Peter Morfeld

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)

Calculation error in the MAK Commission’s document on GBS [3] when using the rule of three in Pauluhn’s volumetric model (we emphasize that the comment did not dispute the arithmetical error lowering Model B’s GBS limit value erroneously from 2.0 mg/m to 0.5 mg/m). Use of an MPPD2 program version in [3] that is outdated and no longer available to enable to replicate the MAK Commission’s conclusions. Input values in [3] that cannot be reproduced from the references listed in [3] or are not state-of-the-art. Inconsistent use of varying input data by the MAK Commission in [3] although explicitly specified as guideline in the same document [3].

What component of coal causes coal workers' pneumoconiosis?

Objective: To evaluate the component of coal responsible for coal workers’ pneumoconiosis (CWP). Methods: A literature search of PubMED was conducted to address studies that have evaluated the risk of CWP based on the components of coal. Results: The risk of CWP (CWP) depends on the concentration and duration of exposure to coal dust. Epidemiology studies have shown inverse links between CWP and quartz content. Coal from the USA and Germany has demonstrated links between iron content and CWP; these same studies indicate virtually no role for quartz. In vitro studies indicate strong mechanistic links between iron content in coal and reactive oxygen species, which play a major role in the inflammatory response associated with CWP. Conclusions: The active agent within coal appears to be iron, not quartz. By identifying components of coal before mining activities, the risk of developing CWP may be reduced.

Assessment of exposure in epidemiological studies: the example of silica dust

Exposure to crystalline silica ranks among the most frequent occupational exposures to an established human carcinogen. Health-based occupational exposure limits can only be derived from a reliable dose–response relationship. Although quartz dust seems to be a well-measurable agent, several uncertainties in the quantification of exposure to crystalline silica can bias the risk estimates in epidemiological studies. This review describes the silica-specific methodological issues in the assessment of exposure. The mineralogical forms of silica, the technologies applied to generate dust, protective measures, and co-existing carcinogens are important parameters to characterize the exposure condition of an occupational setting. Another methodological question concerns the measurement of the respirable dust fraction in the workers breathing zone and the determination of the quartz content in that fraction. Personal devices have been increasingly employed over time, whereas norms for the measurement of respirable dust have been defined only recently. Several methods are available to analyse the content of crystalline silica in dust with limits of quantitation close to environmental exposure levels. For epidemiological studies, the quartz content has frequently not been measured but only calculated. To develop a silica-dust database for epidemiological purposes, historical dust concentrations sampled with different devices and measured as particle numbers have to be converted in a common exposure metric. For the development of a job-exposure matrix (JEM), missing historical data have to be estimated to complete the database over time. Unknown but frequently high-exposure levels of the past contribute largely to the cumulative exposure of a worker. Because the establishment of a JEM is crucial for risk estimates, sufficient information should be made accessible to allow an estimation of the uncertainties in the assessment of exposure to crystalline silica. The impressive number of silica dust measurements and the evaluation of methodological uncertainties allow recommendations for a best practice of exposure assessment for epidemiological studies.

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

BackgroundWe 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.MethodsWe 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.ResultsThe 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.ConclusionClassifying 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.

Computing chronodisruption: How to avoid potential chronobiological errors in epidemiological studies of shift work and cancer

We ask if epidemiological studies into shift work and cancer may be prone to chronobiological errors. We illustrate how ignoring internal time (IT), or chronotype, may lead to what we call IT errors. Errors from truncating relevant external time (ET) information (activities start before and do not end with the shift) we call ET errors. We develop how observational research may avoid potential chronobiological biases and how chronodisruption can be computed. We assess how IT and ET errors may have affected studies published so far with a focus on those that considered chronobiological information but were confined to night work.

Years of Life Lost due to exposure: Causal concepts and empirical shortcomings

Excess Years of Life Lost due to exposure is an important measure of health impact complementary to rate or risk statistics. I show that the total excess Years of Life Lost due to exposure can be estimated unbiasedly by calculating the corresponding excess Years of Potential Life Lost given conditions that describe study validity (like exchangeability of exposed and unexposed) and assuming that exposure is never preventive. I further demonstrate that the excess Years of Life Lost conditional on age at death cannot be estimated unbiasedly by a calculation of conditional excess Years of Potential Life Lost without adopting speculative causal models that cannot be tested empirically. Furthermore, I point out by example that the excess Years of Life Lost for a specific cause of death, like lung cancer, cannot be identified from epidemiologic data without assuming non-testable assumptions about the causal mechanism as to how exposure produces death. Hence, excess Years of Life Lost estimated from life tables or regression models, as presented by some authors for lung cancer or after stratification for age, are potentially biased. These points were already made by Robins and Greenland 1991 reasoning on an abstract level. In addition, I demonstrate by adequate life table examples designed to critically discuss the Years of Potential Life Lost analysis published by Park et al. 2002 that the potential biases involved may be fairly extreme. Although statistics conveying information about the advancement of disease onset are helpful in exposure impact analysis and especially worthwhile in exposure impact communication, I believe that attention should be drawn to the difficulties involved and that epidemiologists should always be aware of these conceptual limits of the Years of Potential Life Lost method when applying it as a regular tool in cohort analysis.

