Is pulmonary inflammation a valid predictor of particle induced lung pathology? The case of amorphous and crystalline silicas.

Although inflammation is a normal and beneficial response, it is also a key event in the pathology of many chronic diseases, including pulmonary and systemic particle-induced disease. In addition, inflammation is now considered as the key response in standard settings for inhaled particles and a critical endpoint in OECD-based sub-acute/ chronic animal inhalation testing protocols. In this paper, we discuss that whilst the role of inflammation in lung disease is undeniable, it is when inflammation deviates from normal parameters that adversity occurs. We introduce the importance of the time course and in particular, the reversibility of inflammation in the progression towards tissue remodelling and neoplastic changes as commonly seen in rat inhalation studies. For this purpose, we used chronic inhalation studies with synthetic amorphous silicas (SAS) and reactive crystalline silica (RCS) as a source of data to describe the time-course of inflammation towards and beyond adversity. Whilst amorphous silicas induce an acute but reversible inflammatory response, only RCS induces a persistent, progressive response after cessation of exposure, resulting in fibrosis and carcinogenicity in rodents and humans. This suggests that the use of inflammation as a fixed endpoint at the cessation of exposure may not be a reliable predictor of particle-induced lung pathology. We therefore suggest extending the current OECD testing guidelines with a recovery period, that allows inflammation to resolve or progress into altered structure and function, such as fibrosis.

Talc Inhalation in Rats and Humans: A Review and Appraisal of Available Evidence.

BACKGROUND: Current information on the health effects and toxicology of talc suggests that this may lead to a specific target organ toxicity arising from repeated exposure (STOT-RE) classification. OBJECTIVE: To provide an assessment of the currently available inhalation toxicity data on talc and to put these data in the perspective of other poorly soluble low-toxicity particles. METHODS: A database of 177 articles was gathered from different sources. RESULTS: Relevant animal data sets were subjected to a quality review, and epidemiological studies on talc and lung effects published since 2016 were reviewed. CONCLUSIONS: Of nine original inhalation studies reviewed, only one study using rats and mice met the criteria that are needed to include for a reliable evaluation for STOT-RE. Together with the pulmonary effects observed in exposed talc miners, a STOT-RE 1 classification is warranted.

Applying Existing Particle Paradigms to Inhaled Microplastic Particles.

Ambient particulate pollution originating from plastic contaminates air, including indoor and urban environments. The recent discovery of ambient microplastic (MP) particles of a size capable of depositing in the thoracic region of the airway, if inhaled, has raised concern for public exposure and health impacts following lessons learned from other particle domains. Current microplastic exposure estimates are relatively low compared to total ambient particulate matter, but optimal analytical techniques and therefore data for risk and health impact assessments are lacking. In the absence of such an evidence base, this paper explores paradigms, metrics and dose-response curves developed in other particle domains as a starting point for predicting whether microplastic are of concern. Bio-persistence, presence of reactive sites and soluble toxicants are likely key properties in microplastic toxicity, but these are not measured in environmental studies and hence are challenging to interpret in exposure. Data from a MP inhalation study in rats is available but the study was conducted using conditions that do not replicate the known human health effects of PM2.5 or surrogate exposures: compromised, aged animal models are recommended to investigate potential parallels between MPs and PM2.5. One of these parallels is provided by tire wear particles (TWP), which form part of current ambient PM and are sometimes regarded as microplastic. A connection to epidemiological studies where PM filters are still available is recommended and consequently analytical advances are required. In summary, established particle domains and existing paradigms provide valuable insight and data that can be used to predict MP toxicity, and direct study design and key properties to consider in this emerging field.

Inflammation as a Key Outcome Pathway in Particle Induced Effects in the Lung.

