Aerosol Inhalation: Recent Research Frontiers

A rapidly growing body of epidemiological data has shown statistically significant associations between the concentrations of particles in the ambient air and rates of mortality and morbidity in populations exposed to concentrations below current USEPA standards and WHO-EURO air quality guidelines. When other known risk factors have been taken into account in regression analyses, it has been possible to show that daily changes of ambient particulate matter (PM) are associated with: 1) changes in daily mortality; 2) hospital admissions for respiratory diseases; 3) emergency room visits for respiratory diseases; 4) respiratory symptoms; and 5) lung function. For these various responses, there is sometimes a lag or one to a few days between exposure and response.

Differences in long-term average levels of PM pollution have been associated with differences in: 1) annual mortality rates; 2) the prevalence of chronic disease and symptoms; 3) lost time from work or school; and 4) reduced lung function baselines. When multiple regressions are performed which include pollutant vapors as well as PM, the PM variable tends to be most influential. The only exceptions appear to be hospital admissions and symptoms, where ozone (O₃) is sometimes as, or more, influential on the regressions than PM.

Despite the consistency and coherence of these findings in human populations, there has been a reluctance by many to accept the associations as causal in the absence of more positive findings in controlled inhalation exposure studies in humans and laboratory animals. Only one PM component, i.e., hydrogen ion (H⁺) and one other ambient air pollutant, i.e., ozone (O₃), have produced any comparable responses at peak ambient concentrations.

This paper reviews the available epidemiologic evidence for PM-associated health effects and possible causes for such effects.

Diesel exhaust soot particles, consisting principally of a carbonaceous core and absorbed organic compounds, are ubiquitous contaminants of the environment because of the widespread use of diesel engines. Carbon black is produced in large quantities and has many commercial uses around the world. Because the particle size of both materials is small, they are readily inhaled and deposited in the lung, giving rise to concern for induction of lung cancer in humans. Concern that exposure to diesel exhaust or carbon black may cause human lung cancer has been heightened by the finding that long-term exposure of rats to high concentrations of either diesel exhaust or carbon black causes an increased incidence of lung cancer. In this article, the available data are reviewed on diesel exhaust and carbon as agents that cause lung cancer in humans and laboratory animals from the perspective of using the data to assess human lung cancer risk. Current mechanistic data on the pathogenesis of lung cancer induced in rats by diesel soot and carbon black are reviewed. The mechanism of lung tumor induction in rats is apparently unique to high-level exposures, and a threshold relationship exists between exposure and lung tumor induction. Furthermore, mice and Syrian hamsters do not respond with increased lung tumors when exposed to high levels of diesel exhaust, suggesting that the lung tumor response may be unique to the rat, even at high levels of exposure. Thus, in my opinion, the rat lung tumor data from high level exposures to either diesel soot or carbon black should not be used in assessing the human lung cancer risk of exposure to either material. The available human data indicate that the human lung cancer risk will not be increased if exposures to these agents are controlled to low levels.

The presence of airborne particulate contaminants and exposure of humans to the elevated levels of such pollutants has been linked to a wide spectrum of diseases. The knowledge of airborne particle sizes and concentrations is substantial for the assessment of a possible health hazard, as well as for the biomedical research linked to inhalation and regional deposition of those contaminants within the human respiratory system.

The role of the upper human airways in modifying incoming air and removing large particles has been well known for many years. Recently, it has become apparent that the upper airways, which include the nasal, oral, pharyngeal, laryngeal and upper tracheal passages, must be viewed as both a filter to protect the more distal airways and a possible site of toxicity. It is also possible that specific deposition sites of these airways may act as portals of entry for molecules which readily pass through the epithelium.

Fibrous particles are those with an elongated shape. They include glass fibres and asbestos. Asbestos has become very widely used because it is a low-cost material with very desirable chemical and physical properties, for instance, excellent heat and fire resistance. This unique combination makes the economical replacement of asbestos very difficult in many applications.

The particle number concentration in ambient air is dominated by nanometer sized particles and most airborne particles carry a few charges. Our deposition studies in hollow airway casts demonstrate that electrical forces can result in significantly enhanced deposition of these particles in human airways. Deposition of highly charged airborne particles by electrical forces has been previously demonstrated experimentally in the respiratory tract in animals and people. Theory predicts that image forces will increase deposition of charged compared with neutral particles. However, modeling and experiments with particles whose deposition is dominated by inertial and gravitational forces suggest the effect is only discernible for highly charged particles. Our results show that the effect of single electrostatic charges carried by ultrafine particles cannot be neglected in modeling lung deposition.

A number of epidemiological studies has been published over the past 5 years which reported an association between low ambient particle concentration (< 100 μg/m³) and acute morbidity and even mortality in the elderly. Since larger particles above ~ 0.3 μm cannot explain such dramatic effects we hypothesize that ultrafine particles (< 50 nm) present in the urban atmosphere at high number concentrations may be causally involved. We have evaluated this hypothesis by using model ultrafine particles of Teflon^® fume with diameters of 10–26 nm. These particles when inhaled by rats proved to be extremely toxic, leading to severe hemorrhagic pulmonary edema and even death at short-exposure durations (10–30 minutes) and particle number concentration of l–5×l0⁵ particles/cm³. The respective calculated mass concentrations are in the range of 30–60 μg/m³. We conclude that certain ultrafine particles when inhaled as singlet particles can be highly toxic and that there is a need to study more closely environmentally occurring ultrafine particles.

Several chemical and epidemiological investigations have been made during the last decade showing that correlations exist between ambient air concentrations of aerodispersed (particulate) pollutants and the health risk for the general population. Since then, changes in air particulate pollution definitions, measurements, analyses, and air quality standards have been proposed. In this review we review the “chemical standpoint” of the problem and its impact on the measurement strategy and on the air quality standard assessment.

