Influences of ambient atmospheric particulate aerosols on health – an evolutionary perspective

By C. Vyvyan Howard
Developmental Toxico-Pathology Research Group, Dept of Human Anatomy and Cell Biology, University of Liverpool, UK

Introduction

Aerosol scientists classify the respirable fraction of particles found in air into size bands. They are generally defined as:

Consideration of the types of particle that our ancestors were exposed to throughout human evolution is illuminating. These mainly consisted of suspended sand and soil particles and biological products such as pollens. Most of these are relatively coarse and become trapped before getting deep into the lung. There have always been ultrafine particles in our environment, mainly consisting of minute crystals of salt, which become airborne through the action of the waves of the sea (Eakins & Lally, 1984), and viruses. These are not normally toxic, as they either consist predominantly of soluble salts or are biodegradable. Clearly, there were few airborne particles of significance to our health smaller than 70 nanometres in diameter throughout our prehistory, until we harnessed fire to our uses about 100,000 years ago. The defence mechanisms that we have evolved to protect the organism from inhaled particles have come about as a result of the challenges set by the environment during that evolutionary process. These do not automatically confer protection when the environment changes.

It has been recognised for many hundreds of years that exposure to high levels of dust can lead to ill health and particularly lung disease. Silicosis was described by Agricola in the sixteenth century (Agricola, 1556). As the Industrial Revolution progressed, it became clear that workers involved in mining, foundry work and stone grinding were particularly at risk of developing silicosis. However, this is a ‘high dose’ disease, requiring prolonged exposure to high levels of dust before the defence mechanisms in the lung are totally overwhelmed. There are now a number of diffuse fibrotic conditions of the lung associated with industrial exposure to particles including; pneumoconiosis in miners, bissinosis in cotton workers and asbestosis amongst laggers and associated trades. The first indication that serious pathology could arise from low-dose exposure to particles came with the recognition that asbestos fibres could cause the, previously rare, tumour pleural mesothelioma. In general, the particles required to cause this type of disease are less than 10 µm average diameter for roughly spherical particles and less than 3 µm in length for fibres.

Epidemiological evidence of the effect of air pollution on mortality had been noted since the mid 18th century, but it was the London ‘smog’ of 1952, with which the deaths of over 4,000 people were associated (Ministry of Health, 1954), that accelerated the introduction of controls for smoke emissions in urban areas in the UK and across Europe and the USA.

The purpose of this paper is to review the latest state of scientific knowledge of the effects of particle exposure on health. The main emphasis will be on low-dose effects on the general population from ambient air, rather than examining special cases in industrial settings.

Sources and composition of ambient particulate aerosols.

The size distribution of particles in the atmosphere is not uniform but tends to be tri-modal (Harrison, 1999). This is associated with their mode of formation.
· Nucleation mode particles are generally < 100nm diameter and are mainly the result of primary combustion particle production such as from traffic fumes. They are not particularly long-lived in the atmosphere in their initial form because of agglomeration and condensation mechanisms.
· Accumulation mode particles are typically found between 100 nm up to 2.5 µm and arise because of the growth of nucleation mode particles. They tend to consist of secondary particles predominantly sulphate nitrates of ammonium. Their lifetime in the atmosphere is longer than for nucleation mode particles and can be typically be over 1 week. They are thus likely to undergo long range transport.
· Coarse particles are the result of grinding mechanical processes and re-suspension processes from the surface of the land of sea. Their size is in general more that 2.5 µm.

The ultrafine range of atmospheric particles varies considerably from location to location. Urban ultrafine composition has been addressed by Cass et al. (2000). The average chemical composition of ultrafine particles in Southern California was found to be 50% organic compounds,
14% trace metal oxides,
8.7% elemental carbon,
8.2% sulphate,
6.8% nitrate,
3.7% ammonium ion,
0.6% sodium and
0.5% chloride.
Mobile or stationary fuel combustion sources predominated, with an estimated consistency of 65% organic compounds, 7% elemental carbon, 7% sulphate and 4% trace elements.

