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Background There is a steadily increasing quantity of silver nanoparticles (AgNP) produced for numerous industrial, medicinal and private purposes, leading to an increased risk of inhalation exposure for both professionals and consumers. Particle inhalation can result in inflammatory and allergic responses, and there are concerns about other negative health effects from either acute or chronic low-dose exposure. Results To study the fate of inhaled AgNP, healthy adult rats were exposed to 11/2-hour intra-tracheal inhalations of pristine Ag-105-radiolabeled, 20 nm AgNP aerosols (with mean doses across all rats of each exposure group of deposited NP-mass and NP-number being 13.5 +/- 3.6 mu g, 7.9 +/- 3.2 center dot 10(11), respectively). At five time-points (0.75 h, 4 h, 24 h, 7d, 28d) post-exposure (p.e.), a complete balance of the [Ag-105]AgNP fate and its degradation products were quantified in organs, tissues, carcass, lavage and body fluids, including excretions. Rapid dissolution of [Ag-105]Ag-ions from the [Ag-105]AgNP surface was apparent together with both fast particulate airway clearance and long-term particulate clearance from the alveolar region to the larynx. The results are compatible with evidence from the literature that the released [Ag-105]Ag-ions precipitate rapidly to low-solubility [Ag-105]Ag-salts in the ion-rich epithelial lining lung fluid (ELF) and blood. Based on the existing literature, the degradation products rapidly translocate across the air-blood-barrier (ABB) into the blood and are eliminated via the liver and gall-bladder into the small intestine for fecal excretion. The pathway of [Ag-105]Ag-salt precipitates was compatible with auxiliary biokinetics studies at 24 h and 7 days after either intravenous injection or intratracheal or oral instillation of [Ag-110m]AgNO3 solutions in sentinel groups of rats. However, dissolution of [Ag-105]Ag-ions appeared not to be complete after a few hours or days but continued over two weeks p.e. This was due to the additional formation of salt layers on the [Ag-105]AgNP surface that mediate and prolonge the dissolution process. The concurrent clearance of persistent cores of [Ag-105]AgNP and [Ag-105]Ag-salt precipitates results in the elimination of a fraction > 0.8 (per ILD) after one week, each particulate Ag-species accounting for about half of this. After 28 days p.e. the cleared fraction rises marginally to 0.94 while 2/3 of the remaining [Ag-105]AgNP are retained in the lungs and 1/3 in secondary organs and tissues with an unknown partition of the Ag species involved. However, making use of our previous biokinetics studies of poorly soluble [Au-195]AuNP of the same size and under identical experimental and exposure conditions (Kreyling et al., ACS Nano 2018), the kinetics of the ABB-translocation of [Ag-105]Ag-salt precipitates was estimated to reach a fractional maximum of 0.12 at day 3 p.e. and became undetectable 16 days p.e. Hence, persistent cores of [Ag-105]AgNP were cleared throughout the study period. Urinary [Ag-105]Ag excretion is minimal, finally accumulating to 0.016.Conclusion The biokinetics of inhaled [Ag-105]AgNP is relatively complex since the dissolving [Ag-105]Ag-ions (a) form salt layers on the [Ag-105]AgNP surface which retard dissolution and (b) the [Ag-105]Ag-ions released from the [Ag-105]AgNP surface form poorly-soluble precipitates of [Ag-105]Ag-salts in ELF. Therefore, hardly any [Ag-105]Ag-ion clearance occurs from the lungs but instead [Ag-105]AgNP and nano-sized precipitated [Ag-105]Ag-salt are cleared via the larynx into GIT and, in addition, via blood, liver, gall bladder into GIT with one common excretional pathway via feces out of the body.

