Abstract  Background: Mechanistic computer models for calculation of total and regional deposition of aerosols in the lungs are important tools for predicting or understanding clinical studies and for facilitating development of pharmaceutical inhalation products. Validation of such models must be indirect since generational in vivo data are lacking. Planar scintigraphy is probably the most common method addressing regional lung deposition in humans. Scintigraphic regions of interest (ROI) contain mixtures of airway generations and can therefore not be directly compared to model results. We propose a method to translate computed deposition per generation to deposition in scintigraphic ROI to be able to compare computed results with corresponding results obtained in humans. Methods: The total and regional lung deposition computed by the one-dimensional algebraic typical-path software Mimetikos Preludium was compared for 18 study legs in 14 published deposition studies involving 9 dry powder inhaler brands to the activity in planar scintigraphic ROIs (oropharyngeal, central [C], intermediate, and peripheral [P]) using for the computed regional lung distribution a generic mapping of the contribution of each airway generation to the ROIs. Results: The computed oropharyngeal and total lung deposition correlated with high significance (p < 0.0001) to the scintigraphic results with a near one-to-one relationship. For the regional lung distribution, computed C, P, and P/C results correlated with high significance (p < 0.01) to the corresponding scintigraphic measures. The computed C (P) deposition was on average about 28% lower (8% higher) than the mean scintigraphic results. The computed P/C ratio was on average 29% higher than the mean scintigraphic ratio. Conclusions: The results indicate that both the computational deposition model and the mapping algorithm are valid. The small underprediction of the C region merits further investigations. We believe that this method may prove useful also for the validation of computational fluid particle dynamic lung deposition models.

Abstract  This report describes an investigation of the respiratory physiology of normal premature and full-term newborn infants. As in previous studies on normals (1-3), minute volumes, rates and tidal volumes have been measured. Additional measurements of CO2 production, plasma CO2 partial pressure, and intraesophageal pressure differences have allowed calculations of effective alveolar ventilation, functional dead space and estimates of the work of respiration. Since certain adaptations were necessary for the study of this age group, the techniques are reported in detail. The data from normal infants are the subject of this report; comparable data for newborns with respiratory distress are reported in a second paper (4).

Abstract  Residual volume (RV), functional residual capacity (TGV) and total lung capacity (TLC) have been measured in 42 adolescents aged 16-22 years (22 young men and 20 young women) and in 60 children aged 12-15 years (29 boys and 31 girls) who were selected as having the same ranges of heights. TLC and TGV were related to height in each age and sex group; the slope of the regression curves did not differ between subgroups. RV was related to height in the boys and girls and not in the adolescents; however the number of subjects in each group was small. Relative to height the residual volumes of boys and girls were similar and in both sexes were larger than those for adolescents. Amongst the latter the values for young women were smaller than those for young men. The possible mechanisms are discussed.

Abstract  Inhalation toxicity testing, which provides the basis for hazard labeling and risk management of chemicals with potential exposure to the respiratory tract, has traditionally been conducted using animals. Significant research efforts have been directed at the development of mechanistically based, non-animal testing approaches that hold promise to provide human-relevant data and an enhanced understanding of toxicity mechanisms. A September 2016 workshop, "Alternative Approaches for Acute Inhalation Toxicity Testing to Address Global Regulatory and Non-Regulatory Data Requirements", explored current testing requirements and ongoing efforts to achieve global regulatory acceptance for non-animal testing approaches. The importance of using integrated approaches that combine existing data with in vitro and/or computational approaches to generate new data was discussed. Approaches were also proposed to develop a strategy for identifying and overcoming obstacles to replacing animal tests. Attendees noted the importance of dosimetry considerations and of understanding mechanisms of acute toxicity, which could be facilitated by the development of adverse outcome pathways. Recommendations were made to (1) develop a database of existing acute inhalation toxicity data; (2) prepare a state-of-the-science review of dosimetry determinants, mechanisms of toxicity, and existing approaches to assess acute inhalation toxicity; (3) identify and optimize in silico models; and (4) develop a decision tree/testing strategy, considering physicochemical properties and dosimetry, and conduct proof-of-concept testing. Working groups have been established to implement these recommendations.

Abstract  BACKGROUND: Nose-to-brain transport of airborne ultrafine particles (UFPs) via the olfactory pathway has been verified as a possible route for particle translocation into the brain. The exact relationship between increased airborne toxicant exposure and neurological deterioration in the human central nervous system, is still unclear. However, the nasal olfactory is undoubtedly a critical junction where the time course and toxicant dose dependency might be inferred.

