Bayan Hosseini
email: hosseinib@students.iarc.fr

Amy L Hall
email: amy.hall2@canada.ca

Kazem Zendehdel

Hans Kromhout
email: h.kromhout@uu.nl

Felix M Onyije
email: onyijef@fellows.iarc.fr

Rahmatollah Moradzadeh
email: moradzadehr@arakmu.ac.ir

Maryam Zamanian
email: m.zamanian@arakmu.ac.ir

Dr Joachim Schüz
email: schuzj@iarc.fr

Ann Olsson
email: olssona@iarc.fr

Caterina Ledda

Venerando Rapisarda

Paolo Boffetta

Occupational Exposure to Carcinogens and Occupational Epidemiological Cancer Studies in Iran: A Review

Keywords: occupation, occupational exposures, exposure measurement, cancer, Iran Workplace

Simple Summary: Occupational cancers can be prevented by eliminating hazardous substances or by reducing workers' exposures. Characterizing the extent of exposure to carcinogens in workplaces and industries is a crucial first step to exposure control. Iran is one of the most industrialized countries in the Middle East, yet lacks an overview of the extent of exposure to carcinogens and comprehensive risk management. This review provides an overview of studies conducted to date and demonstrates the need for interdisciplinary collaboration to inform occupational research and exposure control in Iran and beyond.

Industries in Iran have undergone rapid growth in recent decades. The largest industrial sectors are petroleum industries, followed by the manufacturing of motor vehicles and the pharmaceutical industry, mining and quarrying especially copper and aluminum, and manufacturing of metals and rubber and plastics products [1]. Workers in these industries may be exposed to various known or suspected carcinogens such as BTEXs (benzene, toluene, ethylbenzene, and xylene), crystalline silica, and heavy metals. National efforts to reduce the burden of occupational cancers require evidence-based information on exposures to carcinogenic agents and their related cancer risks in Iranian workers [2]. Exposure assessment is a critical component of all epidemiological studies and can be particularly complex in studies of occupational cancers. The choice of method depends to a large extent on the study's design, resources, and what data are available. Exposure assessment applied in epidemiological studies frequently comprises indirect methods, including self-reports of jobs and/or various job-related exposures, and subsequent assignment of exposures by case-by-case expert assessment or job exposure matrices. In industrial cohort studies, employment records of workers and long-term routine surveillance of exposures in the workplace may be applied to conduct objective, detailed, and quantitative exposure assessment. Quantitative exposure assessment methods include personal air sampling, stationary air sampling, and biomonitoring to represent individual exposures during a specific time period. These direct exposure assessment methods are likely to be the most precise methods but reflect current or very recent exposures, unless repeated regularly over a long time period [3,4].

To our knowledge the presence of occupational carcinogens in workplaces in Iran have not been well characterized, and very little is known about the burden of occupational cancer in Iran and other Middle East countries. This is important because not just materials and technologies but also workplace environments and practices, legislated exposure controls used in industries might be different and unique for this region, making them difficult or impossible to infer from studies conducted elsewhere. For instance, the Iranian government adopted laws prohibiting the use of asbestos in final products in 2000 and the import of white asbestos in 2012, but it is still used in some industries such as automobile manufacturing instead of changing to non-asbestos materials [5]. Other factors determining differences in occupational exposures include the content of respirable crystalline silica in ground construction materials and the standard and types of busses and trucks affecting the motor emissions, etc. [6].

The objective of this review was to identify and characterize epidemiological studies of occupational cancers and exposure monitoring studies with projection of cancer risk in Iran and describe how relevant exposures were assessed and assigned to workers in these studies.

Materials and Methods

Literature Search and Inclusion/Exclusion Criteria

A literature search was conducted to identify publications related to occupational cancer in Iran through three bibliographic databases (PubMed, Web of Science, and Google Scholar) from 1973 to January 2021. Select keywords were searched through title, abstracts, and body text to identify relevant publications.

The search queries (Tables S1 andS2) included keywords according to the PECOs statement (Population: workers, and Iran, Exposure: occupational carcinogenic exposures, Comparison: unexposed/exposed workers, Outcomes: cancer) [7]. The search strategy combined the above terms by Boolean search operations (AND, OR, NOT) and Mesh terms.

We included full publications of epidemiological studies (cohort and case-control studies on occupational cancer) and exposure monitoring studies in which the authors projected the subsequent risk of cancer. Occupational agents were restricted to chemical agents that had been evaluated by the International Agency for Research on Cancer's (IARC) Monograph Programme on the Identification of Carcinogenic Hazards to Humans irrespective of its IARC classification, i.e., Group 1 (carcinogenic to humans), Group 2A (probably carcinogenic to humans), Group 2B (possibly carcinogenic to humans), and Group 3 (not classifiable as to its carcinogenicity to humans). All articles had to be published in English or Farsi.

Data Extraction

Identified articles were imported into EndNote reference manager, and duplicates were removed. Two reviewers (B.H. & F.M.O.) independently screened the articles according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines [8]. Titles and abstracts of all identified references in the primary search were screened to determine potential eligibility. In any case of disagreement between reviewers, the full-text publication was reviewed and discussed to resolve discrepancy; a third reviewer (A.O.) was consulted to reach consensus if needed. Following the primary screening, full texts of the relevant references were obtained. Five full-text articles had to be requested from authors via E-mail or ResearchGate, and all were successful.

The following data were extracted from each retained publication: name of author, publication year, geographical region of Iran (North/South/West/East/Centre/Tehran), study design (Cohort/Case-control/Exposure monitoring with cancer risk projection as an outcome/burden of cancer studies with nonspecific study design, e.g., cancer projection using available data on exposure and outcomes), occupation (Title), industry (Title), exposure agents (Names), population size/sample size (Number of workers/samples), exposure assessment methods (Personal air monitoring/Biological monitoring/Stationary air monitoring/Self-report of job or exposure history/Registries/Expert Assessment), and study outcomes (Overall and specific cancer sites).

Results

The publication selection process is summarized in the modified PRISMA flow diagram in Figure 1. The initial systematic searches identified 1255 publications (718 from PubMed, 391 from Web of Science, 146 from Google scholar). After removing the duplicates (n = 279), 976 publications remained. Of these, 835 were excluded by screening the titles and abstracts (in vitro and in vivo, nutritional studies, editorial, case reports, reviews and systematic reviews, physical and psychosocial exposure in the workplaces).

The remaining 141 full-text publications were reviewed, and 92 were additionally excluded, i.e., studies evaluating occupational exposures in relation to health outcomes other than cancer.

In total, 49 relevant publications (one cohort study, 11 case-control studies, 34 exposure monitoring studies with cancer risk projection as an outcome, and three cancer burden studies using national and international data) were retained for data extraction. The frequency of exposure assessment methods by study design are shown in Table 1.

Epidemiological Studies

The retained epidemiological studies (one cohort study and 11 case-control studies) are summarized in Table 2. The only eligible cohort study included a random selection of 15,162 military veterans from the Iran-Iraq war between 1984 and 1987, who were followed prospectively for up to 25 years, with a particular interest of investigating the association of single exposure to sulfur mustard in relation to cancer incidence. Almost half of the cohort (n = 7570) had been exposed to sulfur mustard (at least one exposure documented in medical records while they were present in the battlefield) during the war and the other half had not been exposed (e.g., injured veterans). Survivors were followed up yearly by medical doctors, via telephone interview to confirm cancer occurrence or death. The outcomes of interest included the incidence of all types of cancer. Verification of cancer was performed by pathological confirmation [9].

Out of the 11 retained case-control studies, five examined bladder and urinary tract cancers. The exposure assessment in all case control studies was based on self-reported job histories and self-reported specific chemical exposures. The largest case-control study was conducted by [START_REF] Khoubi | Association between the high risk occupations and bladder cancer in Iran: A case-control study[END_REF] [10] in the Isfahan Province. Using lifetime occupational history, job titles were coded according to the International Standard Classification of Occupation from 2008 (ISCO-08), and risks were estimated for 22 pre-defined occupational groups. This study observed a significantly increased risk of bladder cancer in certain occupations, including truck and bus drivers, agricultural workers, metal industry workers, construction workers, and domestic housekeepers.