Inflammation is considered a key event in the pathology of many chronic diseases, including pulmonary and systemic particle induced effects. In addition, inflammation is now considered as the key response in standard setting for poorly-soluble low toxicity (PSLT) particles and also the critical endpoint to screen for in OECD based sub-chronic animal inhalation testing protocols. During Particles & Health 2021, an afternoon session was dedicated to the subject and a brief summary of the most important messages are summarized in this paper. In the first part of this session, two speakers (Prof. Lison and Dr Duffin) provided state of the art insight into different aspects and sequels to (persistent) inflammation as a protective or adverse response. Most recent insights on the role of different macrophage cell types were presented as well as perspectives and data provided by inflammatory pathways in humans, such as in asthma and COPD. A brief review of the expert workshop on PSLT particles focusing on the regulatory impact of using persistent inflammation as a key outcome was provided by Kevin Driscoll. The second part of the session focused on the outcomes that are associated with inflammation in animal studies, with an emphasis by Drs. Harkema (Michigan State) and Weber (Anapath) on cell proliferation and other pathologies that need to be considered when comparing human and animal responses, such as outcomes from 14- or 28 day inhalation studies used for specific target organ toxicity classification.

Optimised passive marker device visibility and automatic marker detection for 3-T MRI-guided endovascular interventions: a pulsatile flow phantom study.

BACKGROUND: Passive paramagnetic markers on magnetic resonance imaging (MRI)-compatible endovascular devices induce susceptibility artifacts, enabling MRI-visibility and real-time MRI-guidance. Optimised visibility is crucial for automatic detection and device tracking but depends on MRI technical parameters and marker characteristics. We assessed marker visibility and automatic detection robustness for varying MRI parameters and marker characteristics in a pulsatile flow phantom. METHODS: Guidewires with varying iron(II,III) oxide nanoparticle (IONP) concentration markers were imaged using gradient-echo (GRE) and balanced steady-state free precession (bSSFP) sequences at 3 T. Furthermore, echo time (TE), slice thickness (ST) and phase encoding direction (PED) were varied. Artifact width was measured and contrast-to-noise ratios were calculated. Marker visibility and image quality were scored by two MRI interventional radiologists. Additionally, a deep learning model for automatic marker detection was trained and the effects of the parameters on detection performance were evaluated. Two-tailed Wilcoxon signed-rank tests were used (significance level, p < 0.05). RESULTS: Medan artifact width (IQR) was larger in bSSFP compared to GRE images (12.7 mm (11.0-15.2) versus 8.4 mm (6.5-11.0)) (p < 0.001) and showed a positive relation with TE and IONP concentration. Switching PED and doubling ST had limited effect on artifact width. Image quality assessment scores were higher for GRE compared to bSSFP images. The deep learning model automatically detected the markers. However, the model performance was reduced after adjusting PED, TE, and IONP concentration. CONCLUSION: Marker visibility was sufficient and a large range of artifact sizes was generated by adjusting TE and IONP concentration. Deep learning-based marker detection was feasible but performance decreased for altered MR parameters. These factors should be considered to optimise device visibility and ensure reliable automatic marker detectability in MRI-guided endovascular interventions.

The parallels between particle induced lung overload and particle induced periprosthetic osteolysis (PPOL).

Background: When particles deposit for instance in the lung after inhalation or in the hip joint after local release from a hip implant material they can initiate a defense response. Even though these particles originate from inert materials such as polyethylene (PE) or titanium, they may cause harm when reaching high local doses and overwhelming local defense mechanisms. Main body: This paper describes the parallels between adverse outcome pathways (AOP) and particle properties in lung overload and periprosthetic osteolysis (PPOL). It is noted that in both outcomes in different organs , the macrophage and cytokine orchestrated persistent inflammation is the common driver of events, in the bone leading to loss of bone density and structure, and in the lung leading to fibrosis and cancer. Most evidence on lung overload and its AOP is derived from chronic inhalation studies in rats, and the relevance to man is questioned. In PPOL, the paradigms and metrics are based on human clinical data, with additional insights generated from in vitro and animal studies. In both organ pathologies the total volume of particle deposition has been used to set threshold values for the onset of pathological alterations. The estimated clinical threshold for PPOL of 130 mg/ml is much higher than the amount to cause lung overload in the rat (10 mg/ml),although the threshold in PPOL is not necessarily synonymous to particle overload. Conclusions: The paradigms developed in two very different areas of particle response in the human body have major similarities in their AOP. Connecting the clinical evidence in PPOL to lung overload challenges relevance of rat inhalation studies to the human lung cancer hazard. .