The respiratory system and its natural defence mechanisms

The airways of the respiratory system are lined with a pseudostratified columnar ciliated epithelium from the nose downwards to the respiratory bronchioles, except for a part of the lower pharynx and upper larynx, which have a stratified squamous epithelium. The surfaces of the epithelia are kept moist by secretions of mucus from goblet cells. The lining of the major airways of the trachea and bronchi are covered with a ‘mucociliary escalator’. The cilia beneath the carpet of mucus beat upwards towards the larynx and move it slowly upwards where the mucus is finally swallowed and ingested. Beyond the respiratory bronchioles is the alveolar air space, which has a simple epithelium with no cilia, onto which a surfactant is secreted. The alveolar surface is patrolled by alveolar macrophages, living within the layer of surfactant, which engulf foreign matter arriving at the alveolar surface. It is of interest to note that alveolar macrophages have difficulty in recognising particles of less than 65nm diameter as being ‘foreign’ and that, for such very small ultrafine particles, the engulfing mechanism tends not to be activated. This doubtless is connected in some way with our evolutionary history.

There are three mechanisms by which particle deposition may occur, namely: sedimentation, inertial impaction and diffusion (or Brownian motion).
· Sedimentation occurs under the influence of gravity and tends to increase with increasing particle size.
· Inertial impaction occurs when a particle is being carried in air and the direction of the air changes, the momentum of the particle carrying it forward in its initial path. There is a tendency for particles to impact at bifurcations in the bronchial tree. Deposition is usually determined by the momentum (weight and speed) of the particle. Increased flow tends to increase impaction, especially of larger particles. This turbulent impaction is more common in the upper, larger airways and predominantly affects particles greater than 1mm in diameter.
· Diffusion occurs with very small particles, as a result of being bombarded by other molecules, similar to the behaviour of gas molecules. Movement of these particles is completely random. Therefore, if they are close to a wet mucosa they are likely to deposit. Re-suspension does not happen subsequently. Diffusion is the method of deposition for the smaller ultrafine particles with a diameter less than 10 nm and happens predominantly in the nasal and upper pharyngeal parts of the respiratory tract.

The relative deposition of particles according to their size is shown in Fig 1 (ICRP, 1994). Note that the very smallest particles tend to deposit in the upper airways by diffusion, while the bulk of the ultrafine particles deposit predominantly in the alveolar region of the lung by impaction. Other particles which deposit on the lining of the trachea and bronchi are usually ingested.

Figure 1. Predicted deposition of inhaled particles of different sizes of unit density in the human respiratory tract during nose breathing, light exercise (ICRP, 1994)

Particle size and toxicity

When bulk materials are made into particles, the surface to volume ratio of the material increases. When this process reaches the nano-scale, the proportion of ‘surface’ atoms in the material increases exponentially and the surface chemistry also changes, with the material tending to become more chemically reactive. This is the basis for the production of heterogeneous catalysts in the chemical industry. Platinum in the bulk state is a noble metal and particularly chemically un-reactive. In the form of ultrafine particles, it can facilitate a number of chemical reactions. Jefferson & Tilley (1999) demonstrated that nano-scale particles take on crystalline forms with facets and isolated atoms at vertices and discuss the implications of this morphology to the surface chemistry.

The toxicity and the ability of ultrafine particles to cause inflammation increase as the mean particle size becomes smaller. This has been shown by a series of experiments with laboratory rodents; by Oberdörster (2000) using ultrafine particle inhalation; and by Donaldson et al. (1999, 2000) using UFP instillation. For example, Donaldson et al. (1999) showed that 14nm carbon black was roughly 3 times more toxic than 50nm carbon black and 10 times more toxic than 250nm carbon black. Other experiments (Donaldson et al., 2000) showed that materials as dissimilar as titanium dioxide and latex demonstrated similar levels of toxicity which was dependent on size rather than composition. Oberdörster’s (2000) experiments with exposure to PTFE fume showed genuinely low-dose toxicity (50 µg m-3 for 15 minutes led to very high mortality). However, the instillation experiments must be considered to have been conducted at high dose compared to the levels of particles normally present in ambient air.

