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Association between exposure in the cement production industry and non-malignant respiratory effects: a systematic review

Objectives Based on findings from a systematic literature search, we present and discuss the evidence for an association between exposure to cement dust and non-malignant respiratory effects in cement production workers. Design and setting Systematic literature searches (MEDLINE and Embase) were performed. Outcomes were restricted to respiratory symptoms, lung function indices, asthma, chronic bronchitis, chronic obstructive pulmonary disease, pneumoconiosis, induced sputum or fraction of exhaled nitric oxide (FeNO) measurements. Participants The studies included exposed cement production workers and non-exposed or low-exposed referents. Primary and secondary outcomes The searches yielded 594 references, and 26 articles were included. Cross-sectional studies show reduced lung function levels at or above 4.5 mg/m3 of total dust and 2.2 mg/m3 of respiratory dust. ORs for symptoms ranged from 1.2 to 4.8, while FEV1/FVC was 1–6% lower in exposed than in controls. Cohort studies reported a high yearly decline in FEV1/FVC ranging from 0.8% to 1.7% for exposed workers. 1 longitudinal study reported airflow limitation at levels of exposure comparable to ∼1 mg/m3 respirable and 3.7–5.4 mg/m3 total dust. A dose–response relationship between exposure and decline in lung function has only been shown in 1 cohort. 2 studies have detected small increases in FeNO levels during a work shift; 1 study reported signs of airway inflammation in induced sputum, whereas another did not detect an increase in hospitalisation rates. Conclusions Lack of power, adjustment for possible confounders and other methodological issues are limitations of many of the included studies. Hence, no firm conclusions can be drawn. There are few longitudinal data, but recent studies report a dose–response relationship between cement production dust exposure and declining lung function indicating a causal relationship, and underlining the need to reduce exposure among workers in this industry.


Strengths and limitations of this study
• The study reports results from systematic searches in Medline and Embase, and presents and discusses the evidence of an association between cement production dust exposure and reduced lung function or signs of airway inflammation.
• Cross-sectional studies show reduced lung function levels at or above 4.5 mg/m 3 of total dust and 2.2 mg/m 3 of respiratory dust and a recent longitudinal study reports exposure-response relationships between exposure and decline in lung function, but there is little additional longitudinal data.
• GRADE criteria or similar systems to evaluate the quality of evidence were not applied, but elements used in evaluation criteria according to study design, and if and how the study included sample size, referents or controls, covariates, main outcome variables and findings are included in the tables.
• Most studies report FVC, FEV 1 levels and the FEV 1 /FVC-ratio as outcomes, some report only crude values or percent of predicted and only one study report the lower limit of normal.
• We restricted the review to studies reporting dust measurements, but comparison of exposure assessment between studies could not done because limited information is available regarding sampling and quality of measurements.

INTRODUCTION
The first known report of health effects associated with exposure to cement was published by Bernardino Ramazzini in 1700 and described dermatitis among bricklayers. Some 250 years later, evidence of an association between the chromate sensitivity induced by cement exposure and dermatitis was reported by Jaeger and Pelloni. [1] Since then, a substantial number of studies have reported an increased prevalence of respiratory symptoms, reduced lung function, chronic bronchitis, emphysema, asthma and radiographic abnormalities of the

Cross-sectional studies
Several cross-sectional studies in the second half of the 20th century included evaluation of lung function and dust measurements in cement production workers. Some of these studies did not include a reference population or contained insufficient contrast of exposure between the exposed workers, or failed to adjust for smoking or age as potential confounding variables. The main results from the included cross-sectional studies are summarised in Table   1. Two cross-sectional studies with relevant reference populations have been reported but failed to demonstrate differences in the spirometric measurements between workers and referents. [11,13] The exposure levels reported in studies from the former Yugoslavia, [14] Malaysia, [15] Taiwan, [16] Jordan, [17] Saudi Arabia, [18] Tanzania, [19][20][21][22] Iran, [23,24] and the United Arab Emirates, [25] are twofold or higher compared with the levels reported in cement production plants in the US and Norway. [11,13] This may to some extent explain the contradictory findings from these studies.
One of the first cross-sectional studies that included dust measurements and adjustments for relevant cofactors was a large study of US cement production workers (n=2736) and bluecollar controls (n=755). [13] In this study, cement workers and controls had similar prevalence rates of respiratory symptoms, except that the cement workers reported more dyspnoea compared with controls. Similar levels were reported also for the lung function indices.
In a small Yugoslavian study from 1989, the levels of alfa 1 -antitrypsin (AAT) in serum, spirometry and single-breath transfer factor for carbon monoxide (DL CO ) were measured. [14] FVC and FEV 1 values were negatively related to duration of exposure, and a significant relationship was detected between AAT and respirable dust concentration. However, interpreting the study findings is challenging because a reference group was not included. Another small study, restricted to non-smoking cement production workers and blue-collar controls in Malaysia, included 32 exposed workers. [16] Nevertheless, this study detected a reduced FEV 1 /FVC-ratio among the exposed as compared to the controls.
In two studies from Tanzania, the prevalence of airway symptoms was higher in exposed workers than controls [20] and lower forced vital capacity (FVC), forced expiratory volume in one second (FEV 1) , FEV 1 /FVC [20] and peak expiratory flow (PEF) values [21] were demonstrated in cement production workers compared with controls. In the first study, exposure assessment showed that a cumulative total dust exposure of more than 300 mg/m 3 * years was significantly associated with airflow limitation. [19] In a more recent study by the same group, the cross-shift fractional exhaled nitric oxide (FeNO) levels of cement production workers and controls were assessed. [22] That study failed to show differences in FeNO concentrations across shifts among exposed workers and controls. The use of total dust levels probably does not provide a precise estimate of inhaled particles that deposit in the lower airways. [26] Thus, this study may have been hampered by exposure misclassification, diluting the observed associations between exposure and outcomes.
A study undertaken in Saudi Arabia reported that wheezing and shortness of breath were related to cement dust exposure. [18] A possible confounder in that study may be socioeconomic differences between the exposed group and the references consisting of office workers.
Two studies from Iran report reduced FEV 1 /FVC and reduced FVC levels in exposed workers compared with office workers. [23,24] High crystalline silica levels were reported in these two cement plants, amounting to 27% and 22% of the dust, respectively. Thus, the effects of crystalline silica exposure need to be considered as confounders in studies assessing the respiratory effects of cement production dust.  15 In a study from 2012 conducted among cement production workers in the United Arabic Emirates, elevated odds ratios for cough and phlegm were detected. [25] That study collected total dust samples and used office workers as references, which makes interpretation of the results difficult.
In the first cross-sectional analysis from a prospective study, our research group assessed lung function and respiratory symptoms among 4265 cement production plant workers from 24 plants in eight European countries (Estonia, Greece, Italy, Norway, Spain, Sweden, Switzerland and Turkey). [27] The study demonstrated elevated odds ratios for symptoms and airflow limitation in the higher levels of exposure, using the lowest quartile of exposure as reference. The study findings are strengthened by the large sample size and the use of comprehensive exposure data. A job exposure matrix with personal exposure measurements from samples collected in a group-wise strategy was applied to estimate individual exposure for workers.
In 2014, Tungu and co-workers compared two cross-sectional studies from the same cement plant in Tanzania. [28] Total dust exposure was lower in the second study conducted

