-intensity crystalline silica exposure and provide an important contrast to the low-dose, environmentally mediated exposures emphasized in this review (22). Recent outbreaks of accelerated silicosis associated with engineered (artificial) stone fabrication further underscore the importance of exposure intensity and cumulative dose, providing a sharp contrast to the low-dose, environmentally mediated exposure scenarios emphasized in this review (58).

As described by many previous studies, the dosage of inhaled silica dust and duration of exposure determines the development of the subsequent pneumoconiosis and or silicosis. Silica and its medical impact on human respiratory health, from occupational exposure, was outlined by the International Labor Office in 1930 at the Johannesburg Conference (59). The purpose of this conference was to highlight the health risks and economic impact of silicosis by setting a medicolegal framework to its nosology. The discussion on this condition was largely focused and motivated by the South African mining industry with 52% of the 585-page report detailing the effects of this condition on the mines of Witwatersrand. Due to the focus and economic context of the conference, which also included efforts on how to assess and define disability in miners, there was no mention of other occupations that likely lead to silica exposure. The consensus definition of silicosis excluded the two earliest stages of the disease process. The first being the early inflammatory reaction to inhaled dust and the subsequent bronchiolitis with accumulation of dust laden alveolar macrophages within the pulmonary lymphoid tissue. The second being the development of granulomatosis characterized by focal accumulation of epithelioid and multi-nucleated giant cells. Therefore, silicosis was considered to be present only when the third stage of the pathologic changes was seen: the formation of the silicotic nodule, a focal area of granulomatous inflammation surrounding or containing pigmented, birefringent or partially birefringent crystalloid material. Since the emergence of x-ray diffraction, infrared and mass spectrometry, and electron microscopy, it has become easier for medical investigators to perform more complete analysis of the crystalline characteristics as well as the chemical constituents of mineral particles ranging in size from less than 100 nm to 400 nm. These research tools have allowed for the elucidation of the correlation between size and constituency of particle and its induced pneumotoxicity. These diagnostic developments highlighted the deficiencies in the ILO's (International Labor Organization) approach to defining silicosis, which ignored the possible associations between exposure to inorganic particles and a wide array of diseases, slowing down the research into these associations and the reaching of consensus within the scientific community. The conference conclusions significantly shaped the definition of this disease and led to consequences that continue to impact and influence medical perception on the true clinical manifestations and significance of the presence of silica within lung tissue. This impact has played out in an under-identification of the pathogenic effects of the presence of silica within lung parenchyma (pneumoconiosis) and the lack of research studies to elucidate any other possible pathogenic manifestations of silica exposure (59, 60).

6 Silicosis/silicate pneumoconiosis and secondary disease

The differentiation of attributes of silicosis vs. early silicate pneumoconiosis is not always clearly defined in the literature. Table 2 summarizes a stage comparison of the two based on exposure, clinical data, imaging and microscopy.

Table 2. Stage comparison between different stages of silicate exposure: silicate pneumoconiosis vs. silicosis.

Beyond classical silicate-related patterns, antimony pneumoconiosis has been characterized on CT with exposure-dependent increases in calcific mediastinal lymph nodes, parenchymal micronodules, and fibrotic transformation (61).

Occupational exposure to silica is the most frequently documented form of exposure and has been the most frequently attributed crustal exposure resulting in decreased lung function, increased risk of lung infection, chronic lung disease, or neoplasia. Decreased lung function associated with long term occupational exposure to quartz has been documented through the examination of peak expiratory flow (PEF) of workers in the Indian quartz industry (62). This study included both males and females with mean ages of 33.18 ±10.39 for the males, 30.10 ± 9.3 for the females, and duration of exposure equaling 2.74 ± 1.65 years. The PEF of these workers was significantly reduced in female workers, >35 years, with a duration of exposure >2 years.

A review of epidemiological studies from 1996 to 2005, found a close relation between silicosis and lung cancer, with one study predicting that 19 out of every 1,000 white male workers exposed to respirable crystalline silica would die from lung cancer related to the inhalation of silica (cristobalite) (14). In 1997, a historical cohort mortality study examined the medical records of 2,342 male workers exposed to crystalline silica (predominantly cristobalite) in the California diatomaceous earth industry. The results revealed a strong dose-response relationship for crystalline silica and non-malignant respiratory mortality (chronic respiratory disease) (13). In 2015, a cross-sectional study was conducted to determine if there was evidence of oxidatively damaged DNA in the nasal epithelium of silica-exposed workers (employed in pottery, ceramic, marble manufacturing, and the stone quarry industry) due to previous scientific associations between the generation of reactive oxygen species, by silica within the lungs, and induction of oxidative stress with the carcinogenicity of respirable silica. The results of this study suggested an association between silica exposure and genotoxicity in the nasal epithelium of stone workers (63).

