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Air pollution, oxidative stress and dietary supplementation: a review

¹ Instituto Nacional de Salud Publica, Cuernavaca, Mexico, ² Instituto Municipal de Investigaciones Médicas, and ³ Institut Català de Recerca i Estudis Avançat (ICREA), Barcelona, Spain.

CORRESPONDENCE: I. Romieu, Instituto Nacional de Salud Publica, Av. Universidad No. 655, Col. Santa Maria Ahuacatitlan, Cuernavaca, Morelos 62508, Mexico. Fax: 52 7773111148. E-mail: iromieu{at}correo.insp.mx

Keywords: Air pollution, antioxidants, nutrition, oxidative stress

Received: October 2, 2006
Accepted August 20, 2007

	ABSTRACT

TOP ABSTRACT BIOLOGICAL AND EPIDEMIOLOGICAL... FURTHER EPIDEMIOLOGICAL RESEARCH CONCLUSION ACKNOWLEDGEMENTS REFERENCES

 
The aim of the present review was to provide an up-to-date overview of the biological and epidemiological evidence of the role of oxidative stress as a major underlying feature of the toxic effect of air pollutants, and the potential role of dietary supplementation in enhancing antioxidant defences.

A bibliographic search was conducted through PubMed. The keywords used in the search were "air pollutant", "oxidative stress", "inflammation", "antioxidant polyunsaturated fatty acids" and "genetics". In addition, the authors also searched for biomarkers of oxidative stress and nutrients.

The review presents the most recent data on: the biological and epidemiological evidence of the oxidative stress response to air pollutants; the role of dietary supplementation as a modulator of these effects; and factors of inter-individual variation in human response. The methodology for further epidemiological studies will be discussed in order to improve the current understanding on how nutritional factors may act.

There is substantial evidence that air pollution exposure results in increased oxidative stress and that dietary supplementation may play a modulating role on the acute effect of air pollutants. Further epidemiological studies should address the impact of supplementation strategies in the prevention of air-pollution-related long-term effects in areas where people are destined to be exposed for the distant future.

Epidemiological studies have clearly shown that air pollution exposure is associated with a range of respiratory and cardiovascular health effects and increased mortality 1. Recent research has identified oxidative stress as one potential feature underlying the toxic effect of air pollutants, which trigger a number of redox sensitive signalling pathways, such as those of inflammatory response and cytokine production 2–5. Toxicity may arise from an imbalance of biological pro-oxidant and antioxidant processes 6 linked to increased exposure to oxidants or the presence of impaired antioxidant defences 7, 8. This imbalance has long been recognised in investigations of ozone (O₃) 9, one of the most potent oxidants, and more recent studies have focused on this particular mechanistic hypothesis 10. Since diet is a major source of antioxidants, it is important to examine whether antioxidant defence mechanisms could be increased by dietary means to protect against air pollutants as this could have major public health consequences 11. To provide an up-to-date overview on the biological and epidemiological evidence of the role of oxidative stress as a major underlying feature of the toxic effect of air pollutants and the potential role of dietary supplementation as an enhancer 11 of antioxidant defences, a bibliogaphic search was conducted through PubMed. The keywords used in the search were "air pollutant", "oxidative stress", "inflammation", "antioxidant" (vitamin C, vitamin E, carotenoids), "polyunsaturated fatty acids" (PUFA) and "genetics". In addition, the current authors searched for biomarkers of oxidative stress, biomarkers of antioxidant intake (selenium, flavonoids, carotenoids, vitamin C, vitamin E), and n-3 PUFA. Various recent reviews have been published on these issues 1–5, 7–10, 12–34, therefore, the present authors refer to these and mostly focus on the latest findings. Thus, the purpose of this up-to-date overview is five-fold. First, the relevance of oxidative stress as a common mechanism for effects of ambient air pollutants will be summarised. Secondly, the role of antioxidants in oxidative stress will be briefly discussed. Thirdly, the evidence for dietary supplements as modulating the adverse effects due to air pollution will be reviewed. Fourthly, the relevance of factors that may interact with a subjects' response to exogenous oxidative stress will be discussed. Finally, the need to further investigate the relevance of dietary supplementation as an approach to protect from adverse effects of air pollution will be discussed.

