Modelled lung deposition and retention of welding fume particles in occupational scenarios: a comparison to doses used in vitro.

Translating particle dose from in vitro systems to relevant human exposure remains a major challenge for the use of in vitro studies in assessing occupational hazard and risk of particle exposure. This study aimed to model the lung deposition and retention of welding fume particles following occupational scenarios and subsequently compare the lung doses to those used in vitro. We reviewed published welding fume concentrations and size distributions to identify input values simulating real-life exposure scenarios in the multiple path particle dosimetry (MPPD) model. The majority of the particles were reported to be below 0.1 µm and mass concentrations ranged between 0.05 and 45 mg/m3. Following 6-h exposure to 5 mg/m3 with a count median diameter of 50 nm, the tracheobronchial lung dose (0.89 µg/cm2) was found to exceed the in vitro cytotoxic cell dose (0.125 µg/cm2) previously assessed by us in human bronchial epithelial cells (HBEC-3kt). However, the tracheobronchial retention decreased rapidly when no exposure occurred, in contrast to the alveolar retention which builds-up over time and exceeded the in vitro cytotoxic cell dose after 1.5 working week. After 1 year, the tracheobronchial and alveolar retention was estimated to be 1.15 and 2.85 µg/cm2, respectively. Exposure to low-end aerosol concentrations resulted in alveolar retention comparable to cytotoxic in vitro dose in HBEC-3kt after 15-20 years of welding. This study demonstrates the potential of combining real-life exposure data with particle deposition modelling to improve the understanding of in vitro concentrations in the context of human occupational exposure.

Gold Nanoparticles Dissolve Extracellularly in the Presence of Human Macrophages.

INTRODUCTION: Gold nanoparticles (AuNPs) have the potential to be used in various biomedical applications, partly due to the inertness and stability of gold. Upon intravenous injection, the NPs interact with the mononuclear phagocyte system, first with monocytes in the blood and then with macrophages in tissue. The NP-macrophage interaction will likely affect the stability of the AuNPs, but this is seldom analyzed. This study aimed to elucidate the role of macrophages in the biodissolution of AuNPs and underlying mechanisms. METHODS: With an in vitro dissolution assay, we used inductively coupled plasma mass spectrometry to quantitatively compare the dissolution of 5 and 20 nm AuNPs coated with citrate or PEG in cell medium alone or in the presence of THP1-derived macrophages at 24 hours. In addition, we analyzed the cell dose, compared extra- and intracellular dissolution, and explored the possible role of reactive nitrogen species. RESULTS: The results showed a higher cellular dose of the citrate-coated AuNPs, but dissolution was mainly evident for those sized 5 nm, irrespective of coating. The macrophages clearly assisted the dissolution, which was approximately fivefold higher in the presence of macrophages. The dissolution, however, appeared to take place mainly extracellularly. Acellular experiments demonstrated that peroxynitrite can initiate oxidation of gold, but a ligand is required to keep the gold ions in solution. CONCLUSION: This study suggests extracellular dissolution of AuNPs in the presence of macrophages, likely with the contribution of the release of reactive nitrogen species, and provides new insight into the fate of AuNPs in the body.

Computational modeling of lung deposition of inhaled particles in chronic obstructive pulmonary disease (COPD) patients: identification of gaps in knowledge and data.

Computational modeling together with experimental data are essential to assess the risk for particulate matter mediated lung toxicity and to predict the efficacy, safety and fate of aerosolized drug molecules used in inhalation therapy. In silico models are widely used to understand the deposition, distribution, and clearance of inhaled particles and aerosols in the human lung. Exacerbations of chronic obstructive pulmonary disease (COPD) have been reported due to increased particulate matter related air pollution episodes. Considering the profound functional, anatomical and structural changes occurring in COPD lungs, the relevance of the existing in silico models for mimicking diseased lungs warrants reevaluation. Currently available computational modeling tools were developed for the healthy adult (male) lung. Here, we analyze the major alterations occurring in the airway structure, anatomy and pulmonary function in the COPD lung, as compared to the healthy lung. We also scrutinize the various physiological and particle characteristics that influence particle deposition, distribution and clearance in the lung. The aim of this review is to evaluate the availability of the fundamental knowledge and data required for modeling particle deposition in a COPD lung departing from the existing healthy lung models. The extent to which COPD pathophysiology may affect aerosol deposition depends on the relative contribution of several factors such as altered lung structure and function, bronchoconstriction, emphysema, loss of elastic recoil, altered breathing pattern and altered liquid volumes that warrant consideration while developing physiologically relevant in silico models.