Dose–response relationships, cumulative exposure, and latency are well established in occupational and experimental models of silicosis, where exposure levels and durations can be quantified. In contrast, environmental exposures are typically intermittent, heterogeneous, and difficult to quantify, limiting direct extrapolation of fibrogenic thresholds. As such, environmental silicate exposure is more plausibly linked to early or subclinical lesions and increased susceptibility over time than to immediate development of classical fibrotic silicosis (7, 13–16, 22, 44).

Occupational exposure to silica has also been implicated in the development of human autoimmune diseases. The exact mechanism and pathophysiology of silica-induced autoimmune disease is unknown, although, there is extensive literature which implicates silica, amongst other environmental agents, with the triggering or acceleration of autoimmune diseases (64). One review summarized human epidemiological data which supports the postulation that exposure to an occupational source of silica can be associated with systemic autoimmune diseases, such as scleroderma, rheumatoid arthritis, systemic lupus erythematosus, glomerulonephritis, and small vessel vasculitis (65). The mechanistic model discussed by the authors is based on silica's ability to lead to alveolar macrophage apoptosis. This apoptosis provides excess antigen which is ingested by other macrophages and dendritic cells which is then carried to regional lymph nodes. Once within the lymph node, an immune response is generated to the apoptotic material by the activation of T-cells and B-cells thereby inducing an autoimmune response. Data published from experimental studies illustrating the activity of silica as an adjuvant to nonspecifically enhance the immune response has provided another possible further explanation for the development of silica-induced autoimmune disease. Silica has also been linked to systemic lupus erythematosus, systemic sclerosis, vasculitis, polymyositis/dermatomyositis, and rheumatoid arthritis (64, 66).

The studies defining the association between silica exposure and the development of lung disease are founded on the diagnosis of silicosis, characterized by significant fibrotic change within the lung parenchyma and decreased respiratory function. Within the medical community, pneumoconiosis has long been considered, an incidental finding. This dates back to 1930, since in the previously mentioned International Labor Organization conference, which took place on that year, it was stated that any stage of lung parenchymal change prior to the development of fibrosis, was to be disregarded as insignificant. Since the ILO consensus, there have been several studies which have begun to elucidate the impact that the presence alone of inhaled particulate matter has on the lungs and the risk to overall systemic health. Many of these studies focus on environmental or experimental exposure to silica, in many cases in the absence of silicosis.

The role of silica-induced apoptosis in the initial stages of autoimmune diseases have been previously reviewed as part of occupational exposure (65). Cardiovascular disease has been linked to pneumoconiosis through a population-based study using information from the Taiwan National Health Insurance Research Database on 6,940 pneumoconiosis patients and with comparison to 27,760 non-pneumoconiosis patients matched by age and sex. The results indicated an association between pneumoconiosis and a higher risk of cerebrovascular events. Therefore, suggesting pneumoconiosis patients should be closely monitored and controlled for prevention of potential stroke (67).

In consideration of environmental exposure to crystalline material, the documentation of size of particle and its relationship with impact to health has been thoroughly documented, leading to the development of OSHA criteria for acceptable levels of occupational and environmental breathable particulate matter. Increased risk for cardiovascular disease and hospitalization has been documented to occur with even short-term exposure to any particulate matter that fell into the PM_2.5 category (68). The size of particle has been associated with the development of asthma in children and their need for medical treatment; reported as a strong positive effect on asthma hospitalizations from PM_10–2.5 that persisted within the lung and averaged 6 days for both boys and girls within a sample set from a Toronto-based study. These findings suggested a detrimental effect of relatively low levels of ambient particulate matter on hospitalization for respiratory infections in children (69). Similar results were reported in Turkey based on the evaluation of the possible association between air pollution and hospital admissions for respiratory diseases (including asthma) of children less than 15 years of age in the Turkish city of Zonguldak; a major coal mining center. They examined the impact of three particulate size classes: thoracic (PM₁₀), fine (PM_2.5), and coarse (PM_10–2.5). Their results suggested greater effect of fine and coarse particulate matter, greater than 10 micrometers, on asthma hospital admissions compared with PM₁₀ in children; with PM₁₀ having the most adverse effect within the upper airway (70).

