Abstract  Context: Inhaled nanoparticles can migrate to the brain via the olfactory bulb, as demonstrated in experiments in several animal species. This route of exposure may be the mechanism behind the correlation between air pollution and human neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Objectives: This article aims to (i) estimate the dose of inhaled nanoparticles that deposit in the human olfactory epithelium during nasal breathing at rest and (ii) compare the olfactory dose in humans with our earlier dose estimates for rats. Materials and Methods: An anatomically-accurate model of the human nasal cavity was developed based on computed tomography scans. The deposition of 1-100 nm particles in the whole nasal cavity and its olfactory region were estimated via computational fluid dynamics (CFD) simulations. Our CFD methods were validated by comparing our numerical predictions for whole-nose deposition with experimental data and previous CFD studies in the literature. Results: In humans, olfactory dose of inhaled nanoparticles is highest for 1-2 nm particles with ∼1% of inhaled particles depositing in the olfactory region. As particle size grows to 100 nm, olfactory deposition decreases to 0.01% of inhaled particles. Discussion and Conclusion: Our results suggest that the percentage of inhaled particles that deposit in the olfactory region is lower in humans than in rats. However, olfactory dose per unit surface area is estimated to be higher in humans in the 1--7 nm size range due to the larger inhalation rate in humans. These dose estimates are important for risk assessment and dose-response studies investigating the neurotoxicity of inhaled nanoparticles.

Abstract  The exposure-dose-response characterization of an inhalation hazard established in an animal species needs to be translated to an equivalent characterization in humans relative to comparable doses or exposure scenarios. Here, the first geometry model of the conducting airways for rhesus monkeys is developed based upon CT images of the conducting airways of a 6-month-old male, rhesus monkey. An algorithm was developed for adding the alveolar region airways using published rhesus morphometric data. The resultant lung geometry model can be used in mechanistic particle or gaseous dosimetry models. Such dosimetry models require estimates of the upper respiratory tract volume of the animal and the functional residual capacity, as well as of the tidal volume and breathing frequency of the animal. The relationship of these variables to rhesus monkeys of differing body weights was established by synthesizing and modeling published data as well as modeling pulmonary function measurements on 121 rhesus control animals. Deposition patterns of particles up to 10 µm in size were examined for endotracheal and and up to 5 µm for spontaneous breathing in infant and young adult monkeys and compared to those for humans. Deposition fraction of respirable size particles was found to be higher in the conducting airways of infant and young adult rhesus monkeys compared to humans. Due to the filtering effect of the conducting airways, pulmonary deposition in rhesus monkeys was lower than that in humans. Future research areas are identified that would either allow replacing assumptions or improving the newly developed lung model.

Abstract  BACKGROUND: Lung macrophages, that is, the intravascular, interstitial, pleural, and surface macrophages, are part of the mononuclear phagocyte system. They are derived from the hematopoietic stem cell in the bone marrow with the monocytes as their putative precursors. Macrophages residing on the inner surfaces of the lungs and immersed within the lung lining layer, that is, the alveolar and the airway macrophages, are constantly exposed to the environment; it is those cells that are recognized as first line of cellular host defense.

METHODS AND RESULTS: Phagocytic uptake of inhaled and deposited particles is the main mechanism to remove insoluble micrometer-sized particles from the lung surfaces, where mucociliary transport, cough, or sneezing fail or are absent. Phagocytosis requires an intact cytoskeleton and is most efficient when mediated by Fc-receptors, but complement and scavenger receptors like MARCO and CD206 are just as important. The main pathway for the clearance of macrophage-associated particles is by mucociliary transport; to a lesser degree and species specific, particle-containing macrophages may reenter into the interstitium and go from there to the lymphatics. Inhaled nanometer-sized particles that deposit along the entire respiratory tract, however, are not efficiently phagocytosed by surface macrophages.

CONCLUSIONS: Uptake by spontaneous or stimulated (macro-) pinocytosis or electrokinetic's phenomena may become more important. In addition, translocation of nanometer-sized particles into the interstitium and to the blood circulation brings them into contact with other fluids; altered particle properties may influence particle uptake. Moreover, translocated particles may interact with lung macrophage populations that were previously not considered of great significance for the clearance of inhaled particles.

