Institute for Risk Assessment Sciences
Utrecht University
Health Effects of Nitrogen Dioxide
(NO2) and Particulate Matter (PM)
Jules Bisong, BSc.
Master Thesis
Utrecht University
The Netherlands
August 2010
Supervisor: Dr. Ir. Gerard Hoek
Bisong, Jules
Master Thesis
Utrecht University, August 2010
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Contents:
Page
Abstract
3
Introduction
4
Relevance of Thesis Topic
5
Sources of NO2 and PM
7
Health Effects of NO2
9
Health Effects of PM
12
Risk Groups
15
Conclusion
17
References
18
Bisong, Jules
Master Thesis
Utrecht University, August 2010
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Abstract:
This thesis outlines the health effects of air pollutants such as NO 2 and PM.
They involve a variety of diseases like asthma, heart disease, lung disease,
and allergies. The pollutants are from various sources, including the
combustion of fossil fuel from motor vehicles, and other dust-generating
processes, such as construction and demolition. Certain individuals, such as
asthmatics, people with compromised immunity, etc, are included in the risk
groups for diseases caused by NO2 and PM.
Bisong, Jules
Master Thesis
Utrecht University, August 2010
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Introduction:
Nitrogen dioxide (NO2) and particulate matter (PM) are among the most investigated air
pollutants. Many epidemiological studies have been carried out to pinpoint possible links
between these pollutants and diseases. Asthma, cardiopulmonary disease, and allergies
are among the most important diseases associated with the pollutants (Koren (1995);
Delfino et al. (2006); Bhaskaran et al. (2009). Sulfur dioxide (SO2) used to be of interest
too, but recently, its concentration has reduced and the focus is now on NO2 and PM
(Bernard et al. n.d.). The most important sources of these pollutants include fossil fuel
combustion, e.g. from motor vehicles, trains, boats and industrial processes, gas stoves
and heaters, etc, and from dust-generating processes such as construction and demolition
of buildings, roads, bridges, etc (Bernard et al. n.d.). Current EU limits for the
Netherlands are as follows: 40 µg/m3 for the annual average NO2 concentration, to be met
by 2010, and 50 µg/m3 for the daily average PM10 concentration, not to be exceeded more
often than 35 times a year, from 2005 onwards (Velders and Matthijsen, 2009). The
burden of the diseases caused by these pollutants is a public health issue and measures
need to be taken to address it. It may be possible that certain groups of people are more at
risk of contracting air pollution-related diseases, but this is unlikely the usual case, as air
pollution is a global problem. Polluted air in one part of the world or one part of a
country or even a city can quickly travel to other parts (Reuther, 2000). A detailed outline
of the diseases and their mechanisms of action is given in the following sections of this
thesis.
Bisong, Jules
Master Thesis
Utrecht University, August 2010
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Relevance of Thesis Topic:
The relevance of researching the health effects of NO2 and PM is seen in the various
associations made between exposure to these substances and disease. NO2 is one of the
major pollutants in heavily populated areas, with ambient air levels normally in order of
10 to 50 µg/m3 (Bernard et al. n.d.). In pollution hot spots, such as tunnels or street
canyons, this concentration may reach 100 µg/m3 as a 1-hour average during high
pollution episodes (Bernard et al. n.d.). NO2 has not been proven to be a major health
risk. However, it reacts with components in the fluid lining the respiratory tract (Bernard
et al. n.d.). It has also been found to have the capacity to activate oxidant pathways, in in
vitro animal and human studies (Brunekreef & Holgate, 2002). Asthmatic individuals are
more vulnerable to its effects, which include narrowing of the airways and increased
responsiveness to irritants and allergens (Bernard et al. n.d.). Since it occurs in a mix of
other gases, its concentration can give insight into that of the other gases which have been
proven to be harmful to health. It is therefore a proxy to other known disease-causing
gasses. A human adult inhales 20 m3 PM per day, and this means a handful of particles
can be deposited in the airway epithelium, especially in heavily polluted areas, where
particle concentration may reach 50 µg/m3 (Baeza-Squiban et al, 1999). However,
particle size and aerodynamic diameter determine the level of deposition (Baeza-Squiban
et al, 1999). The respiratory system has defence mechanisms, such as the mucociliary
lining the epithelium, which sweep these particles away (upward) from the respiratory
tract to the throat, where they are swallowed and digested in the stomach, or sneezed out
through the nasal tract (Baeza-Squiban et al, 1999). There are also macrophages in the
alveoli, which engulf these particles by endocytosis (Baeza-Squiban et al, 1999).