Expert workshop on the hazards and risks of poorly soluble low toxicity particles.

'Lung particle overload' refers to the impaired lung particle clearance and increased particle retention occurring with high lung doses of poorly soluble low toxicity (PSLT) particles. In rats, lung particle overload is associated with inflammation, epithelial hyperplasia, and, in extreme cases, lung cancer. While the human relevance of rat lung tumors occurring under overload has been questioned, recent regulatory decisions have considered these outcomes evidence of possible human hazard. To better understand the state-of-the-science on PSLT toxicology, an Expert Workshop was held to document agreements and differences amongst a panel of highly experienced scientists and regulators. Key outcomes included: a functional definition of PSLTs; agreement the rat is a sensitive model for PSLT inhalation toxicology; identifying lung inflammation as a critical endpoint for PSLT risk assessment; and, agreement rat lung cancer occurring only under conditions of lung particle overload does not imply a cancer hazard for humans under non-overloading exposures. Moreover, when asked - should PSLTs be considered as human lung carcinogens based on rat data alone (and no supporting data from other species), the expert consensus was: 'No. However, the experts noted the current default regulatory position on rat lung overload data alone would be the suspicion of human carcinogen hazard.' The many areas of the expert agreement provide guidance for design, interpretation, and extrapolating PSLT inhalation toxicology studies. Considering the workshop outcomes, the authors recommend guidelines for evaluation and classification of PSLT be reassessed; and, prior decisions on PSLT hazard classification be revisited to determine if they remain appropriate.

The hazards and risks of inhaled poorly soluble particles - where do we stand after 30 years of research?

BACKGROUND: In 2006, titanium dioxide and carbon black were classified by IARC as "possibly carcinogenic to humans" and in 2017 the European Chemicals Agency's (ECHA) Committee for Risk Assessment concluded titanium dioxide meets the criteria to be classified as suspected of causing cancer (category 2, through the inhalation route). These classifications were based primarily on the occurrence of lung cancer in rats exposed chronically to high concentrations of these materials, as no such responses have been observed in other animal species similarly exposed. After the EU classification of titanium dioxide, it was suggested that Poorly Soluble particles of Low Toxicity (PSLTs) can be evaluated as a group. MAIN BODY: To better understand the current state of scientific opinion, we sought perspective from several international experts on topics relevant to the classification of carbon black; titanium dioxide; and, the potential future classification of PSLTs. Areas discussed included: grouping of PSLTs; the relevance of rat lung cancer responses to high concentrations of PSLTs; and, clearance overload and implications for interpretation of inhalation toxicology studies. We found there were several areas where a large majority of experts, including ourselves, agreed. These included concerns on the grouping of PSLT and the definition of clearance overload. Regarding the extrapolation of PSLT associated lung cancer in rats there were some strongly held differences, although most experts questioned the relevance when excessive exposures which overwhelm lung clearance were required. SHORT CONCLUSION: Given the ongoing discussion on PSLT classification and safety, we believe it is important to re-activate the public debate including experts and stakeholders. Such an open discussion would serve to formally document where scientific consensus and differences exist. This could form the basis for design of future safety programs and safety assessments.

Labeling of Collagen Type I Templates with a Naturally Derived Contrast Agent for Noninvasive MR Imaging in Soft Tissue Engineering.

In vivo monitoring of tissue-engineered constructs is important to assess their integrity, remodeling, and degradation. However, this is challenging when the contrast with neighboring tissues is low, necessitating labeling with contrast agents (CAs), but current CAs have limitations (i.e., toxicity, negative contrast, label instability, and/or inappropriate size). Therefore, a naturally derived hemin-L-lysine (HL) complex is used as a potential CA to label collagen-based templates for magnetic resonance imaging (MRI). Labeling does not change the basic characteristics of the collagen templates. When hybrid templates composed of collagen type I reinforced with degradable polymers are subcutaneously implanted in mice, longitudinal visualization by MRI is possible with good contrast and in correlation with template remodeling. In contrast, unlabeled collagen templates are hardly detectable and the fate of these templates cannot be monitored by MRI. Interestingly, tissue remodeling and vascularization are enhanced within HL-labeled templates. Thus, HL labeling is presented as a promising universal imaging marker to label tissue-engineered implants for MRI, which additionally seems to accelerate tissue regeneration.