It has been hypothesised (Seaton et al. 1995) that the chronic inhalation of particles can set up a low grade inflammatory process that can damage the lining of the blood vessels, leading to arterial disease. This theory would certainly be supported by observations on the effect of tobacco smoking. While some smokers will develop cancer, nearly all will cause damage to the lining of their arteries (Auerbach et al., 1965).

In vitro studies on living cells have confirmed the increased ability of ultrafine particles to produce free radicals, which then cause cellular damage (Rahman et al. 2002; Li et al. 2003; Uchino et al. 2002). This damage can be manifested in different ways, including genotoxicity (Rahman et al. 2002) and altered rates of cell death, including apoptosis (Rahman et al. 2002; Uchino et al. 2002; Kim et al. 1999; Afaq et al. 1998).

Particle mobility in the body

There appears to be a natural ‘passageway’ for nanoparticles to transocate through the body. This is through the ‘caveolar’ openings in the natural membranes which separate body compartments. These openings are between 40 and 100 nm in size and are thought to be involved in the transport of ‘macromolecules’ such as proteins, including on occasion viruses. They also happen to be about the right size for transporting ultrafine particles. Most of the research on that, to date, has been performed by the pharmaceutical industry, which is interested in finding ways of improving drug delivery to target organs. This is particularly so for the brain, which is protected by the ‘blood-brain barrier’ which can be very restrictive. This topic has been reviewed by Gumbleton (2001). In essence, it appears that chemists are able to design ultrafine particles that can translocate through certain membranes, allowing ‘piggybacking’ of novel chemicals across membranes which are normally impervious. For example, Kreuter et al. (2001 and 2002) have shown that Poly(butyl cyanoacrylate) nanoparticles precoated with polysorbate 80 can be used to enhance the delivery of apolipoproteins to the brain. Alyaudtin et al. (2001) have demonstrated similar UFPs mediate delivery of [3H]-dalargin to the brain.

Although there are clear advantages to the intentional and controlled targeting of ‘difficult’ organs, such as the brain, by using nanoparticles to increase drug delivery, the other implications needs to be considered. When environmental ultrafine particles (such as from traffic pollution) gain unintentional entry to the body, it appears that there may be a pre-existing mechanism which can deliver them to vital organs (Gumbleton, 2001). The body would then be ‘wide open’ to any toxic effects that they can exert. The probable reason that we have not built up any defences is that any such environmental toxic ultrafine particles were not part of the prehistoric environment in which we evolved and therefore there was no requirement to develop such defensive mechanisms. There is considerable evidence to show that inhaled ultrafine particles can gain access to the blood stream and are then distributed to other organs in the body (Kreyling et al. 2002, Oberdörster et al. 2002).

Epidemiological evidence for the health effects of particle aerosols.

There are two approaches to the investigation of negative health effects associated with exposure to particles by inhalation. Firstly, to investigate the long term influence of habitual inhalation of poor quality air on morbidity and mortality. Secondly, to examine the short term sequelae of exposure to high particulate aerosol loading in poor air.

The majority of epidemiological studies that have been performed on large populations have used PM10 as the index of exposure. There is now widely accepted high quality evidence that chronic exposure to typical urban levels of PM10 damages health. Studies which have examined the prevalence or incidence of disease, in relation to the levels of particulate pollution, while controlling for confounding factors, have shown associations between exposure and increased premature mortality, chronic respiratory disease and reduced lung function (Dockery et al. 1989 and 1993; Raizenne et al. 1996; Pope et al. 1995; Abbey et al. 1995; Ackermann-Liebriche et al. 1997; Kunzli et al. 2000). The ‘six city study’ in the USA found a differential mortality between the most and the least polluted cities of 15%, after controlling for confounding factors. The study concluded that 3% of all deaths in the USA were associated with inhalation of particles. The study by Kunzli et al. (2000) concluded that up to 6% of all deaths, in the parts of Europe included in the study, could be associated with particle inhalation. The pathogenic mechanism is not clear, but a large proportion of the increase in pathology in the populations studied is associated with cardiovascular disease, which is similar to the pattern of disease in tobacco smokers and suggests that there may be a common aetiology. The observations of Seaton et al. (1995) may be of considerable relevance.