METHOD: Computational fluid-particle dynamics modeling of inhaled nanoparticles (1 to 100 nm) under low to moderate breathing conditions (5 to 14 L/min - human; and 0.14 to 0.40 L/min - rat) were performed in physiologically realistic human and rat nasal airways. The simulation emphasized olfactory deposition, and variations in airflow and particle flux caused by the inter-species airway geometry differences. Empirical equations were developed to predict regional deposition rates of inhaled nanoparticles on human and rat olfactory mucosa in sedentary breathing. Considering, breathing and geometric differences, quantified correlations between human and the rat olfactory deposition dose against a variety of metrics were proposed.

RESULTS: Regional deposition of nanoparticles in human and the rat olfactory was extremely low, with the highest deposition (< 3.5 and 8.1%) occurring for high diffusivity particles of 1.5 nm and 5 nm, respectively. Due to significant filtering of extremely small particles (< 2 nm) by abrupt sharp turns at front of the rat nose, only small fractions of the inhaled nanoparticles (in this range) reached rat olfactory than that in human (1.25 to 45%); however, for larger sizes (> 3 nm), significantly higher percentage of the inhaled nanoparticles reached rat nasal olfactory than that in human (2 to 32 folds). Taking into account the physical and geometric features between human and rat, the total deposition rate (#/min) and deposition rate per unit surface area (#/min/mm2) were comparable for particles> 3 nm. However, when body mass was considered, the normalized deposition rate (#/min/kg) in the rat olfactory region exceeded that in the human. Nanoparticles < 1.5 nm were filtered out by rat anterior nasal cavity, and therefore deposition in human olfactory region exceeded that in the rat model.

CONCLUSION: Regional deposition dose of inhaled nanoparticles in a human and rat olfactory region was governed by particle size and the breathing rate. Interspecies correlation was determined by combining the effect of deposition dosage, physical\geometric features, and genetic differences. Developed empirical equations provided a tool to quantify inhaled nanoparticle dose in human and rat nasal olfactory regions, which lay the ground work for comprehensive interspecies correlation between the two species. Furthermore, this study contributes to the fields in toxicology, i.e., neurotoxicity evaluation and risk assessment of UFPs, in long-term and low-dose inhalation exposure scenarios.

Abstract  Membrane preparations of guinea-pig lung (containing multiple muscarinic receptor subtypes) and heart (containing M2 receptors only) were incubated with either neuraminidase, parainfluenza virus (which contains neuraminidase), or virus plus 2,3-dehydro-2-deoxy-N-acetylneuraminic acid, a neuraminidase inhibitor. None of these treatments affected [3H]quinuclidinyl benzilate ([3H]QNB) binding. In the lung and heart, carbachol displaced 0.2 nM [3H]QNB from two sites. After treatment with either neuraminidase or virus the high affinity site was shifted to the right, and carbachol displaced QNB from one site with low affinity in the lung. In contrast, neuraminidase or virus decreased the affinity of carbachol for both sites in the heart. The neuraminidase inhibitor completely blocked virus-induced changes in carbachol affinity in both tissues. These results suggest that parainfluenza virus decreases the affinity of agonists for some of the muscarinic receptors in the lung, and for all of the muscarinic receptors in the heart due to its neuraminidase activity, which results in removal of sialic acid. The decreased agonist affinity in the lung may be responsible for the increased vagally induced bronchoconstriction seen in viral respiratory infections.

Abstract  This report is the first in a series of reports replacing Publications 30 and 68 to provide revised dose coefficients for occupational intakes of radionuclides by inhalation and ingestion. The revised dose coefficients have been calculated using the Human Alimentary Tract Model (Publication 100) and a revision of the Human Respiratory Tract Model (Publication 66) that takes account of more recent data. In addition, information is provided on absorption into blood following inhalation and ingestion of different chemical forms of elements and their radioisotopes. In selected cases, it is judged that the data are sufficient to make material-specific recommendations. Revisions have been made to many of the models that describe the systemic biokinetics of radionuclides absorbed into blood, making them more physiologically realistic representations of uptake and retention in organs and tissues, and excretion. The reports in this series provide data for the interpretation of bioassay measurements as well as dose coefficients, replacing Publications 54 and 78. In assessing bioassay data such as measurements of whole-body or organ content, or urinary excretion, assumptions have to be made about the exposure scenario, including the pattern and mode of radionuclide intake, physical and chemical characteristics of the material involved, and the elapsed time between the exposure(s) and measurement. This report provides some guidance on monitoring programmes and data interpretation.

