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Review of Possible Mechanisms of Toxicity
Summary
Reduction of risks to health from inhaling particles depends upon control of the toxic components of the aerosol cloud. In contrast to other pollutants, usually single chemical substances, particles are of complex chemical, physical and biological composition, differing from place to place and from time to time. An understanding of what in this complex mixture determines toxicity would allow determination of the ideal metric for its monitoring and control. Studies of the mechanisms of toxicity contribute to identification of these toxic components.
The ambient atmosphere contains a mass of biological material in the form of bacteria, fungal spores and pollens, many of which are known to cause infectious and allergic disease. Almost all of this material is found in the larger fraction of particles collected as PM10, above about 1 µm in aerodynamic diameter. In addition, ambient air also contains a large number of non-biological particles produced by human activity. The smallest, nucleation mode, particles aggregate into larger, accumulation mode particles, resembling bunches of grapes, which thus have a greater total surface area than if they were a uniformly spherical particle. Both types of particle are less than 1 mm in diameter. Following inhalation, particles <c10 µm in diameter may deposit in the conducting and gas exchanging areas of the lung where they may, if they override local defence mechanisms, initiate tissue injury and inflammation.
Once coming into contact with epithelial cells or phagocytic macrophages, toxic particles may cause the release of oxygen free radicals. This may be due to the effects of chemicals adsorbed onto the surface of the particles, including reactive metals, or to some property of the particle surface itself. These free radicals may initiate a series of biochemical reactions and molecular events, culminating in inflammation. Experimental animal and limited human studies indicate that the smallest, <0.1 µm, particles cause more inflammation in the periphery of the lung than do larger particles. The inflammatory reaction caused by inhalation of toxic particles may lead to worsening of existing lung disease and enhance the sensitivity to allergens of people with hay fever and asthma. It may also have the capacity to alter blood coagulability and circulating red cells and platelets, a mechanism that could explain the adverse influence of inhaled particles on cardiovascular morbidity and mortality.
Experimental evidence and theoretical considerations suggest that small particles, <1 µm in diameter, may be the predominant source of the toxicity of ambient anthropogenic particles. There is therefore an argument for using a metric of this size range, expressed either as mass or numbers, for monitoring and control purposes. The argument needs to be tested by further specific epidemiological and experimental studies of the relationships of particle size and composition to biological and health endpoints. It should however not be forgotten that much toxicity of particles resides in natural biological components, found predominantly in the larger size fraction. While these would not normally be regarded as pollutants, being normal components of the air, they may confound studies of the toxic mechanisms of particulate air pollution.
The Fate of Inhaled Particles
59. The adult human lung, with a surface area of 40-120 square metres, comes into contact with between 10,000 and 20,000 litres of ambient air daily and is exposed from the time of birth to the particles present in the air. Since many of these are micro-organisms, such as pollens, fungal spores and bacteria, with the potential to cause illness, maintenance of health depends upon the mechanisms that the lung has evolved for defending itself against such inhaled particles. These defence mechanisms are usually adequate to deal with a large number of particles deposited onto its surface. In brief, they constitute an effective filtration system provided by the nose and upper airways, onto which the larger particles are deposited, and anti-microbial systems, including mechanical removal, neutralisation and inflammation. Larger particles deposited on the conducting airways, such as the nose, trachea and bronchi, are propelled by the mucociliary clearance mechanisms into the throat and ultimately swallowed or expectorated. Smaller particles which reach the oxygen-absorbing surface of the lung are removed by scavenging cells, macrophages. These either carry the phagocytosed particles up the airways towards the mucociliary clearance system or migrate through the alveolar wall into the lung's internal clearance channels, the lymphatic vessels, which drain into the lymph nodes, where the particles might remain in an inert state, or be transported into the blood.
60. Both chemical and immunological defence mechanisms have evolved in the lung to counter the toxic effects of micro-organisms. Some of these mechanisms include generation of oxidising reactions that will damage bacteria but also have the potential to damage the host. Non-biological particles may also elicit these responses. In the normal lung with a normal load of particles, the resulting oxidation is rapidly neutralised by anti-oxidants such as uric acid, reduced glutathione and ascorbic acid, which are secreted by the lining cells of the respiratory tract or which diffuse into the lung from the circulating blood.