However, clearance by endocytosis can be overwhelmed, leading to a longer duration of
particles in the airway, which creates contact between the particles and the epithelium,
which in turn, can cause cellular damage (Baeza-Squiban et al, 1999). It is worthy of note
that, although macrophages engulf particles, the fate of the latter is unknown (BaezaSquiban et al, 1999). Epidemiological studies have associated increased cardiopulmonary
mortality and hospital admissions with episodes of high particulate air pollution (BaezaSquiban et al, 1999). An AIRNET report of Work Group 2 associated short-term
Bisong, Jules
Master Thesis
Utrecht University, August 2010
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increases in PM air pollution with increased daily mortality and hospital admissions for
respiratory and cardiovascular disease. The report also suggests that daily exposure to
polycyclic aromatic hydrocarbons (PAH) may in addition to causing cancer, have effects
on foetuses and infants. Moreover, there is a correlation between increases in allergic
asthma, nasal allergies, and chronic bronchitis with increased levels of airborne particles
(Baeza-Squiban et al, 1999).
Thus, more awareness of the health impacts of these airborne particles is important and
can motivate the setting up of standards for emission control beneficial to health. Also, it
can stimulate more mapping of high-concentration zones, so that structural measures,
such as re-location of industries or transportation networks can be taken in order to limit
the level of pollution. Although it is not exactly clear what concentration of these
substances is not harmful to health, which means any concentration could be harmful, it
would be, however, useful to know the concentration at a particular place and at a
particular time. This would aid epidemiological research, for instance, in finding a link
between disease and an air pollutant, as with time-series studies.
Bisong, Jules
Master Thesis
Utrecht University, August 2010
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Sources of NO2 and PM:
Natural sources of NO2 include biological processes in soil and the atmospheric oxidation
of ammonia (DEQ, 2003. Anthropogenic (man-made) sources include high-temperature
fuel combustion in motor vehicles and in industrial and utility boilers (EICB, n.d.). NO2
is produced from gas stoves, and other domestic combustion processes, such as butane
gas heaters (EICB, n.d.). These sources are more important because they are concentrated
in the more populated areas and account for the greater share of the NO2 emissions in
such areas (Bernard et al., n.d.).
PM on the other hand, also referred to as fine particles, includes finely divided solids or
liquids such as dust, fly ash, soot, smoke, fumes, mists and condensing vapours that can
be suspended in the air or gas for extended periods of time (EICB, n.d.). Primary sources
of PM include both natural and anthropogenic sources and the latter include agricultural
operations, industrial processes, combustion of wood and fossil fuels, construction and
demolition activities, and entrainment of road dust into the air (EICB, n.d.; Bernard et al.,
n.d.). Natural sources include windblown dust and soot (EICB, n.d.). Secondary sources
of PM directly emit air contaminants into the atmosphere that form or contribute to the
formation of PM (EICB, n.d.; Bernard et al., n.d.). These pollutants are therefore
considered precursors to PM formation. The secondary pollutants include oxides of sulfur
(SOx), oxides of nitrogen (NOx), volatile organic compounds (VOCs), and ammonia
(NH3) (EICB, n.d.). The figure below illustrates the various sources of PM.