An updated review of the genotoxicity of respirable crystalline silica.

Human exposure to (certain forms of) crystalline silica (CS) potentially results in adverse effects on human health. Since 1997 IARC has classified CS as a Group 1 carcinogen [1], which was confirmed in a later review in 2012 [2]. The genotoxic potential and mode of genotoxic action of CS was not conclusive in either of the IARC reviews, although a proposal for mode of actions was made in an extensive review of the genotoxicity of CS by Borm, Tran and Donaldson in 2011 [3]. The present study identified 141 new papers from search strings related to genotoxicity of respirable CS (RCS) since 2011 and, of these, 17 relevant publications with genotoxicity data were included in this detailed review.Studies on in vitro genotoxic endpoints primarily included micronucleus (MN) frequency and % fragmented DNA as measured in the comet assay, and were mostly negative, apart from two studies using primary or cultured macrophages. In vivo studies confirmed the role of persistent inflammation due to quartz surface toxicity leading to anti-oxidant responses in mice and rats, but DNA damage was only seen in rats. The role of surface characteristics was strengthened by in vitro and in vivo studies using aluminium or hydrophobic treatment to quench the silanol groups on the CS surface.In conclusion, the different modes of action of RCS-induced genotoxicity have been evaluated in a series of independent, adequate studies since 2011. Earlier conclusions on the role of inflammation driven by quartz surface in genotoxic and carcinogenic effects after inhalation are confirmed and findings support a practical threshold. Whereas classic in vitro genotoxicity studies confirm an earlier no-observed effect level (NOEL) in cell cultures of 60-70 µg/cm2, transformation frequency in SHE cells suggests a lower threshold around 5 µg/cm2. Both levels are only achieved in vivo at doses (2-4 mg) beyond in vivo doses (> 200 µg) that cause persistent inflammation and tissue remodelling in the rat lung.

Silica-induced NLRP3 inflammasome activation in vitro and in rat lungs.

RATIONALE: Mineral particles in the lung cause inflammation and silicosis. In myeloid and bronchial epithelial cells the inflammasome plays a role in responses to crystalline silica. Thioredoxin (TRX) and its inhibitory protein TRX-interacting protein link oxidative stress with inflammasome activation. We investigated inflammasome activation by crystalline silica polymorphs and modulation by TRX in vitro, as well as its localization and the importance of silica surface reactivity in rats. METHODS: We exposed bronchial epithelial cells and differentiated macrophages to silica polymorphs quartz and cristobalite and measured caspase-1 activity as well as the release of IL-1ß, bFGF and HMGB1; including after TRX overexpression or treatment with recombinant TRX. Rats were intratracheally instilled with vehicle control, Dörentruper quartz (DQ12) or DQ12 coated with polyvinylpyridine N-oxide. At days 3, 7, 28, 90, 180 and 360 five animals per treatment group were sacrificed. Hallmarks of silicosis were assessed with Haematoxylin-eosin and Sirius Red stainings. Caspase-1 activity in the bronchoalveolar lavage and caspase-1 and IL-1ß localization in lung tissue were determined using Western blot and immunohistochemistry (IHC). RESULTS: Silica polymorphs triggered secretion of IL-1ß, bFGF and HMGB1 in a surface reactivity dependent manner. Inflammasome readouts linked with caspase-1 enzymatic activity were attenuated by TRX overexpression or treatment. At day 3 and 7 increased caspase-1 activity was detected in BALF of the DQ12 group and increased levels of caspase-1 and IL-1ß were observed with IHC in the DQ12 group compared to controls. DQ12 exposure revealed silicotic nodules at 180 and 360 days. Particle surface modification markedly attenuated the grade of inflammation and lymphocyte influx and attenuated the level of inflammasome activation, indicating that the development of silicosis and inflammasome activation is determined by crystalline silica surface reactivity. CONCLUSION: Our novel data indicate the pivotal role of surface reactivity of crystalline silica to activate the inflammasome in cultures of both epithelial cells and macrophages. Inhibitory capacity of the antioxidant TRX to inflammasome activation was evidenced. DQ12 quartz exposure induced acute and chronic functional activation of the inflammasome in the heterogeneous cell populations of the lung in associated with its crystalline surface reactivity.