The Toxic Effects of Inhaled Particles
61. The toxic effects of any inhaled particle depend upon its capacity to elicit these responses and cause damage to the lung. Although the healthy lung is capable of dealing effectively with a large number of particles deposited onto its surface, there will come a point at which the defence mechanisms are overwhelmed either by particle numbers or by the inherent toxicity of the particle. In patients with compromised lung function, such as defective mucociliary clearance, the lung is likely to be less well equipped to deal with particle loads, and such people may succumb more readily to infections and notice effects of air pollution on their lungs that well people do not.
62. Injury to the lungs may take many forms, but can be divided into damage to conducting airways and to the gas-exchanging parts. Larger biological particles deposited on airways may cause an allergic reaction, such as hay fever caused by very large (30 µm) grass pollen grains or asthma by particles derived from house dust mites. Other biological particles, bacteria and viruses, may lead to infections such as acute bronchitis. Most biological particles are in the size range >1 µm, an important point to note when considering the relative toxicities of different size fractions, since most allergic reactions are likely to be a response to particles in this relatively large fraction of the ambient aerosol. Non-biological particles may cause chemical bronchial irritation, rarely leading to a non-allergic form of asthma (sometimes called the reactive airways dysfunction syndrome), and may interfere with the airway defence mechanisms, leading to cough and sputum production. Smaller particles, deposited in the alveolar region of the lung, may cause inflammation affecting the cells in the alveoli and of the capillary blood vessels within them. Such inflammation may have immediate effects, such as pneumonia, or longer-term effects causing scarring (fibrosis) and/or destruction (emphysema) of the alveoli. These effects are also familiar as causes of breathlessness and premature death in long-term cigarette smokers.
63. The lung's defence mechanisms serve to deal with both non-biological and biological particles. The formation and size distribution of non-biological particles in the ambient air has been described above (see paragraphs 5-20). Their toxicity depends on both their aerodynamic size and shape, which determine where in the lung they are deposited, and their chemical reactivity, which determines their effect on the defensive cells of the lung and, probably, their ability to penetrate the epithelial lining of the alveoli. In general, particles larger than about 10 µm diameter are deposited in the nose and throat and those between about 4 and 10 µm deposit mainly within the airways; all these are likely to be removed by ciliary action (Figure 13). Particles of less than about 4 µm are able to reach the alveoli, from which they are cleared by macrophages. Generally, as the particle size and breathing rates increase, particles deposit closer to the throat and nose, whereas enhanced deposition in alveoli takes place with smaller sized particles and slower breathing rates (Heyder et al 1986, Iwasa et al 1970). Within the conducting airways, particle deposition tends to be greatest where airways divide, especially for those particles >1 µm in diameter (Kim and Hu 1998). In patients with diseased airways, the pattern of deposition varies and becomes more irregular, with areas of increased deposition. A 30% reduction in airway cross-sectional area may result in a greater than doubled deposition in the airways at the point of division (Kim and Hu 1998). Regional deposition dose, or local tissue burdens, can be different between individuals, even if total lung deposition values are comparable. Therefore it is possible that particle burdens could reach threshold limits in local lung regions under exposure conditions that are normally acceptable, particularly in individuals with compromised lungs.
64. A chemically inert particle reaching an alveolus would be expected to be engulfed by a macrophage and removed either up to the airways, where it would be cleared by ciliary action, or through the alveolar wall into the lung's internal clearance channels, the lymphatic vessels, to the lymph nodes (Figure 14). In either case, direct damage to the lung would have been averted. Chemical reactivity of the particle may however interfere with this process, causing an alteration in the function (activation) of the macrophage leading to release of chemical mediators and to inflammation in the alveolus or in its pathway to the lymph nodes within the lung. An understanding of the toxicity of particles depends on understanding the chemical reactions between the particle and the defence systems of the lung.
Figure 13. Deposition of particles and their biological effects. 