	BIOLOGICAL AND EPIDEMIOLOGICAL EVIDENCE

TOP ABSTRACT BIOLOGICAL AND EPIDEMIOLOGICAL... FURTHER EPIDEMIOLOGICAL RESEARCH CONCLUSION ACKNOWLEDGEMENTS REFERENCES

 
Oxidative stress and air pollutants
Several air pollution components have been related to particulate toxicity. An important determinant of the acute inflammatory response appears to be the dose of bio-available transition metals (such as copper, vanadium, chromium, nickel, cobalt and iron), organic compounds (such as polycyclic aromatic hydrocarbons) and biological fractions (such as endotoxins) 35, 36. The oxidative stress mediated by particulate matter (PM) may arise from: direct generation of reactive oxygen species (ROS) from the surface of soluble compounds; altered function of mitochondria or reduced nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase; and activation of inflammatory cells capable of generating ROS and reactive nitrogen species (RNS), as well as oxidative DNA damage 37, 38. The particle provides a template for electron transfer to molecular oxygen in these reduction and oxidation (redox) cycling events 39. In addition, target cells, such as airway epithelial cells and macrophages, generate ROS in response to particle uptake by biologically catalysed oxidation reactions that occur in the cell membrane and mitochondria 4, 40–42. In vitro studies have shown that inhaled PM causes expression of nuclear factor (NF)-B-related genes and oxidant-dependent NF-B activation 43, 44. The dose of bio-available transition metal, rather than particulate mass, may be the primary determinant of acute inflammatory response 35, 37, 44. However, other studies suggest that the hydrosoluble fraction is responsible for the oxidative damage to DNA 45. The biological component of particles also seems to be related to oxidative stress 46, as well as bacterial endotoxin that induce the liberation of tumour necrosis factor (TNF)- and interleukin (IL)-6 by macrophages 36.

Strong oxidative activity and the effective depletion of lung lining fluid antioxidants have been reported in large studies of ambient PM <2.5 µm (PM_2.5) 17. To defend against the oxidative damage, cells use up their stores of a key antioxidant, glutathione. The glutathione depletion can induce a state of cellular stress, which triggers an increase in the production of antioxidant enzymes through activation of a transcription factor nuclear factor-erythroid 2-related factor 2 17. Failure to overcome oxidative stress leads to the activation of additional intracellular signalling cascades that regulate the expression of cytokine and chemokine genes 15. These products are produced locally in target tissues as well as systemically, and lead to widespread pro-inflammatory effects remote from the site of damage. In addition, PM appears to inhibit protective enzymes involved in oxidative stress responses depending on their toxicity (copper/zinc superoxide dismutase, manganese superoxide dismutase, glutathione peroxidase and glutathione reductase) 47.

Diesel exhaust particles (DEPs) have a high content of elemental and organic carbon and are thought to be particularly toxic 15. These particles consist of a carbon core with adsorbed organic compounds, such as polyaromatic hydrocarbons, quinones and redox-active metals, and the capacity of DEPs to induce oxidative stress is largely related to these adsorbed components. Animal experimental models, cell culture experiments and cell free systems involving DEPs have shown oxidative stress response and oxidative DNA damage. Human studies have shown increased neutrophils, B cells and alveolar macrophages in bronchoalveolar lavage fluid and an increased amount of pro-inflammatory cytokines, chemokines and adhesion molecules 48. Exposure to DEPs has been shown to increase airway resistance, increase IL-6 and IL-8 in lavage fluid, increase IL-8 mRNA expression in bronchial mucosa and upregulate endothelial adhesion molecules P-selectin and vascular cell adhesion molecule-1 49. ROS formed at the epithelial level after DEP exposure upregulate IL-10, promoting antigen-presenting cells and allergy to pollen 15. However, controlled exposure to DEP in human subjects has been shown to respond with an increase in low molecular antioxidants in the alveolar compartment 50. The role of oxidative stress in response to DEPs and other particles is further supported by in vitro studies in which ROS are generated by macrophages, neutrophils, eosiniphils and epithelial cells after stimulation by DEPs or particles 15. Interestingly, low sulphur diesel combined with engine filters blocked a range of responses to DEPs including the oxidative stress responses in mice 51.