Abstract  The success of inhalation therapy is not only dependent upon the pharmacology of the drugs being inhaled but also upon the site and extent of deposition in the respiratory tract. This article reviews the main mechanisms affecting the transport and deposition of inhaled aerosol in the human lung. Aerosol deposition in both the healthy and diseased lung is described mainly based on the results of human studies using nonimaging techniques. This is followed by a discussion of the effect of flow regime on aerosol deposition. Finally, the link between therapeutic effects of inhaled drugs and their deposition pattern is briefly addressed. Data show that total lung deposition is a poor predictor of clinical outcome, and that regional deposition needs to be assessed to predict therapeutic effectiveness. Indeed, spatial distribution of deposited particles and, as a consequence, drug efficiency is strongly affected by particle size. Large particles (>6 μm) tend to mainly deposit in the upper airway, limiting the amount of drugs that can be delivered to the lung. Small particles (<2 μm) deposit mainly in the alveolar region and are probably the most apt to act systemically, whereas the particle in the size range 2-6 μm are be best suited to treat the central and small airways.

Abstract  Airborne engineered nanoparticles undergo agglomeration, and careful distinction must be made between primary and agglomerate size of particles, when assessing their health effects. This study compares the effects on rats undergoing 15-day inhalation exposure to airborne agglomerates of gold nanoparticles (AuNPs) of similar size distribution and number concentration (1 × 10(6) particles/cm(3)), but two different primary diameters of 7 nm or 20 nm. Inhalation of agglomerates containing 7-nm AuNPs resulted in highest deposition by mass concentration in the lungs, followed by brain regions including the olfactory bulb, hippocampus, striatum, frontal cortex, entorhinal cortex, septum, cerebellum; aorta, esophagus, and kidney. Eight organs/tissues especially the brain retained greater mass concentration of Au after inhalation exposure to agglomerates of 7-nm than 20-nm AuNPs. Macrophage mediated escalation followed by fecal excretion is the major pathway of clearing inhaled AuNPs in the lungs. Microarray analyses of the hippocampus showed mostly downregulated genes, related to the cytoskeleton and neurite outgrowth. Together, results in this study indicate disintegration of nanosized agglomerates after inhalation and show impact of primary size of particles on subsequent biodistribution.

Abstract  Determination of the respiratory tract deposition of airborne particles is critical for risk assessment of air pollution, inhaled drug delivery, and understanding of respiratory disease. With the advent of nanotechnology, there has been an increasing interest in the measurement of pulmonary deposition of nanoparticles because of their unique properties in inhalation toxicology and medicine. Over the last century, around 50 studies have presented experimental data on lung deposition of nanoparticles (typical diameter≤100 nm, but here≤300 nm). These data show a considerable variability, partly due to differences in the applied methodologies. In this study, we review the experimental techniques for measuring respiratory tract deposition of nano-sized particles, analyze critical experimental design aspects causing measurement uncertainties, and suggest methodologies for future studies. It is shown that, although particle detection techniques have developed with time, the overall methodology in respiratory tract deposition experiments has not seen similar progress. Available experience from previous research has often not been incorporated, and some methodological design aspects that were overlooked in 30-70% of all studies may have biased the experimental data. This has contributed to a significant uncertainty on the absolute value of the lung deposition fraction of nanoparticles. We estimate the impact of the design aspects on obtained data, discuss solutions to minimize errors, and highlight gaps in the available experimental set of data.

Abstract  While hazard assessment of chemicals can make direct use of descriptive adverse outcome pathways (AOPs), risk assessment requires quantitative relationships from exposure to effect timing and magnitude. To seamlessly integrate the data generated by alternative methods or in vivo testing, quantitative AOPs (qAOPs) providing dose-time-response predictions are more valuable than qualitative AOPs. Here, we compare three approaches to qAOP building: empirical dose-response modeling, Bayesian network (BN) calibration, and systems biology (SB) modeling. These methods were applied to the quantification of a simplified oxidative stress induced chronic kidney disease AOP, on the basis of in vitro data obtained on RPTEC/TERT1 cells exposed to potassium bromate. Effectopedia was used to store the experimental data and the developed models in a unified representation so they can be compared and further analyzed. We argue that despite the fact that dose-response models give adequate fits to the data they should be accompanied by mechanistic SB modeling to gain a proper perspective on the quantification. BNs can be both more precise than dose-response models and simpler than SB models, but more experience with their usage is needed.