A recent prospective cohort study (Dockery, 1993) has shown that particulate pollutants below a few micrometers pose the greatest health hazard. Aerosols of this size range penetrate deep into the distal region of the lung and are likely to deposit in the lung periphery. The mechanisms involved in mixing and deposition of these particles in the alveolar region, however, are still not fully understood. In prior studies it has been assumed that convective (flow-induced) mixing between inhaled particles and acinar residual gas is insignificant since the nature of acinar flow is fully viscous and reversible (Davis, 1972, Ultman, 1978). Reversibility implies that the expired gas retraces the motion of inspired gas. However, experimental data contradict this widely-accepted assertion (e.g. Heyder, et al., 1988, Anderson, et al., 1989). In studies on single breath bolus dispersion in human lung, for example, Heyder, et al., (1988) showed appreciable bolus dispersion in the lung periphery which could not be accounted for solely by the particles’ intrinsic motion (Brownian motion and gravitational sedimentation). This suggested the existence of convective mixing at the level of acinus. Although several mechanisms (Cinkotai, 1974, Yu, et al., 1977, Taulbee, et al., 1978, Otani et al., 1990, 1991, Rosental, 1992, Miki, et al., 1993) have been postulated to resolve this question, none of these mechanisms has been tested fully.

A single alveolus is used to simulate a breathing cycle in human lungs. An alveolus elastic wall lined with liquid is deformed to accommodate the intrapleural pressure changes. The difference in pressure between alveolus and surroundings is established and the air flow is followed. The main focus, however, is on normal and pathological inhomogeneities which are implemented into the model as decreased tissue elasticity, surfactant deficiency, and constriction of airways. Under such conditions, particle transport and deposition patterns distinguish from those observed in normal healthy lungs.

A protocol for the estimating the efficiencies where more than one collection mechanism is present are examined. Theoretical expressions are obtained for collection with more than one mechanism present simultaneously. A protocol is introduced in which the collection mechanisms are classified into four different categories. This protocol is used to examine two cases: the interaction of locally and globally attraction as in sedimentation and electrostatic attraction and in the case where there is global attraction and a stochastic removal process as is the case for diffusion and sedimentation.

Solid and liquid aerosols in the atmosphere originate from both natural and industrial sources. Inhalation of these aerosols from the ambient air results in the introduction and deposition of various particulate substances in the human respiratory tract, creating a potential health hazard. The assessment of this hazard and appropriate countermeasures to be taken require understanding and estimation of the local and regional deposition of inhaled particles in the respiratory tract.

Occupational diseases caused by breathing contaminated air is avoided primarily by engineering control measures that prevent atmospheric contamination. When effective engineering controls are not feasible or while they are being instituted, an appropriate respirator must be used. Respirators can be classified into two types: air-purifying respirators that remove contaminants from the ambient air and atmosphere-supplying respirators that provide air from a source other than the surrounding atmosphere (National Institute for Occupational Safety and Health, 1987a). Except for special cases, air-purifying respirators are used most frequently in routine workpractices because they are smaller, more easily maintained, and restrict the wearer’s movements the least. Thus, the focus of this article is on air-purifying respirators.

The inhaled route is a convenient way to deliver drugs to the lung. Inhaled pharmaceutical drugs can either act locally in the lung or get absorbed into the systemic circulation to exert their effect. Since the lung functions as a filter it is important to know the optimal particle size distribution to get an optimal deposition in the lung for the species to be studied. In the search for better drugs for local treatment of inflammatory diseases in the respiratory tract it is important that new candidate drugs are evaluated in inhalation delivery systems that are well characterised. Aerosols can be delivered either nose-only or by intubating rats or dogs. An aerosol generator can be fitted to the inhalation chamber or to the nose mask which allows for the aerosol to be inhaled. Selective aerosol deposition in the lung can be achieved by use of the endotracheal tube. In both the above cases, the inhaled dose can be calculated from a filter sample drawn in the breathing zone of the animal during exposure. Simultaneously the aerosol can be monitored in real-time to measure changes in the particle concentration. This is an advantage as the aerosol concentration can be adjusted during delivery to give a more accurate dose to the animal. In our exposure systems, a tracer aerosol with Evans blue, is used to verify the estimated lung burden with the actual deposition patterns found in these animals. Finally we will also give an example of how the effect/side effects ratio can vary if a glucocorticosteroid (budesonide) is administered by different routes, and how the estimated inhaled dose correlates with the kinetic profile (area under the curve).

The purpose of this paper is to review the available information related to deposition and fate of particles in order to help interpret health effects data. As a part of this endeavor it is important to consider species differences in order to extrapolate from effects observed in animal toxicology studies to possible effects in humans exposed in the environment, usually at lower concentrations. A large body of information has been developed on deposition and fate of particles in humans. The vast majority of the data, however, have been obtained in normal healthy adults. There are limited data on susceptible populations or on factors that would modulate responses. The extent to which factors such as age, disease, exercise, and cigarette smoking might alter deposition and fate, and consequently health effects needs to be considered. Another issue dealt with in this review is the extent to which there are clues in the experimental data on deposition and fate of particles that might shed light on the apparently linear correlation of mortality with daily pollution levels even at relatively low ambient concentrations. It is also important to understand species difference so that toxicology studies in animals of pollutant effects can be used effectively to extrapolate to human health effects.

Pollen allergens are mainly water soluble proteins representing up to 1% of the pollen dry mass. By themselves they are able to induce allergenic sensitization (allergenicity) in experimental animals as well as symptoms in sensitized individuals.