Alteration of autonomic functions also appears to be partly associated with oxidative stress 14. Long-term exposure to low concentrations of PM_2.5 has been shown to alter vasomotor tone, lead to vascular inflammation and potentiate atherosclerosis induced by high-fat chow in susceptible mice 52. Although epidemiological evidence suggests that it is the fine (PM_2.5) or ultrafine (PM <0.1 µm) fraction that contains the toxic components; the large spectrum of disease end-points (from cardiovascular to asthma attack) suggest that more than one component may be driving the health effects 2.

O₃ is a very reactive gas whose uptake depends on the availability of antioxidants in the lining fluids, and its toxicity appears to be transmitted to the respiratory epithelium by secondary ROS formed by direct ozonisation of respiratory tract lining fluid lipids 16. Alteration of the cell membrane translating an induction of lipid peroxidation and a significant modification of the redox status has been observed 53, as well as the activation of transcription factors such as NF-B and increased expression of a range of pro-inflammatory cytokines and adhesion genes 2, 6. O₃ has been shown to react readily with ascorbic acid, uric acid and thiols, and exposure of these molecular species to O₃ results in their rapid depletion 6. When these defence mechanisms are overwhelmed, O₃ may injure the underlying cells by inducing lipid peroxidation and activating inflammatory gene expression 6, 53. Like O₃, nitrogen dioxide (NO₂) reacts with substrates present in the lung lining fluid compartment. The oxidised species arising from the reaction between NO₂ and lining fluid are responsible for the signalling cascade of inflammatory cells into the lung 54–56.

A hierarchical oxidative stress model has been proposed to explain the dose–dependent response to air pollutant exposure 57. Low exposure would lead to the formation of ROS activating an antioxidant response, followed by the transcription of enzymes important in detoxification, cytoprotective and antioxidant responses. These include phase II enzymes, whose induction serves as a detoxification mechanism (e.g. NAD(P)H:quinone oxidoreductase 1 (Nqo1) and glutathione S-transferase). At higher exposure, the transcription NF-B and activator protein-1 responses would be activated. This would lead to NF-B and mitogen-activated protein kinase signalling, altering the function of mitochondria or NADPH, and to increased expression of pro-inflammatory cytokines (such as TNF- and IL-8 and IL-6) and genes coding adhesion molecules 2, 6, 15, 43, 44. Any enhanced inflammatory response would lead to additional generation of ROS and RNS, together with oxidative DNA damage (fig. 1) 15, 37, 38.

View larger version (34K): [in this window] [in a new window]   Fig. 1— A model of the reaction of oxidants in the airway. Inhaled pollutants, such as ozone (O3), nitrogen dioxide (NO2), particulate matter <2.5 µm (PM2.5) or diesel exhaust particulates (DEPs), react with nonenzymatic antioxidant constituents of the respiratory tract lining fluid including: reduced glutathione (GSH); vitamin C; uric acid; and enzymatic antioxidants, such as extracellular superoxide dismutase (ecSOD), extracellular glutathione peroxidise (ecGSHpx) and thioredoxin. These molecules provide a protective screen against these pollutants. If defences are exceeded, the production of reactive oxygen species (ROS) is increased and oxidants may react with organic molecules, such as proteins or lipids, and alter the epithelium resulting in: cell activation and initiation of the inflammatory process; activation of neutrophils; and liberation of cytokines, chemokines and adhesion molecules. CHO: carbohydrate; NF-B: nuclear factor-B; AP-1: activator protein-1. Modified from 3.

Although the inter-relation among antioxidant levels in RTLF, cellular and plasma levels is not well understood, it appears that the susceptibility of the lung to oxidative injury depends largely on its ability to upregulate protective ROS- and RNS-scavenging systems and that the speed at which lost antioxidant defences can be replaced is a major determinant 58.

As many antioxidants are derived from the diet, several dietary factors have been implicated; mainly because of their potential role in inflammatory reactions. The following section will focus mostly on nutrients that have been used in supplementation studies to modulate the impact of air pollutants or might interact with the immune response. These factors include antioxidant vitamins, omega-3 fatty acids and other micronutrients that might affect the immune response.

