Classic Reducing-type Air Pollution
Reducing-type air pollution, characterized by SO2 and smoke, is capable of producing disastrous human health effects. Empirical studies in human subjects and animals have long stressed the irritancy of SO2 and its role in these incidents, whereas the full potential for interactions among the copollutants in the smoky, sulfurous mix has a mixed record of replication in the human exposure laboratory. Nevertheless, the irritancy of most S-oxidation products in the atmosphere is well documented, and there are both empirical and theoretical reasons to suspect that such products act to amplify the irritancy of fossil fuel emission atmospheres via chemical transformations.
Sulfur dioxide is a water-soluble irritant gas that is absorbed predominantly in the upper airways and stimulates bronchoconstriction and mucus secretion in a number of species, including humans. The concentrations of SO2 likely to be encountered in the United States average less than 0.1 ppm. Mandated use of cleaner (low-S) fossil fuels, emission control devices, and tall emission stacks has largely been responsible for the reductions. However, rare down-drafting of smokestack plumes due to meteorological inversions near point sources may result in levels of SO2 that may pose a health hazard. A 2-min exposure to 0.4 to 1.0 ppm can elicit bronchoconstriction in exercising asthmatics within 5 to 10 min. However, it is the low-level, long-term effects that erode pulmonary defenses that continue to worry some regulators. Studies have shown that SO2 is capable of impairing macrophage-dependent bacterial killing in murine models. Exposed mice have a greater frequency and severity of infection, which has been suggested to be linked to diminished ability to generate endogenous oxidants for bacterial killing.
The penetration of SO2 into the lungs is greater during mouth breathing as opposed to nose breathing. An increase in the airflow rate further augments penetration of the gas into the deeper lung. As a result, persons exercising would inhale more SO2 and, as noted with asthmatics, are likely to experience greater irritation. Once deposited along the airway, SO2 dissolves into surface-lining fluid as sulfite or bisulfite and is readily distributed throughout the body. Sulfite interacts with sensory receptors in the airways to initiate bronchoconstriction.
Pulmonary Function Effects
The basic pulmonary response to inhaled SO2 is mild bronchoconstriction, which is reflected as a measurable increase in airflow resistance due to narrowing of the airways. Concentration-related increases in resistance have been observed in guinea pigs, dogs, cats, and humans.
Sulfuric Acid and Related Sulfates
The conversion of SO2 to sulfate is favored in the environment. During oil and coal combustion or the smelting of metal ores, sulfuric acid condenses downstream of the combustion processes with available metal ions and water vapor to form submicrometer sulfated fly ash. Photochemical reactions in the troposphere also promote acid sulfate formation via both metal-dependent and independent mechanisms. These sulfates may contribute to health hazards and acid rain (Figure 28–3).
Areas in 1988 where precipitation in the east fell below pH 5: acid rain. The acidity of the air in the east is thought to result from air mass transport of fine sulfated particulate matter from the industrial centers of the Midwest. (National Air Pollutant Emission Trends Report, 1998.)
Sulfuric acid irritates respiratory tissues by virtue of its ability to protonate (H+) receptor ligands and other biomolecules. This action can either directly damage membranes or activate sensory reflexes that initiate inflam-mation.
Pulmonary Function Effects
Sulfuric acid produces an increase in flow resistance in guinea pigs due to reflex airway narrowing, which impedes the flow of air into and out of the lungs. This response can be thought of as a defensive measure to limit the inhalation of air containing noxious gases. The magnitude of the response is related to both acid concentration and particle size. Small particles are able to penetrate deep into the lung, reaching receptors that stimulate bronchoconstriction and mucus secretion. The thicker mucus blanket of the nose may blunt (by dilution or neutralization by mucus buffers) much of the irritancy of the deposited acid, thus limiting its effects to mucous cell stimulation and a minor increase in nasal flow resistance. In contrast, the less shielded distal airway tissues, with their higher receptor density, would be expected to be more sensitive to the acid particles reaching that area.
