Evaluation of biological markers for the risk assessment of carbon black in epidemiological studies.

Background/objectives: Engineered nanomaterials (ENMs) have been suggested as being capable of promoting inflammation, a key component in the pathways associated with carcinogenesis, cardiovascular disease, and other conditions. As a result, the risk assessment of biological markers as early-stage indicators has the potential to improve translation from experimental toxicologic findings to identifying evidence in human studies. The study aims to review the possible early biological changes in workers exposed to carbon black (CB), followed by an evidentiary quality evaluation to determine the predictive value of the biological markers. Methods: We conducted a literature search to identify epidemiological studies that assessed biological markers that were involved in the inflammatory process at early stages among workers with exposure to CB. We reviewed the studies with specific reference to the study design, statistical analyses, findings, and limitations. Results: We identified five Chinese studies that investigated the potential impact of exposure to CB on inflammatory markers, bronchial wall thickening, genomic instability, and lung function impairment in CB production workers. Of the five Chinese studies, four were cross-sectional; another study reported results at two-time points over six years of follow-up. The authors of all five studies concluded positive relationships between exposure and the inflammatory cytokine profiles. The weak to very weak correlations between biomarkers and early-stage endpoints were reported. Conclusion: Most inflammatory markers failed to satisfy the proposed evidentiary quality criteria. The significance of the results of the reviewed studies is limited by the cross-sectional study design, inconsistency in results, uncertain clinical relevance, and high occupational exposures. Based on this review, the risk assessment relying on inflammatory markers does not seem appropriate at this time. Nevertheless, the novel research warrants further exploration in assessing exposure to ENMs and corresponding potential health risks in occupational settings.

Comment on Balwierz et al. Potential Carcinogens in Makeup Cosmetics. Int. J. Environ. Res. Public Health 2023, 20, 4780.

We read with interest the article by Balwierz et al. [...].

Coal Miners and Lung Cancer: Can Mortality Studies Offer a Perspective on Rat Inhalation Studies of Poorly Soluble Low Toxicity Particles?

Inhalation studies involving laboratory rats exposed to poorly soluble particles (PSLTs), such as carbon black and titanium dioxide, among others, have led to the development of lung cancer in conditions characterized as lung overload. Lung overload has been described as a physiological state in which pulmonary clearance is impaired, particles are not effectively removed from the lungs and chronic inflammation develops, ultimately leading to tumor growth. Since lung tumors have not occurred under similar states of lung overload in other laboratory animal species, such as mice, hamsters and guinea pigs, the relevance of the rat as a model for human risk assessment has presented regulatory challenges. It has been suggested that coal workers' pneumoconiosis may reflect a human example of apparent "lung overload" of poorly soluble particles. In turn, studies of risk of lung cancer in coal miners may offer a valuable perspective for understanding the significance of rat inhalation studies of PSLTs on humans. This report addresses whether coal can be considered a PSLT based on its composition in contrast to carbon black and titanium dioxide. We also review cohort mortality studies and case-control studies of coal workers. We conclude that coal differs substantially from carbon black and titanium dioxide in its structure and composition. Carbon black, a manufactured product, is virtually pure carbon (upwards of 98%); TiO2 is also a manufactured product. Coal contains carcinogens such as crystalline silica, beryllium, cadmium and iron, among others; in addition, coal mining activities tend to occur in the presence of operating machinery in which diesel exhaust particles, a Type I Human carcinogen, may be present in the occupational environment. As a result of its composition and the environment in which coal mining occurs, it is scientifically inappropriate to consider coal a PSLT. Despite coal not being similar to carbon black or TiO2, through the use of a weight of evidence approach-considered the preferred method when evaluating disparate studies to assess risk- studies of coal-mine workers do not indicate a consistent increase in lung cancer risk. Slight elevations in SMR cannot lead to a reliable conclusion about an increased risk due to limitations in exposure assessment and control of inherent biases in case-control studies, most notably confounding and recall bias. In conclusion, the weight of the scientific literature suggests that coal mine dust is not a PSLT, and it does not increase lung cancer risk.

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.

Extended Investigation of Exposure to Respirable Synthetic Amorphous Silica Dust and Its Potential Impact on Non-malignant Respiratory Morbidity.