A synergistic, if not potentiating, relationship has been heavily documented to exist between silica and tuberculosis. In 1968, a study was published which used cultures of mouse peritoneal macrophages exposed to a virulent strain of M. tuberculosis (H37Rv) to show that the growth of this organism was encouraged by an unknown effect of silica on macrophages. Results proved that there was no effect on cultures of M. tuberculosis when incubated with high concentrations of silica alone, but when macrophage cell cultures were instilled with a sub-lethal dose of silica and M. tuberculosis, there was some relationship between the macrophage and the silica which allowed the multiplication of the mycobacterial organisms. The authors offered two possible explanations for this result. The first was that the organisms were escaping lysosomes, by some unknown mechanism, and multiplying within the cytoplasm. As previously discussed, the potential mechanism for lysosomal membrane penetration would be later elucidated by studies published some years later describing the interaction between the surface profile of the silica and the components of the lysosomal membrane. The second possible explanation was that once silica is ingested by the macrophage there is an alteration to the metabolism of the particles which becomes favorable for the proliferation of M. tuberculosis elsewhere in the cells (71).

The potentiation of sub-lethal doses of silica on the development of pulmonary tuberculosis was further examined in 1998. The authors were motivated by the lack of studies which examined the possible effects of the presence of silica within the lungs and risk for pulmonary tuberculosis. Many previous epidemiological studies had linked silicosis with the substantially increased risk for the development of pulmonary tuberculosis and that the worsening radiographic appearance of lungs correlated with increased risk as well. Results showed that even the presence of silica accumulation within the lungs, in the absence of silicosis, was a “lifelong risk” for development of pulmonary tuberculosis. The authors showed the development of silicosis can occur years after the exposure to dust has ceased and that many silicosis cases were diagnosed at autopsy due to lack of radiographic anomalies. These results suggestively encourage, if not prophylactic antituberculosis treatment, at least lifelong surveillance for the development of silicosis and pulmonary tuberculosis in high-risk areas (72). The findings of this study supported the postulations made before (71) concerning the potentiation of silica on the growth of M. tuberculosis and was further characterized by another study experimentally identifying that silica has a mitogenic and immunosuppressive effect on the T-cell population within lung tissue therefore suppressing cell-mediated immunity which is essential in the response to tuberculoid disease and pulmonary mycosis (73).

Pulmonary mycosis risk in association with silicosis was also described in which mortality data from the National Center for Health Statistics at the CDC was examined for a diagnosis of pulmonary mycosis with concurrent silicosis at time of death in individuals greater than or equal to 45 years of age. The authors showed that the most common infection was aspergillosis but also included coccidioidomycosis and cryptococcosis. Among the total 48 decedents examined, 9 also had concurrent tuberculosis (74).

The clinical impact of pneumoconiosis, within the realm of human medicine, has recently been documented to extend beyond physical health to mental health. A literature review found documentation that pneumoconiosis patients may be at higher risk for developing psychiatric problems. A study was conducted to evaluate the prevalence and correlates of depressive disorders following a random selection of two hundred and one patients diagnosed with pneumoconiosis from the register of the Pneumoconiosis Compensation Fund Board of Hong Kong. The results determined that there were significant correlates between pneumoconiosis and depressive disorders in elderly patients. The direct impairment of macrophages by silica, poor penetration of therapeutics into silicotic nodules, and the potential mental/emotional impairment of pneumoconiosis patients make the treatment of pneumoconiosis and silicosis conditions very difficult, potentially encouraging a more aggressive surveillance for pneumoconiosis to allow for preemptive preventative and treatment protocols (74).

Clinical outcomes of silica exposure beyond fibrosis include:

• - Respiratory morbidity: asthma exacerbations, COPD, and decreased peak expiratory flow (21).
• - Infection susceptibility: tuberculosis potentiation; pulmonary mycoses (e.g., aspergillosis) (23, 73, 75).
• - Autoimmunity: associations with RA, SLE, scleroderma, vasculitis (76–78).
• - Cardiovascular and cerebrovascular risks linked to PM2.5 exposure; mental health correlates (depression in pneumoconiosis cohorts) (79–82).

