Oxidative stress and inflammation generated DNA damage by exposure to air pollution particles

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Oxidative stress and inflammation generated DNA damage by exposure to air pollution particles Peter Møller *, Pernille Høgh Danielsen, Dorina Gabriela Karottki, Kim Jantzen, Martin Roursgaard, Henrik Klingberg, Ditte Marie Jensen, Daniel Vest Christophersen, Jette Gjerke Hemmingsen, Yi Cao, Steffen Loft Department of Public Health, Section of Environmental Health, University of Copenhagen, Øster Farimagsgade 5A, DK-1014 Copenhagen K, Denmark

A R T I C L E I N F O

A B S T R A C T

Article history: Received 15 May 2014 Received in revised form 4 September 2014 Accepted 4 September 2014 Available online xxx

Generation of oxidatively damaged DNA by particulate matter (PM) is hypothesized to occur via production of reactive oxygen species (ROS) and inflammation. We investigated this hypothesis by comparing ROS production, inflammation and oxidatively damaged DNA in different experimental systems investigating air pollution particles. There is substantial evidence indicating that exposure to air pollution particles was associated with elevated levels of oxidatively damaged nucleobases in circulating blood cells and urine from humans, which is supported by observations of elevated levels of genotoxicity in cultured cells exposed to similar PM. Inflammation is most pronounced in cultured cells and animal models, whereas an elevated level of oxidatively damaged DNA is more pronounced than inflammation in humans. There is non-congruent data showing corresponding variability in effect related to PM sampled at different locations (spatial variability), times (temporal variability) or particle size fraction across different experimental systems of acellular conditions, cultured cells, animals and humans. Nevertheless, there is substantial variation in the genotoxic, inflammation and oxidative stress potential of PM sampled at different locations or times. Small air pollution particles did not appear more hazardous than larger particles, which is consistent with the notion that constituents such as metals and organic compounds also are important determinants for PM-generated oxidative stress and inflammation. In addition, the results indicate that PM-mediated ROS production is involved in the generation of inflammation and activated inflammatory cells can increase their ROS production. The observations indicate that air pollution particles generate oxidatively damaged DNA by promoting a milieu of oxidative stress and inflammation. ß 2014 Elsevier B.V. All rights reserved.

Keywords: Biomonitoring Comet assay Inflammation ROS production Animal models Cell culture

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Assessment of effect size and variability in PM-mediated ROS production, inflammation and oxidative damage to DNA ROS production induced by air pollution particles. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acellular ROS production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. ROS production in cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. ROS production in animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Inflammation induced by air pollution particles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Markers of inflammation in cultured cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Pulmonary inflammation in animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Systemic inflammation in animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Pulmonary inflammation in humans exposed to air pollution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. 4.5. Systemic inflammation in humans. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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* Corresponding author at: Section of Environmental Health, Department of Public Health, University of Copenhagen, Øster Farimagsgade 5A, Building 5B, 2nd Floor, DK-1014 Copenhagen, Denmark. Tel.: +45 3532 7654; fax: +45 3532 7686. E-mail address: [email protected] (P. Møller). http://dx.doi.org/10.1016/j.mrrev.2014.09.001 1383-5742/ß 2014 Elsevier B.V. All rights reserved.

Please cite this article in press as: P. Møller, et al., Oxidative stress and inflammation generated DNA damage by exposure to air pollution particles, Mutat. Res.: Rev. Mutat. Res. (2014), http://dx.doi.org/10.1016/j.mrrev.2014.09.001

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DNA damage induced by air pollution particles. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DNA strand breaks induced by air pollution particles . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. DNA strand breaks in acellular conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.1. DNA strand breaks in cultured cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.2. DNA strand breaks in lung tissue of animals . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.3. DNA strand breaks in human cells in biomonitoring studies . . . . . . . . . . . . 5.1.4. Oxidatively damaged nucleobases induced by air pollution particles . . . . . . . . . . . . . 5.2. Oxidatively damaged nucleobases in acellular conditions. . . . . . . . . . . . . . . 5.2.1. 5.2.2. Oxidatively damaged nucleobases in cultured cells. . . . . . . . . . . . . . . . . . . . Oxidatively damaged nucleobases in lung cells from animals . . . . . . . . . . . 5.2.3. Oxidatively damaged nucleobases in human cells in biomonitoring studies 5.2.4. 5.2.5. Oxidatively damaged nucleobases in urine from humans . . . . . . . . . . . . . . . Comparison between effect sizes across experimental systems . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Epidemiological studies have indicated associations between exposure to ambient air particulate matter (PM) and increased mortality from cardiopulmonary diseases [1–3], including lung cancer, chronic obstructive lung disease and myocardial infarction. The concept that especially small size particles generate inflammation by oxidative stress has been used as a paradigm of the mechanism of action of particle-mediated health effects [4,5]. This concept has gained wide acceptance as mechanism of action for other types of particles such as nanomaterials and oxidatively generated biomolecules, recruitment of leukocytes and cytokine signaling are becoming standard tools in the hazard identification of various types of particles [6–8]. In addition, it has been suggested that the dose–response relationship between exposure to poorly soluble particles and pulmonary toxicity had two different thresholds where the first one was defined as a ‘‘dosimetric threshold’’ related to macrophage-mediated clearance and the second was a ‘‘mechanistic threshold’’ that was related to the inability of the antioxidant defense system to counterbalance the production of reactive oxygen species (ROS) by inflammatory cells [9]. This is in keeping with the hypothesis of a stratified hierarchical (three-tier) response where oxidative stress occurs at three levels with adaptive responses at first level and where inflammation does not occur unless the second level is reached, whereas cell death relates to the third level [10]. However, other researchers have regarded PM-mediated inflammation and oxidative stress as more independent phenomena [11–13]. It has actually been difficult to pinpoint whether inflammation, oxidative stress, or DNA oxidation products occur at the lowest dose threshold in animal and human studies. ROS production can increase rapidly after exposure to PM, whereas inflammation develops over time, suggesting that oxidative stress may come first during a bolus exposure to high doses of PM. This has been demonstrated in cultured cells where increased ROS production could be detected within 0.5–1 h of air pollution PM exposure, whereas increased secretion of cytokines was observed at 16–24 h of exposure [14–17]. It takes some time for DNA lesions to accumulate to a level that can be distinguished from the background levels of DNA damage by the methods that are typically used in particle toxicology. It means that oxidatively generated DNA lesions are typically measured at time points when inflammation also occurs. Thus, it is difficult to tease out whether the genotoxicity is caused by inflammation or oxidative stress. It has been proposed that PM-mediated DNA oxidation damage could originate from primary (ROS-mediated) or secondary (inflammation-mediated) pathways [18]. This concept has been further developed to distinguish two types of ‘‘primary genotoxicity’’ (characterized by the absence of inflammation) with

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PM-mediated ROS production either directly from the material or by activating endogenous ROS production by the target cells, or from ‘‘secondary genotoxicity’’ that depends on the ROS production of activated inflammatory cells [19–21]. The level of oxidatively damaged DNA may also depend on the DNA repair activity. Transition metals may damage proteins by direct oxidation, which may be associated with decreased DNA repair activity. In addition, the activity of DNA repair enzyme may be inhibited by some metals in PM. This effect has typically been attributed to non-cytotoxic concentrations of nickel(II), cobalt(II), cadmium(II) and arsenic(III) because they inhibit DNA repair activity in vitro [22]. However, carcinogenic metals such as cadmium(II), arsenic(III), and chromium(VI) have multiple effects on redox regulation and cell signaling [23]. It means that it is difficult to distinguish between effects of oxidative stress and inhibition of DNA repair enzymes in studies on metal-generated DNA damage. In this review we have assessed whether PM-mediated oxidative stress, inflammation and DNA damage are independent phenomena, generated by a common cause (i.e. PM), or if there is a sequence of inter-related events potentially differing in a translational context from cell culture to human population. Fig. 1 outlines three possible relationships where DNA oxidation damage is a secondary phenomenon to ROS production or inflammation. It is possible that either PM-mediated oxidative stress stimulates inflammation (Relationship A) or PM-mediated inflammation causes oxidative stress (Relationship B). However, it is also possible that PM causes both oxidative stress and inflammation by different mechanisms of action (Relationship

Relationship A

Relationship B

Relationship C

Particulate matter

Particulate matter

Particulate matter

Oxidative stress

Inflammation

Inflammation

Inflammation

Oxidative stress

Oxidative stress

OxDNA

OxDNA

OxDNA

Fig. 1. Relationship between exposure to particulate matter (PM) and generation of oxidative stress, inflammation and DNA oxidation damage (OxDNA).

Please cite this article in press as: P. Møller, et al., Oxidative stress and inflammation generated DNA damage by exposure to air pollution particles, Mutat. Res.: Rev. Mutat. Res. (2014), http://dx.doi.org/10.1016/j.mrrev.2014.09.001

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C). A mechanism involving direct interaction between PM and nuclear DNA would require transport across the nuclear membrane, which seems implausible and to the best of our knowledge it has not been documented in experimental systems. However, air pollution PM generate other types of DNA adducts by nonoxidative mechanisms; the best-known example being lesions generated by polycyclic aromatic hydrocarbons (PAH) [24,25]. Attempts have been made to unravel the sequence of events in test systems such as acellular conditions, cultured cells and animal models, but without conclusions that can apply to human exposure conditions. In a systematic approach to the literature we present a comparison of the effects of ambient air PM exposure on inflammation and oxidative damage to DNA in a hierarchy of biological systems from humans to animals, cells and acellular systems. This review covers a large number of studies on PM-mediated ROS production, inflammation and oxidative stressgenerated DNA damage (Fig. 2), which could be subject for critical review in their own right. Indeed such studies exist already as for instance critical reviews on the association between exposure to air pollution and systemic inflammation [26], health effects of exposure to concentrated ambient air particulate matter (CAPs) [27], oxidatively damaged DNA [24,28–30] and coherence between toxicological and epidemiological findings [31]. 2. Assessment of effect size and variability in PM-mediated ROS production, inflammation and oxidative damage to DNA We used PubMed, EMBASE and Web of Science as primary search databases. The reference lists of the identified publications were scanned for relevant publications. We searched for studies on effects in humans or animals after exposure to air pollution particles. In addition, we searched for studies with results from investigations of PM-mediated generation of oxidatively damaged DNA, ROS production or inflammation in animals, cell cultures or under acellular conditions. Studies involving inhalation of air pollution particles can be regarded as unique exposures, which depend on the emission sources and atmospheric conditions in the geographical area. Even within the same exposure study there can be one order of magnitude inter-day variation in the exposure levels. It makes replication difficult because the same exposure situation may not occur again in the same area and much unlikely in another location, whereas this situation is avoided by using model particles where several researchers independently can investigate the same sample [32]. Standard reference materials (SRM) from the National Institute of Standards and Technology have been used for this purpose. SRM1648 and SRM1649 were collected from urban areas in the late 1970s in Washington, DC, and St. Louis, MO, USA, respectively. Another widely used type of PM is Environmental Health Center 93 (EHC93), which was collected in Ottawa, Canada, and represents particles below 10 mm in aerodynamic diameter (PM10) from urban air [33]. Residual oil fly ash (ROFA) also has played a significant role in the delineation of PM-mediated pulmonary toxicity. These ROFA samples are typically very rich in metals [34]. We have included publications on biomonitoring studies of subjects who have been exposed environmentally to air pollution particles. Studies on occupational exposure have not been included in the review unless the subjects have been exposed in urban air (e.g. policemen or bus drivers). A couple of biomonitoring studies of air pollution exposures in North Rhine-Westphalia, Germany, have reported results on 8-oxo-7,8-dihydro-20 -deoxyguanosine (8-oxodG) levels in lymphocytes [35,36]. These studies are welldesigned for analysis of associations between air pollution exposure and genotoxicity. Therefore, the lack of correlation analysis between exposure markers and DNA damage could indicate reporting bias due to statistically non-significant findings. However, correlation analysis between exposure markers and DNA

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damage has not been investigated in these studies (Dr Marczynski, personal communication). Studies on wood smoke exposure have only been included in case they have focused on ambient air exposure, whereas for instance controlled exposure studies have not been included in the review [37–39]. To the best of our knowledge, there are no human studies on controlled diesel exhaust exposure, which have measured oxidatively damaged nucleobase products in cells or urine from humans with methods that detect lesions specifically and do not have methodologic problems. We found one study showing unaltered levels of oxidatively damaged nucleobases in urine following exposure to diesel exhaust [40]. However, the oxidation products were measured by an ELISA method that is considered to be unspecific for the measurement of nucleobase oxidation products as discussed later in the section on DNA damage (Section 5). Therefore, studies on diesel exhaust particles have not been included in the review. The biomonitoring studies typically have assessed levels of DNA damage in white blood cells (WBC), lymphocytes or peripheral blood mononuclear cells (PBMC). A number of publications have imprecise information about the cell isolation protocol, which makes it difficult to assess differences in DNA damage between different subsets of WBC. We have therefore assumed that the PM exposure generated the same effect in all subsets of circulating WBC. The biomonitoring studies with measurement of damaged nucleobases in urine have used either spot urine samples or sampling over a period of time. The different types of urine collection make it difficult to compare concentrations across studies. The biomonitoring studies on air pollution exposures have been grouped into controlled exposures, panel and cross-sectional studies. The controlled exposure studies have well-defined assessment at personal level, whereas they typically have small numbers of subjects. The panel and cross-sectional studies could in principle assess personal exposure to PM over a certain period of time, which for instance has been used in studies on 8-oxodG in lymphocytes [41]. However, it has been more common to use area-based PM exposure assessment by for instance outdoor stationary monitoring stations. Therefore, the panel and cross-sectional studies are typically less suited to assess the association between PM exposure and health effects than the controlled exposure studies. The biomonitoring studies have mainly reported values on mass concentration of total suspended particles (TSP), PM10 or PM2.5 or the particle number concentration (PNC) of ultrafine particles (UFP). Personal proxy-measures of air pollution exposure in panel and cross-sectional studies have typically encompassed PAH or benzene metabolites. The PAH metabolites include 1hydroxypyrene (1-HOP), whereas the benzene metabolites includes S-phenylmercapturic acid (S-PMA) and trans, transmuconic acid (tt-MA). In addition, there is a group of studies of subjects in urban area with focus on O3 as exposure marker, albeit with concurrent exposure to PM. The differences in exposure assessment precluded a comparison of exposure levels across studies and it has therefore not been possible to analyze the exposure-effect relationship in a systematic manner. We have included studies on ‘‘laboratory animals’’ in the review, with the exception of 2 studies on oxidatively damaged DNA in airway epithelial cells from mammal sentinels because of a general shortness of studies on genotoxicity in laboratory animals [42,43]. Animal sentinels can be used as indicator of environmental hazards, but they can also be useful as model system for public health assessment [44]. Using animal sentinels it is possible to obtain samples from the presumed target tissues (e.g. the lungs in air pollution studies), but there are major limitations with regard to the exposure assessment. Some studies have shown pulmonary inflammation in sentinel dogs from areas with high air pollution levels in Mexico City, Mexico [45,46]. Another set of experiments

Please cite this article in press as: P. Møller, et al., Oxidative stress and inflammation generated DNA damage by exposure to air pollution particles, Mutat. Res.: Rev. Mutat. Res. (2014), http://dx.doi.org/10.1016/j.mrrev.2014.09.001

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showed that sentinel rats from Sa˜o Paulo, Brazil, displayed signs of pulmonary inflammation [47]. Nevertheless, we have not included studies on mammalian sentinels because of the inherent issues related to exposure assessment. The relationship between ROS production, inflammation and oxidatively generated DNA lesions has been assessed using two different approaches in the present review. The null hypothesis in these analyses was that there was no difference in variability or effect size between PM-generated oxidative stress (or ROS production as proxy-measure), inflammation and DNA damage which would indicate a direct linkage between these three endpoints. The first analysis was designed to display differences in effect size between markers of ROS production, inflammation and DNA damage across different test systems. We graded the effect size in each study into one of the eight groups on a logarithmic scale. The groups of effect size were as follows: ‘‘Class 0’’: below 10%, ‘‘Class 1’’: above 10%, ‘‘Class 2’’: above 25%, ‘‘Class 3’’: above 50%, ‘‘Class 4’’: above 100% (same as 2-fold), ‘‘Class 5’’: above 2.5-fold, ‘‘Class 6’’: above 5-fold, and ‘‘Class 7’’: above 10fold. The values refer to differences between exposed and control groups (for instance a study showing less than 10% difference in effect between exposed and control groups would obtain class 0 with regard to the effect size). In studies on associations assessed by regression analysis, the classes represent the percent increase in effect per exposure unit (for instance inter-quartile range, one standard deviation or 10 mg/m3 increase in levels of PM). The results on the effect size are reported as fold increases with 95% confidence interval (95% CI). As the effect sizes are derived from logarithmically transformed data, the 95% CIs are skewed on nominal scale. The reported 95% CIs in the review refer to the variation in the groups. In some analyses there are statistically significant results (i.e. P-values below 5%), but the 95% CIs are overlapping. This is because the statistical analyses are based on the pooled standard deviations from the individual groups, which gives rise to the same 95% CIs in all groups. We have compared the highest exposure to control group in studies with more than one exposure group. In principle, it means that the exposure in the experimental systems differs. The exposure contrast decreases in a manner as follows: acellular conditions > cultured cultured cells > animals > humans. However, it should be emphasized that the analysis entails a comparison between effect sizes between biomarkers in different experimental systems. For instance, if the effect size related to inflammation is higher than DNA damage endpoints in cultured cells, it would be expected to be the same in animals and humans if inflammation was the main determinant for DNA damage. A number of studies on the toxicity of air pollution particles have described differences related to the composition and size of particles, as well as spatial and temporal differences. In the present review we refer to spatial differences as variation in effect between different locations, which can be different sites within a relatively small area (e.g. urban background site and busy street in a single city) or within a continent (e.g. different cities in Europe). We define a temporal difference as a variation between PM collected at the same location during different periods that can be either different times of the year (i.e. seasonal variation) or different days (i.e. day-to-day variation). Studies on differences between air pollution particles of different sizes have typically segregated samples to PM10, coarse particles (aerodynamic diameter between 2.5 and 10 mm), fine particles (aerodynamic diameter below 2.5 mm; PM2.5) and UFP (aerodynamic diameter below 100 nm). The drivers behind the differences in PM material are often related to emission sources and atmospheric conditions. The second analysis in the review was designed to display variability in spatial, temporal and particle size differences on markers of ROS production, inflammation and DNA damage across acellular,

cellular and animal experimental systems. For this analysis, we determined the coefficient of variation (CoV) related to spatial, temporal and particle size differences. The CoV was calculated as the standard deviation divided by the mean for the highest concentration or dose in the studies. The rationale of this analysis is that endpoints of ROS production, inflammation and DNA damage should have the same variation related to spatial, temporal and particle size differences if they are related. In certain analyses we have stratified the publications into continents, including mainly Asia, Europe and North America because there are very few publications from other continents (Africa, Australia and South America). The stratification is based on the assumption that both the emission sources and atmospheric conditions of neighboring countries (or states in USA) are more alike than air pollution levels between countries on different continents. The purpose of this analysis has been to assess the extent of bias in the analyzed biomarkers and reported effects between different continents. On the other hand, the analysis does not have sufficient resolution to assess whether the hazards of air pollution exposure differ between urban areas in different continents. Differences in the magnitude of CoV for each endpoint were determined by one-factor ANOVA. The ANOVA included a weight factor for each study, where publications with determination of spatial, temporal and particle size differences weighted highest, studies with two variables had intermediate weight, and studies with only one of the variables had the lowest weight. The difference in effect sizes across experimental systems was analyzed by one-factor ANOVA, whereas post hoc differences were assessed by Fisher least statistical difference. Differences in effect size between publications from different continents were analyzed by one-factor ANOVA. We have used x2-test to assess differences in distribution of cell types that have been used in cell culture experiments, and differences in effect variability in studies related to continent where the PM samples have been collected. As post hoc interpretation of these contingency tables we have highlighted variables that contributed with more than 10% to the x2-value. The statistical approach is based on a semi-quantitative measurement of the effect size in each of the publications. A high effect size could arise from large difference in concentration/dose or samples being particularly rich in specific constituents. The level of inflammation may depend on both oxidative stress and activation of signaling pathways that are not associated with oxidative stress. Likewise, oxidative stress may occur because of endotoxin-mediated inflammation and inhibition of antioxidant enzymes by metals. It is not possible to assess the effect of specific constituents across the studies because the publications do not contain sufficient information on this issue. For instance, some publications may have assessed the content of specific metals, but have not measured the content of endotoxin. However, this does not affect the validity of the statistical approach because it is the same limitation in all experimental models. The statistical analysis contains both a formal assessment of P-values in ANOVA and 95% CIs of group means. The former is vulnerable to differences in homogeneity of variance between groups, whereas the latter does not have this problem because it corresponds to an ANOVA on groups with unequal variance. Nevertheless, the latter has less statistical power than the former and therefore has higher risk of type II error. We have used ANOVA tests in order to increase the statistical power of the analysis. 3. ROS production induced by air pollution particles Oxidative stress is a situation in the cell where the redox balance is shifted toward a pro-oxidant state as compared to an

Please cite this article in press as: P. Møller, et al., Oxidative stress and inflammation generated DNA damage by exposure to air pollution particles, Mutat. Res.: Rev. Mutat. Res. (2014), http://dx.doi.org/10.1016/j.mrrev.2014.09.001

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antioxidant state. This may come about by increased production of oxidant species or decreased levels of free radical scavengers (e.g. ascorbate or glutathione) or antioxidant enzymes (e.g. catalase, superoxide dismutase or glutathione peroxidase). The lung lining fluid is the first antioxidant defense barrier that protects epithelial cells from oxidant injury from inhaled compounds with oxidizing potential. It contains high concentrations of free radical scavengers (e.g. ascorbate, glutathione and tocopherols), antioxidant enzymes (e.g. superoxide dismutase and catalase) and metal-binding proteins (e.g. ceruloplasmin and transferrin) [48]. Ambient air PM-mediated oxidative stress can occur through ROS production by physico-chemical surface properties, soluble compounds such as transition metals or organic compounds, altered function of mitochondria, NADPH-oxidases, disrupted intracellular calcium homeostasis or through activation of inflammatory cells by activation of redox sensitive signaling pathways, including activator protein 1 (AP-1), mitogen-activated protein (MAP) kinases and nuclear factor kappa B (NF-kB) activation with subsequent changes in pro-inflammatory gene expression and production of cytokines [49]. Depletion of specific antioxidants in conditions mimicking compartments such as plasma or lung lining fluid and/or ROS generation in acellular condition has been used to assess the primary oxidative potential of PM [8]. An indication of oxidative stress can be obtained by study of depletion or redox balance of free radical scavenger concentrations (e.g. ratio between oxidized and reduced glutathione or dehydroascorbate and ascorbate) or activity of antioxidant enzymes in cell cultures and in vivo. Decreases in free radical scavengers or antioxidant enzymes can be used as indicators of oxidative stress in acute exposure studies, whereas it is more difficult to interpret changes in long-term studies because altered levels in either direction can be interpreted as direct effect of oxidative stress (i.e. decreased level of antioxidant activity) or as an upregulation of the antioxidant defense system related to ongoing oxidative stress. A number of assays, typically available commercially as kits for measurement of total antioxidant capacity, are sometimes used in research although they are considered inappropriate for use in human intervention studies [50]. Free radicals can be measured by electron spin resonance (ESR) in acellular conditions, especially with spintraps such as 5,5dimethyl-1-pyrroline-N-oxide (DMPO) for the detection of hydroxyl radicals, whereas ESR in living cells is restricted to less reactive radicals [51]. In cell culture experiments, it is therefore more common to use oxidation of molecular probes to assess ROS production [52,53]. The most common probes in cultured cells are 20 ,70 -dichlorofluorescein (DCFH) and dihydroethidine (DHE), whereas consumption of dithiothreitol (DTT) has been popular in studies on acellular ROS production. It is much more challenging to measure ROS in animal and humans and usually secondary effects in terms of oxidized biomolecules, especially DNA, lipids and proteins, are used as indicators of oxidative stress. 3.1. Acellular ROS production The studies on associations between exposure to air pollution particles and generation of ROS in acellular conditions are listed in supplementary Table 1. The studies on authentic air pollution particles are dominated by studies from Europe (19 studies) [54– 73] and North America (19 studies) [74–94]. The ROS production has been measured by ESR with spintrap agents or oxidation products of deoxyribose, DCFH, benzoate, or nitrobluenitrazolium. ROS production in terms of ESR signals has typically been obtained in aqueous suspensions of PM with H2O2 as co-oxidant and DMPO as spintrap, indicating that the assay depends mainly on the presence of transition metals in the samples [60,70,72,83]. This is in keeping with observations that the ROS production by coal fly

