Accumulating evidence suggests that outdoor air pollution may have a significant impact on central nervous system (CNS) health and disease. To address this issue, the National Institute of Environmental Health Sciences/National Institute of Health convened a panel of research scientists that was assigned the task of identifying research gaps and priority goals essential for advancing this growing field and addressing an emerging human health concern. Here, we review recent findings that have established the effects of inhaled air pollutants in the brain, explore the potential mechanisms driving these phenomena, and discuss the recommended research priorities/approaches that were identified by the panel.

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Many epidemiologic reports associate ambient levels of particulate matter (PM) with human mortality and morbidity, particularly in people with preexisting cardiopulmonary disease (e.g., chronic obstructive pulmonary disease, infection, asthma). Because much ambient PM is derived from combustion sources, we tested the hypothesis that the health effects of PM arise from anthropogenic PM that contains bioavailable transition metals. The PM samples studied derived from three emission sources (two oil and one coal fly ash) and four ambient airsheds (St. Louis, MO; Washington; Dusseldorf, Germany; and Ottawa, Canada). PM was administered to rats by intratracheal instillation in equimass or equimetal doses to address directly the influence of PM mass versus metal content on acute lung injury and inflammation. Our results indicated that the lung dose of bioavailable transition metal, not instilled PM mass, was the primary determinant of the acute inflammatory response for both the combustion source and ambient PM samples. Residual oil fly ash, a combustion PM rich in bioavailable metal, was evaluated in a rat model of cardiopulmonary disease (pulmonary vasculitis/hypertension) to ascertain whether the disease state augmented sensitivity to that PM. Significant mortality and enhanced airway responsiveness were observed. Analysis of the lavaged lung fluids suggested that the milieu of the inflamed lung amplified metal-mediated oxidant chemistry to jeopardize the compromised cardiopulmonary system. We propose that soluble metals from PM mediate the array of PM-associated injuries to the cardiopulmonary system of the healthy and at-risk compromised host.

The catastrophic destruction of the World Trade Center (WTC) on 11 September 2001 caused the release of high levels of airborne pollutants into the local environment. To assess the toxicity of fine particulate matter [particulate matter with a mass median aerodynamic diameter < 2.5 microm (PM2.5)], which may adversely affect the health of workers and residents in the area, we collected fallen dust samples on 12 and 13 September 2001 from sites within a half-mile of Ground Zero. Samples of WTC dust were sieved, aerosolized, and size-separated, and the PM2.5 fraction was isolated on filters. Here we report the chemical and physical properties of PM2.5 derived from these samples and compare them with PM2.5 fractions of three reference materials that range in toxicity from relatively inert to acutely toxic (Mt. St. Helens PM; Washington, DC, ambient air PM; and residual oil fly ash). X-ray diffraction of very coarse sieved WTC PM (< 53 microm) identified calcium sulfate (gypsum) and calcium carbonate (calcite) as major components. Scanning electron microscopy confirmed that calcium-sulfur and calcium-carbon particles were also present in the WTC PM2.5 fraction. Analysis of WTC PM2.5 using X-ray fluorescence, neutron activation analysis, and inductively coupled plasma spectrometry showed high levels of calcium (range, 22-33%) and sulfur (37-43% as sulfate) and much lower levels of transition metals and other elements. Aqueous extracts of WTC PM2.5 were basic (pH range, 8.9-10.0) and had no evidence of significant bacterial contamination. Levels of carbon were relatively low, suggesting that combustion-derived particles did not form a significant fraction of these samples recovered in the immediate aftermath of the destruction of the towers. Because gypsum and calcite are known to cause irritation of the mucus membranes of the eyes and respiratory tract, inhalation of high doses of WTC PM2.5 could potentially cause toxic respiratory effects.