Aminian et al. ( 2014) [11] conducted a hospital-based case-control study in men to evaluate the risk of bladder cancer in relation to occupational exposure. The authors stated, "controls were male cases without cancers and occupational exposures". The results were presented for a priori assigned high and low cancer-risk jobs. The statistical analysis section comprised very limited information, and the study reported elevated crude odds ratios for jobs allocated to high-risk occupations including bus and truck drivers, road and asphalt workers, mechanics, refinery and petrochemical workers, plastic manufacturing, metal manufacturing, welding, and pipeline workers.

Farzaneh et al. (2017) [12] conducted a case-control study on bladder cancer in the Yazd Province. Job titles were classified into a priori "high-risk" and "low-risk" jobs based on their potential (according to the literature and expert's opinion) for exposure to bladder carcinogens such as aromatic amines, amino-biphenyl, polycyclic aromatic hydrocarbons [PAH], and azo dyes. An elevated risk of bladder cancer was observed among a priori high-risk jobs including metal manufacturing, textile, driving, agriculture and livestock, and construction.

Ghadimi et al. ( 2015) [13] reported on a hospital-based case-control study on urinary bladder cancer in relation to occupation, smoking, and opium consumption, conducted in the Kurdistan Province. By the occupation classification ISCO-08, univariable analysis showed an elevated risk of bladder cancer in workers in metal manufacturing.

Tajvidi et al. ( 2013) [14] conducted a case-control study of kidney cancer in the Isfahan Province. Study participants were asked about occupations held as well as selected exposures in a questionnaire. Results were reported based on Chi-square and T-test analysis, which compared the occupations and exposure difference between cases and controls. In case subjects the frequency of agriculture and laborers in various industries was higher than that in other occupations. Exposures to pesticides, paint, petrol, chemicals, and mineral agents were significantly more frequent in cases than in control subjects.

A small case-control study of head and neck cancer showed an association with pesticide exposure. Exposure to pesticides was confirmed by residual pesticide from the adipose tissue of the neck of cases and controls. Information on pesticide exposure was classified into non exposed, low, and high exposed based on occupational, residential, and agricultural activities history [17]. A study of malignant lymphoma conducted in the Fars Province observed an elevated risk of Non-Hodgkin lymphoma related to pesticide exposure. Information on all jobs held and exposures for each job, as well as detailed information of agricultural exposures was collected. For the analyses, job titles were classified by major groups of ISCO-68. The results showed elevated risk of lymphoma in farmers compared to all other jobs. The elevated risk was present for any type of pesticide exposure whether occupational or residential [16].

Another hospital-based case-control study of non-Hodgkin and Hodgkin's lymphoma was conducted in the Tehran Province. In this study, job titles were classified into highand low-risk jobs based on the literature. Elevated risks of non-Hodgkin lymphoma were observed in unadjusted analyses for occupations such as welders and metal workers, with increased risk of Hodgkin lymphoma in drivers [15].

Hosseini et al. ( 2009) [18] conducted a hospital-based case-control study to investigate the lung cancer risk related to known and suspected environmental and occupational lung carcinogens. In this study, increased risk of lung cancer was observed for occupational exposure to inorganic dusts, chemical compounds, and heavy metals. The same results were observed in smokers and nonsmokers.

A hospital-based case-control study on gastrointestinal cancer among male patients was conducted in the Tehran Province. One-digit major groups of the ISCO-08 classification were analyzed. The results reported an elevated risk of gastrointestinal cancers in plant and machine operators, assemblers, agricultural workers, and laborers [19].

A case-control study of breast cancer conducted in the Mashhad Province recruited participants among employed women classified into four major groups: teachers, administrative/clerical workers, healthcare workers, and miscellaneous jobs (carpenters, hairdressers, tailors, cooks), and the results showed only an increased risk of breast cancer in teachers compare to the other occupations [20].

All case-control studies were relatively small, with a mean number of 180 cases (range 31-300) and 221 controls (range 32-500). The cases were mostly recruited from hospitals (n = 8) and in three publications from cancer registries. The controls were recruited from hospitals (n = 6), general population (n = 2), neighbors (n = 1), relatives of cases (n = 1), and unclear (n = 1). Most studies included only histologically confirmed cases (n = 8). The exposure assessment in all case-control studies was mostly based on self-reported jobs and/or exposures. Except two studies which allocated jobs to the low-vs high-risk jobs based on the literature review or expert judgement, no subsequent attempt was made to assign exposures to these jobs (e.g., expert assessment or existing job-exposure-matrices). Two publications considered specific exposure to pesticides, while the others addressed jobs and industries as proxies for occupational exposures.

Exposure Monitoring Studies Including Cancer Risk Predictions

Table 3 describes characteristics of the 34 exposure monitoring studies that subsequently estimated cancer risk. Sixteen studies used personal air monitoring, 13 used stationary air monitoring, and three studies applied a combination of personal and stationary air monitoring to estimate the level of exposure of individual workers and workplaces. One additional study estimated the lung cancer risk based on available exposure measurement data from previous studies (used available input parameters, e.g., intensity of nickel and chromium exposure in welders from published studies) [21]. Another study calculated exposure using an exposure index (EI) based on the physical characteristics of the agent, e.g., the olfactory threshold value, inhalable fraction and vapor, the preventive measures including personal and environmental protection, level of benzene exposure, and work duration per week, and estimated the risk of leukemia [22].

The majority of exposure monitoring studies (14/16 of personal air sampling and 12/13 of stationary air sampling) measured the exposure of workers only once over an entire work shift, while two studies collected repeated measurements of the same worker on two or three occasions during an entire work shift [23,24]. One study measured exposure via personal air sampling over the full duration of a work shift for three consecutive months [25]; another assessed exposure by taking four short-term personal air measurements (90 min) in different hours of a work shift for five consecutive weeks [26].

In larger industries, exposures were assigned to workers based on their tasks in relevant production units [24,[27][28][29]. In small workplaces, e.g., beauty salons [30,31], waterpipe cafés [32,33], and gas stations [34], stationary air monitoring was applied to estimate exposure during a work shift.

The most frequently monitored agents in the monitoring studies were volatile organic compounds (VOCs) including benzene, toluene, ethylbenzene, and xylenes (BTEXs). Personal and stationary air sampling of these agents was conducted in a variety of industries, e.g., petroleum industry [23,27,35], manufacture of basic iron and steel [36], automobile manufacturing [37], painting units of automobile manufacturing [38], poultry slaughterhouse [26], and gasoline and Compressed Natural Gas (CNG) refueling stations [39].

In exposure monitoring studies, monitoring results were used to project the risk of cancer using different terms, e.g., Excess Lifetime Cancer Risk (ELCR), Incremental Lifetime Cancer Risk (ILCR), Inhalation Lifetime Cancer Risk (LTCR), and Lifetime Cancer Risk (LCR).

In water pipe cafés [32], and beauty salons [30,31], the investigators used stationary air monitoring exclusively to measure the exposure to BTEXs and PAHs. Exposures were monitored with consideration of sampling sites, e.g., type of ventilation system and the location at which those salons or cafés were located, e.g., ground floor or basement.

Crystalline silica was the second most frequently monitored agent. Workers' exposure was measured by personal and stationary air sampling in a variety of industries such as casting of iron and steel manufacture [40], manufacture of ceramic pin insulators [41], construction workers at building demolition sites [42,43], and in sectors including stone cutting and milling, foundries, glass manufacturing, asphalt manufacturing, construction, sand and gravel mining, sand blasting, and ceramics, bricks and cement manufacturing [44]. Based on the monitoring results, the risk of lung cancer was estimated.

In a few studies, exposure to formaldehyde was monitored in pathology laboratory staff through personal and stationary air sampling [45][46][47], and in one study exposure to formaldehyde was assessed by personal air sampling of plastic product workers to estimate their cancer risk [48].

Exposure to vinyl chloride was measured among plastic manufacturing workers through personal air samplers to estimate the ELCR [49].

