Critical reviews of exposure assessment in carcinogenic hazard identification: the IARC Monographs experience.

OBJECTIVES: To summarise the rationale, workflow and recommendations for the conduct of exposure assessment critiques in key human studies evaluated for International Agency for Research on Cancer (IARC) Monographs on the Identification of Carcinogenic Hazards. METHODS: Approaches to evaluating exposure assessment quality in human cancer and mechanistic studies were reviewed according to the precepts outlined in the IARC Monographs Preamble, using two agents as case studies. Exposure assessment 'domains', that is, salient aspects of exposure assessment for the agent under evaluation, were selected for review across the key human studies. RESULTS: The case studies of night shift work (volume 124) and 1,1,1-trichloroethane (volume 130) used a common approach, tailored to the agents' specific exposure scenarios, to evaluate exposure assessment quality. Based on the experiences of IARC Working Groups to date, the implementation of exposure assessment critique requires the need for agent-specific knowledge, consideration of the validity of time-varying exposure metrics related to duration and intensity, and transparent, concise reviews that prioritise the most important strengths and limitations of exposure assessment methods used in human studies. CONCLUSIONS: Exposure assessment has not historically been a fully appreciated component for evaluating the quality of epidemiological studies in cancer hazard identification. Exposure assessment critique in key human cancer and mechanistic studies is now an integral part of IARC Monographs evaluations and its conduct will continue to evolve as new agents are evaluated. The approaches identified here should be considered as a potential framework by others when evaluating the exposure assessment component of epidemiological studies for systematic reviews.

Surveillance of asbestos related disease among workers enrolled in an exposure registry.

INTRODUCTION: Contemporary asbestos exposure occurs during construction, remediation, and maintenance involving asbestos-containing materials (ACM), as compared to the historical exposure scenarios of asbestos mining and milling. The Ontario Asbestos Workers Register (AWR) was established in 1986 to track asbestos exposure among construction workers. This study reports on the risk of asbestos-related diseases (ARD) among workers in the AWR. METHODS: AWR registrants were linked probabilistically with administrative health databases (1986-2019) to identify cases of ARD including both cancer and chronic respiratory disease. Follow-up began at AWR enrollment and continued prospectively. Incidence rates were compared to the general population using standardized incidence ratios (SIRs). Associations between ACM exposure and ARD were estimated among AWR registrants using Poisson regression. RESULTS: In total, 26,204 (81%) registrants were linked successfully. Common industries of employment were construction (62%), manufacturing (19%) and education (8%). Among men and women mesothelioma (M:SIR 6.83 [95% CI = 5.56-8.31]; W:SIR 19.2 [3.86-56.1]) and pulmonary fibrosis (M:SIR 14.1 [12.2-16.2]; W:SIR 9.25 [2.49-23.7]) rates were higher than the general population. Asbestosis risk was elevated among men (M:SIR 11.2 [9.59-13.1]). Workers with longer reported exposures (≥140 h) had increased rates of lung cancer (RR 1.34 [1.10-1.63]), mesothelioma (RR 2.83 [1.75-4.58]), asbestosis (RR 3.07 [2.12-4.43]), chronic obstructive pulmonary disease (RR 1.42 [1.29-1.57]), and pulmonary fibrosis (RR 1.88 [1.35-2.62]). CONCLUSION: Exposure to asbestos in construction and building maintenance continues to contribute to ARD incidence. Despite a Canadian ban on asbestos in new products, exposures to existing ACM will persist from construction activities. The AWR offers an opportunity for ongoing surveillance of resulting ARD in Ontario.

Incidence of cardiovascular disease in a cohort of mine workers exposed to ultrafine aluminum powder in Ontario, Canada.

