a. Secondary inorganic (acidic) particulate matter (SIA)
A large portion of ambient PM in the Netherlands consists of secondary inorganic aerosol (SIA). These are produced in the atmosphere via chemical reactions involving gaseous pollutant precursors, and are dominated by such chemical species as acidic sulphates and nitrates and their salts. The next section is to a large extent based on a recent survey of the literature
(Schlesinger, 2000, Annex B; Schlesinger and Cassee, 2002) in which the health effects arising from exposure to specific fractions of secondary inorganic
aerosol constituents are based on available data from peer review published papers as well as publicly available reports on controlled animal and human clinical exposure studies involving these chemical species. The acidity of ambient particulate matter in the Netherlands is relatively low, due to
neutralisation by ammonia, and the major components of particulate matter are ammonium sulphate and ammonium nitrate. The evaluation was made for pure sulphates, nitrates and ammonium, and does not consider any possible
interactions between other gaseous or particulate pollutants.
Sulphate and sulphuric acid
The toxicological database for sulphate and sulphuric acid is sufficient for a risk assessment from a toxicological perspective. Exposures to acid sulphates have produced transient changes in pulmonary function in asthmatics, including enhanced non-specific airway responsiveness, and epidemiological evidence indicates that the exacerbation of symptoms in asthmatics may be related to atmospheric particulate acids. The concentrations of acidic sulphates needed to produce any effects in
controlled exposure studies are generally well above those found in the ambient air in the Netherlands. Short-term exposures of healthy animals (with the exception of the guinea pig) to H2SO4 concentrations of 1000 µg/m3 (< 1 µm diameter) generally do
not alter standard lung function tests (US-EPA, 1989). Similarly, healthy adult humans show no consistent effects on pulmonary function or respiratory symptoms with acute exposure to H2SO4 at < 1000 µg/m3, even with exercise (Avol et al.,
1988a; Frampton et al., 1992; US-EPA, 1989). On the other hand, there is some evidence that asthmatics may be more sensitive than healthy individuals to effects on lung function, and that they may experience modest bronchoconstriction following exposure to H2SO4 at < 1000 µg/m3 (Avol et al., 1988a,b ; Koenig et al., 1993; Linn et al., 1989; US-EPA, 1989). While basic lung functional indices may not be affected
some adult asthmatics following exposure to 100 µg/m3
(Utell et al., 1983). But, as above, there appears to be no consistent effect of acute exposure on airway reactivity in either healthy or asthmatic individuals (Avol et al., 1988a,b ; Linn et al., 1989). Although epidemiological studies suggest there may be segments of the population that are susceptible to inhaled acidic sulphates, toxicological studies generally used healthy adult animals, and very limited data are available to allow evaluation of the effects of different disease states, other than asthma, upon response to acid sulphate particles. Acute exposure to H2SO4 at levels as low as 100 µg/m3 alters mucociliary
transport in normal humans (Leikauf et al., 1981; Spektor et al., 1989), without altered particle clearance from the alveolar region. These effects may ultimately be reflected in alterations in the ability of these cells to adequately perform their role in host defences. There is also some evidence that sulphuric acid reduces resistance to bacterial infection, but this seems to depend upon the animal model used (Zelikoff et
al., 1994).
The exact characteristics of ambient acidic PM in epidemiological studies are not certain, and those used in most controlled studies may differ from those to which populations are actually exposed. The relative potency of acidic sulphate aerosols is related to their degree of acidity, i.e. the H+ content within the exposure environment (Koenig et al., 1993; Schlesinger, 1984, 1989; Schlesinger et al.,1990). Furthermore, the number concentration of particles within an exposure atmosphere, as well as the total mass concentration of H+, is an important factor in determining response
following inhalation of acidic sulphates (Chen et al., 1995). Most controlled exposure studies involved pure acidic sulphate droplets. However, in the ambient air acidic sulphates may also occur as a coating on the surface of other particles, such as metals or carbon, especially within combustion aerosols. It has been shown that up to an order of magnitude higher exposure levels of pure acid aerosols were needed to produce comparable biological results in animals than when the exposures involved acid coated on a solid particle (Amdur and Chen, 1989). Such exposures to surface- coated acid produced biological effects at concentrations as low as 20 µg/m3 (as H2SO4). Thus, it is likely that the physical nature of the inhaled acid particle is a key
factor in determining ultimate response.