The carcinogenic action of crystalline silica: a review of the evidence supporting secondary inflammation-driven genotoxicity as a principal mechanism.

In 1987 the International Agency for Research on Cancer (IARC) classified crystalline silica (CS) as a probable carcinogen and in 1997 reclassified it as a Group 1 carcinogen, i.e., that there was sufficient evidence for carcinogenicity in experimental animals and sufficient evidence for carcinogenicity in humans. The Working Group noted that "carcinogenicity in humans was not detected in all industrial circumstances studied, carcinogenicity may be dependent on inherent characteristics of the crystalline silica or on external factors affecting its biological activity or distribution of its polymorphs." This unusual statement that the physicochemical form of the CS influences its carcinogenicity is well understood at the toxicological level and arises as a consequence of the fact that CS activity depends on the reactivity of the CS surface, which can be blocked by a number of agents. We reviewed the literature on CS genotoxicity that has been published since the 1997 monograph, with special reference to the mechanism of CS genotoxicity. The mechanism of CS genotoxicity can be primary, a result of direct interaction of CS with target cells, or indirect, as a consequence of inflammation elicited by quartz, where the inflammatory cell-derived oxidants cause the genotoxicity. The review revealed a number of papers supporting the hypothesis that the CS genotoxic and inflammatory hazard is a variable one. In an attempt to attain a quantitative basis for the potential mechanism, we carried out analysis of published data and noted a 5-fold greater dose required to reach a threshold for genotoxic effects than for proinflammatory effects in the same cell line in vitro. When we related the calculated threshold dose at the proximal alveolar region for inflammation in a published study with the threshold dose for genotoxicity in vitro, we noted that a 60-120-fold greater dose was required for direct genotoxic effects in vitro. These data strongly suggests that inflammation is the driving force for genotoxicity and that primary genotoxicity of deposited CS would play a role only at very high, possibly implausible, exposures and deposited doses. Although based on rat studies and in vitro studies, and therefore with caveats, the analysis supports the hypothesis that the mechanism of CS genotoxicity is via inflammation-driven secondary genotoxicity. This may have implications for setting of the CS standard in workplaces. During the writing of this review (in May 2009), IARC undertook a review of carcinogenic substances, including CS. The Working Group met to reassess 10 separate agents including CS. This was not a normal monograph working group published as a large single monograph, but was published as a two-page report. This review group reaffirmed the carcinogenicity of "silica dust, crystalline in the form of quartz or cristobalite" as a Group 1 agent, with the lung as the sole tumor site. Of special relevance to the present review is that the cited "established mechanism events" for CS are restricted to the words "impaired particle clearance leading to macrophage activation and persistent inflammation." The lack of mention of direct genotoxicity is in line with the conclusions reached in the present review.

Elemental composition and oxidative properties of PM(2.5) in Estonia in relation to origin of air masses - results from the ECRHS II in Tartu.

Fine particulate matter (PM(2.5)) was sampled at an urban background site in Tartu, Estonia over one-year period during the ECRHS II study. The elemental composition of 71 PM(2.5) samples was analyzed for different chemical elements using energy-dispersive X-ray fluorescence spectrometry (ED-XRF). The oxidative activity of 36 samples was assessed by measuring their ability to generate hydroxyl radicals in the presence of hydrogen peroxide. The origin of air masses was determined by computing 96-hour back trajectories of air masses with the HYSPLIT Model. The trajectories of air masses were divided into four sectors according to geographical patterns: "Russia," "Eastern Europe," "Western Europe," and "Scandinavia." During the study period, approximately 30% of air masses originated from "Scandinavia." The other three sectors had slightly lower values (between 18 and 22%). In spring, summer, and winter, higher total PM levels originated from air masses from continental areas, namely "Russia" and "Eastern Europe" (18.51+/-7.33 and 19.96+/-9.23microg m(-3), respectively). In autumn, the PM levels were highest in "Western Europe". High levels of Fe, Ti, and AlCaSi (Al, Ca, and Si) were also detected in air masses from the Eurasian continent. The oxidative properties were correlated to the origin of air masses. The OH values were approximately 1.5 times higher when air masses originated from the direction of "Eastern Europe" or "Russia." The origin of measured particles was evaluated using principal component factor analysis. When comparing the PM(2.5) elemental composition with seasonal variation, factor scores, and other studies, the factors represent: (1) combustion of biomass; (2) crustal dust; (3) traffic; and (4) power plants and industrial processes associated with oil burning. The total PM(2.5) is driven mainly by biomass and industrial combustion (63%) and other unidentified sources (23%). Other sources of PM, such as crustal dust and traffic, contribute a total of 13%.

