Risk Assessment of Silicosis and Lung Cancer Mortality associated with Occupational Exposure to Crystalline Silica in Iran

Background: Exposure to crystalline silica has long been identified to be associated with lung diseases. Therefore, the present study aimed to assess the risk of silicosis and lung cancer associated with occupational exposure to crystalline silica in Iran. Study Design: It is a systematic review study. Methods: Different databases were searched, and the Cochrane method was used for the systematic review. Thereafter, cumulative exposure to crystalline silica (mg/m3 -y) was calculated in every industry. The relative risk of death from silicosis was performed using Mannetje’s method. Based on the geometric mean of exposure, the lung cancer risk of exposure to crystalline silica was also calculated. Results: As evidenced by the results, worker’s exposure to silica ranged from a geometric mean of 0.0212- 0.2689 mg/m3 (Recommended standard by the American Conference of Governmental Industrial Hygienists (ACGIH) was 0.025 mg/m3 ), which is generally higher than the occupational exposure limit recommended by National Institute for Occupational Safety and Health (NIOSH), ACGIH, and occupational exposure limits. The relative risk of silicosis was in the range of 1 to 14 per 1000 people, and the risk of lung cancer in workers ranged from 13-137 per 1000 people. Conclusion: Since workers are at considerable risk of cancer due to exposure to silica in Iran, exposure control programs need to be implemented in workplaces to decrease the concentration of silica.

diseases. 18 There is a dearth of research on the assessment of the risk of lung cancer due to exposure to crystalline silica. [18][19][20][21] Some studies have collected quantitative exposure data for the estimation of risk, for instance, Mannetje et al in IARC used a quantitative method for estimating the rate of silicosis mortality in six cohort studies and reported that the rate of silicosis mortality was above the risk of 1 per 1000 typically deemed acceptable by the Occupational Safety and Health Administration (OSHA). 22 In the other study, Steenland et al examined lung cancer in 10 silicaexposed cohorts and indicated that the estimated excess lifetime risk of lung cancer for a worker exposed from age 20 to 65 at 0.1 mg/m 3 crystalline silica (the permissible level in many countries) was 1.1%-1.7% (The background lifetime risk of death from lung cancer is 3%-6%.). 23 In Iran, Azari et al assessed the relative risk of death from silicosis and lung cancer in traditional brick production and reported that this risk was in the range of 1-63.6 per 1000 people, and the risk of lung cancer was 124.08 per 1000 people. 24 There is not any organized and comprehensive study on the status of exposure to crystalline silica and its health risk in Iranian workplaces. Therefore, the present study aimed to provide a systematic review of exposure to crystalline silica in all silica-related industries, as well as the estimation of the risk of silicosis and lung cancer due to exposure to crystalline silica.

Search strategy
All of the available studies in the field of occupational exposure to crystalline silica, including case-control and cohort studies, were provided. The literature search strategy was conducted using the following keywords: «Silica», "Crystalline silica», «Exposure", «Occupational exposure», "Industrial», «Workplace», «Factory", and "Iran". All of the articles that reported the concentration of crystalline silica in air samples, as well as those published in English and Persian languages, were selected for the study. Due to the numerous applications of silica in recent decades, the query was carried out from 2000-2021. The Cochrane review method was used as a guideline for the systematic review. 25,26 According to this method, PECO (Participants, Exposure, Comparators, and Outcomes) statement is as follows: • Participants: Humans, who had occupational exposure to crystalline silica • Exposure: Exposure to crystalline silica in silicarelated industries • Comparators: People exposed to crystalline silica and other people • Outcomes: Increasing the concentration of crystalline silica in environmental or individual samples Web of Science (WOS), Scopus, PubMed, Google Scholar, and SID (Scientific Information Database) were selected to implement the search strategy. In addition, the manual inspection of reference lists was used in order to gain access to more articles and reduce bias.