Asthmatics appear to be more sensitive to the bronchoconstrictive effects of sulfuric acid than are healthy individuals, owing to hyperresponsive airways. Asthmatic airways are also sensitive to nonspecific airway smooth muscle agonists (e.g., carbachol, histamine, and exercise). The general correlation between airway responsiveness and inflammation that appears to be important in grading asthma severity and risk of negative clinical outcomes may also be predictive of responses to environmental stimuli.
Effects on Mucociliary Clearance and Macrophage Function
Sulfuric acid alters the clearance of particles from the lung and thus can interfere with a major defense mechanism. The impact on mucus clearance appears to vary directly with the acidity ([H+]) of the acid sulfate, with sulfuric acid having the greatest effect and ammonium sulfate the smallest. Acidification of mucus is the primary metric to associate with population health effects affecting mucus rheology, viscosity, and secretion and ciliary function.
As might be expected, sulfuric acid induces qualitatively similar effects along the airways as are found with high concentrations of SO2. As a fine aerosol, sulfuric acid deposits deeper along the respiratory tract, and high specific acidity imparts greater injury on phagocytes and epithelial cells. Thus, a primary concern with regard to chronic inhalation of acidic aerosols is its potential to cause bronchitis, which is a problem in occupational settings in which employees are exposed to sulfuric acid mists (e.g., battery plants).
Inhaled sulfuric acid does not appear to stimulate a classic neutrophilic inflammation. Rather, disturbed eicosanoid homeostasis results in macrophage dysfunction and altered host defense. In fact, chronic daily exposure of humans to sulfuric acid at levels of about 100 μg/m3 may lead to impaired clearance and mild chronic bronchitis. As this is less than an order of magnitude above haze levels of sulfuric acid, the possibility that chronic irritancy may elicit bronchitic-like disease in susceptible individuals appears to be reasonable.
Particulate matter (PM) in the atmosphere is a mélange of organic, inorganic, and biological materials whose compositional matrix can vary significantly depending on local point sources. A large epidemiologic database contends that PM elicits both short- and long-term health effects at current ambient levels.
There have been many standard acute and subchronic rodent inhalation studies with specific metal compounds, often oxides, chlorides, or sulfates. Virtually any metal can be found at some concentration in ambient PM and many have toxic or prooxidant potential. The most common are metals released during oil and coal combustion (e.g., transition and heavy metals), metals derived from the earth's crust as dust (e.g., iron, sodium, and magnesium), and metals released from engine wear. Metals derived from anthropogenic combustion sources tend to enrich the fine fraction (<2.5 μm) of PM, whereas coarse (2.5 to 10 μm) PM is made up of metal compounds of crustal origin (e.g., Fe2O3 and SiO2).
Solubility appears to play a role in the toxicity of many inhaled metals by enhancing metal bioavailability (e.g., nickel from nickel chloride versus nickel oxide), but insolubility can also be a critical factor in determining toxicity by increasing pulmonary residence time within the lung (e.g., insoluble cadmium oxide versus soluble cadmium chloride). Moreover, some metals, either in their soluble forms or when coordinated on the surface of silicate or bioorganic materials, can promote electron transfer to induce the formation of reactive oxidants. These and other mechanisms may be involved in the action of inhaled PM-associated metals.
The coexistence of pollutant gases and particles in the atmosphere raises the concern that these phases may interact chemically or physiologically to yield unpredictable outcomes. These generic interactions are feasible as mechanisms for altering the toxicity of either the particle or the gas.
Metal smelting or the combustion of coal can emit sulfuric acid that is physically associated with ultrafine metal oxide particles. These ultrafine particles are distributed widely and deeply in the lung and enhance the irritant potency beyond that predicted on the basis of the sulfuric acid concentration alone. Moreover, the combination of inert or chemically active particles with a toxic gas is able to enhance the impact of the gas alone, by either altering dose distribution or forming a more toxic product.