65. Whether or not lung damage and inflammation occur as a result of particle inhalation depends on the inherent ability of the particle to damage the defensive cells and on the dose deposited in the lungs. In industrial situations, such as mining or stone-cutting, the very large mass of particles generated may be able to overwhelm these defences, accumulate in the lung and cause inflammation and scarring if the particles are themselves toxic. This is the basis of the diseases called pneumoconioses, which result from long-continued cumulative damage to the lung. If the particles are not toxic, they may simply accumulate in the lung but cause no harm, a situation that is recognised to occur in tin refiners and workers involved in producing barium sulphate, for example. In some special circumstances, the shape of the particle is particularly critical; asbestos itself is chemically rather inert but its shape not only allows long thin fibres to penetrate into the alveoli but also prevents their removal, and leads to a macrophage-orchestrated inflammatory and fibrotic response, the condition known as asbestosis.
66. The means by which toxic particles exert their effects are not fully understood, but may in part be related to the activity of the particle surface in releasing toxic chemicals, free radicals, which then interfere with the functions of the epithelial and macrophage cells of the lung. The classic concept of lung toxicity, as exemplified by the action of quartz, is that these radicals damage the membrane surrounding the particle once it has been taken into the cell, and that this leads to the release of chemical messengers, attraction of other cells and consequent inflammation. However, recent evidence (Samet et al 1999) suggests that release of metals outside the cell may have subtle effects on cell signalling by stimulation of cell surface receptors. Such a quasi-pharmacological mechanism may be relevant to the small doses of air pollutant particles that are apparently associated with the observed effects.
67. From the above arguments it will be clear that in order for particles in ambient air to be harmful they must be both toxic and present in sufficient amount. Conceptually this has caused difficulties, since the concentrations of particles measured by mass in ambient air are generally several hundred times lower than those known to cause ill-health in the industrial workplace. Moreover, their toxicity also has been thought likely to be quite low since they largely consist of relatively inert chemicals, such as carbon, and the simple soluble compounds, ammonium sulphate and nitrate. In addition, the toxic effects ascribed to ambient particles are predominantly short-term whereas those in industrial situations are mainly long-term and chronic. And yet the epidemiological evidence discussed below (see paragraphs 88-129) strongly suggests that some individuals in populations exposed to particulate pollutants in the ambient air suffer ill-health and premature mortality as a consequence. These observations may partly be explained by the concept that in any large population there are always some vulnerable people, usually already suffering from a serious illness, in whom a relatively small influence is required to provoke worsening or even death. Moreover, much of the evidence of the health effects of air pollution has employed pollution data from single outdoor monitoring sites, but there is evidence that this may in some circumstances significantly under-estimate personal exposure to certain pollutants, since such exposure is determined also by activity patterns and proximity to local sources (see paragraphs 43-51). Some studies have demonstrated that the levels measured by personal PM10 monitors may be on average up to 2-5 times higher than those recorded at fixed site monitors (Lioy et al 1990, Watt et al 1995, and see paragraphs 43-51.). These factors, along with factors governing particle deposition in the lung, will all have an effect on lung dose in any individual and the consequential cellular events.
The Relevance of Particle Size and Mass to Toxicity
68. The ambient particulate cloud comprises particles of different sizes, from a few nanometres up to several tens of micrometres, and of these all those below about 10 µm diameter have some potential to reach and be deposited in the airways and alveoli. This forms the basis of the use of the metric PM10, which represents the mass of such particles. However, in a given weight of ambient particles, the large majority of the mass will reside in the fraction greater than 1 mm in diameter, but the greatest number of particles by far will be below this size. In other words, the smallest particles are most numerous but weigh the least. Thus when particles are collected and measured by weight, that weight may disproportionately represent the largest particles. PM10 is therefore dominated by the larger particles above 1 µm and below 10 µm and is thus appreciably affected by local sources of coarser particles, such as may be stirred up by the action of wind and abrasion of roads, soil, the sea surface and so on. This is the size fraction and type of dust that has traditionally been regarded as relatively inert. In certain circumstances, as in rural areas in the summer months, it does however contain much biological material that may be responsible for allergic reactions (Seaton and Crompton 2000), so the toxicity of the larger size fraction cannot be dismissed. With respect to urban, predominantly anthropogenic pollution, if the epidemiological evidence does indeed indicate a causal association between PM10 and ill-health, it seems likely on mechanistic grounds that the component of PM10 that is responsible is that fraction generated by combustion and photochemical reactions. These reside mainly, but not wholly, in the nucleation and accumulation mode particles, generally below about 2 mm in diameter.
