Assessment and Indirect Adjustment for Confounding by Smoking in Cohort Studies Using Relative Hazards Models

Workers' smoking histories are not measured in many occupational cohort studies. Here we discuss the use of negative control outcomes to detect and adjust for confounding in analyses that lack information on smoking. We clarify the assumptions necessary to detect confounding by smoking and the additional assumptions necessary to indirectly adjust for such bias. We illustrate these methods using data from 2 studies of radiation and lung cancer: the Colorado Plateau cohort study (1950–2005) of underground uranium miners (in which smoking was measured) and a French cohort study (1950–2004) of nuclear industry workers (in which smoking was unmeasured). A cause-specific relative hazards model is proposed for estimation of indirectly adjusted associations. Among the miners, the proposed method suggests no confounding by smoking of the association between radon and lung cancer—a conclusion supported by adjustment for measured smoking. Among the nuclear workers, the proposed method suggests substantial confounding by smoking of the association between radiation and lung cancer. Indirect adjustment for confounding by smoking resulted in an 18% decrease in the adjusted estimated hazard ratio, yet this cannot be verified because smoking was unmeasured. Assumptions underlying this method are described, and a cause-specific proportional hazards model that allows easy implementation using standard software is presented

Mortality and cancer incidence among underground uranium miners in the Czech Republic 1977-1992

Objectives Uranium miners in Příbram, Czech Republic were exposed to low and moderate levels of radon gas and other hazards. It is unknown whether these hazards increase the risk of mortality or cancer incidence when compared with the general Czech population. Methods A cohort of 16 434 male underground miners employed underground for at least 1 year between 1946 and 1976, and alive and residing in the Czech Republic in 1977, were followed for mortality and cancer incidence through 1992. We compared observed deaths and cancer incidence to expectation based on Czech rates. Standardised mortality ratios (SMRs), standardised incidence ratios (SIRs) and causal mortality ratios were calculated. Results Underground workers in the Příbram mines had higher rates of death than expected due to all causes (SMR=1.23, 95% CI 1.20 to 1.27), all cancers (SMR=1.52, 95% CI 1.44 to 1.60), lung cancer (SMR=2.12, 95% CI 1.96 to 2.28) and extrathoracic cancer (SMR=1.41, 95% CI 1.15 to 1.77). Similar excess was observed in cancer incidence analyses, with the addition of stomach cancer (SIR=1.37, 95% CI 1.11 to 1.63), liver cancer (SIR=1.70, 95% CI 1.16 to 2.25) and rectal cancer (SIR=1.41, 95% CI 1.16 to 1.66). The SIR was elevated for all leukaemias (SIR=1.51, 95% CI 1.08 to 2.07) and for lymphatic and haematopoietic cancers combined (SIR=1.31, 95% CI 1.05 to 1.61), but results for specific subtypes were imprecise. Deaths due to hazardous mining conditions resulted in 0.33 person-years of life lost per miner. Conclusions Occupational exposure to the Příbram mines resulted in excess cancers at several sites, including sites previously linked to radon and uranium exposure. Incidence analyses showed relative excess of several additional cancer subtypes

Lung and extrathoracic cancer incidence among underground uranium miners exposed to radon progeny in the Příbram region of the Czech Republic: a case-cohort study

OBJECTIVES: Radon is carcinogenic, but more studies are needed to understand relationships with lung cancer and extrathoracic cancers at low exposures. There are few studies evaluating associations with cancer incidence or assessing the modifying effects of smoking. METHODS: We conducted a case-cohort study with 16 434 underground uranium miners in the Czech Republic with cancer incidence follow-up 1977-1996. Associations between radon exposure and lung cancer, and extrathoracic cancer, were estimated with linear excess relative rate (ERR) models. We examined potential modifying effects of smoking, time since exposure and exposure rate. RESULTS: Under a simple ERR model, assuming a 5-year exposure lag, the estimated ERR of lung cancer per 100 working level months (WLM) was 0.54 (95% CI 0.33 to 0.83) and the estimated ERR of extrathoracic cancer per 100 WLM was 0.07 (95% CI -0.17 to 0.72). Most lung cancer cases were observed among smokers (82%), and the estimated ERR of lung cancer per 100 WLM was larger among smokers (ERR/100 WLM=1.35; 95% CI 0.84 to 2.15) than among never smokers (ERR/100 WLM=0.12; 95% CI -0.05 to 0.49). Among smokers, the estimated ERR of lung cancer per 100 WLM decreased with time since exposure from 3.07 (95% CI -0.04 to 10.32) in the period 5-14 years after exposure to 1.05 (95% CI 0.49 to 1.87) in the period 25+ years after exposure. CONCLUSIONS: We observed positive associations between cumulative radon exposure and lung cancer, consistent with prior studies. We observed a positive association between cumulative radon exposure and extrathoracic cancers, although the estimates were small. There was evidence that the association between radon and lung cancer was modified by smoking in a multiplicative or super-multiplicative fashion

Occupational Radon Exposure and Lung Cancer Mortality: Estimating Intervention Effects Using the Parametric g-Formula

Traditional regression analysis techniques used to estimate associations between occupational radon exposure and lung cancer focus on estimating the effect of cumulative radon exposure on lung cancer, while public health interventions are typically based on regulating radon concentration rather than workers’ cumulative exposure. Moreover, estimating the direct effect of cumulative occupational exposure on lung cancer may be difficult in situations vulnerable to the healthy worker survivor bias

Risk of Bias Assessments and Evidence Syntheses for Observational Epidemiologic Studies of Environmental and Occupational Exposures: Strengths and Limitations.