Cohort studies
The main design and results from the included cohort studies are summarised in  25-75% ) were significantly greater in the high-level exposed workers than in unexposed controls. However, the readings were not adjusted for height and confounding due to differences in socioeconomic status between groups was likely.
In a retrospective cohort study of 119 present and former employees and 50 blue-collar referents from a cement plant in Norway, we used a system for weighting previous exposure based on interviews with a group of 18 long-term workers (focus group). [11] We observed similar prevalence of symptoms, mean pulmonary function indices and prevalence of COPD in exposed workers and referents. High FVC levels among exposed workers indicated the presence of healthy worker effects, whereas FEV 1 /FVC showed a slight tendency towards lower levels in the highest exposed group.
A small cross-shift study detected cross-shift reductions in PEF, which were most pronounced among high-level exposed workers. [31] A high prevalence of respiratory symptoms was reported among workers exposed to high levels of cement dust during production. Dust levels were associated with increased cross-shift decrease in PEF. Because the study sample was small and the analyses were not adjusted for age, the results should be interpreted with caution. In another Ethiopian study 71 Ethiopian cement production workers were followed for one year. [32] Increased prevalence of morning cough, cough with sputum and lower lung function indices were demonstrated among high-exposed workers compared In a recent study from Iran of 200 workers, increased prevalence of respiratory symptoms and reduced lung function indices were reported post-shift.
[34] Multivariate analysis demonstrated an association between these changes and exposure to cement production dust.
However, it is not clear if the 100 low-exposed and 100 high-exposed workers were randomly selected or whether all workers volunteered for the study. If workers with respiratory symptoms were overrepresented, this may have resulted in overestimation of the effects.
In a study of long-term exposure to cement dust and later hospitalisation with respiratory disease, 546 Danish cement production workers were compared with other blue-collar workers (n=847) and with the general population.
[35] Cement workers did not have an increased rate of hospitalisation during the 10-year follow-up period compared with controls.
Nevertheless, a tendency towards increasing rates of hospitalisation due to COPD was observed with increasing duration of exposure up to 30 years. Thereafter, the hospitalisation rates declined, possibly due to a healthy worker effect.
Our research group also conducted a study in which 35 healthy dust-exposed, non-smoking cement production workers performed induced sputum measurements analysis and spirometry after a period of exposure and again after five days without work or exposure.
[36] An external control group (students and hospital workers) and an internal reference group of non-exposed or very low-exposed workers were established (29 and 15 workers, respectively). A  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   F  o  r  p  e  e  r  r  e  v  i  e  w  o  n  l  y   18   significantly higher percentage of neutrophil white blood cells was observed in cement   production workers after the exposure period compared with both internal and external reference groups. The elevated percentage of neutrophils in blood corresponded to an increased level of interleukin-1β in sputum, but no associations between the exposure measurements and inflammatory cells or markers were detected.
In 2015, a one-year follow-up of respiratory symptoms among 134 Tanzanian cement production workers and 63 controls detected significantly lower prevalence of cough, cough with sputum, dyspnoea and wheeze among exposed workers assessed before and after a campaign promoting the use of personal respiratory protection equipment.
[37] There were no changes in the prevalence of symptoms among the controls and total dust exposure levels among exposed workers did not differ between the two time points. Limitations of that study included a short follow-up (one year) and lack of lung function measurements.

Exposure-response evaluations
Few studies of health effects of dust inhalation exposure in cement production workers have provided sufficient exposure information to allow evaluation of exposure-response relationships. There is only one study, which has used a job exposure matrix to assess differences in exposure between job categories [3]. Another problem that arises when the health effects of cement dust are considered is the lack of historical quantitative exposure measurements of airborne cement dust.  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   F  o  r  p  e  e  r  r  e  v  i  e  w  o  n  l  y 20 mg/m 3 ) and cement dust (inhalable cement dust GM = 33 mg/m 3 ) can occur, especially during cleaning tasks in cement plants. [42] In that study, variability within the job groups and the temporal variability in the exposure concentrations generally outweighed the differences in the average concentrations between workers. "Using a broom", "outdoor wind speed" and "presence of rain" were the most influential factors affecting exposure to inhalable cement dust.
In the first cross-sectional phase of our study of 24 plants, we found an exposureresponse relationship for FEV 1 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  If non-positive studies assessing respiratory health were not published and thus not included in the review, publication bias may have occurred. However, some non-positive studies were identified. [12,14] Of the 15 cross-sectional studies, ten reported lung function indices. Two studies did not include controls, to other studies did not adjust for smoking and one study did not include variance of the outcome estimates. Assessment of publication bias through a funnel plot was thus not considered meaningful.
Our search strategy may have been incomplete. The so-called "grey literature" was assessed through Google Scholar, but no further studies fulfilling the review criteria were detected. Another possible bias is selective reporting within the included studies. The quality of the included studies varied. Nevertheless, we have examined the included studies also with reporting bias in mind, but assessment has been difficult due to lack of available protocols from the published studies and limited information especially in older studies.
One of the main difficulties when comparing the results from included studies is the difference in outcome definitions. Most studies report FVC, FEV 1 levels and the FEV 1 /FVCratio, but some report only crude values whereas other report only percent of predicted. Few  22 studies include information about the prediction equations that were applied to calculate expected values. We identified only one study which reported lower limit of normal. [14] Another major difficulty when reviewing this literature is the non-comparability of exposure assessment between studies. We restricted the review to those reporting dust measurements, but limited information is available regarding sampling and quality of measurements, e.g. type of equipment, calibration of pumps, weighing of the filters, weather conditions, and grouping of measurements Furthermore, different fractions of dust were measured (total, respirable, inhalable, and thoracic). To allow assessment of these differences for each study, information regarding the type and level of exposure measurement is included in table 1 and 2.
Adjustment for potential confounders varies between studies. We considered applying stricter inclusion criteria, but since this strategy would have left a limited number of references for review, we chose to include also studies without control groups and without proper adjustment for potential confounders. We report such limitations in the tables.