7 Environmental exposure magnitude, pathways, and epidemiologic context

Ambient environmental exposure to particulate matter containing silicates occurs at concentrations substantially lower than those encountered in occupational settings, but with markedly different exposure patterns. During Saharan dust intrusion events, reported PM₁₀ concentrations in Caribbean and downwind regions commonly range from approximately 30–150 μg/m³, with PM_2.5 generally between 10 and 50 μg/m³, although short-term peaks may exceed these levels (7–9). Mineralogical analyses indicate that crystalline silica typically represents a small fraction of total particulate mass during such events, generally estimated at ≤1–2% of PM (8). In contrast, occupational exposure limits for respirable crystalline silica are defined based on sustained, daily inhalation in workplace environments (e.g., 8-hour time-weighted averages) and reflect substantially higher cumulative doses over months or years (10–12). These regulatory thresholds are therefore not directly transferrable to environmental exposure scenarios, but provide contextual benchmarks for interpreting dose magnitude rather than direct risk equivalence.

From an environmental epidemiology perspective, chronic low-dose exposure to silicate-containing particulate matter is unlikely, in isolation, to result in classical fibrotic silicosis as defined in occupational cohorts (15, 22). Instead, intermittent but repeated exposure at the population level may plausibly contribute to early or subclinical pulmonary changes, cumulative susceptibility, or modification of risk for other respiratory outcomes, including asthma exacerbation, infection susceptibility, and impaired pulmonary clearance (7, 8, 44).

Such effects are consistent with observational environmental studies, which typically detect associations with symptom burden, health-care utilization, or subtle functional impairment rather than end-stage fibrotic disease, and with experimental data demonstrating biological activity of silicates at doses below those producing overt fibrosis (15, 16).

Environmental exposure to silicate-containing particulates arises through multiple non-occupational pathways, often acting simultaneously. These include long-range transport of desert dust, resuspension of soil particulates during dry seasons, agricultural activities, land disturbance and desertification, volcanic ash fallout, and construction-related dust within urban environments (5, 10, 28, 31, 32, 43). Unlike occupational exposure, these pathways typically affect large populations at low intensity, with exposure characterized by spatial heterogeneity, seasonality, and limited individual-level exposure quantification.

Importantly, crystalline silica in environmental settings is rarely encountered in isolation, but rather as a component of complex particulate mixtures that may include iron-containing minerals, layered silicates, sea salt, and anthropogenic combustion-derived pollutants (27, 35). Experimental and observational data suggest that such mixed particle environments may modulate toxicity through oxidative stress, surface reactivity, and inflammatory signaling, particularly when iron or other transition metals are present (1, 25, 48, 51). These interactions complicate simple dose-response extrapolation but are highly relevant to real-world environmental exposure scenarios.

7.1 Dose–response relationships, cumulative exposure, latency, and fibrogenic thresholds

Dose-response relationships, cumulative exposure, and latency are foundational concepts in the epidemiology of pneumoconiosis and silicosis and are best characterized in occupational and experimental settings, where exposure intensity and duration can be quantified with relative precision. Across multiple cohort and experimental studies, both exposure intensity (concentration of respirable crystalline silica) and exposure duration contribute to disease risk, with cumulative exposure often serving as the strongest predictor of fibrotic outcomes rather than peak intensity alone. In occupational cohorts, cumulative exposure models incorporating intensity × duration have demonstrated clear dose-response relationships for non-malignant respiratory disease, progressive massive fibrosis, and lung cancer, particularly in industries with sustained high-level exposure such as mining, stone processing, and diatomaceous earth production. Experimental inhalation studies further support these relationships by demonstrating progressive inflammatory and fibrogenic responses with increasing retained lung burden of crystalline silica (13–16).

The concept of fibrogenic thresholds has emerged primarily from occupational and experimental data, where prolonged exposure above specific cumulative doses is required for the development of classical nodular silicosis and progressive massive fibrosis. However, whether a strict threshold exists remains debated, and some models support a continuum of biological response in which lower-level exposures produce early or subclinical lesions without overt fibrosis (1, 3, 25, 53).

Latency represents a defining feature of silicosis epidemiology and varies substantially depending on exposure intensity. Accelerated silicosis develops after relatively short latency periods following high-intensity exposure, while chronic silicosis typically manifests decades after sustained occupational exposure. In contrast, environmental exposure is generally characterized by intermittent, low-intensity inhalation over long timeframes, complicating direct latency assessment and limiting the ability to define precise exposure–response relationships (2, 22, 48).