Burden of Cancer Studies

In addition, there were three relevant publications that used secondary data to project occupational cancer risk [55][56][57]. Of these, two publications by Mosavi-Jarrahi et al. projected the fraction of leukemia and lung cancer incidence in Iran attributable to exposure to occupational carcinogens, e.g., benzene, ionizing radiation, and ethylene oxide for leukemia, and silica, cadmium, nickel, arsenic, chromium, diesel fumes, beryllium, and asbestos for lung cancer [55,56]. Both publications applied available country-specific workforce survey data from the International Labour Organization (ILO) and estimated the proportion of exposed workers in each industry using the European CARcinogen Exposure (CAREX) database and relative risk estimates from the literature to predict the burden of occupational cancer [58]. The authors reported that 0.08% of male workers and 0.02% of female workers were exposed to the major occupational lung carcinogens (silica, cadmium, nickel, arsenic, chromium, diesel fumes, beryllium, and asbestos), resulting in an attributable fraction of lung cancer due to occupational exposures of 12% in men and 1.5% in women [55], and that 0.016% of male workers and 0.02% of female workers were exposed to leukemogens (benzene, ionizing radiation, and ethylene oxide), estimating that 7.6% of leukemia in men and 3.6% in women were attributable to occupational exposures [56].

Abtahi et al. [57], estimated age-, sex-, and cause-specific mortality attributable to occupational risks for the years 1990, 2005, and 2015 using the methods provided in the Global Burden of Disease project (GBD) 2015 [57]. The occupational carcinogens included in the projections were asbestos, arsenic, benzene, beryllium, cadmium, chromium, diesel exhaust engine, formaldehyde, nickel, polycyclic aromatic hydrocarbons, second-hand smoke, silica, and sulfuric acid. Information on industry patterns was extracted from National Population and Housing censuses in 1986,1996,2006,2011, and 2016, and exposures by industry were derived primarily from the European CAREX database [59,60]. The results of this study showed that exposure to particulate matter, gases, and fumes, and asbestos was among the highest contributions to the national attributable DALYs in 2015 among occupational risks. In addition, from 1990 to 2015, the increase in total DALYs attributable to occupational carcinogens (112%) was higher than that for other occupational risks.

Publications over Time and Location

There were no relevant publications before 2009; in the subsequent years, the trend fluctuated between two to four publications per year until 2015. In 2016 to 2021, the trend was between five to seven publications per year. Only a few epidemiological studies per year were published between 2009 and 2021. Figure S1 provides a full summary of the time trends.

In terms of the geographical trend of publications, the greatest number (n = 15 or 31%) were at the national level or in non-specified areas of Iran in various manufacturing industries. The second most frequent geographical area was Tehran 11 (22%), the capital of Iran with a population of around 9 million, including multiple types of economic activities. Studies in Tehran were conducted across diverse workplaces such as manufacturing of plastic products, manufacturing of parts and accessories for motor vehicles, hairdressing and other beauty treatment, hospitals, and the construction industry. Studies conducted in the central part of Iran (Isfahan, Arak, Yazd, and Kashan; n = 8) included mostly heavy industries such as casting of iron and steel (n = 2), the manufacture of basic metals including iron and steel, and plastic products (n = 6) (Figure S1).

Discussion

This review identified 49 articles on occupational exposure to carcinogens and associated cancer risk in Iran. The studies consisted of one cohort study and 11 case-control studies directly investigating the association between occupational exposures and the risk of various cancers, as well as 34 studies with exposure monitoring including projections of associated cancer risks, and three studies investigating the burden of cancer related to occupational carcinogen exposure based on secondary national and international survey data.

The first relevant article published in 2009 indicates that occupational cancer epidemiology is a relatively new topic in Iran, with the number of publications increasing in recent years. The relatively low number of published articles on occupational cancers overall may be due to several reasons including (1) occupational physicians and hygienists focusing on acute effects of occupational exposure rather than cancers that take many years to develop, (2) limited tradition of collaboration across disciplines, e.g., hospitals, cancer registries, universities, and relevant ministries, (3) it may be that some research is conducted but not published in national and international journals, and (4) a lack of training and capacity in this particular area of research.

Even though the petroleum industry is a major industry in Iran [1], only six publications focused on this industry. This could be due to confidential matter and safety precautions in this industry that would require permission and special security training for external researchers [61].

Regarding the epidemiological studies, the only identified prospective cohort study with a long-term follow-up examined cancer incidence in relation to a single exposure to sulfur mustard in military service personnel in the Iran-Iraq war (which has been evaluated by IARC monograph as an occupational exposure agent with sufficient evidence for lung cancer) [62]. This cohort study also included volunteers who joined the armed forces temporally to defend their cities with unknown job histories, so it is not a classical occupational cohort with precise exposure information.

In case-control studies, occupational information was collected via interviews, by self-reporting of jobs and/or occupational exposures, with no further attempt to assign occupational exposures. Some of the case-control studies featured design aspects (e.g., choice of controls, potential confounding, and power) that will have led to limitations in the interpretation of the results. One of the case-control studies appeared to have selected controls in an inappropriate way (by selecting them based on the absence of exposure), but could be related to authors' uncertainty about the study design or mistranslation from Farsi to English in the English publication [11].

This review found that exposure monitoring studies in Iran mostly focused on the projection of cancer risk based on a limited number of exposure measurements (personal and stationary air sampling). Thirteen out of 34 studies assessed the exposure through stationary measurements that provide only a very crude indication of personal exposure. Moreover, exposure agents such as BTEXs, crystalline silica, formaldehyde, and chromium in the workplaces were mostly measured on single occasions, although it is well known that exposure levels often differ between and within workers form day-to-day and are not constant over time (months, seasons, and years) [63,64]. Estimating the risk of cancer based on the exposure level derived from a single (personal) exposure measurement may overor underestimate risk as this value may not be representative for the individual's exposure over time [63]. A few of the studies used previously established exposure databases, e.g., CAREX to project the occupational cancer burden [58]. CAREX is a database which contains estimates of numbers of workers occupationally exposed to carcinogens by European industries (exposure data from 1990-1993). As shown by the two studies applying CAREX and GBD data to estimate the occupational cancer burden in Iran, the burden appears relevant, but these estimations have large uncertainties and do not provide insight into targeted prevention measures, as they are based on extrapolating exposure from other countries, workforce, and risk data instead of structured representative (exposure and risk) data from Iran.

This review provides the first overview of the status of occupational cancer research in Iran. A major limitation of the review is that carcinogenic exposures summarized in non-cancer studies are not captured here. Further, studies that have not been published in journals indexed by the searched databases might have been missed. Some studies were Cancers 2021, 13, 3581 20 of 23 not sufficiently detailed to retrieve all relevant information, e.g., "questionnaires assessed occupational exposures" but did not indicate the type of exposure.

Conclusions

Identifying the burden of occupational cancers is an important step to identify the extent of a problem and develop prevention measures to reduce risks [2]. Since industrial and regulatory circumstances vary across countries, well-designed occupational cancer studies of sufficient size that include relevant exposure assessment methods for each study design are needed in Iran. Enhanced collaboration, between, e.g., occupational physicians, cancer researchers, industrial hygienists, and workplace representatives, as well as collaborations and participation in international conferences [65], would be an asset to conduct informative studies.

Additionally, further systematic exposure monitoring surveys will help to identify potential high-risk occupational environments for future risk management planning and facilitate and can inform the exposure assessment and assignment of future epidemiological studies [64,66].

We recommend that further work be focused in three key areas. First, given that there are large-scale ongoing cancer epidemiology studies in Iran (for example, the Persian cohort study [67] and the IROPICAN case-control study [68]), proper occupational exposure assessment and assignment should be included in these studies, which requires the development of valid job-exposure matrices specifically for Iran. Second, large-scale cohort studies in major industries should be initiated to inform cancer control in Iran and efforts on a global scale, as data from emerging economies are lacking worldwide [69]. Third, occupational exposure monitoring needs to be more systematic, with data made (centrally) available for (epidemiological) research and to develop risk reduction measures.

All these efforts will support the ultimate goal of occupational cancer prevention in Iran. Further, the documentation of exposure levels, contexts, and cancer risks in Iran will contribute to the scientific understanding of occupational cancers and related exposure factors on a global scale.