FUTURE RESEARCH AND RECOMMENDATIONS
Studies are needed to explore further the mechanisms and pathways of airway inflammation and non-malignant respiratory effects of exposure to dust generated during cement production. Future studies should consider including also measurement of CRP and fibrinogen levels in blood, to investigate systemic effects of exposure to cement dust as a risk factor for cardiovascular disease.   Contributorship statement: AKMF has substantial contributed to the conception and design of the work, analysis and interpretation of data, and has written the manuscript, revised it critically for important intellectual content; and has given final approval of the version to be published. KCN has substantial contributed to the conception and design of the work, analysis and interpretation of data, and drafting of the work, revised it critically for important intellectual content; and has given final approval of the version to be published.
We are grateful to Mirjam Håndlykken and Jane Andreassen at the Medical Library, Telemark Hospital, Skien, Norway for excellent guidance and help with the search strategy and conduction of searches.
Competing interests: None.    Fig. 1 Identification, eligibility and inclusion of studies on non-malignant respiratory effects of cement production dust from systematic searches in Medline and Embase from November 2015. *Some articles are registered more than once in the databases; †Based on the inclusion criteria for outcomes: respiratory symptoms, lung function indices, asthma, chronic bronchitis, COPD, pneumoconiosis, and outcomes identified by analysis of induced sputum, or fraction of exhaled nitric oxide (FeNO) measurements.  Please see cover-letter Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale.

5
Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.

5
Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.

5, 6
Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis).

6
Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators. 6, fig. 1 Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.

6
Risk of bias in individual studies 12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.

7
Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means).

Study selection
17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.

Fig. 1
Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations. Table 1 and 2 Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). Table 1  and 2 Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.

ABSTRACT
Objectives: Based on findings from a systematic literature search, we present and discuss the evidence for an association between exposure to cement dust and non-malignant respiratory effects in cement production workers.
Design and setting: Systematic literature searches (Medline and Embase) were performed.
Participants: The studies included exposed cement production workers and non-or low exposed referents.
Primary and secondary outcomes: The searches yielded 594 references, and 26 articles were included. Cross-sectional studies show reduced lung function levels at or above 4.5 mg/m 3 of total dust and 2.2 mg/m 3 of respiratory dust. Odds ratios for symptoms ranged from 1.2-4.8, while forced expiratory volume in one second/forced vital capacity (FEV 1 /FVC) was 1-6% lower in exposed than in controls. Cohort studies reported a yearly excess decline in FEV 1 /FVC ranging from 0.8-1.7% for exposed workers. One longitudinal study reported airflow limitation at levels of exposure comparable to approximately 1 mg/m 3 respirable and 3.7-5.4 mg/m 3 total dust. A dose-response relationship between exposure and decline in lung function has only been shown in one cohort. Two studies have detected small increases in FeNO levels during a work shift, one study reported signs of airway inflammation in induced sputum, whereas another did not detect an increase in hospitalisation rates.
Conclusions: Lack of power, adjustment for possible confounders and other methodological issues are limitations of many of the included studies. Hence, no firm conclusions can be drawn. There is few longitudinal data, but recent studies reports a dose-response relationship between cement production dust exposure and declining lung function indicating a causal relationship, and underlining the need to reduce exposure among workers in this industry.

STRENGTHS AND LIMITS OF THIS STUDY
Systematic searches in Medline and Embase were performed, along with the so-called "grey literature" assessed through Google Scholar.
The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) criteria or similar systems used to evaluate the quality of evidence were not applied, but elements used as evaluation criteria are presented according to study design, sample size, inclusion of controls, adjustment for covariates, and relevant outcome variables.
Many of the 15 cross-sectional studies did not include controls and/or adjust for smoking and one study did not include variance in the outcome estimates; thus, assessment of publication bias through a funnel plot was not performed.
We restricted the review to studies reporting dust measurements, but comparison of exposure assessment between studies was not possible due to limited information regarding, the number of measurements sampling strategy, and quality of measurements.

INTRODUCTION
Health effects associated with exposure to cement were reported by Bernardino Ramazzini as early as 1700. Some 250 years later, evidence of an association between the chromate The modern cement manufacturing process is based on crushing and grinding limestone with quartz or other sources of silica, iron ore and other additives. The mixture is fed into a rotating kiln with burning fuels, consisting of coal, natural gas, oil, and/or alternative fuels (e.g household waste, car tyres) and the temperature is increased to approximately 1450 °C. A series of chemical reactions causes the materials to fuse and form grey nodules called "cement clinker". The clinker is mixed with gypsum and other additives, and then ground to a fine particulate powder to yield cement.
Portland cement, one of the most commonly used cements, is a mixture of calcium oxide (60%-67%), silicon dioxide (17%-25%), aluminium trioxide (3%-8%) and ferric oxide (0%-5%). [2] Cement production processing generates large amounts of dust during quarrying, grinding, and when the finished cement is blended, packed and shipped. Our aim was to present and discuss the evidence for an association between exposure to cement production dust and non-malignant respiratory effects, and to recommend measures for exposure prevention.