BACKGROUND: Increasingly, risk of bias tools are used to evaluate epidemiologic studies as part of evidence synthesis (evidence integration), often involving meta-analyses. Some of these tools consider hypothetical randomized controlled trials (RCTs) as gold standards. METHODS: We review the strengths and limitations of risk of bias assessments, in particular, for reviews of observational studies of environmental exposures, and we also comment more generally on methods of evidence synthesis. RESULTS: Although RCTs may provide a useful starting point to think about bias, they do not provide a gold standard for environmental studies. Observational studies should not be considered inherently biased vs. a hypothetical RCT. Rather than a checklist approach when evaluating individual studies using risk of bias tools, we call for identifying and quantifying possible biases, their direction, and their impacts on parameter estimates. As is recognized in many guidelines, evidence synthesis requires a broader approach than simply evaluating risk of bias in individual studies followed by synthesis of studies judged unbiased, or with studies given more weight if judged less biased. It should include the use of classical considerations for judging causality in human studies, as well as triangulation and integration of animal and mechanistic data. CONCLUSIONS: Bias assessments are important in evidence synthesis, but we argue they can and should be improved to address the concerns we raise here. Simplistic, mechanical approaches to risk of bias assessments, which may particularly occur when these tools are used by nonexperts, can result in erroneous conclusions and sometimes may be used to dismiss important evidence. Evidence synthesis requires a broad approach that goes beyond assessing bias in individual human studies and then including a narrow range of human studies judged to be unbiased in evidence synthesis. https://doi.org/10.1289/EHP6980

Global, regional and national burdens of non-melanoma skin cancer attributable to occupational exposure to solar ultraviolet radiation for 183 countries, 2000-2019: A systematic analysis from the WHO/ILO Joint Estimates of the Work-related Burden of Disease and Injury.

A World Health Organization (WHO) and International Labour Organization (ILO) systematic review reported sufficient evidence for higher risk of non-melanoma skin cancer (NMSC) amongst people occupationally exposed to solar ultraviolet radiation (UVR). This article presents WHO/ILO Joint Estimates of global, regional, national and subnational occupational exposures to UVR for 195 countries/areas and the global, regional and national attributable burdens of NMSC for 183 countries, by sex and age group, for the years 2000, 2010 and 2019. We calculated population-attributable fractions (PAFs) from estimates of the population occupationally exposed to UVR and the risk ratio for NMSC from the WHO/ILO systematic review. Occupational exposure to UVR was modelled via proxy of occupation with outdoor work, using 166 million observations from 763 cross-sectional surveys for 96 countries/areas. Attributable NMSC burden was estimated by applying the PAFs to WHO's estimates of the total NMSC burden. Measures of inequality were calculated. Globally in 2019, 1.6 billion workers (95 % uncertainty range [UR] 1.6-1.6) were occupationally exposed to UVR, or 28.4 % (UR 27.9-28.8) of the working-age population. The PAFs were 29.0 % (UR 24.7-35.0) for NMSC deaths and 30.4 % (UR 29.0-31.7) for disability-adjusted life years (DALYs). Attributable NMSC burdens were 18,960 deaths (UR 18,180-19,740) and 0.5 million DALYs (UR 0.4-0.5). Men and older age groups carried larger burden. Over 2000-2019, attributable deaths and DALYs almost doubled. WHO and the ILO estimate that occupational exposure to UVR is common and causes substantial, inequitable and growing attributable burden of NMSC. Governments must protect outdoor workers from hazardous exposure to UVR and attributable NMSC burden and inequalities

Cancer incidence among capacitor manufacturing workers exposed to polychlorinated biphenyls

We evaluated cancer incidence in a cohort of polychlorinated biphenyl (PCB) exposed workers. Incident cancers, identified using state registries, were compared to those in a national population using standardized incidence ratios. Trends in prostate cancer incidence with cumulative PCB exposure were evaluated using standardized rate ratios and Cox regression models. For selected sites, cumulative PCB exposure was compared between aggressive (fatal/distant stage) and localized/regional cancers. We identified 3,371 invasive first primary cancer diagnoses among 21,317 eligible workers through 2007. Overall relative incidence was reduced. Elevations were only observed for respiratory cancers and among women, urinary organ cancers. Among men, prostate cancer incidence was reduced and not associated with cumulative PCB exposure although median exposures were significantly higher for aggressive compared to localized/regional prostate cancers. Previously observed associations between cumulative PCB exposure and prostate cancer mortality were not confirmed in this analysis; prostate cancer stage at diagnosis may explain the discrepancy. Am. J. Ind. Med. 60:198-207, 2017. Published 2016. This article is a U.S. Government work and is in the public domain in the USA