Bisong, Jules
Master Thesis
Utrecht University, August 2010
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Figure 1: Possible Sources of PM (Polichetti et al., 2009)
Bisong, Jules
Master Thesis
Utrecht University, August 2010
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Health Effects of NO2:
Primary health problems associated with NO2 are acute pulmonary function responses,
acute respiratory infectious disease and chronic lung disease (Hodgkins et al., 2010;
McKee and Rodriguez, 1993). NO2 can act as an adjuvant, thereby allowing for allergic
sensitization to an innocuous inhaled antigen and the generation of an antigen-specific
Th2 immune response manifesting in an allergic asthma phenotype (Hodgkins et al.,
2010). This occurs through NO2 exposure, which causes pulmonary CD11c+ cells to
acquire a phenotype capable of increased antigen uptake, migration to the draining lymph
node, expression of MHCII and co-stimulatory molecules required to activate naïve T
cells, and secretion of polarizing cytokines to shape a Th2/Th17 response (Hodgkins et
al., 2010). Some asthmatics experience increased airway response as a result of NO2
exposure (McKee and Rodriguez, 1993). Young children have been found to have
increased acute respiratory illnesses (McKee and Rodriguez, 1993). Also, individuals
who exercise in places with NO2, exposed to indoor NO2 sources, or are concurrently
exposed to other pollutants, have been found to have increased risk of respiratory
illnesses (McKee and Rodriguez, 1993). Acute exposure to less than 1 ppm NO2 (typical
outdoor ambient levels) does not seem to affect pulmonary function in healthy, normal
individuals (McKee and Rodriguez, 1993). This suggests that the respiratory health
effects of NO2 are only experienced after long-term exposure. According to
epidemiological studies, there is a relation between long-term NO2 exposure and an
increase in respiratory illness (McKee and Rodriguez, 1993). This relation is supported
by human and animal studies which indicate that NO2 can cause alterations of host
immunity and result in increased susceptibility to viral and bacterial pulmonary infections
(McKee and Rodriguez, 1993). Animal studies can be used to draw conclusions on
humans in relation to NO2 exposure and pulmonary disease because humans share the
same pulmonary defense mechanisms with animals (mammals) (McKee and Rodriguez,
1993). Animal studies show that NO2 causes structural alterations in the ciliated cells of
the mucociliary escalator (McKee and Rodriguez, 1993). The alveolar macrophage is the
primary host defense affected by acute, long-term NO2 exposure (McKee and Rodriguez,
Bisong, Jules
Master Thesis
Utrecht University, August 2010
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1993). The effects include: decrease in bactericidal and viricidal activity; decrease in the
production of a radical involved in bactericidal activity; decrease in phagocytosis;
morphological and metabolic changes; and other functional changes (McKee and
Rodriguez, 1993; Nitschke et al., 1999). These effects were shown by most studies at
exposure levels between 1 and 5 ppm (McKee and Rodriguez, 1993). Other studies
showed effects such as suppression of T and B cell responsiveness to mitogens, decrease
in the number of T cells, and suppression of primary antibody responsiveness, in animals
(McKee and Rodriguez, 1993).
Air pollution, it should be noted, is not only an external problem. Many people are
affected by internal sources too. A study by Kawamoto et al. (1993) measured personal
exposure to indoor NO2 sources in students using filter badges attached to their chests or
collars, for 1 week. The urinary hydroxyproline/creatinine ratio (HOP/C) was examined
as a biomarker for health effects. Outdoor NO2 concentration during the study period was
13.5 – 13.7 µg/m3, whereas indoor concentration was 219 µg/m3 for students using a
kerosene heater and 474 µg/m3 for students using an oil fan heater. Smoking and the use
of electric heaters did not influence exposure to NO2. The correlation between the period
of cooking and personal exposure was also observed, with NO2 levels being 290 µg/m3.
Neither smoking nor NO2 exposure where found to cause an increase in urinary HOP/C.
This could be due to the very short exposure time. The non increase does not mean that
there were no health effects. A week may just have been too short to detect any changes.
The important thing to grasp here is that, there is that much increase in exposure when we
do not use environmentally-friendly technology. This gives insight into how easily health
effects can occur.
Beckett et al. (1995) carried out a study to investigate the effects of nitrous acid on lung
function in asthmatics. Nitrous acid is a primary product of combustion and may also be a
secondary product when NO2 reacts with water, in this case, in the linings of the lungs. In
the double-blinded crossover chamber exposure study, researchers exposed 11 mildly
asthmatic adult subjects for 3 hours to 650 ppb nitrous acid and to filtered room air with
three 20-minute episodes of moderate cycle exercise. Symptoms, respiratory parameters
during exercise, and spirometry after exercise were measured. Statistically, there was a
significant decrease in forced vital capacity on days when subjects were exposed to
Bisong, Jules
Master Thesis
Utrecht University, August 2010
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nitrous acid. Aggregate respiratory and mucous membrane symptoms were also
significantly higher when exposed to nitrous acid. Thus, the concentration and duration of
exposure to nitrous acid altered lung mechanics slightly and produced mild irritant
symptoms in asthmatics.