Objectives: The present analysis aims to study the health impact of an occupational exposure to respirable synthetic amorphous silica (SAS) dusts, based on the available data from the German study. Methods: The effect of cumulative exposure to respirable SAS dust on respiratory morbidity were investigated in 462 exposed male workers. Multiple exposure assessments was performed anchored by a most recent measurement series. Internal regression models in addition to Monte Carlo-Multi Model were fitted. Results: An averaged cumulative respirable SAS dust concentration of 6.44 mg/m3-years was estimated. Internal regression models suggested a reduction of 8.11 ml (95% confidence interval: 0.49-15.73) in forced vital capacity (FVC) per 1 mg/m3-year increase of exposure. But no effect on forced expiratory volume in 1 s (FEV1) and the ratio of the parameters FEV1/FVC was observed in association with exposure to a respirable fraction of SAS. No adverse effects on the occurrence of respiratory diseases were indicated. Conclusion: This study provides no clear evidence of adverse health effects from occupational exposure to respirable SAS. Sponsor: Evonik Operations GmbH/Smart Materials, Cabot Corporation, Wacker Chemie AG.

Iatrogenic CSF Leak from CT Myelogram Leading to Cauda Equina Compression: A Case Report.

Introduction: Although magnetic resonance imaging (MRI) is the preferred imaging modality for diagnosing cauda equina syndrome (CES), computerized tomography (CT) myelogram may be used in patients who are unable to undergo MRI. When inserting the needle for CT myelogram, there is a risk of cerebrospinal fluid (CSF) leak, which theoretically could lead to CES. To the best of our knowledge, there are no reports of CT myelogram resulting in cauda equina compression. Case Report: We report the case of a 38-year-old man who underwent surgical decompression for CES and developed an iatrogenic CSF leak from a pre-operative CT myelogram causing recurrent thecal sac compression requiring repeat surgery and dural repair. Conclusion: Although CT myelogram may be used to aid in the diagnosis of CES, consideration should be given to the potential risk for causing a CSF leak and resultant thecal sac compression.

Comment on Saber et al. (2019), "Commentary: the chronic inhalation study in rats for assessing lung cancer risk may be better than its reputation".

In their Commentary Saber et al. (Part Fibre Toxicol 16: 44, 2019) argue that chronic inhalation studies in rats can be used for assessing the lung cancer risk of insoluble nanomaterials. The authors make several significant errors in their interpretation and representation of the underlying science. In this Letter to the Editor we discuss these inaccuracies to correct the scientific record. When the science is recounted accurately it does not support Saber et al's statements and conclusions.

Carbon Black and Lung Cancer Mortality-A Meta-regression Analysis Based on Three Occupational Cohort Studies.

OBJECTIVES: We review three large cohort studies of occupational exposure to carbon black and association with lung cancer mortality, and conduct a meta-regression to derive an exposure-response relationship. METHODS: Meta-regression analysis of cumulative exposure to carbon black and lung cancer mortality was conducted based on the relative risk estimates reported by three cohort studies of production workers from US, UK, and Germany. RESULTS: A 10 mg/m yr increase in cumulative exposure to carbon black was associated with a relative risk decrease of 1% (relative risk [RR] = 0.99; 95% confidence interval [CI]: 0.87-1.13) for lung cancer mortality. No exposure-response relationship was observed. CONCLUSIONS: This meta-regression analysis of three large occupational mortality studies reports that historic workplace exposures to carbon black were not associated with a significant risk of lung cancer.

The relationship of elbow alignment and kinematics on shoulder torque during the softball pitch: a biomechanical analysis of female softball pitchers.

BACKGROUND: Female softball pitchers commonly throw more pitches per game and season than their baseball counterparts. The greatest stress to the shoulder during a softball windmill pitch is at ball release (BR). This study investigated shoulder torques at BR among female softball pitchers and identified relationships to the kinematics of the elbow and forearm and alignment of the elbow (carrying angle and elbow extension). METHODS: High-speed 3-dimensional biomechanical analyses were performed in 33 pitchers (25 high school, 8 collegiate). Elbow and shoulder biomechanics at BR during fastball pitches and goniometric measures of carrying angle and elbow extension were collected and analyzed. RESULTS: Carrying angle correlated positively with shoulder extension torque at BR (rs = 0.371, P = .048) and forearm pronation at BR (rs = 0.370, P = .048). During the windmill pitch, the greater the elbow flexion, the greater shoulder adduction torque at BR (rs = -0.522, P = .007). Multiple regression analysis revealed that the carrying angle, passive elbow extension, and elbow flexion/extension angle at BR predicted shoulder flexion/extension torque at BR (F3,24 = 3.463, R2 = .302, P = .032.) CONCLUSIONS: Our findings demonstrate that shoulder torques during the softball fastpitch are influenced by the carrying angle and the kinematic elbow flexion angle at BR. Sports medicine clinicians and coaches should consider the role that the elbow carrying angle plays in creating shoulder stress when treating and training fastpitch softball players.

Cross-Sectional Study on Nonmalignant Respiratory Morbidity due to Exposure to Synthetic Amorphous Silica.

