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The key unanswered question in the particulate matter (PM)related health concern is the biological plausibility of the association between PM and the observed adverse cardiopulmonary health effects. These adverse health outcomes have been demonstrated by both cross-sectional and time-series epidemiological studies. Key to the validity of the biological plausibility is the need to identify the component(s) of airborne PM responsible for adverse effects as well as the populations at risk. The plausibility of the association between PM and increases in morbidity and mortality has been strongly questioned because the adverse cardiopulmonary effects have been observed at very low PM concentrations, often below the current NAAQS for PM10. Researchers have even suggested that there appears to be no concentration threshold for these effects. Most importantly, adverse cardiovascular outcomes have been demonstrated at ambient PM concentrations which apparently do not produce experimental pulmonary inflammation or injury in healthy individuals or test animals. Logic, as well as epidemiological evidence, suggests that such small inhaled PM concentrations may be more likely to affect a sensitive subpopulation with compromised health. In fact, controlled studies using healthy animals exposed to concentrated ambient PM have not demonstrated effects that are likely to lead to life-threatening consequences in healthy individuals (Table 1). Studies by Gordon and colleagues have observed a limited number of small increases in heart rate and no pulmonary effects in normal and compromised animals after a single exposure to inhaled concentrated ambient PM at concentrations as high as 919mg/m (Gordonet al., 2000). Likewise, Godles ki’s animal studies have observed adverse outcomes only in dogs and rats with compromised health exposed to inhaled concentrated ambient PM (Godleski et al., 2000). Epidemiological studies have begun to explore the issue of sensitive subpopulations. Initial findings are consistent with the observations from the 1952 and 1962 London episodes, which found that pollution-associated mortality is age-dependent, with the elderly being the most susceptible. PM-associated changes in heart rate or heart rate variability have been reported in panel studies by 3 groups of investigators (Peters et al., 2000; Popeet al., 1999; Liaoet al., 1999). Pope reported results from a panel study of 90 elderly subjects in Utah Valley, an area that has periodic episodes of increased PM during the winter. A small (5–10 beats/min) increase in daily heart rate was found to be significantly associated with increased PM levels on the previous 1–5 days. Heart rate response to PM was similar in healthy subjects and in subjects with chronic cardiac or respiratory disease. Peters reanalyzed heart rate data from the MONICA study, an epidemiological study of randomly selected adults aged 25–64 in southern Germany. Analysis of data from over 2500 adults indicated that the pollution episode was associated with a small, but statistically significant increase (2–3 beats/min) in daily heart rate. The association of increased heart rate and PM was not affected by adjustment for weather, age, or cardiovascular risk factors. In a similar fashion, Liao and colleagues have demonstrated that heart rate variability changes in residents of a retirement home were consistently associated with daily PM levels. The study by Gardner and colleagues in this issue of Toxicological Sciences(pp. 175–180) has determined that an inflammatory dose of residual oil fly ash (ROFA) delivered by intratracheal instillation produces an increase in plasma fibrinogen in healthy rats. Because fibrinogen is a known risk factor for ischemic heart disease and stroke, the authors suggest that this alteration in the coagulation pathway could take part in the triggering of cardiovascular events in susceptible individuals. Such reasoning is consistent with the epidemiology studies that have demonstrated an association between episodic exposure to PM and increased cardiovascular morbidity and mortality in elderly people. These data are supported by Peters and colleagues, who have demonstrated that plasma viscosity changes are associated with ambient PM concentrations. Abundant evidence suggests the route of administration affects the outcome in inhalation toxicology studies. Logically, 1 To whom correspondence should be addressed. Fax: (914) 351-5472. E-mail: gordont@env.med.nyu.edu. TOXICOLOGICAL SCIENCES56, 2–4 (2000) Copyright © 2000 by the Society of Toxicology

Cardiovascular Toxicity of Inhaled Ambient Particulate Matter