Occupational lung cancer screening: A Collegium Ramazzini statement

Lung cancer is the most common cause of death from cancer in the world. It is also the most common lethal work-related cancer. After tobacco smoking, occupational exposures present the most frequent specific cause of lung cancer that is amenable to intervention. Early detection and treatment can identify and cure primary lung cancer. Randomized controlled trials have demonstrated the efficacy of low dose computed tomography (LDCT) screening among persons at high risk of lung cancer. Guidelines for determining eligibility for LDCT screening have been established for the general population but have largely neglected those for whom occupational exposure to lung carcinogens is a risk factor. The Collegium recommends that persons at risk for lung cancer from occupational exposures be offered annual LDCT if their cumulative risk of lung cancer approximates the level of risk endorsed by the guidelines promulgated by the United States Preventive Services Task Force (USPSTF) in 2021 and the National Comprehensive Cancer Network (NCCN) in the United States in 2021. At present, these agencies recommend screening for people aged 50 and over who have smoked at least 20 pack-years of cigarettes. The Collegium recommends that additional lung cancer risk factors, including exposure to known or suspected occupational and environmental lung carcinogens; family history of lung cancer (especially among first degree relatives and relatives 15 years) is another factor that should be considered. If the presence of these additional risk factors, in combination with age and smoking history, is associated with a level of risk that meets or exceeds the level of risk identified by the USPSTF and NCCN, then an annual low dose chest CT for lung cancer screening should be offered. We do not favor a specific age cut-off at which to end screening, but we recognize that only persons who are sufficiently healthy and have sufficient life expectancy to undergo diagnostic work-up and potentially curative treatment should be offered screening for lung cancer. In view of the rising risk of occupational lung cancer over time and the potential or actual interaction between occupational lung carcinogens and cigarette smoking even after quitting, screening programs may choose to screen workers with occupational lung cancer risk for prolonged periods after they have quit smoking cigarettes. The Collegium acknowledges that there are uncertainties and assumptions entailed in this approach and that risk assessment for individual workers necessitates application of significant professional judgement. We encourage the implementation of well-organized screening programs that can further our knowledge about optimal occupation-inclusive lung cancer screening strategies. Workers with a history of exposure to known or suspected lung carcinogens or working in occupations/trades or work tasks that are known to elevate the risk for lung cancer form the target population for lung cancer screening. Important examples of lung carcinogens include asbestos, silica, diesel exhaust, welding fumes, selected metals, and radiation. Screening participants should be provided with complete and comprehensible information about risks and benefits. Screening should be offered annually and continuously. Screening should be achieved through the application of low dose computed tomography (LDCT) to minimize the radiation dose delivered. Proper CT scan interpretation should be performed by experienced radiologists or other well-trained readers. Prompt, appropriate follow-up of abnormal CT scans involving relevant medical expertise is mandatory. Patients who are current smokers should be offered smoking cessation programs. The Collegium calls upon occupational health and medical professionals and stakeholders (governments, employers, insurance companies, and labor unions) to identify worker populations that have excess lung cancer risk, to promote lung cancer screening, and to develop and support well-organized programs to conduct such screening in these populations. While elimination or minimization of exposure to lung carcinogens in the workplace through environmental controls is critical for lung cancer prevention, lung cancer screening is an essential secondary intervention for reducing deaths and disabling disease from exposure to workplace lung carcinogens. Lung cancer is the most common cause of death from cancer in the world, causing one in five (20.4%) cancer deaths in 2019.1 It is the most common cause of cancer death for males in most countries, including low-, middle-, and high-income nations, and the most frequent cause of cancer death among women in China, the United States, Australia, Scandinavia, and Canada. Tobacco smoking is the dominant cause of lung cancer, and the maturity of the cigarette smoking epidemic and variable uptake and adoption of smoking