BACKGROUND: A retrospective cohort study was conducted to estimate associations between an ultrafine aluminum powder, McIntyre Powder (MP), and cardiovascular disease incidence in a cohort of mine workers from Ontario, Canada. Disease outcomes included ischemic heart disease (IHD), acute myocardial infarction (AMI), congestive heart failure (CHF), and strokes and transient ischemic attacks (STIA). METHODS: Using work history records from the Ontario Mining Master File (MMF) mine workers were followed for disease incidence in administrative health records. The analysis included 25,813 mine workers who were exposed to MP between 1943 and 1979 and followed for cardiovascular disease (CVD) diagnoses between 2006 and 2018. Cardiovascular disease cases were ascertained using physician, hospital, and ambulatory care records. Poisson regression models were used to estimate age and birth-year adjusted incidence rate ratios (RR) and 95% confidence intervals (CI) for associations between MP exposure and CVD outcomes. RESULTS: Ever-exposure to MP was positively associated with modest increases in the incidence rate of IHD, AMI, and CHF, but not STIA, using both assessment approaches. Duration of self-reported MP exposure was positively associated with monotonically increasing rates of IHD and AMI compared to never-exposed miners, with the greatest association observed among miners with >20 years of exposure (for IHD: RR 1.24, 95% CI: 0.91-1.68; and for AMI: RR 1.52, 95% CI 1.01-2.28). CONCLUSION: Mine workers ever-exposed to MP had modestly elevated rates of CVD. The rate of CVD diagnoses appeared to increase with longer duration of exposure when assessed by both self-reported exposure and through historical records.

Comparison of internal and external reference populations for occupational cancer surveillance in a cohort drawn from a diverse workforce.

OBJECTIVES: Prior analyses of the Occupational Disease Surveillance System (ODSS) have compared cancer rates using internal referent groups. As an exploratory analysis, we sought to estimate cancer risk using general population reference rates to evaluate the impact that the comparison population has on findings from our surveillance program. METHODS: A cohort of approximately 2.3 million workers in Ontario, Canada with an accepted lost-time workers' compensation claim were followed for all cancer diagnoses between 1983 and 2018. Standardized incidence ratios (SIRs) and 95% confidence intervals were calculated for workers in specific occupational groups using (1) all other workers in the ODSS cohort, and (2) the general population of Ontario. RESULTS: SIRs using the general population reference group were generally equal to or modestly lower compared to SIRs using the internal reference group. Within occupation groups, SIRs had a discordant direction of association (increased rate in the internal comparison and decreased in the external comparison) for some cancer sites including urinary, prostate, and colorectal. CONCLUSIONS: Findings emphasize the importance of the choice of reference group when evaluating cancer risks in large occupational surveillance cohorts. Importantly, the magnitude of confounding and the healthy worker hire bias may depend on the occupation group and cancer site of interest.

Radon exposure and risk of neurodegenerative diseases among male miners in Ontario, Canada: A cohort study.

BACKGROUND: Environmental radon has been examined as a risk factor for neurodegenerative diseases in a small number of previous studies, but the findings have been inconsistent. This study aims to investigate the association between occupational radon exposure and neurodegenerative disease in a cohort of male miners with work experience in multiple ore types in Ontario, Canada. METHODS: Radon exposure (1915-1988) was assessed using two job-exposure matrices (JEM) constructed from using historical records for 34,536 Ontario male miners. Neurodegenerative outcomes were ascertained between 1992 and 2018. Poisson regression models were used to estimate incidence rate ratios (RR) and 95% confidence intervals (CI) between cumulative radon exposure in working level months (WLM) and each neurodegenerative outcome. RESULTS: Levels of cumulative radon exposure showed variability among cohort members with a mean of 7.5 WLM (standard deviation 24.4). Miners in uranium mines or underground jobs had higher levels and more variability in exposure than workers in non-uranium work or surface jobs. Compared to the reference group (radon < 1 WLM), increased rates of Alzheimer's (RR 1.23, 95% CI 1.05-1.45) and Parkinson's disease (RR 1.43, 95% CI 1.08-1.89) were observed among workers with >1-5 WLM and >5-10 WLM, respectively, but not among higher exposed workers (>10 WLM). CONCLUSION: This study did not observe a positive monotonic dose-response relationship between cumulative radon exposure and Alzheimer's or Parkinson's disease in Ontario mining workers. There was no association observed with motor neuron disease.

Cancer risk among firefighters and police in the Ontario workforce.