3.3

ABSTRACT Background Globally, lung cancer is the most frequent occupational cancer, but the risk associated with the occupations or occupational environment in Iran is not clear. We aimed to assess occupations with the risk of lung cancer. Methods We used the IROPICAN nationwide casecontrol study data including 658 incident lung cancer cases and 3477 controls. We assessed the risk of lung cancer in relation to ever working in major groups of International Standard Classification of Occupations, high-risk occupations for lung cancer and duration of employment and lung cancer subtype among construction workers and farmers while controlling for cigarette smoking and opium consumption. We used unconditional regression logistic models to estimate ORs for the association between increased lung cancer risk and occupations. Results We observed elevated ORs for lung cancer in male construction workers (OR=1.4; 95% CI: 1.0 to 1.8), petroleum industry workers (OR=3.2; 95% CI: 1.1 to 9.8), female farmers (OR=2.6; 95% CI: 1.3 to 5.3) and female bakers (OR=5.5; 95% CI: 1.0 to 29.8). A positive trend by the duration of employment was observed for male construction workers (p< 0.001). Increased risk of squamous cell carcinoma was observed in male construction workers (OR=1.9; 95% CI: 1.2 to 3.0) and female farmers (OR=4.3; 95% CI: 1.1 to 17.2), who also experienced an increased risk of adenocarcinoma (OR=3.8; 95% CI: 1.4 to 9.9). Discussion Although we observed associations between some occupations and lung cancer consistent with the literature, further studies with larger samples focusing on exposures are needed to better understand the occupational lung cancer burden in Iran. 2 (1.0 to 1.5) 1.6 (0.2 to 8.9) 1.2 (0.9 to 1.5) 1.7 (0.3 to 9.5) X: Military force 14/147 -0.4 (0.2 to 0.7) -0.5 (0.2 to 0.8) -0.5 (0.2 to 0.9) -XI: Housewives -132/874 -0.9 (0.5 to 1.5) 0.9 (0.6 to 1.5) -0.9 (0.5 to 1. The following are available at the supplementary materials, Table S1: The 5-digit ISCO-68 codes corresponding to each specific selected job, Table S2: Risk of lung cancer associated with the duration of employment as a construction worker, in male, Table S3: Risk of lung cancer associated with the duration of employment as a farmer, stratified sex. Table S3: Risk of lung cancer associated with the duration of employment as a farmer, stratified by sex. BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s)

INTRODUCTION

viii 8 Figure 1

 81 Figure 1.7: ..........................................................

Figure 1 . 8 :Figure 1 . 7 :Figure 1 . 8 :

 181718 Figure 1.8: Estimated age-standardized incidence rates worldwide in 2020, female bladder cancer .................................................................... ........................ ........

Figure 1 .

 1 Figure 1. PRISMA flow diagram.

44 Chapter 3 :

 443 Occupational lung cancer in Iran

  , 2023 at HQ WHO Consortia. Protected by http://oem.bmj.com/ Occup Environ Med: first published as 10.1136/oemed-2022-108463 on 7 September 2022. Downloaded from

  , number; OR, odds ratio; CI, confidence interval. a Model 0 (M0) is adjusted for age categories (5-year categories) and residence (provinces) b Model 1 (M1) is adjusted for M0 plus cigarette smoking status and intensity. c Model 2 (M2) is adjusted for M1 plus opium consumption.

  , number; OR, odds ratio; CI, confidence interval. a Model 0 (M0) is adjusted for age categories (5-year categories) and residence (provinces) b Model 1 (M1) is adjusted for M0 plus cigarette smoking status and intensity. c Model 2 (M2) is adjusted for M1 plus opium consumption.

Table 1 .

 1 Relative frequencies of exposure assessment methods and study outcomes by study design.

	Study Characteristics	Cohort n = 1 (%)	Case-Control n = 11 (%)	Exposure Monitoring n = 34 (%)	Cancer Burden Studies n = 3 (%)
	Direct exposure assessments	-	0 (0.0)	32 (94.1)	-
	Personal Air Sampling	-	-	16 (47.0)	-
	Stationary Air Monitoring	-	-	13(38.2)	-
	Stationary/Personal Air Sampling	-	-	3(8.8)	-
	Indirect Exposure Assessment Methods:	1 (100)	11 (100.0)	2 (5.8)	3 (100)
	Self-report of job or exposure history	-	11 (100.0)	-	-
	Available databases	-	-	1 (2.9)	3 (100)
	Expert Assessment	-	-	1 (2.9)	-
	Not applicable	1 (100)	-	-	-

Table 1 .

 1 Cont.

	Study Characteristics	Cohort n = 1 (%)	Case-Control n = 11 (%)	Exposure Monitoring n = 34 (%)	Cancer Burden Studies n = 3 (%)
	Cancer Outcomes
	Cancer, general 1	1 (100)	-	24 (70.5)	1 (33.3)
	Lung cancer	-	1 (9.0)	8 (24.3)	-
	Bladder and urinary tract cancer	-	5 (45.4)	-	1 (33.3)
	Hematological cancer	-	2 (18.1)	2 (8.1)	1 (33.

Table 2 .

 2 Characteristics of epidemiological studies.

	Reference/Location/

Study Year Cancer Sites Population Size/Description Source of Exposure Assessment Exposure Duration Measure Covariates Controlled for in Modelling Outcome (Risk of Cancer)

				Yes							Yes						Yes					Yes	Yes
			Stratified by age, smoking	status, educational level,	marital status			Age, sex, smoking status	(never/current/former	smoker, duration of smoking	(year), average number of	cigarettes per day)			Sex		Age, sex, family history of	bladder cancer, chronic	urinary tract infections (times	per year), kidney and bladder	stones, hair dyeing, and	educational level	Age, sex, and place of	residence,	univariable analysis
			Single exposure to sulfur	mustard during the war				Lifetime occupation	history: Jobs held >	6 months				Current and former jobs			Lifetime occupation	history: jobs held >	1 year	Last 20 years jobs
		Documented medical records on	at least one acute exposure	while the participant presented	in the battlefield between 1984	and 1987		Questionnaire;	Phone/face-to-face interview;	Collected data on industry title,	duration, hours of work per day,	self-report of exposures	Study specific questionnaire;	Face-to-face interview; Collected	data on job title, duration,	exposure to the specific	chemicals in each job, history of	cancer occurrence in coworkers	Questionnaire; Face-to-face	interview; Collected data on	job titles	Semi-structured questionnaire;	Interview; Collected data on job	titles, and tasks
	7570; Male veterans, Exposed	to sulfur mustard during the	Iran-Iraq war (1984-1987);	7592; Male veterans,	unexposed to sulfur mustard	(instead, e.g., physical	injuries).	Cases: 300; bladder cancer	patient recruited from registry	Controls: 500;	population-based controls	Cases: 160; Male-	Histologically confirmed	Controls: 160 Male without	occupational exposure to the	chemicals (source of controls	recruitment is unclear)	Cases: 200; Histologically	confirmed	Controls: 200 healthy	neighbors	Cases: 152; Histologically	confirmed recruited from	cancer registries	Controls: 152, Hospital based
				Cancer							Bladder						Bladder					Bladder	Bladder
	Prospective cohort		Zafarghandi/Iran/	1984-2010 [9]		Case-control			Khoubi/Isfahan,	Iran/2004-2009 [10]					Aminian/Tehran,	Iran/2007-2009 [11]				Farzaneh/Yazd,	Iran/2009-2013 [12]	Ghadimi/Kurdestan,	Iran/2012-2015 [13]

Table 2 . Cont. Reference/Location/ Study Year Cancer Sites Population Size/Description Source of Exposure Assessment Exposure Duration Measure Covariates Controlled for in Modelling Outcome (Risk of Cancer)

 2

			Yes							Yes							Non-Hodgkin	lymphoma: Yes	Hodgkin	lymphoma: No			Yes
			Age, sex							Age, sex										Age, sex, center						Age, sex, smoking status
			Not clear						Current and former jobs:	Jobs held > 1 year							Lifetime occupation	history: Jobs held >	1 year				At least 1 year of	agriculture
		Semi-structured questionnaire;	Collected data on job title, and	self-report of exposures		Semi-structured questionnaire;	Interview; Collected data on job	title, duration, exposure to the	specific chemicals in each job,	history of cancer occurrence in	coworkers	Semi-structured questionnaire;	Face-to-face interview; Collected	data on job history, specific	exposures for each job, a	question on extra jobs in	farming including pesticides	exposure (herbicides, fungicides,	insecticides), reason for	exposure, duration	Structured questionnaire;	Face-to-face interview; Collected	data on type of crops, tasks,	duration, farming surface size,	name of pesticide, frequency of	apply per year, and methods,	personal protective equipment;	biomonitoring (residual	pesticide was	extracted from adipose tissue)
	Cases: 200; kidney cancer	cases recruited from	cancer registry	Controls: 400; healthy	population based	Cases: 150; male;	Histologically confirmed	Controls: 150; relative controls	(case's brother or	close relative)				Cases: 200;	Histologically confirmed	Controls: 200; Hospital based				Cases: 31;	Histologically confirmed	Controls: 32; Hospital based
			Kidney					Non-Hodgkin/	Hodgkin's	lymphoma							Malignant	lymphoma					Head and neck
		Tajvidi/Isfahan,	Iran/2001-2010 [14]					Aminian/Tehran,	Iran/2011-2015 [15]								Zakerinia/Fars,	Iran/2007-2008 [16]					Amizadeh/Not	clear [17]