5

ash correlated with the release of iron [95,96]. Other transition metals also can be important catalysts for ROS production as shown in studies on PM2.5 from San Joaquin Valley, CA, USA [90– 92]. Treatment with metal chelators such as deferoxamine (DFO) or Chelex, antioxidant enzyme (i.e. catalase) or antioxidants such as dimethyl sulphoxide (DMSO) or dimethylthiourea (DMTU) diminished PM-induced ROS production in different assays, including ESR and oxidation products of DCFH or deoxyribose [60,80–83,85,87,97]. PM2.5 from urban air in 19 different European cities showed temporal and spatial variability in the ROS production by ESR, which was associated with levels of copper, iron, manganese, lead, vanadium and titanium [61,62]. A similar study of PM2.5 from 5 cities in USA also showed spatial differences in ROS production [78]. Studies with smaller geographical spread have indicated differences in the ROS production by comparison of PM collected in urban, suburban or rural sites [56,67,89]. In addition, there are several single city studies having shown increased ROS production by various size fractions of PM [57,58,60,64,65,70–72,81,82,90– 92]. Studies on different size fractions have produced mixed results on ROS production by ESR; certain studies have shown that coarse particles generated more ROS than fine particles on the basis of mass [54,66–68], whereas other studies have shown no or inconsistent effect of the particles size on the basis of mass [55,59,73]. PM may contain quinoid compounds that can undergo redox cycling [98]. This has been assessed by the DTT consumption assay, although it is not specific for quinones. It has been shown that transition metals also can contribute to the DTT consumption [75]. Nevertheless, the DTT consumption rate correlated with the presence of three different quinones in extractable organic matter (EOM) samples from TSP in Fresno, CA, USA [77]. There was a temporal variation in the DTT consumption rate by PM2.5 from Atlanta, GE, and Los Angeles, CA, in USA [93,94]. In addition, it has been shown that the DTT consumption rate on the basis of mass decreased with the particle size fraction of UFP, fine and coarse particles [76,79,84,86,88], although there is also a study showing no effect of the particle size [69]. Studies on model particles (SRM1648) or air pollution particles from single cities also have shown increased ROS production by the DTT assay [63,74]. It has only been possible to calculate the effect size from half of the studies on acellular ROS production because of insufficient information about the concentration–effect relationship. In these studies there was increased ROS production after exposure to air pollution particles (7.19 fold, 95% CI: 5.54–9.44 fold, n = 20). A stratified analysis of the effect size in studies on authentic air pollution particles showed slightly lower effect size in studies from Europe (5.52 fold, 95% CI: 3.43–9.40 fold, n = 9) as compared to studies from North America (8.94 fold, 95% CI: 5.93–13.8 fold, n = 8) (Table 1). The assessment of variability in ROS production related to spatial (46.9%, 95% CI: 40.7–54.2%, n = 19), temporal (42.7%, 95% CI: 35.3–51.8%, n = 18) and particle size fraction (34.4%, 95% CI: 23.9–49.5%, n = 13) differences showed relatively high variability of all variables (Fig. 3). To summarize, we have collected information on acellular ROS production from 41 studies, including 38 studies on authentic air pollution particles. The studies have shown evidence for association between exposure to air pollution particles and ROS production in acellular systems. The types of ROS encompass both transition-metal catalyzed oxidants such as hydroxyl radicals and quinone compounds. There seemed to be a tendency that ROS production measured by the DTT assay correlated negatively with particle size (small particles have the highest effect on the basis of mass). By contrast, the ROS production by ESR seems to show the opposite association (large particles have the highest effect on the basis of mass). The reported effect sizes generally have been high,

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O

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CH3 OH

N

N

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1,N6-εAde

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N H

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3,N4-εCyt

M1Gua

Fig. 2. Types of oxidatively damaged nucleobase lesions. FPG-sensitive sites encompass 8-oxo-7,8-dihydro-guanine (8-oxoGua), 4,6-diamino-5-formamidopyrimidine (FapyGua) and 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyAde). ENDOIII-sensitive sites encompass uracil glycol, thymine glycol, 5-hydroxycytosine (5-OHCyt) and 5-hydroxyuracil (5-OHUra). Examples of exocyclic nucleobase lesions include pyrimido[1,2-a]purin-10(3H)-one (M1G), 1,N6-ethenoadenine (1-N6-eAde) and 1,N4ethenocytosine (1,N4-eCyt).

which possibly is related to the high concentrations of PM that have been used in the studies. These concentrations may not be relevant for in vivo studies, whereas they can be used to distinguish between the ROS production potential of particles in different locations and size modes. 3.2. ROS production in cells The predominant cell types for the assessment of intracellular ROS production have been A549 cells (10 studies), other respiratory epithelial cells (6 studies), alveolar macrophages (9 studies) and various types of blood cells including monocytes,

lymphocytes and WBC (4 studies). The studies on intracellular ROS production are outlined in supplementary Table 2. Exposures to standard air pollution particles, including SRM1648, EHC93 and ROFA, have consistently shown increased intracellular ROS production, detected as oxidation products of DCFH or DHE or chemiluminescence [14–17,56,94,96,99–115]. The studies on authentic air pollution particles encompass samples from a wide range of locations in Europe (9 studies) [14,56,100,101,107,108,116–118], North America (8 studies) [15,16,94,99,106,113,115,119] and Asia (6 studies) [103,104,111,114,120–122]. There seem to be temporal differences between PM samples’ ability to promote intracellular ROS production [15,16,94,115–119], whereas there appears to be

Table 1 Summary of effect sizes of exposure to air pollution particles in studies stratified by continent. Biomarker

Asia

Acellular ROS Cellular ROS Cellular inflammation Pulmonary inflammation (animals)a

NA 2.78 NA NA 5.07 1.34 NA 1.05 NA 4.23 1.30 NA NA 1.83 1.44

Systemic inflammation (animals) Pulmonary inflammation (humans) Systemic inflammation (humans)b Acellular SB Cellular SBc Human SB Acellular OxDNAd Cellular OxDNAe OxDNA in blood cells (humans) OxDNA in urine (humans)

(1.67–5.69)

(1.19–86.2) (1.16–1.72) (1.02–1.10) (2.17–9.95) (1.10–1.89)

(1.28–3.47) (1.24–1.80)

Europe

North America

5.52 1.28 5.92 1.09 5.92 1.10 1.21 1.07 6.40 1.92 1.17 NA 1.50 1.31 1.09

8.94 1.69 3.85 1.40 5.41 1.05 1.08 1.06 NA 1.45 NA NA NA NA NA

(3.43–9.40) (1.16–1.49) (3.81–9.61) (1.01–1.55) (3.80–9.64) (1.06–1.17) (1.08–1.50) (1.05–1.13) (5.29–7.52) (1.52–2.64) (1.09–1.32) (1.15–2.62) (1.09–2.05) (1.04–1.20)

(5.93–13.8) (1.22–3.16) (2.28–7.36) (1.11–1.55) (1.70–29.0) (1.05–1.06) (1.05–1.15) (1.05–1.07) (1.06–4.37)

NA: not assessed. a The first and second row is effect size after inhalation and instillation, respectively. The effect size of the studies on inhalation exposure to PM from Asia is not shown because there are only two studies with large difference in effect size. b The results encompass pooled results from effects on WBC counts and protein inflammation markers. c The results encompass levels of SB in both aqueous extracts and EOMs. For studies that have assessed levels of SB by both aqueous extracts and EOM, we have calculated the average effect size. d The effect size is not reported because there were only two studies from Europe with detection of 8-oxodG by a reliable method (both studies had class 7 as effect size). e The effect size in the European studies includes effects obtained by both aqueous extract and EOM.

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ROFA (1.7 mg/m3 for 30 min) was associated with increased production of ROS in lung tissue, assessed by chemiluminescence [123]. In another study, rats were exposed to oil fly ash (500 mg/rat by intratracheal (i.t.) instillation) for 24 h and subsequently injected with a free radical spintrap in the peritoneum at 1 h before sacrifice. This showed a presence of carbon-centered alkyl radicals in lung homogenates from exposed rats, which was suspected to originate from peroxidation reactions of lipids [124].

160

Variability (CoV, %)

140 120 100 80 60 40 20 0 Spatial

Temporal

Particle size

Fig. 3. Coefficient of variation (CoV) in acellular ROS production related to spatial, temporal or particle size fraction differences in air pollution particles. Each symbol represents one study. The horizontal lines are mean values.

less difference in the ROS production ability between different size fractions of particles [15,117,118]. A few studies have assessed the potential of EOM from PM to generate intracellular ROS production in cultured cells. The exposure to EOM has been associated with increased intracellular ROS production, for instance in MCF-7 cells exposed to EOM from urban and rural sites [120], HepG2 cells exposed to EOM of PM10 from an industrial area [121], and A549 cells exposed to EOM from road tunnel particles [122]. The results have shown that the exposure of PM to cultured cells was associated with increased levels of ROS production (1.69 fold, 95% CI: 1.42–2.14 fold, n = 28). A stratified analysis of authentic air pollution particles indicated a difference in effect size from Asia (2.78-fold, 95% CI: 1.67–5.69 fold, n = 6), North America (1.69 fold: 95% CI: 1.22–3.16 fold, n = 7) and Europe (1.28 fold, 95% CI: 1.16–1.49 fold, n = 9) (Table 1). The temporal variability (23.2%, 95% CI: 10.5–51.3%, n = 7) was slightly higher than the spatial (10.7%, 95% CI; 2.9–39.3%, n = 4) and particle size fraction (7.6%, 95% CI: 3.8–15.3%, n = 3) variability (Fig. 4). To summarize, we have assessed the results from 30 studies, including 23 studies on authentic air pollution particles. There is compelling evidence that air pollution particles generate ROS in cultured cells. The ROS production by air pollution particles might be more dependent on temporal variability than differences between locations and particle size fractions. Studies from authentic air pollution particles from Asian countries, mainly China, might have had higher effect size as compared to PM from Europe and North America. 3.3. ROS production in animals There are relatively few studies on ROS production in vivo after pulmonary exposure. Inhalation of CAPs (300 mg/m3 for 5 h) or 168

Variability (CoV, % )

7

80 60 40 20 0

Spatial

Temporal Particle size

Fig. 4. Coefficient of variation (CoV) in cellular ROS production related to spatial, temporal or particle size fraction differences in air pollution particles. Each symbol represents one study. The horizontal lines are mean values.

4. Inflammation induced by air pollution particles The acute inflammation response after exposure to foreign compounds follows a sequence of events that recruit WBC, remove the source of inflammation and resolve the inflammatory reaction. This process is regulated by mediators that are secreted by tissue and inflammatory cells. The human airway epithelial cells produce a variety of mediators that can be grouped into chemotactic cytokines [interleukin 8 (IL8), chemokine (C-C) motif ligand 2 (CCL2), also known as monocytes chemoattractant protein 1 (MCP1) and chemokine (C-C) motif ligand 5 (CCL5, also known as regulated on activation, normal T cell expressed and secreted (RANTES))], multifunctional cytokines [interleukin 1b (IL1b), interleukin 6 (IL6) and tumor necrosis factor (TNF)], colony stimulating factors and growth factors [125]. The expression of IL8 is regulated by NFkB and AP-1. Rodents lack a direct homologue of human IL8, whereas chemokine (C-X-C) motif ligand 2 (CXCL2, also known as macrophage inflammatory protein 2 (MIP2)) and chemokine (C-X-C) motif ligand 1 (CXCL1, also known as keratinocyte chemoattactant (KC)) are regarded as functional homologues of human IL8. Elevated levels of IL1, IL6 and TNF in the circulation promote the acute phase response by stimulating the liver to release acute phase proteins. The acute phase proteins are considered to be markers of inflammation (or a consequence of inflammation), which is not the same as they are involved in the inflammation reaction (such as cytokines). The major acute phase proteins in humans are C-reactive protein (CRP) and serum amyloid A (SAA). However, there are species differences in the major acute phase proteins where mice produce SAA, serum amyloid P and haptoglobin as major acute phase proteins and rats produce a1-acid glycoprotein and a2-macroglobulin [126]. Fibrinogen is a minor acute phase protein in humans, mice and rats. A number of studies on air pollution exposure have measured levels of von Willebrand factor (vWF) in plasma or serum. This protein, produced by endothelial cells, megakaryocytes and connective tissue cells, is best known for its role in hemostasis, although it is also involved in extravasation of WBC [127]. The secretion of vWF is increased in cultured endothelial cells following exposure to cytokines in vitro and vWF is frequently described as an acute phase reactant, although clinical studies focus more on the association with endothelial cell damage and usefulness as a prognostic marker of cardiovascular disease events [128,129]. The most convincing sign of pulmonary inflammation is the presence of increased levels of leukocytes, especially polymorphonuclear (PMN) leukocytes in the air space. Air pollution particle mediated recruitment of PMNs to the airspace is typically dominated by influx of neutrophils, which is also considered to be a hallmark of pulmonary inflammation. This is typically observed in bronchoalveolar lavage fluid (BALF), although histology can also reveal the presence of inflammatory cells in the alveoli or structural alterations in the tissue architecture as a consequence of sustained inflammation, tissue damage or regeneration. A noninvasive alternative to bronchoalveolar lavage in humans is measurement of inflammation markers in exhaled breath, including exhaled nitric oxide (eNO). In the circulation, there might be a

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transient leukocytosis (possibly neutrophilia) and presence of immature inflammation cells from the bone marrow. However, it is also common to assess inflammation by measurement of markers related to inflammatory signaling and cell activation in the lungs or circulation. Especially cytokines and acute phase proteins have been widely applied in studies on associations between air pollution and health effects, whereas other endpoints such as soluble adhesion molecules have mainly been assessed in studies on cardiovascular hazards. 4.1. Markers of inflammation in cultured cells The most predominant cell types for the assessment of inflammation markers have been macrophages (30 studies), alveolar type 2 epithelial cells (14 studies on A549 cell line), bronchial epithelial cells (10 studies on BEAS-2B cell line) and various other types of airway epithelial cells (13 studies). Supplementary Table 3 summarizes the studies that have assessed markers of inflammation in various types of cultured cells. The level of inflammation has been assessed by either gene expression levels of cytokines or measurements of cytokines in cell culture medium by ELISA. The analysis of cytokine proteins has the obvious advantage of measuring the actual bioactive product, whereas there might be post-transcriptional regulation of mRNA of the same cytokine gene. The mRNA levels are typically measured by RT-PCR, which is not carried out as an absolute measurement where information of the copy number is reported. Nevertheless, it has been observed that particles in cell culture medium can bind to cytokines [130]. This may affect the biological activity and possibly also the measurement of cytokines, which is not a problem in studies of mRNA. A substantial number of studies have documented increased levels of biomarkers of inflammation, with regard to NFkB activation, release of cytokines, and production of NO in various mono-cultures or co-cultures of cells after exposure to model particles such as EHC93, SRM1648, SRM1649 or ROFA [14– 17,74,83,101,102,110,112,131–154]. However, there have been a few null effect studies on ROFA, SRM1649, CAPs and PM10 in monocultures of lung epithelial cells or alveolar macrophages, which have assessed the same cytokines (MIP2, TNF, IL1b, IL6 or IL8) as the studies showing increased cytokine secretion [117,152,155]. The studies on authentic air pollution particles have been dominated by reports from Europe (26 studies) [14,56,63,64,68,69,73,100, 101,117,118,133,134,141,156–168] and North America (22 studies) [15,16,74,80,81,83,85,87,99,113,138,142,143,146,148,155,169–174], whereas there have been few studies from Asia [122,175] and Africa [176,177]. PM from urban air in Amsterdam (Netherlands), Ło´dz´ (Poland), Rome (Italy) or Oslo (Norway) displayed both spatial and temporal differences in the potential to promote MIP2, IL6 and TNF secretion in macrophages and lung epithelial cells [133,134]. Another study of PM from urban background sites in Duisburg (Germany), Prague (Czech Republic), Amsterdam (Netherlands), Helsinki (Finland), Barcelona (Spain) or Athens (Greece) showed different spatial potential of inflammogenicity, although it should be noted that the samples were collected in different seasons of the year in the cities [160]. Differences in the potential to increase IL8 expression in BEAS-2B cells were observed in a study of fine particles from Manhattan (NY), New York City (NY), Sterling Forest (NY), Phoenix (AZ), Seattle (WA) and Salt Lake City (UT) in USA [171]. Spatial differences within the same area have been observed in a study from Senegal where PM2.5 samples from urban sites were more inflammogenic than a similar material from a rural site [176]. In addition, a study of PM10 samples from Mexico City indicated that particles from a business area were more inflammogenic than particles from industrial or residential areas [169]. However, there

also has been a study showing no difference between PM2.5 from urban background and a busy street, both types of particles increasing the expression of IL6 and IL8 in A549 cells [168]. In addition, there was no difference in gene expression of CCL2, IL8 and TNF in THP-1 cells after exposure to PM from town or rural background in Denmark [56]. A temporal difference in the inflammogenicity was observed for aqueous extracts of PM10 from Utah Valley, UT, USA where the lowest inflammogenicity was obtained for samples that were collected during a strike at the steel mill in the area [80]. No difference was observed for PM collected in a tunnel street at seasons with use of studded or non-studded tires in Oslo, Norway [164]. Another study found that the water-soluble fraction of PM10 had highest inflammogenicity when it was collected during the summer/autumn as compared to winter/spring in Switzerland [166]. PM10 samples that were collected during the spring were more inflammogenic than samples collected during the winter in Helsinki, Finland [64]. The same was observed for PM10 from Milan, Italy, where samples collected during the summer increased the secretion of IL1b from THP-1 cells, whereas there was no effect for samples that were collected during the winter [156]. PM2.5 sampled either outdoors or indoors in different homes in Boston, MA, USA and analyzed for TNF secretion by rat alveolar macrophages showed highest inflammogenic potential for the outdoor samples, whereas there was no clear difference related to the season [142]. Several studies have shown an inverse relationship between inflammogenic potential and particle size (coarse > fine > UFP) from different cities in Europe and USA [15,68,69,117,133,134, 143,148,160,161,167]. However, there are also studies showing the opposite relationship or that coarse, fine and ultrafine particles had similar inflammogenicity [73,146,170,175]. It has been shown that the water-soluble fraction as compared to the insoluble fraction of ROFA, SRM1649, CAPs (Boston, MA, USA), TSP (Provo, UT, USA) and PM10 (Helsinki, Finland) generated higher levels of cytokine secretion [64,81,138]. However, the water-insoluble fraction of SRM1648 was more inflammogenic as compared to the water-soluble fraction in A549 cells, based on IL8 secretion [74]. The stronger effect on cytokine secretion by the water-soluble constituents of PM could be mediated by transition metal-mediated oxidative stress. In support of this notion are a number of studies on ROFA and air pollution particles showing decreased cytokine secretion (TNF, IL6, IL8) or gene expression in macrophages, BEAS-2B and microvascular endothelial cells by treatment with transition metal chelators [16,63,85,87, 131,143,146,147]. However, there are also some studies showing no effect of DFO treatment on IL6, TNF or NFkB activation in macrophages or alveolar type 2 cells exposed to SRM1648 or PM10 [14,64,113]. Studies on antioxidant supplementation have likewise produced mixed results with some studies showing attenuated TNF, IL6 and IL8 secretion in macrophages or bronchial or alveolar epithelial cells after exposure to ROFA and air pollution particles [17,63,83,85,131,147], whereas one study on SRM1648 showed unaltered TNF secretion by antioxidant treatment in alveolar macrophages [132]. Other evidence of oxidative stress mediated inflammation in macrophages comes from studies showing that the TNF secretion by PM10 exposure in macrophages was dependent on calcium signaling through a pathway that involved ROS production [157,158]. There is compelling evidence that inhibition of the endotoxin activity has been associated with diminished secretion of cytokines (IL6, IL8, MIP2 and TNF) especially in macrophages and PBMC after exposure to ROFA, SRM1648, EHC93 or air pollution particles [132,134,143,150,166,173,175]. However, there are also studies showing that treatment with a lipolysaccharide binding compound (i.e. polymyxin B) did not affect

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4.2. Pulmonary inflammation in animals

140

Variability (CoV, % )

9

120 100 80 60 40 20 0

Spatial

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Fig. 5. Coefficient of variation (CoV) in inflammation markers in cultured cells related to spatial, temporal or particle size fraction differences in air pollution particles. Each symbol represents one study. The horizontal lines are mean values.

the inflammogenicity of PM10, coarse or fine particles, based on measurements of NFkB activation in A549 cells or cytokine (MIP2, IL6 and TNF) secretion in alveolar macrophages [134,162]. Inflammogenicity has mainly been assessed in exposure models with aqueous suspensions of particles or constituents thereof, whereas there are only few studies on EOM from PM. It has been shown that a dichloromethane (DCM) extract of air pollution particles from El Paso County, TX, USA did not increase the expression of IL6 and IL8 in BEAS-2B cells [172]. DCM extracts of PM from Shanghai, China showed increased expression of IL6 and IL8, whereas the expression levels of CCL2 and RANTES were unaltered in A549 cells [122]. Another study showed that DCM extracts from road tunnel street particles from Oslo, Norway, were less potent than the native particles to induce TNF, IL1b and IL8 release by THP-1 cells [164]. The studies on cytokine production or gene expression indicated a strong inflammatory potential of air pollution particles in cultured cells (4.88 fold, 95% CI: 3.66–6.42 fold, n = 71). A stratified analysis on authentic air pollution particles showed slightly higher effect size in studies from Europe (5.92 fold, 95% CI: 3.81–9.61 fold, n = 26) as compared to studies from North America (3.85 fold, 95% CI: 2.28–7.36 fold, n = 21) (Table 1). Variability related to the differences in spatial, temporal and particle size differences are shown in Fig. 5. The CoV for the spatial (20.7%, 95% CI: 15.1–28.5%, n = 17) and temporal (27.2%, 95% CI: 19.8–37.2%, n = 18) were somewhat lower than the particle size fraction CoV (47.2%, 95% CI: 34.1–65.3%, n = 17). We have summarized results from 71 studies on inflammation markers, including 51 studies on authentic air pollution particles. There was evidence showing that exposure to PM in cultured cells was associated with inflammatory reactions, assessed mainly as increased secretion of cytokines, which may be elicited secondary to oxidative stress in the cells. The observations originate from a large body of studies on especially lung epithelial cells and macrophages. The inflammation potential seemed to be higher for coarse particles as compared to fine particles, which is likely to be related to the content of endotoxin in the coarse fraction. Inhibition of endotoxin activity in most studies diminished the PM-mediated inflammogenicity. There was also experimental evidence linking inflammation in cultured cells to oxidative stress and metal-catalyzed ROS production, although it should be noted that the observations are mixed and the linkage between oxidative stress and inflammation might depend on constituents in PM that differ with regard to spatial, temporal and particle size variability.