Antioxidant nutrients
Vitamin C
Vitamin C, a water-soluble vitamin, is an abundant antioxidant substance and is widely distributed throughout the body including the extracellular lining fluid of the lung 17. Ascorbate is an excellent reducing agent and scavenges free radical and oxidants. In vitro evidence suggests that vitamin C has a role as a chemical reducing agent both intracellularly and extracellularly. Intracellular vitamin C might prevent protein oxidation and regulate gene expression and mRNA translation. This is particularly relevant for the lung which is exposed to oxidative substances. Extracellular vitamin C protects against oxidants and oxidant-mediated damage 61. It contributes to antioxidant activity through scavenging a variety of free radicals and oxidants, in vitro, including superoxide radical (O^2–), peroxyl radicals, hydrogen peroxide, hypochlorous acid, singlet oxygen, oxidant air pollutants and oxidants that leak from activated neutrophils and macrophages 59, 61. While the terminating product dehydroascorbate can be regenerated to ascorbate by intracellular enzymes, in particular thioredoxin reductase, which catalyses its regeneration 62, this regeneration is unlikely in the RTLF because of the lack of enzymes. Therefore, the maintenance of ascorbate level in the RTLF requires transportation from cellular sources or from the plasma pool 59. Ascorbate also acts indirectly to prevent lipid peroxidation 59 and contributes to the regeneration of membrane-bound oxidised vitamin E 63. Ascorbate plays a role in immune function and is transported into neutrophils and lymphocytes 18. Whilst ascorbate has many antioxidant actions, it also has the capacity to act as a pro-oxidant in the presence of transition metals 64.

Vitamin E
Vitamin E, a lipid-soluble vitamin, represents the principal defence against oxidant-induced membrane injury in human tissue because of its role in breaking the lipid peroxidation chain reaction 64. It is a potent peroxyl radical scavenger and especially protects PUFAs within the phosphsolipid biological membrane and in plasma liproteins 65. It also decreases production of prostaglandin E₂, a metabolite of arachidonic acid produced by lipid peroxidation of lung cells after O₃ exposure 19. Vitamin E appears to play a major role as an integral constituent of alveolar surfactant, whose quantity and composition conditions normal lung function 66.

β-Carotene
β-Carotene, a precursor to vitamin A and other carotenoids, accumulates in tissue membranes, scavenges O^2– and reacts directly with peroxyl free radicals generated by O₃ 67. It could, therefore, play a role in the control of inflammation and immune response through its antioxidant properties. However, recent research has shown that high-dose carotenoid supplementation may lead to both antioxidant and pro-oxidant reactions 68, depending on the redox potential of the biological environment in which it acts 69.

Other antioxidants, such as flavonoids, are scavengers of superoxide anions and peroxyl radicals 70. In addition to antioxidant activities, flavonoids can modulate cell signalling pathways 20. Selenium, an essential trace element that plays a role in the detoxification of peroxides and free radicals 67, could also play an important role in the prevention of lung injury 21. As an integral part of the glutathione peroxidases and thioredoxin reductase, selenium probably interacts with every nutrient that affects the pro-oxidant/antioxidant balance of the cell. It also appears to support the activity of vitamin E in limiting lipid oxidation 71.

Omega-3 PUFA
Increased intake of omega-3 PUFA (n-3 PUFA) can decrease the inflammatory reaction by changing the contents of lipid membranes and other substrates, which are in turn the substrates for eicosanoid production 72. The substitution of n-3 PUFA (-linoleic acid; 18:3n-3 and eicosapentaenoic acid (EPA); 20:5n-3) for n-6 fatty acids (linoleic acid; 18:2n-6) in the membrane leads to the production of less potent inflammatory mediators (prostaglandin E₃ instead of prostaglandin E₂, and leukotriene 5 instead of leukotriene 4) 72. Prostaglandin E₂ has been shown to act on T-lymphocytes to reduce the formation of interferon (IFN)- without affecting the formation of IL-4. This may lead to the development of allergic sensitisation, since IL-4 promotes the synthesis of immunoglobulin E whereas IFN- has the opposite effect 73. Leukotriene 4, a potent stimulator of airway smooth muscle cells, increases post-capillary vascular permeability and mediates asthma by vasoconstriction and mucus secretion. The competitive interactions between n-6 PUFA and n-3 PUFA determine the cellular contents of arachidonic acid and EPA.