Abstract  Identification and treatment of obstructive airway disorders (OADs) are greatly aided by imaging of the geometry of the airway lumen. Anatomical optical coherence tomography (aOCT) is a promising high-speed and minimally invasive endoscopic imaging modality for providing micrometer-resolution scans of the upper airway. Resistance to airflow in OADs is directly caused by the reduction in luminal cross-sectional area (CSA). It is hypothesized that aOCT can produce airway CSA measurements as accurate as that from computed tomography (CT). Scans of machine hollowed cylindrical tubes were used to develop methods for segmentation and measurement of airway lumen in CT and aOCT. Simulated scans of virtual cones were used to validate 3-D resampling and reconstruction methods in aOCT. Then, measurements of two segments of a 3-D printed pediatric airway phantom from aOCT and CT independently were compared to ground truth CSA. In continuous unobstructed regions, the mean CSA difference for each phantom segment was 2.2 ± 3.5 and 1.5 ± 5.3 mm2 for aOCT, and -3.4 ± 4.3 and -1.9 ± 1.2 mm2 for CT. Because of the similar magnitude of these differences, these results support the hypotheses and underscore the potential for aOCT as a viable alternative to CT in airway imaging, while offering greater potential to capture respiratory dynamics.

Abstract  Lung disease accounts for every sixth death globally. Profiling the molecular state of all lung cell types in health and disease is currently revolutionizing the identification of disease mechanisms and will aid the design of novel diagnostic and personalized therapeutic regimens. Recent progress in high-throughput techniques for single-cell genomic and transcriptomic analyses has opened up new possibilities to study individual cells within a tissue, classify these into cell types, and characterize variations in their molecular profiles as a function of genetics, environment, cell-cell interactions, developmental processes, aging, or disease. Integration of these cell state definitions with spatial information allows the in-depth molecular description of cellular neighborhoods and tissue microenvironments, including the tissue resident structural and immune cells, the tissue matrix, and the microbiome. The Human Cell Atlas consortium aims to characterize all cells in the healthy human body and has prioritized lung tissue as one of the flagship projects. Here, we present the rationale, the approach, and the expected impact of a Human Lung Cell Atlas.

Abstract  The National Heart, Lung, and Blood Institute is funding an effort to create a molecular atlas of the developing lung (LungMAP) to serve as a research resource and public education tool. The lung is a complex organ with lengthy development time driven by interactive gene networks and dynamic cross talk among multiple cell types to control and coordinate lineage specification, cell proliferation, differentiation, migration, morphogenesis, and injury repair. A better understanding of the processes that regulate lung development, particularly alveologenesis, will have a significant impact on survival rates for premature infants born with incomplete lung development and will facilitate lung injury repair and regeneration in adults. A consortium of four research centers, a data coordinating center, and a human tissue repository provides high-quality molecular data of developing human and mouse lungs. LungMAP includes mouse and human data for cross correlation of developmental processes across species. LungMAP is generating foundational data and analysis, creating a web portal for presentation of results and public sharing of data sets, establishing a repository of young human lung tissues obtained through organ donor organizations, and developing a comprehensive lung ontology that incorporates the latest findings of the consortium. The LungMAP website (www.lungmap.net) currently contains more than 6,000 high-resolution lung images and transcriptomic, proteomic, and lipidomic human and mouse data and provides scientific information to stimulate interest in research careers for young audiences. This paper presents a brief description of research conducted by the consortium, database, and portal development and upcoming features that will enhance the LungMAP experience for a community of users.

Abstract  BACKGROUND: Previous histological and imaging studies have shown the presence of variability in the degree of bronchoconstriction of airways sampled at different locations in the lung (i.e., heterogeneity). Heterogeneity can occur at different airway generations and at branching points in the bronchial tree. Whilst heterogeneity has been detected by previous experimental approaches, its spatial relationship either within or between airways is unknown.