Supplementary Table 4 lists studies that have assessed pulmonary inflammation in animals after exposure to PM by either inhalation or instillation. The level of pulmonary inflammation has been assessed by increased number of leukocytes, predominantly PMNs, or elevated concentrations of pro-inflammatory cytokines in BALF. We have not found animal studies that have assessed inflammation markers in nasal lavage or induced sputum. These samples are typically collected in human exposure studies as a more comfortable procedure than the sampling of BALF, whereas the animal studies usually collect BALF under anesthesia immediately prior to sacrifice. The publications are mainly derived from studies of authentic air pollution particles from Europe (15 studies) [68,178–191] and North America (22 studies) [81,85,87,113,192–209], whereas there were fewer studies from Asia (6 studies) [202,210–214] and South America (3 studies) [215–218]. In addition, there were a number of studies on model particles such as EHC93, SRM1648, SRM1649 and ROFA (21 studies) [102,180,185,186,192,197,203,215,216,219–232]. Inflammation has been observed after inhalation of CAPs (74– 1060 mg/m3) from Boston, MA, USA [193–195,199,205,206]. Studies on inhalation of CAPs from Tuxedo, NY, or Manhattan, NY, with a concentration range of 100–360 mg/m3 have generated mixed results on pulmonary inflammation [113,200,204,209]. Inhalation of CAPs from downtown Chicago, IL, USA (885 mg/m3, 8 h/day on 3 consecutive days) increased levels of IL6, CCL2 and TNF in BALF [192]. However, it has also been reported that exposure to CAPs from Grand Rapids, MI, USA (493 mg/m3, 8 h/day for 13 days) or Chapel Hill, NC, USA (475–907 mg/m3, 6 h/day for 2–3 days) was not associated with pulmonary inflammation [201,203]. Studies on inhalation of CAPs in the Netherlands have likewise generated mixed results with increased pulmonary inflammation after exposure to air from industrial and traffic tunnel sites (414– 3720 mg/m3 for 6 h) and null effect after inhalation of CAPs from a background site (399–3612 mg/m3, 6 h/day for 2 days) in Bilthoven [179,188]. There was increased pulmonary inflammation in rats after inhalation of CAPs from Hsin-Chuan, Taiwan (372 mg/m3, 6 h/ d) for 3 consecutive days [212]. Inhalation of CAPs from Yokohama, Japan (600–1500 mg/m3, 4.5 h/day for 4 days) had no effect on the expression of IL1b and TNF in lung tissue of rats [211]. It is likely that the studies on inhalation of CAPs have shown mixed results because of high inter-day variability in the ambient air level as well as variation between locations. A number of other inhalation studies on ambient air particles have also shown mixed results with null effects in studies of road tunnel air (55 and 94 mg/m3) in Antwerp, Belgium [178,182] and pulmonary inflammation by inhalation of ambient air (110–140 mg/m3) in downtown Porto Alegre, Brazil [217]. The exposure concentrations do not appear to be different between the studies with null effect and those showing pulmonary inflammation. Other studies have shown that a short period of inhalation of EHC93 (57 mg/m3 for 4 h), EHC-6802 (42 mg/m3 for 4 h) or ROFA (12 mg/m3 for 6 h) was associated with pulmonary inflammation [220,224,231]. Inhalation of oil fly ash (1.4 mg/m3 of PM2.5 for 4 h/day) for 3 consecutive days was associated with an increased number of neutrophils in BALF of rats [229]. However, inhalation of World Trade Center fine particles (425 mg/m3 for 8 h) or simulated downwind coal combustion emissions (117–1015 mg/m3, 6 h/day, 7 days/week for 1–6 weeks) was not associated with pulmonary inflammation [197,233]. I.t. instillation of EHC93 (5–10 mg/kg) has been associated with increased numbers of neutrophils in BALF at 24–48 h after exposure, whereas earlier (4 h) and later (days 4–7) time points showed less effect [185,186,223,232]. The exposure to EHC93 (2 mg/kg twice weekly for 4 weeks) was only associated with elevated numbers of macrophages in the lungs of rabbits [230]. A

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direct comparison of the inflammogenicity of PM from Ottawa, Canada (probably identical to EHC93), SRM1648, SRM1649, ROFA and PM from Du¨sseldorf, Germany, indicated that the different types of model particles had the same inflammogenicity at both equal mass concentration and equivalent amount of total transition metal content [180]. Another study on i.t. instillation of EHC93 in mice showed that the soluble fraction was more inflammogenic than the insoluble fraction [219]. Especially the content of zinc was found to be an important contributor to inflammogenicity, although redox active transition metals also had some effect on the inflammation response after i.t. instillation of EHC93 [221]. I.t. instillation of the water-soluble fraction of TSP from Provo (UT) USA was associated with higher levels of neutrophils in BALF as compared to instillation of the insoluble fraction of particles [81,85]. It has also been shown that i.t. instillation of SRM1648 (1.6 mg/lung in mice or 0.48–0.96 mg/ mouse in two different studies, respectively), SRM1649 (200 mg/ mouse), ROFA (0.1 or 0.5 mg/rat) and PM from Edinburgh (UK), Du¨sseldorf (Germany), Augsberg (Germany) and Taipei (Taiwan) increased the number of neutrophils, IL6, TNF or MIP2 in BALF [102,189,191,192,213,222,224,226,228]. There has been a relatively large number of studies that have assessed spatial, temporal or particle size fraction variability of effects of air pollution particles on parameters of pulmonary inflammation after i.t. instillation. It was shown that fine particles from Amsterdam (Netherlands), Ło´dz´ (Poland), Oslo (Norway) and Rome (Italy) were more inflammogenic than coarse particles on the basis of mass after i.t. instillation of 1.0 or 2.5 mg in rats [186]. This study also showed temporal variability of particles, especially those from Oslo for the influx of neutrophils in BALF, whereas the levels of TNF and MIP2 in BALF depended on both the season and location [186]. Another study with sampling of particles in Munich (Germany), Hendrik-Ido-Ambacht (Netherlands), Dordrecht (Netherlands), Rome (Italy) and Lycksele (Sweden) showed that coarse particles were more inflammogenic than fine particles after i.t. instillation of 3 or 10 mg/kg in rats [184]. This is in keeping with a third European study of PM from Duisburg (Germany), Prague (Czech Republic), Amsterdam (Netherlands), Helsinki (Finland), Barcelona (Spain) and Athens (Greece) showing that coarse particles were more inflammogenic than fine particles by i.t. instillation of 1, 3 or 10 mg/kg in mice [187]. Studies from Milan (Italy) and Borken and Duisburg (Germany) have also indicated that coarse particles were more inflammogenic than fine particles [68,183]. Results from comparisons of air pollution particles from Seattle (WA), Salt Lake City (UT), Sterling Forest (NY) and South Bronx (NY) in USA showed higher inflammogenicity of coarse particles as compared to fine particles and UFP after aspiration of 25 or 100 mg/mouse of PM [198]. By contrast, i.t. instillation of small size particles from Chapel Hill, NC, USA was associated with a higher influx of neutrophils compared with the effect of fine or coarse particles [196]. In addition to the potency of particles with different sizes, the European studies have also revealed both temporal and spatial variation in the potency of PM [183,184,186,187]. PM from Pensacola (FL), Atlanta (GE), Birmingham (AL) and Centreville (AL) in USA had higher spatial variability as compared to temporal variation between samples that were collected during the summer or winter [207]. I.t. instillation of PM2.5 as compared to the same dose of PM10 (7.5 mg/kg) from Beijing, China generated higher levels of TNF, IL6 and IL1 in lung tissue homogenate and particles collected closest to traffic generated the highest level of inflammation [214]. It has also been shown that desert dust from Arizona (USA), Shapotou district (Tengger desert, China) or Beijing (China) was associated with different degrees of pulmonary inflammation after i.t. instillation with 0.1 mg/mouse four times over 8 weeks [202,210]. Oropharyngeal aspiration of 32–100 mg/mouse of ROFA

or SRM1649 was associated with a higher degree of pulmonary inflammation than the same dose of World Trade Center fine particles [197]. A few studies have used intra-nasal instillation, showing that PM2.5 from the air in Sao Paulo (Brazil), PM from Buenos Aires (Argentina) or CAPs (Boston, MA, USA) increased the level of pulmonary inflammation [208,215,216,218]. Experimental studies indicate that oxidative stress is implicated in the generation of pulmonary inflammation as shown by a study where mice with over-expression of superoxide dismutase, as compared to wild type counterparts, had lower levels of neutrophils, TNF and MIP2 in BALF after i.t. instillation of 50 mg/ mouse (corresponding to 2 mg/kg) of ROFA [225]. Pre-treatment with a superoxide dismutase mimic (MnTBAD) inhibited the production of ROS in the lung and abrogated influx of neutrophils in BALF after i.t. instillation of SRM1649 in rats [227]. Similarly, pre-treatment with an antioxidant (DMTU) decreased the level of particle-mediated pulmonary inflammation after i.t. instillation of PM from Chapel Hill, NC, USA [196]. The effect size has been different between the studies on inhalation exposure (1.35 fold, 95% CI: 1.15–1.79 fold, n = 26) and direct exposures by various types of i.t. instillation or aspiration (6.14 fold, 95% CI: 4.54–8.47 fold, n = 35). A stratification of the publications according to the continent of the study indicated similar effect size for studies from Asia (5.07 fold, 95% CI: 1.19–86.2 fold, n = 4), Europe (5.92 fold, 95% CI: 3.80–9.64 fold, n = 11) and North America (5.41 fold, 95% CI: 1.70–29.0 fold, n = 7) for i.t. instillation of authentic air pollution particles. For inhalation exposure there was similar effect size between studies from Europe (1.09 fold, 95% CI: 1.01–2.45 fold, n = 4) and North America (1.40 fold, 95% CI: 1.11–1.55 fold, n = 14) (Table 1). The variability related to spatial, temporal or particle size fraction differences have mainly been investigated in studies with i.t. instillation (Fig. 6). There was not much difference in the variability related to spatial (25.1%, 95% CI: 16.5–38.4%, n = 9), temporal (21.6%, 95% CI: 10.9–42.8%, n = 4) and particle size fraction (31.4%, 95% CI: 22.5– 43.8%, n = 8). We have summarized the results from 60 studies on pulmonary inflammation in animals, including 42 studies on authentic air pollution particles. To summarize, there is evidence that airway exposure to air pollution particles or model particles has been associated with pulmonary inflammation in animals. The effect was higher in studies that have exposed animals by i.t. or nasal instillation as compared to inhalation exposure, which is possibly related to the bolus exposure of high doses. In addition, there has been some evidence of a stronger effect of coarse particles as compared to smaller particle sizes in the inflammogenic potential after instillation of particles. However, it should be emphasized that such studies on comparisons between coarse and fine particles on the basis of mass are mainly useful for toxicological purposes, 100 80

Variability (CoV, %)

10

60 40 20 0 Spatial

Temporal

Particle size

Fig. 6. Coefficient of variation (CoV) in inflammation markers in animal airways related to spatial, temporal or particle size fraction differences in air pollution particles. Each symbol represents one study. The horizontal lines are mean values. Only one study has used inhalation (indicated by an open square).

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whereas they are not necessarily relevant for the assessment of inhalation exposure to air pollution because coarse particles show limited penetration to the lower airways and exposure is usually more local because of fast sedimentation. 4.3. Systemic inflammation in animals Supplementary Table 5 lists studies that have assessed markers of systemic inflammation in animals after pulmonary exposure to air pollution particles. The studies encompass experiments on PM from Europe (7 studies) [178,179,182,184,185,188,191], North America (7 studies) [194,195,204,209,234–236] and Asia (2 studies) [213,237]. In addition, there are a number of studies on model particles such as EHC93 and fly ashes (9 studies) [185,229, 230,232,233,238–241]. Inhalation of urban air PM, CAPs or coal fly ash had no or inconsistent effect on circulating levels of WBC, fibrinogen, IL6, vWF and SAA [178,179,182,188,194,195,204, 209,229,230,233,236]. However, one study showed a borderline statistically significant increase in the number of neutrophils [194]. There was a study that showed decreased levels of WBC in the circulation after inhalation of CAPs [188]. In general, there seems to be no consistency of effects in either direction with regard to the doses, strains of animals or time points of measurements. Studies on i.t. or intrapharyngeal instillation of air pollution particles have shown unaltered [239], increased [230], or decreased numbers of WBC [234,235,240,241]. However, certain studies have also shown increased levels of fibrinogen or IL6 [232,235,240]. There are also certain studies having shown responses with regard to systemic inflammation such as increased levels of CRP [191,213,237] and fibrinogen [184,185] as well as a more modest increase in the percentage neutrophils in rats after three i.t. instillations (1 exposure/day for 3 days) to 1.6–40 mg/kg [237]. Only one study has investigated spatial differences on fibrinogen levels, showing virtually no variability between samples from cities in Germany, Netherlands, Italy and Sweden [184]. It has also been shown that i.t. instillation of ROFA was associated with increased levels of fibrinogen, whereas Mount Saint Helens dust had no effect [238]. It is rather modest effect sizes on systemic inflammation that have been observed in the studies of exposure to air pollution particles. The number of WBC in blood increased by 1.08 fold (95% CI: 1.04–1.18, n = 8) and 1.06 fold (95% CI: 1.05–1.07, n = 8) in the studies on inhalation and i.t. instillation exposure, respectively. The level of inflammation proteins increased by 1.07 fold (95% CI: 1.04–1.10, n = 11) and 1.28 fold (95% CI: 1.11–1.71 fold, n = 8) for the studies on inhalation and i.t. instillation, respectively. The studies of PM from Asia had slightly higher effect size (1.34 fold, 95% CI: 1.16–1.72 fold, n = 2) as compared to studies from Europe (1.10, 95% CI: 1.06–1.17 fold, n = 6) and North America (1.05 fold, 95% CI: 1.05–1.06 fold, n = 6) (Table 1). To summarize, we have assessed results from 24 studies on associations between pulmonary exposure to PM and systemic inflammation, including 16 studies on authentic air pollution particles. There was weak evidence that exposure to air pollution particles was associated with increased levels of WBC in blood, although transient fluctuations may occur because of recruitment of cells from the bone marrow to the lung. There was a slightly increased effect size of blood inflammation markers in i.t. instillation studies, although it has mainly been driven by one study with very high exposure level (40 mg/kg) that has no relevance for the exposure levels in humans [237]. 4.4. Pulmonary inflammation in humans exposed to air pollution Studies on pulmonary inflammation in humans after exposure to air pollution have mainly investigated cytokines in lavaged fluid

11

or eNO. Analysis of inflammation markers in exhaled breath is a relatively easy and non-invasive method, which is substantially more comfortable for the subjects than bronchial lavage. As with animal models, pulmonary inflammation can also be measured by counting the total leukocytes or influx of PMNs in BALF as well as measurement of cytokines. The publications on PM-mediated pulmonary inflammation in humans are grouped into controlled exposure, panel and cross-sectional studies (supplementary Table 6). These originate mainly from North America (13 studies) [82,242–257] and Europe (7 studies) [65,258–263], whereas there is only one study from Asia [264]. It has been shown that young and healthy humans, who were exposed by bronchial instillation to 500 mg of aqueous extracts of PM10 from Utah Valley, UT, USA had higher levels of neutrophils and pro-inflammatory cytokines (IL1b, TNF and IL8) in BALF at 24 h after the exposure [82]. I.t. instillation of PM2.5 (100 mg, corresponding to 24 h inhalation of 100 mg/m3) from locations with mining/smelter industry or non-polluted area in Germany increased the total number of cells in BALF, whereas there was no difference in differential cell counts of neutrophils, lymphocytes and monocytes [65]. Only particles from the area with high level of air pollution was associated with increased concentration of some pro-inflammatory cytokines in BALF (IL6 and TNF, but not IL1 and IL8) [65]. A study on inhalation exposure to CAPs (23–311 mg/m3) from Chapel Hill, NC, USA for 2 h with moderate exercise and analysis of pulmonary inflammation at 18 h after cessation of the exposure showed a mild increase of neutrophils in BALF, whereas there were unaltered levels of IL6, IL8 and PGE2 [248]. The same was observed after 2 h inhalation exposure to CAPs (24–160 mg/ m3) from Chapel Hill, NC, USA where there was a mild pulmonary inflammation with increased percentage of neutrophils in BALF, whereas there were unaltered levels of IL6, IL8 and PGE2 [249]. Inhalation of ultrafine CAPs from Chapel Hill, NC, USA (1.2–50 mg/m3 for 2 h) was associated with decreased number of leukocytes in BALF, unaltered levels of PMNs, and mixed responses of cytokines in BALF [256]. Inhalation of CAPs (48–199 mg/m3) from Toronto, Canada, for 2 h did not alter the number of total leukocytes or PMNs in induced sputum samples from asthmatics or non-asthmatics at 3 h after the exposure [257]. A CAPs study from Edinburgh, UK (190 mg/m3 for 2 h) showed a statistically non-significantly increased 3-nitrotyrosine level in exhaled breath condensate [261]. Controlled exposure to air in a road tunnel in Stockholm, Sweden (80 mg/m3 of PM2.5 for 2 h) also had no effect on eNO in asthmatics and there were inconsistent associations between exposure and levels of IL1b, IL6, IL8, IL10 and TNF in nasal lavage fluid [258]. Elderly subjects with asthma had unaltered levels of eNO as well as unaltered number of neutrophils and IL8 in BALF after a 2 h walk along a traffic-intense street in London [260]. It has been shown that controlled exposure of healthy young subjects to air from a major road (PNC = 252,290 particles/cm3) while exercising lowered the concentrations of eNO and nitrate, which was hypothesized to be due to formation of peroxynitrite [255]. Inhalation exposure at traffic or urban sites in Utrecht, Netherlands for 5 h with intermittent exercise showed a positive association between the PNC and eNO [262]. The panel studies have typically focused on children or elderly with lung or cardiovascular diseases. In Seattle, WA, USA, there was a positive association between personal PM2.5 exposure and eNO in children with asthma who did not take corticosteroid medication [251–253]. A study from Los Angeles, LA, USA showed a positive association between personal PM2.5 exposure and eNO in children with asthma [245]. Moreover, the eNO levels correlated with acellular (DTT assay) and cellular (DCFH assay in macrophages) ROS production by PM [246]. However, another study on children with asthma from Ontario, Canada, showed no association between air pollution exposure and eNO [254]. Studies on healthy

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children in Steubenville, OH, USA or Mexico City, Mexico, have indicated positive associations between air pollution exposure and eNO in exhaled breath and IL8 in nasal fluid [242–244]. Elderly subjects with asthma or chronic obstructive pulmonary disease from Seattle, WA, USA had a positive association between outdoor concentrations of PM2.5 and eNO, whereas there was no association with personal exposure to PM2.5 [250]. In addition, elderly with coronary artery disease in the Los Angeles basin, CA, USA had a positive association between exposure markers (PM2.5 and O3) and eNO [247]. There was decreased eNO in young and healthy subjects as well as improved ambient air pollution levels during the Olympics in Beijing, China as compared to periods before and after the event [264]. A cross-sectional study on subjects with lung diseases (asthma or chronic obstructive pulmonary disease) in Helsinki (Finland), Athens (Greece), Amsterdam (Netherlands) and Birmingham (UK) showed an association between levels of coarse particles at central monitoring stations and levels of NOx in exhaled breath condensate, whereas there was no association with personal exposure to PM2.5, PM10 or coarse particle fraction as measured either near or inside homes [259]. Another cross-sectional study on children from Utrecht, Netherlands showed a positive association between PM10 exposure and eNO [263]. The same study also showed that children in urban locations had higher nasal lavage levels of IL8 and NOx as compared to children in a suburban area [263]. The assessment of the effect size indicates an overall 1.13 fold (95% CI: 1.08–1.22 fold, n = 21) increase of pulmonary inflammation after exposure to air pollution particles. There was a similar effect in the controlled exposure studies on short-term and high dose exposure (1.17 fold, 95% CI: 1.08–1.40 fold, n = 11) as compared to the panel and cross-sectional studies (1.09 fold, 95% CI: 1.08–1.22 fold, n = 10). The studies from Europe (1.21 fold, 95% CI: 1.08–1.50 fold, n = 7) and North America (1.08 fold, 95% CI: 1.05–1.15 fold, n = 13) had similar effect size (Table 1). To summarize, we have assessed results from 21 studies on associations between exposure to air pollution and pulmonary inflammation in humans. There was evidence of a weak association between exposure to air pollution particles and markers of pulmonary inflammation in humans. The effect in controlled exposure studies was modest, which could be due to the relative short exposure time (typically a few hours). The low effect in panel and cross-sectional studies might be due to low exposure concentration or it might be related to regression dilution because of exposure misclassification. 4.5. Systemic inflammation in humans Supplementary Table 7 describes the studies on systemic inflammation markers in humans. These publications originate mainly from studies in Europe (25 studies) [258,261,265–288] and North America (23 studies) [247–249,256,257,289–308], whereas there have been fewer studies from Asia (11 studies) [154,309– 317]. The studies on systemic inflammation have mainly focused on markers of cardiovascular diseases, including acute phase proteins (fibrinogen, CRP), platelets, vWF, hematocrit, whole blood viscosity and WBC counts [318]. There are also some studies on SAA [266,272,279,302], IL8 [273,288], PGE2 [291] and nitrate/ nitrite in plasma or serum [312,319]. Especially the measurement of CRP has been popular in air pollution studies because it is used clinically, it can increase more than three orders of magnitude during an acute phase response, and it has a relatively short halflife in plasma (approximately 19 h). A recent review of the association between air pollution exposure and plasma concentrations of CRP in humans encompassed a total of 44 publications, stratified into cross-sectional, panel and randomized cross-over trials [26]. The most important observation from that review was

an association between air pollution exposure and elevated levels of CRP in children in cross-sectional studies, whereas there were inconsistent results on adults that might be related to the inclusion of subjects with prescribed statins or anti-inflammatory drugs. It was also noted that the randomized cross-over trials mainly showed no association between air pollution exposure and CRP levels in plasma, which could be because these studies have few subjects and relatively short exposure duration [26]. For the assessment of systemic inflammation, we have assessed WBC counts, CRP, IL6, TNF, vWF and fibrinogen because these markers have been investigated in many studies originating from Europe (including Belgium, Denmark, Finland, Germany, Italy, Netherlands, Serbia and Switzerland), North America (including California, North Carolina, Massachusetts, Missouri and Utah in USA as well as locations in Canada and Mexico) and Asia (China, India, Iran, Israel and Taiwan). A substantial number of the reports have shown statistically significant association between at least one inflammation marker and PM in either linear models or logistic regression, although consistency is lacking with regard to certain inflammation markers being more strongly associated with PM levels than others. Fig. 7 shows the distribution of effects (statistically significantly increased or null/decreased effect) for WBC, IL6, fibrinogen, TNF, CRP and vWF. There seems to be a trend toward the total number of WBC, or subsets of WBC in blood, being increased less often than the protein inflammation markers appear to be, although it is not statistically significant (x2 = 6.0, P > 0.05). This analysis does not indicate a difference in the response between different markers of inflammation with regard to associations to PM levels. As this is based on reported statistically significant associations, it must be expected that there is a publication bias because of less publication of null effect associations. This is most likely associated with higher effect size in the reported publications. However, a number of the studies have reported the associations as percent increase per change in PM mass or PNC from stationary monitoring station samplings. This is associated with exposure misclassification, which may drive the effect toward null because of regression dilution. It is therefore difficult to estimate the true effect size of the various inflammation markers. Nevertheless, we do not expect a differential bias toward some inflammation markers being more likely to be reported as null effects as compared to others. Controlled exposure to CAPs in Edinburgh, UK (190 mg/m3 and 99,400 particles/cm3 for 2 h) had no effect on CRP levels and total WBC counts at 6 or 24 h after the exposure [261]. Inhalation of CAPs from Toronto, Canada (149 mg/m3 for 2 h) was associated with a slightly increased number of WBC in blood immediately

Positive

Null/decreased

100%

Distribution of studies

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80%

60%

6 18

13

18

10

25

40% 9 20% 6

5

9

5

WBC

IL6

Fib.

TNF

17

0% CRP

vWF

Fig. 7. Distribution of studies that have measured markers of inflammation in plasma or serum from humans in terms of white blood cells (WBC), IL6, fibrinogen (FIB), TNF, CRP or vWF. Numbers in the columns refer to the number of studies.

