Alveolar clearance deposition

After inhalation exposure, the absorption of Cd compotmds varies greatly depending on the physico-chemical properties of the Cd compounds involved, site of deposition in the lungs and particle size [22]. In the Itmgs, deposition, mucociliary clearance, and alveolar clearance determine the absorption of inhaled particles. Large particles, dusts (>10 pm in diameter) tend to be deposited in the upper airways, while small particles, fumes, cigarette smoke (approximately 0.1 pm in diameter) penetrate into the alveoli, which are the major site of absorption. Between 50-100% of Cd in the alveoli are transferred to the blood. In the average... 

Recent studies in healthy subjects have suggested that a sizeable If action of particles deposited in the bronchiolar region is retained for more than 72-96 hr, and that these particles clear more similarly to alveolarly deposited particles. An increased deposition with retentions in the smallest ciliated airways is supported by the similarity in the clearance patterns from these airways, by healthy subjects, for particles inhaled by bolus and particles inhaled expemely slowly (0.05 L/sec), with an intermediate phase of continued clearance between 24 and 96 hr (17,54). From these studies, clearance in the smallest ciliated airways seems to be incomplete, with retentions of about 40% of the particles assumed to have been deposited in the tracheobronchial region, probably because of ineffective mucociliary transport and cough clearance in small airways. Clearance from the bronchiolar region may have features in common with alveolar clearance (65). This region may thus eonstitute a vulnerable zone in which small airway diseases eventually may arise after repeated exposures to noxious agents. 

If particles reach and become deposited in the alveoli, they tend to stay imbedded in the fluid on the alveolar surface or move into the lymph nodes. The one mechanism by which particles are physically resuspended and removed from the AI region is coughing. For modeling purposes, the AI region is divided into three subcompartments to represent different clearance rates, all of which are slow. 

From a drug delivery perspective, the components of the host defence system comprise barriers that must be overcome to ensure efficient drug deposition as well as retention in and absorption from the respiratory tract. Important non-absorptive clearance mechanisms include mucociliary clearance, alveolar macrophages and metabolism (Figure 6.2). 

If the site of injury or deposition is the alveoli, alveolar maerophages (AM) scavenge and ingest the foreign particulate matter, serving anti-infection and clearance functions. Macrophages have a life span averaging 60 days and... 

The size of the fibrous particles that appear to induce disease in the animal models is compatible with the measured respiratory range in humans (Lipp-man, 1977). Most particulate deposition takes place not in the upper or conducting portion of the airways but in the alveolar region of the pulmonary tree (the respiratory unit). Some surface deposition may occur at bifurcations in the bronchial tree, but the actual amount at each location is influenced by anatomy, specific to the species—probably to an individual—as well as the variety of fiber. A large proportion of airborne particulates are rejected as part of the normal clearance mechanisms in animals, but in humans clearance mechanisms may be compromised by smoking, for example. We are unaware of any experiments on fiber toxicity using smoking rats ... 

On the other hand, particles from fossil fuel combustion and gas-to-particle conversion are generally much smaller (< 2.5-/Am diameter) and fall in the respirable size range. These particles can reach the alveolar region where gas exchange occurs. This region is not coated with a protective mucus layer, and here the clearance time for deposited particles is much greater than in the upper respiratory tract hence the potential for health effects is much greater (Phalen, 1984). 

To estimate inhalation contact exposure, some assumptions must be made which err on the side of conservatism and which should be modified as more complete data become available. It is necessary to know the droplet size spectrum of the spray because the diameter of the droplet influences its movement down the respiratory system (11). The functional unit of the lung is the alveolus, which is the terminal branch in the system. It is presumed that pesticide particles which are soluble in respiratory tract fluid and are 5p or less in diameter will reach the alveolus where they will be readily absorbed through the cells of the alveolar membrane into the pulmonary capillary beds and hence into the circulatory system. A recent review by Lippmann at al. (12) discusses in depth the deposition, retention and clearance of inhaled particles. 

Tracheobronchial deposition of such carriers may not be desirable as clearance on the mucociliary escalator will occur in a relatively short time providing insufficient time for release from these controlled-release systems. Alveolar deposition will, in contrast, result in extended clearance times which are dependent on the nature of the carrier particle and may therefore be a better option for the effective use of such carrier systems for pulmonary drag delivery. 

In several disease states, the mucociliary clearance is impaired, and in such subjects the clearance from the tracheobronchial tree almost certainly exceeds 24 hours [33,34], making the concept of alveolar deposition in terms of retention in excess of 24 hours invalid. The slowly cleared material in normal subjects has... 

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