METHODS: In this study, distribution of airway narrowing responses across a portion of the porcine bronchial tree was determined in vitro. The portion comprised contiguous airways spanning bronchial generations (#3-11), including the associated side branches. We used a recent optical imaging technique, anatomical optical coherence tomography, to image the bronchial tree in three dimensions. Bronchoconstriction was produced by carbachol administered to either the adventitial or luminal surface of the airway. Luminal cross sectional area was measured before and at different time points after constriction to carbachol and airway narrowing calculated from the percent decrease in luminal cross sectional area.

RESULTS: When administered to the adventitial surface, the degree of airway narrowing was progressively increased from proximal to distal generations (r = 0.80 to 0.98, P < 0.05 to 0.001). This 'serial heterogeneity' was also apparent when carbachol was administered via the lumen, though it was less pronounced. In contrast, airway narrowing was not different at side branches, and was uniform both in the parent and daughter airways.

CONCLUSIONS: Our findings demonstrate that the bronchial tree expresses intrinsic serial heterogeneity, such that narrowing increases from proximal to distal airways, a relationship that is influenced by the route of drug administration but not by structural variations accompanying branching sites.

Abstract  The xenobiotic metabolism in the lung, an organ of first entry of xenobiotics into the organism, is crucial for inhaled compounds entering this organ intentionally (e.g. drugs) and unintentionally (e.g. work place and environmental compounds). Additionally, local metabolism by enzymes preferentially or exclusively occurring in the lung is important for favorable or toxic effects of xenobiotics entering the organism also by routes other than by inhalation. The data collected in this review show that generally activities of cytochromes P450 are low in the lung of all investigated species and in vitro models. Other oxidoreductases may turn out to be more important, but are largely not investigated. Phase II enzymes are generally much higher with the exception of UGT glucuronosyltransferases which are generally very low. Insofar as data are available the xenobiotic metabolism in the lung of monkeys comes closed to that in the human lung; however, very few data are available for this comparison. Second best rate the mouse and rat lung, followed by the rabbit. Of the human in vitro model primary cells in culture, such as alveolar macrophages and alveolar type II cells as well as the A549 cell line appear quite acceptable. However, (1) this generalization represents a temporary oversimplification born from the lack of more comparable data; (2) the relative suitability of individual species/models is different for different enzymes; (3) when more data become available, the conclusions derived from these comparisons quite possibly may change.

Abstract  This concise, well illustrated monograph on respiratory deposition and retention of inhaled aerosols is of special interest to the industrial hygenist or physician, and to specialists in radiation health, infectious diseases and pollution. Starting with initial intake-anatomical and physiological characteristics of the respiratory system- and the physical factors in the deposition of aerosols, the book includes: Experimental studies on the deposition of inhaled aerosols; Pulmonary clearance; Experimental studies on pulmonary clearance; Disease risk from inhaled aerosols; and, concludes with the measurement of resparable aerosol exposure. There are 237 references, author and subject indexes

Abstract  A sample of 144 male, and 117 female healthy adults was selected to determine the normal ventilatory functions for Jordanians. Forced vital capacity, FEV1, and FMF 25-75% were determined using a dry bellows spirometer. Linear regression curves and nomograms were constructed for predicted values. Jordanian values for FVC and FEV1 were similar to those of Caucasians living in the western hemisphere.

Abstract  As the field of colloidal science continues to expand, tools for rapid and accurate physiochemical characterization of colloidal particles will become increasingly important. Here, we present Particle Scattering Diffusometry (PSD), a method that utilizes dark field microscopy and the principles of particle image velocimetry to measure the diffusivity of particles undergoing Brownian motion. PSD measures the diffusion coefficient of particles as small as 30 nm in diameter and is used to characterize changes in particle size and distribution as a function of small, label-free, surface modifications of particles. We demonstrate the rapid sizing of particles using three orders-of-magnitude less sample volume than current standard techniques and use PSD to quantify particle uniformity. Furthermore, PSD is sensitive enough to detect biomolecular surface modifications of nanometer thickness. With these capabilities, PSD can reliably aid in a wide variety of applications, including colloid sizing, particle corona characterization, protein footprinting, and quantifying biomolecule activity.