Many of the controlled animal studies and all of the human clinical studies involved acute exposures. The available evidence suggests that the minimally effective concentration of sulphuric acid to alter pulmonary mechanical function, including non-specific airway responsiveness, in normal humans following acute exposure is > 1000 µg/m3, but in asthmatics it may be around 68–100 µg/m3
. However, effects on asthmatics, especially at these low concentrations, are quite inconsistent. This may be due to the normally large variability in asthmatic responses to low level air
contaminant exposure and also to susceptibility differences within segments of the asthmatic population. For example, elderly asthmatics do not seem to be especially susceptible, but adolescent asthmatics may be more susceptible. In any case, the extent of effect on pulmonary function is small at low acid exposure concentrations, with changes of < 10% in one commonly measured parameter, namely FEV1, following exposures of asthmatic subjects to sulphuric acid aerosols at concentrations 500 µg/m3
cardiopulmonary function is concerned, from ambient levels of sulphate or nitrate aerosols, even in presumably more sensitive asthmatics.
Another biological endpoint which has been extensively examined with acute
exposure of humans is mucociliary clearance from the tracheobronchial tree. This has been shown to be transiently altered in normal individuals by sulphuric acid aerosol at a concentration of 100 µg/m3
, with no evidence for any susceptibility difference for asthmatics. The nature of the effect at this concentration can be acceleration or slowing of clearance, depending upon the region within the tracheobronchial tree that is being examined. However, the pathological significance, if any, of such transient effects is not certain.
Perhaps more relevant to repeated ambient exposures are the results of longer-term controlled exposure studies. These all involved animals and indicate the potential for the production of non-specific airway hyperresponsiveness, persistently retarded mucociliary clearance and changes in airway secretory cell function with repeated exposures to sulphuric acid at concentrations ranging from 100–250 µg/m3
. The development of hyperresponsive airways in healthy animals at exposure levels below that producing any change in standard lung function indices may have implications for the pathogenesis of airway disease, and alterations in mucociliary function could have implications in terms of the development of chronic obstructive pulmonary disease. However, as noted, considerations of dose equivalency must be included in any evaluation in this regard.
The suggestion can be made that the controlled exposure studies do not adequately resemble the ambient conditions in which PM should be regarded as a very complex mixture of particulate matter. For a few years now, both animal and human exposure studies have been performed using concentrated ambient PM (see 4.3.1). Most of these studies determine sulphates and nitrates in a manner similar to that for air quality measurements. Unfortunately, very little information has so far been published in the literature, but a few examples can be discussed here.
Recently, twelve normal subjects were exposed to CAPs at an overall mass
concentration ranging from 99 to 215 µg/m3 at the University of Southern California. The corresponding nitrate measurements ranged from 16 to 72 µg/m3, and sulphate from 1.7 to 17.5 µg/m3. In California, nitrate was positively correlated with total PM mass (R = 0.58), but sulphate was not (R = -0.19). The group showed small and equivocal biological responses, if any, to CAPs exposure. Comparing these results with Table 2.1 (total SIA 10–14 µg/m3), one might assume that SIA did not cause a serious adverse effect in healthy humans, albeit that the number of measurements is limited (Linn, personal communication).
The daily dose for inhaled Dutch ambient sulphates is at most 200 µg. Sulphates are highly soluble components that will cross the lung-blood barrier rapidly. The amount that is deposited in the airways is most likely only a fraction of what is already present in the body. For instance, sulphate itself is already present in concentrations ranging between 240 and 420 micromol/litre in serum. There are numerous endogenous forms
for its ability to inhibit arterial wound healing (Ravn et al., 1996). Although a
transient decrease in blood pressure was observed during the initial bolus infusion of MgSO4, this effect was due to magnesium rather than sulphate. These facts also make
it less likely that airborne sulphate at ambient levels is a serious threat to human health.
