DOSIMETRIC ISSUES RELATING TO PARTICULATE TOXICITY

An increasing number of epidemiological studies have reported excess mortality and morbidity thought to be associated with elevated levels of particulate matter air pollution. These studies call into question the adequacy of the current National Ambient Air Quality Standard for particulate matter in terms of being protective of human health. The lack of data from the animal toxicology literature supportive of the types of effects seen in the epidemiology studies has raised issues of biological plausibility, adequacy of animal models, and relevance of endpoints measured in these models. We focused on various aspects of interspecies differences (rat vs. human) in the dosimetry of particles that may help explain the apparent lack of consistency between the toxicological and epidemiological findings. We adjusted the predicted thoracic deposition fractions in rats for the probability of inhaling particles up to 10 mu m in diameter. While deposition of particles on a mass per unit alveolar surface area is not different between these species, dose metrics based upon particle number per various anatomical parameters (ventilatory unit, alveolus, or alveolar macrophage) exhibit some striking differences between rats and humans. This is particularly the case for particles 0.1-0.3 mu m in size (i.e., those in the condensation mode of atmospheric aerosol fine particles). Particle deposition studies in smokers and in subjects with lung diseases, such as asthma and chronic obstructive pulmonary disease, show that these subpopulations are likely to De at increased risk from exposure to particulate air pollution. For dose metrics based upon particle number per anatomical parameter, we found that the trend of differences between rats and humans was even more pronounced for these ''compromised lung'' individuals compared with ''normal'' subjects. We hypothesize that ''localized overload'' of particulate clearance mechanisms in individuals with compromised lung status may be part of the biological plausibility story, and we examine various dosimetry model predictions and dose metrics that point in this direction. While our analyses and conclusions should be currently viewed as preliminary and speculative in nature, they underscore the need for additional research to identify and understand the role of factors leading to acute mortality and morbidity associated with episodic particulate air pollution excursions.