Table 2 . Cont. Reference/Location/ Study Year Cancer Sites Population Size/Description Source of Exposure Assessment Exposure Duration Measure Covariates Controlled for in Modelling Outcome (Risk of Cancer)

 2

					Yes							Yes						Yes
					Age, sex, and-place of resident							Age						Not clear
					Not clear						Childhood until 5 years	before cancer diagnosis					Not clear
	Structured questionnaire;	Face-to-face interview; Collected	data on workplace conditions,	exposure to suspected	occupational lung carcinogens	Questionnaire; Interview; In the	method the author stated,	"occupational history" but no	details provided on the	collected data		Questionnaire; Face-to-face	Interview; Collected data on	recent job title; In the methods	"occupational exposures" are	stated, with no details provided
	Cases: 242; primary cases;	Histologically confirmed	Controls: 484; Hospital based	(242; Healthy visitors and 242;	patients except oncology	ward patients)	Cases: 243; Male;	Histologically confirmed	Controls: 243; Male; Hospital	based (cancer patient other	than gastrointestinal cancer)	Cases: 104; Histologically	confirmed (employed women)	Controls: 112; Women;	Healthy controls (who	referred to the health care	centers to receive routine	examination);	Employed women
					Lung							Gastrointestinal						Breast
				Hosseini/Tehran,	Iran/2002-2005 [18]					Aghilinejad/Tehran,	Iran/2014-2015 [19]					Rafeemanesh/Khorasan-	Razavi,	Iran/2010-2014 [20]

Table 3 .

 3 Characteristics of studies with exposure monitoring design.

	Outcome/Results	Elevated ELCR 2 in tanker	loading and tank-gauging	workers attributable to tasks,	e.g., dispensing, loading, and	unloading of petrol	Elevated LCR 4 for all	workers attributed to VOC	carcinogenic components; the	highest LCR was attributable	to benzene exposure	Elevated LCR for all workers,	highest LCR attributable to	1,3-butadiene observed in	safety and fire-fighters of	petroleum complexes	Elevated ILCR 5 in exposed	group in both asthmatic and	healthy welders	Elevated risk of leukemia	attributable to benzene	exposure in all workers
	Type of Assessment/Frequency of	Measurement			Personal air sampling; over one 8-h	work shift			Personal air sampling; two samples	taken over a work shift for each	subject; each sample duration	3.5-4 h			Personal air sampling; 90 min for	each sample (beginning, middle,	and end of work shift)		Personal air measurement data;	parameters (e.g., intensity and	duration of exposure) were used	from previous studies; information	on daily work hours, daily tasks	collected by questionnaires	Exposure data used from previous	prospective study in rubber	industry workers; exposure index	(EI) determined by experts using	physical characteristics of exposure	agent (e.g., the olfactory threshold	value, inhalable fraction and	vapor), and preventive measures	including personal and	environmental protection.
	Exposure Agents Assessed			BTEXs 1 (benzene, toluene,	ethylbenzene, and xylene)			VOCs 3 (benzene,	epiclorohydrine,	trichloroethylene, styrene,	ethyl benzene, and	1,3-butadiene)					1,3-butadiene				Nickel and hexavalent	chromium from	welding fumes	Benzene
	Population/Sample	Size/Description	50 workers selected randomly	(tanker loading workers,	tank-gauging workers, drivers,	firefighters, and office workers)	338 samples from 169 workers in	21 petrochemical complexes	including mechanics, security,	samplers, site men, technicians,	laboratory staff, and office workers	150 samples from 50 workers	including fire-fighters,	polybutadiene latex (PBL), dryer,	and coagulation workers,	mechanics, electricians, packing,	and laboratory workers	30 welders were assigned to	different groups by exposure to Ni	and Cr (VI) and also health	situation (healthy and	asthmatic welders)	Not applicable
	Industry				Petroleum							Petroleum								Petroleum				Petroleum	Petrochemical
	Reference/Location/	Study Year			Heibati/North of	Iran/2016 [27]					Shanh/Iran/2013-	2014 [23]						Sadeghi-Yarandi/Isfahan,	Iran/2018 [24]			Barkhordari/Iran/2013 [21]	Golbabaie/Iran/study	year is unknown [22]

Table 3 .

 3 Cont.

	Outcome/Results		Elevated ELCR in workers	attributable to benzene	exposure in all workers	Elevated long-term exposure	cancer risk related to BTEX	compound exposure	Elevated risk of cancer	attributable to benzene	exposure			Elevated LCR attributable to	benzene exposure	Elevated LCR attributable to	styrene exposure in plastic	injection operators and shift	supervisors	ELCR not increased in	high-risk exposed group
	Type of Assessment/Frequency of	Measurement	Personal air sampling; two samples	from each worker (one to measure	VOCs, another to measure H 2 S),	and 3 control samples; details on	sampling duration were	not provided	Personal air sampling over a full	work shift		Personal air sampling and	stationary air sampling over a full	work shift	Personal air sampling; 4 samples in	a different hours of a full work	shift; sampling repeated in	5 consecutive weeks for each	worker; each sampling duration	was between 50 and 90 min	Personal air sampling, details on	sampling duration were	not provided	Personal air sampling over a full	work shift
	Exposure Agents Assessed		VOCs (benzene, toluene,	xylene, pentane, hexane,	heptane, octane, and nonane),	and hydrogen sulfide (H 2 S)			BTEXs				BTEXs			VOCs (benzene, toluene,	ethylbenzene), and CS2	(Carbon disulphide)	Styrene	Lead
	Population/Sample	Size/Description				123 samples from 60 workers			Samples from 24 refueling stations	including 15 petrol and 9 CNG	stations; the population sample	size was not clarified	24 samples from 12 refueling	stations (12 workers, 12 stationary	air sampling)			200 samples and 40 blank samples	from all workers	141 samples from 59 workers	including primary granule	warehouse, plastic injection	workers, shift managers,	miscellaneous (forklift drivers,	quality control engineers,	and crew)	40 samples from 40 female	soldering workers (cutting	electrical wires and coating, initial	soldering, voltage testing and	secondary soldering workers, and	shift supervisors)
	Industry				Petrochemical				Gasoline and CNG 6	refueling stations		Gasoline and CNG	refueling stations			Poultry	slaughterhouse	Electronic	manufacturing,	plastic compress unit	Electronics	manufacturing
	Reference/Location/	Study Year				Harati/Iran/2016 [35]			Hazrati/Ardabil,	Iran/study year is	unknown [39]	Javadi/Isfahan,	Iran/2016 [34]			Omidi/Tehran,	Iran/2018 [26]	Mohammadyan/Neyshabur,	Iran/2017-2018 [50]	Mohammadyan/Neyshabur,	Iran/2017-2018 [28]

Table 3 .