All these studies have focused on the role of acidity of H2SO4. In the Netherlands,
about 80% of the secondary inorganic aerosol is found within the fine mode of PM10
(Visser et al., 2001). The annual average PM10 mass concentration ranges from 27 to
42 µg/m3
and of this the secondary inorganic particulate component accounts for about 10–14 µg/m3
(Keuken et al., 1999; Weijers et al., 2000; Visser et al., 2001). Since the acidity of ambient particulate matter in the Netherlands is relatively low, due to neutralisation by ambient ammonia, the major secondary components are
ammonium sulphate and ammonium nitrate.
Nitrate
The toxicological database on health effects from inhaled nitrates is very limited. Those studies which did evaluate toxicological responses generally involved exposure to nitric acid in the vapour state (e.g. Abraham et al., 1982; Koenig et al., 1983; Nadziejko et al., 1992; Aris et al., 1993; Schlesinger et al., 1994; Wong et al., 1996). These exposures (in the g/m3 range) were noted to produce various effects on
pulmonary functional and lung defence parameters. These effects can be attributed to the acidity rather than to nitrate itself. As mentioned in the previous paragraph, the acidity of secondary inorganics is largely reduced by ammonia. Dose estimates for inhaled Dutch ambient nitrate are in the order of 100 µg or less. There are not likely to be any adverse effects, as far as measured cardiopulmonary function is concerned, from ambient levels of nitrate aerosols, even in presumably more sensitive asthmatic members of the general population (Annex B). It should, however, be noted that some of the potentially more sensitive cardiopulmonary indices of response, such as heart rate variability (HRV), have not been assessed in controlled studies. Nitrate in itself is not very toxic, but the principal effects may arise as a result of the conversion of nitrate to nitrite. Nitrite is formed from nitrate by bacterial conversion in the oral cavity and/or stomach and not in the respiratory tract. Nitrite oxidises haemoglobin to methaemoglobin, which interferes with the transport of oxygen by the blood
(methaemoglobinaemia). There are also large uncertainties about the conversion of nitrate together with other gaseous pollutants in ambient air into more potent substances like radical forming agents. This evaluation focuses only on the pure nitrate as a causative agent. Clearly, information on atmospheric chemistry and the actual nitrogen species to which people are exposed are largely unknown.
Consequently, it is not yet possible to estimate the risks of nitrogen species covered by nitrate as a proxy.
Although the route of exposure may have profound implications for the effect at the target site, systemic1 effects based on systemic nitrate delivery as a result of airborne
1 Assuming a 50% deposition efficiency in the respiratory tract, a 24-hour outdoor exposure, a minute volume of 15 lpm and an ambient nitrate level of about 10–14 µg/m3, average daily intake of nitrate by inhalation is in the range of 100–150 µg/day. However, the exposure pathway for nitrate is estimated to be 95% through the diet. Dietary nitrate intake has been estimated to be 50 000–140 000 µg/day,
nitrate exposures do not seem likely. This alone does not rule out the fact that nitrate may very specifically affect the lung tissue. The studies that have been published on nitrate exposure do not provide clear evidence for risk of exposure to ambient aerosolised nitrate.
Ammonia
The average ammonia concentration in air in the Netherlands of 3.6 µg/m3
is substantially below the threshold limit value (TLV) of 25 ppm (about 18 000 µg/m3
) recommended by ACGIH (1996), which is intended to protect against ocular and respiratory irritation and may serve as the basis for a Reference Dose. Since 360 µg/m3
is the lower bound limit of the range of concern, it should not be necessary to apply an uncertainty factor of 10 for unusually sensitive individuals. Using a 70 kg human reference body and an inhalation rate of 20 m3/day, the corresponding dosage is 100 µg/kg/day or 7000 µg/day for ammonia. This is an estimate for a healthy worker. An additional safety factor of 10 may be applicable to protect risk groups.
Considerations
In the evaluation of effects from ambient pollution, an important consideration is the potential for special susceptibility of specific subgroups within the general population. Adolescent asthmatics may represent a sensitive segment of the population with respect to the bronchoconstrictive effects of fine mode acidic aerosols. Controlled exposures have produced transient changes in pulmonary function in asthmatics, including enhanced non-specific airway hyperresponsiveness in some cases. Although epidemiological evidence indicates that the exacerbation of symptoms in asthmatics may be related to atmospheric particulates, the contribution of chronic ambient particulate exposure to the development of airway hyperresponsiveness in normal individuals remains unclear.
