Diesel exhaust in miners study: how to understand the findings?

Abstract The Diesel Exhaust in Miners Study (DEMS) is an outstanding epidemiological project on the association between occupational diesel exhaust exposures, measured as long-term respirable elemental carbon (REC) estimates, and lung cancer mortality in a large cohort of US miners. Two articles published recently (Attfield et al. (J Natl Cancer Inst Epub, 2012), Silverman et al. (J Natl Cancer Inst Epub, 2012)) dsescribed the epidemiological findings. These papers are expected to have considerable impact on the evaluation of the carcinogenic potential of diesel exhaust and, furthermore, on occupational and environmental limit value discussions related to diesel motor emissions and particle exposures. DEMS found remarkable exposure-response relationships between REC exposure estimates and lung cancer mortality - conditional on a pronounced effect of surface vs. underground work on lung cancer risk. If this risk factor is ignored the estimated REC-lung cancer association is attenuated substantially. The authors relied on this risk factor in their main analyses. However, this factor “surface/underground work” remained unexplained. The factor lead the authors to introduce unusual cross-product terms of location and smoking in adjustment procedures and even caused the authors to hypothesize that high REC exposures are protective against lung cancer excess risks due to smoking. To understand the reliability of these conclusions, we should ask basic questions about the data collection process in DEMS: Did the mortality follow-up procedures suffer from errors like those that affected the NCI formaldehyde cohort study? Are the REC and/or smoking data reliable, and are these data collected/constructed in such a way that the procedures allow valid comparisons between surface and underground workers? Without clarifying the issues raised in this Commentary the Diesel Exhaust in Miners Study remains to be difficult to interpret.</p

Bayesian bias adjustments of the lung cancer SMR in a cohort of German carbon black production workers

<p>Abstract</p> <p>Background</p> <p>A German cohort study on 1,528 carbon black production workers estimated an elevated lung cancer SMR ranging from 1.8-2.2 depending on the reference population. No positive trends with carbon black exposures were noted in the analyses. A nested case control study, however, identified smoking and previous exposures to known carcinogens, such as crystalline silica, received prior to work in the carbon black industry as important risk factors.</p> <p>We used a Bayesian procedure to adjust the SMR, based on a prior of seven independent parameter distributions describing smoking behaviour and crystalline silica dust exposure (as indicator of a group of correlated carcinogen exposures received previously) in the cohort and population as well as the strength of the relationship of these factors with lung cancer mortality. We implemented the approach by Markov Chain Monte Carlo Methods (MCMC) programmed in R, a statistical computing system freely available on the internet, and we provide the program code.</p> <p>Results</p> <p>When putting a flat prior to the SMR a Markov chain of length 1,000,000 returned a median posterior SMR estimate (that is, the adjusted SMR) in the range between 1.32 (95% posterior interval: 0.7, 2.1) and 1.00 (0.2, 3.3) depending on the method of assessing previous exposures.</p> <p>Conclusions</p> <p>Bayesian bias adjustment is an excellent tool to effectively combine data about confounders from different sources. The usually calculated lung cancer SMR statistic in a cohort of carbon black workers overestimated effect and precision when compared with the Bayesian results. Quantitative bias adjustment should become a regular tool in occupational epidemiology to address narrative discussions of potential distortions.</p

Response to the Reply on behalf of the ‘Permanent Senate Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area’ (MAK Commission) by Andrea Hartwig Karlsruhe Institute of Technology (KIT)

Prof. Hartwig commented [1] as chair of the MAK Commission on Morfeld et al. 2015 [2]. We would like to thank the Commission for commenting on our review. However, the MAK Commission did not address a number of important issues raised in our paper

Occupational Exposure to Poorly Soluble Low Toxicity Particles and Cardiac Disease: A Look at Carbon Black and Titanium Dioxide

