Assessment of deposition of inhaled aerosol in the respiratory tract of man using three-dimensional multimodality imaging and mathematical modeling.

Multimodality medical imaging enables measurement of the three-dimensional spatial distribution of a radiolabeled aerosol within the lung. Using a conceptual spatial morphological model these data may be transformed to provide information on deposition per airway generation. This methodology has been used to study the intrapulmonary deposition patterns of two formulations of a metered dose inhaler and two nebulizers in control subjects. The nebulizer study has also been stimulated using a computer model of deposition. The comparison between derived experimental results and those from computer modeling shows areas of agreement, although there are also areas of discrepancy. The new methodology has considerable potential value in the fields of inhalation therapy and deposition modeling, although more detailed validation is still required.     

Chronic Inhalation Toxicity and Carcinogenicity Testing of Respirable Fibrous Particles

On May 8–10, 1995, a workshop on chronic inhalation toxicity and carcinogenicity testing of respirable fibrous particles was held in Chapel Hill, North Carolina. The workshop was sponsored by the Office of Pollution Prevention and Toxics, U.S. Environmental Protection Agency (EPA), in collaboration with the National Institute of Environmental Health Sciences (NIEHS), the National Institute for Occupational Safety and Health (NIOSH), and the Occupational Safety and Health Administration (OSHA). The goal of the workshop was to obtain input from the scientific community on a number of issues related to fiber testing. Major issues for discussion were: (i) the optimal design and conduct of studies of the health effects of chronic inhalation exposure of animals to fibers; (ii) preliminary studies which would be useful guides in designing the chronic exposure study; (iii) mechanistic studies which would be important adjuncts to the chronic exposure study to enable better interpretation of study results and extrapolation of potential effects in exposed humans; and (iv) available screening tests which can be used to develop a minimum data set for (a) making decisions about the potential health hazard of the fibers and (b) prioritizing the need for further testing in a chronic inhalation study. After extensive discussion and debate of the workshop issues, the general consensus of the expert panel is that chronic inhalation studies of fibers in the rat are the most appropriate tests for predicting inhalation hazard and risk of fibers to humans. A number of guidances specific for the design and conduct of prechronic and chronic inhalation studies of fibers in rodents were recommended. For instance, it was recommended that along with other information (decrease in body weight, systemic toxicity, etc.), data should be obtained on lung burdens and bronchoalveolar lavage fluid analysis to assist in establishing the chronic exposure levels. Lung burden data are also important for quantifying aspects of risk assessment related to dosimetric adjustments before extrapolation. Although mechanistic studies are not recommended as part of the standard chronic inhalation studies, the expert panel stressed the need for obtaining mechanistic information as far as possible during the course of subchronic or chronic inhalation studies. At present, no single assay and battery of short-term assays can predict the outcome of a chronic inhalation bioassay with respect to carcinogenic effects. Meanwhile, several short-termin vitroandin vivostudies that may be useful to assess the relative potential of fibrous substances to cause lung toxicity/carcinogenicity have been identified.     

Factors affecting the deposition of inhaled porous drug particles

Recent findings indicate that the inhalation of large manufactured porous particles may be particularly effective for drug delivery. In this study, a mathematical model was employed to systematically investigate the effects of particle size, particle density, aerosol polydispersity, and patient ventilatory parameters on deposition patterns of inhaled drugs in healthy human lungs. Aerodynamically similar particles with densities of 0.1, 1.0, and 2.0 g/cm(3) were considered. Particle size distributions were defined with mass median aerodynamic diameters (MMADs) ranging from 1 to 3 microm and geometric standard deviations ranging from 1.5 to 2.5, representing particles in the respirable size range. Breathing rates of 30 and 60 L/min with tidal volumes of 500 to 3000 mL were assumed, simulating shallow to deep breaths from a dry powder inhaler. Particles with a high density and a small geometric diameter had slightly greater deposition fractions than particles that were aerodynamically similar, but had lower density and larger geometric size (typical of manufactured porous particles). This can be explained by the fact that particles with a small geometric diameter deposit primarily by diffusion, which is a function of geometric size but is independent of density. As MMAD increased, the effect of density on deposition was less pronounced because of the decreased efficiency of diffusion for large particles. These data suggest that polydisperse aerosols containing a significant proportion of submicron particles will deposit in the pulmonary airways with greater efficiency than aerodynamically similar aerosols comprised of geometrically larger porous particles.     