There are, however, some caveats in this overall evaluation of potential health effects from exposure to ambient secondary aerosols. It is important to consider the
relationship between animal exposure studies and actual human exposures, both in terms of particle size and inhaled dose. It is also necessary to consider the
physicochemical characteristics of chemical species in the ambient air compared to those used in controlled studies. Although sulphates themselves may seem harmless, we cannot rule out the fact that they carry other, reactive constituents on their surface. Clearly, atmospheric chemistry should try to find out in what way sulphates appear in ambient air. As a final point, the potential for interactions between particulate matter and ambient gases must be considered in developing conclusions as to effective levels of the former.
depending on the quantity of vegetables, which implies that intake through the respiratory system is roughly 70 µg/day. The Acceptable Daily Intake (ADI) for nitrate set by the European Commission's Scientific Committee for Food is 1600 µg/kg/day (Ysart et al., 1999). These values are even lower for sulphate. In addition, assuming a drinking-water consumption of 2 l/day and a daily consumption of 100 g of vegetables, overall daily nitrate consumption may easily range from 200 000–400 000 µg. It is
The issue of exposure concentration (C) and duration (T) comes into play when evaluating acute exposure responses in terms of circumstances where repeated exposures are the pattern of concern. Evaluation of the role of C and T must be
performed using the acute exposure database, since the database for chronic exposures is much too sparse in this regard. The response to acute exposures, at least in terms of their effect on two of the most commonly evaluated endpoints, namely
tracheobronchial mucociliary clearance and respiratory region clearance, appears to be a function of both C and T. In the rabbit, for example, a concentration of 75 µg/m3 sulphuric acid was at or below the no-observed-effect level for altering mucociliary clearance, even when the C x T was equivalent to that obtained using concentrations at 100 or 200 µg/m3. Exposure to 50 µg/m3
for two hours a day for fourteen days was found to be ineffective in altering alveolar region clearance. It appears that a threshold exists for both the number of deposited acid particles as well as the mass
concentration needed to produce any biological response, at least for some endpoints. One important consideration in evaluating the health effects from secondary inorganic aerosols is this issue of threshold. The current epidemiological database for ambient particulate matter suggests that the concentration-response relationship presents no indication of a clear threshold. However, for some specific chemical constituents of ambient particulate matter, a threshold may exist. For example, the occurrence of a threshold concentration, exposure to which would not result in any effect regardless of the exposure duration, is not unexpected for acidic particles. The response to acid sulphates and other inorganic acidic chemical species is likely due to the deposition of hydrogen ions on airway surfaces. The extent of available hydrogen ions may be altered in the inhaled air, or once the aerosol deposits on airway surfaces, due to the presence of endogenous ammonia in the respiratory tract and buffers in airway surface fluids respectively. Thus, it is likely that a certain threshold concentration is needed to overcome these processes and result in deposition of sufficient hydrogen ions so as to alter localised airway surface or cellular pH. The occurrence of such a threshold may also contribute to the inconsistencies which are often noted in human exposure studies involving low acid concentrations.
In addition to a threshold for exposure concentration, a threshold for exposure
duration also seems to occur, such that acute exposure for longer than this critical time is needed at some effective exposure concentration in order to overwhelm the
buffering capacity of the airway surface fluids and to produce an observable response. For example, exposures to sulphuric acid aerosol for 30–40 min at 1000 µg/m3
were required before any effect on mucociliary clearance could be observed in animal studies (Schlesinger et al., 1978). Thus, a normal individual should be able to tolerate certain exposure regimes with no observable effect. However, the particular C and T values which do not result in observed responses could differ for people with airway disease, and the product is probably not a constant value. Furthermore, the specific threshold for C or T probably depends upon both the sensitivity of the endpoint being examined and the exact exposure protocol.
The available database for acidic sulphates strongly suggests that long duration exposures to low concentrations and short duration exposures to high concentrations may not necessarily be toxicologically equivalent. This is likely to apply to other inhaled acidic particulates as well. Given this database, it can be concluded that acute
effects at 100 ug/m3 on potentially sensitive human asthmatics are small and very inconsistent, and that the observed change in airway epithelial secretory cells in rabbits chronically exposed at 125 µg/m3
was not associated with a persistent or