OBJECTIVE: Firefighters and police often work in high-stress, complex environments with known and suspected carcinogenic exposures. We aimed to characterise cancer incidence among firefighters and police. METHODS: The Occupational Disease Surveillance System (ODSS) was used to identify workers employed as firefighters or police in Ontario. A cohort of workers were identified using lost-time workers' compensation claims data and followed for cancer in the Ontario Cancer Registry (1983-2020). Cox proportional hazard models were used to estimate HRs and 95% CIs for primary site-specific cancer diagnoses adjusted for age at start of follow-up, birth year and sex. RESULTS: A total of 13 642 firefighters and 22 595 police were identified in the cohort. Compared with all other workers in the ODSS, firefighters and police had increased risk of prostate cancer (firefighters: HR=1.43, 95% CI 1.31 to 1.57; police: HR=1.47, 95% CI 1.35 to 1.59), colon cancer (firefighters: HR=1.39, 95% CI 1.19 to 1.63; police: HR=1.39, 95% CI 1.21 to 1.60) and skin melanoma (firefighters: HR=2.38, 95% CI 1.99 to 2.84; police: HR=2.27, 95% CI 1.96 to 2.62). Firefighters also had increased risk of cancer of the pancreas, testis and kidney, as well as non-Hodgkin's lymphoma and leukaemia. Police had increased risk of thyroid, bladder and female breast cancer. When compared directly with the police, firefighters had an elevated risk of mesothelioma and testicular cancer. CONCLUSIONS: Firefighters and police demonstrated some similar as well as some unique cancer risks. Findings from this larger worker population may have important implications for workplace and policy-level changes to improve preventative measures and reduce potential exposures to known carcinogenic hazards.

Incidence of mesothelioma and asbestosis by occupation in a diverse workforce.

OBJECTIVE: We sought to characterize detailed patterns of mesothelioma and asbestosis incidence in the workforce as part of an occupational disease surveillance program in Ontario, Canada. METHODS: The Occupational Disease Surveillance System (ODSS) cohort was established using workers' compensation claims data and includes 2.18 million workers employed from 1983 to 2014. Workers were followed for mesothelioma and asbestosis diagnoses in Ontario Cancer Registry, physician, hospital, and ambulatory care records through 2016. Trends in incidence rates were estimated over the study period. Cox proportional hazard models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: A total of 854 mesothelioma and 737 asbestosis cases were diagnosed during follow-up. Compared with all other workers in the ODSS, those employed in construction trades occupations had the greatest adjusted incidence rate of both mesothelioma (223 cases; HR, 2.38; 95% CI: 2.03-2.78) and asbestosis (261 cases; HR, 3.64; 95% CI: 3.11-4.25). Rates were particularly elevated for insulators, pipefitters and plumbers, and carpenters. Workers in welding and flame cutting, boiler making, and mechanic and machinery repair occupations, as well as those in industrial chemical and primary metal manufacturing industries, had strongly elevated rates of both diseases. Rates were greater than anticipated for workers in electrical utility occupations and education and related services. CONCLUSIONS: Results substantiate the risk of mesothelioma and asbestosis in occupation and industry groups in the Ontario workforce with known or suspected asbestos exposure. Sustained efforts to prevent the occurrence of additional cases of disease in high-risk groups are warranted.

Incidence of acute myocardial infarction in the workforce: Findings from the Occupational Disease Surveillance System.

BACKGROUND: Increased risks of acute myocardial infarction (AMI) may be attributable to the workplace, however, associations are not well-established. Using the Occupational Disease Surveillance System (ODSS), we sought to estimate associations between occupation and industry of employment and AMI risk among workers in Ontario, Canada. METHODS: The study population was derived by linking provincial accepted lost-time workers' compensation claims data, to inpatient hospitalization records. Workers aged 15-65 years with an accepted non-AMI compensation claim were followed for an AMI event between 2007 and 2016. Adjusted Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for each industry and occupation group, compared to all other workers in the cohort. Sex-stratified analyses were also performed. RESULTS: In all, 24,514 incident cases of AMI were identified among 1,502,072 Ontario workers. Increased incidence rates of AMI were found across forestry (HR 1.37, 95% CI 1.19-1.58) and wood processing (HR 1.50, 1.27-1.77) job-titles. Elevated rates were also detected within industries and occupations both broadly related to mining and quarrying (HR 1.52, 1.17-1.97), trucking (HR 1.32, 1.27-1.38), construction (HR 1.32, 1.14-1.54), and the manufacturing and processing of metal (HR 1.41, 1.19-1.68), textile (HR 1.41, 1.07-1.88), non-metallic mineral (HR 1.30, 0.82-2.07), and rubber and plastic (HR 1.42, 1.27-1.60) products. Female food service workers also had elevated AMI rates (HR 1.36, 1.23-1.51). CONCLUSION: This study found occupational variation in AMI incidence. Future studies should examine work-related hazards possibly contributing to such excess risks, like noise, vibration, occupational physical activity, shift work, and chemical and particulate exposures.