69. The difficulty of understanding the association between adverse health effects and the low mass of particles present in ambient air might be resolved if the factor responsible for the toxicity of particles were to lie on their surface, thus making their toxicity at least in part dependent upon the surface area rather than the mass reaching the alveoli. This concept has arisen from the original observations of Ferin and colleagues (1992), who showed that titanium dioxide, a substance previously regarded as inert, becomes highly toxic to the lungs of rats when inhaled as particles around 0.02 µm in diameter. This and other studies have led to the suggestion that the best indicator of toxicity may be the total surface area of particles inhaled (Oberdörster et al 1994, 1995).
70. A key factor in promoting the toxicity of particles is their capacity to be transferred from the alveolar space into the interstitium of the lung. For this to occur, two barriers have to be penetrated. The first of these is a layer of waterproofing material, surfactant (Hills 1981). Interactions between particles and surfactant have been little studied, but some evidence suggests that they become clothed in the material and move below its surface (Schürch et al 1990). Once through the surfactant layer, the particles have to pass through the second barrier, the alveolar epithelium. This process would be assisted by the physical forces exerted by surfactant, but may also be effected by active transfer through the cells by a process known as pinocytosis.
71. A plausible biological explanation of why pathological effects may differ, depending on the size of particles, is that large numbers of small particles cause inflammation even when their total mass is relatively low. This concept is not unfamiliar to the medical profession, being true, for example, of grass pollen and hay fever and of asbestos and asbestosis. Whatever the mechanisms, the next step to consider is whether such inflammation at alveolar or airway level could be responsible for the effects observed in studies of human populations. From the point of view of chronic lung disease, it is relatively easy to see that increasing alveolar inflammation could cause a deterioration in the condition of individuals who already have disease of the small airways of the lung. It is less easy to see how such inflammation, in the alveoli, could cause worsening of the condition of people with asthma, which is a disease of the airways. For this to be plausible, either inflammation would require to be initiated in the airways directly by the particles, perhaps enhancing the response to allergen in sensitised individuals, or the alveolar inflammation would need to release substances that caused the airways to narrow. While possible mechanisms, such as a nerve reflex or release of substances carried by the blood to the airways, may be hypothesised, there is no direct evidence relating to this. Alternatively, of course, the worsening may be due to an allergic reaction to the biological matter in the larger size fraction deposited directly on the airways.
Mechanisms of Toxicity of Particles to the Lung
72. Studies of toxicity have mostly used either experimental animals or isolated cell systems, although some limited experiments have been carried out in healthy humans. These sorts of studies have been used to test hypotheses generated from epidemiological findings or to dissect out different components of the hypothesised mechanisms of lung damage. In interpreting these studies it should be remembered that the health effects associated with air pollution are diverse and complex, and may not be a consequence of a single pathogenic mechanism. For example, it seems implausible that worsening of asthma in children could result from the same injury as the increased risk of cardiac death in elderly people. It thus seems unlikely that a single toxic fraction responsible for all effects will be identifiable, although it is possible that a single process, such as oxidative stress, may initiate different reactions in different individuals with differing susceptibilities. Moreover, most experimental studies, because of their limited time frames and the healthy condition of the animal, human or cellular subjects, use concentrations of particles far higher than are ever encountered in the ambient air, while some also use particles that are quite untypical of those found in ambient air.