Search
Electronic databases were searched from inception to 4 November 2015. The databases Medline and Embase were searched using the Ovid interface. In addition, the authors brought forward three other relevant publications for further review. We also searched the so-called "grey literature" (references not indexed in medical databases such as Medline and Embase) using Google Scholar and the search term: cement AND lung.

Selection of published studies for review
The following inclusion criteria were defined: • Peer-reviewed articles.
• Design: human studies; cross-sectional, case-control, retrospective or prospective cohort studies.
• Exposure: occupational exposure to cement production dust, and exposure measurements including information regarding how the measurements were obtained (individual or group). • Data analysis: the analysis techniques must have been reported.
Studies meeting each of these inclusion criteria were review. We used a two-level screening approach to evaluate the identified studies. First, titles and abstracts were screened for eligibility. This was done independently by two reviewers (AKMF and KCN). Second, the full text articles were evaluated. Agreement was reached in consensus meetings on the selection of full text articles and article inclusion.
The search strategy yielded 594 references. Of these, 56 full text articles were selected for evaluation. Three relevant articles were added by the authors and assessed in the same manner as the others. Twenty-six articles met the inclusion criteria. Figure 1 shows the flow chart for study identification, screening, eligibility, inclusion and exclusion.
The Google Scholar search identified 170 000 records, of which the first (most relevant) 400 was assessed by the first author, but none that had not already been identified or included by the authors met inclusion criteria.

Quality of evidence
A limited number of studies assessing the association between non-malignant respiratory effects and exposure to cement dust were anticipated. Thus, we decided not to use either the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) criteria [4] or any other similar system to evaluate the quality of evidence but instead summarise in the tables some of the elements used as evaluation criteria according to study design, as well as whether and how the study included evaluation of sample size, referents or low-exposed controls, adjustment for covariates, and relevant outcome variables.

RESULTS
The characteristics and findings from 15 cross-sectional and 11 cohort studies are summarised in Tables 1 and 2, respectively.

Cross-sectional studies
Seven out of 10 cross-sectional studies reported reduced lung function in exposed workers as compared to controls. One of the first studies that included dust measurements and adjusted for relevant cofactors was a large survey of US cement production workers (N=2736) and blue-collar controls (N=755). [5] In that study, exposed workers and controls had similar prevalence rates of respiratory symptoms, except that the cement workers reported more dyspnoea compared with controls. Similar levels were also reported for the lung function indices.
In a small (N=48) Yugoslavian study from 1989, the levels of alfa 1 -antitrypsin (AAT) in serum, spirometry, and single-breath transfer factor for carbon monoxide (DL CO ) were measured. [6] FVC and FEV 1 values were negatively related to duration of exposure, and a significant relationship was detected between AAT and respirable dust concentration. No reference group was included in that study. Another small study, restricted to non-smoking cement production workers and blue-collar controls in Malaysia, included 32 exposed workers. [7] Nevertheless, that study detected a reduced FEV 1 /FVC-ratio among the exposed as compared to the controls. A study from Taiwan (N=147) reported significantly elevated odds ratio (OR) for cough: 1.6 (1. A relatively large study from Jordan (N=348) did not find differences in symptoms or lung function indices between groups of cement production workers with low, medium and high exposure levels. [9] In that study adjustments for age and smoking were made, but no control group was included. A study undertaken in Saudi Arabia reported that wheezing and shortness of breath were related to cement dust exposure. [10] A possible confounder in that study may 14 be socioeconomic differences between the exposed group and the references who were workers.In two studies from Tanzania, the prevalence of airway symptoms was higher in exposed workers than controls, [11] and lower forced vital capacity (FVC), forced expiratory volume in one second (FEV 1) , FEV 1 /FVC [20] and peak expiratory flow (PEF) values [12] were demonstrated in the cement production workers. In the first study, exposure assessment showed that a cumulative total dust exposure of more than 300 mg/m 3 *years was significantly associated with airflow limitation. In a third study from the same group, exposure < 2 mg/m 3 was associated with cough OR 7.9 (1.8; 35), and dyspnoea 4.2 (1.1; 15). [13] Peak expiratory flow showed a 4.5% decrease per unit log-transformed dust. In a more recent study from Tanzania, the fractional exhaled nitric oxide (FeNO) levels of cement production workers and controls were assessed. [14] No differences in FeNO concentrations were detected.
Two studies from Iran reported reduced FEV 1 /FVC and reduced FVC levels in exposed workers compared to office workers. [15,16] High crystalline silica levels were reported in these two cement plants, amounting to 27% and 22% of the dust, respectively. Thus, the effects of crystalline silica exposure need to be considered as confounders in these studies. In a study from 2012 conducted among cement production workers in the United Arabic Emirates, elevated ORs for cough and phlegm were detected. [17] That study collected only total dust samples and used office workers as references.
In the first cross-sectional analysis from a prospective study, our research group assessed lung function and respiratory symptoms among 4265 cement production plant workers from 24 plants in eight European countries (Estonia, Greece, Italy, Norway, Spain, Sweden, Switzerland and Turkey). [18] Odds ratios were elevated for symptoms and airflow limitation in the higher levels of exposure, using the lowest quartile of exposure as reference.
FEV 1 /FVC decreased with age and the prevalence of airflow limitation increased with age, by the use of either FEV 1 /FVC<0.7 or FEV 1 /FVC<lower limit of normal (LLN). FEV 1 showed were significantly greater in the high-level exposed workers than in unexposed controls.
These readings were unadjusted for height and socioeconomic status.
In a retrospective cohort study of 119 present and former employees and 50 blue-collar referents from a cement plant in Norway, we used a system for weighting previous exposure based on interviews with a group of 18 long-term workers (i.e a focus group). [22] We observed similar prevalence of symptoms, mean pulmonary function indices and prevalence of COPD in exposed workers and referents. High FVC levels among exposed workers indicated the presence of healthy worker effects, whereas FEV 1 /FVC showed a slight tendency towards lower levels in the highest exposed group.
A small Ethiopian cross-shift study detected cross-shift reductions in PEF, which were most pronounced among high-level exposed workers. [23] A high prevalence of respiratory  16 symptoms was reported among workers exposed to high levels of cement dust during production. Dust levels were associated with increased cross-shift decrease in PEF. The study sample was small and the analyses were not adjusted for age. In another Ethiopian study, 71 Ethiopian cement production workers were followed for one year. [24] Increased prevalence of morning cough, cough with sputum and lower lung function indices were demonstrated among high-exposed workers compared with workers to low exposure. Extremely high levels In a recent study from Iran of 200 workers, increased prevalence of respiratory symptoms and reduced lung function indices were reported post-shift. [26] Multivariate analysis demonstrated an association between these changes and exposure to cement production dust.
However, it is not clear whether the 100 low-exposed and 100 high-exposed workers were randomly selected or whether all workers volunteered for the study. In a study of long-term exposure to cement dust and later hospitalisation with respiratory disease, 546 Danish cement Our group also conducted a study in which 35 healthy dust-exposed, non-smoking cement production workers performed induced sputum measurements analysis and spirometry after a period of exposure and again after five days without work or exposure. [28] An external control group (students and hospital workers) and an internal reference group of non-exposed or very low-exposed workers were established (29 and 15 workers, respectively). A significantly higher percentage of neutrophil white blood cells was observed in cement production workers after the exposure period compared to both internal and external reference groups. The elevated percentage of blood neutrophils corresponded to an increased level of IL-1β in sputum.
In 2015, a one-year follow-up of respiratory symptoms among 134 Tanzanian cement production workers and 63 controls detected significantly lower prevalence of cough, cough with sputum, dyspnoea and wheeze among exposed workers assessed before and after a campaign promoting the use of personal respiratory protection equipment. [29] There were no changes in symptom prevalence among the controls and total dust exposure levels among exposed workers did not differ between the two time points. In a recent prospective study, we