Aerosol Deposition as a Function of Airway Disease: Cystic Fibrosis

A mathematical model of aerosol deposition has been developed for drug delivery protocols and used successfully to simulate inhalation exposure tests with human subjects. Therefore, we have used the validated model to address the delivery of inhaled pharmaceuticals as a function of disease-induced changes in airway structure. Clinical data from the literature had suggested that progressive lung disease associated with cystic fibrosis (CF) could compromise the successful administration of pharmacologic drugs used in its treatment, hence it was studied. We described the lungs of patients inflicted with CF by different morphologies (representing the processes of airway obstruction, infection and inflammation) than healthy (control) subjects. Affected ventilatory parameters were also examined to demonstrate their effects upon drug disposition. Particle distributions were computed on a generation-by-generation basis. Deposition patterns were dramatically affected by CF-produced alterations in dimensions. The reduced airway caliber in CF enhanced the total dose delivered to the tracheobronchial compartment by 200-300% relative to controls. The spatial distributions of aerosols were completely different in CF patients, being selectively deposited within congested airways. In medical practice the model can be tailored to any specific airway disease. Regarding targeted delivery, the results have relevance to (1) site-specific acting pharmaceuticals in tracheobronchial airways and (2) drugs designed for systemic delivery via deposition in alveolated airways.     

Risk assessment dosimetry model for inhaled particulate matter: I. Human subjects

Pollutant particulate matter (PM) is a serious global problem, presenting a threat to the health and well being of human subjects. Inhalation exposures tests with surrogate animals can be performed to estimate the threat. However, it is difficult to extrapolate the findings of animal tests to human conditions. In this two-part series, interspecies dosimetry models especially designed for implementation with risk assessment protocols are presented. In Part I, the mathematical integrity of the source model per se was tested with data from human subjects, and theoretical predictions agreed well with experimental measurements. In Part II, for surrogate (rat) simulations, appropriate algorithms for morphologies and ventilatory parameters were used as subroutines in the validated model. We conducted a comprehensive series of computer simulations describing the behavior of a representative air pollutant, secondary cigarette smoke. For risk assessment interests, a range of states from rest to exercise was considered. PM hygroscopicity had a pronounced effect on deposition in a complex but systematic manner, in humans and rats: deposition was increased for particles larger than about 1 microm, but was decreased for particles smaller than about 0.1 microm. The results clearly indicate that dosimetry models can be effectively used to a priori determine the laboratory conditions necessary for animals tests to accurately mimic human conditions. Moreover, the use of interspecies models is very cost effective. We propose, therefore, that mathematical models be used in a complementary manner with inhalation exposure experiments and be actively integrated into PM risk assessment protocols.     

Fluid dynamics in airway bifurcations: III. Localized flow conditions

Localized flow conditions (e.g., backflows) in transition regions between parent and daughter airways of bifurcations were investigated using a computational fluid dynamics software code (FIDAP) with a Cray T90 supercomputer. The configurations of the bifurcations were based on Schreck s (1972) laboratory models. The flow intensities and spatial regions of reversed motion were simulated for different conditions. The effects of inlet velocity profiles, Reynolds numbers, and dimensions and orientations of airways were addressed. The computational results showed that backflow was increased for parabolic inlet conditions, larger Reynolds numbers, and larger daughter-to-parent diameter ratios. This article is the third in a systematic series addressed in this issue; the first addressed primary velocity patterns and the second discussed secondary currents.     

Fluid dynamics in airway bifurcations: I. Primary flows

The subject of fluid dynamics within human airways is of great importance for the risk assessment of air pollutants (inhalation toxicology) and the targeted delivery of inhaled pharmacologic drugs (aerosol therapy). As cited herein, experimental investigations of flow patterns have been performed on airway models and casts by a number of investigators. We have simulated flow patterns in human lung bifurcations and compared the results with the experimental data of Schreck (1972). The theoretical analyses were performed using a third-party software package, FIDAP, on the Cray T90 supercomputer. This effort is part of a systematic investigation where the effects of inlet conditions, Reynolds numbers, and dimensions and orientations of airways were addressed. This article focuses on primary flows using convective motion and isovelocity contour formats to describe fluid dynamics; subsequent articles in this issue consider secondary currents (Part II) and localized conditions (Part III). The agreement between calculated and measured results, for laminar flows with either parabolic or blunt inlet conditions to the bifurcations, was very good. To our knowledge, this work is the first to present such detailed comparisons of theoretical and experimental flow patterns in airway bifurcations. The agreement suggests that the methodologies can be employed to study factors affecting airflow patterns and particle behavior in human lungs.     

Particle deposition in children's lungs: theory and experiment.

A mathematical model of inhaled aerosol particle deposition for children is presented and validated with data from two published experimental studies. The model accurately predicts deposition fraction (DF) in children as a function of particle size for particles in the size range 1-3 microns for both sedentary and exercise breathing conditions. When the experimental data are grouped according to age, the model is able to predict age-dependent trends in DF at the studied particle sizes under sedentary breathing conditions. The model predicts that when ventilatory conditions are held constant, age-dependent changes in morphology result in decreasing DF with age; however, under realistic conditions these changes may be masked by age-dependent changes in ventilation. Despite the fact that mean DF differs significantly from adult values only in children younger than 9, the model predicted that dose-per-surface area may still be greater in children due to smaller lung sizes.