Increased intake of n-3 PUFA appears to decrease the risk of sudden and nonsudden death from myocardial infarction and nonfatal myocardial infarction 74–76. The protective effect of n-3 PUFA may be linked, in part, to its cardiac and arrhythmic effects, including increasing heart rate variability (HRV) 22, 74, 77. There is a positive correlation between the baseline cell membrane concentrations of n-3 PUFA and the degree of HRV, both in healthy subjects and in patients with coronary artery disease 23, 78. Along with increasing HRV, other anti-arrhythmic mechanisms of n-3 PUFA have also been described, including the capacity to stabilise the electrical activity of cardiac myocytes by modulating sarcolemmal ion channels and voltage-dependent sodium channels 24, and the capacity to reduce myocardial infarct size in animal models of ischaemia and reperfusion 24. N-3 PUFA also appear to: decrease the risk of thrombosis; decrease serum triglyceride levels, slowing the growth of atherosclerotic plaque; improve vascular endothelial function; lower blood pressure; and decrease inflammation 79.

Other micronutrients and immune functions
Micronutrients such as zinc, vitamin A and folic acid can also influence several components of immunity, altering the function of macrophages and thus their role in innate immunity and inflammation. Studies have shown that deficiencies in these micronutrients can significantly alter macrophage phagocytosis and their production of cytokines (IL-1 and IL-6, TNF- and IFN-). These deficiencies also alter natural killer cell function, neutrophil motility and antimicrobial activity 25.

Nutrient supplementation and effects of air pollution
The effects on air pollutant toxicity of nutrient supplementation at levels higher than is physiologically required have been studied in both animals and humans and summarised previously 2, 11, 17, 80.

Experimental animal studies
Results of animal studies suggest that supplementation with vitamin C and vitamin E modulates the pulmonary response to exposure to photo-oxidants, such as O₃ or NO₂ 17, 81, and that vitamin C, uric acid and glutathione located in the respiratory tract lining fluid are consumed on exposure to O₃ and NO₂ 16, 82, 83. Dietary deficiency of vitamin C appears to quickly translate to decreased levels of vitamin C in blood and RTLF 84. Temporary vitamin E deficiency may induce reversible changes in the expression of pro-inflammatory markers, reduce surfactant lipid synthesis in alveolar type II cells and favour the development of injury in response to air pollution insults 66. Further experimental studies using antioxidants, iron chelators or other substances support the role of ROS as mediators of the effects of particulates 37, 54. Oxidative stress appears to play a critical role in the activation of NF-B, and cytokine-induced NF-B activation is prevented after treatment with antioxidants or metal chelators 54. N-acetylcysteine, a powerful antioxidant, had a protective effect on inflammatory response and oxidative stress damage in rats exposed to coal dust 85 and on changes in heart rate and decrease in HRV in rats exposed to urban air particles 86.

Human studies
There is little information on the impact of antioxidant supplementation on the acute effects of air pollution exposure in humans. Most existing studies have focused on the changes of acute lung function. Other outcomes included bronchial airway reactivity, inflammatory response and changes in HRV but are less numerous and consistent. All these studies were experimental studies using supplements.

Antioxidant supplementation
Lung function and airway reactivity
Early studies used experimental protocols with single pollutants and a small number of healthy adults. Levels of O₃ and NO₂ were very high (usually close to 1,000 µg·m^–3 and >3,000 µg·m^–3, respectively) and subjects were supplemented for a relatively short period of time with high doses of vitamin C or vitamin E (eight to 16 times the USA recommended daily allowance of vitamin C (60 mg·day^–1) and vitamin E (8 mg·day^–1)) 2, 87–89. A modulating effect of antioxidant supplementation was observed in some studies of acute lung function changes 89 and airway reactivity 87 but not in others.

More recent experimental studies have addressed conditions in which the O₃ level and supplement doses were lower. In a study of asthmatic adults, a cocktail of vitamin C (500 mg) and vitamin E (400 UI) protected against a decrease in peak expiratory flow from SO₂ challenge after O₃ exposure 90. In another study 91, subjects were first deprived of vitamin C and then supplemented with a relatively low dose of vitamin C (250 mg), vitamin E (100 mg) and vegetable cocktail. Supplementation protected against acute change in lung function (forced expiratory volume in one second and forced vital capacity) after O₃ challenge. However, in well nourished individuals sensible to O₃, supplementation with vitamin C (500 mg) and vitamin E (100 mg) provide no protective effect on inflammatory response or lung function decrease after O₃ challenge. This lack of protection was observed despite elevated plasma vitamin C (+60.1%) and vitamin E (+51.4%) concentrations following supplementation, and increased vitamin C concentrations in the airways after supplementation following O₃ exposure 92.

