National Ambient Air Quality Objectives For Particulate Matter - Executive Summary

Human Health Effects

It has generally been accepted since the 1970s that there is an association between respiratory health and high levels of particulate air pollution. What has not been clear until more recently is that adverse effects also occur at ambient concentrations that are experienced today in North America and Western Europe. At issue still is to what extent the observed effects should be attributed to air pollution as a whole, comprised of multiple air pollutants, or rather to particulate matter specifically, and if so, to which component of particulate matter, either in terms of particle size or chemistry.

A decade and more has now passed since physiologically relevant measures of PM were incorporated into monitoring programs. Many studies have now been published that have used PM₁₀ measurements and attempted to associate these levels with various health effects. Additionally, several studies that measure fine particles, as PM_2.5 or PM₅, British Smoke Shade (BSS), sulphate and /or particle strong acidity (PSA or H⁺) have recently become available. The role of chemical speciation of particles has been investigated to only a very limited extent, although several epidemiological studies have used sulphate as the particle metric, and a small number of studies, particle acidity. Very little epidemiological testing of the role of ultrafine particles (< 0.1 µm) has as yet taken place since the current ambient monitoring data do not support such studies.

Epidemiological studies of the effects of PM on human health explore statistical associations between changes in ambient levels of PM and changes in the occurrence of cardiorespiratory health problems in the general population. Five basic health variables have been examined in epidemiological studies: mortality, hospital admissions/emergency department visits, respiratory health (symptoms, medication use, reduced activity days, elementary school absenteeism), pulmonary function, and cancer (the latter in only a few studies, incidental to other endpoints). All of the epidemiological studies are observational in nature; that is, the investigator has no control over the exposure or treatment of the subjects in the study, which differentiates them from the controlled human exposure studies discussed below.

Acute Effects

Daily or short-term variations in particulate matter, as PM₁₀, BSS, PM_2.5 or sulphate, were significantly associated with increases in all-cause mortality in 43 regressions carried out in 20 cities across North and South America and Europe. Virtually all of these studies demonstrated consistent associations between air pollution and acute mortality. These associations could not be explained by the influence of weather (temperature and humidity were most commonly found to have independent associations with mortality), season, yearly trends, day-to-day variations and variations due to holidays, epidemics, or other non-pollutant factors, since all the analyses looked for some or all of these potential biases and accounted for them in various ways in the analysis. Most of the studies also examined one or more gaseous pollutant in addition to PM.

The magnitude of the risk for PM₁₀ was small, varying between 0.4% and 1.7% per 10 µg/m³ increase, with an unweighted mean of 0.8% and a weighted mean of 0.5% for concentrations weighted by sample size averaging 25-78 µg/m³ except in the two South American studies where concentrations averaged 82 and 115 µg/m³. The results were highly consistent under differing PM₁₀ exposure conditions. The magnitude of the increase was about the same for BSS as for PM₁₀ but even fewer studies included more than one or two co-occurring gaseous pollutants.

Far fewer studies have investigated the relationship between PM_2.5 concentrations and mortality. In the best-conducted and most reliable study which examined PM_2.5 (and sulphate), an overall increase in mortality for six U.S. cities of 1.5% per 10 µg/m³ increase in PM_2.5 was observed, with a range of 0.85 - 2.2% per 10 µg/m³ for the six cities individually, at average PM_2.5 concentrations that ranged form 11-30 µg/m³ The increase in PM_2.5 related risk of mortality is thus about twice that for PM₁₀. Although the magnitude of the mortality risk was greater in the six city study for sulphate compared to PM_2.5 (2.2% vs. 1.5% per 10 µg/m³), the strength of the association was greater for PM_2.5 than sulphate.