Abstract  The aim of this study was to investigate exposure-dose relationships in humans with working lifetime exposures to respirable particulates, by using a bio-mathematical exposure-dose model to predict lung and lymph node dust burdens in coalminers with long-term exposure to respirable dust. To meet this aim, statistical and mathematical modelling techniques were used to analyse data from an autopsy study of UK miners held at the Institute of Occupational Medicine. In this study, we validated an existing lung dosimetry model for consistency with observed human lung and lymph burden data. The results of our test suggested that, for humans, the sequestration of dusts in the interstitial compartment is a more prominent feature than the retention of dust due to overload that is observed in animal studies. Modelling and statistical analyses have shown that quartz is more likely to be retained in the lung and lymph nodes than the non-quartz fraction of lung burden and that the quartz fraction may play an important role in the development of PMF. The results of statistical analyses have also shown that the translocation to the lymph nodes is not simply a linear function of lung burden, but may terminate beyond a threshold in lung burden. Our assessment of the variation in the model parameters yielded a distribution of values for the clearance rate and the translocation rate to the lymph nodes respectively. While other sources of uncertainty (e.g. uncertainty in exposure estimation) were not investigated in this study, the results suggested that variability can be quantified and incorporated in the current modelling framework. This approach may be useful for assessing risk in humans to dust exposure.

Abstract  We present the results of an automated analysis of the morphometry of the pulmonary airway trees of the Sprague-Dawley rat. Our work is motivated by a need to inform lower-dimensional mathematical models to prescribe realistic boundary conditions for multiscale hybrid models of rat lung mechanics. Silicone casts were made from three age-matched, male Sprague-Dawley rats, immersed in a gel containing a contrast agent and subsequently imaged with magnetic resonance (MR). From a segmentation of this data, we extracted a connected graph, representing the airway centerline. Segment statistics (lengths and diameters) were derived from this graph. To validate this MR imaging/digital analysis method, airway segment measurements were compared with nearly 1,000 measurements collected by hand using an optical microscope from one of the rat lung casts. To evaluate the reproducibility of the MR imaging/digital analysis method, two lung casts were each imaged three times with randomized orientations in the MR bore. Diameters and lengths of randomly selected airways were compared among each of the repeated imaging datasets to estimate the variability. Finally, we analyzed the morphometry of the airway tree by assembling individual airway segments into structures that span multiple generations, which we call branches. We show that branches not segments are the fundamental repeating unit in the rat lung and develop simple mathematical relationships describing these structures for the entire lung. Our analysis shows that airway diameters and lengths have both a deterministic and stochastic character.

Abstract  Driven by major scientific advances in analytical methods, biomonitoring, computation, and a newly articulated vision for a greater impact in public health, the field of exposure science is undergoing a rapid transition from a field of observation to a field of prediction. Deployment of an organizational and predictive framework for exposure science analogous to the "systems approaches" used in the biological sciences is a necessary step in this evolution. Here we propose the aggregate exposure pathway (AEP) concept as the natural and complementary companion in the exposure sciences to the adverse outcome pathway (AOP) concept in the toxicological sciences. Aggregate exposure pathways offer an intuitive framework to organize exposure data within individual units of prediction common to the field, setting the stage for exposure forecasting. Looking farther ahead, we envision direct linkages between aggregate exposure pathways and adverse outcome pathways, completing the source to outcome continuum for more meaningful integration of exposure assessment and hazard identification. Together, the two frameworks form and inform a decision-making framework with the flexibility for risk-based, hazard-based, or exposure-based decision making.

Abstract  Computational fluid dynamics (CFD) modeling is well suited for addressing species-specific anatomy and physiology in calculating respiratory tissue exposures to inhaled materials. In this study, we overcame prior CFD model limitations to demonstrate the importance of realistic, transient breathing patterns for predicting site-specific tissue dose. Specifically, extended airway CFD models of the rat and human were coupled with airway region-specific physiologically based pharmacokinetic (PBPK) tissue models to describe the kinetics of 3 reactive constituents of cigarette smoke: acrolein, acetaldehyde and formaldehyde. Simulations of aldehyde no-observed-adverse-effect levels for nasal toxicity in the rat were conducted until breath-by-breath tissue concentration profiles reached steady state. Human oral breathing simulations were conducted using representative aldehyde yields from cigarette smoke, measured puff ventilation profiles and numbers of cigarettes smoked per day. As with prior steady-state CFD/PBPK simulations, the anterior respiratory nasal epithelial tissues received the greatest initial uptake rates for each aldehyde in the rat. However, integrated time- and tissue depth-dependent area under the curve (AUC) concentrations were typically greater in the anterior dorsal olfactory epithelium using the more realistic transient breathing profiles. For human simulations, oral and laryngeal tissues received the highest local tissue dose with greater penetration to pulmonary tissues than predicted in the rat. Based upon lifetime average daily dose comparisons of tissue hot-spot AUCs (top 2.5% of surface area-normalized AUCs in each region) and numbers of cigarettes smoked/day, the order of concern for human exposures was acrolein > formaldehyde > acetaldehyde even though acetaldehyde yields were 10-fold greater than formaldehyde and acrolein.