Another potential interaction may result from the ability of gaseous pollutants to influence the clearance of particles from the lung or alter the metabolism or cellular interactions with lung-deposited particles. Gaseous and particulate pollutants can interact through either chemical or physiologic mechanisms to enhance either immediate or associated long-term risks of complex polluted atmospheres.
Ultrafine Carbonaceous Matter
Carbonaceous material often forms the core of fine PM. The organic materials, which can be of a semivolatile or nonvolatile nature, are more often dispersed within the structure of PM, forming layers or sheaths. Estimates of the carbonaceous content vary considerably but are nominally considered to be about 30 to 60 percent of the total mass of fine PM.
Ultrafine carbon (<0.1 μm) has been suggested to be more toxic than the same substance in the larger range (2.5 μm). Diesel PM is made up of aggregated ultrafine carbon with small amounts of various combustion-derived complex polycyclic and nitroaromatic compounds and only a trace of metals. However, whole diesel exhaust also contains significant amounts of NOx, CO, SOx, formaldehyde, acrolein, and other aldehyde compounds, which are known irritants. Diesel exhaust mix is inflammogenic and cytotoxic to airway cells.
Photochemical Air Pollution
Photochemical air pollution arises from a series of complex reactions in the troposphere activated by the ultraviolet (UV) spectrum of sunlight. It consists of a mixture of ozone, nitric oxides, aldehydes, peroxyacetyl nitrates (PANs), and myriad reactive hydrocarbon radicals. If SO2 is present, sulfuric acid PM may also be formed; likewise, the complex chemistry can generate organic PM, nitric acid vapor, and condensate. Of the photochemical air pollutant gases, O3 is the toxicant of greatest concern, being highly reactive and more toxic than NOx. Ozone generation is fueled through cyclic hydrocarbon radicals, and it reaches greater concentrations than the hydrocarbon radical intermediates. In general, concentrations of the hydrocarbon precursors in ambient air do not reach levels high enough to produce acute toxicity. Their importance stems largely from their roles in the chain of photochemical reactions that leads to the formation of oxidant smog or haze.
Although O3 is of toxicologic importance in the troposphere, in the stratosphere it plays a critical protective role. About 10 km above the earth's surface, there is sufficient short-wave UV light to directly split molecular O2 to atomic O·, which can then recombine with O2 to form O3. This O3 accumulates to several hundred ppm within a thin strip of the stratosphere and absorbs incoming short-wavelength UV radiation. The O3 forms and decomposes and reforms to establish a “permanent” barrier to UV radiation, which lately has become an issue of concern. This barrier had, in recent years, been threatened by various anthropogenic emissions (Cl2 gas and certain fluorocarbons) that enhance O3 degradation. Recent restrictions in the use of these degrading chemicals seem to have been effective in reversing this process. The benefits are believed to be reduction of excess UV light infiltration to the earth's surface and a reduced skin cancer risk and less risk of immune system dysfunction.
The issue is different in the troposphere, where accumulation of O3 serves no known purpose and poses a threat to the respiratory tract. Near the earth's surface, NO2 from combustion processes efficiently absorbs longer-wavelength UV light, cleaving a free O atom and initiating the following simplified series of reactions:
This process is inherently cyclic, with NO2 regenerated by the reaction of the NO· and O3. In the absence of unsaturated hydrocarbons, this series of reactions would approach a steady state with no excess or buildup of O3. The hydro-carbons, especially olefins and substituted aromatics, are attacked by the free atomic O·, resulting in oxidized compounds and free radicals that react with NO· to produce more NO2. Thus, the balance of the reactions shown in equations (1) to (3) is tipped to the right, leading to buildup of O3. This reaction is particularly favored when the sun's intensity is greatest at midday, utilizing the NO2 provided by morning traffic. Aldehydes are also major by-products of these reactions. Formaldehyde and acrolein account for about 50 and 5 percent, respectively, of the total aldehyde in urban atmospheres. PAN (CH3COONO2) and its homologs also arise in urban air, most likely from the reaction of the peroxyacyl radicals with NO2.
