**2. Air pollution**

Air pollution can be composed by a cocktail of different substances that in large amounts can be harmful to the ecosystem. The industrial revolution marks the beginning of an accelerated global urbanization process. As a result, large urbanized areas suffer from, amongst other problems, a high concentration of air pollutants. The most evident form of air pollution is a dark layer of gas – also known as smog – present above big cities. Nevertheless, there are different kinds of air pollution that are not as visible. Sources include natural processes, such as volcano emissions, and also industrialized sources found in urban centres linked to human activities. The latter includes power plants, factories, burning of fossil fuel and transportation.

© 2014 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **2.1. Classification of air pollutants**

Air pollutants can be found in different forms and sizes. They can be solid particles, liquid molecules or gases. According to the way they are generated these pollutants can be consid‐ ered as primary (directly produced) or secondary (formed by the interaction of primary pollutants). Some pollutants can be both produced directly as well as formed by the reaction of other pollutants. In addition, there are indoor and outdoor pollutants, all of which can be detrimental to human health. Although indoor pollution is generally low, its levels can be augmented by the use of several chemical products (e.g. cleaning products, paints), heaters, stoves and indoor smoking. Fortunately, various countries have already adopted policies that ban smoking in closed public spaces. Description and classification of the main pollutants resulting from human activity are listed in table 1 below.

**3. General health consequences of exposure to air pollution**

consequences of air pollution exposure [5, 11, 12].

economic issue to countries affected [14].

stroke [20, 22-24].

The analyses of recent epidemiological studies, conducted in various urban centres, have provided coherent evidence that elevated levels of air pollution are associated with an increased risk of respiratory diseases, chronic obstructive lung diseases (COPD), cancers, cerebrovascular-strokes, cardiovascular diseases and mortality. These occur due to the nature of the pollutants and via their impacts on the respiratory and cardiovascular systems [1-7]. Air pollution does not only affect individuals that are directly exposed to it, but it also has a deleterious effect on foetal development and preterm birth. Various studies have shown that decreases in neonate birth weight are associated with exposure to air pollu‐ tion [8-10]. Children are also very susceptible to the harmful effects of pollution expo‐ sure. This is reflected by an increase in the number of young children admitted to hospitals for acute lower respiratory infection: pneumonia and bronchiolitis. These respiratory infections are the largest causes of mortality among young children worldwide, especially in developing countries. Within these countries a low socioeconomic status potentiates the

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These adverse effects on health, caused by air pollution, have been shown to occur in both developed and developing countries. However, its health-related burden falls most heavily on developing countries [3, 6, 13-15]. According to the World Health Organisation [16], air pollution is responsible for over 800, 000 premature deaths each year, with more than 6 million years of life lost annually. Asia alone would account for approximately two thirds of these numbers [2]. It goes without saying that this air pollution disease-burden is a great

The World Health Organisation, together with governments of various countries, have proposed guidelines for maximum concentrations of the different pollutants (see table 2). Nevertheless, this does not always translate into national policies and various cities are unable to maintain pollution levels within the suggested guidelines. The implementation of anti-pollution measures is not always straight forward. At times, for example, it means there is a need to change energy sources and invest in green technology. As a conse‐ quence, some countries are more reluctant than other to execute such measures [3, 17].

In relation to indoor air pollutants, on March 2004, the Republic of Ireland became the first country to completely ban smoking from workplaces. More and more countries gradually adopted this public-space smoking ban. Nowadays, most countries in the world have some kind of law pertaining to the issue. There is a growing body of evidence on the positive health outcomes and the economic benefits related to the adoption of smoke-free laws. Improvements in lung function, airway and systemic inflammation, and adverse respiratory symptoms were observed in individuals working in bars [18, 19]. Hospital admissions of children and adults presenting asthma and other pulmonary illnesses also decreased as a result of reduced exposure to environmental tobacco smoke [20-22]. Smoking bans also positively impacted individuals with heart diseases which include myocardial infarction, unstable angina and


**Table 1.** Main primary pollutants resulting from human activity

## **3. General health consequences of exposure to air pollution**

**2.1. Classification of air pollutants**

2 Lung Inflammation

resulting from human activity are listed in table 1 below.

