archival list of Science’s Compass: Enhanced Perspectives
ATMOSPHERE:
Enhanced: Air Pollution-Related Illness: Effects of Particles
André Nel[HN12]
Worldwide epidemiological studies show a consistent increase in cardiac and respiratory morbidity and mortality from exposure to particulate matter [HN1] (PM) (1-3). PM is a key ingredient of polluted air and is estimated to kill more than 500,000 people each year (4). To prevent this staggering loss of life we must understand the characteristics of the toxic particles and gain insight into how these characteristics are related to adverse health effects [HN2] (5). As our understanding increases, we can use this knowledge to develop biomarkers in the hope of identifying susceptible individuals and reducing their exposure to PM.

PM is composed of solid and liquid particles that come from sources such as vehicle exhaust, road dust, smokestacks, forest fires, windblown soil, volcanic emissions, and sea spray (6). Particle size, surface area, and chemical composition determine the health risk posed by PM (7). PM can be classified into coarse, fine, or ultrafine particles (6). Coarse particles, which have a diameter of more than 2.5 m, are mostly derived from soil and sea salts. Fine particles (0.1 to 2.5 m in diameter) and ultrafines (<0.1 m in diameter) [HN3] are predominantly derived from combustion of fossil fuel (see the first figure). Combustion particles have a core of elemental carbon that is coated with a layer of chemicals, including organic hydrocarbons, metals, nitrates, and sulfates. All of these components may play a role in particle toxicity (7).

Dangerous dirt. (Left) Electron micrograph of a fine mode particle collected by an impactor from air outside an engineering laboratory at the University of California, Los Angeles. A halo surrounds residues of what are probably inorganic salts and polar organic compounds dissolved in the original aqueous droplet. Sootlike particles are also present. (Right) Aggregates of ultrafine particles collected on the last stage of an eight-stage impactor. These are soot particles emitted from diesel engine sources such as buses. More volatile particles may have evaporated in the electron microscope.
CREDIT: SHELDON K. FRIEDLANDER/UCLA

Currently, government and air-quality monitoring agencies track and regulate 10-m-diameter (PM10) and 2.5-m-diameter (PM2.5) particles. Unfortunately, the unregulated ultrafine particles are potentially the most dangerous. Ultrafines are the major component in vehicle emissions–the largest source of air pollution in urban areas (8)–and they have the largest surface area and highest content of potentially toxic hydrocarbons among all PM sources. They can also penetrate deeper into lung tissue than fine or coarse particles (8).
Pulmonary effects of PM [HN4] include the triggering of inflammation [HN5] in the smaller airways, which can lead to the exacerbation of asthma and chronic bronchitis, airway obstruction, and decreased gas exchange (1, 2, 9). PM can also interfere with the clearance and inactivation of bacteria in lung tissue. More recently, there has been a growing awareness that PM is a cardiovascular risk factor [HN6] that is associated with heart attacks, stroke, heart rhythm disturbances, and sudden death (3).

A number of mechanisms have been proposed to explain the adverse health impact of PM (5). Effects of PM that have experimental support are inflammation, cytokine [HN7] and chemokine [HN8] release, production of white blood cells, oxygen free-radical production in the lungs, endotoxin-mediated cellular and tissue responses, stimulation of irritant receptors, and covalent modification of key cellular enzymes (5, 9). Best characterized in humans are the effects of PM on airway inflammation (10). In human and animal studies, inhalation of particles elicits proinflammatory effects, cytokine production, and enhancement of allergic responses in the upper and lower airways (9-11). PM exposure is likely linked to inflammation through the generation of reactive oxygen species [HN9] and oxidative stress [HN10] (9, 12-14). Although there is still debate about which particle components are responsible for producing reactive oxygen species, there is accumulating evidence that pro-oxidative organic hydrocarbons, such as polycyclic aromatic hydrocarbons and quinones, and transition metals, such as copper, vanadium, chromium, nickel, cobalt, and iron, play a role (15, 16). The particle provides a template for electron transfer to molecular oxygen in these reduction and oxidation (redox) cycling events (7). In addition, target cells, such as airway epithelial cells and macrophages, generate reactive oxygen species in response to particle uptake by biologically catalyzed redox reactions that occur in the cell membrane and mitochondria (9, 13, 15). The second figure shows mitochondrial damage to a macrophage caused by ultrafine particles.

Reactive oxygen species can damage cellular proteins, lipids, membranes, and DNA. To defend against this damage, cells use up their stores of a key antioxidant, glutathione [HN11]. The glutathione depletion can induce a state of cellular stress, called oxidative stress, that triggers an increase in the production of antioxidant enzymes through activation of a transcription factor Nrf2 (17). Failure to overcome oxidative stress leads to the activation of additional intracellular signaling cascades that regulate the expression of cytokine and chemokine genes (14, 16). These products are produced locally in target tissues as well as systemically, and lead to widespread proinflammatory effects remote from the site of damage.

Toxic particles. The effect of ultrafine particles (UFP) in a macrophage cell line. (Left) An untreated macrophage with healthy mitochondria (M). (Right) The same cell type treated with ambient ultrafine particles, collected in the Los Angeles basin. The enlarged images show that the untreated cell has healthy mitochondria with cristae, whereas the treated cell has damaged mitochondria that lack cristae. The vacuolar structures in the treated cell each represent a mitochondrion with included particles (P). Whether the particles gain access to and then damage the mitochondria or gain access to already damaged mitochondria is unknown. [Modified from (15)]

Some individuals may be more prone to the development of inflammation, asthma, and allergic responses, because of mutations in the genes involved in the induction of the antioxidant defense (18). Other conditions that predispose to PM susceptibility include old age, preexisting chronic heart and lung disease, and diabetes mellitus, all of which are associated with oxidative stress and inflammation.
Although oxidative stress and inflammation may explain aspects of cardiovascular disease such as the growth of atherosclerotic plaques, other adverse outcomes, such as sudden death, may result from altered autonomic regulation of heart rate and changes in the clotting abilities of the blood (3). Although the cause of altered autonomic nervous activity is unknown, the systemic release of cytokines from the lung and vasculature may affect the production of clotting factors and anticoagulant enzymes in the liver. This could lead to the formation of a dense clot on top of a ruptured atherosclerotic plaque, the pathological hallmark of fatal heart attacks. The role of adsorbed particle chemicals in these cardiovascular events is uncertain. However, it is noteworthy that the ultrafine particles may gain access to the systemic circulation by penetrating alveolar membranes in lung tissue (19).

Public concern about the adverse health impact of PM should drive future research. We need to determine which chemical components are most important and whether, in addition to the PM mass, we also need to monitor particle number when considering the effects of ultrafine particles. Products of oxidative stress, inflammation, or tissue damage can be used as biomarkers for early indication of adverse effects of PM exposure. These biomarkers could be monitored in population studies to find susceptible subsets and to determine whether regulatory efforts are sufficient to protect against PM-induced or PM-exacerbated disease.

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Funded by the U.S. Environmental Protection Agency (EPA), National Institute of Allergy and Infectious Diseases, and National Institute of Environmental Health Sciences. This manuscript has not been subjected to the U.S. EPA peer and policy review.