Innovations in applied decision theory for health and safety.

OBJECTIVES: There are established methods for occupational epidemiological cohort analysis, such as proportional hazards regression, that are well suited to aetiological research and yield parameter estimates that allow for succinct communication among academics. However, these methods are not necessarily well suited for evaluation of health impacts of policy choices and communication to decision makers. An informed decision about a policy that impacts health and safety requires a valid estimate of the policy's potential impact. METHODS: We propose methods for data summarisation that may facilitate communication with managers, workers and their advocates. We calculate measures of effect in a framework for competing events, graphically display potential impacts on cause-specific mortality under policy alternatives and contrast these results to estimates obtained using standard Poisson regression methods. Methods are illustrated using a cohort mortality study of 28 546 Ontario uranium miners hired between 1950 and 1996 and followed through 2007. RESULTS: A standard regression analysis yields a positive association between cumulative radon progeny exposure and all-cause mortality (log(RR per 100 WLM)=0.09; SE=0.02). The proposed method yields an estimate of the expected gain in life expectancy (approximately 6 months per worker) and reduction of 261 lung cancer deaths under a policy that eliminated occupational radon progeny exposure. CONCLUSIONS: The proposed method shifts attention from covariate-adjusted risk ratios or rate ratios to estimates of deaths that are avoided or delayed under a potential policy. The approach may help inform decision-making and strengthen the connection of epidemiological approaches to data analysis with developments in decision theory and systems engineering to improve health and safety.

Neurodegenerative diseases among miners in Ontario, Canada, using a linked cohort.

OBJECTIVES: We examined employment in mining occupations and industries and its association with neurological disease incidence in a linkage cohort from Ontario, Canada. Outcomes included Alzheimer's disease (alone and with other dementias), Parkinson's disease, parkinsonism, motor neuron disease and amyotrophic lateral sclerosis (ALS). METHODS: The Occupational Disease Surveillance System cohort was created by linking workers' compensation data and healthcare usage records. This analysis included over 1.1 million male workers, followed between 1999 and 2016. Neurological diseases were ascertained using physician billing and hospital discharge records. Adjusted Poisson regression models were used to estimate incidence rate ratios (RR) comparing mining to non-mining workers overall and by ore (industry) and occupation group. RESULTS: Suggested elevations in incidence rates were observed for ALS among workers of metal mines (RR 2.21, 95% CI 1.04 to 4.69) and for motor neuron disease among those employed in mining occupations within metal mining industries (RR 1.96, 95% CI 1.01 to 3.79), though these were based on relatively few cases. In miscellaneous metal mines, workers who held mining occupations had an elevated rate of Alzheimer's disease (RR 1.27, 95% CI 0.92 to 1.77). Parkinson's disease rate was elevated among workers with rock and soil drilling occupations (RR 1.60, 95% CI 1.04 to 2.45). CONCLUSIONS: Mining hazards may be associated with elevated rates of neurodegenerative diseases among workers in mining occupations and industries. More work is needed to better understand mining exposures and their associations with neurodegenerative diseases.

Cancer surveillance among workers in plastics and rubber manufacturing in Ontario, Canada.