While the increases in mortality risks associated with different particle metrics are small, they nonetheless signify substantial numbers of avoidable deaths due to the very large size of populations impacted by air pollution. These increases in relative risk due to air pollution have been observed at particulate matter concentrations well within the range of normal ambient concentrations and substantially below current standards and objectives (the current Canadian 24 hour acceptable TSP objective is approximately equivalent to a PM₁₀ level of 60-80 µg/m³ and to a PM_2.5 level of about 30-50 µg/m³). Furthermore, there was little evidence in the PM₁₀ and PM_2.5 data that the dose-response curveincluded a threshold; instead the response was observed to increase monotonically with increasing concentration, in the PM₁₀ concentration range below 80-100 µg/m³ and average PM_2.5 concentrations 14.7-21 µg/m³. The lack of a threshold down to low concentrations suggests that it will be difficult to identify a level at which no adverse effects would be expected to occur as a result of exposure to particulate matter.

On a population basis, the hypothesis is that what we're seeing is exacerbation of pre-existing disease, or enhanced response of a subpopulation of sensitive individuals. Suggestions that the elderly are a susceptible population, more so than young adults, remains unsolved in the absence of pathology. However, overall the results suggested a surprisingly modest increase in relative risk for the elderly compared to the whole population. This does not support the suggestion that it is only the elderly who are being affected and dying from air pollution, and that their lives are being shortened by air pollution episodes by only a few days or weeks before they would have died anyway.

In all of the analyses that examined one or more air pollutants together in the same statistical model with particulate matter, the association of particulate matter with daily mortality was remarkably robust, despite the problems of disentangling the effects of PM from other air pollutants. This was the case for all four of the normally considered gaseous pollutants, SO₂, NO₂, CO andozone. Moreover, in most locations, the magnitude of the PM association was greater than any other air pollutant considered, the exception being ozone, in a few cases. The magnitude, robustness and consistency of this association across so many locations with differing air pollutant mixtures indicates that PM is the best indicator of the air pollution effect on mortality, and is considered to give some support to PM of some kind, possibly acting together with other air pollutant(s), as a causal agent.

Particulate matter of some kind has been shown to have significant associations with increased hospitalizations in most of the 26 studies examined. All of the 16 studies that examined PM₁₀ and one or more respiratory endpoints requiring hospitalization showed significant associations, varying between 0.45% and 4.7% pe r 10 µg/m³ increase in PM₁₀ at mean concentrations varying between 25 and 53 µg/m³. Particulate matter was shown to have associations with cardiovascular disease in addition to its associations with respiratory disease, but the magnitudes of the cardiovascular associations were generally smaller than those for respiratory disease. Only three hospitalizations studies, two in Toronto and one in Montréal, directly examined the association between PM_2.5 and respiratory or cardiac effects, with an increase in respiratory effects observed in all three studies. At mean PM_2.5 concentrations 12.2-18.6 µg/m³, respiratory hospitalization and emergency room visits increased 2.5-9.6% per 10 µg/m³ PM_2.5 increase. Five different air pollutants were considered in addition to PM in single, bivariate and multiple analyses in various locations. Particulate matter was the air pollutant with the most consistent and stable association with increases in hospitalizations. Ozone and carbon monoxide were judged to have independent associations as well as PM.

The strongest and most consistent association of particulate matter with respiratory hospitalizations is considered to be with sulphate. A 2.0% - 2.7% increase per 10 µg/m³ increase in sulphate (co-regressed with ozone) was indicated in southern Ontario in the best conducted study of the series of eight examined. This was calculated to be equivalent to a 1.1% increase per 10 µg/m³ increase in PM_2.5, based on site-specific monitoring and conversion factors. The correlations between ozone and sulphate were high (0.5 - 0.8) in all eight studies, which causes difficulties in separating out the effects of one from the other. Overall, there is good evidence for an association between sulphate and respiratory hospitalizations and sulphate is considered to be a good surrogate for fine particles from combustion sources. This does not mean that the sulphate is itself directly toxic however. An association between BSS (a somewhat smaller particle than PM₁₀) and respiratory hospitalizations exists, but is considered to be weak, presumably because this PM metric does not adequately represent secondary PM (much of which is colourless), being an optical measurement of dark coloured particles. Results for acidity (H⁺) were inconsistent, with strong associations and high significance in some studies, and none in others.