It may be confusing, however, to find that some studies dispute the health effects
attributed to NO2. For example, in the PATY study by Pattenden et al (2006), NO2 was
not linked to the health effects mentioned earlier. It was rather associated with very few
effects, such as indirect contribution to inhalation allergies. Therefore, bronchitis or
asthma were not caused by NO2, according to the study. That notwithstanding, NO2 was
ruled as a possible indicator of traffic related air pollutants, which refers us to earlier
sections of this thesis, in which NO2 is mentioned to be an indicator of other air
pollutants. What stands firm is that NO2, be it a direct or indirect cause of respiratory
diseases, is a good indicator of the concentration of other pollutants that may be more
directly associated with respiratory diseases.
Bisong, Jules
Master Thesis
Utrecht University, August 2010
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Health Effects of PM:
There are more studies carried out to investigate the health effects of PM. The
mechanisms by which PM affects human health are more understood than those of NO2.
Meng and Zhang (2006), investigated in vitro toxicological effects of PM2.5 suspensions,
their water-soluble fractions and solvent-extractable organics from dust storm on the
viability and DNA of rat alveolar macrophages and in vivo toxicological effects of PM2.5
suspensions on DNA of lung cells of rats. In their results, they found that in vitro, PM2.5
suspensions, their water-soluble fraction and solvent-extractable organics from both dust
storm and normal weather caused a decrease of the cell viability and an increase of DNA
damage of rat alveolar macrophages in a dose-response manner. In vivo, PM2.5 from both
dust storm and normal weather caused an increase of DNA damage of rat lung cells in a
dose-response manner. How exactly, PM and other pollutants affect health can only be
seen in in vivo and in vitro toxicological studies. It may not be easy to determine what
parts of PM cause what types of health effect, using epidemiological studies. It is in light
of this, that different effects can be seen from the same pollutant, but of different sources.
For example, toxicological studies have shown that source influences the toxicity of
particles in in vivo and in vitro models (Gordon, 2007). Adverse lung changes observed
in rats instilled with ambient PM from different cities were dependent on the urban or
rural environment in which the particles were collected (Costa and Dreher, 1997). Gavett
et al. (2003) also found significant differences in the effects on rodents treated with PM
collected from two German cities. They found ambient particles from the industrial city
of Hettstedt to have more potential in causing allergic asthma than those collected from
the agricultural and administrative centre of Zerbst. On the other hand, toxicological
studies show health effects of exposure only at much higher than ambient levels
(Schlesinger, 2000). Therefore, both toxicological and epidemiological approaches to
finding links between exposure and disease should be employed. Toxicological evidence
can be used to support epidemiological evidence if necessary. Epidemiological studies
have shown associations between PM exposure and cardiopulmonary health outcomes
(Heal et al. 2009). However, this study by Heal et al. (2009) was aimed at finding
whether the water-soluble and extractable metal content in PM was responsible for
Bisong, Jules
Master Thesis
Utrecht University, August 2010
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cardiopulmonary health effects. Their findings did not show any significant association
between the metal content alone and the health effects. Other researchers, though, hold
that metals in PM generate oxidative stress (Li et al, 2008). Mehta et al. (2008) found
that transition metals such as nickel and chromium, and oxidative stress-induced lipid
peroxidation metabolites such as aldehydes can greatly inhibit nucleotide excision repair
(NER) and enhance carcinogen-induced mutations. They also tested the effect of PM on
DNA repair capacity in cultured human lung cells using in vitro DNA repair synthesis
and host cell reactivation assays. Their findings show that PM greatly inhibits NER for
ultraviolet (UV) light and benzo(a)pyrene diol epoxide (BPDE)-induced DNA damage in
human lung cells. Furthermore, they demonstrated that PM exposure can significantly
increase both spontaneous and UV-induced mutagenesis. They also suggest from their
results that the carcinogenicity of PM may act through its combined effect on suppression
of DNA repair and enhancement of DNA replication errors. The principal health effect of
PM on the pulmonary system is the exacerbation of inflammation and this is especially
the case with susceptible individuals (Li et al, 2008). A mechanism by which it occurs is
the generation of oxidative stress by its chemical compounds and metals (Li et al, 2008).