Abstract  Dosimetry, safety and the efficacy of drugs in the lungs are critical factors in the development of inhaled medicines. This article considers the challenges in each of these areas with reference to current industry practices for developing inhaled products, and suggests collaborative scientific approaches to address these challenges. The portfolio of molecules requiring delivery by inhalation has expanded rapidly to include novel drugs for lung disease, combination therapies, biopharmaceuticals and candidates for systemic delivery via the lung. For these drugs to be developed as inhaled medicines, a better understanding of their fate in the lungs and how this might be modified is required. Harmonised approaches based on 'best practice' are advocated for dosimetry and safety studies; this would provide coherent data to help product developers and regulatory agencies differentiate new inhaled drug products. To date, there are limited reports describing full temporal relationships between pharmacokinetic (PK) and pharmacodynamic (PD) measurements. A better understanding of pulmonary PK and PK/PD relationships would help mitigate the risk of not engaging successfully or persistently with the drug target as well as identifying the potential for drug accumulation in the lung or excessive systemic exposure. Recommendations are made for (i) better industry-academia-regulatory co-operation, (ii) sharing of pre-competitive data, and (iii) open innovation through collaborative research in key topics such as lung deposition, drug solubility and dissolution in lung fluid, adaptive responses in safety studies, biomarker development and validation, the role of transporters in pulmonary drug disposition, target localisation within the lung and the determinants of local efficacy following inhaled drug administration.

Abstract  An in vitro study was conducted with the goal of developing empirical correlations to predict the deposition of particles with an aerodynamic diameter of 0.5-5.3 mu m in nasal airways of children with ages 4-14 years. CT images of nasal airways of thirteen healthy subjects and one with congested nasal airways were used for fabricating the replicas by rapid prototyping. Replicas included nasal airways to the level of the upper trachea as well as the face. Four physiological breathing patterns (sinusoidal waves) of children were simulated by a pulmonary waveform generator. Using an Electrical Low Pressure Impactor (ELPI) we measured deposition of sunflower oil particles generated by a Collison atomizer. Moreover, using the same setup, particle deposition in five adult replicas fabricated using MRI images was measured for direct comparison with the child replicas and in vivo data available for adults. Deposition increased by increasing particle size and flow rate, indicating impaction as the dominant deposition mechanism. Existing correlations for adults were unable to reduce the scatter in the deposition data for children. A correlation was developed for prediction of deposition including the relevant non-dimensional numbers (Stokes and Reynolds numbers) that were calculated considering the dimensions of the airways. The corrected correlations should be useful for exposure estimation of children and for efficient pediatric drug delivery using face masks. (C) 2011 Elsevier Ltd. All rights reserved.

Abstract  Despite increasing use of pigs as surrogates for humans in inhalation studies, measurements of particle deposition in the lungs of pigs are lacking. No comprehensive models are available for deposition of inhaled particles in the lungs of pigs to bridge the gap between exposure and biological response. In this study, a mathematical model was developed for the deposition of particles in the respiratory tract of pigs. Semi-empirical equations were developed to relate particle deposition efficiency in the pig nasal passages to non-dimensional parameters for diffusion and impaction deposition. The conducting airway tree of pigs was reconstructed from scanned images and other morphometric data in the literature. The pulmonary airway region was reconstructed assuming geometric similarities between humans and pigs due to a lack of information available on the pulmonary airways of pigs. The tracheobronchial and alveolar trees were combined to obtain a limited-monopodial lung geometry for pigs. A lung ventilation model was developed in this geometry based on lung compliance, airway resistance, and airflow inertance using breathing parameters from the literature. The lung deposition model was constructed based on models for lung ventilation, particle transport, and deposition in the asymmetric (monopodial) lung structure to predict particle deposition in the lungs of pigs. Model predictions indicated that the largest airflow and particle deposition occurred in the basal (diaphragmatic) lobes, which possessed the largest airway dimensions and volumes. The predicted site of deposition was related to particle size with larger particles depositing proximally and smaller particles depositing distally. There was limited penetration of coarse particles into the alveolar region because most of these particles were removed from inhaled air in the nasal and tracheobronchial regions. The deposition model developed in this study is a powerful tool to relate exposure environment to biological response and assess the dose of the delivered particles to the lungs. (C) 2016 Elsevier Ltd. All rights reserved.