• Strong pungent smell

• Brownish-red colour • Strong smell

**Air Pollutant Characteristics Source**

• No colour

• No smell

• No colour • Strong smell

particles

• No colour • Strong smell

and liquids

• Strong smell

**Table 1.** Main primary pollutants resulting from human activity

• Gases emitted from solids

Ozone (O3)

or Tropospheric O3 or ground level O3

Volatile Organic Compounds (VOCs)

Air pollutants can be found in different forms and sizes. They can be solid particles, liquid molecules or gases. According to the way they are generated these pollutants can be consid‐ ered as primary (directly produced) or secondary (formed by the interaction of primary pollutants). Some pollutants can be both produced directly as well as formed by the reaction of other pollutants. In addition, there are indoor and outdoor pollutants, all of which can be detrimental to human health. Although indoor pollution is generally low, its levels can be augmented by the use of several chemical products (e.g. cleaning products, paints), heaters, stoves and indoor smoking. Fortunately, various countries have already adopted policies that ban smoking in closed public spaces. Description and classification of the main pollutants

Ammonia (NH3) • Gas Produced industrially. Mostly used as fertiliser to agricultural crops (over

Carbon monoxide (CO) • Gas A major source of this poisonous gas is vehicular exhaust. It is also a

Nitrogen dioxides (NO2) • Gas Released by internal combustion engines and power-plants. Indoor

• No colour product of incomplete combustion of carbon-containing fuels.

the formation of O3 pollution.

Particulate Matter (PM) • Solid or liquid This pollutant can vary in size, form and composition being made up by a

Sulfur oxides (SOx) • Gas Amongst the highly reactive gases of this group is the sulphur dioxide

are precursors of O3.

• Gas This highly oxidant pollutant is formed by the reaction of nitrogen oxides

in large urban areas but also in rural areas.

circulation and affect other organs.

80%). Also used, for example, in the fermentation and textile industry, as cleaning product, and as antimicrobial agent for food products.

sources of this pollutant include gas and kerosene heaters. It is also released by electric discharge during storms. NO2 is also a precursor for

and volatile organic compounds in the presence of sunlight. As it is easily transported by the wind it can be found in high concentrations not only

mixture of extremely small particles (metals, soil, dust) and liquid droplets (acids, organic compounds). The smaller the PM size the deeper it can penetrate into the lungs and might even be able to pass to the systemic

(SO2) that is produced by the burning of fuels such as petrol, diesel, and coal. It is naturally released into the atmosphere by activated volcanoes.

VOCs are mainly indoor pollutants because they can be released by a variety of materials and products which are used in the households and offices such as paints, disinfectant, air-fresheners and photocopy machines. VOCs are also released by fuels. As mentioned previously they The analyses of recent epidemiological studies, conducted in various urban centres, have provided coherent evidence that elevated levels of air pollution are associated with an increased risk of respiratory diseases, chronic obstructive lung diseases (COPD), cancers, cerebrovascular-strokes, cardiovascular diseases and mortality. These occur due to the nature of the pollutants and via their impacts on the respiratory and cardiovascular systems [1-7]. Air pollution does not only affect individuals that are directly exposed to it, but it also has a deleterious effect on foetal development and preterm birth. Various studies have shown that decreases in neonate birth weight are associated with exposure to air pollu‐ tion [8-10]. Children are also very susceptible to the harmful effects of pollution expo‐ sure. This is reflected by an increase in the number of young children admitted to hospitals for acute lower respiratory infection: pneumonia and bronchiolitis. These respiratory infections are the largest causes of mortality among young children worldwide, especially in developing countries. Within these countries a low socioeconomic status potentiates the consequences of air pollution exposure [5, 11, 12].

These adverse effects on health, caused by air pollution, have been shown to occur in both developed and developing countries. However, its health-related burden falls most heavily on developing countries [3, 6, 13-15]. According to the World Health Organisation [16], air pollution is responsible for over 800, 000 premature deaths each year, with more than 6 million years of life lost annually. Asia alone would account for approximately two thirds of these numbers [2]. It goes without saying that this air pollution disease-burden is a great economic issue to countries affected [14].

The World Health Organisation, together with governments of various countries, have proposed guidelines for maximum concentrations of the different pollutants (see table 2). Nevertheless, this does not always translate into national policies and various cities are unable to maintain pollution levels within the suggested guidelines. The implementation of anti-pollution measures is not always straight forward. At times, for example, it means there is a need to change energy sources and invest in green technology. As a conse‐ quence, some countries are more reluctant than other to execute such measures [3, 17].