Increased micronucleus frequencies in surrogate and target cells from workers exposed to crystalline silica-containing dust.

Mining, crushing, grinding, sandblasting and construction are high-risk activities with regard to crystalline silica exposure, especially in developing countries. Respirable crystalline silica (quartz and cristobalite) inhaled from occupational sources has been reclassified as a human carcinogen in 1997 by the International Agency for Research on Cancer. However, the biological activity of crystalline silica has been found to be variable among different industries, and this has formed the basis for further in vivo/in vitro mechanistic research and epidemiologic studies. This study was conducted for genotoxicity evaluation in a population of workers (e.g. glass industry workers, sandblasters, and stone grinders) mainly exposed to crystalline silica in four different workplaces in Turkey. The micronucleus (MN) assay was applied both in peripheral blood lymphocytes (PBL) as a surrogate tissue and in nasal epithelial cells (NEC) as a target tissue of the respiratory tract. Our study revealed significantly higher MN frequencies in the workers (n = 50) versus the control group (n = 29) (P < 0.001) and indicated a significant effect of occupational exposure on MN induction in both of the tissues. For the NEC target tissue, the difference in MN frequencies between the workers and control group was 3-fold, whereas in peripheral tissue, it was 2-fold. Respirable dust and crystalline silica levels exceeding limit values and mineralogical/elemental dust composition of the dust of at least 70% SiO(2) were used as markers of crystalline silica exposure in each of the workplaces. Moreover, 24% of the current workers were found to have early radiographical changes (profusion category of 1). In conclusion, although the PBL are not primary target cells for respiratory particulate toxicants, an evident increase in MN frequencies in this surrogate tissue was observed, alongside with a significant increase in NEC and may be an indicator of the accumulated genetic damage associated with crystalline silica exposure.

Associations of urban air particulate composition with inflammatory and cytotoxic responses in RAW 246.7 cell line.

Epidemiological studies show heterogeneities in the particulate pollution-related exposure-effect relationships among cardiorespiratory patients, but the connection to chemical composition and toxic properties of the inhaled particles is largely unknown. To identify the chemical constituents and sources responsible for the diverse inflammatory and cytotoxic effects of urban air, fine (PM(2.5-0.2)) and coarse (PM(10-2.5)) particulate samples were collected during contrasting air pollution situations. We exposed mouse RAW 246.7 macrophages for 24 hrs to PM(2.5-0.2) and PM(10-2.5) samples from six European cities. The concentrations of proinflammatory cytokines (IL-6, TNFalpha), chemokine (MIP-2), and nitric oxide were measured from the cell culture medium, and the cytotoxicity was assayed. Spearman's correlations between the chemical constituents and cellular responses were analyzed. In the PM(2.5-0.2) size range, the tracers of photo-oxidation of organics in the atmosphere (oxalate, succinate, malonate), some transition metals (Ni, V, Fe, Cu, Cr), and insoluble soil constituents (Ca, Al, Fe, Si) correlated positively with the response parameters. In contrast, the tracers of incomplete biomass (monosaccharide anhydrides) and coal (As) combustion, and polycyclic aromatic hydrocarbons (PAHs), had negative correlations with the inflammatory activity. The compositions of PM(10-2.5) samples were more uniform and there were only occasional high correlations between the chemical constituents, endotoxin, and the response parameters. The present results suggest that the local sources of incomplete combustion and resuspended road dust are important producers of harmful fine particulate constituents that may, however, operate via diverse toxicity mechanisms. The results agree well with our recent findings in the mouse lung.