cessation determines much of the geographic and gender variation in lung cancer incidence and mortality.2 Lung cancer is also the dominant cause of occupational cancer (excluding nonmelanoma skin cancers), causing more than 50% of all workplace-related cancers.3 A recent analysis associated with the Global Burden of Disease Study 2016 estimated that 300,000 lung cancer deaths occurred as a result of exposure to 10 IARC Group 1 lung carcinogens in 2016, representing 86% of all occupational cancer deaths.4 Work-related lung cancer deaths increased 55% from 1990 to 2016, from an estimated 193,000–300,000 deaths per year (GBD 2016 Occupational Carcinogens Collaborators 2020). Excellent reviews of occupational cancer in general are readily available.5-7 Occupational lung cancer remains grossly neglected by public health surveillance, clinical medicine, and worker compensation systems, despite its enormous burden of illness and death. Studies in diverse populations and industries across three continents (Asia, Europe, and North America) have demonstrated that a very small fraction—less than 3%—of the total number of estimated occupational lung cancers have been attributed to occupation. In Korea, where an estimated 630 to 1181 occupational lung cancers occur annually, only 179 work-related lung cancers, or 10 per year on average, were compensated by the Korean national worker compensation system over a nearly two-decade period.8, 9 In Great Britain, where 5442 occupational lung cancer cases are estimated to occur each year,10 only 21 cases per year (or 392 cases over a 19 year period, 1996–2014) were recorded in Surveillance of Work-Related and Occupational Respiratory Disease (SWORD), a national voluntary reporting system.11 Similarly, in Canada, of the estimated 4150 annual occupational lung cancer cases, only 120 occupational lung cancers were compensated each year between 2005 and 2009.7, 12 Over the past five decades, the International Agency for Research on Cancer (IARC) has identified 20 IARC Group 1 occupational lung carcinogens (substances or mixtures) and an additional 7 occupations, industries or work processes in which occupational epidemiology studies were instrumental in establishing specific lung carcinogenicity.5 These agents, occupations and industries are listed in Table 1, adapted from IARC sources.5, 13 Four in ten of all agent-specific IARC Group 1 carcinogens cause lung cancer. In addition, two-thirds of all occupations, industries, or processes that cause occupational cancer cause lung cancer (Table 1). Arsenic and inorganic arsenic compounds Asbestos (all forms) Beryllium and beryllium compounds Bis(chloromethy)ether; chloromethyl methyl either (technical grade) Cadmium and cadmium compounds Chromium (VI) compounds Coal, indoor emissions from household combustion Coal tar pitch Engine exhaust, diesel Nickel compounds Outdoor air pollution Particulate matter in outdoor air pollution Plutonium Radon-222 and its decay products Silica dust, crystalline, in the form of quartz or cristobalite Soot Tobacco smoke, secondhand Welding fumes X-, and Gamma-radiation Acid mists, strong organic Benzene Biomass fuel (primarily wood), indoor emissions from household combustion of Bitumens, occupational exposure to hard bitumens and their emissions during mastic asphalt work alpha-Chlorinated toluenes (benzyl chloride, benzotrichloride, benzyl chloride) and benzoyl chloride (combined exposures) Cobalt metal with tungsten carbide Creosotes Diazinon Hydrazine Nonarsenical insecticides (occupational exposures in spraying and application of) Silicon carbide, fibrous 2,3,7,8 Tetrachlorordibenzo-para-dioxin Trivalent antimony Uranium, mixture of isotopes Acheson process, occupational exposures associated with Aluminum production Coal gasification Coke production Hematite mining (underground) Iron and steel founding Painter (occupational exposure) Rubber manufacturing industry Art glass, glass containers and pressed ware (manufacture of) Carbon electrode manufacture Frying, emissions from high-temperature Printing processes (occupational exposures in) Further, there is limited evidence for an association with lung cancer of numerous other exposures, though less broadly recognized within the occupational health community. They include cobalt,2, 3, 7, 8 tetrachlorordibenzo-para-dioxin (dioxin), and high temperature frying emissions and total eight agents or mixtures and four occupations, industries or processes (Table 1).13 The number of occupational lung carcinogens are increasing. In the past decade alone, IARC has added common exposures such as diesel engine exhaust (2013), outdoor air pollution (2016), and welding fumes (2017) to its Group 1 list of carcinogens (Table 1).5, 13 For additional carcinogens, there is limited evidence for an association with lung cancer: emissions from combustion of biomass fuel (2010); bitumens from roofing (2013); diazinon (2017); and hydrazine (2018). The occupational lung cancer burden is likely to grow. Only a small fraction of the tens of thousands of chemical agents in commercial use have been evaluated for toxicity. In five decades, IARC has evaluated more than 1000 agents, occupations and industries, but found that available scientific studies are inadequate or lacking in approximately one-half of the evaluations.5, 14 For context, there are an estimated 86,000 chemicals in the United States Environmental Protection Agency's Toxic Substances Control Act Inventory.15 Given the frequency of exposure of the respiratory system to inhaled toxicants and the demonstrated carcinogenicity of many chemical agents, it is likely that only a fraction of occupational lung carcinogens has been identified and the total burden of occupational lung cancer remains undefined. Exposure to occupational lung carcinogens has been and remains reasonably common. National and cross-national surveys of workplace exposures have been conducted in high income countries for 4 decades, including the US National Occupational Hazard and Exposure Surveys (1972–1974 and 1981–1983); CAREX (carcinogen exposure) project in the European Union (1990–1993)16; FINJEM (Finnish job-exposure matrix) system in Finland17; and the Canadian version of FINJEM.18 The most prevalent occupational lung carcinogens in high income countries over the past 30 years have been diesel exhaust, welding fumes, and silica. Based on data from Europe, Finland, and Canada, more than 2% of the employed population has been exposed to each of these three mixtures or agents. This proportion has not changed in the past three decades. Exposure to asbestos had been a dominant exposure in these countries, but its use declined markedly in recent decades due to widely accepted bans and restrictions. Asbestos exposure continues in these countries, however, due to large quantities of asbestos-containing materials still in place. For middle- and low-income countries, national estimates of the prevalence of exposure to occupational lung carcinogens have not been identified. Given the extent and lack of adequate regulation of manufacturing, mining, and construction, exposures to said agents is likely to be more common and at higher levels than in high income countries. For the purpose of lung cancer screening, workplace exposures that were prominent 20–40 years ago are highly relevant today due to the latency of asbestos-related lung cancer. Asbestos exposure was common in worksites in many high-income countries before the 1980s, though exposure in recent decades has declined. The prior and continuing high use of asbestos in China, Russia, India, and selected other countries is almost certainly associated with elevated risk of asbestos-related lung cancer for large populations of workers at, both at present and well into the future.19, 20 Other highly relevant exposures, such as silica, diesel exhaust, and welding fumes, were prevalent in the past and remain prevalent in countries of all national income levels. Salient industries and examples of occupations with current exposure to occupational lung carcinogens are provided in Table 2.21 Many construction workers are exposed to the most common lung carcinogens: asbestos, diesel exhaust, silica, and welding. Diesel engine exhaust exposure is highly prevalent among workers who drive or maintain diesel vehicles, including buses, trucks, trains, ships, and heavy equipment. Many workers in mining are exposed to diesel exhaust from mining equipment. Miners and workers in many manufacturing industries continue to have exposure to carcinogenic metals and silica. Metal fabricators, assemblers Metal processors, shaping workers Clay, stone, glass processors Forging workers Boilermakers, platers Silica, diesel exhaust, painting, welding, coal-tar pitch, asbestos Outdoor air pollution Excavators Welders Painters Plumbers Other construction Bus drivers Truck drivers Mechanical maintenance Drillers, blasters Miners, quarry workers Mineral ore treaters Occupation and, more generally, social class, are closely associated with cigarette smoking. In the United States, one-quarter or more of workers in construction, manufacturing, mining, and transportation smoke cigarettes compared to 10% of workers in professional or managerial positions.22 In China, for example, the prevalence of smoking among male machine operators (67%) was nearly twice that of male medical/health personnel or teaching staff (36%–38%).23 It is well-established that occupational lung carcinogens and cigarette smoke act in concert in some circumstances to increase the risk of lung cancer. They share mechanistic pathways and have been repeatedly shown in epidemiologic studies to increase lung cancer risk above that expected by the presence of each risk factor alone. Asbestos is the best-known example of this phenomenon. Asbestos frequently shows at least a