73. A number of animal models have been developed to investigate different aspects of the toxic effects of particles. These have generally involved intratracheal instillation of suspensions of particles collected from ambient air or particles of specific composition, such as diesel particles, residual oil fly ash (ROFA), carbon black or titanium dioxide. Airway epithelial cells and macrophages are the initial target cells for particle interaction and deposition, and are therefore the cells most likely to be affected by the toxic effects of particles. Following deposition in the lung, particles are rapidly phagocytosed by alveolar macrophages (Kobzik 1995) which migrate towards the bronchoalveolar junction (Mauderly et al 1987, 1994, Strom et al 1990). Large numbers of particles, however, may overwhelm the macrophage phagocytic system and result in increased numbers of particles coming into contact with the respiratory epithelium. Impairment of clearance of particles by macrophages begins when the particles occupy 6% of the macrophage volume and is completely inhibited when 60% of macrophage volume is occupied (Morrow et al 1988). This inhibition occurs at a lower percentage if the particles are of very small size, suggesting that the effect is less due to the volume than to the surface area in contact with the inside of the cell (Oberdörster et al 1994). Oxidative damage mediated by particles then leads to activation of macrophages with the subsequent release of pro-inflammatory mediators (MacNee et al 1997, Yang et al 1997). These studies have of necessity used higher concentrations of particles than are inhaled in natural circumstances, and it remains unclear as to how far, if at all, overload of macrophages contributes in the real life situation.
74. Human airway epithelial cells in culture also phagocytose diesel exhaust particles and then release several pro-inflammatory cytokines in a dose-related manner (Steerenberg et al 1998, Bayram et al 1998, Ohtoshi et al 1998). This suggests that these cells can perform phagocytic functions in the same manner as macrophages and neutrophils, and may also act as initiators of inflammatory responses. Similar responses have been seen on exposure to particles collected from ambient urban air (Kennedy et al 1998) or to ROFA, a contributor to the >2 µm size fraction of urban ambient particulate matter in some circumstances (Carter et al 1997).
75. Some studies have used concentrated particles derived from urban air or, as a surrogate, diesel exhaust, unclassified as to size, in investigating mechanisms. Diesel exhaust particles in high concentration have been shown to enhance allergic responses in guinea pigs and mice (Kobayashi and Ito 1995, Schlesinger 1995). In mice with allergic airways disease, a condition with similarities to human asthma, large doses of fine particulate matter obtained from the ambient urban atmosphere have increased airway hyperreactivity (Takano et al 1997, Miyabara et al 1998). The carbon core of diesel particles has also been shown to have a significant adjuvant effect on the local immune-mediated inflammatory response as well as on the systemic specific IgE response to allergen (Lovik et al 1997). Diesel exhaust particles have also been shown to adsorb allergens from grass pollen onto their surface, thus potentially increasing allergen deposition in the respiratory tract (Knox et al 1997). Such studies give support to the hypothesis that allergic individuals may be made more sensitive to allergens as a result of exposure to particulate pollution.
76. Healthy human volunteers, when exposed to diesel exhaust particles of uncharacterised size distribution and at high mass concentrations for 1 hour, show evidence of airway, alveolar and a more general inflammatory reaction (Rudell et al 1999, Salvi et al 1999). These exposures were, however, very much higher than those experienced by populations in whom health effects have been shown epidemiologically. Nasal instillation of diesel particles, with or without allergen, in atopic human subjects has produced an increase in the allergic antibody, IgE, in nasal lavage fluid (Diaz-Sanchez et al 1994, 1997). These, and other studies of the mechanism of ragweed allergy (Fujieda et al 1998), suggest that diesel particles can contribute to the enhancement of mucosal allergy in humans.