Particle induced toxicity in relation to transition metal and polycyclic aromatic hydrocarbon contents.

Exposure to ambient particulate matter (PM) is statistically significantly associated with morbidity and mortality. The objectives of this study were (a) to investigate in vivo pulmonary and systemic cytotoxicity and inflammatory activity in compromised animals exposed to PM and (b) to investigate the relationships of the outcomes to the chemical compositions of particular polycyclic aromatic hydrocarbons (PAH) and transition metals in the PM. The PM samples were collected in European cities representing contrasting situations. Exposure of spontaneously hypertensive rats (7 mg of PM/kg) resulted in pulmonary inflammation, cellular toxicity and the induction of blood fibrinogen. Coarse PM generally caused stronger effects per mg than fine particles. Positive correlations between lactate dehydrogenase, proteins, and some inflammation parameters and the particle metal and PAH content were found. PM rich in PAH also led to increased blood fibrinogen. Removal of particles but not the organics (i.e., PAH) of a sample led to reduced inflammation in the lungs. The present study highlights the importance of metals as well as PM-bound PAH in particle biological outcomes. It supports the hypothesis that, on an equal mass basis, particle health effects differ due to differences in compositions and size.

Expert elicitation on ultrafine particles: likelihood of health effects and causal pathways.

BACKGROUND: Exposure to fine ambient particulate matter (PM) has consistently been associated with increased morbidity and mortality. The relationship between exposure to ultrafine particles (UFP) and health effects is less firmly established. If UFP cause health effects independently from coarser fractions, this could affect health impact assessment of air pollution, which would possibly lead to alternative policy options to be considered to reduce the disease burden of PM. Therefore, we organized an expert elicitation workshop to assess the evidence for a causal relationship between exposure to UFP and health endpoints. METHODS: An expert elicitation on the health effects of ambient ultrafine particle exposure was carried out, focusing on: 1) the likelihood of causal relationships with key health endpoints, and 2) the likelihood of potential causal pathways for cardiac events. Based on a systematic peer-nomination procedure, fourteen European experts (epidemiologists, toxicologists and clinicians) were selected, of whom twelve attended. They were provided with a briefing book containing key literature. After a group discussion, individual expert judgments in the form of ratings of the likelihood of causal relationships and pathways were obtained using a confidence scheme adapted from the one used by the Intergovernmental Panel on Climate Change. RESULTS: The likelihood of an independent causal relationship between increased short-term UFP exposure and increased all-cause mortality, hospital admissions for cardiovascular and respiratory diseases, aggravation of asthma symptoms and lung function decrements was rated medium to high by most experts. The likelihood for long-term UFP exposure to be causally related to all cause mortality, cardiovascular and respiratory morbidity and lung cancer was rated slightly lower, mostly medium. The experts rated the likelihood of each of the six identified possible causal pathways separately. Out of these six, the highest likelihood was rated for the pathway involving respiratory inflammation and subsequent thrombotic effects. CONCLUSION: The overall medium to high likelihood rating of causality of health effects of UFP exposure and the high likelihood rating of at least one of the proposed causal mechanisms explaining associations between UFP and cardiac events, stresses the importance of considering UFP in future health impact assessments of (transport-related) air pollution, and the need for further research on UFP exposure and health effects.

MR-compatible polyetheretherketone-based guide wire assisting MR-guided stenting of iliac and supraaortic arteries in swine: feasibility study.