supra-additive interaction with smoking in determining lung cancer risk.24-28 Several large studies addressing the lung cancer risk among silica-exposed workers have been completed in the past decade, generally suggesting a supra-additive effect with cigarette smoke.29-33 Other occupational lung carcinogens that have been studied for interaction include diesel exhaust34, 35; and radon.36-38 Occupational exposures also indirectly increase lung cancer risk by causing chronic lung diseases, namely, chronic obstructive lung disease (COPD) and pneumoconioses, such as silicosis and asbestosis.21, 39 In fact, since occupational exposures to vapors, gases, dusts, or fumes raise the risk of COPD,40 for example, the occupational contribution to lung cancer should be considered more broadly than simply the role of the occupational agents causing lung cancer. Smoking works similarly as a major cause of COPD and as an established risk factor for idiopathic pulmonary fibrosis.41, 42 Figure 1 illustrates the complexity of these relationships. Key aspects of these relationships have been well-studied (e.g., the smoking and asbestos interaction noted above and the contribution of asbestosis and silicosis to risk of lung cancer). Other relationships, such as the interaction between work-related COPD and lung cancer, have received relatively less attention. Three decades of research provide strong evidence that periodic low dose chest CT scans can identify lung cancers at an early stage and can reduce lung cancer mortality. In Japan and the United States, Sone et al.43 and Henschke et al.44 separately demonstrated that low dose chest CT scanning in high risk populations detected ~85% of lung cancers at Stage I. In 2006, Henschke and colleagues further showed that treated early CT-detected lung cancers had excellent survival: a group of 412 Stage 1 lung cancers detected by CT screening had an estimated 88% 10-year survival.45 Of those who underwent surgical resection within 1 month of diagnosis, 10-year survival was 92%, 95% CI 88–95%. These remarkable results of nonrandomized studies stimulated intense interest and the initiation of randomized controlled trials of the impact of low dose CT scans on lung cancer mortality. Two large complementary randomized clinical trials of populations at high risk of lung cancer—the US National Lung Screening Trial (NLST) and the Dutch–Belgian Nederlands–Leuvens Longkanker Screenings Onderzoek (NELSON)—conclusively demonstrated that periodic low dose chest CT scanning reduces lung cancer mortality.46, 47 The NLST, conducted by the United States National Cancer Institute, included 53,454 enrollees aged 55–74 who had smoked at least 30 pack-years and, for former smokers, had quit within the past 15 years. The CT versus chest X-ray (CXR) study arms were screened annually for 5 years and followed for a median of 6.5 years. The CT scan screening arm showed a 20% reduction in lung cancer mortality versus the CXR screening arm.46 The NELSON trial included 13,195 men and 2594 women aged 50–74 years who had smoked at least 15–20 pack-years and, if former smokers, had quit 10 or fewer years before the entry date into the study. NELSON compared an intervention group who underwent four rounds of CT screening (baseline, year 1, year 3, and year 5.5) with a reference group who had no screening; all were followed for at least 10 years. NELSON observed a 24% and 33% lung cancer mortality reduction among men and women, respectively, in the trial.47 Neither the NLST nor the NELSON trials were designed to evaluate the efficacy of lung cancer among screenees defined other than by age and smoking. Other factors would include occupational exposures, chronic lung disease, family history of lung cancer, personal history of cancer, or environmental exposure to radon, air pollution, or other nonoccupational toxins. An alternative to the use of age and smoking history alone to estimate lung cancer risk and to determine screening eligibility is the employment of a broader set of lung cancer risk factors in lung cancer risk models. More than 20 lung cancer risk prediction models based on large lung cancer data sets (e.g., prostate, lung, colorectal, and ovarian cancer screening trial PLCO, developed in North America48; liverpool lung project LLP, developed in England49) have been developed, and many are inclusive of a broader and more detailed set of lung cancer risk factors than the NLST and NELSON trials.50 These additional risk factors variably include gender, race, body mass index (BMI), intensity and duration of smoking, number of years since smoking cessation, chronic lung disease, especially chronic obstructive pulmonary disease (COPD), personal history of cancer, family history of lung cancer, education, and asbestos exposure. Among the better-performing models, the only occupational carcinogen included is asbestos, which is part of the Liverpool Lung Project (LLP) and Bach models.49, 51 No other occupational or environmental exposures have been included in the risk prediction models. Lung cancer risk calculators derived from these models use no or little information about occupation in determining risk. In a noteworthy comparison of the risk factor versus risk prediction approaches to the use of LDCT, ten Haaf52 applied nine established lung cancer risk prediction models to the large data sets of the NLST and the PLCO and compared results to the risk factor eligibility criteria used in the NLST, using 5- and 6-year lung cancer incidence and mortality as outcomes. The specificity of the risk prediction models versus the NLST criteria were very similar (~62.2%–62.6%), but four models had substantially higher levels of sensitivity (>78%) compared to that of the NLST criteria (71.4%) with respect to lung cancer incidence. The contrast in sensitivity for lung cancer mortality between the NLST criteria and the model predictions was even greater: 73.5% for the NLST versus 85.2% for the PLCOm2012 model and 83.8% for the two-stage clonal expansion (TSCE) and Bach models.52 In a US National Cancer Institute study of this issue, investigators compared the lung cancer mortality benefits of a risk prediction-based model versus a USPSTF guidelines-based model (restricted to age and smoking) and concluded that the former approach, which used family history, self-reported emphysema, body mass index, age, and a broader range of smoking history as eligibility criteria, prevented a greater number of lung cancer deaths than a model based on USPSTF screening guidelines (see below).53, 54 Based principally on the results of the NLST, the United States Preventive Service Task Force (USPSTF) recommended in 2013 that annual low dose CT scanning be offered to individuals at high risk of lung cancer, who were defined as people aged 55–74 years who had smoked at least 30 pack-years of cigarettes and currently smoke or quit less than 15 years previously. In 2021, after publication of the NELSON trial results, the USPSTF revised its recommendations for annual LDCT eligibility to include people aged 50–80 years who have at least a 20 pack-year smoking history and currently smoke or have quit within the past 15 years.55 These recommendations were adopted by the US federal government and private insurance companies for use in health insurance coverage and clinical preventive practice. Recommendations based in Europe to date have adopted a more heterogeneous approach. In a March 2022 report prepared by Science Advice for Policy by European Academies (SAPEA), a consortium effort of European Scientific Academies and released, lung cancer screening with LDCT is recommended, using either a combination of age and smoking or the PLCOm2012 model.56 An expert group of European physicians and scientists who are leaders in lung cancer screening in Europe have developed a set of consensus recommendations on lung cancer screening, which were published in June 2020.57 They recommended the use of lung cancer risk thresholds (e.g., 1.51% over a 6-year period) applied to results of risk prediction models to determine who should be eligible for LDCT-based lung cancer screening. Of the numerous risk prediction models that have been developed, the expert group favored those derived from the Liverpool Lung Project (LLPv2) and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCOm2012). In China, a multidisciplinary lung cancer early detection and treatment expert group (appointed by the Chinese National Health and Family Planning Commission) established the China National Lung Cancer Screening Guidelines, recommending annual lung cancer screening with LDCT for people aged 50–74 years who have at least a 20 pack-year smoking history and who currently smoke or have quit within the past 5 years.58 The latest Chinese guidelines developed by the National Cancer Center of China recommends lung cancer screening eligibility including: (1) current smokers with ≥30 pack-years or former smokers with ≥30 pack-years who have quit within 15 years; (2) secondhand smokers who have lived or worked with smokers for at least 20 years; (3) people with COPD; (4) participants who have exposure ≥1 year to asbestos, radon, beryllium, chromium, cadmium, nickel, silica, or soot; (5) people with first degree relatives have confirmed lung cancer.59 The South African Thoracic Society recently issued recommended guidelines for lung cancer screening. They recommend that annual LDCT should be offered to people between 55 and 74 years of age who are current or former smokers (having quit less than 15 years previously) with a history of ≥30-pack years of smoking. Participants should have no history of lung cancer and be in reasonable health and able and willing to be treated for lung cancer. They note that the high prevalence of tuberculosis in South Africa requires that only lung nodules ≥6 mm need