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after the exposure, whereas there was no effect at 24 h and CRP, IL6 and TNF levels were unaltered as well [290]. Another study on inhalation of CAPs from Toronto (48–199 mg/m3 for 2 h) among asthmatics or healthy subjects showed increased IL6 levels at 3 h after the exposure, whereas there were unaltered levels of TNF [257]. Inhalation of CAPs from Chapel Hill, NC, USA (23–311 mg/m3 for 2 h with exercise) was associated with slightly higher fibrinogen levels at 18 h after the exposure, whereas WBC counts were unaltered [248]. A later study on exposure to CAPs from Chapel Hill (15–358 mg/m3 for 2 h) showed decreased WBC counts, increased fibrinogen and unaltered levels of CRP, IL6, TNF and vWF [297]. Another study of inhalation of CAPs from Chapel Hill (24– 160 mg/m3 for 2 h) showed no effect on levels of CRP, vWF or fibrinogen at 1 or 20 h after the exposure [249]. Inhalation of ultrafine CAPs from Chapel Hill (PNC = 120,662 particles/cm3 or 50 mg/m3) for 2 h with exercise had no effect on WBC counts, CRP, fibrinogen or vWF at 18 h after the exposure [256]. Inhalation of emissions in a road tunnel in Stockholm, Sweden (PM2.5 > 80 mg/ m3) had no effect on WBC levels [258]. In addition, two studies on indoor air filtration of traffic-generated particles in Copenhagen, Denmark for 24–48 h had relatively low exposure gradients in terms of PNC (less than 10,000 particles/cm3) and showed no effect on CRP, IL6, TNF and fibrinogen [266,267]. A study on air filtration for 7 days in homes in a wood smoke impacted area in British Columbia, Canada, showed a decrease in CRP levels, whereas there was no association with IL6 levels [289]. Controlled exposure at different locations in Utrecht, Netherlands showed positive associations between the mass concentration exposure (PM2.5 or PM10) and CRP and vWF, whereas there was no association with fibrinogen, and PNC levels were not associated with inflammation markers [283]. The panel studies have shown mixed results with only few investigations showing generally positive associations between PM exposure and inflammation markers. It has been shown that patients with coronary artery disease had positive associations between exposure to small size particles (PM0.25) and CRP, IL6 and TNF in plasma [292–294]. A study of subjects in Singapore showed elevated serum levels of TNF, IL1b and IL6 during a period of haze with high ambient air pollution concentrations (PM10 = 125 mg/ m3) as compared to a period afterwards with low air pollution level (PM10 = 4 mg/m3) [154]. There were positive associations between PM10 and CRP and fibrinogen in subjects from Taipei (Taiwan); PM2.5 levels showed the same trend albeit not with statistical significance [309]. A study among highway troopers in Wake County, NC, USA also showed positive associations between PM2.5 and levels of neutrophils and vWF [304]. However, a number of panel studies have shown no associations between PM exposure levels and inflammation markers, including WBC, CRP, IL1b, IL6, IL8, TNF, vWF, SAA and fibrinogen in blood [280,282,288,299, 300,302,306,307,315]. In addition, there are several panel studies that have shown associations between PM and inflammation markers in subgroup analysis or have obtained mixed results on associations between PM levels and inflammation markers (WBC, CRP, vWF, IL1b, IL6, IL8, TNF, SAA or fibrinogen) without an apparent pattern with regard to certain biomarkers being more consistent in effect than other biomarkers [268,272,273, 279,281,287,292,296,316]. One study reported only results on decreased plasma levels of vWF in subjects during the summer Olympics in Beijing [317], whereas another study showed mixed results with decreased levels of CRP, vWF and unaltered levels of WBC and fibrinogen [313]. The cross-sectional studies encompass relatively small investigations with fewer than 100 subjects and large studies with up to 25,000 subjects. The small investigations have typically reported null effects on vWF [301], CRP [274] and WBC [286]. This could be due to low statistical power in those studies. Some of the larger

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studies (233–1373 subjects) have shown statistically significant associations between PM levels and CRP, fibrinogen and WBC counts [269,275,277,305,310]. However, studies with 1392 and 1218 subjects have shown null effects on CRP and fibrinogen, respectively [265,311]. A cross-sectional study of 5634 subjects in 6 different study sites in USA showed no association between PM2.5 levels and CRP levels [295]. In addition, one study of adults in a health survey in UK found no associations between PM10 concentrations and levels of CRP or fibrinogen in blood samples from 17,000 to 25,000 subjects [270]. Two studies encompassing 3999 and 5067 subjects in Ruhr area (Germany) and Rotterdam (Netherlands) showed positive associations between PM levels and CRP [271,285]. In addition, there was a positive association between PM10 levels and fibrinogen in 7205 subjects in London, UK [276]. A number of cross-sectional studies with substantial differences in sample size (52–10,208 subjects) have assessed more than one inflammation marker [278,284,291,298,303, 308,314]. These studies have shown mixed results on CRP, TNF, vWF, IL6, fibrinogen and WBC counts without a clear tendency for one marker to be more strongly associated to PM levels than others and the effect does not appear to be dependent on the sample size. The cross-sectional and panel studies have assessed inflammation markers in healthy humans or specific groups of the population such as children, elderly, pregnant women or patients with cardiovascular diseases or diabetes. Some of the specific groups can be regarded as susceptible populations to disease (elderly), yet medical treatment of the patients may affect inflammation markers. The effect size in putatively susceptible subjects could therefore be different as compared to the healthy adult population. Nevertheless, the assessment of effects in specific groups in cross-sectional studies has not indicated a different pattern of associations as compared to studies on healthy adults. Cross-sectional studies on the elderly or on subjects with prior myocardial infarction showed mixed effects on CRP, IL6, fibrinogen and WBC counts [278,308]. Two studies on subjects with diabetes have shown no association between PM exposure and levels of CRP or vWF [301,311], whereas one study showed a modest association between PM10 and vWF in a subgroup analysis of subjects who were stratified into groups of diabetics or non-diabetics [298]. Four studies on children have produced mixed results [274,275, 286,291]. The panel studies have shown mainly positive associations between PM levels and inflammation markers in patients with cardiopulmonary diseases [272,273,279,287,292–294], with a few studies showing no association in patients with asthma [307] or coronary artery disease [306]. One panel study showed a positive association between PM levels and WBC counts, whereas CRP and IL6 were not associated with PM levels [296]. Another study on elderly subjects showed no association between outdoor or personal PM2.5 exposure and CRP, IL6 or TNF levels [300]. Two panel studies on patients with diabetes have shown no associations between PM levels and CRP, IL1b, IL6, TNF, SAA and fibrinogen levels [299,302]. The cross-sectional and panel studies on susceptible groups do not indicate a systematic trend of either increased or decreased responsiveness toward PM-induced lowgrade inflammation. The effect sizes on systemic inflammation have been rather modest in the studies on exposure to air pollution in humans. The number of WBC in blood increased by 1.05 fold (95% CI: 1.05–1.06, n = 23). Protein inflammation markers (CRP, IL6, fibrinogen, IL6 and vWF) increased by 1.07 fold (95% CI: 1.06– 1.09, n = 51). A stratification of publications to continents of origin indicated similar effect size for studies in Asia (1.05 fold, 95% CI: 1.02–1.10 fold, n = 8), Europe (1.07 fold, 95% CI: 1.05– 1.13, n = 23) and North America (1.06 fold, 95% CI: 1.06–1.07 fold, n = 22) (Table 1).

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To summarize, we have assessed results from 58 studies on associations between exposure to ambient air pollution and systemic inflammation in humans. The studies suggest a weak association between exposure to air pollution and low-grade systemic inflammation, although it should be emphasized that the results have been mixed. The controlled exposure studies have mainly shown null effects, which could be related to low statistical power, despite the exposure being higher than the exposures in panel and cross-sectional studies. PM-induced low-grade inflammation seems to occur in both healthy subjects and susceptible groups. Nevertheless, the same level of low-grade inflammation could be more hazardous in susceptible groups as compared to healthy subjects because it may elicit clinical events such as myocardial infarction.

5. DNA damage induced by air pollution particles The most widely used assays to measure DNA damage in human air pollution studies have been adducts generated by PAH, oxidatively damaged DNA, strand breaks (SB) and cytogenetic markers [24,25]. The oxidatively damaged DNA lesions can be grouped into small nucleobase lesions and lipid peroxidationderived exocyclic adducts (Fig. 2). The level of oxidatively damaged bases in DNA is an important general indicator of intracellular oxidative stress capable of reaching the nucleus, thus reflecting a specific mechanism of carcinogenesis [320]. The most widely studied oxidatively generated DNA lesion is 8-oxo-7,8-dihydroguanine (8-oxoGua), which is commonly measured as the 20 deoxynucleoside 8-oxodG [321]. The levels of 8-oxodG can be measured by high performance liquid chromatography (HPLC) with electrochemical detection (ECD) or liquid chromatography with tandem mass spectrometry (LC-MS/MS). There are also other oxidatively related DNA modifications and lipid peroxidation mediated etheno adducts, including pyrimido[1,2-a]purin-10(3H)one (M1G), 1,N6-ethenoadenine (1-N6-eAde) and 1,N4-ethenocytosine (1,N4-eCyt), which can be measured by chromatographic methods or antibody-based techniques [322]. These lesions are relevant, although they appear to be only assessed sporadically in studies of PM-mediated DNA damage. The 8-oxoGua lesion in DNA is mutagenic upon replication if left unrepaired and these lesions are frequently found in lung cancer tissue [323]. 8-OxoGua can be excised from the DNA by oxoguanine DNA glycosylase 1 (OGG1) and subsequently excreted in the urine. It is relatively difficult to measure 8-oxoGua in urine and there has been some concern about contributions of 8-oxoGua from diet [324]. Therefore, it has been common practice to measure urinary excretion of 8-oxodG, which is correlated with 8-oxoGua [324]. Nevertheless, there is uncertainty about the source of urinary excretion of 8-oxodG, which is considered to arise from oxidation of 8-oxodGTP in the nucleotide pool and cell turnover [325]. The urinary excretion of 8-oxoGua is associated with increased risk of lung cancer [326], whereas urinary excretion of 8-oxodG is associated with increased risk of both lung and breast cancer in a prospective cohort study [327,328]. Oxidatively damaged DNA can also be measured as formamidopyrimidine DNA glycosylase (FPG) and endonuclease III (ENDOIII) sensitive sites in DNA by the comet assay, which has become quite popular in particle toxicology [329,330] as well as studies on environmental and occupational exposures in humans [331,332]. The FPG-sensitive sites encompass 8-oxoGua and ring-opened formamidopyrimidine lesions, namely 4,6-diamino-5-formamidopyrimidine (FapyGua) and 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyAde). Human OGG1 is commercially available and it has been suggested to be more specific toward 8-oxoGua than the FPG protein in the comet assay [333]. ENDOIII detects oxidized

pyrimidine lesions, including uracil glycol, thymine glycol, 5hydroxycytosine and 5-hydroxyuracil [334]. There has been controversy about the reliability of assays for the detection of oxidatively damaged nucleobases. This has especially been related to the use of gas chromatography coupled with mass spectrometry for the detection of oxidative damage to DNA because it may generate oxidation during the processing of samples. However, liquid chromatography with mass spectrometry may also generate high background levels of 8-oxodG if protocols without precaution to avoid spurious oxidation have been used. Thus, the recommendation from the European Standards Committee on Oxidative DNA Damage (ESCODD) has been that studies, which have reported more than 5 lesions/106 dG of 8-oxodG in cells from young and healthy subjects should be interpreted with caution [335,336]. However, some studies on particle exposure have analyzed samples from older animals because of extended exposure times and there seems to be an agedependent accumulation of 8-oxodG in tissues of animals [337]. A number of studies have measured ENDOIII- or FPG-sensitive sites by the comet assay. This assessment has been validated in multilaboratory trials by the European Comet Assay Validation Group (ECVAG), which showed high concordance in results from different laboratories that had analyzed coded samples from the same batch of cells [338–343]. In addition, the FPG-based detection of oxidatively damaged DNA does not have the same problems of spurious oxidation as some of the chromatographic assays and indirect calibration of the comet assay with ionizing radiationgenerated DNA damage indicates that the number of FPG-sensitive sites in unexposed cells is less 5 lesions/106 dG [344]. The assessment of 8-oxodG by immunochemical detection has been quite popular as for instance evidenced by at least 11 different suppliers of commercial ELISA kits [345]. Nonetheless, there are serious shortcomings related to the use of these assays because the antibodies are unspecific [346–348]. This has been clearly demonstrated in the European Standards Committee on Urinary DNA Lesion Analysis (ESCULA) inter-laboratory validation trials where antibody-based methods measured much higher levels of 8oxodG in urine samples as compared to chromatographic methods [349,350]. 5.1. DNA strand breaks induced by air pollution particles 5.1.1. DNA strand breaks in acellular conditions Studies on PM-mediated SB generation have been carried out with assays on relaxation of plasmid or bacteriophage DNA where uncoiling occurs because of strand cleavage. Supplementary Table 8 shows studies that have assessed SB generation by exposure to air pollution particles. The studies on authentic air pollution particles are dominated by studies from Europe (10 studies) [58,189,351–358], whereas there are only few studies from Asia [359,360] and North America [78]. Pioneering studies showed that PM10 from Edinburgh, UK caused relaxation of supercoiled DNA and this was decreased by treatment with an antioxidant (mannitol) or metal chelator (DFO) [58,189,351]. The generation of SB by PM2.5 samples from Baton Rouge, LA, USA was decreased in the presence of superoxide dismutase or catalase, indicating the involvement of superoxide anion radicals and H2O2 [78]. The role of iron mobilization was demonstrated by studies on SRM1648 and SRM1649, where the presence of ascorbate was required as a reductant to generate SB [361]. Coal fly ash and PM collected in London, UK, in 1958 have also been shown to generate SB [96,358]. Studies on different PM size fractions have generated mixed results indicating either higher potency of small particles with respect to plasmid supercoil relaxation [353–355,357,360] or coarse particles being more potent than fine particles [352]. In addition, a study on PM collected near a busy motorway or

Please cite this article in press as: P. Møller, et al., Oxidative stress and inflammation generated DNA damage by exposure to air pollution particles, Mutat. Res.: Rev. Mutat. Res. (2014), http://dx.doi.org/10.1016/j.mrrev.2014.09.001

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Variability (CoV, %)

80 60 40 20 0 Spatial

Temporal Particle size

Fig. 8. Coefficient of variation (CoV) in acellular DNA strand break formation related to spatial, temporal or particle size fraction differences in air pollution particles. Each symbol represents one study. The horizontal lines are mean values.

steelwork showed that the strand breaking potency depended on the wind direction, with the highest potency of strand scission activity observed when the wind came from the motorway [356]. Another study showed that PM2.5 from an urban site in Shanghai, China generated more SB as compared to samples from a suburban site and samples collected during the winter were more potent than samples collected during the summer [359]. The effect size of acellular DNA strand breakage induction was 4.7 fold (95% CI: 2.3–8.8 fold, n = 11). Fig. 8 depicts the studies that have assessed the variation attributed to spatial, temporal and particle size fraction differences. The CoVs of differences related to spatial (57.4%, 95% CI: 46.6–70.6%, n = 3) and particle size fraction (55.7%, 95% CI: 34.5–89.9%, n = 6) variability was slightly higher than the variability attributed to temporal differences (31.2%, 95% CI: 21.8–44.8%, n = 5). To summarize, we have assessed the results from 15 studies, including 13 studies on authentic air pollution particles. The studies indicated that aqueous suspensions of PM and watersoluble constituents from particles generated SB in DNA and it was mainly driven by ROS production by transition metals. There appears to be a stronger dependency of spatial and particle size fraction variability of air pollution PM on acellular SB formation as compared to temporal variability. 5.1.2. DNA strand breaks in cultured cells The studies on PM-mediated SB generation in cultured cells have predominantly used the alkaline single cell gel electrophoresis (comet) assay on either aqueous suspensions of particles or EOM from the various size fractions of particles. The lesions therefore include both alkaline labile sites and SB. Nevertheless, we refer to these lesions as ‘‘SB’’ in this review in order to distinguish them from other types of lesions that can be measured by the comet assay such as oxidatively damaged nucleobases. Supplementary Table 9 lists studies that have assessed levels of SB in cultured cells. The predominant cell types have been lung cells (24 studies) and myeloid types of cells (14 studies). Especially A549 cells have been used in studies on air pollution particles and EOM samples (21 studies). Primary cultures of myeloid cells from blood or cell lines of monocytes (e.g. THP-1 cells) also have been used in several investigations (13 studies). Fibroblasts and hepatocytes (HepG2 cells) have been used in some studies on SB generation ability by EOM. Nevertheless there appears to be no general trend toward some cell types being more susceptible to generation of SB by PM exposure than other cell types. The studies on authentic air pollution particles are dominated by reports from Europe (23 studies) [56,60,67,116–118,163,168,353,362–375] as compared to studies from Asia (11 studies) [114,120–122,376– 382] and North America (4 studies) [78,79,169,383]. There is also a study on SB formation by PM from Argentina [384].

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Direct comparisons within the same study have indicated that aqueous suspensions of air pollution particles and EOM of PM generate similar levels of SB in cultured cells [353,364,383]. In addition, extraction of constituents in SRM1649 by treatment with different solvents including hexane, acetone, DCM, DMSO or water showed that particles retained the ability to generate SB in human fibroblasts [385]. It has also been shown that washed particles of SRM1648 and the DCM-extract generated lower levels of SB in THP-1 and A549 cells as compared to untreated SRM1648 [386]. Other studies have shown that air pollution particles from cities in China, as well as the water and DCM extracts, generated SB in cells [114,378]. This indicates that although the EOM content is important for PM-mediated DNA damage, the particles themselves have the ability to cause genotoxicity in cells. Several studies have found no clear spatial difference in the SB generating potential of aqueous suspensions of air pollution particles that have been collected at different locations [56,67,78,79,118,168,169,380]. Similarly, PM10 collected from a traffic-intense street in Stockholm, Sweden, had the same potency of SB generation on the basis of mass as particles obtained in a road simulator [163]. By contrast, aqueous extracts of PM2.5 samples from industrial sites were associated with increased levels of SB in A549 cells, whereas PM2.5 from a highway site did not generate SB [363]. It has also been reported that samples of PM0.4, PM1, PM2.5 and PM10 collected during the winter on a background site in Milan, Italy were more potent than the same fractions collected during the summer [116,117], whereas three studies reported no temporal variation in PM samples’ SB-generating ability [56,366,367]. Studies on differences in aqueous suspensions of particle size fractions have indicated that the urban background PM2.5 fraction was more potent than PM10 on the basis of mass [371]. This is in keeping with observations from studies of urban air PM in Leeds, UK, showing that finer size fractions were more potent in SB generation than coarse particles [353]. However, a number of studies have shown relatively little difference in the ability of different particle size fractions to generate SB [79,117,118,383]. Other studies on particles from a single site or model particles have shown increased levels of SB [96,372,375,387], which was only decreased slightly by treatment with DFO [60,105]. This suggests that the content of soluble transition particles such as iron is not the predominant constituent for the SB formation by air pollution particles in cells. The studies of EOM of air pollution particles have mainly used DCM, although there are some studies that have used other organic solvents. For instance, it has been shown that acetonitrileextracted material from PM2.5 that was collected from a location close to heavy traffic generated SB in HeLa cells [362]. EOM of PM2.5 from a highway site (with high traffic intensity) generated higher levels of SB in A549 cells as compared to extracts from both an urban (with medium traffic intensity) and an industrial site near a foundry [363]. There was also higher SB generating activity of samples that were collected from an industrial area of Kaifaqu district, Dalian, as compared to three other areas in China [121]. DCM extracts from PM10 samples from the urban air in Prague (Czech Republic), Kosice (Slovak Republic) and Sofia (Bulgaria) generated SB in HepG2 cells, although there were no clear spatial or temporal differences in the potency [369,370]. A study found relatively large differences between DCM extracts of PM10 from different locations in Saudi Arabia [376]. Another study of EOM from Parma, Italy showed that PM2.5 was more potent than TSP and PM10 in generating SB in WBC [365]. It has also been shown that the strand breaking ability of EOM of PM10 or TSP in PBMC depended on the concentration in cell culture medium, where PM10 was most potent at low concentrations and TSP was most potent at high concentrations [368].

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EOM of PM2.5 or PM10 from samples that were collected in the winter had higher SB generating potential than extracts from the summer [362,384]. EOMs from PM10 samples, collected during the winter in an industrial area in China, were more potent in generating SB in HepG2 cells than samples collected during the summer [121]. Another study showed that air pollution particles from a site about 1000 m from a coal power plant had higher SB generating potential than PM from a site at a background monitoring station [377]. DCM extract of PM2.5 collected from a low-traffic area in Hong Kong showed that samples from the winter were more potent than samples from the summer [381]. EOM of PM10 from Teplice, Czech Republic, generated SB in HepG2 and Caco-2 cells and the samples that were collected during the summer had stronger effect than those collected during the winter [373]. In addition, EOM of PM2.5 collected on days with haze had higher SB generating potential than extracts from days without haze [382]. Studies on EOM of PM from China, Republic of Korea or France have also shown increased levels of SB in cultured cells, albeit without assessment of temporal, spatial or particle size differences [120,122,374,379]. The effect size of SB generation by PM in aqueous suspension was 1.88 fold (95% CI: 1.50–2.54 fold, n = 28). The effect size of EOM of air pollution particles was 2.37 fold (95% CI: 1.87–3.16 fold, n = 22). A stratified analysis indicates that studies from Asia (mainly China) showed higher effect size (4.23 fold, 95% CI: 2.17– 9.95 fold, n = 10) as compared to studies from Europe (1.92 fold, 95% CI: 1.52–2.64 fold, n = 24) and North America (1.45 fold, 95% CI: 1.06–4.37, n = 4) (Table 1). The variability related to differences in effect of spatial, temporal and particle size fractions is shown in Fig. 9. The results from the studies on aqueous suspensions have relatively low CoV related to spatial (12.7%, 95%: 8.1–20.2%, n = 13), temporal (8.4%, 95% CI: 2.1–34.3%, n = 7) and particle size fraction (10.0%, 95% CI: 5.9–16.9%, n = 6) differences. There was slightly higher CoV for EOM from air pollution particles as compared to aqueous suspensions, although there were no difference between CoVs related to spatial (26.1%, 95% CI: 12.7– 53.8%, n = 11), temporal (21.7%, 95% CI: 14.2–33.3% fold, n = 9) or particle size fraction (25.1%, 95% CI: 14.6–43.0% fold, n = 5) differences. To summarize, we have assessed results from 44 studies, including 39 studies on authentic air pollution particles, on SB production by aqueous suspension of PM or EOM. The studies indicate that aqueous suspensions of PM and EOM thereof posses the ability to generate SB in cellular DNA. There appears to be a similar dependency of spatial, temporal and particle size fraction variability on generation of SB in cultured cells.

Variability (Cov, %)

223

100 80 60 40 20 0 Spatial

Temporal

Particle size

Fig. 9. Coefficient of variation (CoV) in cellular DNA strand break formation related to spatial, temporal or particle size fraction differences in air pollution particles. Each symbol represents one study. Open and closed symbols represent studies on aqueous suspensions of PM and extractable organic matter (EOM) thereof, respectively. The horizontal lines are mean values.