Macrophage-Assisted Dissolution of Gold Nanoparticles.

Gold nanoparticles (AuNPs) are readily functionalized and considered biocompatible making them useful in a wide range of applications. Upon human exposure, AuNPs will to a high extent reside in macrophages, cells that are designed to digest foreign materials. To better understand the fate of AuNPs in the human body, their possible dissolution needs to be explored. In this study, we tested the hypothesis that macrophages, and especially stimulated macrophages, can impact the dissolution of AuNPs in a size-dependent manner. We developed an in vitro method to compare the dissolution of citrate coated 5 and 50 nm-sized AuNPs, in terms of released gold ions as measured by inductive coupled mass spectrometry (ICP-MS), in (i) cell medium (alone) (ii) in medium with macrophages present and (iii) in medium with lipopolysaccharide (LPS) triggered macrophages (simulating inflammatory conditions). We found an evident, time-dependent dissolution of AuNPs in cell medium, corresponding to 3% and 0.6% of the added amounts of 5 and 50 nm AuNPs, respectively, after 1 week (168 h) of incubation. The dissolution of 5 nm AuNPs was further increased to 4% in the presence of macrophages and, most strikingly, 14% was dissolved in case of LPS-triggering. In contrast, only a minor increase was observed for 50 nm AuNPs after 1 week in the presence of LPS-triggered macrophages compared to medium alone. Dissolution experiments in the absence of cells highlighted the importance of biomolecules. Our findings thus show dissolution of citrate coated AuNPs that is dependent on size, presence of macrophages, and their inflammatory state. These findings have implications for understanding the transformation/dissolution and fate of AuNPs.

Physiologically based pharmacokinetic modeling of nanoceria systemic distribution in rats suggests dose- and route-dependent biokinetics.

BACKGROUND: Cerium dioxide nanoparticles (nanoceria) are increasingly being used in a variety of products as catalysts, coatings, and polishing agents. Furthermore, their antioxidant properties make nanoceria potential candidates for biomedical applications. To predict and avoid toxicity, information about their biokinetics is essential. A useful tool to explore such associations between exposure and internal target dose is physiologically based pharmacokinetic (PBPK) modeling. The aim of this study was to test the appropriateness of our previously published PBPK model developed for intravenous (IV) administration when applied to various sizes of nanoceria and to exposure routes relevant for humans. METHODS: Experimental biokinetic data on nanoceria (obtained from various exposure routes, sizes, coatings, doses, and tissues sampled) in rats were collected from the literature and also obtained from the researchers. The PBPK model was first calibrated and validated against IV data for 30 nm citrate coated ceria and then recalibrated for 5 nm ceria. Finally, the model was modified and tested against inhalation, intratracheal (IT) instillation, and oral nanoceria data. RESULTS: The PBPK model adequately described nanoceria time courses in various tissues for 5 nm ceria given IV. The time courses of 30 nm ceria were reasonably well predicted for liver and spleen, whereas the biokinetics in other tissues were not well captured. For the inhalation, IT instillation, and oral exposure routes, re-optimization was difficult due to low absorption and, hence, low and variable nanoceria tissue levels. Moreover, the nanoceria properties and exposure conditions varied widely among the inhalation, IT instillation, and oral studies, making it difficult to assess the importance of different factors. CONCLUSION: Overall, our modeling efforts suggest that nanoceria biokinetics depend largely on the exposure route and dose.

In vivo biodistribution and physiologically based pharmacokinetic modeling of inhaled fresh and aged cerium oxide nanoparticles in rats.