Background: A rich literature exists that has demonstrated adverse human health effects following exposure to ambient air particulate matter (PM), with strong support for an important role for ultrafine (nano-sized) particles. At present, relatively little human health or epidemiology data exists for engineered nanomaterials (NM) despite clear parallels in their physicochemical properties and biological actions in in vitro models. Objectives: NMs are available in a range of physicochemical characteristics which allow a more systematic toxicological analysis. Therefore, the study of ultrafine particles (UFP

Toxicological studies have provided evidence of the toxicity of ultrafine particles (UFP), but epidemiological evidence for health effects of ultrafines is limited. No quantitative summary currently exists of concentration-response functions for ultrafine particles that can be used in health impact assessment. The goal was to specify concentration-response functions for ultrafine particles in urban air including their uncertainty through an expert panel elicitation. Eleven European experts from the disciplines of epidemiology, toxicology, and clinical medicine selected using a systematic peer-nomination procedure participated. Using individual ratings supplemented with group discussion, probability distributions of effect estimates were obtained for all-cause mortality and cardiovascular and respiratory hospital admissions. Experts judged the small database of epidemiological studies supplemented with experimental studies sufficient to quantify effects of UFP on all-cause mortality and to a lesser extent hospital admissions. Substantial differences in the estimated UFP health effect and its uncertainty were found between experts. The lack of studies on long-term exposure to UFP was rated as the most important source of uncertainty. Effects on hospital admissions were considered more uncertain. This expert elicitation provides the first quantitative evaluation of estimates of concentration response functions between urban air ultrafine particles and all-cause mortality and hospital admissions.

Industrially manufactured titanium dioxide nanoparticles have been successfully radiolabelled with V-48 by irradiation with a cyclotron-generated proton beam. Centrifugation tests showed that the V-48 radiolabels were stably bound within the nanoparticle structure in an aqueous medium, while X-ray diffraction indicated that no major structural modifications to the nanoparticles resulted from the proton irradiation. In vitro tests of the uptake of cold and radiolabelled nanoparticles using the human cell line Calu-3 showed no significant difference in the uptake between both batches of nanoparticles. The uptake was quantified by Inductively Coupled Plasma Mass Spectrometry and high resolution gamma-ray spectrometry for cold and radiolabelled nanoparticles, respectively. These preliminary results indicate that alterations to the nanoparticles' properties introduced by proton bombardment can be controlled to a sufficient extent that their further use as radiotracers for biological investigations can be envisaged and elaborated.

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 peernomination 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.

BACKGROUND: Ambient particulate matter (PM)-associated metals have been shown to play an important role in cardiopulmonary health outcomes. To study the modulation of PM-induced inflammation by leached off metals, we investigated intracellular solubility of radio-labeled iron oxide ((59)Fe(2)O(3)) particles of 0.5 and 1.5 mum geometric mean diameter. Fe(2)O(3 )particles were examined for the induction of the release of interleukin 6 (IL-6) as pro-inflammatory and prostaglandin E(2 )(PGE(2)) as anti-inflammatory markers in cultured alveolar macrophages (AM) from Wistar Kyoto (WKY) rats. In addition, we exposed male WKY rats to monodispersed Fe(2)O(3 )particles by intratracheal instillation (1.3 or 4.0 mg/kg body weight) to examine in vivo inflammation. RESULTS: Particles of both sizes are insoluble extracellularly in the media but moderately soluble in AM with an intracellular dissolution rate of 0.0037 +/- 0.0014 d(-1 )for 0.5 mum and 0.0016 +/- 0.0012 d(-1 )for 1.5 mum (59)Fe(2)O(3 )particles. AM exposed in vitro to 1.5 mum particles (10 mug/mL) for 24 h increased IL-6 release (1.8-fold; p < 0.05) and also PGE(2 )synthesis (1.9-fold; p < 0.01). By contrast, 0.5 mum particles did not enhance IL-6 release but strongly increased PGE(2 )synthesis (2.5-fold, p < 0.005). Inhibition of PGE(2 )synthesis by indomethacin caused a pro-inflammatory phenotype as noted by increased IL-6 release from AM exposed to 0.5 mum particles (up to 3-fold; p < 0.005). In the rat lungs, 1.5 but not 0.5 mum particles (4.0 mg/kg) induced neutrophil influx and increased vascular permeability. CONCLUSIONS: Fe(2)O(3 )particle-induced neutrophilic inflammatory response in vivo and pro-inflammatory cytokine release in vitro might be modulated by intracellular soluble iron via PGE(2 )synthesis. The suppressive effect of intracellular released soluble iron on particle-induced inflammation has implications on how ambient PM-associated but soluble metals influence pulmonary toxicity of ambient PM.