Supplementation studies conducted in free-living populations of healthy exercising adults (the Netherlands) or adults exposed to high levels of air pollutants (Mexico) support the hypothesis that antioxidant supplementation protects against the acute effects of O₃ on lung function. In these studies, healthy adults were randomised to receive vitamin C (650 mg), vitamin E (75 mg) and β-carotene (15 mg) for several weeks 80, 93–95. More recently, a study of asthmatic children exposed to high levels of air pollutants in Mexico City also suggested that supplementation with vitamin C (250 mg·day^–1) and vitamin E (50 mg·day^–1) had a modulating effect on acute lung function changes 96. The positive effect of antioxidant supplementation was mostly found in children genetically susceptible to the effects of oxidants (glutathione S-transferases (GST)M1 null genotypes) 97.

Inflammatory response
Only three studies have evaluated the impact of antioxidant supplementation on airway inflammatory response to air pollutant exposure. Samet et al. 91 observed no difference in the bronchoalveolar lavage content of polynuclear cells and other inflammatory markers between supplement and placebo groups after O₃ challenge. Similarly, Mudway et al. 92 reported no effect of supplementation with vitamin C and vitamin E on O₃-induced neutrophilia in healthy individuals responsive to O₃. In contrast, asthmatic children heavily exposed to air pollutants and supplemented with vitamin C and vitamin E had significantly lower levels of IL-6 and IL-8 in nasal lavage than children receiving placebo 98.

n-3 PUFA supplementation
Lung function and inflammatory response
The impact of n-3 PUFA supplementation on asthmatic symptoms and exercise-induced bronchoconstriction has been examined among asthmatic subjects in various recently reviewed studies 12, 34, 99. Most of these studies enrolled a small number of asthmatic patients randomly assigned to receive a high dose of n-3 PUFA (3–4 g of EPA) for a short time-period (6–10 weeks); results were inconsistent. Studies with longer intervention periods, from 6 months to 1 yr, also led to inconsistent results with some studies showing improvement in lung function 100, 101 or inflammatory markers 101–103, or no effect 104. The dosage and duration of n-3 PUFA supplementation, and the type of asthmatic patients differed between studies and may explain the discrepancy between these studies 12, 34. The Cochrane database of systematic reviews identified 22 studies but included only nine that fulfilled the inclusion criteria and concluded that data were insufficient to determine the effect of n-3 PUFA in asthma. None of these studies include information on air pollution.

Cardiovascular effect
Increased intake of n-3 PUFA either from dietary sources or as a pharmacological supplementation has been shown to decrease the risk of mortality from coronary heart disease 105. In a randomised trial conducted in nursing home residents, supplementation with 2 g·day^–1 of fish oil (each 1 g capsule contained 83.2 % of omega-3 fatty acids) significantly decreased the effect of PM_2.5 on time and frequency domain parameters of HRV 106 This is one of two studies providing evidence that oxidant stress is one of the mechanisms explaining the effect of particle air pollution on the cardiovascular system 107. The other study reported that statins had a mitigating effect on the HRV effects of particulate air pollution in subjects genetically susceptible to oxidative stress (lacking the GSTM1 allele) 108.

Modifiers of an individual's response to oxidative stress
Under the biological model of oxidative stress one would expect factors that modify the response to oxidative stress to also alter the effects of air pollution. Thus, nutritional status, chronic diseases and genetic factors are candidates to determine susceptibility to oxidative stress-related effects of air pollution 26 as all these conditions are related to poor antioxidant defence.

Nutritional status
Antioxidant vitamin supplementation provides some protection against the adverse effect of O₃ on lung function in asthmatic children with slight deficiencies in these nutrients 96, and to adults depleted in vitamin C 91. In contrast, vitamin supplementation did not protect against O₃-induced lung function decrement in well nourished subjects 109.

Chronic diseases
Most chronic diseases are associated with chronic inflammation 13, 27, 28, 110–112, which might increase susceptibility to the additional oxidative stress caused by air pollution exposure. In particular, subjects with asthma 29, chronic obstructive lung diseases 113, diabetes 114 and cardiovascular diseases 115 have all been shown to have antioxidant deficiency 13 and be more susceptible to the effects of air pollution 108, 115. As observed in the case of cigarette smoke, a significant source of oxidative stress, air pollutants would lower antioxidant defences, with deleterious health consequences 116, 117. Evidence of the potential beneficial effect of antioxidants can be found in studies of elderly subjects in which treatment with statins 108 and n-3 PUFA supplementation 106 had a beneficial effect on response to particulate exposure.