Discussion
Fifteen cross-sectional and 11 cohort studies addressing the association between exposure and non-malignant respiratory effects in the cement production workers were identified. In crosssectional studies odds ratios for symptoms ranged from 1.2-4.8, while forced expiratory volume in one second/forced vital capacity (FEV 1 /FVC) was 1-6% lower in exposed than in controls suggesting a small effect only. Larger effects were reported in cohort studies, which detected a yearly excess decline in FEV 1 /FVC ranging from 0.8-1.7% for exposed workers.
One of the cross-studies did not include a reference population [6], three failed to adjust for smoking [7,15,16], and four did not adjust for age [7,[14][15][16] as potential confounding variables. Two cross-sectional studies with relevant reference populations were reported, but failed to demonstrate differences in the spirometric measurements between workers and referents. [5,9] Exposure levels reported in studies from the former Yugoslavia, [6] Malaysia, [7] Taiwan, [8] Jordan, [9] Saudi Arabia, [10] Tanzania, [11][12][13][14] Iran, [15,16] and the United Arab Emirates, [17] were twofold or higher than in cement production plants in the US. [5] The use of total dust levels in several studies probably does not provide a precise estimate of inhaled particles that deposit in the lower airways. [31,32] Thus, these studies may have been hampered by exposure misclassification, diluting the A limited number of cohort studies were identified. Six out of 11 had very short follow-up times ranging from a single work shift to a year. The first cohort study from 1988 had a follow-up time of 11 years, but included only 68 workers and no control group. [20] The second cohort study published in 1998 included 149 exposed workers, but did not adjust for height.
[21] In addition, confounding due to differences in socioeconomic status between groups was likely. In the first Norwegian study from 2003, no differences in respiratory symptoms or lung function indices between exposed worker and blue-collar controls were detected. [22] The results were adjusted for possible confounders, and assessment of current and previous exposure was included. However, workers from an ammonium plant were used as references because they were presumably unexposed to ammonia as the plant that had a closed production process. Nevertheless, rest-confounding due to background exposure in the control plant may have occurred, resulting in underestimation of effects.
The first Ethiopian cohort study published in 2010 assessed only PEF, had a small sample size (N=40) and did not adjusted for age. [23] The second Ethiopian study was larger  20 (N=100), but had a follow-up of only one year, was unadjusted for smoking, and the extremely high dust levels recorded may not reflect actual levels. [24] Thus, these findings should be interpreted with caution. A Norwegian cross-shift study detected changes of inflammatory markers and lung function in exposed workers as compared to controls, but the only association between exposure and outcome was for fibrinogen. [25] Thus, further studies are needed to confirm these findings. Another cross-shift study included 100 Iranian cement production workers, a control group of office workers and was adjusted for age and smoking; however only total dust was measured and not respirable or thoracic dust fractions. [26] Moreover, the inclusion criteria were unclear; if workers with respiratory symptoms were overrepresented, this may have resulted in overestimation of the effects.
One study assessed hospitalisation among 546 Danish cement production workers. [27] That study included crude levels of FEV 1, and adequate adjustment for possible confounders.
Cement workers did not have an increased rate of hospitalisation during the 10-year follow-up period compared to controls. Nevertheless, a tendency towards increasing rates of hospitalisation due to COPD was observed with increasing duration of exposure up to 30 years. Thereafter, the hospitalisation rates declined, probably due to a healthy worker effect.
The only study assessing inflammatory changes in induced sputum samples showed elevated percentage of blood neutrophils corresponding to an increased level of IL-1β in sputum. [28] That study included both internal (low-level exposed office workers) and external controls (healthy non-exposed volunteers), but no associations between the exposure measurements and inflammatory cells or markers were detected. Thus, it is unclear whether the findings were markers of exposure or signs of airway inflammation.
Interestingly, a Tanzanian study from 2015 showed lower a prevalence of respiratory symptoms among exposed workers assessed before and after a campaign promoting the use of personal respiratory protection equipment. [29] That study is important because it assessed the the assessment of the quality of the included studies. If non-positive studies assessing respiratory health were not published, and thus not included in this review, publication bias may have occurred. However, this concern is ameliorated by the fact that non-positive studies were identified. [5,22] Assessment of publication bias through a funnel plot was not considered meaningful, because many of the 15 cross-sectional studies, did not include controls, adjust for smoking and/or include variance of the outcome estimates.
Our search strategy may have been incomplete. The so-called "grey literature" was assessed through Google Scholar, but no further studies fulfilling the inclusion criteria were  We identified only one study that reported the lower limit of normal. [18] Another major difficulty in reviewing this literature was the non-comparability of exposure assessments between studies. We restricted the review to those studies reporting dust measurements, but limited information was available regarding sampling and quality of measurements (e.g. type of equipment, calibration of pumps, weighing of the filters, weather conditions, and grouping of measurements). Furthermore, different fractions of dust were measured (i.e total, respirable, inhalable, and thoracic). To allow assessment of these differences across studies, information regarding the type and level of exposure measurement is included in Tables 1 and 2.In addition, adjustment for potential confounders varied between studies. We considered applying stricter inclusion criteria, but this strategy would have left a limited number of references for review. Thus, we chose to include studies that lacked control groups and/or did not use proper adjustments for potential confounders. Additional studies are needed to further explore the mechanisms and pathways of airway inflammation and nonmalignant respiratory effects of exposure to dust generated during cement production.
Researcher conducting future studies should also consider including also measurement of creactive protein and fibrinogen levels, to investigate the systemic effects of exposure to cement dust as a risk factor for cardiovascular disease.       Fig. 1 Identification, eligibility and inclusion of studies on non-malignant respiratory effects of cement production dust from systematic searches in Medline and Embase from November 2015. *Some articles are registered more than once in the databases; †Based on the inclusion criteria for outcomes: respiratory symptoms, lung function indices, asthma, chronic bronchitis, COPD, pneumoconiosis, and outcomes identified by analysis of induced sputum, or fraction of exhaled nitric oxide (FeNO) measurements.  Please see cover-letter Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale.

