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The dissolution of inhaled drug particles in the lungs is a challenge to model using biorelevant methods in terms of (i) collecting a respirable emitted aerosol fraction and dose, (ii) presenting this to a small volume of medium that is representative of lung lining fluid, and (iii) measuring the low concentrations of drug released. We report developments in methodology for each of these steps and utilize mechanistic in silicomodeling to evaluate the in vitrodissolution profiles in the context of plasma concentration–time profiles. The PreciseInhale aerosol delivery system was used to deliver Flixotide aerosol particles to DissolvItapparatus for measurement of dissolution. Different media were used in the DissolvItchamber to investigate their effect on dissolution profiles, these were (i) 1.5% poly(ethylene oxide) with 0.4% l-alphaphosphatidyl choline, (ii) Survanta, and (iii) a synthetic simulated lung lining fluid (SLF) based on human lung fluid composition. For fluticasone proprionate (FP) quantification, solid phase extraction was used for sample preparation with LC–MS/MS analysis to provide an assay that was fit for purpose with a limit of quantification for FP of 312 pg/mL. FP concentration–time profiles in the flow-past perfusate were similar irrespective of the medium used in the DissolvItchamber (∼0.04–0.07%/min), but these were significantly lower than transfer of drug from air-to-perfusate in isolated perfused lungs (0.12%/min). This difference was attributed to the DissolvItsystem representing slower dissolution in the central region of the lungs (which feature nonsink conditions) compared to the peripheral regions that are represented in the isolated lung preparation. Pharmacokinetic parameters (Cmax, Tmax, and AUC0-∞) were estimated from the profiles for dissolution in the different lung fluid simulants and were predicted by the simulation within 2-fold of the values reported for inhaled FP (1000 μg dose) administered via Flixotide Evohaler 250 μg strength inhaler in man. In conclusion, we report methods for performing biorelevant dissolution studies for orally inhaled products and illustrate how they can provide inputs parameters for physiologically based pharmacokinetic (PBPK) modeling of inhaled medicines.

Palladium (Pd) nanoparticles are recognized as components of airborne automotive pollution produced by abrasion of catalyst materials in the car exhaust system. Here we produced dispersions of hydrophilic spherical Pd nanoparticles (Pd-NP) of uniform shape and size (10.4 ± 2.7 nm) in one step by Bradley’s reaction (solvothermal decomposition in an alcohol or ketone solvent) as a model particle for experimental studies of the Pd particles in air pollution. The same approach provided mixtures of Pd-NP and nanoparticles of non-redox-active metal oxides, such as Al2O3. Particle aggregation in applied media was studied by DLS and nanoparticle tracking analysis. The putative health effects of the produced Pd nanoparticles and nanocomposite mixtures were evaluated in vitro, using human primary bronchial epithelial cells (PBEC) and a human alveolar carcinoma cell line (A549). Viability of these cells was tracked by vital dye exclusion, and apoptosis was also assessed. In addition, we monitored the release of IL-8 and PGE2in response to noncytotoxic doses of the nanoparticles. Our studies demonstrate cellular uptake of Pd nanoparticles only in PBEC, as determined by TEM, with pronounced and dose-dependent effects on cellular secretion of soluble biomarkers in both cell types and a decreased responsiveness of human epithelial cells to the pro-inflammatory cytokine TNF-α. When cells were incubated with higher doses of the Pd nanoparticles, apoptosis induction and caspase activation were apparent in PBEC but not in A549 cells. These studies demonstrate the feasibility of using engineered Pd nanoparticles to assess the health effects of airborne automotive pollution.

Polycyclic aromatic hydrocarbons (PAHs) are formed during incomplete combustion. Domestic wood burning and road traffic are the major sources of PAHs in Sweden. In Stockholm, the sum of 14 different PAHs is 100–200 ng/m[sup 3] at the street-level site, the most abundant being phenanthrene. Benzo[a]pyrene (B[a]P) varies between 1 and 2 ng/m[sup 3]. Exposure to PAH-containing substances increases the risk of cancer in humans. The carcinogenicity of PAHs is associated with the complexity of the molecule, i.e., increasing number of benzenoid rings, and with metabolic activation to reactive diol epoxide intermediates and their subsequent covalent binding to critical targets in DNA. B[a]P is the main indicator of carcinogenic PAHs. Fluoranthene is an important volatile PAH because it occurs at high concentrations in ambient air and because it is an experimental carcinogen in certain test systems. Thus, fluoranthene is suggested as a complementary indicator to B[a]P. The most carcinogenic PAH identified, dibenzo[a,l]pyrene, is also suggested as an indicator, although it occurs at very low concentrations. Quantitative cancer risk estimates of PAHs as air pollutants are very uncertain because of the lack of useful, good-quality data. According to the World Health Organization Air Quality Guidelines for Europe, the unit risk is 9 X 10[sup -5] per ng/m[sup 3] of B[a]P as indicator of the total PAH content, namely, lifetime exposure to 0.1 ng/m[sup 3] would theoretically lead to one extra cancer case in 100,000 exposed individuals. This concentration of 0.1 ng/m[sup 3] of B[a]P is suggested as a health-based guideline. Because the carcinogenic potency of fluoranthene has been estimated to be approximately 20 times less than that of B[a]P, a tentative guideline value of 2 ng/m[sup 3] is suggested for fluoranthene. Other significant PAHs are phenanthrene, methylated phenanthrenes/anthracenes and pyrene (high air concentrations), and large-molecule PAHs such as dibenz[a... [ABSTRACT FROM AUTHOR]