No evidence for a threshold of effects for respiratory hospitalizations associated with particulate matter or other air pollutants was found at the low (10 to 100 µg/m³ PM₁₀) concentration ranges examined. Curves appear to increase monotonically, with steep slopes at low concentrations and some suggestion of curvilinear responses (lower slope) at higher concentrations. The effect of age on hospitalizations or emergency department visits was examined in several locations, since historical data from episodes of high air pollution had strongly suggested that it was the elderly, the young and those with pre-existing respiratory and/or cardiovascular conditions who were responding to air pollution. While some studies found that the elderly were at increased risk compared to other age groups in the population, the increases observed in cardiorespiratory hospitalizations were by no means predominantly due to effects on the elderly. Children were also shown to be a high risk group for increased respiratory disease in a few, but not all, studies. Those with preexisting COPD were also identified as a susceptible subgroup.

In addition to its effects on mortality and hospitalizations, increases in particulate matter have been shown to cause small, reversible decrements in lung function in normal asymptomatic children, and in both adults and children who have some form of pre-existing respiratory condition, particularly asthma. These changes were often accompanied, especially in adults, by increases in symptoms such as chronic bronchitis or cough. Respiratory-related restrictions in activity severe enough to result in an increased number of days lost to work in adult workers and in school absences in children were also demonstrated to be associated with high ambient particulate matter, in some cases PM₁₀, and in others, PM_2.5 or other fine particulate components such as sulphate. Effects on respiratory health (lung function symptoms, absenteeism etc.), although much less serious than hospitalizations, and most certainly than mortality, nonetheless have the potential to impact much more of the population.

Longer Term and Chronic Effects

In contrast to the larger number of studies on daily variations in pollution associated with mortality and morbidity, relatively few studies are available that examine the effects of long term or chronic exposure on health endpoints. Such exposures, varying in duration between one and 16-20 years exposure, were associated with increases in mortality, respiratory disease symptoms, decrements in lung function and, possibly, with increases in lung cancer in both cross-sectional and the more powerful prospective cohort studies. In the first of two cohort mortality studies (six cities), average mortality was increased by 9%, 14% and 35% for each 10 µg/m³ increase in PM₁₀, PM_2.5 or sulphate. In the same study, the probablility of survival over a 14 year period was reduced from approximately 88% in the least polluted city to 79% in the most polluted city. Based on the mean pollutant level across the six cities, lifespan was estimated to have been reduced by about two years over the 14 year period, an observation incompatible with suggestions that most or all the observed deaths related to PM are due to harvesting, (the accelerated deaths of persons already ill by a few days or weeks). In a larger study covering 151 cities, mortality increases associated with a 10 µg/m³ annual increase in fine particle concentrations ( PM_2.5 and sulphate) were lower, at 7% over a period of seven years.

The effects on mortality cannot with certainty be ascribed to a true chronic effect, since they could equally be the result of cumulative effects of daily variations in PM. However, the increases in incidence of chronic bronchitis and decreases in lung function, capacity, growth and development that were shown in cohorts of children across North America after chronic or lifetime exposure to acidity, sulphate and fine particulate pollution, must be considered to be true chronic effects. There were indications also from a long term (20-25 years) cohort study in older adults that this increased incidence of disease, and probably also the reduced lung capacity that accompanies it, are carried over into adulthood as increased susceptibility to adverse effects of air pollutants. Although the development of lung cancer was also associated with fine particulate air pollution, the associations were weak by comparison with other lifestyle factors such as smoking.

Fine Particles versus Coarse Particles

The attributes that determine the toxicity of particles are poorly understood; however, particle size is known to be a very important determinant of inhalability and eventual deposition within the respiratory tract. In order to be inhalable and to reach the tracheobronchial area of the respiratory tract, particles must be smaller than about 10 µm in diameter (or up to 15 µm with mouth breathing). Particles 2-3 µm and smaller are able to reach the alveoli in the distal parts of the lung, and have been termed respirable (hence the general reference to PM_2.5 as respirable particles). The chemical composition of particulate matter has also been hypothesized to play an important role in its toxicity and certainly fine PM is far more complex chemically than coarse PM, which derives mainly from crustal material. Particle number, rather than mass, has also been suggested as an important determinant of toxicity, since large numbers of very small particles have a very high surface to volume ratio. They therefore present greater opportunities for surface adsorption of toxic substances such as heavy metals or PAHs, and subsequent deposition in the lungs.

