DOSIMETRIC ISSUES RELATING TO PARTICULATE TOXICITY

An increasing number of epidemiological studies have reported excess m ortality and morbidity thought to be associated with elevated levels o f particulate matter air pollution. These studies call into question t he adequacy of the current National Ambient Air Quality Standard for p articulate matter in terms of being protective of human health. The la ck of data from the animal toxicology literature supportive of the typ es of effects seen in the epidemiology studies has raised issues of bi ological plausibility, adequacy of animal models, and relevance of end points measured in these models. We focused on various aspects of inte rspecies differences (rat vs. human) in the dosimetry of particles tha t may help explain the apparent lack of consistency between the toxico logical and epidemiological findings. We adjusted the predicted thorac ic deposition fractions in rats for the probability of inhaling partic les 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 param eters (ventilatory unit, alveolus, or alveolar macrophage) exhibit som e striking differences between rats and humans. This is particularly t he case for particles 0.1-0.3 mu m in size (i.e., those in the condens ation 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 subpopulat ions are likely to De at increased risk from exposure to particulate a ir pollution. For dose metrics based upon particle number per anatomic al parameter, we found that the trend of differences between rats and humans was even more pronounced for these ''compromised lung'' individ uals compared with ''normal'' subjects. We hypothesize that ''localize d overload'' of particulate clearance mechanisms in individuals with c ompromised lung status may be part of the biological plausibility stor y, and we examine various dosimetry model predictions and dose metrics that point in this direction. While our analyses and conclusions shou ld 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 associat ed with episodic particulate air pollution excursions.