5
Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.

5
Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.

5, 6
Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis).

6
Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators. 6, fig. 1 Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.

Study selection
17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.

Fig. 1
Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations. Table 1 and 2 Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). Table 1  and 2 Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.  Participants: The studies included exposed cement production workers and non-or low exposed referents.
Primary and secondary outcomes: The searches yielded 594 references, and 26 articles were included. Cross-sectional studies show reduced lung function levels at or above 4.5 mg/m 3 of total dust and 2.2 mg/m 3 of respiratory dust. Odds ratios for symptoms ranged from 1.2-4.8, while forced expiratory volume in one second/forced vital capacity (FEV 1 /FVC) was 1-6% lower in exposed than in controls. Cohort studies reported a yearly excess decline in FEV 1 /FVC ranging from 0.8-1.7% for exposed workers. One longitudinal study reported airflow limitation at levels of exposure comparable to approximately 1 mg/m 3 respirable and 3.7-5.4 mg/m 3 total dust. A dose-response relationship between exposure and decline in lung function has only been shown in one cohort. Two studies have detected small increases in FeNO levels during a work shift, one study reported signs of airway inflammation in induced sputum, whereas another did not detect an increase in hospitalisation rates.
Conclusions: Lack of power, adjustment for possible confounders and other methodological issues are limitations of many of the included studies. Hence, no firm conclusions can be drawn. There is few longitudinal data, but recent studies reports a dose-response relationship  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   F  o  r  p  e  e  r  r  e  v  i  e  w  o  n  l  y   3 between cement production dust exposure and declining lung function indicating a causal relationship, and underlining the need to reduce exposure among workers in this industry.

STRENGTHS AND LIMITS OF THIS STUDY
Systematic searches in Medline and Embase were performed, along with the so-called "grey literature" assessed through Google Scholar.
The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) criteria or similar systems used to evaluate the quality of evidence was not applied, but elements used as evaluation criteria are presented according to study design, sample size, inclusion of controls, adjustment for covariates, and relevant outcome variables.
Many of the 15 cross-sectional studies did not include controls and/or adjust for smoking and one study did not include variance in the outcome estimates; thus, assessment of publication bias through a funnel plot was not performed.
We restricted the review to studies reporting dust measurements, but comparison of exposure assessment between studies was not possible due to limited information regarding, the number of measurements sampling strategy, and quality of measurements.

INTRODUCTION
Health effects associated with exposure to cement were reported by Bernardino Ramazzini as early as 1700. Some 250 years later, evidence of an association between the chromate  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   F  o  r  p  e  e  r  r  e  v  i  e  w  o  n  l  y   4 sensitivity induced by cement exposure and dermatitis was reported. [1] Since then, a substantial number of studies have reported increased prevalence of respiratory symptoms, reduced dynamic lung function, chronic bronchitis, emphysema, asthma, and radiographic abnormalities of the lungs, although, many of these studies have been hampered by limitations. [2,3] The modern cement manufacturing process is based on crushing and grinding limestone with quartz or other sources of silica, iron ore and other additives. The mixture is fed into a rotating kiln with burning fuels, consisting of coal, natural gas, oil, and/or alternative fuels (e.g household waste, car tyres) and the temperature is increased to approximately 1450 °C. A series of chemical reactions causes the materials to fuse and form grey nodules called "cement clinker". The clinker is mixed with gypsum and other additives, and then ground to a fine particulate powder to yield cement.
Portland cement, one of the most commonly used cements, is a mixture of calcium oxide (60%-67%), silicon dioxide (17%-25%), aluminium trioxide (3%-8%) and ferric oxide (0%-5%). [2] Cement production processing generates large amounts of dust during quarrying, grinding, and when the finished cement is blended, packed and shipped. Our aim was to present and discuss the evidence for an association between exposure to cement production dust and non-malignant respiratory effects, and to recommend measures for exposure prevention.

Selection of published studies for review
The following inclusion criteria were defined: • Peer-reviewed articles.
• Design: human studies; cross-sectional, case-control, retrospective or prospective cohort studies.
Studies meeting each of these inclusion criteria were review. We used a two-level screening approach to evaluate the identified studies. First, titles and abstracts were screened for eligibility. This was done independently by two reviewers (AKMF and KCN). Second, the full text articles were evaluated. Agreement was reached in consensus meetings on the selection of full text articles and article inclusion.
The search strategy yielded 594 references. Of these, 56 full text articles were selected for evaluation. Three relevant articles were added by the authors and assessed in the same manner as the others. Twenty-six articles met the inclusion criteria. Figure 1 shows the flow chart for study identification, screening, eligibility, inclusion and exclusion.
The Google Scholar search identified 170 000 records, of which the first (most relevant) 400 was assessed by the first author, but none that had not already been identified or included by the authors met inclusion criteria.