 3 Cont.

	Outcome/Results	Elevated ELCR attributable to	duration of chloride vinyl	exposure	Elevated risk of cancer	attributable to formaldehyde	exposure in all units; the	highest level of exposure was	in stoning and pressing units	Elevated risk of leukemia	attributable to benzene and	toluene exposure in	shoemakers; the level of	exposure was higher than the	threshold limit value (TLV)	Elevated ELCR attributable to	benzene exposure; level of	exposure to sulfuric acid in	washing lines and manganese	in the manufacturing unit	were higher than in	other units	Elevated lung ELCR	attributable to crystalline	silica exposure;	All workers exposed to a	higher level than the definite	acceptable limit	recommended by OSHA 7
	Type of Assessment/Frequency of	Measurement		Personal air sampling over a full	work shift		Stationary air sampling over a full	work shift. Indoor air temperature,	pressure, and relative humidity	used in analyses		Personal air sampling, once a	month during 3 consecutive	months, details on sampling	duration were not provided			Stationary air sampling; details on	sampling duration were not	provided; indoor air temperature,	pressure, and humidity used in	analyses	Stationary air sampling, 4 h during	a work shift
	Exposure Agents Assessed			Chloride vinyl						Formaldehyde						Benzene, toluene			Chemical exposure including	aluminum products, silica,	rock wool, iron oxide,	manganese, sulfuric acid,	benzene, ethylbenzene,	toluene and xylene	Crystalline silica
	Population/Sample	Size/Description	100 workers from mixing, winder,	coating, finishing, rewinder,	warehouse used to manufacture	two plastic products		54 samples from 4 workshops in	different units including cutting,	stoning, pressing, and packing			Sample from 48 workers in	12 workshops including cutting,	modelling, fitting, and	finishing tasks					103 samples from different units	including slabbing, production,	painting, and washing workshops	Sampling of breathing zone of	55 workers from different units	including machine operator,	painting, furnace, and cleaning;	information on number of samples	was not provided
	Industry		Manufacturing of	plastics products				Manufacturing of	plastics products					Manufacturing	of shoes								Aluminum rolling	Foundry
	Reference/Location/	Study Year	Tayfeh Rahimian/Tehran,	Iran/study year is	unknown [49]		Mazinani/Tehran,	Iran/study year is	unknown [48]				Azari/Iran/study year is	unknown [25]							Sanjari/Iran/study year	is unknown [51]	Zarei/Tehran,	Iran/2017 [40]

Table 3 .

 3 Cont.

	Outcome/Results	Elevated risk of lung cancer	mortality; 50 percent of	workers exposed to greater	than the acceptable threshold	limit value by OSHA	Elevated cancer risk	attributable to benzene	exposure; exposure to BTEX	components in the benzol	refinement unit was higher	than in other units	Elevated ELCR of lung cancer	attributable to crystalline	silica exposure in workers	Elevated ELCR of lung cancer	attributable to crystalline	silica exposure in	construction work; batching	and concrete workers had the	highest average exposure that	was greater than the	threshold limit recommended	by OSHA	Elevated ELCR for lung	cancer attributable to	crystalline silica exposure
	Type of Assessment/Frequency of	Measurement			Personal air sampling over a full	work shift						Stationary air sampling over a full	work shift			Personal air sampling over a full	work shift, meteorological	parameters including air	temperature and wind speed were	used in the analysis			Personal air sampling over a full	work shift	Stationary air sampling;	information on sampling duration	was not provided
	Exposure Agents Assessed				Crystalline silica								BTEXs						Crystalline silica					Crystalline silica	Crystalline silica
	Population/Sample	Size/Description	80 samples of 80 workers from	workshops used for 29 small	foundries including 10 iron cast,	3 brass, and an aluminum foundry	50 samples from the breathing	zone of 372 workers in energy and	biochemistry units, benzol	refinement and experimental	furnace units	60 demolition workers from	4 demolition sites; 15 samples from	each site			85 samples from 85 construction	workers including supervisors,	stonemason, batching and concrete	workers, and labors	Sampling of breathing zone of	72 workers from autoclave	units, wing tube and cutter line,	mixing, packing, and quality	control units; information on	number of samples was	not provided
	Industry				Foundry								Steel manufacturing						Construction					Construction	Concrete	manufacturing
	Reference/Location/	Study Year			Omidianidost/Tehran,	Iran/2011 [52]						Omidi/Iran/study year is	unknown [36]				Normohammadi/Tehran,	Iran/2010-2011 [42]				Tavakol/Tehran,	Iran/study year is	unknown [43]	Moghadam/Neyshabour,	Iran/2015 [53]

Table 3 .

 3 Cont.

	Outcome/Results		Elevated lung ELCR	attributable to cumulative	exposure of crystalline silica	(direct correlation between	the level of exposure and	lung cancer risk)	The highest mortality risk of	lung cancer attributable to	crystalline silica exposure	was estimated for	furnace workers	Elevated individual lifetime	cancer risk 100-1000 times	higher than the acceptable	cancer risk in all exposed	laboratory staff; exposure	level in all staff members was	higher than the acceptable	level by OSHA	Elevated LCR attributable to	intensity of formaldehyde	exposure greater than the	recommended acceptable	limit by OSHA	Highest LCR attributable to	formaldehyde in lab	technicians
	Type of Assessment/Frequency of	Measurement						Personal air sampling over a full	work shift						Stationary air sampling;	information on sampling duration	was not provided			Personal air sampling during direct	exposure to formaldehyde (8:00	and 12:00 a.m.); 25 min for each	task; stationary air sampling	during a full work shift	Stationary air sampling during one	full work shift	Stationary air sampling during one	full work shift
	Exposure Agents Assessed							Crystalline silica									Crystalline silica									Formaldehyde	Formaldehyde	Formaldehyde
	Population/Sample	Size/Description		200 workers from 50 workplaces	(4 workers in each) including stone	cutting and milling, foundry, glass	manufacturing, asphalt	preparation, ceramic, brick and	concrete manufacturing,	and construction	60 samples from 5 units including	pressing, production, coating,	furnace, and packing (12 samples	in each unit)			65 employees in pathology labs	including pathologist, lab	technician, office worker,	service workers	68 samples from the breathing	zone of 72 hospital staff	Sampling of breathing zone of	60 pathology laboratory staff	members; information on number	of samples was not provided
	Industry	Stone cutting and	milling, foundry	work, glass	manufacturing,	asphalt,	construction, sand	and gravel mining,	sand blast, ceramics,	bricks and cement		Ceramic pin insulator	manufacturing								Hospital	Hospital	Hospital
	Reference/Location/	Study Year						Azari/Tehran, Iran/study	year is unknown [44]							Mohammadi/Markazi,	Iran/2015 [41]							Yahyaei/Rasht,	Iran/2018 [47]	Pourtaghi/Tehran,	Iran/2018 [46]	Jalali/Iran/2019 [45]

Table 3 .

 3 Cont.

	Outcome/Results	Elevated risk of lung cancer	ELCR attributable to	cumulative exposure of	asbestos; exposure levels for	all workers far greater than	the occupational exposure	limits recommended	by OSHA	Elevated risk of lung,	mesothelioma, and	gastrointestinal cancer	mortality after 20 years of	exposure; greater risk in the	dry cutting unit than the wet	cutting unit	Elevated hematological	cancer risk corresponding to	cumulative exposure to	benzene and crystalline silica	Elevated risk of cancer in	painting unit workers	attributable to benzene and	ethyl benzene with 30 years	of exposure	Elevated LTCR 8 attributable	to BTEX components
	Type of Assessment/Frequency of	Measurement				Personal air sampling; 4 h over a	full work shift						Personal air sampling; samples	collected from different units of the	factory over a full work shift			Personal air sampling (2 times for	each worker over a full work shift),	and 6 stationary air samples over a	full work shift		Stationary air sampling over a full	work shift	Stationary air sampling; indoor air	temperature, pressure, and relative	humidity were used in the analysis,	samples taken during the	afternoon (14:00 to 19:00)
	Exposure Agents Assessed					Asbestos								Asbestos					BTEXs, Silica				BTEXs	BTEXs
	Population/Sample	Size/Description			61 workers including weighing,	mixing, pressing, and finishing	occupations					97 workers from 4 units including	milling, cutting, and cutting				46 samples from 20 workers			34 samples from breathing zones of	workers: cabin maker, pre-paint,	and painting units	50 beauty salons across the	Ardabil Province
	Industry				Brake shoe and clutch	disk manufacturing						Asbestos-cement	products	manufacturing				Automobile	manufacturing			Automobile	manufacturing	Beauty salons
	Reference/Location/	Study Year				Zarei/Tehran/Iran/	2010 [29]						Jafari/Isfahan,	Iran/study year is	unknown [54]				Harati/Iran/2015 [37]				Dehghani/Iran/2016 [38]	Baghani/Ardabil,	Iran/2017 [31]

Cancers 2021,

13, 3581

Table 3 .