Genetic susceptibility
As oxidative stress is an important pathway activated/involved in the adverse effects of air pollution, the genes involved are of primary interest. Most studies have focused on single gene polymorphisms; however, it is likely that there will be a hierarchy of genes determining susceptibility, rather than one individual gene driving this process 15.

GST enzymes: GSTM1, GSTP1
GST are phase II xenobiotic metabolising enzymes that participate in the detoxification of ROS by catalysing their conjugation with glutathione 118, 119. The common null allele of GSTM1 results in a complete lack of the enzyme and reduced or no conjugation activity 120. It has been associated with an increase in asthma and wheezing among children exposed to environmental tobacco smoke in utero, with a decrease in lung function growth 121, 122, and also with a rapid decline in lung function in smokers 123. In addition, polymorphic GSTM1 has been shown to act as a modifier of the lung response to fire smoke 124 and O₃ 125_. Antioxidant supplementation with vitamin C and E appears to modulate the effect of O₃ in asthmatic children homozygous for the GSTM1 null allele 97. Allergen sensitive subjects with low responsive genotypes show enhanced susceptibility to the adjuvant effects of DEP 126. A GSTM1 polymorphism has also been shown to increase sensitivity to PM, as evidenced by greater changes in HRV 108. Moreover, glutaryl coenzyme A inhibitors, i.e. statins, with known antioxidant and anti-inflammatory properties mitigate against the effects of ambient particles on HRV in subjects lacking the GSTM1 allele 107, 108.

Other genes
The Toll-like receptor 4 (TLR4; xr 4) gene has been implicated in innate immunity and endotoxin susceptibility 127 and has been hypothesised to play a role in O₃-induced hyperpermeability 26. TNF- (Xr17) has been related to lung function changes after O₃ exposure 128 and to an increased risk of asthma and wheezing that can be modified by O₃ exposure 129. TNF has been identified as a candidate gene for O₃-induced airway inflammation and hyperresponsiveness 130. Polymorphisms in TNF and lipoteichoic acid have been associated with respiratory effects of O₃ in humans 128. Arginase II has been associated with an increased risk of asthma in children, and the association appeared stronger among children with a smoking parent 131 suggesting that air pollutants could also play a role.

Gene–gene interactions
O₃-induced acute effects on respiratory function have been shown to be smaller in subjects with GSTM1 null and NOQ1 Pro/Pro genotypes 132. Similarly, a study examining asthma risk in a population highly exposed to O₃ showed that the risk of asthma was significantly associated with the NOQ1 genotype in subjects with the null genotype for GSTM1 133. Both genes have a specific function in antioxidative activities.

	FURTHER EPIDEMIOLOGICAL RESEARCH

TOP ABSTRACT BIOLOGICAL AND EPIDEMIOLOGICAL... FURTHER EPIDEMIOLOGICAL RESEARCH CONCLUSION ACKNOWLEDGEMENTS REFERENCES

 
There is now substantial evidence that air pollution exposure results in increased oxidative stress, alterations in immune regulation and repeated inflammatory responses that overcome lung defences to disrupt the normal regulatory and repair processes 10, 15. As summarised previously, despite a plausible mechanistic model linking air pollution, oxidative stress and dietary supplementation, evidence is not sufficient. Further randomised controlled trials (RCTs) are needed in order to better understand the potential protective effect of nutrient supplementation on the effect of air pollution on respiratory and cardiovascular functions and inflammatory responses.

RCTs provide a good alternative to maximise contrast in nutrient intake for evaluating the interaction of dietary factors and air pollutants and should be conducted in both the controlled setting and in free-living populations. A controlled setting will allow assignment of air pollutant exposure and, therefore, provide an accurate representation of the health effects and potential modulating effects of supplementation, while RCT conducted in free-living populations will have the advantage of representing real-life conditions.