Chronic Exposures to Smog
Studies in animals and human populations have attempted to link degenerative lung disease with chronic exposure to photochemical air pollution. Cross-sectional and prospective field studies have suggested an accelerated loss of lung function in people living in areas of high pollution. However, as with many studies of this type, there are problems with confounding factors (meteorology, imprecise exposure assessment, and population variables). Studies conducted in children living in Mexico City, with very high oxidant and PM levels, found severe epithelial damage and metaplasia as well as permanent remodeling of the nasal epithelium. When children who migrated into Mexico City from cleaner, nonurban regions were evaluated, even more severe damage was observed, suggesting that the remodeling in the permanent residents imparted some degree of incomplete adaptation. Because the children were of middle-class origin, these observations were not likely confounded by socio-economic variables. These dramatic nasal effects have raised concerns for the more fragile, deep lung tissues, where substantial deposition of oxidant air pollutants may occur.
Current mitigation strategies for O3 have been largely unsuccessful as a result of population growth. With the spread of suburbia and the downwind transport of air masses from populated areas to more rural environments, the geographic distribution of those exposed has spread, as has the temporal profile of potential exposure. In other words, O3 exposures are no longer stereotyped as brief 1- to 2-h peaks. Instead, there are prolonged periods of exposure of 6 h or more at or near the NAAQS level that may occur either downtown or in the formerly cleaner suburban or rural areas downwind.
Ozone induces a variety of effects in humans and experimental animals at concentrations found in many urban areas. These effects include morphologic, functional, immunologic, and biochemical alterations. Because of its low water solubility, a substantial portion of inhaled ozone penetrates deep into the lung, but its reactivity is such that about 17 and 40 percent is scrubbed by the nasopharynx of resting rats and humans, respectively. However, regardless of species, the region of the lung that is predicted to have the greatest O3 deposition (dose per surface area) is the centriacinar region, from the terminal bronchioles to the alveolar ducts. Because O3 penetration increases with increased tidal volume and flow rate, exercise increases the dose to the target area. Thus, it is important to consider the role of exercise in a study of O3 or any inhalant before making cross-study comparisons, especially if that comparison is across species.
The acute morphologic response to O3 involves epithelial cell injury along the entire respiratory tract, resulting in cell loss and replacement. Ciliated cells appear to be most sensitive to O3, whereas Clara cells and mucus-secreting cells are the least sensitive.
As a powerful oxidant, O3 seeks to extract electrons from other molecules. The surface fluid lining the respiratory tract and cell membranes that underlie the lining fluid contain a significant quantity of polyunsaturated fatty acids (PUFA), either free or as part of the lipoprotein structures of the cell. The double bonds within these fatty acids have a labile, unpaired electron that is easily attacked by O3 to form ozonides that ultimately recombine or decompose to lipohydroperoxides, aldehydes, and hydrogen peroxide. These pathways are thought to initiate propagation of lipid radicals and autooxidation of cell membranes and macromolecules (Figure 28–4).
Major reaction pathways of O3 with lipids in lung-lining fluid and cell membranes. (Adapted with permission from the Air Quality Criteria Document for Ozone and Photochemical Oxidants, 600/P-93/004cF, NCEA. Research Triangle Park, NC: U.S. EPA, 1996.)
Pulmonary Function Effects
Exercising human subjects exposed to 0.12 to 0.4 ppm O3 experience reversible concentration-related decrements in forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) after 2 to 3 h of exposure. Interestingly, the human lung dysfunction resulting from O3 does not appear to be vagally mediated, but the response can be abrogated by analgesics such as ibuprofen and opiates, which also reduce pain and inflammation. Thus, pain reflexes involving C-fiber networks are thought to be important in the reductions in forced expiratory volumes. On the other hand, animal studies show a prominent role for vagal reflexes in altered airway reactivity and bronchoconstriction. It is widely thought that hyperreactive airways may predispose responses to other pollutants such as sulfuric acid or aeroallergens.