5.1.3. DNA strand breaks in lung tissue of animals We have found few studies that have assessed the level of SB in lung tissue of animals after pulmonary exposure to air pollution particles (Supplementary Table 10). Three studies have observed increased levels of SB in lung tissue after i.t. instillation of relatively high doses of air pollution particles from urban areas in China (7.5 and 37 mg/kg) [214,378,388]. A study on i.t. instillation of SRM1649 (0.5 mg/kg administered at 26 and 2 h before sacrifice) showed statistically non-significantly increased levels of SB in lung tissue in mice [389]. Researchers in Brazil showed that levels of SB in WBC of native rodents (Ctenomys minutus) correlated with environmental exposure to automobile emissions [42]. Free-living dogs from different locations in Sao Paulo, Brazil, with similar ambient air PM10 levels had the same level of SB in cells from the olfactory or respiratory epithelium [43]. The i.t. instillation studies have shown a 2.07 fold (95% CI: 1.58– 2.94 fold, n = 4) increased level of SB in lung tissue. There was insufficient number of studies to carry out an analysis of the variability related to spatial, temporal or particle size differences. To summarize, we found few studies that had investigated levels of SB in lung tissue after i.t. instillation of PM. The inhalation studies from free-living animals in Brazil are informative, although they have limitations with regard to the exposure characterization. There is limited evidence of association between exposure to air pollution particles and elevated levels of SB in lung tissue of animals. 5.1.4. DNA strand breaks in human cells in biomonitoring studies The majority of the studies on levels of SB in cells from humans originate from either controlled exposure or cross-sectional studies of subjects in different areas, seasons or occupations. Supplementary Table 11 lists an overview of studies that have assessed the association between air pollution exposure and SB levels in various types of blood and nasal epithelial cells from humans. The majority of the publications on SB in cells from humans originate from studies in Europe (15 studies) [41,390– 406], with few studies from Asia (3 studies) [407–411], Africa [412], South America [413,414] and North America (5 studies) [415–420]. Traffic-related personal UFP exposure through bicycling for approximately 90 min in the laboratory or in traffic-intense streets in Copenhagen, Denmark, was not associated with increased SB levels in PBMC [406]. A later study from Copenhagen on controlled exposure among subjects who inhaled air from a traffic-intense street showed a correlation between the level of particles in median size mode of 57 nm (representing carbonaceous soot) and levels of SB in PBMC, whereas a size mode of 23 nm (representing semi-volatile organic compounds of diesel exhaust) was not associated with elevated levels of SB [392]. A panel study of students in Copenhagen, Denmark, showed no association between personal exposure to PM2.5 (10–24.5 mg/m3) and levels of SB in lymphocytes [41]. Another study showed that young adults, who moved to Mexico City from non-polluted towns, had increased number of nasal cells with elevated levels of SB during the first 2 weeks after arrival [415]. The level of SB in nasal epithelial cells from subjects in Mexico City was higher in samples collected during the autumn with high air pollution levels as compared to samples that were collected during the summer with low air pollution levels [419]. A number of cross-sectional studies from the Czech Republic have assessed SB levels in blood cells from humans with different jobs or residence in areas with different air pollution levels. The latter included studies in Teplice (industrial area) and Prachatice (low-polluted area). It has been shown that the Teplice area had higher air pollution level than Prachatice; for instance the PM2.5 levels during the winter of 1993 were 122 and 44 mg/m3 in Teplice

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and Prachatice, respectively [421]. During the summer of 1993, the levels of PM2.5 were 29 and 18 mg/m3 in Teplice and Prachatice, respectively [421]. The air pollution measurements in later years have shown the same exposure contrast, although it has not been as pronounced as the winter of 1993 [422]. With this exposure contrast, it was shown that personal exposure to respirable particles correlated with levels of SB in lymphocytes [391]. However, a relatively large study with more than 500 subjects (mothers and children) showed no difference in SB levels in WBC between Teplice and Prachatice areas [402]. Another cross-sectional study of residents in Copenhagen, showed no association between urinary excretion of S-PMA and levels of SB in lymphocytes [404]. Subjects in locations with heavy industry in Flanders, Belgium, had increased levels of SB in WBC as compared to subjects in low polluted areas, which correlated with O3 levels as well as urinary excretion of 1-HOP, tt-MA and o-cresol in univariate models [398,403]. A later study showed that subjects in Belgium who lived close to air pollution sites had high levels of SB in WBC, whereas there was no correlation with exposure markers (tt-MA and 1-HOP) and SB levels [395,396]. Non-smoking subjects from Athens, Greece, had higher levels of SB in lymphocytes as compared to subjects in a rural area, whereas there was no difference related to air pollution in smokers [401]. A study from Florence, Italy, showed a positive association between ambient air O3 concentrations, measured at a stationary monitoring station, and levels of SB in lymphocytes [397]. There was also a positive association between ambient air concentrations of O3 (approximately 75 and 17 mg/m3 in June and January, respectively) and levels of SB in nasal epithelial cells in subjects from Florence, and these subjects had higher levels of SB and O3 exposure as compared to subjects from a town with low air pollution level in Sardinia (45 mg/m3 in June) [400]. Policemen in Prague had the same level of SB in lymphocytes as compared to a reference group with less exposure to PAH [394]. However, policemen had higher levels of SB in lymphocytes in the season with high level of air pollution exposure (PM2.5 = 33 mg/m3) as compared to the season with low air pollution exposure (PM2.5 = 15 mg/m3) [399]. Bus drivers and garagemen from Prague had higher levels of SB in lymphocytes than subjects in the control group of office workers [390]. Policemen from Rome, Italy, had similar levels of SB in PBMC as compared to a control group of office workers, despite a clear exposure difference in benzene levels (9.5 versus 3.8 mg/m3) during the work shift [393]. Another study among traffic and office policemen in Thailand showed no difference in levels of SB in WBC, despite a relatively large benzene exposure gradient (8–50 mg/m3), whereas there was a correlation between the levels of 1,3butadiene and SB [407]. Four groups of exposed subjects in Benin, encompassing taxi-moto drivers in the capital of the country, residents living near roads with heavy traffic or in the suburb, and village controls had a wide difference in air pollution exposure, assessed as urinary excretion of S-PMA and a similar gradient in number concentration of UFP at specific sites in the capital or village (midday hourly average: 6961–265,145 particles/cm3). The levels of SB in PBMC between the subjects living in the different areas correlated with the difference in air pollution level [412]. Subjects living near an oil refining plant in Brazil had higher levels of SB in lymphocytes as compared to subjects from a city that was characterized as having little traffic and industry [413]. Another study from Brazil showed no difference in SB levels in lymphocytes between subjects from urban industrialized and nonindustrialized areas [414]. Subjects in Mexico City, Mexico, had both higher O3 exposure levels and higher number of nasal epithelial cells with elevated levels of SB as compared to subjects in a low-polluted town by the Pacific coast [415–417]. Students in two different areas in Mexico City, defined as exposed compared to

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controls with regard to ambient O3 levels, had elevated number of SB in both nasal epithelial cells and circulating WBC [418]. Similarly, students living at locations with high ambient air concentration of O3 in Mexico City had higher levels of SB in exfoliated tear duct cells as compared to subjects from a location with less O3 [420]. Air pollution exposed school children in Bangkok had higher levels of SB in WBC as compared to children in a provincial area [408–411]. The results show that exposure to air pollution was associated with 1.20 fold (95% CI: 1.12–1.33 fold, n = 21) higher levels of SB in circulating blood cells, including WBC, lymphocytes and PBMC. A stratification of publications into continents, showed a similar effect size in circulating blood cells of studies from Europe (1.17 fold, 95% CI: 1.09–1.32 fold, n = 14) and Asia (1.30 fold, 95% CI: 1.10–1.89 fold, n = 3) (Table 1). In addition, studies from especially Mexico City have shown increased levels of SB in nasal epithelial or exfoliated tear duct cells of subjects exposed to high levels of air pollution (1.64 fold, 95% CI: 1.25–2.64 fold, n = 6). To summarize, we have assessed results from 26 studies on associations between air pollution exposure and levels of SB in circulating leukocytes and respiratory epithelial cells. There is evidence from studies in different areas of association between air pollution exposure and elevated levels of SB in various types of WBC and airway epithelial cells. Nevertheless, it should be noted that the effect sizes of SB are based predominantly on crosssectional studies comparing residential areas with an inherent risk of confounding and exposure misclassification, especially due to crude area based exposure assessment. 5.2. Oxidatively damaged nucleobases induced by air pollution particles 5.2.1. Oxidatively damaged nucleobases in acellular conditions The studies on PM-generated oxidatively damaged nucleobases in acellular conditions have measured 8-oxodG by either chromatographic assays or antibody-based methods (Supplementary Table 12). The publications on authentic air pollution particles are dominated by studies from Europe (11 studies) [60,64,66,67,71,366,372,423–426]. It has been shown that PM10 from an urban street in Stockholm, Sweden, only generated 8-oxodG by oxidation of 20 -deoxyguanosine in the presence of H2O2 [372], whereas oxidation of 20 deoxyguanosine to 8-oxodG in the absence of H2O2 was possible if the concentration of particles was one order of magnitude higher [372]. The generation of 8-oxodG in acellular aqueous solution is most likely mediated by oxidations that are catalyzed by transition metals. This is in keeping with observations that 8-oxodG generation by ROFA, which contains high levels of transition metals, was decreased in the presence of catalase or DFO, whereas SRM1649 and urban dust from Du¨sseldorf, Germany, did not generate 8-oxodG at the same concentration as ROFA [424,427]. Still, SRM1649 generated 8-oxodG from 20 -deoxyguanosine [385]. Using this experimental system with PM and H2O2 treatment for oxidation of nucleobases, it was shown that TSP from a busy street in Copenhagen, Denmark, generated 8-oxodG in calf thymus DNA, whereas there was no difference in the potency between particles that were collected on different days [366]. Another study used co-exposure of particles and H2O2 to generate 8oxodG from 20 -deoxyguanosine and showed that TSP, PM10 and PM2.5 from Athens, Greece, had similar oxidation potential [71]. A number of studies, which have used antibody-based methods for the detection of 8-oxodG, have generally shown the same results as the studies with chromatographic detection of 8-oxodG. PM only generated 8-oxodG in calf thymus DNA in the presence of H2O2 [60]. PM from a rural and three urban locations in Germany had the same potency of 8-oxodG generation, whereas the coarse

Please cite this article in press as: P. Møller, et al., Oxidative stress and inflammation generated DNA damage by exposure to air pollution particles, Mutat. Res.: Rev. Mutat. Res. (2014), http://dx.doi.org/10.1016/j.mrrev.2014.09.001

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particles were slightly more potent than the same mass of fine particles [66,67]. This is in accordance to observations of no difference in 8-oxodG generation between PM10 sampled during the winter or spring in Helsinki, Finland, whereas all samples were associated with a concentration-dependent generation of 8-oxodG [64]. A study on aqueous extracts of coal fly ash showed that a very high concentration (1000 ppm) generated a 2-fold increase of 8oxodG in calf thymus DNA [96]. We have not found publications describing association between EOM from air pollution particles and levels of oxidatively damaged nucleobases, measured by chromatographic assays. However, there are studies that have used antibody-based detection of 8oxodG for investigations of spatial and particle size variability of air pollution particles. DCM-extracted materials of PM2.5 from various locations in the Czech Republic had similar potency on the basis of mass to generate 8-oxodG in calf thymus DNA, although it should be emphasized that the levels of 8-oxodG in negative controls were not reported and there may thus not be any increase at all in comparison to the baseline levels [425,426]. Another study showed that DCM extracts of PM2.5, PM10 and TSP from Maastricht, Netherlands, showed differences in 8-oxodG generating potential, whereas there was no association between samples from locations with different traffic intensity and ability to generate 8-oxodG [423]. The effect size of 8-oxodG generation in acellular conditions is relatively strong (4.4-fold, 95% CI: 2.9–6.9 fold, n = 8). However, it should be emphasized that the effect size is based on relatively few studies on 8-oxodG generation by chromatographic methods and high exposure concentrations. The variability related to spatial, temporal and particle size differences is shown in Fig. 10. This indicated that the CoV of spatial variation was highest (31.1%, 95% CI: 15.9–61.0%, n = 4), although it is based on a relatively few studies. The CoVs of the temporal (16.2%, 95% CI: 0.1–4358%, n = 2) and particle size fraction (9.4%, 95% CI: 0.8–106%, n = 5) variability are only determined with very wide 95% CI. To summarize, we have assessed results from 14 studies, including 11 studies on authentic air pollution particles. There is evidence for PM mediated oxidation of 20 -deoxyguanosine or DNA in acelluar aqueous conditions, which is mainly attributed to metal-catalyzed ROS generation. 5.2.2. Oxidatively damaged nucleobases in cultured cells The predominant cell types, which have been used in studies of oxidatively damaged nucleobases, have been lung epithelial cells, including A549 cells and BEAS-2B cells (13 studies), although there also have been a number of studies on HepG2 cells (5 studies). By

Variability (CoV, %)

100 80 60 40 20 0

Spatial

Temporal

Particle size

Fig. 10. Coefficient of variation (CoV) in acellular oxidatively damaged nucleobase formation related to spatial, temporal or particle size fraction differences in air pollution particles. Each symbol represents one study. The horizontal lines are mean values.

contrast we found only two studies on THP-1 cells and no studies on macrophages. The studies that have assessed levels of oxidatively damaged nucleobases in cells are listed in supplementary Table 13. The publications on authentic air pollution particles were dominated by studies from Europe (15 studies) [56,66,73,159,363,366,367,370–374,424,428,429], with a few publications from Asia (2 studies) [121,379]. Exposure of A549 or THP-1 cells to aqueous suspensions of PM from traffic-intense streets was associated with increased levels of FPG-sensitive sites [73,366,367]. PM2.5 and PM10 from a background site in Milan, Italy, did not generate FPG-sensitive sites in BEAS-2B cells [371]. It was also shown that PM10 collected from a busy street in Stockholm, Sweden, did not generate 8-oxodG in A549 cells [372]. Studies of spatial differences have shown that aqueous extracts of PM from an industrial site generated higher levels of FPG-sensitive sites in A549 cells as compared to particles from a highway site in Piedmont, Italy [363]. There were higher levels of FPG-sensitive sites in both A549 and THP-1 cells after exposure to PM from a town with many wood stoves as compared to samples from a rural site in Denmark [56]. It has also been shown that oil fly ash particles and PM from Du¨sseldorf, Germany, generated 8-oxodG in cells, although the baseline levels were relatively high and not reported, respectively [95,424]. A number of studies have used antibody-based methods for the detection of 8-oxodG in cellular DNA. These observations should be interpreted with caution because the antibodies are not specific for 8-oxodG. It has been reported that exposure to coarse and fine particles in A549 cells generated the same level of 8-oxodG that was measured by immunocytochemistry [66]. It has also been shown that human lung epithelial cells (A549 or L132) had increased levels of 8-oxodG after exposure to PM from Dunkirk, France, measured by ELISA after DNA extraction and digestion with nuclease P1 and alkaline phosphatase [159,428]. Studies on EOM from PM10 in Teplice, Czech Republic, showed higher levels of oxidatively damaged DNA, measured as additional SB after treatment with both ENDOIII and FPG enzymes in HepG2 cells, although this was without a clear concentration-response relationship [373]. EOM from PM10 in Prague (Czech Republic), Kosice (Slovak Republic) and Sofia (Bulgaria) did not consistently generate FPG-sensitive sites in HepG2 cells, except for samples collected during the summer in Kosice [370]. Other studies with only one concentration of EOM have shown increased levels of ENDOIIIand FPG-sensitive sites as well as 8-oxodG in cells by DCM extracts from PM collected in traffic or industrial sites [374,379]. In addition, studies of EOM from Kaifaqu district, Dalian (China) or Prague (Czech Republic) showed concentration dependent increases of 8oxodG in cells by immunostaining and ELISA, respectively [121,429]. We have based the assessment of effect size of oxidatively damaged DNA on studies with FPG-sensitive sites or chromatographic measurement of 8-oxodG. There is a relatively strong effect of particle exposure in cultured cells (1.68 fold, 95% CI: 1.26– 2.76 fold, n = 12). The majority of the studies originate from Europe (1.50 fold, 95% CI: 1.15–2.62 fold, n = 10). The studies on variability related to spatial, temporal and particle size fraction differences have also been based on studies of oxidatively damaged DNA by the comet assay or chromatographic assays. Fig. 11 shows the results, where the data from aqueous extracts and EOM have been pooled because there are relatively few studies overall and they do not seem to differ with regard to spatial, temporal or particle size fraction variation. We have included the only study on ELISA in the graph, although it is not included in the statistical analysis [429]. The variability related to spatial (44.7%, 95% CI: 23.8–84.0%, n = 5) and temporal (54.8%, 95% CI: 40.2–74.7%, n = 4) differences in PM were not overtly different. The variation related to particle size differences was slightly lower, although there are relatively few studies (16%, 95% CI: 4.2–61.4%, n = 2).

Please cite this article in press as: P. Møller, et al., Oxidative stress and inflammation generated DNA damage by exposure to air pollution particles, Mutat. Res.: Rev. Mutat. Res. (2014), http://dx.doi.org/10.1016/j.mrrev.2014.09.001

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published studies with reliable measurements of oxidatively damaged DNA have used relatively low doses of PM.

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Variability (CoV, % )

19

80 60 40 20 0

Spatial

Temporal Particle size

Fig. 11. Coefficient of variation (CoV) in cellular oxidatively damaged DNA formation related to spatial, temporal or particle size fraction differences in air pollution particles. Each symbol represents one study, except the open square that represents one study that has measured oxidatively damaged DNA by ELISA. The horizontal lines are mean values.

To summarize, we have assessed the results from 18 studies, including 17 studies on authentic air pollution particles, on PMmediated generation of oxidatively damaged DNA in cultured cells. There is evidence from studies with reliable methods showing association between exposure to air pollution particles and elevated levels of oxidatively damaged DNA in cultured cells. This is supported by studies with suboptimal antibody-based assays for the detection of 8-oxodG. Spatial and temporal variability in sampling may be more important variables for the generation of oxidatively damaged DNA in cultured cells than the particle size fraction. 5.2.3. Oxidatively damaged nucleobases in lung cells from animals We have found only few studies that have assessed the level of oxidatively damaged DNA in the lungs of animals after exposure to air pollution (supplementary Table 14). One study showed that i.t. instillation of 500 mg/mouse twice a week for 12 weeks (total dose = 12 mg/mouse) of dust storm particles from Korea was associated with increased immunostaining of 8-oxodG in the lungs [430]. Another study exposed ApoE/ mice to 0.5 mg/kg of SRM1649 by i.t. instillation twice during 26 h (total dose = 1 mg/ kg) and observed unaltered levels of FPG-sensitive sites in lung tissue [389]. A third study administered 0.64 mg/kg to rats and observed no effect on 8-oxodG or lipid peroxidation-derived etheno adducts (1-N6-eAde and 1,N4-eCyt) in lung tissue after i.t. instillation of air pollution particles from a town with many wood stoves or rural background samples in Denmark [181]. It is clear that both the dose and the unspecific detection of 8-oxodG by immunohistochemistry distinguishes the positive study on dust storm particles from the null effect studies. A recent critical review of the literature on oxidatively damaged DNA in animals exposed to particles concluded that studies with unspecific endpoints had higher tendency to show effect of particle exposure in terms of oxidatively damaged DNA in lung tissue irrespectively of the administered dose, which was speculated to be related to publication bias [30]. However, it should also be noted that the null effect studies administered low doses, which were lower than the doses that typically promote pulmonary overload in rats. Results from studies of oxidatively damaged DNA in lung tissue of rodents after exposure to diesel exhaust particles have indicated positive associations [431–434]. To summarize, there is presently little evidence for associations between exposure to air pollution particles and oxidatively damaged DNA in lung tissue of experimental animals. The

5.2.4. Oxidatively damaged nucleobases in human cells in biomonitoring studies The associations between air pollution and levels of oxidatively damaged nucleobases in circulating blood cells have been assessed in controlled exposure, panel and cross-sectional studies (supplementary Table 15). A previous assessment of studies measuring oxidized nucleobases highlighted that approximately half of the published studies had used unspecific biomarkers [29]. The assessment of the biomonitoring studies adheres to this critical assessment of the studies. The majority of studies originate from Europe (11 studies) [41,390,392,397,399,404–406,435–437], whereas there are fewer studies from Asia (3 studies) [407– 410,438–440], North America [417] and Africa [412,441]. Personal exposure to UFP while bicycling for approximately 90 min in traffic-intense streets in Copenhagen, Denmark, was associated with elevated levels of FPG-sensitive sites in PBMC [406]. In a different study with personal exposure to UFP, the number concentration of size fractions with median particle size modes of 23 nm and 57 nm, which represent semi-volatile organic compounds of diesel exhaust and carbonaceous soot of air from a busy street in Copenhagen correlated with the level of FPG sites in PBMC [392]. A panel study of students, who were living in the center of Copenhagen, Denmark, with measurements in each of the four seasons showed a positive association between personal exposure to PM2.5 (10–24.5 mg/m3) and the level of 8-oxodG in lymphocytes, whereas the exposure did not correlate with levels of FPG-sensitive sites [41]. The levels of 8-oxodG correlated with the concentration of water-soluble transition metals in PM2.5 filters that was collected over a 2-day period for each subject [405]. The same study also showed that there was no correlation between background mass concentration of PM2.5 measured at stationary monitoring stations and levels of 8-oxodG in lymphocytes. A cross-sectional study of residents in Copenhagen, Denmark, showed a positive association between urinary excretion of S-PMA and 8-oxodG in lymphocytes, whereas the levels of ENDOIII and FPG-sensitive sites were unaltered [404]. Studies from Florence, Italy, showed positive correlations between ambient O3 concentrations and levels of FPG-sensitive sites in WBC from healthy subjects [397,435]. A number of cross-sectional studies from the Czech Republic have assessed oxidatively damaged DNA in humans with different occupations with high or low air pollution levels. A study showed higher levels of ENDOIII/FPG sites in lymphocytes from policemen in the season with the high level of air pollution (PM2.5 = 33 mg/m3), whereas there was no effect in the season with low air pollution (PM2.5 = 15 mg/m3) [399]. Studies of bus drivers, garagemen and controls (office workers) indicated no associations between air pollution measures and levels of ENDOIII/FPG sites in lymphocytes [390]. This research group also participated in a study on associations between air pollution exposure in Prague (Czech Republic), Kosice (Slovak Republic) and Sofia (Bulgaria) and biomarkers of genotoxicity in samples from policemen, bus drivers and office workers [442]. This showed that policemen from Kosice had higher levels of 8-oxodG in lymphocytes as compared to controls, whereas there was no effect in policemen from Prague [437]. However, it should be emphasized that there were very high levels of 8-oxodG in the reference group (i.e. 54 lesions/106 nucleotides, corresponding to 244 lesion/ 106 dG), indicating spurious oxidation of DNA during either the isolation of DNA or the measurement by LC-MS/MS. This study also showed that PAH-exposed subjects from Sofia had higher levels of lipid peroxidation-derived M1dG adducts in lymphocytes, measured by immunoslot blot, than controls from the same city had