OBJECTIVE: Occupational exposure to agents in plastics and rubber manufacturing has been associated with elevated risk of certain cancers. We sought to evaluate cancer risk among workers employed in occupations and industries with these exposures as part of an ongoing surveillance programme in Ontario, Canada. METHODS: The Occupational Disease Surveillance System (ODSS) cohort was established using workers' compensation claims data and includes 2.18 million workers employed from 1983 to 2014. Workers were followed for site-specific cancer diagnoses in the Ontario Cancer Registry through 2016. Cox proportional hazard models were used to estimate adjusted HR and 95% CI. RESULTS: We identified 81 127 workers employed in plastics and rubber manufacturing industries or materials processing and product fabricating occupations. Compared with all other women in the ODSS, those in materials processing occupations had an elevated rate of lung cancer (HR 1.38, 95% CI 1.20 to 1.58) that was not observed among men. An elevated rate of breast cancer was observed among female labourers (HR 1.36, 95% CI 1.01 to 1.82) and moulders (HR 1.47, 95% CI 0.91 to 2.37) in plastics and rubber product fabricating occupations. Overall, elevated rates were observed for oesophageal, liver, stomach, prostate and kidney cancer in job-specific subgroups, including mixing and blending, bonding and cementing, and labouring. There was little evidence of association for lymphatic or haematopoietic cancers. CONCLUSIONS: Findings for lung and breast cancer in women are consistent with other studies and warrant further attention in Ontario. Given the relatively young age at end of follow-up, surveillance in these workers should continue as the cohort ages.

Cancer and noncancer mortality among aluminum smelting workers in Badin, North Carolina.

BACKGROUND: Badin, North Carolina, hosted an aluminum smelting plant from 1917 to 2007. The Concerned Citizens of West Badin reported suspected excess cancer mortality among former employees. This study aimed to investigate these concerns. METHODS: The study cohort was enumerated from United Steel Workers' records of workers employed from 1980 to 2007. Cause-specific mortality rates in the cohort were compared with North Carolina population mortality rates using standardized mortality ratios (SMRs), standardized by age, sex, race, and calendar period. We estimated cause-specific adjusted standardized mortality ratios (aSMRs) using negative controls to mitigate healthy worker survivor bias (HWSB). Standardized rate ratios (SRRs) were calculated to compare mortality rates between workers ever employed vs never employed in the pot room. RESULTS: All-cause mortality among Badin workers was lower than in the general population (SMR: 0.81, 95% confidence interval [CI]: 0.71-0.92). After adjusting for HWSB, excesses for all cancers (aSMR: 1.55, 95% CI: 1.10-2.21), bladder cancer (3.47, 95% CI: 1.25-9.62), mesothelioma (17.33, 95% CI: 5.40-55.59), and respiratory cancer (1.24, 95% CI: 0.77-1.99) were observed. Black males worked the highest proportion of their employed years in the pot room. Potroom workers experienced higher respiratory cancer (SRR: 2.99, 95% CI: 1.23-7.26), bladder cancer (SRR: 1.58, 95% CI: 0.15-15.28), and mesothelioma (SRR: 3.36, 95% CI: 0.21-53.78) mortality rates than never workers in the pot room. CONCLUSIONS: This study responds to concerns of a group of former aluminum workers. The results, while imprecise, suggest excess respiratory and bladder cancers among pot room workers in a contemporary cohort of union employees at a US smelter.

Employment characteristics and cause-specific mortality at automotive electronics manufacturing plants in Huntsville, Alabama.

BACKGROUND: This study was carried out in response to worker concerns over their exposure to lead solder and chlorinated solvents at automotive electronics manufacturing plants in Huntsville, Alabama. METHODS: A study of 4396 United Autoworkers members ever-employed at the plants between 1972 and 1993 was conducted with mortality follow-up through 2016. Poisson regression was used to estimate mortality rate ratios (RR) according to employment characteristics, including calendar period of employment. RESULTS: Pre-1977 hires exhibited elevated adjusted rates of all-cause (RR, 1.29; 95% confidence interval [CI], 1.09-1.52), cardiovascular (RR, 1.38; 95% CI, 1.03-1.86), and digestive system (RR, 2.31; 95% CI, 1.04-5.10) disease mortality relative to the most recent hire group (1984-1993). Never- versus ever-employment in a skilled trade job was associated with elevated adjusted rates of all-cause, all-cancer, and cardiovascular disease mortality. Nervous system disorder mortality was greatest among 1977-1983 hires. CONCLUSIONS: Elevated mortality among pre-1977 hires is consistent with worker concerns over greater exposure to hazards at the original plant building.

Mortality among autoworkers manufacturing electronics in Huntsville, Alabama.