As a result, environmental silicate exposure is more plausibly associated with early or non-fibrotic pulmonary changes, accumulation of silicate-laden macrophages, and modification of susceptibility to respiratory disease, rather than with the classical fibrotic end-points used to define silicosis in occupational settings. This distinction underscores the importance of differentiating exposure context when interpreting dose-response, cumulative exposure, and latency, and cautions against direct extrapolation of occupational risk models to population-level environmental exposure (7, 8, 15, 44). Taken together, these frameworks highlight why occupational silicosis models cannot be directly applied to environmental exposure scenarios, yet remain essential for interpreting biological plausibility and risk gradients.

8 Surveillance for environmental exposure

In the evaluation of exposure to environmental contaminants, animals have been suggested as potential sentinels to assess human risk, especially regarding pulmonary health and the impact to ecosystem health. Animals exposed to contaminants are referred to as “animal sentinel systems.” Sentinel animal pathology offers a means of detecting biologically relevant exposure in complex environmental settings where individual human exposure assessment is difficult, thereby informing environmental health surveillance rather than serving as a direct measure of human disease risk. These systems are designed to identify and monitor a variety of environmental contaminants that could pose a significant risk to human and animal health. A sentinel animal is defined as “one which points out or directs attention to something” or, more precisely, “whose presence acts as a sign of particular environmental conditions” (55). In an effort to bridge the terminology gap between animal-based vs. human-based studies in environmental health research, the term determined to be the most appropriate for the use of animals to assess potential threat to human health was sentinel, defined as: “An organism in which changes in known characteristics can be measured to assess the extent of environmental contamination and its implications for human health and to provide early warning of those implications” (54). Animals can serve as good sentinels because of their ability, in many cases, to more rapidly develop clinical signs secondary to exposure (83).

The rapid development of clinical signs in a sentinel species is especially true for avian species due to their unique respiratory physiology and ubiquitous distribution (84). Birds have been used to monitor pollutants in mines and considered by many, when living in polluted environments, to be useful sources of information relevant to human disease (85). Dogs have also been documented to successfully serve as sentinels and have been the species of choice for experimental models of pulmonary response to long term air pollutant exposure. Light and electron microscopy were used to evaluate the lungs of dogs within Mexico City and compare them with those of dogs from three less polluted Mexican cities. The results of the study proved that environmental exposure, predominately to particulate matter and ozone, was leading to histopathologic changes in young and old dogs in Mexico City. The pulmonary lesion most commonly associated with lifelong air pollutant exposure in these dogs was epithelial and endothelial injury leading to persistent chronic parenchymal inflammation. These findings raised serious concerns from the authors due to previously reported significant association between lifetime exposure to southwest Mexico City atmosphere and thoracic radiograph abnormalities in healthy children, as well as a greater than 6.9% infant mortality in the same region associated with an increase of 10micrograms/m³ in concentrations of particulate matter 3–5 days prior to the children's demise (86). The pulmonary findings observed in these dogs from a high air pollutant region of Mexico City at or above acceptable concentrations set by current standards, could motivate future mechanistic studies to elucidate the risk of increased cardiorespiratory morbidity and mortality in susceptible populations, including humans.

9 Conclusions

From an environmental epidemiology perspective, the findings synthesized here are most appropriately interpreted at the population level, where widespread low-dose exposure may contribute to incremental risk, susceptibility, or disease modification rather than overt fibrotic lung disease. The integration of mechanistic and pathology evidence provides biological context supporting observed associations in ecological and observational studies, without implying direct equivalence to occupational exposure risk.

From a translational perspective, the findings summarized here have implications for environmental monitoring and prevention. Sentinel animal surveillance, combined with targeted histopathologic and mineralogical analyses, may complement ambient air monitoring in regions affected by dust or ash events. Climate-driven increases in dust transport may further expand low-dose, chronic exposure scenarios, underscoring the importance of early lesion recognition rather than reliance on advanced fibrotic disease. Detailed regulatory, mitigation, and intervention strategies are beyond the scope of this review but represent important areas for future interdisciplinary work.

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Footnotes

Edited by: Mara Amalia Bălteanu, Titu Maiorescu University, Romania

Reviewed by: Ahmet Cemal Pazarlı, Gaziosmanpaşa University, Türkiye

Irina-Luciana Gurzu, Grigore T. Popa University of Medicine and Pharmacy, Romania