Cells respond to this oxidative stress by activating oxidant defense, inflammation, and
toxicity (Li et al, 2008). In the lung, proinflammation by PM causes increased
cytokine/chemokine production and adhesion molecule expression (Li et al, 2008). It has
also been found that ambient PM can act as an adjuvant for allergic sensitization, which
suggests that long-term PM exposure may lead to increased prevalence of asthma (Li et
al, 2008). Short-term increases in PM concentration are associated with increased daily
mortality and hospital admissions for respiratory and cardiovascular disease (Downs et
al. n.d.). However, long-term effects may have more health impact than short-term
effects (Downs et al. n.d.). It is not easy, though, to determine whether a health effect is a
result of short-term and/or long-term exposure because the effect of an acute exposure to
PM could easily be superimposed to that of a chronic exposure (Polichetti et al., 2009).
Increased mortality risks seem to be more attributed to anthropogenic (e.g. from motorvehicle emissions) than to natural PM sources (Downs et al. n.d.). Many studies attribute
the larger part of PM toxicity to its smaller fractions, that is, fine and ultrafine particles
(Polichetti et al., 2009). However, considerations need to be made on the fact that these
Bisong, Jules
Master Thesis
Utrecht University, August 2010
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size fractions make up part of the internal constituents of PM10. Freitas et al. (2010)
found statistically significant (p < 0.001) associations between atmospheric levels of
PM10 and hospital admissions due to respiratory conditions in a study carried out in
Lisbon. In their review, Brunekreef and Holgate (2002) associated PM exposure with
increased mortality and hospital admissions for respiratory and cardiovascular diseases.
The effects were found in short-term studies relating day-to-day variations in air pollution
and health, and long-term studies in which cohorts of exposed individuals were followed
over time (Brunekreef and Holgate, 2002). Since effects were found at very low exposure
levels, it is unclear whether a threshold at which there is no effect exists (Brunekreef and
Holgate, 2002). A WHO 2008 health quality report asserts that PM affects more people
than any other pollutant and its effects occur at exposure levels currently experienced by
most urban and rural populations in both developed and developing countries (WHO,
2008). Long-term PM exposure contributes to the risk of developing cardiovascular and
respiratory diseases, as well as lung cancer (WHO, 2008). Some health effects of PM
exposure in developing countries include increased risk of acute lower respiratory
infections and associated mortality among young children (WHO, 2008). Other effects
include increased risk of chronic obstructive pulmonary disease and lung cancer among
adults (WHO, 2008). The occurrence of these health effects in developing countries is
attributed to indoor combustion of solid fuels on open fires or traditional stoves (WHO,
2008). Cities with high levels of pollution show 15-20 % more mortality than relatively
cleaner cities (WHO, 2008). Average life expectancy in the EU is 8.6 months lower, due
to exposure to PM from anthropogenic sources (WHO, 2008).
Bisong, Jules
Master Thesis
Utrecht University, August 2010
- 14 -
Risk Groups:
The effects of air pollution are widespread and indiscriminate. However, variations in
human behaviour may make them manifest with different levels of severity; some
affected individuals experience severe effects, while others only mild effects. Other
factors that make some people more susceptible to the effects of air pollution are age,
asthma, exercise in the presence of a pollutant (McKee and Rodriguez, 1993). Children
and the elderly have less immunity and are therefore more vulnerable (McKee and
Rodriguez, 1993). People with compromised immunity (e.g. AIDS patients) also have a
higher risk of suffering from the effects of air pollution McKee and Rodriguez, 1993).