In relation to indoor air pollutants, on March 2004, the Republic of Ireland became the first country to completely ban smoking from workplaces. More and more countries gradually adopted this public-space smoking ban. Nowadays, most countries in the world have some kind of law pertaining to the issue. There is a growing body of evidence on the positive health outcomes and the economic benefits related to the adoption of smoke-free laws. Improvements in lung function, airway and systemic inflammation, and adverse respiratory symptoms were observed in individuals working in bars [18, 19]. Hospital admissions of children and adults presenting asthma and other pulmonary illnesses also decreased as a result of reduced exposure to environmental tobacco smoke [20-22]. Smoking bans also positively impacted individuals with heart diseases which include myocardial infarction, unstable angina and stroke [20, 22-24].


On the other hand, free radicals and reactive species are essential to our well-being. This happens because these molecules are necessary for a variety of reactions to occur. For example, they are used by the immune system to attack and kill pathogens in a process called respiratory burst. They are also used for gene stimulation, cell signalling, vasoregulation and inflamma‐

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Antioxidants are often reducing agents capable of being promptly oxidized by free radicals and reactive species, eliminating their pro-oxidant nature before they react with cell compo‐ nents. There is a wide range of antioxidants in body fluids, tissues and organs. They are present both intracellular and extracellular, working synergistically in a network to balance the free radicals and reactive species. Therefore, the action of one antioxidant may depend on the

Antioxidants are both synthesized *in vivo* and absorbed through the diet and they can be divided into two groups: enzymatic and non-enzymatic. Enzymatic antioxidants include superoxide dismutase (SOD), glutathione peroxidase (GPX) and catalase (CAT). Each of these enzymes is responsible for the reduction of different pro-oxidants and they are located in different cellular compartments. Glutathione, vitamin C, vitamin E, carotenoids, and uric acid are some examples of non-enzymatic antioxidants. Similarly to the enzymatic antioxidant, these are present in different cellular compartments and elicit distinct antioxidant properties which maximize their effectiveness [29]. Antioxidants can also be classified according to their soluble nature: hydrophilic (water soluble) or lipophilic (lipid soluble). It is this characteristic

tory processes [31, 32].

**Figure 1.** Redox balance

**4.2. Antioxidants**

correct function of other antioxidants in the system.

that allows them to be present in different parts of the cells.

**Table 2.** Updated WHO air guideline values

#### **4. Oxidative stress and air pollution**

The mechanism responsible for the adverse effect of oxidant pollutants – ozone, PM – in the lungs, which might possibly also lead to a systemic outcome, would be its direct and indirect oxidative reaction with molecules and cells present in the airways [25, 26]. This might result in oxidative stress in the airway tissues [27]. But what is oxidative stress?

#### **4.1. Oxidative stress**

Oxidative stress can be defined as damage that might occur in cell components, such as membranes, RNAs and DNA, as a result from an imbalance in the body's ability to neutralize certain molecules or to repair the resulting damage. Free radicals and reactive species (reactive oxygen species and reactive nitrogen species) are molecules that easily react with other molecules to become more stable. This is an oxidation reaction, because there is transfer of electrons from a substance to the free radicals/reactive species (oxidaizing agents). When in our organism these reactions occur with cell components, which could have detrimental effects such as cell function impairment and cell death. Nevertheless, the body has an elaborate antioxidant defence system that neutralizes the reactive species and free radicals so as to maintain a redox homeostasis. This balance, however, can be disturbed if the concentration of pro-oxidants (reactive species and free radicals) overwhelms the available antioxidants or if the antioxidants are depleted due to disease or poor diet. This associated with reduced repairing process, can result in oxidative stress, and impaired cellular function may occur. In humans, oxidative stress has been shown to be the cause and consequence of various diseases (Fig 1). These include, but are not limited to, cancers, atherosclerosis, Alzheimer's disease, Parkinson's disease, dementia, heart diseases and pulmonary disorders [28-30].

On the other hand, free radicals and reactive species are essential to our well-being. This happens because these molecules are necessary for a variety of reactions to occur. For example, they are used by the immune system to attack and kill pathogens in a process called respiratory burst. They are also used for gene stimulation, cell signalling, vasoregulation and inflamma‐ tory processes [31, 32].