The most valuable health studies for the purpose of attributing effects to a specific particle size and composition are those studies in which several particle metrics were employed, and particularly if these were not too highly correlated with each other. Typically, when PM₁₀ and PM_2.5 concentrations are both measured, it is often not possible to distinguish the effects of one from another, because PM_2.5 is a part of PM₁₀, and the two are usually highly correlated (r 0.6). However, the coarse fraction of PM₁₀ (particles of size 2.5-10 µm) is often not highly correlated with PM_2.5 (particles 2.5m) because it stems from different sources than the fine fraction. A few recent carefully conducted studies that included large databases have directly compared the coarse fraction of PM₁₀ to fine particles.

The results of these and other studies have shown that in almost all cases, in both acute and subchronic mortality studies, fine particles as PM_2.5, had a stronger and more significant association with mortality than coarse particles, as either the coarse fraction, or PM₁₀ and/or TSP. In only two cases was there an association between the coarse fraction and mortality, and even these were of questionable validity. Sulphate, which is part of the fine fraction of PM, appears to have as strong or stronger an association than PM_2.5 with increased mortality and hospitalizations. In one study in which sulphate and the non-sulphate fraction of PM_2.5 were directly compared, the non-sulphate portion was equally as, or more toxic than sulphate itself however, suggesting that sulphate would be an inadequate surrogate for all fine particle effects.

Overall, these studies support the hypothesis very well that the fine particle fraction is more important as a predictor of toxicity than the coarse fraction. However, coarse particles have not yet been eliminated from consideration, as there is some indication they may play a role in cardiovascular disease and COPD.

Experimental Data

Carefully controlled, quantitative studies of exposed humans in laboratory settings offer a complementary approach to epidemiological investigations. Advantage is taken of the highly controlled environment to identify responses to individual pollutants or sometimes pollutant mixtures and to characterize exposure response relationships where possible. In addition, such a controlled environment provides the opportunity to examine interactions with other environmental variables, such as exercise, humidity or temperature. Insofar as individuals with acute and chronic respiratory diseases can participate in exposure protocols, potentially susceptible populations may also be studied, although those with more severe preexisting disease and hence those most likely to be affected by air pollutants, are naturally excluded. Clinical studies also have other limitations: for practical and ethical reasons, studies must be limited to small groups, which may not be representative of larger populations; exposure must also be limited to short durations and to concentrations of pollutants that are expected to produce mild and transient responses; and exposures are often limited to a single pollutant, or to a very limited pollutant mix, which never replicates the complex mixture to which populations are actually exposed. Furthermore, transient responses in clinical studies have never been validated as predictors of more chronic and persistent effects.

Controlled human exposures to acidic and inert particles at relatively high levels compared to those generally experienced in the environment have not caused significant alterations in respiratory function in healthy individuals. However, acidity has been shown to slow mucociliary clearance of particles from small airways at concentrations as low as 100 µg/m³. The clinical studies identify asthmatics as a susceptible population, but not persons with chronic obstructive pulmonary disease (COPD), or the elderly, at least not for acidic particles. Asthmatics, especially children and adolescents, may experience adverse effects on airway function at concentrations experienced on occasion in ambient air (~35 µg/m³ H₂SO₄ for 40 min).

Almost all of the human clinical studies have been based on observations of pulmonary function changes and subjective symptom reports. There are hardly any data published on particle-induced airway inflammatory responses. No data on changes to the cardiovascualr system have been documented. There is reason also to suspect that decrements in pulmonary function may not be a sensitive indicator for particle-induced lung injury. Moreover, based on the assumption that the response of pulmonary function to air pollutants may be a protective mechanism for the lungs from receiving further insults in the deep airways, failure of certain subjects, such as COPD patients, to have pulmonary function responses to particles might render these patients more vunerable to the pulmonary injury. Neither have the human clinical studies used particle generation systems that reflect the complexity of ambient particles.