The purpose of this study was to demonstrate first magnetic resonance (MR)-guided stenting of iliac and supraaortic arteries using a polyetheretherketone-based (PEEK) MR-compatible guide wire. In vitro and animal experiments were performed in a short magnet wide-bore scanner (1.5 Tesla, Espree, Siemens Healthcare, Erlangen, Germany). For all experiments, a 0.035'' MR-compatible guide wire prototoype was used. This wire had a compound core of PEEK with reinforcing fibres, a soft and atraumatic tip and a hydrophilic coating. For its passive visualization, paramagnetic markings were attached. All experiments were performed through a vascular introducer sheath under MR-guidance. In vitro repetitive selective over the wire catheterizations of either the right carotid artery and the left subclavian artery were performed. In vivo, selective catheterization and over-the-wire stenting of the brachiocephalic trunk and the left subclavian artery were performed. The common iliac arteries were catheterized retrogradely (left) and cross-over (right). Angioplasty and stenting were performed over-the-wire. All procedures were successful. Visibility of the PEEK-based guide-wire was rated good in vitro and acceptable in vivo. Guide wire pushability and endovascular device support were good. The PEEK-based MR-compatible guide wire is well visible and usable under MR-guidance. It supports over-the-wire treatment of iliac arteries and supraaortic arteries.

Feasibility of real-time magnetic resonance-guided angioplasty and stenting of renal arteries in vitro and in Swine, using a new polyetheretherketone-based magnetic resonance-compatible guidewire.

OBJECTIVES: Demonstrate the usability of a new polyetheretherketone (PEEK)-based MR-compatible guidewire for renal artery catheterization, angioplasty, and stenting under MR-guidance using MR-visible markers, in vitro and in vivo. MATERIAL AND METHODS: The new 0.035'' guidewire with fiber-reinforced PEEK core, a soft tip, and a hydrophilic coating was used. Paramagnetic markings were coated on the wire and nonbraided catheters for passive visualization. Bending stiffness of the guidewire was compared with available hydrophilic guidewires (Terumo Glidewire Stiff and Standard). A human aortic silicon phantom and 2 pigs were used. The study was animal care and use approved by the committee. Under MR-guidance, renal arteries were catheterized, balloon angioplasty was performed, and balloon expandable renal artery stents were deployed in vivo. Post mortem autopsy was performed. Guidewire visibility, pushability, steerability, and device-support capabilities of the marked guidewire were qualitatively assessed. Procedure times were recorded. RESULTS: Bending stiffness of the new PEEK-based wire was comparable with Standard Glidewire. In vitro and in vivo guidewire guidance, catheter configuration, renal artery catheterization, and balloon angioplasty were successful. In pigs, stent deployments were successful in both renal arteries. Autopsy revealed acceptable stent positioning. Guidewire visibility through applied markers was acceptable. Steerability, pushability, and device support were good in vitro and in vivo. CONCLUSIONS: The PEEK-based guide allows percutaneous MR-guided renal artery angioplasty and stenting with sufficient visibility, good steerability, pushability, and device support.

First magnetic resonance imaging-guided aortic stenting and cava filter placement using a polyetheretherketone-based magnetic resonance imaging-compatible guidewire in swine: proof of concept.

The purpose of this study was to demonstrate feasibility of percutaneous transluminal aortic stenting and cava filter placement under magnetic resonance imaging (MRI) guidance exclusively using a polyetheretherketone (PEEK)-based MRI-compatible guidewire. Percutaneous transluminal aortic stenting and cava filter placement were performed in 3 domestic swine. Procedures were performed under MRI-guidance in an open-bore 1.5-T scanner. The applied 0.035-inch guidewire has a PEEK core reinforced by fibres, floppy tip, hydrophilic coating, and paramagnetic markings for passive visualization. Through an 11F sheath, the guidewire was advanced into the abdominal (swine 1) or thoracic aorta (swine 2), and the stents were deployed. The guidewire was advanced into the inferior vena cava (swine 3), and the cava filter was deployed. Postmortem autopsy was performed. Procedural success, guidewire visibility, pushability, and stent support were qualitatively assessed by consensus. Procedure times were documented. Guidewire guidance into the abdominal and thoracic aortas and the inferior vena cava was successful. Stent deployments were successful in the abdominal (swine 1) and thoracic (swine 2) segments of the descending aorta. Cava filter positioning and deployment was successful. Autopsy documented good stent and filter positioning. Guidewire visibility through applied markers was rated acceptable for aortic stenting and good for venous filter placement. Steerability, pushability, and device support were good. The PEEK-based guidewire allows either percutaneous MRI-guided aortic stenting in the thoracic and abdominal segments of the descending aorta and filter placement in the inferior vena cava with acceptable to good device visibility and offers good steerability, pushability, and device support.