**Figure 1.** Redox balance

**4. Oxidative stress and air pollution**

**Table 2.** Updated WHO air guideline values

PM2.5 1year 10

PM10 1year 20

O3 8 h, daily maximum 100 NO2 1year 40

SO2 24 h 20

**4.1. Oxidative stress**

Source: (WHO 2012)

4 Lung Inflammation

The mechanism responsible for the adverse effect of oxidant pollutants – ozone, PM – in the lungs, which might possibly also lead to a systemic outcome, would be its direct and indirect oxidative reaction with molecules and cells present in the airways [25, 26]. This might result

**Pollutant Averaging time Air quality guideline values (ug/m3)**

24 h (99th percentile) 25

24 h (99th percentile) 50

1 h 200

10 min 500

Oxidative stress can be defined as damage that might occur in cell components, such as membranes, RNAs and DNA, as a result from an imbalance in the body's ability to neutralize certain molecules or to repair the resulting damage. Free radicals and reactive species (reactive oxygen species and reactive nitrogen species) are molecules that easily react with other molecules to become more stable. This is an oxidation reaction, because there is transfer of electrons from a substance to the free radicals/reactive species (oxidaizing agents). When in our organism these reactions occur with cell components, which could have detrimental effects such as cell function impairment and cell death. Nevertheless, the body has an elaborate antioxidant defence system that neutralizes the reactive species and free radicals so as to maintain a redox homeostasis. This balance, however, can be disturbed if the concentration of pro-oxidants (reactive species and free radicals) overwhelms the available antioxidants or if the antioxidants are depleted due to disease or poor diet. This associated with reduced repairing process, can result in oxidative stress, and impaired cellular function may occur. In humans, oxidative stress has been shown to be the cause and consequence of various diseases (Fig 1). These include, but are not limited to, cancers, atherosclerosis, Alzheimer's disease,

in oxidative stress in the airway tissues [27]. But what is oxidative stress?

Parkinson's disease, dementia, heart diseases and pulmonary disorders [28-30].

#### **4.2. Antioxidants**

Antioxidants are often reducing agents capable of being promptly oxidized by free radicals and reactive species, eliminating their pro-oxidant nature before they react with cell compo‐ nents. There is a wide range of antioxidants in body fluids, tissues and organs. They are present both intracellular and extracellular, working synergistically in a network to balance the free radicals and reactive species. Therefore, the action of one antioxidant may depend on the correct function of other antioxidants in the system.

Antioxidants are both synthesized *in vivo* and absorbed through the diet and they can be divided into two groups: enzymatic and non-enzymatic. Enzymatic antioxidants include superoxide dismutase (SOD), glutathione peroxidase (GPX) and catalase (CAT). Each of these enzymes is responsible for the reduction of different pro-oxidants and they are located in different cellular compartments. Glutathione, vitamin C, vitamin E, carotenoids, and uric acid are some examples of non-enzymatic antioxidants. Similarly to the enzymatic antioxidant, these are present in different cellular compartments and elicit distinct antioxidant properties which maximize their effectiveness [29]. Antioxidants can also be classified according to their soluble nature: hydrophilic (water soluble) or lipophilic (lipid soluble). It is this characteristic that allows them to be present in different parts of the cells.


Numerous studies have investigated the effects by which O3 affects the human lungs. Never‐ theless, the mechanisms responsible for such adverse effects, such as an increase in the airway inflammation and impairment in lung function, are only partly understood. It is known that when O3, or indeed any gas, is inhaled, it first comes into contact with the RTLF. Indeed, ozone is not able to infiltrate further than the RTLF and the membranes of cells from the lung-air interface, yet it is still known to cause damage beyond the lungs. Once O3 comes into contact with the RTLF, it induces oxidative stress by two different mechanisms. The first would be by reacting directly with the constituents of the RTLF and the underlying epithelium [26]. It has been suggested that antioxidants present in the RTLF, such as glutathione, uric acid and ascorbic acid have an important role in neutralizing part of the radical generation, hence reducing the ozone induced oxidative stress [35]. Studies analysing the effect of ozone inhalation and airway antioxidant consumption have indeed shown significant alterations in

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7

The second mechanism by which ozone can increase the oxidation process is indirectly because, even though O3 does not react directly with the epithelial cells, these cells do react in response to the oxidation products produced in the RTLF. As a consequence they release a variety of pro-inflammatory mediators and more reactive species [25, 26]. These processes combined could overwhelm the local and systemic antioxidant network leading to an increase in the oxidative process, the intensity of which varies depending on the O3 inhaled dose and also on the antioxidants present in the lining fluid. If the oxidative stress is sufficient, the activation of an inflammatory response occurs and is characterized by the intense arrival and activation of neutrophils. These neutrophils produce further ROS through the respiratory burst process. Hence, the overproduction of ROS might result in oxidative stress in the airway tissues. The hypothesis is that the antioxidants present in the epithelial lining fluid of the lungs would neutralize the excess production of free radicals and ROS, consequently reducing lung injury induced by air pollution [27, 35]. This will be discussed in the following sections.