77. Most importantly with respect to the relevance of particle size to toxicity, experimental studies in rats have shown that nanometre-sized particles cause more lung injury than the same deposited mass of fine respirable particles of the same material (Oberdörster et al 1994, Donaldson et al 1998). More free radical activity is generated by ultrafine particle samples than by coarser samples of the same substance (Donaldson et al 1998, Zhang et al 1998) and hence the differences in their ability to cause lung inflammation may be explained on the basis of different amounts of free radical activity, probably related to the greater surface area available. In vitro exposure of phagocytic cells to ambient particles collected from different urban settings causes oxidative stress which correlates with the iron content of the particles (Prahalad et al 1999). PM2.5 collected from the ambient air induces the expression of genes for stress-related proteins, such as heat shock proteins and the magnitude of this has been correlated with the amount of soluble copper in the particle preparations (Vincent et al 1997). It has thus been suggested that the lung dose of bio-available transition metal, rather than instilled particulate mass, may be the primary determinant of the acute inflammatory response (Costa and Dreher 1997). However, two notes of caution need to be sounded. First, Brown et al (2000) have shown that ultrafine particles themselves, without transition metals, may induce inflammation in rat lungs. Secondly, Monn and Becker (1999) have drawn attention to the important cytotoxicity of endotoxin derived from biological components of the summer air, almost certainly in their case from pollen and fungal spores, and which is found predominantly in the larger fraction 10-2.5 µm in diameter.
78. A large number of transition metals appear to be adsorbed onto the surface of particles (see paragraphs 15 and 16), and these are capable of generating reactive oxygen intermediate species from various airway cells. These in turn activate factors that lead to the release of a large number of pro-inflammatory molecules such as cytokines, cell adhesion molecules and inflammatory mediator receptors (Meyer et al 1994, Jimenez et al 2000). The ROFA response mentioned in paragraph 74 above is inhibited by the inclusion of either a metal chelator or free radical scavenger, suggesting that the metals present in these particles produce oxidative stress and thus release of inflammatory mediators (Carter et al 1997).
79. Overall, the experimental evidence points towards a central hypothesis explaining the initiation of the pathological effects associated with exposure to particles. This is that something associated with the particle surface, most likely adsorbed transition metals but also possibly some other physico-chemical property, is able to initiate oxidative stress when it comes into contact with lung cells. This then activates chemical messengers that switch on genes for inflammation. The inflammation may then have different consequences in individuals with differing susceptibilities.
Particles and the Cardiovascular System
80. Ambient particles have been associated with cardiovascular mortality and morbidity, especially among the elderly population (Dockery et al 1993, Poloniecki et al 1997). While it is intuitively possible that inhalation of particles may lead to exacerbation of an underlying respiratory condition, why this should lead to an effect on the cardiovascular system might not seem immediately apparent. Seaton et al (1995) suggested that low grade inflammation, caused by ultrafine particles deposited in the alveoli, might lead to increased coagulability and that the altered blood flow characteristics might therefore be a part of the pathological mechanism linking particulate pollution with cardiovascular mortality and morbidity. Several haematological factors, including plasma viscosity, fibrinogen, factor VII and plasminogen activator inhibitor occurring as a consequence of inflammatory reactions, are predictive of cardiovascular disease. Release of IL-6 from macrophages following particle phagocytosis, as has been demonstrated in vitro (Terashima et al 1997), could stimulate hepatocytes to secrete fibrinogen (Akira and Kishimoto 1992) and increase blood viscosity.
81. In support of this hypothesis, Peters et al (1997) have shown increased plasma viscosity, a measurement largely determined by fibrinogen concentrations, in a large population sample coinciding with an air pollution episode in Europe. However, it is not certain that adequate account was taken in this study of concurrent falls in temperature. In a direct test of the hypothesis, Seaton and colleagues (1999) showed that exposure to PM10 (measured both at a central point and as estimated personal exposures) correlated inversely with haemoglobin, red cell count, packed cell volume and platelet count, but not with coagulation factors. These relationships persisted after correction for plasma albumin concentration, suggesting that the blood changes were due to red cell and platelet sequestration. This study was carried out over two years in cities in which the ambient concentrations of PM10 never exceeded 100 µg/m3. The authors argued that alveolar inflammation may lead to alterations in red cell and platelet adhesiveness, and that consequential sludging in capillaries may be a factor in cardiovascular morbidity.