follow-up.60 Occupation is generally ignored in current screening recommendations, whether they are based on selected risk factors (age and smoking) or on risk prediction models. Exceptions in the US include guidelines developed by the National Comprehensive Cancer Network (NCCN) and the American Society of Thoracic Surgeons. Their guidelines include using additional risk factors to determine screening eligibility, that is, family history, history of chronic lung disease and occupational exposures. Specifically, NCCN Group 2 eligibility criteria, first used in 2014, recommended screening people aged ≥50 years with a 20 pack-year smoking history if they have an additional risk factor for lung cancer, such as exposure to occupational lung carcinogens, chronic lung disease, or a family history of lung cancer and had an aggregate 6 year risk of lung cancer ≥1.3%.61 More recently, NCCN recommended a 20 pack-year screening threshold for everyone aged 50 years and over but occupation and other risk factors can additionally be considered in determining eligibility for screening.62 Occupational lung carcinogens named include silica, cadmium, asbestos, arsenic, beryllium, chromium, diesel exhaust, nickel, coal smoke, and soot. In 2014, a group of international experts in asbestos-related diseases met in Helsinki and recommended that the lung cancer risk level associated with the NLST study population be used as the threshold risk level in organized low dose CT scan programs for screening asbestos-exposed workers for lung cancer.63 The Helsinki recommendation was made before completion of the NELSON clinical trial, numerous modeling studies, and revision of the USPSTF eligibility guidelines in 2021. In 2017, an expert working group in France made recommendations for the application of LDCT for lung cancer screening for workers who have a history of exposure to Group 1 IARC occupational lung carcinogens, including asbestos.64 They conducted a scientific literature review and developed an expert consensus on how to identify the magnitude of lung cancer risks associated with these Group 1 carcinogens, alone and in combination with cigarette smoking, and identified the combinations that equaled or exceeded the lung cancer risk associated with NLST eligibility criteria. They assumed a multiplicative (and not a supra-additive or additive) joint effect between the occupational carcinogenic agent and tobacco in estimating the relative risks. They estimated that the relative risk of lung cancer associated with the NLST study eligibility criteria (≥30 pack-year history of cigarette smoking) was 30. Using the target relative risk level of 30, exposure to each of the IARC Group 1 lung carcinogens in combination with 20–29 pack years of smoking met or exceeded the target risk level. Never smokers who were occupationally exposed to lung carcinogens at any level did not reach a relative risk sufficient to justify lung cancer screening with the possible exceptions of plutonium and bis-chloromethyl ether.64 Since the publication of this set of French recommendations in 2017, the results of the NELSON trial and modeling studies led the USPSTF to lower the age and smoking levels for eligibility for LDCT-based lung cancer screening (≥age 50 years and ≥20 pack-years). The associated estimated relative risk level of lung cancer in the French analysis would be 20. Accordingly, under these French guidelines, workers with intermediate asbestos exposure ≥10 years and workers with ≤5 years of high asbestos exposure would be recommended for lung cancer screening even among ever smokers with a smoking history of less than 20 pack-years. Studies of lung cancer screening among occupational populations at high risk of lung cancer are limited to date. Two types of occupational settings have been studied: asbestos-exposed groups and US nuclear weapons workers. Nine nonrandomized studies of asbestos-exposed populations with ≥150 participants reported results of LDCT screening for lung cancer between 2002 and 2019.65-74 Age, smoking history, and asbestos exposure were principal or exclusive eligibility criteria with frequent use of broader age and smoking ranges than those used in NLST or NELSON. These studies were included in a published systematic review and meta-analyses by Ollier et al.75 and Maisonneuve et al.73 None of these studies used risk prediction models, NLST, or NELSON eligibility criteria to determine eligibility. Comparison with NLST or the NELSON results is precluded by the heterogeneity of the study populations and the lack of sufficient detail on smoking history and age in the published studies. Combining the screening yield results of these nine studies yielded 86 lung cancers detected among 5548 ever smokers (1.55%) and 6 lung cancers detected among 1787 never smokers (0.33%). Parameters of asbestos exposure varied widely among the nine studies by industry, occupation, duration of em