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[437]. A study showed that benzene-exposed traffic policemen in Bangkok, Thailand, had higher level of 8-oxodG in WBC as compared to office policemen [407]. Factory workers (6.0  0.5 lesions/108 nucleotides) and residents living near steel, oil refining and petrochemical factories (3.7  0.4 lesions/108 nucleotides) had higher levels of M1dG adducts in WBC than subjects from an area with a low air pollution level (2.9  0.4 lesions/108 nucleotides) in Thailand [438,439]. There was a positive association between PM2.5 exposure (183  37 mg/m3) and levels of 8-oxodG in lymphocytes from subjects in a traffic congested area of Bangkok, Thailand [440]. The first of two studies of taxi-moto drivers in Cotonou, the capital of Benin, showed high ambient levels of air pollution, including total PAH (39–103 ng/m3) and urinary excretion of SPMA (6.8–9.3 mmol/mol creatinine) as compared to a reference group of subjects in a village (PAH: 7.3 ng/m3; S-PMA: 4.2 mmol/mol creatinine). The taxi-moto drivers had higher levels of 8-oxodG in lymphocytes (21 lesions/106 dG) as compared to controls in the village (11 lesions/106 dG) [441]. Still, the high background level of 8oxodG suggests spurious oxidation of the DNA during the HPLC-ECD measurement and the study design with comparison of subjects in the city and village was not optimal because of risk of confounding. A subsequent study on taxi-moto drivers and village controls, as well as groups of subjects with intermediate exposure to air pollution as determined by urinary excretion of benzene metabolites and UFP (midday hourly average: 6961–265,145 particles/cm3), showed gradients in level of both air pollution levels (assessed as S-PMA) and levels of FPG-sensitive sites in PBMC [412]. A number of studies on school children in Bangkok, Thailand, compared to children in a provincial area (Chonburi) showed that the air pollution exposed children had higher levels of 8-oxodG in WBC [408–410]. It was shown that nasal biopsies from children living in areas with low level of air pollution (Pacific town, PM10 < 14 mg/m3) had lower levels of immunostaining intensity for 8-oxodG as compared to biopsies from children in Mexico City, Mexico, with high air pollution level (53–61 mg/m3 of PM10) [417]. However, the antibody-based detection of 8-oxodG by immunohistochemistry is not a specific assay for the measurement of oxidatively damaged DNA. There was no difference in placental levels of 8-oxodG, measured by ELISA, from mothers in the areas of Teplice and Prachatice, Czech Republic, as well as lack of association between air pollution exposure levels and 8-oxodG in multivariable-adjusted models [436]. The exposure to ambient air pollution was associated with a 1.44 fold (95% CI: 1.21–1.91 fold, n = 12) higher level of oxidatively damaged nucleobases in circulating blood cells, based on studies with reliable chromatographic assays for the detection of 8-oxodG or FPG-sensitive sites by the comet assay. A stratification of publications into the continent of origin suggests that studies from Asia might show higher exposure-related levels of oxidatively damaged DNA in WBC (1.83 fold, 95% CI: 1.28–3.47 fold, n = 3) as compared to European studies (1.31 fold, 95% CI: 1.09–2.05 fold, n = 8) (Table 1). There are too few studies on other endpoints such as M1dG to assess the effect size. To summarize, we have assessed results from 17 studies on oxidatively damaged DNA in cells from humans. There is evidence for associations between exposure to PM and oxidatively damaged DNA lesions in WBC, which have used reliable methods such as the comet assay with FPG detection of oxidatively damaged DNA lesions or chromatographic assays with low risk of spurious oxidation. 5.2.5. Oxidatively damaged nucleobases in urine from humans The excretion levels of 8-oxodG or other oxidatively generated nucleobases in urine have been analyzed by chromatographic or antibody-based assays. The studies on associations between exposure and oxidatively damaged nucleobases in urine are

outlined in supplementary Table 16. These publications are dominated by studies with cross-sectional design, whereas there are only a few panel studies and no studies on controlled exposure. The publications are dominated by studies from Europe (12 studies) [41,390,395,396,398,403–405,443–451] and Asia (12 studies) [264,312,319,408–410,452–461], whereas there are few studies from North America (2 studies) [462–464]. One of the earliest panel studies showed that the urinary excretion of 8-oxoGua was increased in three subjects who were exposed to ambient air at a traffic intersection for 4 h in Tokyo, Japan [458]. A later and larger panel study on students, who were living in the center of Copenhagen, Denmark, showed no association between personal exposure to PM2.5 (10–24.5 mg/ m3) and urinary excretion of 8-oxodG [41,405]. The Beijing Olympics in 2008 has formed the basis for a panel study on the association between the improvements in ambient air pollution levels. There was less air pollution during the Olympics (PM2.5 = 71.9 mg/m3) as compared to periods before and after the Olympics (98.9 and 85.3 mg/m3, respectively); similarly the urinary excretion of 8-oxodG (using a reliable HPLC-ECD technique) were lower in young and healthy subjects during the Olympics as compared to periods before and after the event [264]. Two security guards had higher excretion of 8-oxodG (measured by ELISA) in spot urine samples after work as compared to samples obtained before work [459,460]. Apart from the measurement of 8-oxodG by ELISA, it should also be noted as limitation that the study was sequential without control for diurnal variation. A number of the cross-sectional studies have focused on elderly people or children as susceptible groups to disease by air pollution exposure. A study of elderly people in Boston, MA, USA with antibody-based detection of 8-oxodG showed correlations between concentrations of PM2.5, PNC, NO2, O3 and sulphate and urinary excretion of 8-oxodG [463,464]. Another study showed no association between PM2.5 (18.4 mg/m3) and 8-oxodG levels, measured by ELISA in subjects with or without hypertension from the Boston area, MA, USA [462]. There was no difference in urinary excretion of 8-oxodG (measured by HPLC-ECD) between children in a school near heavy road traffic and children in a kindergarten in a non-polluted area in Guangzhou, China [452]. However, a study of children in rural and urban areas in Italy found positive associations between benzene exposure markers (S-PMA and ttMA) and urinary excretion of oxidized nucleobases (8-oxoGua or 8oxodG) measured by LC-MS/MS [443]. A number of publications from Thailand have shown that air pollution exposed children from Bangkok had higher levels of 8-oxodG in urine as compared to children from a provincial area [408–410]. There was a positive association between exposure markers (urinary excretion of arsenic and chromium) and 8-oxodG levels in urine among children living in different towns with coal-fired power plants or major roads in Taiwan [461]. Another study reported a positive correlation between urinary excretion of 1-HOP and 8-oxodG (measured by ELISA) in preschool children in Tokyo, Japan, in a cross-sectional study that did not assess air pollution measures other than 1-HOP [456]. A number of studies with cross-sectional design from the Czech Republic have assessed urinary excretion of 8-oxodG in subjects with different occupations or populations living in areas characterized by high or low air pollution levels. It was shown that bus drivers had higher urinary excretion of 8-oxodG as compared to controls [446,447]. Studies of bus drivers, garage men and controls (office workers) showed associations between air pollution measures and elevated levels of urinary excretion of 8-oxodG [390]. Another study showed that policemen from Prague had unaltered urinary excretion levels of 8-oxodG in two seasons, despite relatively large differences in personal exposure to

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exposure to ambient air particles. The studies are predominantly cross-sectional or panel studies and there is equal number of studies having used chromatographic and ELISA methods. There is evidence to suggest that exposure to air pollution is associated with increased urinary excretion of oxidatively damaged nucleobases.

6. Comparison between effect sizes across experimental systems The studies on authentic air pollution particles have mainly originated from Asia, Europe and North America. Fig. 12 depicts the number of studies that have been conducted on authentic air pollution particles on these three continents. It is clear that the investigated endpoint differs with regard to the continents where they have been obtained (x2 = 97.9, P < 0.001). The strongest variable for this deviation was a high proportion of studies on oxidatively damaged nucleobases in urine from Asia (15% of total x2-value). Other strong contributors to the x2-value were differences in SB in cells (more than expected studies from Asia and fewer than expected studies from North America; 10.4% of the total x2-value), acellular generation of 8-oxodG (more than expected studies from Europe and fewer than expected studies from North America; 10.4% of total x2-value), oxidatively damaged nucleobases in cells (more than expected studies from Europe and fewer than expected studies from North America; 10.2% of total x2value) and acellular ROS production (fewer than expected studies from Europe and more than expected studies from North America; 10.0% of total x2-value). As shown in Table 1, there appears to be some variation in the estimated effect size between continents for the endpoints that have shown predominance to one continent. Nevertheless, the results did not show an association between the effect size and the number of studies per continent (R = 0.07, P = 0.26, general linear model with continent as categorical variable and number of studies as continuous variable). This

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benzo[a]pyrene [448]. Later studies on subjects in areas with high (Ostrava region) or low (Prague) air pollution levels showed no difference in urinary excretion levels of 8-oxodG [449,450]. A large study, encompassing 894 children showed no difference in urinary excretion of 8-oxodG between two areas characterized as having either low (Prachatice, median PM2.5 = 16.8 mg/m3) or high (Teplice, median PM2.5 = 22.7 mg/m3) air pollution level [451]. The measurement of 8-oxodG from the Czech Republic has mainly been carried out with ELISA methods. Another study showed that traffic policemen in Hyderabad, India had higher level of PM2.5 exposure (130 versus 60 mg/m3 in non-exposed controls) and elevated excretion of 8-oxodG, which was measured by HPLC [457]. A study from Copenhagen, Denmark, showed that bus drivers in the city center had higher level of urinary 8-oxodG excretion, measured by HPLC, as compared to bus drivers from a rural/suburban area [444,445]. It should be noted that the study had a relatively poor characterization of the air pollution levels without ambient air measurements and only personal exposure in terms of urinary excretion of 1-HOP. Taxi drivers in Taiwan had higher urinary excretion of 8-oxodG, measured by ELISA, than men in the reference group, who had low exposure to air pollution as determined by urinary excretion of 1-HOP [319]. Highway toll station workers in Taiwan had higher urinary excretion of 8oxodG, measured by ELISA, as compared to office workers [312]. Another study from Taiwan showed that traffic conductors had higher urinary excretion of 8-oxodG in post-shift samples than office workers, which correlated with the urinary excretion of PAH metabolites [455]. The same group of authors has published another report from what appears to be the same group of subjects and on urinary excretion; this publication is therefore regarded as a double publication of results from the same study [454]. It has also been shown that long-distance bus drivers from Taiwan had higher level of urinary excretion of 8-oxodG than office workers, although it should be noted that the study did not assess exposures to components in air pollution and 8-oxodG was measured by ELISA [453]. A study of residents in Copenhagen, Denmark, used benzene as marker of urban air pollution exposure and showed no association between urinary excretion of S-PMA and 8-oxodG levels in urine [404]. Subjects in locations with heavy industry in Belgium had increased urinary 8-oxodG excretion as compared to subjects in low polluted areas [403]. There were also positive associations between exposure markers (O3 and o-cresol) and 8-oxodG excretion in multivariate models [398]. A later cross-sectional study of subjects in areas of Flanders, Belgium, with different types of air pollution showed a positive association between urine concentrations of exposure markers (tt-MA and 1-HOP) and 8oxodG, which was measured by ELISA [395,396]. The effect size for studies with chromatographic (1.20 fold, 95% CI: 1.12–1.35 fold, n = 12) and ELISA methods (1.14 fold, 95% CI: 1.08–1.24 fold, n = 14) was not overtly different. Nevertheless, it should be emphasized that the chromatographic assays provide actual molar concentrations of 8-oxodG or 8-oxoGua, which can be compared between studies. By contrast, there is large interlaboratory variation in the reported levels of 8-oxodG by ELISA methods, because the antibodies are unspecific. An analysis of the effect of air pollution exposure, stratified by continent indicated that studies from Asia (1.44 fold, 95% CI: 1.24–1.80 fold, n = 6) had higher effect size as compared to studies from Europe (1.09 fold, 95% CI: 1.04–1.20, n = 5) (Table 1). Studies from North America have been omitted from this stratified analysis because they have all used antibody-based methods for the detection of oxidatively damaged nucleobases. To summarize, we have assessed 26 studies on association between air pollution exposure and urinary excretion of oxidatively damaged nucleobases. There were few studies on controlled

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Fig. 12. Distribution of studies originating from Asia, Europe or North America. The studies include measurements of strand breaks in acellular conditions (aSB), cultured cells (cSB) and humans (hSB); oxidatively damaged nucleobases in acellular conditions (aOxDNA), cultured cells (cOxDNA), human blood cells (hOxDNA) and urine (uOxDNA); ROS production in acellular conditions (aROS) and cultured cells (cROS); inflammation in cultured cells (cInflam), pulmonary tissue in animals (pInflamA), systemic inflammation in animals (sInflamA), pulmonary tissue in humans (pInflamH) and systemic inflammation in humans (sInflamH). The number of studies is shown on the top of each column. The symbols refer to variables that contribute with more than 10% to the overall x2-value. §More £ (Asia) and less (North America) studies than expected on cSB. More (Europe) and less (North America) studies than expected for aOxDNA and cOxDNA. ¤More (Asia) and less (North America) studies than expected for uOxDNA. $More (North America) and less (Asia) studies than expected for aROS.

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22 (N = 79)

100%

(N = 48)

(N = 34)

(N = 21)

Percent of all studies

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BEAS-2B Other lun g

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0% Inf lm.

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Fig. 13. Distribution of studies on cell types that have been used in studies on cellular ROS production (ROS), inflammation (Inflm), strand breaks (SB) and oxidatively damaged DNA (OxDNA) in cultured cells. Asterisks denote cell types that are more (inflammation in macrophages) or less (SB in macrophages) prevalent as compared to other biomarkers.

indicates that the statistical approach is not biased by specific types of air pollution particles being investigated in only some experimental models. This is not surprising because researchers have sought to collect representative particles for studies in nonhuman experimental models. From the preceding sections it is clear that the types of cells that have been used for measurements of ROS production, inflammation and DNA damage differs, although the predominant cell types originate from the airway epithelium or myeloid cells, which can even be subdivided into primary cultures or cell lines. Fig. 13 shows a stratification of cell types that have been used in different experimental systems. There is a strong dependency between the 10

cell type and investigated endpoint (x2 = 59.3, P < 0.001). The most important contributors to the deviation in distribution was a high number of studies on macrophages in assessment of inflammation and low number of studies on SB generation in macrophages (15% of total x2-value). It should be noted that the exposure to air pollution particles generated inflammatory responses, ROS production and DNA damage in all tested cell lines. The choice of cell type may therefore reflect the mechanism of action and target tissue rather than susceptible types of cells. Fig. 14 summarizes the effect sizes across the experimental systems from the preceding sections. There appeared to be a slightly higher effect size for ROS production as compared to the generation of SB and oxidatively damaged nucleobases in acellular condition, although this did not reach statistical significance (Fig. 14A, P > 0.05). In cellular conditions, there was a stronger effect of air pollution particle exposure on inflammation than on other endpoints (Fig. 14B, P < 0.001) and the effect on SB generation was slightly higher than the effect on ROS production (Fig. 14B, P < 0.05), whereas the effect size of oxidatively damaged DNA lesions did not differ from the effect sizes of SB and ROS production (Fig. 14C, P > 0.05). The instillation/aspiration exposure generated higher effect size on pulmonary inflammation than other endpoints in animals (Fig. 14C, P < 0.001). The second largest effect was SB generation in lung tissue after i.t. instillation, whereas the systemic responses were smaller as compared to the pulmonary effects (Fig. 14C, P < 0.05). The effect on pulmonary inflammation after inhalation exposure was also higher as compared to systemic inflammation after inhalation (Fig. 14C, P < 0.001) or instillation/aspiration exposure (Fig. 14C, P < 0.05). In the human exposure studies, there was larger effect size related to SB generation in respiratory epithelial cells as compared to

A

7

B

Fold induction

Fold induction

P<0.001 7

4

1

5

P<0.05 3

1 SB

ROS

OxDNA

Inflammation

Acellular biomarker

9

C

P<0.05 Fold induction

Fold induction

5

OxDNA

D P<0.001

7

P<0.05

SB

Cellular biomarker

3

P<0.001

ROS

P<0.001 P<0.05

P<0.001 P<0.05

2

3

1

1 Inflm. lung (i.t.)

Inflm. lung Inflm. blood Inflm. blood (Inhal) (i.t.) (Inhal) Biomarker (animal)

SB (lung)

Inflm. (lung)

SB (lung)

Inflm. (blood)

SB (blood)

OxDNA (blood)

OxDNA (urine)

Biomarker (human)

Fig. 14. Effect sizes of ROS production, levels of SB, oxidatively damaged nucleobases and inflammation markers across experimental test systems of acellular conditions (A), cultured cells (B), animals (C) and humans (D). The bars and whiskers are mean and 95% intervals.

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pulmonary inflammation (Fig. 14D, P < 0.001). In the circulation, there was smaller effect size of inflammation markers as compared to oxidized DNA lesions (Fig. 14D, P < 0.001). The effect size of oxidized DNA lesions in circulating blood cells was higher than the effect sizes of SB in cells and oxidized nucleobases in urine (P < 0.05). Overall, there seems to be a different pattern of effect size of the biomarkers across the different experimental systems, which also show a general trend of decreasing effect with decreasing concentration (or dose) from acellular conditions, cell cultures, animals to humans. At very high concentrations (acellular conditions), there seems to be stronger effect on ROS production than DNA damage. At intermediate exposure concentrations or doses (cells and animals), inflammation is more pronounced than genotoxicity and ROS production, possibly with the ROS production being less pronounced than the generation of DNA lesions. At low exposure levels in humans, there is virtually no detectable airway inflammation and the effect on systemic inflammation is small, whereas there are higher effects on levels of DNA lesions in nasal epithelium and circulating blood cells and related products in the urine. The PM-mediated effects on ROS production, inflammation and genotoxicity are clearly non-identical across experimental systems. However, the effect size should not be interpreted stoichiometrically because they are expressed in different units. The results in acellular conditions indicate that PM-mediated DNA damage formation can be explained by direct particle-mediated ROS production. The relative contributions of inflammation and oxidative stress cannot be teased out in cell culture and animal studies in the present analysis. However, there seems to be a relatively low PM-mediated ROS production in cultured cells, despite a substantially increased inflammation response. It follows from this interpretation that the association between pronounced inflammation and levels of oxidatively damaged DNA in cell cultures and animal studies cannot directly be extrapolated to human studies on air pollution exposure where the subjects have high levels of genotoxicity and little low-grade systemic inflammation. The data can also be interpreted as a higher specificity of oxidized DNA lesions in relation to exposure to ambient air particles in comparison to inflammation, which is a stereotype response to multiple different acute and chronic insults including infections, allergens, exercise, aging, autoimmune disease and obesity. Fig. 15 summarizes differences in variability related to spatial (e.g. geographical variation), temporal (seasonal or day-to-day

Spatial

Temporal

Particle size

160

Variability (CoV, %)

140 120

*

100 80

*

*

60 40

*

20 0 Acellular Acellular SB ROS

Cellular OxDNA

Cellular Inflam.

Animal Inflam.

Acellular OxDNA

Cellular SB

Cellular ROS

Fig. 15. Comparison of coefficient of variation (CoV) from different experimental systems on biomarkers of ROS production, inflammation and oxidatively damaged DNA. The asterisks denote the four most important contributors to the variation in distribution.

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variation) and particle size dependent variation in the PM of exposure across the different experimental systems of acellular conditions, cultured cells and animals. Overall, there is a large difference in the CoV values from the different experimental systems (x2 = 62.6, P < 0.001). The four strongest contributors to the statistical significance in the x2 test, each contributing more than 10% to the total x2 value, were cell inflammation (larger than expected effect of particle size fraction), oxidatively damaged DNA in cells (smaller than expected effect of particle size fraction and larger than expected effect of temporal variability) and cellular ROS production (larger effect than expected effect of temporal variability). There was the same variability related to spatial, temporal and particle size differences for SB, whereas the ROS production and inflammation were mainly influenced by temporal and particle size variability. For oxidatively damaged DNA in cells there was not much difference between spatial and temporal variability, whereas the particle size seemed not to be a strong variable in the two studies that investigated this variable of variability. These observations are at odds with a notion that generation of oxidatively damaged DNA can be explained simply by either PM-mediated ROS production or inflammation. It seems that differences related to the particle size fractions and temporal variability affects the ROS production, inflammation and genotoxicity differently in different experimental systems. 7. Conclusions The overall impression of the studies in this review is that the exposure to air pollution particles is associated with ROS production, inflammation and oxidative damage to DNA. Not surprisingly, there is a strong dependency of the concentration (or dose) with very strong effects observed in acellular conditions, strong effects in cultured cells, moderate effects in animals and subtle effects in humans. There are too many deviations across experimental systems with regard to effect size and variability related to spatial, temporal and particle size fraction to uphold a notion of a sequential mode of action where ROS production (proxy-measure of oxidative stress) leads to inflammation or vice versa. Our analysis supports a more complex series of events where PM exposure causes oxidative stress and inflammation, with one promoting the effect of the other, consequently leading to the generation of DNA damage (cf. relationship C in Fig. 1). Indeed, cell culture studies have shown increased levels of DNA damage (SB and FPG-sensitive sites) concomitantly with increased levels of ROS production or inflammation [56,60,67,73,79,105,116– 118,121,122,163,168,169]. However, at high dose exposure in animals local inflammation prevails, whereas at ambient air levels DNA damage appears to prevail in exposed humans. The analysis shows inconsistency with regard to the concept that the small particle fraction generally is more potent than the large particle size fraction. Interestingly, early observations that coarse particles were more inflammogenic than fine particles was regarded as a surprising finding [143], whereas later reports seem to have accepted the same finding at face value or highlighted it as being at odds with the hypothesis that UFP are the most potent fraction of air pollution particles [15,117,133,134,148,161,167]. It is likely that a combination of PM characteristics determine the toxicity, including the PM composition and oxidative stress potential. This is supported by observations that the coarse PM fraction of air pollution collected near schools in London, UK, was associated with strongest depletion of ascorbic acid and glutathione in synthetic respiratory tract lining fluid [465]. ROFA and SRM1648, which contain coarse size particles, were similarly associated with strong depletion of ascorbate and glutathione in synthetic respiratory tract lining fluid [466]. The notion that the particle size may not be a highly significant variable for toxicity is

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supported by a recent expert elicitation of the effect of ambient air UFP where the rating of lung cancer effects related to UFP ranged from very low to high [467]. Nevertheless, it should be emphasized that the inconsistent results regarding the effect of particle size may not be extrapolated to engineered nanoparticles. The different size fractions of air pollution particles vary substantially in many aspects such as chemical composition, whereas engineered nanoparticles of the same material should in principle only vary by size. In addition, there is convincing evidence from cultured cells and animal models that for model nanoparticles there is a strong association between particle size and inflammation [468,469]. It has also been described that the intracellular ROS production by nanoparticles was negatively associated with the particle surface area [470,471]. Nevertheless, particle-mediated ROS production does not seem to be a suitable predictor of the ability to induce inflammation in cultured cells, possibly because of the importance of chemical constituents on inflammation [472]. For instance, the level of endotoxin is likely to be important for the inflammation response of air pollution particles, although it is not the only constituent. It should also be acknowledged that endotoxins have different inflammogenic potency. It has been shown that there was a 7-fold difference in IL8 secretion by A549 cells after exposure to lipopolysaccharide from different Gramnegative bacteria strains and this did not correlate with the potency in the limulus amebocyte lysate assay [473]. Nevertheless, high levels of oxidatively damaged DNA are expected to occur by exposure to PM that contains high level of inflammogenic endotoxin, metals and organic compounds. The summary findings in Figs. 14 and 15 give an impression of the odds of finding effects in the various experimental systems, which may be relevant in planning future studies on toxicity of air pollution PM. Studies on differences related to air pollution PM from differences in locations, periods and particle sizes naturally should use assays that can reveal such variability in effects. Moreover, biomarkers with high effect size level are preferred for assessment of variability of effect related to temporal, special and particle size differences in air pollution PM samples. It should be emphasized that high levels of biomarker variability related to temporal, spatial and particle size differences is favored because it indicates that differences can be detected between samples in the same experiment. This type of variability should not be confused with experimental variation (e.g. assay or residual variation) that should be as low as possible. Irrespectively of experimental variation, the highest likelihood of finding effects in humans seems to be through the measurement of genotoxicity because those biomarkers have the highest effect size (Fig. 14C). Interestingly, the assessment of oxidatively damaged DNA in cultured cells has also shown high level of temporal, spatial and particle size differences (Fig. 15). Such assays for genotoxicity are also relevant in tests for PM exhaust from different engines or combustion conditions, comparing old versus new technology or other improvements such as insertion of particle filters in the exhaust system. High effect size and variability between samples is obtained in simple acellular test systems of genotoxicity and ROS production, but the lack of the normal reducing environment and compartments in the cell makes it a highly artificial test system. Nevertheless a similar difference in the temporal, spatial and particle size variability is observed in cultured cells (Fig. 15), although the lower effect size (Fig. 14A) indicates less statistical power and there is substantially more laboratory work involved in the cell culture assays. The acellular condition provides a suitable test system for screening a large number of samples. Simple test systems seem to be relevant for hazard identification. Slightly better assessment of variability related to temporal, spatial and particle size differences can be obtained for inflammation endpoints in cultured cells as compared to animal models.