Based on the extremely limited clinical database available on various species of particles, acidic aerosols produce the most significant bronchoconstriction, while the toxicity of sulfate is related to acidity per se. The toxicity of nitrates was not considered, since previous work had shown it not to exert effects on lung function at concentrations below 1000 µg/m³ in clinical studies. Inert particles appeared to have no effect on lung function in either healthy or asthmatic volunteers in the few studies available. Very little work has been done on the effect of particle size specifically on airway mucociliary function, although limited studies have shown that fine particles (less than 2.5 µm) are cleared from the lung more slowly than larger particles, and that submicrometre (< 1.0 µm) particles clear very slowly indeed, taking more than one to two years in a few cases, especially in patients with obstructive lung diseases.

Overall, the clinical data do not lend much support to the observations seen in the epidemiology studies, particularly to the observations that high ambient particulate concentrations are associated with mortality within hours or a few days at most. Despite the fact that the ranges of particle concentrations tested usually exceed those experienced by the general population, little evidence for a dose response relationship has been documented in the clinical toxicological literature. Even at high particle concentrations in susceptible subpopulations, acidic aerosols have been found to produce only small decrements in lung function. The data do identify one susceptible subpopulation, asthmatics, who currently comprise five to eight percent of the Canadian population, a percentage that has been rising in the past decade in Canada as well as in other western countries.

The discrepancy between clinical and epidemiological data may be related to a number of factors, many of which are related to the general limitations of clinical studies described earlier. Furthermore, the pulmonary function parameters that are most often used in clinical studies may not be sensitive enough to indicate particle-induced adverse health effects. Particle size and type may also be an issue. In most clinical studies, artificial particles were used, which do not reflect the complexity of real world particles. The sizes of particles often used are above 0.5 µm, which does not include the full range of the particle size distribution found in ambient air. In particular, nanometre-sized ultrafine particles, that have been found in animal studies to induce acute pulmonary inflammation and death at very low concentrations, and are present in ambient air, have not been examined in clinical trials.

Studies on experimental animals (or tissue samples) have many of the same advantages and disadvantages of controlled human studies. A wide range of pollutants and concentrations can be tested under controlled laboratory conditions, and autopsies of study animals can be performed to investigate tissue damage from exposure to pollutants. However, for the most part, experimental studies involve well-defined particle species and do not by any means reflect the full ra nge of complex ambient particle mixtures to which humans are exposed, a problem noted above with respect to Clinical Studies also. There is considerable uncertainty also in extrapolating results from animal inhalation studies and applying these results to humans for the purpose of risk assessment. Therefore, such studies are most appropriately used to explore mechanistic aspects of the toxicity of particles. A summary of the effects of PM from the animal toxicology literature is reviewed below prior to a discussion of mechanistic aspects of the toxicity of PM.

Studies using experimental animals have not provided convincing evidence of particle toxicity at ambient levels. Acute exposures (4-6 hour single exposures) of laboratory animals to a variety of types of particles, almost always at concentrations well above those occurring in the environment, have been shown to cause:

• decreases in ventilatory lung function;
• changes in mucociliary clearance of particles from the lower respiratory tract (front line of defence in the conducting airways);
• increased number of alveolar macrophages and polymorphonuclear leukocytes in the alveoli (primary line of defence of the alveolar region against inhaled particles);
• alterations in immunologic responses (particle composition a factor, since particles with known cytotoxic properties, such as metals, affect the immune system to a significantly greater degree);
• changes in airway defence mechanisms against microbial infections (appears to be related to particle composition and not strictly a particle effect);
• increase or decrease in the ability of macrophages to phagocytize particles (also related to particle composition);
• a range of histologic, cellular and biochemical disturbances, including the production of proinflammatory cytokines and other mediators by the lungs alveolar macrophages (may be related to particle size, with greater effects occurring with ultrafine particles);
• increased electrocardiographic abnormalities (an indication of cardiovascular disturbance);
• increased mortality.

Bronchial hypersensitivity to non-specific stimuli and increased morbidity and mortality from cardio-respiratory symptoms occurs most likely in animals with pre-existing cardio-respiratory diseases.