Airway inflammation and any other inflamed tissue can be characterized by an increase in inflammatory cells, such as neutrophils and macrophages, as well as inflammatory mediators: interleukin-6 (IL-6), interleukin-8 (IL-8), and prostaglandins. An increase in neutrophil numbers and percentage is a good indicator of the beginning of an inflammatory response because these cells account for 50-60% of the total white blood cells in the circulation and are the first cell type to migrate to sites of injury and inflammation. When a tissue is inflamed, an increase in the expression of adhesion molecules of the selectin family (E-and P-selectin molecules) occurs in the local endothelium. This process is mediated by cytokines and other inflammatory mediators. Neutrophils present in the blood recognise the site of inflammation because of these adhesion molecules which bind to the other molecules (mucin-like celladhesion molecules, CAM) on the neutrophil surface. This step is referred to as rolling: the first step to the attachment of neutrophils onto the endothelium. In order for them to adhere firmly and be able to migrate through the endothelial to the inflamed site, the neutrophils are

airway antioxidants, such as uric acid, ascorbic acid and GSH [36-38].

**5. Lung inflammation and air pollution**

**Table 3.** Important antioxidants

Most antioxidants undergo redox cycling. This means that once oxidized they can be reduced to their former state and act again as an antioxidant. Nevertheless, this redox cycling allows the antioxidant to act as pro-oxidant promoting free radical formation. This would happen if there is an unbalance in the antioxidant network system. Vitamin C and vitamin E are examples of antioxidants with this characteristic, while melatonin is considered a terminal antioxidant because it cannot be recycled.

**Figure 2.** Redox cycling of vitamin E (vit E) by vitamin C (Vit. C)

#### **4.3. Lung oxidative stress**

Oxidant air pollutants such as ozone, particulate matter and nitrogen dioxide have been shown to induce lung inflammation through stimulation of the oxidative stress process. Little is known, however, about their effects as oxidant compounds in the lungs or about the role and the effectiveness of the antioxidants present in the respiratory tract lining fluid (RTLF) in scavenging and protecting against their harmful effects. A great variety of antioxidants can be found in human RTLF. Their concentration and distribution throughout the airways, however, is not homogeneous, with high levels of GSH in the alveolar epithelial regions and uric acid predominating in the upper airways [33, 34].

Numerous studies have investigated the effects by which O3 affects the human lungs. Never‐ theless, the mechanisms responsible for such adverse effects, such as an increase in the airway inflammation and impairment in lung function, are only partly understood. It is known that when O3, or indeed any gas, is inhaled, it first comes into contact with the RTLF. Indeed, ozone is not able to infiltrate further than the RTLF and the membranes of cells from the lung-air interface, yet it is still known to cause damage beyond the lungs. Once O3 comes into contact with the RTLF, it induces oxidative stress by two different mechanisms. The first would be by reacting directly with the constituents of the RTLF and the underlying epithelium [26]. It has been suggested that antioxidants present in the RTLF, such as glutathione, uric acid and ascorbic acid have an important role in neutralizing part of the radical generation, hence reducing the ozone induced oxidative stress [35]. Studies analysing the effect of ozone inhalation and airway antioxidant consumption have indeed shown significant alterations in airway antioxidants, such as uric acid, ascorbic acid and GSH [36-38].

The second mechanism by which ozone can increase the oxidation process is indirectly because, even though O3 does not react directly with the epithelial cells, these cells do react in response to the oxidation products produced in the RTLF. As a consequence they release a variety of pro-inflammatory mediators and more reactive species [25, 26]. These processes combined could overwhelm the local and systemic antioxidant network leading to an increase in the oxidative process, the intensity of which varies depending on the O3 inhaled dose and also on the antioxidants present in the lining fluid. If the oxidative stress is sufficient, the activation of an inflammatory response occurs and is characterized by the intense arrival and activation of neutrophils. These neutrophils produce further ROS through the respiratory burst process. Hence, the overproduction of ROS might result in oxidative stress in the airway tissues. The hypothesis is that the antioxidants present in the epithelial lining fluid of the lungs would neutralize the excess production of free radicals and ROS, consequently reducing lung injury induced by air pollution [27, 35]. This will be discussed in the following sections.