Ozone Interactions with Copollutants
An approach simplifying the complexity of synthetic smog studies yet addressing the issue of pollutant interactions involves the exposure of animals or humans to binary or tertiary mixtures of pollutants known to occur together in ambient air. Such studies have had a number of permutations, but most have attempted to address the interactions of O3 and nitrogen dioxide or O3 and sulfuric acid. Depending on study design, there has been evidence supporting either augmentation or antagonism of lung function impairments, lung pathology, or other indices of injury. This apparent conflict only emphasizes the need to carefully consider the myriad factors that might affect studies involving multiple determinants and the nature of the exposure that is most relevant to reality.
As the number of interacting variables increases, so does the difficulty in interpretation. Studies of complex atmospheres involving acid-coated carbon combined with O3 at near-ambient levels show variable strength of evidence of interaction on lung function and macrophage receptor activities. The statistical separation of the interacting variables and responses from the individual or combined components is difficult. However, it is the complex mixture to which people are exposed that we wish to evaluate. Creative approaches to understanding mixture responses must be addressed in the next decade.
Nitrogen dioxide, like O3, is a deep lung irritant that can produce pulmonary edema if it is inhaled at high concentrations. Potential life-threatening exposure is a real-world problem for farmers, as sufficient amounts of NO2 can be liberated from fermenting fresh silage. Typically, shortness of breath ensues rapidly with exposures nearing 75 to 100 ppm NO2, with delayed edema and symptoms of pulmonary damage, collectively characterized as silo-filler's disease. Nitrogen dioxide is also an important indoor pollutant, especially in homes with unventilated gas stoves or kerosene heaters. Under such circumstances, very young children and their caregivers who spend considerable time indoors may be especially at risk. Sidestream tobacco smoke can also be a source of low levels of indoor NO2.
Damage to the respiratory tract is most apparent in the terminal bronchioles. At high concentrations, the alveolar ducts and alveoli are also affected, with type I cells again showing their sensitivity to oxidant challenge. There is also damage to epithelial cells in the bronchioles, notably with loss of ciliated cells, as well as a loss of secretory granules in Clara cells.
Inflammation of the Lung and Host Defense
NO2 does not induce significant neutrophilic inflammation in humans at exposure concentrations approximating those in the ambient outdoor environment. There is some evidence for bronchial inflammation after 4 to 6 h at 2.0 ppm, which approximates the likely highest transient peak indoor level of this oxidant. Exposures at 2.0 to 5.0 ppm have been shown to affect T lymphocytes, particularly CD8+ cells and natural killer cells that function in host defenses against viruses. Although these concentrations may be high, epidemiologic studies variably show enhanced viral infection associated with NO2 exposure, especially during seasonal use of unvented gas-heating indoors. Susceptibility to infection appears to be governed more by the peak exposure concentration than by exposure duration. The effects are ascribed to suppression of macrophage function and clearance from the lung.
Whereas a number of reactive oxidants have been identified in photochemical smog, most are short-lived because of their reaction with copollutants. One reactive, irritating constituent of the oxidant atmosphere is PAN, which is thought to be responsible for much of the eye-stinging activity of smog. More soluble and reactive than ozone, PAN rapidly decomposes in mucous membranes before it can get to tissues deep into the lungs. The cornea has many irritant receptors and responds readily, whereas the PAN absorbed into the thicker mucous fluids of the proximal nose and mouth presumably never reaches its target.