 3 Cont.

	Reference/Location/ Industry Study Year Population/Sample Size/Description Exposure Agents Assessed Type of Assessment/Frequency of Measurement Outcome/Results	Elevated risk of cancer	attributable to benzene,	Hadei/Tehran, Beauty salons Iran/2016-2017 [30] 180 samples each for indoor and outdoor; (3 samples for each component including BTEXs, BTEXs, formaldehyde, and acetaldehyde work shift during 3 consecutive months; air temperature, pressure, and relative humidity were used in acetaldehyde exposure; 360 samples from 20 beauty salons, Stationary air sampling; over a full formaldehyde, and exposure to different components affected by tasks: benzene and toluene (hair formaldehyde, and acetaldehyde) the analysis dying), formaldehyde (hair	style and nail treatments),	and xylene (hair styling)	Stationary air sampling; each	sample duration lased for 50 min;	Hazrati/Ardabil, sampling from 14:00 to 19:00; 6 additional samples taken directly Iran/study year is Waterpipe café 87 samples from 81 waterpipe cafés BTEXs from the smoke mainstream of the unknown [32] waterpipe (4 from fruit flavored Elevated long-term exposure cancer risk attributable to benzene exposure	tobacco and 2 from	regular tobacco).	Stationary air sampling; from	Rostami/Ardabil, Waterpipe café Iran/2018 [33] 51 samples from 51 waterpipe cafés PAHs 9 breathing zone of smokers and employees; air temperature, pressure, and relative humidity Elevated risk of cancer attributable to PAH component inhalation	were used in the analysis	Safety and Health Administration; 8 Benzene, Toluene, Ethylbenzene and Xylenes; Inhalation Lifetime Cancer Risk; 9 Excess Lifetime Cancer Risk; Volatile Organic Compound; Lifetime Cancer Risk; Incremental Lifetime Cancer Risk; Compressed Natural Gas; Occupational Polycyclic Aromatic Hydrocarbons (PAH), 16 PAH compounds including Naphthalene (Naph), Acenaphthylene (Acy), Acenaphthene (Ace),

Fluorene (Flu), Phenanthrene (Phen), Anthracene (Anth), Fluoranthene (Flt), Pyrene (Pyr), Benzo[a]anthracene (BaA), Chrysene (Chr), Benzo[b]fluoroanthene (BbF), Benzo[k]fluoroanthene (BkF), Benzo[a]pyrene (BaP), Dibenzo[a,h]anthracene (DahA), Benzo [ghi]perylene (BghiP), and Indeno[123-cd]pyrene (Ind).

WHAT IS ALREADY KNOWN ON THIS TOPIC?

	Workplace MATERIALS AND METHODS	⇒ Most evidence regarding occupational lung cancer derives from industry-based and community-based epidemiological studies conducted in high-income countries. ⇒ While the industrial structure in Iran is developing in an opposite direction compared with what we observe in western countries, our understanding of the risk of lung cancer in occupational settings in Iran is limited. WHAT THIS STUDY ADDS? ⇒ This is the largest case-control study on lung cancer in Iran holding occupational information to date. ⇒ So far, occupational epidemiological studies have considered smoking as the most important confounding factor. ⇒ In this study, we discovered that opium consumption also is a confounding factor to be accounted for, and opium consumption varies Data collection	copyright.	Occup Environ Med: first published as 10.1136/oemed-2022-108463 on 7 September 2022. Downloaded from
		across economical activities. ⇒ In several major International Standard Classification of Occupations groups, lung cancer risk was reduced when adjusting for opium consumption.		http://oem.bmj.com/
	Study population	Statistical analysis		on January 30, 2023 at HQ WHO Consortia. Protected by

832 Hosseini B, et al. Occup Environ Med 2022;79:831-838. doi:10.1136/oemed-2022-108463 834 Hosseini B, et al. Occup Environ Med 2022;79:831-838. doi:10.1136/oemed-2022-108463 Workplace

Table 1

 1 Characteristics of the study population by case-control status and sex

	Study participants' characteristics Age categories, years <40 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85+ Cigarette smoking status Never smokers Current smokers Former smokers Intensity of smoking (pack/year) in ever smokers <10 10-20 >20 Opium consumption status (times/day) Never <1/day 1-2/day >2/day Waterpipe smoking Never Ever Environmental tobacco smoke Never Ever	Male n (%) Cases 501 (17.3) N (%) 12 (2.4) 16 (3.2) 38 (7.6) 58 (11.6) 106 (21.1) 103 (20.6) 77 (15.4) 46 (9.2) 27 (5.4) 17 (3.4) 1 (0.2) 103 (20.6) 212 (42.3) 186 (37.1) 55 (11) 48 (9.6) 295 (58.9) 213 (42.5) 103 (20.6) 120 (23.9) 65 (13.0) 455 (90.8) 46 (9.2) 317 (63.3) 184 (36.7)	Controls 2398 (82.7) N (%) 204 (8.5) 95 (3.9) 222 (9.2) 325 (13.5) 423 (17.6) 430 (17.9) 331 (13.8) 206 (8.6) 99 (4.1) 47 (1.2) 16 (0.7) 1442 (60.1) 440 (18.4) 515 (21.5) 359 (15.0) 167 (7.0) 430 (17.9) 1970 (82.1) 295 (12.3) 99 (4.1) 34 (1.4) 2245 (93.6) 153 (6.4) 1752 (73.1) 646 (26.9)	P value* <0.001 <0.001 <0.001 <0.001 0.024 0.047	Female n (%) Cases 157 (12.7) N (%) 8 (5.1) 6 (3.8) 14 (8.9) 22 (14.0) 24 (15.3) 22 (14.0) 32 (20.4) 15 (9.5) 7 (4.5) 3 (1.2) 4 (2.5) 146 (93.0) 5 (3.2) 6 (3.8) 4 (2.5) 4 (2.5) 3 (1.9) 133 (84.7) 5 (3.2) 11 (7.0) 8 (5.1) 127 (80.9) 30 (19.1) 88 (56.1) 69 (43.9)	Controls 1079 (87.3) N 114 (10.6) 73 (6.8) 108 (10.0) 149 (13.8) 173 (16.0) 184 (17.0) 147 (13.6) 83 (7.7) 26 (2.4) 15 (1.4) 7 (0.6) 1036 (96.0) 18 (1.7) 25 (2.3) 27 (2.5) 5 (0.5) 11 (1.0) 1056 (97.8) 19 (1.8) 2 (0.2) 2 (0.2) 993 (92.0) 86 (8.0) 693 (64.2) 386 (35.8)	P value* 0.070 0.216 0.026 <0.001 <0.001 <0.001	copyright.	Occup Environ Med: first published as 10.1136/oemed-2022-108463 on 7 September 2022. Downloaded from
	Respiratory disease history Never Ever Histopathology classification Epithelial tumours Adenocarcinoma Squamous cell carcinoma	451 (90.0) 50 (10.0) 168 (33.5) 148 (29.5)	2259 (94.2) 139 (5.8)	<0.001	131 (83.4) 26 (16.6) 81 (51.6) 28 (17.8)	1026 (95.1) 53 (4.9)	<0.001		http://oem.bmj.com/
	Neuroendocrine tumours Other epithelial neoplasm Non-epithelial tumours Missing The longest occupation held (major groups of ISCO-68) 0/1: Professional, technical and related workers 2: Administrative and managerial workers 3: Clerical and related workers 4: Sales workers 5: Service workers 6: Agricultural, animal husbandry and forest 7: Craft and related trades workers 8: Plant and machine operators 9: Elementary occupations X: Military force X1: Housewives	99 (19.7) 57 (11.4) 15 (3.0) 14 (2.8) 31 (6.2) 4 (0.8) 27 (5.4) 38 (7.6) 22 (4.4) 140 (27.9) 29 (5.6) 48 (9.6) 152 (30.3) 9 (1.8) -	266 (11.1) 61 (2.5) 212 (8.8) 181 (7.5) 125 (5.2) 541 (22.6) 147 (6.1) 172 (7.2) 554 (23.1) 130 (5.4) -	<0.001	15 (9.5) 21 (13.4) 7 (4.5) 5 (3.2) 7 (4.5) 2 (1.3) 2 (1.3) 0 (0.0) 0 (0.0) 8 (5.1) 6 (3.8) 0 (0.0) 1 (0.6) -131 (83.4)	53 (4.9) 10 (0.9) 16 (1.4) 11 (1.0) 32 (3.0) 58 (5.4) 39 (3.6) 1 (0.1) 4 (0.4) -849 (78.7)	0.6	continued		on January 30, 2023 at HQ WHO Consortia. Protected by