Quality of evidence
A limited number of studies assessing the association between non-malignant respiratory effects and exposure to cement dust were anticipated. Thus, we decided not to use either the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) criteria [4] or any other similar system to evaluate the quality of evidence but instead summarise in the tables some of the elements used as evaluation criteria according to study design, as well as whether and how the study included evaluation of sample size, referents or low-exposed controls, adjustment for covariates, and relevant outcome variables.

Cross-sectional studies
Eight out of the 11 cross-sectional studies that included lung function measurements reported reduced lung function in exposed workers as compared to controls. One of the first studies that included dust measurements and adjusted for relevant cofactors was a large survey of US cement production workers (N=2736) and blue-collar controls (N=755). [5] In that study, exposed workers and controls had similar prevalence rates of respiratory symptoms, except that the cement workers reported more dyspnoea compared with controls. Similar levels were also reported for the lung function indices.
In a small (N=48) Yugoslavian study from 1989, the levels of alfa 1 -antitrypsin (AAT) in serum, spirometry, and single-breath transfer factor for carbon monoxide (DL CO ) were measured. [6] FVC and FEV 1 values were negatively related to duration of exposure, and a significant relationship was detected between AAT and respirable dust concentration. No reference group was included in that study. Another small study, restricted to non-smoking cement production workers and blue-collar controls in Malaysia, included 32 exposed workers. [7] Nevertheless, that study detected a reduced FEV 1 /FVC-ratio among the exposed as compared to the controls. A study from Taiwan (N=147) reported significantly elevated odds ratio (OR) for cough: 1.6 (1. A relatively large study from Jordan (N=348) did not find differences in symptoms or lung function indices between groups of cement production workers with low, medium and high exposure levels. [9] In that study adjustments for age and smoking were made, but no control group was included. A study undertaken in Saudi Arabia reported that wheezing and shortness of breath were related to cement dust exposure. [10] A possible confounder in that study may 14 be socioeconomic differences between the exposed group and the references who were office workers. In two studies from Tanzania, the prevalence of airway symptoms was higher in exposed workers than controls, [11] and lower forced vital capacity (FVC), forced expiratory volume in one second (FEV 1) , FEV 1 /FVC [20] and peak expiratory flow (PEF) values [12] were demonstrated in the cement production workers. In the first study, exposure assessment showed that a cumulative total dust exposure of more than 300 mg/m 3 *years was significantly associated with airflow limitation. In a third study from the same group, exposure < 2 mg/m 3 was associated with cough OR 7.9 (1.8; 35), and dyspnoea 4.2 (1.1; 15). [13] Peak expiratory flow showed a 4.5% decrease per unit log-transformed dust. In a more recent study from Tanzania, the fractional exhaled nitric oxide (FeNO) levels of cement production workers and controls were assessed. [14] No differences in FeNO concentrations were detected.
Two studies from Iran reported reduced FEV 1 /FVC and reduced FVC levels in exposed workers compared to office workers. [15,16] High crystalline silica levels were reported in these two cement plants, amounting to 27% and 22% of the dust, respectively. Thus, the effects of crystalline silica exposure need to be considered as confounders in these studies. In a study from 2012 conducted among cement production workers in the United Arabic Emirates, elevated ORs for cough and phlegm were detected. [17] That study collected only total dust samples and used office workers as references.
In the first cross-sectional analysis from a prospective study, our research group assessed lung function and respiratory symptoms among 4265 cement production plant workers from 24 plants in eight European countries (Estonia, Greece, Italy, Norway, Spain, Sweden, Switzerland and Turkey). [18] Odds ratios were elevated for symptoms and airflow limitation in the higher levels of exposure, using the lowest quartile of exposure as reference.
FEV 1 /FVC decreased with age and the prevalence of airflow limitation increased with age, by the use of either FEV 1 /FVC<0.7 or FEV 1 /FVC<lower limit of normal (LLN). FEV 1 showed

Cohort studies
Eight out of eleven cohort studies report reduced lung function in exposed workers as compared to controls. In a study following 68 Italian cement workers from 1973 to 1984, small, non-significant reductions in FVC and FEV 1 for all workers were detected over the follow-up period. [20] However, that study did not include a control group. Ali et al.