BACKGROUND: Workers raised concerns over suspected excesses of mortality at automotive electronics manufacturing facilities in Huntsville, Alabama. METHODS: A study of 4396 UAW members ever-employed at Huntsville facilities between 1972 and 1993 was conducted with mortality follow-up through 2016. Standardized Mortality Ratios (SMRs) were estimated using U.S. and Alabama reference rates. RESULTS: Relative to U.S. rates, there was a modest excess of all-cause mortality among White female workers (SMR 1.08, 95%CI: 0.99-1.18) and among all workers hired <1977 at the original plant building (SMR 1.10, 95%CI: 0.99-1.22). There was excess nervous system disorder (SMR 1.24, 95%CI: 0.91-1.65) and brain and nervous system cancer (SMR 1.31, 95%CI: 0.67-2.28) mortality. Estimates for several causes of interest were imprecise. CONCLUSIONS: All-cause mortality estimates were greater than anticipated based on results from other UAW cohorts. The excess of nervous system disease mortality is consistent with other studies of electronics workers exposed to lead-solder and chlorinated solvents.

Leukemia Incidence by Occupation and Industry: A Cohort Study of 2.3 Million Workers from Ontario, Canada.

Although a significant body of evidence has attributed certain occupational exposures with leukemia, such as benzene, formaldehyde, 1,3-butadiene and ionizing radiation, more research is needed to identify work environments at increased risk for this disease. Our study aimed to identify occupational and industry groups associated with an elevated incidence of leukemia using a diverse cohort of workers' compensation claimants from Ontario, Canada. A total of 2,363,818 workers in the Occupational Disease Surveillance System (ODSS) cohort, with claims between 1983-2019, were followed for malignant leukemia diagnoses up to 31 December 2019. We used a Cox proportional-hazards model to estimate the relative incidence of leukemia in specific occupation and industry groups. After adjusting for age and birth year, males in protective services (HR = 1.17, 95% CI = 1.02-1.35), metal machining (HR = 1.23, 95% CI = 1.07-1.41), transport (HR = 1.15, 95% CI = 1.06-1.25), and mining occupations (HR = 1.28, 95% CI = 1.02-1.60) had elevated risks of leukemia compared to other workers in the ODSS, with comparable findings by industry. Among female workers, slight risk elevations were observed among product fabricating, assembling, and repairing occupations, with other increased risks seen in furniture and fixture manufacturing, storage, and retail industries. These findings underscore the need for exposure-based studies to better understand occupational hazards in these settings.

Firefighting and Cancer: A Meta-analysis of Cohort Studies in the Context of Cancer Hazard Identification.

Objective: We performed a meta-analysis of epidemiological results for the association between occupational exposure as a firefighter and cancer as part of the broader evidence synthesis work of the IARCMonographs program. Methods: A systematic literature search was conducted to identify cohort studies of firefighters followed for cancer incidence and mortality. Studies were evaluated for the influence of key biases on results. Random-effects meta-analysis models were used to estimate the association between ever-employment and duration of employment as a firefighter and risk of 12 selected cancers. The impact of bias was explored in sensitivity analyses. Results: Among the 16 included cancer incidence studies, the estimated meta-rate ratio, 95% confidence interval (CI), and heterogeneity statistic (I2) for ever-employment as a career firefighter compared mostly to general populations were 1.58 (1.14-2.20, 8%) for mesothelioma, 1.16 (1.08-1.26, 0%) for bladder cancer, 1.21 (1.12-1.32, 81%) for prostate cancer, 1.37 (1.03-1.82, 56%) for testicular cancer, 1.19 (1.07-1.32, 37%) for colon cancer, 1.36 (1.15-1.62, 83%) for melanoma, 1.12 (1.01-1.25, 0%) for non-Hodgkin lymphoma, 1.28 (1.02-1.61, 40%) for thyroid cancer, and 1.09 (0.92-1.29, 55%) for kidney cancer. Ever-employment as a firefighter was not positively associated with lung, nervous system, or stomach cancer. Results for mesothelioma and bladder cancer exhibited low heterogeneity and were largely robust across sensitivity analyses. Conclusions: There is epidemiological evidence to support a causal relationship between occupational exposure as a firefighter and certain cancers. Challenges persist in the body of evidence related to the quality of exposure assessment, confounding, and medical surveillance bias.