Screening of articles
The screening of articles was performed by title, abstract, and full text of the articles, separately. The inclusion criteria were all articles performed on occupational exposure to crystalline silica in Iran. On the other hand, the exclusion criterion entailed the articles on the biomonitoring of individuals. Moreover, abstracts (without their fulltext available online), review and mini-review articles, conference papers, meta-analyses, modeling studies, books, and unpublished studies were excluded.
We used EndNote X9® (Thomson Reuters, Toronto, Canada) software 27 to prepare the list of the articles and finally downloaded the full text of the screened articles. In order to reduce the error, search strategies were used by two researchers in this study separately. When there were disagreements, a third researcher was involved.

Data extraction
As illustrated in Table 1, data extraction was performed based on year, monitoring station number, mean and standard deviation concentration of crystalline silica, method of detection, city, occupation, and industrial activity.

Risk assessment
Prior to conducting risk assessment, we investigated the homogeneity of data; moreover, in order to detect and remove outliers, we used the box plot at a 95% confidence level. Mean and geometric standard deviation were calculated for every industrial activity. Thereafter, cumulative exposure to crystalline silica (mg/m 3 -y) (Mean of concentration × Years of exposure) was calculated for risk assessment. The relative risk of death from silicosis was determined using Mannetje's method. 23 In this method, the exposure history and crystalline silica concentration are two main factors. In addition, the exposures of all industrial workers in different studies were classified according to the Mannetje category for cumulative exposure. 23 Table 2 displays the exposurerelated mortality rates and mortality rate ratios from silicosis in Mannetje's method.
The lung cancer risk of crystalline silica was calculated according to the model of Rice et al 12   The studies were performed in 17 industrial activities, such as cement manufacturing, mining, construction, foundry, furnace, stone deformation, glass manufacturing, asphalt manufacturing, sand and gravel production, sandblast, tile, and ceramic industry, brick production, insulator industry, excavation, concrete, food industry, and machine industry. Most studies were performed in mines and foundries (n = 6). One study was carried out in the food industry and another in machine industry. The box plot demonstrated that four studies encompassed outliers. As depicted in Table 1, these data were highlighted by Italic font. 28,33,36,47 Outliers were deleted and not used in risk assessment; therefore, 2, 036 measuring stations in various industries were selected from 32 studies for risk assessment. In most studies, laborers worked six days a week and their working hours were more than 8 hours.
The geometric mean concentration for workers' exposure to crystalline silica ranged from 0.0212-0.2689 mg/m 3 (Table 3). In addition, the mean concentration of crystalline silica was obtained at 0.1476 ± 0.1628 in Iranian industries, which is higher than recommended exposure standard limit by the American Conference of Governmental Industrial Hygienists (ACGIH), Iran's national occupational exposure limits (0.025 mg/m 3 ), 55 NIOSH (0.05 mg/m 3 ), 56 as well as OSHA (0.01 mg/m 3 ). 57 As presented in Tables 1 and 2, workers in various industries were exposed to different grades of crystalline silica. In this study, we observed that iron-stone miners were exposed to the highest amount of crystalline silica (Table 1) 33 ; nonetheless, to maintain homogeneity, the data related to the study by Naghizadeh et al on ironstone miners were removed from the risk assessment process. It seems that health risk for iron-stone miners can be at the highest level; therefore, this issue needs more assiduous attention in the future. Furthermore, according to Table 3, workers in excavations are exposed to the highest concentration of crystalline silica (0.2689 ± 0.1046 mg/m 3 ). The geometric mean concentration of crystalline silica was the lowest in the food industry (0.008 ± 0.004 mg/m 3 ).