investigated changes in pulmonary function during work shifts among workers in Saudi
Arabian cement plants.
[21] Mean reductions in FEV 1 , FEV 1 /FVC ratio and forced expiratory flow (FEF 25-75% ) were significantly greater in the high-level exposed workers than in unexposed controls. These readings were unadjusted for height and socioeconomic status.
In a retrospective cohort study of 119 present and former employees and 50 blue-collar referents from a cement plant in Norway, we used a system for weighting previous exposure based on interviews with a group of 18 long-term workers (i.e a focus group). [22] We observed similar prevalence of symptoms, mean pulmonary function indices and prevalence of COPD in exposed workers and referents. High FVC levels among exposed workers indicated the presence of healthy worker effects, whereas FEV 1 /FVC showed a slight tendency towards lower levels in the highest exposed group.
A small Ethiopian cross-shift study detected cross-shift reductions in PEF, which were most pronounced among high-level exposed workers. [23] A high prevalence of respiratory  16 symptoms was reported among workers exposed to high levels of cement dust during production. Dust levels were associated with increased cross-shift decrease in PEF. The study sample was small and the analyses were not adjusted for age. In another Ethiopian study, 71 Ethiopian cement production workers were followed for one year. [24] Increased prevalence of morning cough, cough with sputum and lower lung function indices were demonstrated among high-exposed workers compared with workers to low exposure. Extremely high levels In a recent study from Iran of 200 workers, increased prevalence of respiratory symptoms and reduced lung function indices were reported post-shift. [26] Multivariate analysis demonstrated an association between these changes and exposure to cement production dust.
However, it is not clear whether the 100 low-exposed and 100 high-exposed workers were randomly selected or whether all workers volunteered for the study. In a study of long-term exposure to cement dust and later hospitalisation with respiratory disease, 546 Danish cement  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  Our group also conducted a study in which 35 healthy dust-exposed, non-smoking cement production workers performed induced sputum measurements analysis and spirometry after a period of exposure and again after five days without work or exposure. [28] An external control group (students and hospital workers) and an internal reference group of non-exposed or very low-exposed workers were established (29 and 15 workers, respectively). A significantly higher percentage of neutrophil white blood cells was observed in cement production workers after the exposure period compared to both internal and external reference groups. The elevated percentage of blood neutrophils corresponded to an increased level of IL-1β in sputum.
In 2015, a one-year follow-up of respiratory symptoms among 134 Tanzanian cement production workers and 63 controls detected significantly lower prevalence of cough, cough with sputum, dyspnoea and wheeze among exposed workers assessed before and after a campaign promoting the use of personal respiratory protection equipment. [29] There were no changes in symptom prevalence among the controls and total dust exposure levels among exposed workers did not differ between the two time points. In a recent prospective study, we report results from a 4-year follow-up of 4966 employees of 24 cement production plants in eight countries. [30] Personal measurements of thoracic dust for eight job categories were collected, lung function measurements performed, and questionnaires completed at baseline, and at follow-up. The arithmetic mean (AM) exposure level among non-administration employees was estimated from group-based analysis of the measurement results, showing  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59

Discussion
Fifteen cross-sectional and 11 cohort studies addressing the association between exposure and non-malignant respiratory effects in the cement production workers were identified. In crosssectional studies odds ratios for symptoms ranged from 1.2-4.8, while forced expiratory volume in one second/forced vital capacity (FEV 1 /FVC) was 1-6% lower in exposed than in controls suggesting a small effect only. Larger effects were reported in cohort studies, which detected a yearly excess decline in FEV 1 /FVC ranging from 0.8-1.7% for exposed workers.
[21] In addition, confounding due to differences in socioeconomic status between groups was likely. In the first Norwegian study from 2003, no differences in respiratory symptoms or lung function indices between exposed worker and blue-collar controls were detected. [22] The results were adjusted for possible confounders, and assessment of current and previous exposure was included. However, workers from an ammonium plant were used as references because they were presumably unexposed to ammonia as the plant that had a closed production process. Nevertheless, rest confounding due to background exposure in the control plant may have occurred, resulting in underestimation of effects.
The first Ethiopian cohort study published in 2010 assessed only PEF, had a small sample size (N=40) and did not adjust for age. [23] The second Ethiopian study was larger  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   F  o  r  p  e  e  r  r  e  v  i  e  w  o  n  l  y 20 (N=100), but had a follow-up of only one year, was unadjusted for smoking, and the extremely high dust levels recorded may not reflect actual levels. [24] Thus, these findings should be interpreted with caution. A Norwegian cross-shift study detected changes of inflammatory markers and lung function in exposed workers as compared to controls, but the only significant association between exposure and outcome was for fibrinogen. [25] Thus, further studies are needed to confirm these findings. Another cross-shift study included 100 Iranian cement production workers, a control group of office workers, and was adjusted for age and smoking; however only total dust was measured and not respirable or thoracic dust fractions. [26] Moreover, the inclusion criteria were unclear; if workers with respiratory symptoms were overrepresented, this may have resulted in overestimation of the effects.
One study assessed hospitalisation among 546 Danish cement production workers. [27] That study included crude levels of FEV 1, and adequate adjustment for possible confounders.
Cement workers did not have an increased rate of hospitalisation during the 10-year follow-up period compared to controls. Nevertheless, a tendency towards increasing rates of hospitalisation due to COPD was observed with increasing duration of exposure up to 30 years. Thereafter, the hospitalisation rates declined, probably due to a healthy worker effect.
The only study assessing inflammatory changes in induced sputum samples showed elevated percentage of blood neutrophils corresponding to an increased level of IL-1β in sputum. [28] That study included both internal (low-level exposed office workers) and external controls (healthy non-exposed volunteers), but no associations between the exposure measurements and inflammatory cells or markers were detected. Thus, it is unclear whether the findings were markers of exposure or signs of airway inflammation.
Our search strategy may have been incomplete. The so-called "grey literature" was assessed through Google Scholar, but no further studies fulfilling the inclusion criteria were detected. Another possible bias is selective reporting within the included studies. The quality of the included studies varied. Although we have examined the included studies with reporting bias in mind, assessment was difficult due to lack of protocol descriptions in the published reports and other limited information especially in older studies.
One of the primary difficulties when comparing results across studies is the difference in outcome definitions. Most of the included studies reported FVC, FEV 1 levels and the We identified only one study that reported the lower limit of normal. [18] Another major difficulty in reviewing this literature was the non-comparability of exposure assessments between studies. We restricted the review to those studies reporting dust measurements, but limited information was available regarding sampling and quality of measurements (e.g. type of equipment, calibration of pumps, weighing of the filters, weather conditions, and grouping of measurements). Furthermore, different fractions of dust were measured (i.e total, respirable, inhalable, and thoracic). To allow assessment of these differences across studies, information regarding the type and level of exposure measurement is included in Tables 1 and 2.In addition, adjustment for potential confounders varied between studies. We considered applying stricter inclusion criteria, but this strategy would have left a limited number of references for review. Thus, we chose to include studies that lacked control groups and/or did not use proper adjustments for potential confounders. Additional studies are needed to further explore the mechanisms and pathways of airway inflammation and nonmalignant respiratory effects of exposure to dust generated during cement production.

5
Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.

5
Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.

5, 6
Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis).

6
Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators. 6, fig. 1 Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.

6
Risk of bias in individual studies 12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.

7
Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means).

7
Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified.

Study selection
17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.

Fig. 1
Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations. Table 1 and 2 Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). Table 1  and 2 Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.

DISCUSSION
Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).

6-19
Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).

20, 21
Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research.