During the last few years, research on toxicologically relevant properties of engineered nanoparticles has increased tremendously. A number of international research projects and additional activities are ongoing in the EU and the US, nourishing the expectation that more relevant technical and toxicological data will be published. Their widespread use allows for potential exposure to engineered nanoparticles during the whole lifecycle of a variety of products. When looking at possible exposure routes for manufactured Nanoparticles, inhalation, dermal and oral exposure are the most obvious, depending on the type of product in which Nanoparticles are used. This review shows that (1) Nanoparticles can deposit in the respiratory tract after inhalation. For a number of nanoparticles, oxidative stress-related inflammatory reactions have been observed. Tumour-related effects have only been observed in rats, and might be related to overload conditions. There are also a few reports that indicate uptake of nanoparticles in the brain via the olfactory epithelium. Nanoparticle translocation into the systemic circulation may occur after inhalation but conflicting evidence is present on the extent of translocation. These findings urge the need for additional studies to further elucidate these findings and to characterize the physiological impact. (2) There is currently little evidence from skin penetration studies that dermal applications of metal oxide nanoparticles used in sunscreens lead to systemic exposure. However, the question has been raised whether the usual testing with healthy, intact skin will be sufficient. (3) Uptake of nanoparticles in the gastrointestinal tract after oral uptake is a known phenomenon, of which use is intentionally made in the design of food and pharmacological components. Finally, this review indicates that only few specific nanoparticles have been investigated in a limited number of test systems and extrapolation of this data to other materials is not possible. Air pollution studies have generated indirect evidence for the role of combustion derived nanoparticles (CDNP) in driving adverse health effects in susceptible groups. Experimental studies with some bulk nanoparticles (carbon black, titanium dioxide, iron oxides) that have been used for decades suggest various adverse effects. However, engineered nanomaterials with new chemical and physical properties are being produced constantly and the toxicity of these is unknown. Therefore, despite the existing database on nanoparticles, no blanket statements about human toxicity can be given at this time. In addition, limited ecotoxicological data for nanomaterials precludes a systematic assessment of the impact of Nanoparticles on ecosystems.

In connection with the pending amendment of threshold values for airborne particles in ambient air of the European Union, a working group of the Commission on Air Pollution Prevention of VDI and DIN has critically reviewed the actual data on exposure and health effects of fine particulate matter. The limit values to be met by January 2005 are exceeded at certain measuring points influenced by traffic. PM2.5 exposure can be estimated only roughly due to the few measuring points available. The ratio PM10/PM 2.5 amounts generally to 0.8 - 0.9. There are only occasional data on ultra-fine particles (< 0.1 m) available. During the past 10 years a great number of new toxicological and epidemiological studies on health effects of particular matter have been published. They are critically reviewed in this report. Several large population studies demonstrate clear associations between certain health indicators and PM the association being stronger for finer particles. Time se ries studies show significant associations between the exposure to fine particles on one hand and cardiovascular and respiratory mortality and morbidity on the other hand. The epidemiological studies do not permit an estimation of a threshold value for health effects. The working group concludes that a further reduction of the limit values will significantly reduce health risks due to particulate air pollution. Because of the strong correlation between PM10 and PM2.5 at most European sites there is no need for special limit values regarding PM2.5.

Intracellular dissolution of inhaled particles is an important pathway of clearance of potentially toxic materials. To study this process, monolayers of human and canine alveolar macrophages (AM) were maintained alive and functional in vitro for more than 2 wk. Complete phagocytosis of moderately soluble, monodisperse 57Co3O4 test particles of four different sizes was obtained by optimizing the cell density of the monolayer and the particle-to-cell ratio. The fraction of the initial particle mass that was soluble increased over time when the particles were ingested by AM but remained constant when in culture medium alone. Smaller particle sizes had a faster characteristic intracellular dissolution rate constant than did larger particles. The dissolution rates differed between AM obtained from two human volunteers as compared to those obtained from six mongrel dogs. These in vitro dissolution rates were very similar to in vivo translocation rates previously obtained from human and canine lung clearance studies after inhalation of the same or similar monodisperse, homogeneous 57Co3O4 test particles. We believe an important clearance mechanism for inhaled aerosol particles deposited in the lungs can be simulated in vitro in a cell culture system.