82. Other workers have observed changes in heart rate variability on exposure to sulphur dioxide and to the acid derived from sulphur dioxide (sulphuric acid) in human exposure studies (Tunnicliffe et al in press). Changes in components of the electrocardiograph with natural exposures to concentrated urban particles in dogs have also been described (Stone and Godleski 1999). It has been suggested that such changes may represent direct stimulation of the autonomic nervous system, which could, in some circumstances, lead to cardiac dysrhythmias such as might cause sudden death. Some support for this hypothesis comes from a study of heart rate variability, an index which may be a predictor of acute cardiac episodes, in elderly people in Baltimore USA (Liao et al 1999). These investigators showed rises in PM2.5 to be associated with reductions in heart rate variability, suggesting an effect on neural control of the heart. A pilot study of subjects with implanted cardiac defibrillators showed a tendency for increased episodes of arrhythmia to occur following rises in several indices of traffic-related pollution including black carbon and PM2.5 (Peters et al 2000). The delay between the initial rise in pollution and the onset of arrhythmias suggested that haematological rather than reflex stimuli were responsible, and it should be noted that in general ischaemic stress is a more likely initiator of an arrhythmia than is a neural reflex.
Particles and Long-Term Health Effects
83. No studies have directly addressed the explanation of the observed long-term increases in risk of death associated with exposure to particulate air pollution (see paragraphs 118-122). This apparent excess of mortality applies to death from cardio-respiratory disease and lung cancer. From the discussion above, it is possible to hypothesise that pulmonary inflammation could increase risks of chronic obstructive lung disease in the same way that it does as an effect of smoking; inflammation from one cause is likely to add to the effects of inflammation from another. With respect to lung cancer, it is known that urban particles carry polycyclic aromatic hydrocarbons, several of which are bronchial carcinogens (EPAQS 1999). They will therefore act as a vehicle for their transport into the lungs, again adding to the risks derived from other sources such as cigarette smoke. If particles do indeed increase risks of death from heart disease, the effect is likely to be mediated through modulation of biochemical or cellular risk factors, such as by increasing levels of blood fibrinogen leading to increased atheroma formation in arteries. At present such mechanisms remain wholly speculative.
Conclusions
84. In summary, these mechanistic possibilities can be divided into two broad areas, the physical journey of particles into the lung and the biochemical/cellular mechanisms. The physical journey is clearly influenced by particle size. In general, smaller particles are more efficiently deposited in alveoli and small airways, especially in subjects with lung disease. Removal by macrophages is hindered if the cells become overloaded, and this is more likely with large numbers of very small particles than with small numbers of much larger ones.
85. The precise mechanisms of lung toxicity have yet to be fully clarified but most likely invoke the uptake of particles by phagocytic and epithelial cells, generation of extra- and intra-cellular reactive oxygen species, and subsequent release of pro-inflammatory and tissue damaging mediators. Once released, these attract other cells to the site of the response and, in the case of cardiovascular disease, may alter the coagulability and flow characteristics of the blood. In the case of allergic disease, such as asthma and hay fever, a synergistic interaction between tissue responses to inhaled particles and allergic responses to inhaled allergens may amplify the allergic tissue response, and it should not be forgotten that such allergens are themselves included mainly in the larger size fraction of PM10. Thus pulmonary inflammation provides at least a theoretical explanation for most of the observed associations between exposure to particulate pollution and ill health, either by direct effects on the lung, by synergistic reactions with allergens or by secondary effects on the blood.
86. It is possible that movement of particles into the lung interstitium, where the inflammatory process may be initiated, is an important factor in the lung's reaction. This appears to occur predominantly by uptake of very small particles by epithelial cells. There is evidence that the toxic effects demonstrated experimentally are dependent not only on the dose in mass terms, but also on the size of the particles, the effects being greater (on a mass-for-mass basis), the greater the number of particles. This effect is likely to be related to surface area and probably due to substances on that surface. Current evidence suggests that transition metals initiating the release of free radicals are the most likely candidates for this toxic component.
87. For future epidemiological studies and for monitoring purposes it would be desirable to identify the components of the ambient aerosol most closely related to its toxicity, and to use this as a metric rather than PM10. Experimental studies indicate that these components would be likely to be included in the mass metrics, PM1.0 and PM2.5. However, particle number, particle surface area, or even content of certain transition metals that connect the measurement with cellular mechanisms linked to health outcomes may in the future prove more useful.
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Published 17 May 2001
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