Susceptible subjects, such as those with pre-existing respiratory or cardiac disease, micronutrient deficiency or genetic susceptibility, are the most likely to benefit from nutritional intervention (see Modifier of response section); therefore, RCTs should focus on these population subgroups. Short- and long-term effects can be studied; however, the major challenge in long-term effect studies is to assess the appropriate time-frame of exposure for the induction of the disease and, therefore, the relevant period and duration of the supplementation. There is accumulating evidence that exposure during lung development in foetal life and early childhood plays a major role, as in the case of maternal smoking 134–136. Therefore, RCTs of pregnant females with specific risks (such as asthmatic or atopic mothers) might provide some insight into the role of antioxidants and n-3 PUFA as modulators of the air pollution effect. In these studies, a major challenge is the accurate assessment of air pollution exposure, oxidative stress, biomarkers of nutritional status and health outcomes. Standardisation of these factors within and between studies is crucial to allow comparability of results. In the following section some issues to be considered in future studies will be discussed.

Air pollution exposure
Contrasts in exposure need to be maximised to be able to distinguish between effects in the placebo group and smaller or no effects in the supplemented groups. Depending on the study design and hypotheses tested, either temporal or spatial contrast should be large. Multicentre studies including areas with contrasting air pollution levels and the enrolment of random samples of participants within each centre might be an option. Moreover, the design of the exposure assessment must take into account the relationship between measured or measurable markers of oxidant pollution and personal exposure to the pollutant relevant to the hypothesis. For example, there are often large indoor/outdoor ratios in O₃ concentrations and these can be very heterogeneous across homes. Personal O₃ concentration may be very poorly correlated with ambient levels in certain areas. It might be useful to measure the redox activity of ambient pollutants or the antioxidant depletion rates, as these may be the most relevant characteristics in the hypothesised pathways of redox imbalance. Various assays have been developed to measure the redox activity of particles, such as OH radical formation or antioxidant depletion rates 137. However, the measurement methods may need further development to be applicable in epidemiological studies, in particular, for personal exposure assessment.

Biomarkers of oxidative stress
The advantage of using biomarkers is that they integrate both the effects of oxidant exposure and the full range of antioxidant protective mechanisms in vivo 30. However, samples can be oxidised during handling, processing and analysis, so there is potential for artefacts in estimates of baseline levels of oxidation markers. The magnitude of this problem varies between biomarkers 31, 138. Most of these biomarkers include measures of lipid, DNA and protein oxidation. Recent review articles provide broad coverage of this topic 30, 139. Table 1 presents a summary of oxidative stress biomarkers useful for clinical and epidemiological studies including: the type of marker; the biological media for measurement; the laboratory techniques most frequently used; an appreciation of its sensitivity and specificity based on the literature review; and some additional comments 140–195.

	CONCLUSION

TOP ABSTRACT BIOLOGICAL AND EPIDEMIOLOGICAL... FURTHER EPIDEMIOLOGICAL RESEARCH CONCLUSION ACKNOWLEDGEMENTS REFERENCES

 
Oxidative stress is one of the main mechanisms by which air pollutants affect respiratory and cardiovascular health. Short-term randomised supplementation trials suggest that antioxidant vitamins and n-3 polyunsaturated fatty acids might protect against the acute effect of these pollutants, particularly in vulnerable subgroups 80, 96, 106. However, the evidence is still limited because of the small sample size in most studies and the lack of comprehensive assessment of baseline nutritional status and oxidative stress response. Future studies should include randomised control trials of antioxidant or n-3 polyunsaturated fatty acid supplementation in susceptible populations and measure clinical, as well as intermediate, outcomes and biomarkers of oxidative stress and nutrient intake considering factors, such as reproducibility, inter- versus intra-person variability, detection limits and specificity and sensitivity of these markers. Doses and duration are still under debate but harmonisation between studies is desirable for comparison purposes.

	ACKNOWLEDGEMENTS

TOP ABSTRACT BIOLOGICAL AND EPIDEMIOLOGICAL... FURTHER EPIDEMIOLOGICAL RESEARCH CONCLUSION ACKNOWLEDGEMENTS REFERENCES

 
The authors would like to thank G. Evans for reviewing the English of the manuscript.

	REFERENCES

TOP ABSTRACT BIOLOGICAL AND EPIDEMIOLOGICAL... FURTHER EPIDEMIOLOGICAL RESEARCH CONCLUSION ACKNOWLEDGEMENTS REFERENCES

 

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