However, the few studies on genotoxicity in animals do not provide information about the ability to detect temporal, spatial and particle size variability. The relationship between inflammation and oxidatively damaged DNA in cultured cells are not convincing, suggesting that the assessment of inflammation in animal tissues is not a good proxy-measure for increased likelihood of genotoxicity following exposure to air pollution PM. The results of our analysis indicate that PM-mediated oxidative stress and inflammation to some extent are entwined. It is unresolved whether there is an additive or synergistic effect. For instance, it is expected that a situation of PM-mediated oxidative stress and inflammation would generate higher levels of oxidatively damaged DNA as compared to a situation without PM mediated inflammation. Full-factorial intervention studies with antioxidants and anti-inflammatory drug administrations are required to disentangle the contribution of oxidative stress and inflammation in PM-mediated oxidatively damaged DNA in animal models or humans. Nevertheless, the results in this review indicate that the exposure to air pollution particles promotes a pro-oxidant and pro-inflammation milieu that is associated with oxidative damage to DNA in lung tissue and circulating blood cells. Funding The work was supported by The Center for Indoor Environment and Health in Housing (CISBO, www.cisbo.dk), established on the basis of a grant from Realdania (www.realdania.dk), and the Danish Research Councils. Conflict of interest statement The authors declare that they have no conflict of interest. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.mrrev.2014.09.001. References [1] G. Hoek, R.M. Krishnan, R. Beelen, A. Peters, B. Ostro, B. Brunekreef, J.D. Kaufman, Long-term air pollution exposure and cardio-respiratory mortality: a review, Environ. Health 12 (2013) 43. [2] O. Raaschou-Nielsen, Z.J. Andersen, R. Beelen, E. Samoli, M. Stafoggia, G. Weinmayr, B. Hoffmann, P. Fischer, M.J. Nieuwenhuijsen, B. Brunekreef, W.W. Xun, K. Katsouyanni, K. Dimakopoulou, J. Sommar, B. Forsberg, L. Modig, A. Oudin, B. Oftedal, P.E. Schwarze, P. Nafstad, U. De Faire, N.L. Pedersen, C.G. Ostenson, L. Fratiglioni, J. Penell, M. Korek, G. Pershagen, K.T. Eriksen, M. Sorensen, A. Tjonneland, T. Ellermann, M. Eeftens, P.H. Peeters, K. Meliefste, M. Wang, B. Bueno-deMesquita, T.J. Key, K. de Hoogh, H. Concin, G. Nagel, A. Vilier, S. Grioni, V. Krogh, M.Y. Tsai, F. Ricceri, C. Sacerdote, C. Galassi, E. Migliore, A. Ranzi, G. Cesaroni, C. Badaloni, F. Forastiere, I. Tamayo, P. Amiano, M. Dorronsoro, A. Trichopoulou, C. Bamia, P. Vineis, G. Hoek, Air pollution and lung cancer incidence in 17 European cohorts: prospective analyses from the European Study of Cohorts for Air Pollution Effects (ESCAPE), Lancet Oncol. 14 (2013) 813–822. [3] A.S. Shah, J.P. Langrish, H. Nair, D.A. McAllister, A.L. Hunter, K. Donaldson, D.E. Newby, N.L. Mills, Global association of air pollution and heart failure: a systematic review and meta-analysis, Lancet (2013), pii:S0140-6736(13)60898-3. [4] K. Donaldson, V. Stone, A. Seaton, W. MacNee, Ambient particle inhalation and the cardiovascular system: potential mechanisms, Environ. Health Perspect. 109 (Suppl. 4) (2001) 523–527. [5] K. Donaldson, L. Tran, L.A. Jimenez, R. Duffin, D.E. Newby, N. Mills, W. MacNee, V. Stone, Combustion-derived nanoparticles: a review of their toxicology following inhalation exposure, Part. Fibre Toxicol. 2 (2005) 10. [6] G. Oberdo¨rster, A. Maynard, K. Donaldson, V. Castranova, J. Fitzpatrick, K. Ausman, J. Carter, B. Karn, W. Kreyling, D. Lai, S. Olin, N. Monteiro-Riviere, D. Warheit, H. Yang, Principles for characterizing the potential human health effects from exposure to nanomaterials: elements of a screening strategy, Part. Fibre Toxicol. 2 (2005) 8. [7] P.J. Borm, D. Robbins, S. Haubold, T. Kuhlbusch, H. Fissan, K. Donaldson, R. Schins, V. Stone, W. Kreyling, J. Lademann, J. Krutmann, D. Warheit, E. Oberdorster, The potential risks of nanomaterials: a review carried out for ECETOC, Part. Fibre Toxicol. 3 (2006) 11.

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MUTREV-8090; No. of Pages 34 P. Møller et al. / Mutation Research xxx (2014) xxx–xxx [8] J.G. Ayres, P. Borm, F.R. Cassee, V. Castranova, K. Donaldson, A. Ghio, R.M. Harrison, R. Hider, F. Kelly, I.M. Kooter, F. Marano, R.L. Maynard, I. Mudway, A. Nel, C. Sioutas, S. Smith, A. Baeza-Squiban, A. Cho, S. Duggan, J. Froines, Evaluating the toxicity of airborne particulate matter and nanoparticles by measuring oxidative stress potential – a workshop report and consensus statement, Inhal. Toxicol. 20 (2008) 75–99. [9] G. Oberdo¨rster, Toxicokinetics and effects of fibrous and nonfibrous particles, Inhal. Toxicol. 14 (2002) 29–56. [10] J.A. Araujo, A.E. Nel, Particulate matter and atherosclerosis: role of particle size, composition and oxidative stress, Part. Fibre Toxicol. 6 (2009) 24. [11] K. Donaldson, P.J. Borm, V. Castranova, M. Gulumian, The limits of testing particle-mediated oxidative stress in vitro in predicting diverse pathologies; relevance for testing of nanoparticles, Part. Fibre Toxicol. 6 (2009) 13. [12] M. Sørensen, H. Autrup, P. Møller, O. Hertel, S.S. Jensen, P. Vinzents, L.E. Knudsen, S. Loft, Linking exposure to environmental pollutants with biological effects, Mutat. Res. 544 (2003) 255–271. [13] B.T. Mossman, P.J. Borm, V. Castranova, D.L. Costa, K. Donaldson, S.R. Kleeberger, Mechanisms of action of inhaled fibers, particles and nanoparticles in lung and cardiovascular diseases, Part. Fibre Toxicol. 4 (2007) 4. [14] S. Becker, J.M. Soukup, M.I. Gilmour, R.B. Devlin, Stimulation of human and rat alveolar macrophages by urban air particulates: effects on oxidant radical generation and cytokine production, Toxicol. Appl. Pharmacol. 141 (1996) 637–648. [15] S. Becker, L.A. Dailey, J.M. Soukup, S.C. Grambow, R.B. Devlin, Y.C. Huang, Seasonal variations in air pollution particle-induced inflammatory mediator release and oxidative stress, Environ. Health Perspect. 113 (2005) 1032–1038. [16] C.A. Goldsmith, A. Imrich, H. Danaee, Y.Y. Ning, L. Kobzik, Analysis of air pollution particulate-mediated oxidant stress in alveolar macrophages, J. Toxicol. Environ. Health A 54 (1998) 529–545. [17] B. Stringer, L. Kobzik, Environmental particulate-mediated cytokine production in lung epithelial cells (A549): role of preexisting inflammation and oxidant stress, J. Toxicol. Environ. Health A 55 (1998) 31–44. [18] H. Greim, P. Borm, R. Schins, K. Donaldson, K. Driscoll, A. Hartwig, E. Kuempel, G. Oberdorster, G. Speit, Toxicity of fibers and particles. Report of the workshop held in Munich, Germany, 26–27 October 2000, Inhal. Toxicol. 13 (2001) 737–754. [19] A.M. Knaapen, P.J. Borm, C. Albrecht, R.P. Schins, Inhaled particles and lung cancer, Pt. A: Mech. Int. J. Cancer 109 (2004) 799–809. [20] R.P. Schins, A.M. Knaapen, Genotoxicity of poorly soluble particles, Inhal. Toxicol. 19 (Suppl. 1) (2007) 189–198. [21] K. Donaldson, C.A. Poland, R.P. Schins, Possible genotoxic mechanisms of nanoparticles: criteria for improved test strategies, Nanotoxicology 4 (2010) 414–420. [22] A. Hartwig, Role of DNA repair in particle- and fiber-induced lung injury, Inhal. Toxicol. 14 (2002) 91–100. [23] A. Hartwig, Metal interaction with redox regulation: an integrating concept in metal carcinogenesis? Free Radic. Biol. Med. 55 (2013) 63–72. [24] D.M. DeMarini, Genotoxicity biomarkers associated with exposure to traffic and near-road atmospheres: a review, Mutagenesis 28 (2013) 485–505. [25] C.A. Demetriou, O. Raaschou-Nielsen, S. Loft, P. Møller, R. Vermeulen, D. Palli, M. Chadeau-Hyam, W.W. Xun, P. Vineis, Biomarkers of ambient air pollution and lung cancer: a systematic review, Occup. Environ. Med. 69 (2012) 619–627. [26] Y. Li, K. Rittenhouse-Olson, W.L. Scheider, L. Mu, Effect of particulate matter air pollution on C-reactive protein: a review of epidemiologic studies, Rev. Environ. Health 27 (2012) 133–149. [27] M. Lippmann, L.C. Chen, Health effects of concentrated ambient air particulate matter (CAPs) and its components, Crit. Rev. Toxicol. 39 (2009) 865–913. [28] P. Møller, J.K. Folkmann, L. Forchhammer, E.V. Bra¨uner, P.H. Danielsen, L. Risom, S. Loft, Air pollution, oxidative damage to DNA, and carcinogenesis, Cancer Lett. 266 (2008) 84–97. [29] P. Møller, S. Loft, Oxidative damage to DNA and lipids as biomarkers of exposure to air pollution, Environ. Health Perspect. 118 (2010) 1126–1136. [30] P. Møller, P.H. Danielsen, K. Jantzen, M. Roursgaard, S. Loft, Oxidatively damaged DNA in animals exposed to particles, Crit. Rev. Toxicol. 43 (2013) 96–118. [31] R.B. Schlesinger, N. Kunzli, G.M. Hidy, T. Gotschi, M. Jerrett, The health relevance of ambient particulate matter characteristics: coherence of toxicological and epidemiological inferences, Inhal. Toxicol. 18 (2006) 95–125. [32] L. Risom, P. Møller, S. Loft, Oxidative stress-induced DNA damage by particulate air pollution, Mutat. Res. 592 (2005) 119–137. [33] R. Vincent, P. Kumarathasan, P. Goegan, S.G. Bjarnason, J. Guenette, D. Berube, I.Y. Adamson, S. Desjardins, R.T. Burnett, F.J. Miller, B. Battistini, Inhalation toxicology of urban ambient particulate matter: acute cardiovascular effects in rats, Res. Rep. Health Eff. Inst. (2001) 5–54. [34] A.J. Ghio, R. Silbajoris, J.L. Carson, J.M. Samet, Biologic effects of oil fly ash, Environ. Health Perspect. 110 (Suppl. 1) (2002) 89–94. [35] M. Wilhelm, G. Eberwein, J. Holzer, D. Gladtke, J. Angerer, B. Marczynski, H. Behrendt, J. Ring, D. Sugiri, U. Ranft, Influence of industrial sources on children’s health – hot spot studies in North Rhine Westphalia, Germany, Int. J. Hyg. Environ. Health 210 (2007) 591–599. [36] M. Wilhelm, U. Ewers, J. Wittsiepe, P. Furst, J. Holzer, G. Eberwein, J. Angerer, B. Marczynski, U. Ranft, Human biomonitoring studies in North Rhine-Westphalia, Germany, Int. J. Hyg. Environ. Health 210 (2007) 307–318. [37] L. Forchhammer, S. Loft, M. Roursgaard, Y. Cao, I.S. Riddervold, T. Sigsgaard, P. Møller, Expression of adhesion molecules, monocyte interactions and oxidative stress in human endothelial cells exposed to wood smoke and diesel exhaust particulate matter, Toxicol. Lett. 209 (2012) 121–128.

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[38] L. Forchhammer, P. Møller, I.S. Riddervold, J. Bonlokke, A. Massling, T. Sigsgaard, S. Loft, Controlled human wood smoke exposure: oxidative stress, inflammation and microvascular function, Part. Fibre Toxicol. 9 (2012) 7. [39] I.S. Riddervold, J.H. Bonlokke, A.C. Olin, T.K. Gronborg, V. Schlunssen, K. Skogstrand, D. Hougaard, A. Massling, T. Sigsgaard, Effects of wood smoke particles from wood-burning stoves on the respiratory health of atopic humans, Part. Fibre Toxicol. 9 (2012) 12. [40] J. Allen, C.A. Trenga, A. Peretz, J.H. Sullivan, C.C. Carlsten, J.D. Kaufman, Effect of diesel exhaust inhalation on antioxidant and oxidative stress responses in adults with metabolic syndrome, Inhal. Toxicol. 21 (2009) 1061–1067. [41] M. Sørensen, H. Autrup, O. Hertel, H. Wallin, L.E. Knudsen, S. Loft, Personal exposure to PM2.5 and biomarkers of DNA damage, Cancer Epidemiol. Biomarkers Prev. 12 (2003) 191–196. [42] V.D. Heuser, S.J. da, H.J. Moriske, J.F. Dias, M.L. Yoneama, T.R. de Freitas, Genotoxicity biomonitoring in regions exposed to vehicle emissions using the comet assay and the micronucleus test in native rodent Ctenomys minutus, Environ. Mol. Mutagen. 40 (2002) 227–235. [43] K.C. Kimura, H. Fukumasu, L.M. Chaible, C.E. Lima, M.A. Horst, P. Matsuzaki, D.S. Sanches, C.G. Pires, T.C. Silva, T.C. Pereira, M.L. Mello, J.M. Matera, R.A. Dias, A. Monnereau, A.J. Sasco, P.H. Saldiva, M.L. Dagli, Evaluation of DNA damage by the alkaline comet assay of the olfactory and respiratory epithelia of dogs from the city of Sao Paulo, Brazil, Exp. Toxicol. Pathol. 62 (2010) 209–219. [44] J.S. Reif, Animal sentinels for environmental and public health, Public Health Rep. 126 (Suppl. 1) (2011) 50–57. [45] L. Calderon-Garciduenas, A. Mora-Tiscareno, L.A. Fordham, C.J. Chung, R. Garcia, N. Osnaya, J. Hernandez, H. Acuna, T.M. Gambling, A. Villarreal-Calderon, J. Carson, H.S. Koren, R.B. Devlin, Canines as sentinel species for assessing chronic exposures to air pollutants: Part 1. Respiratory pathology, Toxicol. Sci. 61 (2001) 342–355. [46] B. Vanda, N. de Buen, R. Jasso, G. Valero, M.H. Vargas, R. Olmos, J.L. Arreola, P. Santillan, P. Alonso, Inflammatory cells and ferruginous bodies in bronchoalveolar lavage in urban dogs, Acta Cytol. 42 (1998) 939–944. [47] P.H.N. Saldiva, G.M. Bohm, Animal indicators of adverse effects associated with air pollution, Ecosyst. Health 4 (1998) 230–235. [48] F.J. Kelly, C. Dunster, I. Mudway, Air pollution and the elderly: oxidant/antioxidant issues worth consideration, Eur. Respir. J. Suppl. 40 (2003) 70s–75s. [49] N. Li, T. Xia, A.E. Nel, The role of oxidative stress in ambient particulate matterinduced lung diseases and its implications in the toxicity of engineered nanoparticles, Free Radic. Biol. Med. 44 (2008) 1689–1699. [50] H.R. Griffiths, L. Møller, G. Bartosz, A. Bast, C. Bertoni-Freddari, A. Collins, M. Cooke, S. Coolen, G. Haenen, A.-M. Hoberg, S. Loft, J. Lunec, R. Olinski, J. Parry, A. Pompella, H. Poulsen, H. Verhagen, S.B. Astley, European research on the functional effects of dietary antioxidants – EUROFEDA (Biomarkers), Mol. Aspects Med. 23 (2002) 101–208. [51] B. Halliwell, M. Whiteman, Measuring reactive species and oxidative damage in vivo and in cell culture: how should you do it and what do the results mean? Br. J. Pharmacol. 142 (2004) 231–255. [52] P. Wardman, Fluorescent and luminescent probes for measurement of oxidative and nitrosative species in cells and tissues: progress, pitfalls, and prospects, Free Radic. Biol. Med. 43 (2007) 995–1022. [53] B. Kalyanaraman, V. Darley-Usmar, K.J. Davies, P.A. Dennery, H.J. Forman, M.B. Grisham, G.E. Mann, K. Moore, L.J. Roberts, H. Ischiropoulos, Measuring reactive oxygen and nitrogen species with fluorescent probes: challenges and limitations, Free Radic. Biol. Med. 52 (2012) 1–6. [54] H. Boogaard, N.A. Janssen, P.H. Fischer, G.P. Kos, E.P. Weijers, F.R. Cassee, S.C. van der Zee, J.J. de Hartog, B. Brunekreef, G. Hoek, Contrasts in oxidative potential and other particulate matter characteristics collected near major streets and background locations, Environ. Health Perspect. 120 (2012) 185–191. [55] J.J. Briede, T.M. de Kok, J.G. Hogervorst, E.J. Moonen, C.L. Op Den Camp, J.C. Kleinjanst, Development and application of an electron spin resonance spectrometry method for the determination of oxygen free radical formation by particulate matter, Environ. Sci. Technol. 39 (2005) 8420–8426. [56] P.H. Danielsen, P. Møller, K.A. Jensen, A.K. Sharma, H. Wallin, R. Bossi, H. Autrup, L. Molhave, J.L. Ravanat, J.J. Briede, T.M. de Kok, S. Loft, Oxidative stress, DNA damage, and inflammation induced by ambient air and wood smoke particulate matter in human A549 and THP-1 cell lines, Chem. Res. Toxicol. 24 (2011) 168–184. [57] T.M. de Kok, J.G. Hogervorst, J.C. Kleinjans, J.J. Briede, Radicals in the church, Eur. Respir. J. 24 (2004) 1069–1070. [58] K. Donaldson, D.M. Brown, C. Mitchell, M. Dineva, P.H. Beswick, P. Gilmour, W. MacNee, Free radical activity of PM10: iron-mediated generation of hydroxyl radicals, Environ. Health Perspect. 105 (Suppl. 5) (1997) 1285–1289. [59] J.G. Hogervorst, T.M. de Kok, J.J. Briede, G. Wesseling, J.C. Kleinjans, C.P. van Schayck, Relationship between radical generation by urban ambient particulate matter and pulmonary function of school children, J. Toxicol. Environ. Health A 69 (2006) 245–262. [60] A.M. Knaapen, T. Shi, P.J.A. Borm, R.P.F. Schins, Soluble metals as well as the insoluble particle fraction are involved in cellular DNA damage induced by particulate matter, Mol. Cell. Biochem. 234–235 (2002) 317–326. [61] N. Kunzli, I.S. Mudway, T. Gotschi, T. Shi, F.J. Kelly, S. Cook, P. Burney, B. Forsberg, J.W. Gauderman, M.E. Hazenkamp, J. Heinrich, D. Jarvis, D. Norback, F. Payo-Losa, A. Poli, J. Sunyer, P.J. Borm, Comparison of oxidative properties, light absorbance, total and elemental mass concentration of ambient PM2.5 collected at 20 European sites, Environ. Health Perspect. 114 (2006) 684–690. [62] T.S. Nawrot, N. Kuenzli, J. Sunyer, T.M. Shi, T. Moreno, M. Viana, J. Heinrich, B. Forsberg, F.J. Kelly, M. Sughis, B. Nemery, P. Borm, Oxidative properties of

Please cite this article in press as: P. Møller, et al., Oxidative stress and inflammation generated DNA damage by exposure to air pollution particles, Mutat. Res.: Rev. Mutat. Res. (2014), http://dx.doi.org/10.1016/j.mrrev.2014.09.001

G Model

MUTREV-8090; No. of Pages 34 26

[63]

[64]

[65]

[66]

[67]

[68]

[69]

[70]

[71]

[72]

[73]

[74]

[75]

[76]

[77]

[78]

[79]

[80]

[81]

[82] [83]

[84] [85]

P. Møller et al. / Mutation Research xxx (2014) xxx–xxx ambient PM2.5 and elemental composition: heterogeneous associations in 19 European cities, Atmos. Environ. 43 (2009) 4595–4602. J. Lindbom, M. Gustafsson, G. Blomqvist, A. Dahl, A. Gudmundsson, E. Swietlicki, A.G. Ljungman, Wear particles generated from studded tires and pavement induces inflammatory reactions in mouse macrophage cells, Chem. Res. Toxicol. 20 (2007) 937–946. R.O. Salonen, A.I. Halinen, A.S. Pennanen, M.R. Hirvonen, M. Sillanpaa, R. Hillamo, T. Shi, P. Borm, E. Sandell, T. Koskentalo, P. Aarnio, Chemical and in vitro toxicologic characterization of wintertime and springtime urban-air particles with an aerodynamic diameter below 10 mm in Helsinki, Scand. J. Work. Environ. Health 30 (Suppl. 2) (2004) 80–90. F. Schaumann, P.J. Borm, A. Herbrich, J. Knoch, M. Pitz, R.P. Schins, B. Luettig, J.M. Hohlfeld, J. Heinrich, N. Krug, Metal-rich ambient particles (particulate matter 2.5) cause airway inflammation in healthy subjects, Am. J. Respir. Crit. Care Med. 170 (2004) 898–903. T. Shi, A.M. Knaapen, J. Begerow, W. Birmili, P.J. Borm, R.P. Schins, Temporal variation of hydroxyl radical generation and 8-hydroxy-20 -deoxyguanosine formation by coarse and fine particulate matter, Occup. Environ. Med. 60 (2003) 315–321. T. Shi, R. Duffin, P.J. Borm, H. Li, C. Weishaupt, R.P. Schins, Hydroxyl-radicaldependent DNA damage by ambient particulate matter from contrasting sampling locations, Environ. Res. 101 (2006) 18–24. R.P. Schins, J.H. Lightbody, P.J. Borm, T. Shi, K. Donaldson, V. Stone, Inflammatory effects of coarse and fine particulate matter in relation to chemical and biological constituents, Toxicol. Appl. Pharmacol. 195 (2004) 1–11. M. Steenhof, I. Gosens, M. Strak, K.J. Godri, G. Hoek, F.R. Cassee, I.S. Mudway, F.J. Kelly, R.M. Harrison, E. Lebret, B. Brunekreef, N.A. Janssen, R.H. Pieters, In vitro toxicity of particulate matter (PM) collected at different sites in the Netherlands is associated with PM composition, size fraction and oxidative potential – the RAPTES project, Part. Fibre Toxicol. 8 (2011) 26. A. Valavanidis, A. Salika, A. Theodoropoulou, Generation of hydroxyl radicals by urban suspended particulate air matter. The role of iron ions, Atmos. Environ. 34 (2000) 2379–2386. A. Valavanidis, T. Vlahoyianni, K. Fiotakis, Comparative study of the formation of oxidative damage marker 8-hydroxy-20 -deoxyguanosine (8-OHdG) adduct from the nucleoside 20 -deoxyguanosine by transition metals and suspensions of particulate matter in relation to metal content and redox reactivity, Free Radic. Res. 39 (2005) 1071–1081. A. Valavanidis, K. Fiotakis, E. Bakeas, T. Vlahogianni, Electron paramagnetic resonance study of the generation of reactive oxygen species catalysed by transition metals and quinoid redox cycling by inhalable ambient particulate matter, Redox Rep. 10 (2005) 37–51. A. Wessels, W. Birmili, C. Albrecht, B. Hellack, E. Jermann, G. Wick, R.M. Harrison, R.P. Schins, Oxidant generation and toxicity of size-fractionated ambient particles in human lung epithelial cells, Environ. Sci. Technol. 44 (2010) 3539–3545. U.S. Akhtar, R.D. McWhinney, N. Rastogi, J.P. Abbatt, G.J. Evans, J.A. Scott, Cytotoxic and proinflammatory effects of ambient and source-related particulate matter (PM) in relation to the production of reactive oxygen species (ROS) and cytokine adsorption by particles, Inhal. Toxicol. 22 (Suppl. 2) (2010) 37–47. J.G. Charrier, C. Anastasio, On dithiothreitol (DTT) as a measure of oxidative potential for ambient particles: evidence for the importance of soluble transition metals, Atmos. Chem. Phys. 12 (2012) 11317–11350. A.K. Cho, C. Sioutas, A.H. Miguel, Y. Kumagai, D.A. Schmitz, M. Singh, A. EigurenFernandez, J.R. Froines, Redox activity of airborne particulate matter at different sites in the Los Angeles Basin, Environ. Res. 99 (2005) 40–47. M.Y. Chung, R.A. Lazaro, D. Lim, J. Jackson, J. Lyon, D. Rendulic, A.S. Hasson, Aerosol-borne quinones and reactive oxygen species generation by particulate matter extracts, Environ. Sci. Technol. 40 (2006) 4880–4886. B. Dellinger, W.A. Pryor, R. Cueto, G.L. Squadrito, V. Hegde, W.A. Deutsch, Role of free radicals in the toxicity of airborne fine particulate matter, Chem. Res. Toxicol. 14 (2001) 1371–1377. A. De Vizcaya-Ruiz, M.E. Gutierrez-Castillo, M. Uribe-Ramirez, M.E. Cebrian, V. Mugica-Alvarez, J. Sepulveda, I. Rosas, E. Salinas, C. Garcia-Cuellar, F. Martinez, E. Alfaro-Moreno, V. Torres-Flores, A. Osornio-Vargas, C. Sioutas, P.M. Fine, M. Singh, M.D. Geller, T. Kuhn, A.H. Miguel, A. Eiguren-Fernandez, R.H. Schiestl, R. Reliene, J. Froines, Characterization and in vitro biological effects of concentrated particulate matter from Mexico City, Atmos. Environ. 40 (2006) S583–S592. M.W. Frampton, A.J. Ghio, J.M. Samet, J.L. Carson, J.D. Carter, R.B. Devlin, Effects of aqueous extracts of PM10 filters from the Utah valley on human airway epithelial cells, Am. J. Physiol. 277 (1999) L960–L967. A.J. Ghio, J. Stonehuerner, L.A. Dailey, J.D. Carter, Metals associated with both the water-soluble and insoluble fractions of an ambient air pollution particle catalyze an oxidative stress, Inhal. Toxicol. 11 (1999) 37–49. A.J. Ghio, R.B. Devlin, Inflammatory lung injury after bronchial instillation of air pollution particles, Am. J. Respir. Crit. Care Med. 164 (2001) 704–708. A. Imrich, Y. Ning, J. Lawrence, B. Coull, E. Gitin, M. Knutson, L. Kobzik, Alveolar macrophage cytokine response to air pollution particles: oxidant mechanisms, Toxicol. Appl. Pharmacol. 218 (2007) 256–264. H.A. Jeng, Chemical composition of ambient particulate matter and redox activity, Environ. Monit. Assess. 169 (2010) 597–606. T. Kennedy, A.J. Ghio, W. Reed, J. Samet, J. Zagorski, J. Quay, J. Carter, L. Dailey, J.R. Hoidal, R.B. Devlin, Copper-dependent inflammation and nuclear factor-kappaB activation by particulate air pollution, Am. J. Respir. Cell Mol. Biol. 19 (1998) 366–378.