With respect to acute mortality and exposure to particulate aerosols, there is another body of evidence which supports the hypothesis that they can be the cause of ‘deaths brought forward’. Figure 2 shows the results of studies on daily mortality performed in 19 cities around the globe. The % increase in mortality for an associated increase of 10 µg m-3 in PM10 is shown. Although not all the studies reach statistical significance, they do all point in the same direction. This is strongly indicative of a causal relationship.

Figure 2. PM10 and daily mortality from cities around the world. Expressed as a percentage change in daily mortality associated with a 10 µg m-3 increase in PM10. (Anderson, 2000)

The increase in mortality is expressed through respiratory failure and cardiovascular events, such as myocardial infarctions and strokes. In general, the temporal trend is predicable, the respiratory deaths occurring within the first 24 hours after the onset of poor air quality, while some studies show that the cardiovascular events peak after a lag of about 4 days after the onset of poor air quality. This is indicated in Figure 3.

Figure 3. Effects of ultrafine particles (UP) and fine particles (PM2.5) on mortality for prevalent diseases (total, cardiovascular, respiratory, others). Best day-lag model. There seems to be a stronger immediate effect (lag O or 1 days) on respiratory causes and a stronger delayed effect (lag 4 or 5 days) on cardiovascular causes. (Wichman and Peters, 2000).

Discussion

Populations living in urban locations are routinely exposed to ambient levels of particulate aerosols that did not exist throughout evolution. There is strong evidence that our respiratory systems are not well adapted to cope with the smaller size fractions such as aerosols. In particular, the ultrafine fraction tends to be preferentially deposited in the alveolar portion of the lung, beyond the mucociliary escalator. In the alveolar region the alveolar macrophages, the final defence mechanism before particle internalisation occurs, have difficulty recognising the smallest particles and in addition they are easily overloaded by the numbers of particles arriving. Once internalised, insoluble particles appear to have the ability to translocate to other body compartments.

The influence of the size of particles on their toxicity is currently the subject of increasing research. The indication from current research is that there is a general tendency for acute toxicity, expressed through an ability to induce inflammation, to increase as the particle size decreases, particularly below 100nm diameter. The precise mechanism of this effect remains unknown but there are indications that it is associated with changes in the surface chemistry, possibly through an ability to produce free radicals. There are parallels with the action of heterogeneous catalysts.

Although many countries continue to use PM10 as the standard metric for assessing particle exposure, some countries are changing to the use of PM2.5. There is a debate within the scientific community concerning which fraction of PM10 is responsible for its toxicity. CAFÉ, a European scientific committee studying the effects of air pollution on health has recently recommended that the EU adopt a PM2.5 regulatory standard.

What appears to be beyond dispute is that health effects at the population level have been associated with both chronic and acute particulate aerosol exposure. The science is widely accepted and recognised to be of a high standard, despite some reservations from certain industries (HEI, 2000).

The positive aspect of this problem is that particulate aerosols are short lived and, unlike some other forms of pollution, do not persist in the environment. The associated health problems are therefore open to remediation. It is simply a matter of political willpower being sufficient for policy implementation to take place.

The negative aspect is that the ultrafine fraction of particulate aerosols, arguably the most hazardous part, is the most stubbornly resistant to abatement through regulation (Wichmann and Peters, 2000). Additionally, the major source of particulate emissions in cities is vehicular traffic. Exclusion of vehicles from areas of high population density is currently a difficult political problem. However, reduction in particulate aerosol concentrations would definitely lead to tangible health benefits in the relatively short term, and therefore should be actively pursued.

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