Some of the effects these risk groups are likely to suffer include acute symptoms and
lung function impairment, increased susceptibility to acute respiratory infection, and
possibly conditions leading to chronic long disease (McKee and Rodriguez, 1993). Pope
(2000), though, explains that it is difficult to draw a straight line between who is at risk
and who is not. He further distinguishes risk groups into short term, acute exposure risk
group and long term, chronic exposure risk group. In this view, the short term risk group
comprises those whose condition would be worsened (mortality) by an episode of acute
exposure, such as in the 1952 London smog. They include the elderly, the very young,
persons with chronic cardiopulmonary disease, influenza or asthma (Pope, 2000).
However, recent research has showed that these persons may not be the only ones to be
included in the group (Pope, 2000). Study data from Philadelphia and Pennsylvania
suggest that mortality for many may be advanced substantially, rather than by just a few
days or weeks, as in cases of mortality by acute exposure (Pope, 2000). The data also
suggest that those at increased risk of mortality from acutely elevated exposure may
include more than just the most old and frail who are already very near death (Pope,
2000). The long term group, on the other hand, comprises every exposed person. There is
no evidence that mortality due to cumulative exposure is unique to a particular group
(Pope, 2000). Therefore, adults, children, diseased and healthy people are all susceptible
to mortality from chronic exposure. However, since the relative risk is small, the long
term cumulative effects are most likely to be observed in older people with relatively
higher baseline risks of mortality (Pope, 2000).
Bisong, Jules
Master Thesis
Utrecht University, August 2010
- 15 -
It is sometimes suggested that socioeconomic status (SES) is a determinant of
susceptibility to the effects of air pollution. Some examples used in making such
suggestions include the installation of refuse disposal facilities in low income
neighbourhoods, garbage disposal jobs by low income earners, the use of inefficient
technology (home appliances like gas stoves, heaters, etc), etc. In a study, though,
Charafeddine and Boden (2007) investigated whether income inequality may modify the
association between fine particulate pollution and self-reported health. They found that
the odds of reporting fair or poor health for a 10 µg/m3 increase in particulate pollution is
1.34 (95% confidence interval 1.21 – 1.48) when income inequality is low. The similar
odds ratio for higher income inequality is 1.11 (95% confidence interval 1.06 – 1.16)
(Charafeddine and Boden, 2007). Income inequality was therefore found to be an effect
modifier of the association between general self-reported health and particulate pollution
(Charafeddine and Boden, 2007). The researchers also say that these findings contradict
their hypothesis that people living in higher income inequality areas are more vulnerable
to the impact of air pollution. Note that information for this study was self-reported,
which does not rule out the possibility of recall bias. Burra et al (2009) investigated
socioeconomic variation in ambulatory physician consultations for asthma and assessed
possible effect modification of SES on the association between physician visits and air
pollution for children aged 1 – 17 and adults aged 18 – 64 in Toronto, Canada, between
1992 and 2001. In their results, they found a socioeconomic gradient in the number of
physician visits among children and adults and both sexes. SO2, NO2 and PM2.5 had
positive associations with physician visits and the risk ratios for the low socioeconomic
group were significantly greater than those for the high socioeconomic group in many of
the models of SO2 and PM2.5.
Bisong, Jules
Master Thesis
Utrecht University, August 2010
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Conclusion:
Air pollution causes respiratory, cardiovascular and other diseases. It has also been
associated with increased hospital admissions and mortality in young children and adults.
Sources of NO2 and PM include fossil fuel combustion, dust-generating activities, such as
construction and demolition, amongst others. Individuals with Asthma, compromised
immunity, etc, are particularly at higher risk of experiencing health effects of pollution.
Developing countries experience significant air pollution-related health effects, due to
indoor solid fuel combustion in open fires. The reduction of average life expectancy in
the EU is one of the effects of PM-related air pollution.
Bisong, Jules
Master Thesis
Utrecht University, August 2010
- 17 -
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Master Thesis
Utrecht University, August 2010
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Bisong, Jules
Master Thesis
Utrecht University, August 2010
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WHO
(2008).
Air
quality
and
health.
Fact
http://www.who.int/mediacentre/factsheets/fs313/en/
Bisong, Jules
Master Thesis
sheet
Utrecht University, August 2010
N°
- 20 -
313.