OBJECTIVES: The aim of this study was to assess the health impact of chronic exposure to synthetic amorphous silica (SAS) on nonmalignant respiratory morbidity. METHODS: We used multiple linear and logistic regression models and Monte Carlo multimodel analyses of two exposure scenarios to evaluate the effect of cumulative exposure to inhalable SAS dust on symptoms, spirometry, and chest films in 462 male workers from five German SAS-producing plants. RESULTS: Exposure to SAS was associated with a reduction in forced vital capacity (FVC) in one of the two exposure scenarios but had no effect on forced expiratory volume in 1 second (FEV1) or FEV1/FVC in either exposure scenario. Monte Carlo analysis indicated a decline in FVC of -11 mL per 10 mg/m-years exposure (-6 to -0.4). Chest films showed no evidence of pneumoconiosis. CONCLUSION: This study provides limited evidence of minor dose-related effects of chronic exposure to SAS on lung function.

Meta-Analysis of Cardiac Mortality in Three Cohorts of Carbon Black Production Workers.

Epidemiological studies have demonstrated associations between airborne environmental particle exposure and cardiac disease and mortality; however, few have examined such effects from poorly soluble particles of low toxicity such as manufactured carbon black (CB) particles in the work place. We combined standardised mortality ratio (SMR) and Cox proportional hazards results from cohort studies of US, UK and German CB production workers. Under a common protocol, we analysed mortality from all causes, heart disease (HD), ischemic heart disease (IHD) and acute myocardial infarction (AMI). Fixed and random effects (RE) meta-regression models were fit for employment duration, and for overall cumulative and lugged quantitative CB exposure estimates. Full cohort meta-SMRs (RE) were 1.01 (95% confidence interval (CI) 0.79-1.29) for HD; 1.02 (95% CI 0.80-1.30) for IHD, and 1.08 (95% CI 0.74-1.59) for AMI mortality. For all three outcomes, meta-SMRs were heterogeneous, increased with time since first and time since last exposure, and peaked after 25-29 or 10-14 years, respectively. Meta-Cox coefficients showed no association with lugged duration of exposure. A small but imprecise increased AMI mortality risk was suggested for cumulative exposure (RE-hazards ratio (HR) = 1.10 per 100 mg/m³-years; 95% CI 0.92-1.31), but not for lugged exposures. Our results do not demonstrate that airborne CB exposure increases all-cause or cardiac disease mortality.

Wind turbines and health: An examination of a proposed case definition.

Renewable energy demands have increased the need for new wind farms. In turn, concerns have been raised about potential adverse health effects on nearby residents. A case definition has been proposed to diagnose "Adverse Health Effects in the Environs of Industrial Wind Turbines" (AHE/IWT); initially in 2011 and then with an update in 2014. The authors invited commentary and in turn, we assessed its scientific merits by quantitatively evaluating its proposed application. We used binomial coefficients to quantitatively assess the potential of obtaining a diagnosis of AHE/IWT. We also reviewed the methodology and process of the development of the case definition by contrasting it with guidelines on case definition criteria of the USA Institute of Medicine. The case definition allows at least 3,264 and up to 400,000 possibilities for meeting second- and third-order criteria, once the limited first-order criteria are met. IOM guidelines for clinical case definitions were not followed. The case definition has virtually no specificity and lacks scientific support from peer-reviewed literature. If applied as proposed, its application will lead to substantial potential for false-positive assessments and missed diagnoses. Virtually any new illness that develops or any prevalent illness that worsens after the installation of wind turbines within 10 km of a residence could be considered AHE/IWT if the patient feels better away from home. The use of this case definition in the absence of a thorough medical evaluation with appropriate diagnostic studies poses risks to patients in that treatable disorders would be overlooked. The case definition has significant potential to mislead patients and its use cannot be recommended for application in any health-care or decision-making setting.

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.

Wind turbines and health: a critical review of the scientific literature.

OBJECTIVE: This review examines the literature related to health effects of wind turbines. METHODS: We reviewed literature related to sound measurements near turbines, epidemiological and experimental studies, and factors associated with annoyance. RESULTS: (1) Infrasound sound near wind turbines does not exceed audibility thresholds. (2) Epidemiological studies have shown associations between living near wind turbines and annoyance. (3) Infrasound and low-frequency sound do not present unique health risks. (4) Annoyance seems more strongly related to individual characteristics than noise from turbines. DISCUSSION: Further areas of inquiry include enhanced noise characterization, analysis of predicted noise values contrasted with measured levels postinstallation, longitudinal assessments of health pre- and postinstallation, experimental studies in which subjects are "blinded" to the presence or absence of infrasound, and enhanced measurement techniques to evaluate annoyance.