Dose-Response and Threshold Analysis of Tumor Prevalence after Intratracheal Instillation of Six Types of Low- and High-Surface-Area Particles in a Chronic Rat Experiment

Over a period of 20 years, rat experiments have consistently shown tumorigenic responses after exposure to poorly soluble low-toxicity particles (PSP). We performed a rigorous dose threshold analysis of a large previous rat study. Seven hundred and nine rats were intratracheally exposed to five different PSP: carbon black and titanium dioxide of low and high surface area, diesel emission particles (low surface area), and one soluble dust (amorphous silica, high surface area), at varying instilled total mass doses ranging from 3.0 mg to 120 mg. A multivariable Cox model was applied to analyse lung tumor prevalence. The model was extended by a dose threshold or a dose saturation parameter. This statistical approach, which is new in animal studies, showed no better fit when using surface area or volume as dose metrics but found significantly higher tumor prevalence in animals instilled with high-surface-area dust particles. Interestingly, a dose threshold of about 10 mg mass dose (0.95 CI: 5 mg to 15 mg) emerged from our calculations. In addition, our statistical analysis demonstrated that tumor prevalence is saturated beyond 20 mg mass dose. In summary, our analyses showed that these data are compatible with earlier observations that high-surface-area particles induce more lung tumors and support the concept of a dose threshold for lung tumor after PSP exposures in the rat. However, collinearities in the data (particle type and dose were correlated by design) and the saturation phenomenon (506 out of 709 rats were exposed above the estimated saturation dose) limit generalization of these findings.

Lung Cancer Mortality and Carbon Black Exposure: Cox Regression Analysis of a Cohort From a German Carbon Black Production Plant

Objective: We undertook a lung cancer mortality analysis of 1528 German carbon black workers, followed between the years of 1976–1998, who produced furnace black, lamp black, and gas black. Methods: We used Cox modeling across age with time-dependent covariates, ie, cumulative and mean carbon black exposure, duration of work in departments, adjusting for calendar time, a smoking indicator, and age at hire. Exposures were lagged up to 20 years. Analyses were performed with the full cohort and after restriction to an inception cohort. Results: A total of 50 lung cancer deaths occurred. No positive association was found with carbon black exposure indices. Some models indicated an increasing risk across duration of work in the lamp black producing department. Conclusions: Our results do not suggest that carbon black exposure is a human lung carcinogen. The lamp black results, if no artifact, may point at historical exposures to gaseous polycyclic aromatic hydrocarbons.

Deposition behavior of inhaled nanostructured TiO2 in rats: fractions of particle diameter below 100 nm (nanoscale) and the slicing bias of transmission electron microscopy.

Context: In experimental studies with nanomaterials where translocation to secondary organs was observed, the particle sizes were smaller than 20 nm and were mostly produced by spark generators. Engineered nanostructured materials form microsize aggregates/agglomerates. Thus, it is unclear whether primary nanoparticles or their small aggregates/agglomerates occur in non-negligible concentrations after exposure to real-world materials in the lung. Objective: We dedicated an inhalation study with nanostructured TiO2 to the following research question: Does the particle size distribution in the lung contain a relevant subdistribution of nanoparticles? Methods: Six rats were exposed to 88 mg/m3 TiO2 over 5 days with 20% (count fraction) and <0.5% (mass fraction) of nanoscaled objects. Three animals were sacrificed after cessation of exposure (5 days), others after a recovery period of 14 days. Particle sizes were determined morphometrically by transmission electron microscopy (TEM) of ultra-thin lung slices. Since the particles visible are two-dimensional surrogates of three-dimensional structures we developed a model to estimate expected numbers of particle diameters below 100 nm due to the TEM slicing bias. Observed and expected numbers were contrasted in 2 × 2 tables by odds ratios. Results: Comparisons of observed and expected numbers did not present evidence in favor of the presence of nanoparticles in the rat lungs. In simultaneously exposed satellite animals agglomerates of nanostructured TiO2 were observed in the mediastinal lymph nodes but not in secondary organs. Conclusions: For nanostructured TiO2, the deposition of nanoscaled particles in the lung seem to play a negligible role.

Lung cancer mortality and carbon black exposure: uncertainties of SMR analyses in a cohort study at a German carbon black production plant.

Objective: We undertook a sensitivity analysis of the lung cancer standardized mortality ratios (SMRs) in a study of 1522 German carbon black workers from 1976 to 1998. Methods: We applied results from a case–control study to adjust the SMR for smoking habits and exposures experienced before the carbon black job. In addition, sensitivity to reference rates was explored. Results: On the basis of 47 lung cancer deaths, the SMRs were 1.62, 1.72, and 2.08 (local, state, and national rates, respectively). Adjustment for previous exposures and smoking yielded additional correction factors of 0.64 or 0.74, varying with the chosen reference. Conclusions: Lung cancer SMRs (95% confidence intervals) for the full cohort ranged from 1.20 (0.88–1.59) to 2.08 (1.53–2.77) in this sensitivity analysis. Thus, overall SMRs are only weak measures of causal associations and should be complemented by internal modeling of exposure effects whenever possible.