Abstract  Visual evoked potentials were recorded in eight children during hypothermia and circulatory arrest. The potentials were lost in all children recorded in late arrest. The evoked potential is a more sensitive indicator of CNS stress as provoked by combined hypothermia and hypoxia than is the EEG. EEG activity persisted in six of the eight children in this series even during circulatory arrest. The EEG had been seen to do the same in more than half of a larger series of children recorded at that stage. The results suggest that evoked potentials may be a sensitive indicator of early impairment of cerebral function and may demonstrate useful change sooner than the EEG. The examination may be useful in following children with illnesses producing hypoxia or anoxia. The N1 component was as easily and as frequently identifiable as the P2 component. Under the stress of this procedure, the latency of the P2 component became more variable than the N1 peak. The results suggest the N1 component may be as useful and perhaps more useful than the P2 wave in following the effect of some CNS stresses in children.

Abstract  Blood binding of almitrine, a highly lipophilic drug, was investigated in vitro. [3H]-Almitrine was incubated in a serum pool and isolated protein and lipoprotein fractions. The investigations were performed by using ultracentrifugation and another method which measures the uptake by proteins from glass beads coated with almitrine. Our results with ultracentrifugation show that the distribution of almitrine in serum takes place predominantly in the lipoprotein fraction (78%) and to a minor extent (22%) in the fraction of d greater than 1.20 (albumin-rich fraction). Experiments using glass beads coated with almitrine were then conducted to measure the binding of almitrine to isolated plasma proteins. The maximal uptake values (mol almitrine/mol lipoprotein) of almitrine by isolated lipoproteins decrease from VLDL (260) to LDL (20) to HDL (3) and seem to be related to the lipid content of the particles. The uptake by albumin and alpha 1-acid glycoprotein was low. The molar ratios of [almitrine]/[lipoprotein] are roughly proportional to almitrine concentrations within the therapeutic range. When almitrine was incubated in erythrocytes suspended in several dilutions of serum, almitrine partitioned less in erythrocytes as the serum protein concentration increased in the suspension.

Abstract  This report describes a revision of the model used in ICRP Publication 30 to calculate radiation doses to the respiratory tract of workers resulting from the intake of airborne radionuclides. This revision was motivated by the availability of increased knowledge of the anatomy and physiology of the respiratory tract and of the deposition, clearance, and biological effects of inhaled radioactive particles, and by greatly expanded dosimetry requirements. To meet fully the needs of radiation protection, a dosimetric model for the respiratory tract should: - provide calculations of doses for individual members of the populations of all ethnic groups, in addition to workers; - be useful for predictive and assessment purposes as well as for deriving limits on intakes; - account for the influence of smoking, air pollutants, and respiratory tract diseases; - provide for estimates of respiratory tract tissue doses from bioassay data; and - be equally applicable to radioactive gases as well as to particles. Addressing all of these requirements has resulted in a dosimetry model that is more complex than previous models.

Abstract  Objective: The objectives are to develop inhalation dosimetry models of the flavoring agents diacetyl, 2, 3-pentanedione, and acetoin to predict uptake throughout the rat and human respiratory tracts and use the results with histopathology data from 2-week, nose-only inhalation exposures in Sprague-Dawley rats to assess relationships between predicted dose and in vivo responses. Methods: Computational fluid dynamics (CFD) models of the nasal passages were used to simulate inspiratory airflow and vapor uptake and mechanistic models of the lung airways were used to simulate vapor uptake during a breathing cycle. Results: Diacetyl and 2, 3-pentanedione demonstrated similar uptake and wall mass flux patterns throughout the respiratory tract. Acetoin, being more soluble, was rapidly absorbed in the nasal and upper lung airways. At a 10 ppm exposure concentration and resting breathing conditions, nasal uptake of diacetyl, 2, 3-pentanedione, and acetoin was 30.9, 30.3, and 73.6% in the rat, and 8.7, 9.3, and 32.5% in the human, respectively; total respiratory tract uptake was 76.5, 76.8, and 93.0% in the rat and 79.6, 81.1, and 85.9% in the human, respectively. Wall mass flux patterns aligned with previously reported in vivo observations of histopathological effects in the rat respiratory tract following 8.75, 17.5, or 35 ppm diacetyl or 2, 3-pentanedione exposure and can be used to evaluate dose-response behavior. Conclusions: Dose-response assessment of inhaled vapors demonstrates the utility of dosimetry models for interspecies extrapolation and chemical comparisons and how their use is an important part of risk characterization as non-animal alternatives are more widely considered.