Various aldehydes in polluted air are formed as reaction products of the photooxidation of hydrocarbons. Formaldehyde (HCHO) and acrolein (H2C=CHCHO) contribute to the odor as well as eye and sensory irritations of photochemical smog. Formaldehyde accounts for about 50 percent of the estimated total aldehydes in polluted air, whereas acrolein, the more irritating of the two, may account for about 5 percent of the total. Acetaldehyde (C3HCHO) and many other longer chain aldehydes make up the remainder, but they are not as irritating because of their low concentration and lesser solubility in airway fluids. Formaldehyde and acrolein are found in mainstream tobacco smoke (about 90 and 8 ppm, respectively, per puff) and in sidestream smoke as well. Formaldehyde is also an important indoor air pollutant and can often achieve higher concentrations indoors than outdoors due to outgassing by new upholstery or other furnishings.
Empirical studies have shown that formaldehyde and acrolein are competitive agonists for similar irritant receptors in the airways. Thus, irritation may be related not to “total aldehyde” concentration but to specific ratios of acrolein and formaldehyde. Their relative difference in solubility, with formaldehyde being somewhat more water-soluble and thus having more nasopharyngeal uptake, may distort this relationship under certain exposure conditions (e.g., exercise). Acrolein is very reactive and may interact easily with many tissue macromolecules.
Formaldehyde is a primary sensory irritant. It is absorbed in mucous membranes in the nose, upper respiratory tract, and eyes. The dose–response curve for formaldehyde is steep: 0.5 to 1 ppm yields a detectable odor; 2 to 3 ppm produces mild irritation; and 4 to 5 ppm is intolerable to most people. Formaldehyde is thought to act via sensory nerve fibers that signal through the trigeminal nerve (CN-V) to reflexively induce bronchoconstriction through the vagus nerve (CN-X). The introduction of formaldehyde through a tracheal cannula to bypass nasal scrubbing greatly augments the irritant response, indicating that deep lung irritant receptors can also be activated. Formaldehyde can interact with water-soluble salts, such as submicrometer sodium chloride, and with carbon-based particles during inhalation and produce irritancy beyond that expected for the gas alone.
Two aspects of formaldehyde toxicology have brought it to the forefront of attention in recent years. One is its presence in indoor atmospheres as an off-gassed product of construction materials such as plywood, furniture, or improperly polymerized urea-formaldehyde foam insulation. This irritant vapor has the potential to cause respiratory effects at commonly experienced exposure levels. Formaldehyde is also a weak allergen. Recent findings suggest that formaldehyde causes nasopharyngeal cancer in humans and could be linked to leukemia and sinonasal cancer.
Acrolein is an unsaturated aldehyde that is more irritating than formaldehyde. Concentrations below 1 ppm cause irritation of the eyes and the mucous membranes of the respiratory tract. The mechanism of increased pulmonary flow resistance after acrolein appears to be mediated through both a C-fiber and centrally mediated cholinergic reflex. Ablation of the C-fiber network and atropine (muscarinic blocker) block this response. On the other hand, aminophylline, isoproterenol, and epinephrine (sympathetic agonists) partially or completely reversed the changes, whereas the antihistamines pyrilamine and tripelennamine had no effect.
Carbon monoxide is classed toxicologically as a chemical asphyxiant because its toxic action stems from its formation of carboxyhemoglobin, preventing oxygenation of the blood for systemic transport (see Chapter 11).
Analysis of data from air-monitoring programs in California indicates that 8-h average values can range from 10 to 40 ppm CO. Depending on the location in a community, CO concentrations can vary widely. Concentrations predicted inside the passenger compartments of motor vehicles in downtown traffic were almost three times those for central urban areas and five times those expected in residential areas. Occupants of vehicles traveling on expressways had CO exposures somewhere between those in central urban areas and those in downtown traffic. Concentrations above 87 ppm have been measured in underground garages, tunnels, and buildings over highways.
No overt human health effects have been demonstrated for COHb levels below 2 percent, and levels above 40 percent can be fatal due to asphyxia. At COHb levels of 2.5 percent resulting from about 90-min exposure to about 50 ppm CO, there is an impairment of time-interval discrimination; at approximately 5 percent COHb, there is an impairment of other psychomotor faculties. Cardiovascular changes also may be produced by exposures sufficient to yield COHb in excess of 5 percent.