Subchronic and chronic exposure tests involved repeated exposures for at least half the lifetime of the test species, often on a schedule that mimicked workplace conditions (e.g. 6h/day, 5 days/wk). Particle mass concentrations to which test animals were exposed were very high (> 1 mg/m³), greatly exceeding levels reported in the ambient environment. Exposure resulted in significant compromises in various lung functions similar to those seen in the acute studies, but including also:

• reductions in lung clearance;
• induction of histopathologic and cytologic changes (regardless of particle types, mass, concentration, duration of exposure or species examined);
• production of chronic alveolitis and fibrosis;
• production of lung cancer (a particle and/or chemical effect).

The epidemiological finding of an association between 24 hour ambient particle levels below 100 µg/m³ and mortality has not been substantiated by animal studies as far as PM ₁₀ and PM _2.5 are concerned. With the exception of ultrafine particles (- 0.1µm), none of the other particle types and sizes used in animal inhalation studies cause such acute dramatic effects, including high mortality at ambient concentrations. The lowest concentration of PM_2.5 reported that caused acute death in rats with acute pulmonary inflammation or chronic bronchitis was 250 g/m³ (3 days, 6 hr/day), using continuous exposure to concentrated ambient particles.

The extrapolation of results from experimental animals to humans is, however, fraught with uncertainty. This uncertainty relates to the dosimetry of the respiratory tract, differences in the sensitivities of specific target cells, differences in cell populations in the individual airway generations of animal species, differences in metabolic activity of lung cells, and differences in the lifespan between laboratory animals and humans. A recent comparative dosimetric analysis conducted by Miller and colleagues has yielded some interesting results, namely that, based on the calculations per ventilatory unit or per alveolus, humans receive much greater numbers of particles than do rats when exposed to the same concentration of PM. This trend is even more pronounced for individuals with compromised lungs (smokers, asthmatics, and patients with chronic obstructive lung disease) compared to normal subjects. Therefore, rats exposed to 1000-1500 µg/m³ of particles may actually have received a level of particles equivalent to 120-150 µg/m³ in humans. Given the caution which must be exercised in extrapolating risks from animals to humans, animal studies are best used to help elucidate the mechanism(s) of particle toxicity.

The animal studies clearly show effects on the lungs resulting from the inhalation of particulate matter, effects that can be attributed to a particle effect per se, as described above. No firm conclusions can be drawn, however, from the results of the numerous animal toxicology studies to answer the question of which particle type and size is most likely to cause the adverse effects. Particle size does appear to be a very critical character, however, with smaller particles having more pronounced effects, and particle size is believed to be the most important characteristic influencing deposition in the human respiratory system.

The significance of particle size is linked also to particle number and surface area. Ultrafine particles (- 0.1 µm), by virtue of their greater numbers (2.4 million particles of 0.02 µm diameter correspond in mass to 1 particle 2.5 µm in diameter), greater surface area and slow clearance from the pulmonary interstitium, may be of particular toxicological importance and may also provide an answer to the puzzle of observed epidemiological effects at low particle mass levels. Ambient monitoring of the ultrafine particle mode of the urban aerosol is very difficult, and therefore, few data are yet available to carry out epidemiological testing of the role of ultrafine particles in contributing to cardio-respiratory illness and death.

Chemical composition of the particle may also play a role. From the toxicological evidence, the particle types most likely to induce acute adverse effects include metals, organics, acids and acidic sulphates of the fine particle mode, possibly occurring as coatings on fine or even ultrafine carrier particles. The coarse particle mode is less likely to induce acute adverse responses than are either the fine or ultrafine modes, a fact attributed to both size and composition. However, these larger particles may well contribute in some way to effects.

The impact of interactions between different constituents of air pollution has been examined in animal studies to only a limited degree, mostly focusing on particulate and one gas-phase compound only. Such combined exposures have resulted in mixed responses, showing either no effect of the combination or some synergism depending on endpoint, but overall the results are equivocal. However, realistic environmental conditions are far more complex than those utilized in experimental settings. The actual mechanism of particle induced cardiovascular response is not yet clear. Some recent studies have suggested that it may involve the oxidation of low density lipoprotein by reactive oxygen species accompanying particulate pollution. Oxidized low density lipoprotein is known to be very cytotoxic.