Discussion
Scarselli et al studied some workers potentially at risk of silica exposure selected from the Italian database of workplaces. They reported that the most involved sectors at high risk of silica exposure were construction, mining and quarrying, metalworking, and manufacturing of nonmetallic products. In addition, they reported that workers in the manufacturing and construction industries were  exposed to the highest level of crystalline silica. 58 On the contrary, among the 16 industrial activities classified in this study, the manufacturing and construction industries were the eighth industries.
In 2015, according to OSHA compliance data from 1979 to 2015, Doney et al reported that workers in the poured  concrete foundation had the highest exposure to crystalline silica. Moreover, out of 100 000 workers, 99.7% of cases were potentially exposed to crystalline silica at higher than the occupational exposure limit recommended by NIOSH in 2014. 59 Concrete workers in Iran had the lowest mean airborne silica exposure levels (0.0212 ± 0.0291), which is lower than the occupational exposure limit recommended by NIOSH, ACGIH, and occupational exposure limits. The relative risk of silicosis-related mortality based on Mannetje's method and cumulative exposure categories was estimated to be in the range of 1-24 per 1000 people, ranging in the cumulative exposure categories of 0-0.99 to 9.58-13.21 in Mannetje's method. In general, the mean rate of silicosis mortality in Iranian industries was 14 per 1000 people. These rates are above the risk of 1 per 1000 usually deemed acceptable by the US OSHA. 3 According to Table 4, the risk of lung cancer due to exposure to crystalline silica based on the Rice model was in the range of 13-137 per 1000 people. In a 44-year cohort study on 34 018 workers, Liu et al reported the risk of lung cancer mortality as 128 per 1000 when the mean cumulative concentration (using a 25-year lag) was 0.01 to 1.12 mg/m 3 -y. 60 In present study, most investigations were exposed-nonexposed studies. Since risk assessment is calculated by considering the history of exposure to silica, retrospective cohort studies may demonstrate more accurate estimations than other studies. The results of present study demonstrated that the risk of lung cancer was at the highest level among the stone deformation operations (1-137 per 1000). Inconsistent with this finding, Poinen-Rughooputh et al reported that miners were exposed to the highest risk of lung cancer mortality (in the range of 1-104 per 1000). 61 Moreover, in present study, the lowest risk of lung cancer mortality was estimated in concrete workers in the range of 1-13 per 1000 people.
In 2016, in a meta-analysis study, based on worldwide studies up to April 2016, the highest pooled concentration mortality ratio of exposure to crystalline silica was estimated at 6.03 (95% CI: 5.29-6.77) in mixed industries of Japan. Moreover, Italy had the highest number of observed lung cancer deaths (798 cases) before 2006. 61 In their study, although the estimated health risk was high in Asian countries after Canada, the studies in Iran have been neglected. According to the results of the current research, the risk of both silicosis and lung cancer mortality is high in Iranian industries, and even numerous studies were conducted before 2016 in Iran.
Among the notable limitations of this study, we can refer to incomplete information on workers of all industries; therefore, we could not estimate the risk of mortality based on the percentage of exposed workers in industries. The expression of mortality based on the percentage of exposed cases can provide a better understanding of the hazard. Due to the high risk of silicosis and lung cancer mortality, it seems that the prevalent occupational health engineering strategies are not sufficient to protect workers; therefore, workers' exposure to crystalline silica dust should be controlled in Iranian workplaces.

Conclusion
The authors provided a lung cancer risk assessment of occupational exposure to crystalline silica in Iranian industrials based on the collected quantitative exposure data. As evidenced by the obtained results, occupational exposure to crystalline silica was higher than occupational exposure limits. Furthermore, the relative risk of death from silicosis was in the range of 1-24 per 1000 people, and the risk of lung cancer ranged from 13-137 per 1000 people. It seems that the prevalent occupational health engineering strategies are not sufficient to protect workers; therefore, workers' exposure to crystalline silica dust should be controlled in Iranian workplaces. • The present study estimated silicosis and lung cancer caused by crystalline silica. • Workers' exposure to crystalline silica ranged from 0.0212-0.2689 mg/m3. • This range was higher than the recommended standard limit by ACGIH (0.025 mg/m3). • The relative risk of silicosis mortality was in the range of 1-14 per 1000.