Environmental particulate exposure and the potential risk to people with various types of cardiac diseases, most notably cardiovascular disease, have aroused scientific and regulatory interest worldwide. Epidemiological studies have shown associations between exposure to airborne environmental particulate matter (PM) and mortality from cardiovascular disease (CVD). The associations reported, however, are complex and may not involve a direct role for PM, since air pollutants are diverse and highly correlated. This study examines the potential role of occupational exposure to two types of particles, namely, manufactured carbon black (CB) and titanium dioxide (TiO2), on the risk of cardiovascular disease. To address the risk of cardiovascular disease from exposure to carbon black and titanium dioxide, as reflective of poorly soluble low toxicity particles, we reviewed the published cohort mortality studies of occupational exposure to carbon black and titanium dioxide. Mortality studies of carbon black have been conducted in the United States, Germany, and the United Kingdom. Five mortality studies related to workers involved in the manufacture of titanium dioxide in the United States and Europe have also been conducted. In addition, a meta-analysis of the three-carbon black mortality studies was performed. In the random-effects meta-analysis, full cohort meta-SMRs were 1.01 (95% confidence interval (CI): 0.79–1.29) for heart disease; 1.02 (95% CI: 0.80–1.30) for ischemic heart disease; and 1.08 (95% CI: 0.74–1.59) for acute myocardial infarction (AMI) mortality. A small but imprecise increased AMI mortality risk was suggested for cumulative exposure by a meta-HR = 1.10 per 100 mg/m3-years (95% CI: 0.92–1.31) but not for lugged exposures, that is, for recent exposures. Results of five cohort mortality studies of titanium dioxide workers in the United States and Europe showed no excess in all heart disease or cardiovascular disease. In the most recent study in the United States, an internal analysis, that is, within the cohort itself, with no lag time, showed that the exposure group 15–35 mg/m3-years yielded a significantly increased risk for heart disease; however, there was no evidence of increasing risk with increasing exposure for any of the exposure categories. In contrast to environmental studies, the results of cohort mortality studies do not demonstrate that airborne occupational exposure to carbon black and titanium dioxide particulates increases cardiovascular disease mortality. The lack of a relationship between carbon black and titanium dioxide and CVD mortality suggests that the associations reported in air pollution studies may not be driven by the particulate component

Translational toxicology in setting occupational exposure limits for dusts and hazard classification – a critical evaluation of a recent approach to translate dust overload findings from rats to humans

Background We analyze the scientific basis and methodology used by the German MAK Commission in their recommendations for exposure limits and carcinogen classification of “granular biopersistent particles without known specific toxicity” (GBS). These recommendations are under review at the European Union level. We examine the scientific assumptions in an attempt to reproduce the results. MAK’s human equivalent concentrations (HECs) are based on a particle mass and on a volumetric model in which results from rat inhalation studies are translated to derive occupational exposure limits (OELs) and a carcinogen classification. Methods We followed the methods as proposed by the MAK Commission and Pauluhn 2011. We also examined key assumptions in the metrics, such as surface area of the human lung, deposition fractions of inhaled dusts, human clearance rates; and risk of lung cancer among workers, presumed to have some potential for lung overload, the physiological condition in rats associated with an increase in lung cancer risk. Results The MAK recommendations on exposure limits for GBS have numerous incorrect assumptions that adversely affect the final results. The procedures to derive the respirable occupational exposure limit (OEL) could not be reproduced, a finding raising considerable scientific uncertainty about the reliability of the recommendations. Moreover, the scientific basis of using the rat model is confounded by the fact that rats and humans show different cellular responses to inhaled particles as demonstrated by bronchoalveolar lavage (BAL) studies in both species. Conclusion Classifying all GBS as carcinogenic to humans based on rat inhalation studies in which lung overload leads to chronic inflammation and cancer is inappropriate. Studies of workers, who have been exposed to relevant levels of dust, have not indicated an increase in lung cancer risk. Using the methods proposed by the MAK, we were unable to reproduce the OEL for GBS recommended by the Commission, but identified substantial errors in the models. Considerable shortcomings in the use of lung surface area, clearance rates, deposition fractions; as well as using the mass and volumetric metrics as opposed to the particle surface area metric limit the scientific reliability of the proposed GBS OEL and carcinogen classification.International Carbon Black Associatio

Fatigue, reduced sleep quality and restless legs syndrome in Charcot-Marie-Tooth disease: a web-based survey

To investigate the prevalence of fatigue, daytime sleepiness, reduced sleep quality, and restless legs syndrome (RLS) in a large cohort of patients with Charcot-Marie-Tooth disease (CMT) and their impact on health-related quality of life (HRQoL). Participants of a web-based survey answered the Epworth Sleepiness Scale, the Pittsburgh Sleep Quality Index, the Multidimensional Fatigue Inventory, and, if the diagnostic criteria of RLS were met, the International RLS Severity Scale. Diagnosis of RLS was affirmed in screen-positive patients by means of a standardized telephone interview. HRQoL was assessed by using the SF-36 questionnaire. Age- and sex-matched control subjects were recruited from waiting relatives of surgical outpatients. 227 adult self-reported CMT patients answered the above questionnaires, 42.9% were male, and 57.1% were female. Age ranged from 18 to 78 years. Compared to controls (n = 234), CMT patients reported significantly higher fatigue, a higher extent and prevalence of daytime sleepiness and worse sleep quality. Prevalence of RLS was 18.1% in CMT patients and 5.6% in controls (p = 0.001). RLS severity was correlated with worse sleep quality and reduced HRQoL. Women with CMT were affected more often and more severely by RLS than male patients. With regard to fatigue, sleep quality, daytime sleepiness, RLS prevalence, RLS severity, and HRQoL, we did not find significant differences between genetically distinct subtypes of CMT. HRQoL is reduced in CMT patients which may be due to fatigue, sleep-related symptoms, and RLS in particular. Since causative treatment for CMT is not available, sleep-related symptoms should be recognized and treated in order to improve quality of life