Phagocytosis of three types of fluorescein-labeled test particles by rat alveolar macrophages (AM) were studied: spherical silica (3.2 μm), heat-killedCandida albicans (3.8 μm), and heat-killedCryptococcus neoformans (6.1 μm) opsonized with specific IgG. These particles should attach to scavenger, mannose, and Fc receptors, respectively. Both control AM and AM pretreated for 20 h with interferon-γ (12.5 or 50 U/ml) were studied. The sum of the number of attached and ingested particles per AM (accumulated attachment) was used as a measure of the attachment process, and the number of ingested particles per AM divided by the accumulated attachment (ingested fraction) was used as a measure of the ingestion process. The average ingestion time (IT), which is also a measure of the ingestion process, was calculated from the experimental data. The ingestion process was independent of the attachment process. IT increased with the time of observation. This is explained by the fact that IT determined from observation times shorter than the whole distribution of IT for a certain particle results in a shorter IT than the real average IT. C. albicans (mannose receptor) had the fastest ingestion process, C. neoformans opsonized with specific IgG (Fc receptor) had ingestion that was nearly as fast, and the silica particles (scavenger receptors) had the slowest ingestion process. Treatment with interferon-γ markedly impaired the attachment process for all three types of particles (and three types of receptors) but clearly impaired the ingestion process only for silica particles (scavenger receptors).

Alveolar macrophages (AM) were collected by bronchoalveolar lavage from healthy volunteers. The AM were loaded with small masses (0.03–3 μg/106AM) of ultrafine carbon particle aggregates. The phagocytic activity of the cells was studied 20 h after the loading. Fluorescein-labeled silica particles (3 μm) were used as test particles and the attachment and ingestion processes were studied separately. In some experiments, AM were incubated with interferon-γ(IFN-γ) for 20 h before and during the test of phagocytic activity and during measurement of oxidative metabolism. The ingested carbon particles induced a dose-related impairment of both the attachment and the ingestion processes with a marked impairment down to a carbon particle dose around 0.2 μg/106AM. Such levels should reasonably occur after inhalation of existing concentrations of urban air particles, which to a considerable extent consist of aggregates of ultrafine particles with a carbon skeleton. Incubation with IFN-γ(12.5 U/ml) also induced significant impairments in both the attachment and the ingestion processes. Loading with carbon further aggravated the effect of IFN-γ. In contrast to earlier studies in rat AM, IFN-γdid not impair the oxidative metabolism at rest in these human AM; instead the oxidative metabolism was increased. This difference was due to a difference between rat and human AM and not between rat and human IFN-γ. Our results suggest that ingested environmental particles in AM, e.g., after an episode of high particle concentration, may impair phagocytic capacity of the cells, especially after infections that induce an increased production of IFN-γ. Consequently, there might be a risk for additional infections. Moreover, inhaled particles not phagocytized by AM might damage the lung tissue.

Advances in Biologically Based Models for Respiratory Tract Uptake of Inhaled Volatiles. Medinsky, M. A., Kimbell, J. S., Morris, J. B., Gerde, P., and Overton, J. H. (1993). Fundam. Appl. Toxicol. 20, 265-272. Physiologically based pharmacokinetic models for volatile organic chemicals typically describe the respiratory tract as a single compartment in which chemicals in the alveolar air space and the arterial blood are in instantaneous equilibrium. These models also assume that the distribution of chemical in the airstream is uniform throughout the respiratory tract and that uptake is significant only in the alveolar region. A functional role for the upper respiratory tract in the uptake of volatile chemicals has been largely ignored. While these models have worked well for chemicals with low aqueous solubility in biological fluids, systemic uptake of highly soluble volatiles is overestimated. Thus, there is a significant effort to describe the critical determinants for uptake of soluble chemicals and to formulate models with more biologically relevant descriptions of respiratory tract structure and function. Investigators have addressed this problem from several viewpoints. Airflow patterns in the respiratory tract, regional metabolism, diffusion-dependent uptake, and the cyclic nature of respiration are now being incorporated into current models. Use of dosimetric models that incorporate relevant biology for inhaled chemicals will ultimately result in more meaningful human risk assessments. Copyright 1993, 1999 Academic Press

The adsorption of phospholipids from lung surfactant onto inhaled asbestos fibres may create a unique opportunity for lipophilic carcinogens of tobacco smoke, e.g. polycyclic aromatic hydrocarbons (PAH), to diffuse within an all-lipid environment across the aqueous regions of the bronchial lining layer into the cellular membranes of the bronchial epithelium. This suggested ‘lipid-link’ mechanism can give very local but extremely high cellular doses of carcinogens at the preferential sites of asbestos and smoke deposition in the lung. Consequently, this may contribute to the strong synergism observed between smoking and asbestos exposure for the induction of bronchial cancer.