In an effort to improve risk assessments for ozone (O3) we compared the incorporation of inhaled oxygen-18-labeled O3 (18O3) into the lungs of humans and laboratory rats. Cells and fluids obtainable through bronchoalveolar lavage (BAL) were examined after exposure to 18O3 to determine whether excess 18O concentrations (presumed to be reaction products of 18O3) could be detected and equated to the O3 dose to the lung. Three O3 effect measurements (increased BAL protein and neutrophils and decreased BAL macrophages) were also made in subjects or animals exposed in parallel to determine whether there was a correspondence between dose and effect measurements. Eight human male volunteers 18 to 35 yr of age were exposed to 18O3 (0.4 ppm for 2 h) with 15-min alternating periods of heavy treadmill exercise and rest. Rats (F344) were exposed identically, except without exercise. 18O3 was generated directly from pure 18O2. BAL cells and centrifugally separable surfactant material were freeze-dried and analyzed by mass spectrometer for excess 18O. Results showed that the exercising humans had four- to fivefold higher 18O concentrations in all of their BAL constituents than did the rats. The humans also had significant increases in all of the effects markers after 0.4 ppm O3, whereas the rats did not. Rats that were exposed to higher concentrations of 18O3 (2.0 ppm) had levels of 18O in BAL that were more comparable to but still lower than those of exercising humans. Changes in all of the effects markers in these rats were comparable or higher than in exercising humans.(ABSTRACT TRUNCATED AT 250 WORDS)

We tested the hypothesis that particulate air pollutants are associated with metals that have a capacity to transport electrons and that biologic activity of the particulates can correlate with the concentrations of these metals. The metals studied were titanium, vanadium, chromium, manganese, iron, cobalt, nickel, and copper. Measurements included ( 1 ) oxidized products of deoxyribose catalyzed by particulates, (2) induction of a neutrophilic alveolitis after particdate instillation, (3) increments in airway reactivity after particulate instillation, and (4) mortality after exposures to both dusts and a microbial agent. Employing 10 different dusts of either natural or anthropogenic origin, in vitro generation of oxi- ~ dized products of deoxyribose increased with ionizable concentrations of all metals, except for titanium, associated with the particles. After tracheal instillation of dust into rats, both the neutrophil influx and lavage protein increased with ionizable concentrations of these same metals. Changes in airway reactivity following instillation of dusts in rats alsoappeared to be associated with the ionizable concentrations of these metals. Similarly, mortality after injection of particles in mice with subsequent exposure to aerosolized Streptococcus zooepidemicus reflected metal concentrations. We conclude that particulate air pollutants are associated with metals which have a capacity to catalyze electron transfer. An in vitro measure of oxidant production increased with ionizable concentrations of the metals. Indices of in vivo lung injury also corresponded to concentrations of these same metals.

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Background: Diesel exhaust (DE), which is emitted from on- and off-road sources, is a complex mixture of toxic gaseous and particulate components that leads to triggered adverse cardiovascular effects such as arrhythmias.Objective: We hypothesized that increased risk of triggered arrhythmias 1 day after DE exposure is mediated by airway sensory nerves bearing transient receptor potential (TRP) channels [e.g., transient receptor potential cation channel, member A1 (TRPA1)] that, when activated by noxious chemicals, can cause a centrally mediated autonomic imbalance and heightened risk of arrhythmia.Methods: Spontaneously hypertensive rats implanted with radiotelemeters were whole-body exposed to either 500 μg/m3 (high) or 150 μg/m3 (low) whole DE (wDE) or filtered DE (fDE), or to filtered air (controls), for 4 hr. Arrhythmogenesis was assessed 24 hr later by continuous intravenous infusion of aconitine, an arrhythmogenic drug, while heart rate (HR) and electrocardiogram (ECG) were monitored.Results: Rats exposed to wDE or fDE had slightly higher HRs and increased low-frequency:high-frequency ratios (sympathetic modulation) than did controls; ECG showed prolonged ventricular depolarization and shortened repolarization periods. Rats exposed to wDE developed arrhythmia at lower doses of aconitine than did controls; the dose was even lower in rats exposed to fDE. Pretreatment of low wDE–exposed rats with a TRPA1 antagonist or sympathetic blockade prevented the heightened sensitivity to arrhythmia.Conclusions: These findings suggest that a single exposure to DE increases the sensitivity of the heart to triggered arrhythmias. The gaseous components appear to play an important role in the proarrhythmic response, which may be mediated by activation of TRPA1, and subsequent sympathetic modulation. As such, toxic inhalants may partly exhibit their toxicity by lowering the threshold for secondary triggers, complicating assessment of their risk.