BACKGROUND: Cerium oxide (CeO2) nanoparticles used as a diesel fuel additive can be emitted into the ambient air leading to human inhalation. Although biological studies have shown CeO2 nanoparticles can cause adverse health effects, the extent of the biodistribution of CeO2 nanoparticles through inhalation has not been well characterized. Furthermore, freshly emitted CeO2 nanoparticles can undergo an aging process by interaction with other ambient airborne pollutants that may influence the biodistribution after inhalation. Therefore, understanding the pharmacokinetic of newly-generated and atmospherically-aged CeO2 nanoparticles is needed to assess the risks to human health. METHODS: A novel experimental system was designed to integrate the generation, aging, and inhalation exposure of Sprague Dawley rats to combustion-generated CeO2 nanoparticles (25 and 90 nm bimodal distribution). Aging was done in a chamber representing typical ambient urban air conditions with UV lights. Following a single 4-hour nose-only exposure to freshly emitted or aged CeO2 for 15 min, 24 h, and 7 days, ICP-MS detection of Ce in the blood, lungs, gastrointestinal tract, liver, spleen, kidneys, heart, brain, olfactory bulb, urine, and feces were analyzed with a mass balance approach to gain an overarching understanding of the distribution. A physiologically based pharmacokinetic (PBPK) model that includes mucociliary clearance, phagocytosis, and entry into the systemic circulation by alveolar wall penetration was developed to predict the biodistribution kinetic of the inhaled CeO2 nanoparticles. RESULTS: Cerium was predominantly recovered in the lungs and feces, with extrapulmonary organs contributing less than 4 % to the recovery rate at 24 h post exposure. No significant differences in biodistribution patterns were found between fresh and aged CeO2 nanoparticles. The PBPK model predicted the biodistribution well and identified phagocytizing cells in the pulmonary region accountable for most of the nanoparticles not eliminated by feces. CONCLUSIONS: The biodistribution of fresh and aged CeO2 nanoparticles followed the same patterns, with the highest amounts recovered in the feces and lungs. The slow decrease of nanoparticle concentrations in the lungs can be explained by clearance to the gastrointestinal tract and then to the feces. The PBPK model successfully predicted the kinetic of CeO2 nanoparticles in various organs measured in this study and suggested most of the nanoparticles were captured by phagocytizing cells.

Toward a general physiologically-based pharmacokinetic model for intravenously injected nanoparticles.

To assess the potential toxicity of nanoparticles (NPs), information concerning their uptake and disposition (biokinetics) is essential. Experience with industrial chemicals and pharmaceutical drugs reveals that biokinetics can be described and predicted accurately by physiologically-based pharmacokinetic (PBPK) modeling. The nano PBPK models developed to date all concern a single type of NP. Our aim here was to extend a recent model for pegylated polyacrylamide NP in order to develop a more general PBPK model for nondegradable NPs injected intravenously into rats. The same model and physiological parameters were applied to pegylated polyacrylamide, uncoated polyacrylamide, gold, and titanium dioxide NPs, whereas NP-specific parameters were chosen on the basis of the best fit to the experimental time-courses of NP accumulation in various tissues. Our model describes the biokinetic behavior of all four types of NPs adequately, despite extensive differences in this behavior as well as in their physicochemical properties. In addition, this simulation demonstrated that the dose exerts a profound impact on the biokinetics, since saturation of the phagocytic cells at higher doses becomes a major limiting step. The fitted model parameters that were most dependent on NP type included the blood:tissue coefficients of permeability and the rate constant for phagocytic uptake. Since only four types of NPs with several differences in characteristics (dose, size, charge, shape, and surface properties) were used, the relationship between these characteristics and the NP-dependent model parameters could not be elucidated and more experimental data are required in this context. In this connection, intravenous biodistribution studies with associated PBPK analyses would provide the most insight.

Physiologically based pharmacokinetic modeling of polyethylene glycol-coated polyacrylamide nanoparticles in rats.

Nanoparticles' health risks depend on their biodistribution in the body. Phagocytosis may greatly affect this distribution but has not yet explicitly accounted for in whole body pharmacokinetic models. Here, we present a physiologically based pharmacokinetic model that includes phagocytosis of nanoparticles to explore the biodistribution of intravenously injected polyethylene glycol-coated polyacrylamide nanoparticles in rats. The model explains 97% of the observed variation in nanoparticles amounts across organs. According to the model, phagocytizing cells quickly capture nanoparticles until their saturation and thereby constitute a major reservoir in richly perfused organs (spleen, liver, bone marrow, lungs, heart and kidneys), storing 83% of the nanoparticles found in these organs 120 h after injection. Key determinants of the nanoparticles biodistribution are the uptake capacities of phagocytizing cells in organs, the partitioning between tissue and blood, and the permeability between capillary blood and tissues. This framework can be extended to other types of nanoparticles by adapting these determinants.