Table 1 continuedTable 2

 12 Risk of lung cancer related to ever having worked in ISCO-68 major occupational groups (compared with those that have not worked in respective group) stratified by sex

		Ever worked	Model 0*		Model 1 †		Model 2 ‡
		(cases/controls)	OR (95% CI)		OR (95% CI)		OR (95% CI)
	ISCO-68 major groups	Male	Female Male	Female	Male	Female	Male	Female
	0/1: Professional, technical and related workers 37/319 9/74	0.5 (0.3 to 0.7) 0.8 (0.3 to 1.7)	0.6 (0.4 to 0.9) 0.8 (0.4 to 1.7) 0.8 (0.5 to 1.1) 0.9 (0.4 to 1.8)
	2: Administrative and managerial workers	8/93	2/11	0.4 (0.2 to 0.8) 1.4 (0.3 to 6.4)	0.4 (0.2 to 0.7) 1.1 (0.2 to 5.8) 0.4 (0.2 to 1.0) 1.5 (0.3 to 7.5)
	3: Clerical and related workers	31/252 2/23	0.5 (0.3 to 0.7) 0.6 (0.1 to 2.6)	0.6 (0.4 to 1.0) 0.5 (0.1 to 2.3) 0.7 (0.5 to 1.1) 0.6 (0.1 to 2.7)
	4: Sales workers	62/282 3/16	1.1 (0.8 to 1.5) 1.5 (0.4 to 5.6)	1.0 (0.7 to 1.4) 1.5 (0.4 to 5.5) 1.0 (0.7 to 1.4) 1.1 (0.3 to 5.1)
	5: Service workers	40/147 1/54	1.1 (0.8 to 1.6) 0.1 (0.0 to 1.0)	1.1 (0.7 to 1.7) 0.1 (0.0 to 0.9) 1.2 (0.8 to 1.9) 0.1 (0.0 to 1.2)
	6: Agricultural, animal husbandry and forest	161/678 18/69	1.2 (0.9 to 1.5) 2.3 (1.2 to 4.5)	1.1 (0.9 to 1.4) 2.4 (1.2 to 4.6) 1.0 (0.8 to 1.3) 2.6 (1.3 to 5.3)
	7: Craft and related trades workers	41/196 11/75	0.9 (0.6 to 1.4) 1.0 (0.5 to 2.0)	0.9 (0.6 to 1.3) 1.0 (0.5 to 2.0) 0.9 (0.6 to 1.4) 0.9 (0.4 to 2.0)
	8: Plant and machine operators	61/229 0/3	1.4 (1.0 to 1.9) No cases	1.1 (0.8 to 1.6) No cases	0.9 (0.6 to 1.3) No cases
	9: Elementary occupations	187/723 2/8	1.4 (1.2 to 1.7) 2.2 (0.4 to 11.4) 1.

  5) Each occupational group is individually compared with the respective remaining group of samples. *Model 0 (M0) is adjusted for age categories (5-year categories) and residence (provinces). †Model 1 (M1) is adjusted for M0 plus cigarette smoking status and intensity. ‡Model 2 (M2) is adjusted for M1 plus opium consumption. -, no data; ISCO-68, International Standard Classification of Occupations.

Table S1 :

 S1 The 5-digit ISCO-68 codes corresponding to each specific selected job .70, 7-51.10 to 7-59.90, 7-91.00 to 7-91.90, 7-93.00 to 7-99.90, 8-35.60 Painters 9-31.00 to 9-39.90 Construction workers 9-51.00 to 9-52.90, 9-55.00 to 9-59.99, 9-75.24 to 9-74.40, 9-72.20, 9-73.35, 9-99.10 Drivers 6-28.20, 6-31.40, 9-83.20 to 9-83.90, 9-85.20 to 9-85-90, 9-79.30 to 9-79.90, 9-83.00 to 9-83.90, 9-85.00 to 9-85.90, 9-89.90 Road drivers 9-85.20 to 9-85-50, 9-85-70, 9-85-90 Heavy vehicles drivers 6-28.20, 6-31.40, 9-79.30 to 9-79.90, 9-83.00 to 9-83.90, 9-85-60, 9-89.90 .00 to 6-12.30, 6-12.70, 6-12.90, 6-21.05 to 6-23.90, 6-28.20 to 6-28.90, 6-29.40 to 6-29.60, 6-29.90, 6-31.10 to 6-32.90 Only animal farmers 6-12.40 to 6-12.60, 6-12.90, 6-24.10 to 6-26.90, 6-29.20 to 6-29.30, 6-29.90, 6-41.00 to 6-49.90 Petroleum industry workers 7-13.20 to 7-13.90, 7-43.50, 7-45.20 to 7-45.90, 9-69.40, 9-72.50 .90, 9-01.20 to 9-01.50, 9-02.20 to 9-02.90 Note: ISCO-68, International Standard Classification of Occupations.BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s)

	Selected specific occupations from (ISCO-68) Five-digits codes 7-49Occup Environ Med Textile industry workers 7-00Welders 8-72.10 -8-72.90 Farmers 6-11.00 to 6-49.90 Only field farmers Rubber industry workers 6-11Bakers 7-76.10 to 7-76.90	doi: 10.1136/oemed-2022-108463 -8. :1 0 2022; Occup Environ Med , et al. Hosseini B

Table S2 :

 S2 Risk of lung cancer associated with the duration of employment as a construction worker, in males.

	Model 2 c	OR (95% CI)	ref	1.1 (0.7, 1.6)	1.6 (1.1, 2.
	Model 1 b	OR (95% CI)	ref	1.2 (0.8, 1.8)	1.7 (1.2, 2.4)
	Model 0 a	OR (95% CI)	ref	1.4 (1.0, 2.1)	1.8 (1.3, 2.5)
	N	(Cases/Controls)		48/ 190	47/ 128
	Duration of employment as a construction	worker (years)	Never being employed	<=28	>28

General term representing lifetime cancer risk, long-term exposure cancer risk, risk of any cancer, etc.

Supplementary Materials:The following are available online at https://www.mdpi.com/article/10 .3390/cancers13143581/s1, FigureS1: Temporal trend of publications on cancer research in occupational settings in Iran, TableS1: Search query used in PubMed to retrieve relevant publications from initiation up to January 2021, TableS2: Search query used in Web of Sciences to retrieve relevant publications from initiation up to January 2021.

John Wiley & Sons, Inc.International Journal of Cancer

Acknowledgements

The authors would like to thank the IROPICAN study team for collecting these data. The authors are indebted to the study participants who accepted to be interviewed. The authors would like to thank the interviewers of the collaborative centres for their efforts in recruiting participants. The authors also wish to thank the Union for International Cancer Control (UICC) for the Technical Fellowship Award to Ms Bayan Hosseini allowing her to acquire the knowledge of coding occupational text into the International Standard Classification of Occupations (ISCO), which was hosted by Environment and Lifestyle Epidemiology Branch of IARC-WHO in 2018 and preceded this project. The authors would like to extend their sincere thanks to Dr Evgenia Ostroumova, scientist at IARC, for helping in the confirmation of morphopathology classification.

Funding: This research received no external funding.

Data Availability Statement:

All full-texts are available by the first author.

Acknowledgments:

The authors would like to thank Teresa Lee and Latifa Bouanzi of IARC Library for their guidance with the literature search strategy.

Conflicts of Interest:

The authors declare no conflict of interest.

Disclaimer: Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization or the Government of Canada, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer/World Health Organization or the Government of Canada.

Original research

Lung cancer risk in relation to jobs held in a nationwide case-control study in Iran Bayan Hosseini , 1,2 Ann Olsson , 1 Liacine Bouaoun, 1 Amy Hall, 3 Maryam Hadji, 2,4 Hamideh Rashidian, 2 Ahmad Naghibzadeh-Tahami, 5,6 Maryam Marzban, 7 Farid Najafi, 8,9 Ali Akbar Haghdoost, 10 Paolo Boffetta , 11,12 Farin Kamangar, 13 Eero Pukkala, 14,15 Arash Etemadi, 16 Elisabete Weiderpass , 1 Joachim Schüz, 1 Kazem Zendehdel 2,17 Workplace