[86] N. Li, C. Sioutas, A. Cho, D. Schmitz, C. Misra, J. Sempf, M. Wang, T. Oberley, J. Froines, A. Nel, Ultrafine particulate pollutants induce oxidative stress and mitochondrial damage, Environ. Health Perspect. 111 (2003) 455–460. [87] A.R. Molinelli, M.C. Madden, J.K. McGee, J.G. Stonehuerner, A.J. Ghio, Effect of metal removal on the toxicity of airborne particulate matter from the Utah Valley, Inhal. Toxicol. 14 (2002) 1069–1086. [88] L. Ntziachristos, J.R. Froines, A.K. Cho, C. Sioutas, Relationship between redox activity and chemical speciation of size-fractionated particulate matter, Part. Fibre Toxicol. 4 (2007) 5. [89] R. Quintana, J. Serrano, V. Gomez, B. de Foy, J. Miranda, C. Garcia-Cuellar, E. Vega, I. Vazquez-Lopez, L.T. Molina, N. Manzano-Leon, I. Rosas, A.R. Osornio-Vargas, The oxidative potential and biological effects induced by PM10 obtained in Mexico City and at a receptor site during the MILAGRO Campaign, Environ. Pollut. 159 (2011) 3446–3454. [90] H. Shen, C. Anastasio, Formation of hydroxyl radical from San Joaquin Valley particles extracted in a cell-free surrogate lung fluid, Atmos. Chem. Phys. 11 (2011) 9671–9682. [91] H. Shen, C. Anastasio, A comparison of hydroxyl radical and hydrogen peroxide generation in ambient particle extracts and laboratory metal solutions, Atmos. Environ. 46 (2012) 665–668. [92] H. Shen, A.I. Barakat, C. Anastasio, Generation of hydrogen peroxide from San Joaquin Valley particles in a cell-free solution, Atmos. Chem. Phys. 11 (2011) 753–765. [93] V. Verma, R. Rico-Martinez, N. Kotra, L. King, J.M. Liu, T.W. Snell, R.J. Weber, Contribution of water-soluble and insoluble components and their hydrophobic/ hydrophilic subfractions to the reactive oxygen species-generating potential of Fine Ambient Aerosols, Environ. Sci. Technol. 46 (2012) 11384–11392. [94] V. Verma, A. Polidori, J.J. Schauer, M.M. Shafer, F.R. Cassee, C. Sioutas, Physicochemical and toxicological profiles of particulate matter in Los Angeles during the October 2007 southern California wildfires, Environ. Sci. Technol. 43 (2009) 954–960. [95] J.M.S. van Maanen, P.J.A. Borm, A. Knaapen, M. van Herwijnen, P.A.E.L. Schilderman, K.R. Smith, A.E. Aust, M. Tomatis, B. Fubini, In vitro effects of coal fly ashes: hydroxyl radical generation, iron release, and DNA damage and toxicity in rat lung epithelial cells, Inhal. Toxicol. 11 (1999) 1123–1141. [96] S. Dwivedi, Q. Saquib, A.A. Al-Khedhairy, A.Y. Ali, J. Musarrat, Characterization of coal fly ash nanoparticles and induced oxidative DNA damage in human peripheral blood mononuclear cells, Sci. Total Environ. 437 (2012) 331–338. [97] J.C. Ball, A.M. Straccia, W.C. Young, A.E. Aust, The formation of reactive oxygen species catalyzed by neutral, aqueous extracts of NIST ambient particulate matter and diesel engine particles, J. Air Waste Manag. Assoc. 50 (2000) 1897–1903. [98] G.L. Squadrito, R. Cueto, B. Dellinger, W.A. Pryor, Quinoid redox cycling as a mechanism for sustained free radical generation by inhaled airborne particulate matter, Free Radic. Biol. Med. 31 (2001) 1132–1138. [99] Y. Mo, R. Wan, S. Chien, D.J. Tollerud, Q. Zhang, Activation of endothelial cells after exposure to ambient ultrafine particles: the role of NADPH oxidase, Toxicol. Appl. Pharmacol. 236 (2009) 183–193. [100] F. Auger, M.C. Gendron, C. Chamot, F. Marano, A.C. Dazy, Responses of welldifferentiated nasal epithelial cells exposed to particles: role of the epithelium in airway inflammation, Toxicol. Appl. Pharmacol. 215 (2006) 285–294. [101] A. Baulig, M. Sourdeval, M. Meyer, F. Marano, A. Baeza-Squiban, Biological effects of atmospheric particles on human bronchial epithelial cells. Comparison with diesel exhaust particles, Toxicol. In Vitro 17 (2003) 567–573. [102] R. Becher, A. Bucht, J. Ovrevik, J.K. Hongslo, H.J. Dahlman, J.T. Samuelsen, P.E. Schwarze, Involvement of NADPH oxidase and iNOS in rodent pulmonary cytokine responses to urban air and mineral particles, Inhal. Toxicol. 19 (2007) 645–655. [103] X. Deng, W. Rui, F. Zhang, W. Ding, PM2.5 induces Nrf2-mediated defense mechanisms against oxidative stress by activating PIK3/AKT signaling pathway in human lung alveolar epithelial A549 cells, Cell Biol. Toxicol. 29 (2013) 143– 157. [104] X. Deng, F. Zhang, W. Rui, F. Long, L. Wang, Z. Feng, D. Chen, W. Ding, PM2.5induced oxidative stress triggers autophagy in human lung epithelial A549 cells, Toxicol. In Vitro 27 (2013) 1762–1770. [105] A. Di Pietro, G. Visalli, F. Munao, B. Baluce, S. La Maestra, P. Primerano, F. Corigliano, S. De Flora, Oxidative damage in human epithelial alveolar cells exposed in vitro to oil fly ash transition metals, Int. J. Hyg. Environ. Health 212 (2009) 196–208. [106] C.A. Goldsmith, C. Frevert, A. Imrich, C. Sioutas, L. Kobzik, Alveolar macrophage interaction with air pollution particulates, Environ. Health Perspect. 105 (Suppl. 5) (1997) 1191–1195. [107] H.L. Karlsson, A. Holgersson, L. Moller, Mechanisms related to the genotoxicity of particles in the subway and from other sources, Chem. Res. Toxicol. 21 (2008) 726–731. [108] O. Kamdar, W. Le, J. Zhang, A.J. Ghio, G.D. Rosen, D. Upadhyay, Air pollution induces enhanced mitochondrial oxidative stress in cystic fibrosis airway epithelium, FEBS Lett. 582 (2008) 3601–3606. [109] Z. Li, X. Hyseni, J.D. Carter, J.M. Soukup, L.A. Dailey, Y.C. Huang, Pollutant particles enhanced H2O2 production from NAD(P)H oxidase and mitochondria in human pulmonary artery endothelial cells, Am. J. Physiol. Cell Physiol. 291 (2006) C357– C365. [110] E.A. Mutlu, P.A. Engen, S. Soberanes, D. Urich, C.B. Forsyth, R. Nigdelioglu, S.E. Chiarella, K.A. Radigan, A. Gonzalez, S. Jakate, A. Keshavarzian, G.R. Budinger, G.M. Mutlu, Particulate matter air pollution causes oxidant-mediated increase in gut permeability in mice, Part. Fibre Toxicol. 8 (2011) 19.

Please cite this article in press as: P. Møller, et al., Oxidative stress and inflammation generated DNA damage by exposure to air pollution particles, Mutat. Res.: Rev. Mutat. Res. (2014), http://dx.doi.org/10.1016/j.mrrev.2014.09.001

G Model

MUTREV-8090; No. of Pages 34 P. Møller et al. / Mutation Research xxx (2014) xxx–xxx [111] M. Ohyama, T. Otake, S. Adachi, T. Kobayashi, K. Morinaga, A comparison of the production of reactive oxygen species by suspended particulate matter and diesel exhaust particles with macrophages, Inhal. Toxicol. 19 (Suppl. 1) (2007) 157–160. [112] J.C. Schneider, G.L. Card, J.C. Pfau, A. Holian, Air pollution particulate SRM 1648 causes oxidative stress in RAW 264.7 macrophages leading to production of prostaglandin E2, a potential Th2 mediator, Inhal. Toxicol. 17 (2005) 871–877. [113] A. Shukla, C. Timblin, K. BeruBe, T. Gordon, W. McKinney, K. Driscoll, P. Vacek, B.T. Mossman, Inhaled particulate matter causes expression of nuclear factor (NF)-kappaB-related genes and oxidant-dependent NF-kappaB activation in vitro, Am. J. Respir. Cell Mol. Biol. 23 (2000) 182–187. [114] S. Yi, F. Zhang, F. Qu, W. Ding, Water-insoluble fraction of airborne particulate matter (PM(10)) induces oxidative stress in human lung epithelial A549 cells, Environ. Toxicol. 29 (2014) 226–233. [115] Y. Zhang, J.J. Schauer, M.M. Shafer, M.P. Hannigan, S.J. Dutton, Source apportionment of in vitro reactive oxygen species bioassay activity from atmospheric particulate matter, Environ. Sci. Technol. 42 (2008) 7502–7509. [116] M. Gualtieri, E. Longhin, M. Mattioli, P. Mantecca, V. Tinaglia, E. Mangano, M.C. Proverbio, G. Bestetti, M. Camatini, C. Battaglia, Gene expression profiling of A549 cells exposed to Milan PM2.5, Toxicol. Lett. 209 (2012) 136–145. [117] E. Longhin, E. Pezzolato, P. Mantecca, J.A. Holme, A. Franzetti, M. Camatini, M. Gualtieri, Season linked responses to fine and quasi-ultrafine Milan PM in cultured cells, Toxicol. In Vitro 27 (2013) 551–559. [118] M.G. Perrone, M. Gualtieri, V. Consonni, L. Ferrero, G. Sangiorgi, E. Longhin, D. Ballabio, E. Bolzacchini, M. Camatini, Particle size, chemical composition, seasons of the year and urban, rural or remote site origins as determinants of biological effects of particulate matter on pulmonary cells, Environ. Pollut. 176 (2013) 215–227. [119] J.M. Soukup, A.J. Ghio, S. Becker, Soluble components of Utah Valley particulate pollution alter alveolar macrophage function in vivo and in vitro, Inhal. Toxicol. 12 (2000) 401–414. [120] S.T. Chen, C.C. Lin, Y.S. Liu, C. Lin, P.T. Hung, C.W. Jao, P.H. Lin, Airborne particulate collected from central Taiwan induces DNA strand breaks, poly(ADP-ribose) polymerase-1 activation, and estrogen-disrupting activity in human breast carcinoma cell lines, J. Environ. Sci. Health A: Tox. Hazard. Subst. Environ. Eng. 48 (2013) 173–181. [121] L. Jiang, H. Dai, Q. Sun, C. Geng, Y. Yang, T. Wu, X. Zhang, L. Zhong, Ambient particulate matter on DNA damage in HepG2 cells, Toxicol. Ind. Health 21 (2011) 87–95. [122] Y. Shang, L. Fan, J. Feng, S. Lv, M. Wu, B. Li, Y.S. Zang, Genotoxic and inflammatory effects of organic extracts from traffic-related particulate matter in human lung epithelial A549 cells: the role of quinones, Toxicol. In Vitro 27 (2013) 922–931. [123] S.A. Gurgueira, J. Lawrence, B. Coull, G.G. Murthy, B. Gonzalez-Flecha, Rapid increases in the steady-state concentration of reactive oxygen species in the lungs and heart after particulate air pollution inhalation, Environ. Health Perspect. 110 (2002) 749–755. [124] M.B. Kadiiska, A.J. Ghio, R.P. Mason, ESR investigation of the oxidative damage in lungs caused by asbestos and air pollution particles, Spectrochim. Acta. A. Mol. Biomol. Spectrosc. 60 (2004) 1371–1377. [125] P.R. Mills, R.J. Davies, J.L. Devalia, Airway epithelial cells, cytokines, and pollutants, Am. J. Respir. Crit. Care Med. 160 (1999) S38–S43. [126] C. Cray, J. Zaias, N.H. Altman, Acute phase response in animals: a review, Comp. Med. 59 (2009) 517–526. [127] P.J. Lenting, C. Casari, O.D. Christophe, C.V. Denis, von Willebrand factor: the old, the new and the unknown, J. Thromb. Haemost. 10 (2012) 2428–2437. [128] P.M. Mannucci, von Willebrand factor: a marker of endothelial damage? Arterioscler. Thromb. Vasc. Biol. 18 (1998) 1359–1362. [129] A.O. Spiel, J.C. Gilbert, B. Jilma, von Willebrand factor in cardiovascular disease: focus on acute coronary syndromes, Circulation 117 (2008) 1449–1459. [130] J. Seagrave, Mechanisms and implications of air pollution particle associations with chemokines, Toxicol. Appl. Pharmacol. 232 (2008) 469–477. [131] J.D. Carter, A.J. Ghio, J.M. Samet, R.B. Devlin, Cytokine production by human airway epithelial cells after exposure to an air pollution particle is metaldependent, Toxicol. Appl. Pharmacol. 146 (1997) 180–188. [132] W. Dong, J. Lewtas, M.I. Luster, Role of endotoxin in tumor necrosis factor alpha expression from alveolar macrophages treated with urban air particles, Exp. Lung Res. 22 (1996) 577–592. [133] E. Dybing, T. Lovdal, R.B. Hetland, M. Lovik, P.E. Schwarze, Respiratory allergy adjuvant and inflammatory effects of urban ambient particles, Toxicology 198 (2004) 307–314. [134] R.B. Hetland, F.R. Cassee, M. Lag, M. Refsnes, E. Dybing, P.E. Schwarze, Cytokine release from alveolar macrophages exposed to ambient particulate matter: heterogeneity in relation to size, city and season, Part. Fibre Toxicol. 2 (2005) 4. [135] T. Fujii, S. Hayashi, J.C. Hogg, R. Vincent, S.F. van Eeden, Particulate matter induces cytokine expression in human bronchial epithelial cells, Am. J. Respir. Cell Mol. Biol. 25 (2001) 265–271. [136] T. Fujii, S. Hayashi, J.C. Hogg, H. Mukae, T. Suwa, Y. Goto, R. Vincent, S.F. van Eeden, Interaction of alveolar macrophages and airway epithelial cells following exposure to particulate matter produces mediators that stimulate the bone marrow, Am. J. Respir. Cell Mol. Biol. 27 (2002) 34–41. [137] T. Fujii, J.C. Hogg, N. Keicho, R. Vincent, S.F. van Eeden, S. Hayashi, Adenoviral E1A modulates inflammatory mediator expression by lung epithelial cells exposed to PM10, Am. J. Physiol. Lung Cell Mol. Physiol. 284 (2003) L290–L297. [138] A. Imrich, Y.Y. Ning, H. Koziel, B. Coull, L. Kobzik, Lipopolysaccharide priming amplifies lung macrophage tumor necrosis factor production in response to air particles, Toxicol. Appl. Pharmacol. 159 (1999) 117–124.

27

[139] H. Ishii, T. Fujii, J.C. Hogg, S. Hayashi, H. Mukae, R. Vincent, S.F. van Eeden, Contribution of IL-1b and TNF-a to the initiation of the peripheral lung response to atmospheric particulates (PM10), Am. J. Physiol. Lung Cell Mol. Physiol. 287 (2004) L176–L183. [140] H. Ishii, S. Hayashi, J.C. Hogg, T. Fujii, Y. Goto, N. Sakamoto, H. Mukae, R. Vincent, S.F. van Eeden, Alveolar macrophage-epithelial cell interaction following exposure to atmospheric particles induces the release of mediators involved in monocyte mobilization and recruitment, Respir. Res. 6 (2005) 87. [141] P. Jalava, R.O. Salonen, A.I. Halinen, M. Sillanpaa, E. Sandell, M.R. Hirvonen, Effects of sample preparation on chemistry, cytotoxicity, and inflammatory responses induced by air particulate matter, Inhal. Toxicol. 17 (2005) 107–117. [142] C.M. Long, H.H. Suh, L. Kobzik, P.J. Catalano, Y.Y. Ning, P. Koutrakis, A pilot investigation of the relative toxicity of indoor and outdoor fine particles: in vitro effects of endotoxin and other particulate properties, Environ. Health Perspect. 109 (2001) 1019–1026. [143] C. Monn, S. Becker, Cytotoxicity and induction of proinflammatory cytokines from human monocytes exposed to fine (PM2.5) and coarse particles (PM10– 2.5) in outdoor and indoor air, Toxicol. Appl. Pharmacol. 155 (1999) 245–252. [144] H. Mukae, J.C. Hogg, D. English, R. Vincent, S.F. van Eeden, Phagocytosis of particulate air pollutants by human alveolar macrophages stimulates the bone marrow, Am. J. Physiol. Lung Cell Mol. Physiol. 279 (2000) L924–L931. [145] J. Overocker, J.C. Pfau, Cytokine production modified by system Xc after PM10 and asbestos exposure, J. Young Investig. 23 (2012) 34–39. [146] S. Qu, E.N. Liberda, Q. Qu, L.C. Chen, In vitro assessment of the inflammatory response of respiratory endothelial cells exposed to particulate matter, J. Toxicol. Environ. Health A 73 (2010) 1113–1121. [147] J.L. Quay, W. Reed, J. Samet, R.B. Devlin, Air pollution particles induce IL-6 gene expression in human airway epithelial cells via NF-kappaB activation, Am. J. Respir. Cell Mol. Biol. 19 (1998) 98–106. [148] K. Sawyer, S. Mundandhara, A.J. Ghio, M.C. Madden, The effects of ambient particulate matter on human alveolar macrophage oxidative and inflammatory responses, J. Toxicol. Environ. Health A 73 (2010) 41–57. [149] J.C. Seagrave, K.J. Nikula, Multiple modes of responses to air pollution particulate materials in A549 alveolar type II cells, Inhal. Toxicol. 12 (Suppl. 4) (2000) 247–260. [150] J. Shoenfelt, R.J. Mitkus, R. Zeisler, R.O. Spatz, J. Powell, M.J. Fenton, K.A. Squibb, A.E. Medvedev, Involvement of TLR2 and TLR4 in inflammatory immune responses induced by fine and coarse ambient air particulate matter, J. Leukoc. Biol. 86 (2009) 303–312. [151] H.H. Tan, M.I. Fiel, Q. Sun, J. Guo, R.E. Gordon, L.C. Chen, S.L. Friedman, J.A. Odin, J. Allina., Kupffer cell activation by ambient air particulate matter exposure may exacerbate non-alcoholic fatty liver disease, J. Immunotoxicol. 6 (2009) 266–275. [152] F. Tao, L. Kobzik, Lung macrophage-epithelial cell interactions amplify particlemediated cytokine release, Am. J. Respir. Cell Mol. Biol. 26 (2002) 499–505. [153] A.I. Totlandsdal, M. Refsnes, T. Skomedal, J.B. Osnes, P.E. Schwarze, M. Lag, Particle-induced cytokine responses in cardiac cell cultures – the effect of particles versus soluble mediators released by particle-exposed lung cells, Toxicol. Sci. 106 (2008) 233–241. [154] S.F. van Eeden, W.C. Tan, T. Suwa, H. Mukae, T. Terashima, T. Fujii, D. Qui, R. Vincent, J.C. Hogg, Cytokines involved in the systemic inflammatory response induced by exposure to particulate matter air pollutants (PM(10)), Am. J. Respir. Crit. Care Med. 164 (2001) 826–830. [155] B. Stringer, A. Imrich, L. Kobzik, Lung epithelial cell (A549) interaction with unopsonized environmental particulates: quantitation of particle-specific binding and IL-8 production, Exp. Lung Res. 22 (1996) 495–508. [156] R. Bengalli, E. Molteni, E. Longhin, M. Refsnes, M. Camatini, M. Gualtieri, Release of IL-1 beta triggered by Milan summer PM10: molecular pathways involved in the cytokine release, Biomed. Res. Int. 2013 (2013) 158093. [157] D.M. Brown, L. Hutchison, K. Donaldson, V. Stone, The effects of PM10 particles and oxidative stress on macrophages and lung epithelial cells: modulating effects of calcium-signaling antagonists, Am. J. Physiol. Lung Cell Mol. Physiol. 292 (2007) L1444–L1451. [158] D.M. Brown, K. Donaldson, V. Stone, Effects of PM10 in human peripheral blood monocytes and J774 macrophages, Respir. Res. 5 (2004) 29. [159] G. Garcon, Z. Dagher, F. Zerimech, F. Ledoux, D. Courcot, A. Aboukais, E. Puskaric, P. Shirali, Dunkerque City air pollution particulate matter-induced cytotoxicity, oxidative stress and inflammation in human epithelial lung cells (L132) in culture, Toxicol. In Vitro 20 (2006) 519–528. [160] P.I. Jalava, R.O. Salonen, A.S. Pennanen, M. Sillanpaa, A.I. Halinen, M.S. Happo, R. Hillamo, B. Brunekreef, K. Katsouyanni, J. Sunyer, M.R. Hirvonen, Heterogeneities in inflammatory and cytotoxic responses of RAW 264.7 macrophage cell line to urban air coarse, fine, and ultrafine particles from six European sampling campaigns, Inhal. Toxicol. 19 (2007) 213–225. [161] P.I. Jalava, R.O. Salonen, A.I. Halinen, P. Penttinen, A.S. Pennanen, M. Sillanpaa, E. Sandell, R. Hillamo, M.R. Hirvonen, In vitro inflammatory and cytotoxic effects of size-segregated particulate samples collected during long-range transport of wildfire smoke to Helsinki, Toxicol. Appl. Pharmacol. 215 (2006) 341–353. [162] L.A. Jimenez, J. Thompson, D.A. Brown, I. Rahman, F. Antonicelli, R. Duffin, E.M. Drost, R.T. Hay, K. Donaldson, W. MacNee, Activation of NF-kB by PM10 occurs via an iron-mediated mechanism in the absence of IkB degradation, Toxicol. Appl. Pharmacol. 166 (2000) 101–110. [163] H.L. Karlsson, A.G. Ljungman, J. Lindbom, L. Moller, Comparison of genotoxic and inflammatory effects of particles generated by wood combustion, a road simulator and collected from street and subway, Toxicol. Lett. 165 (2006) 203–211.

Please cite this article in press as: P. Møller, et al., Oxidative stress and inflammation generated DNA damage by exposure to air pollution particles, Mutat. Res.: Rev. Mutat. Res. (2014), http://dx.doi.org/10.1016/j.mrrev.2014.09.001

G Model

MUTREV-8090; No. of Pages 34 28

P. Møller et al. / Mutation Research xxx (2014) xxx–xxx

[164] A. Kocbach, E. Namork, P.E. Schwarze, Pro-inflammatory potential of wood smoke and traffic-derived particles in a monocytic cell line, Toxicology 247 (2008) 123–132. [165] S. Michael, M. Montag, W. Dott, Pro-inflammatory effects and oxidative stress in lung macrophages and epithelial cells induced by ambient particulate matter, Environ. Pollut. 183 (2013) 19–29. [166] C. Monn, R. Naef, T. Koller, Reactions of macrophages exposed to particles <10 microm, Environ. Res. 91 (2003) 35–44. [167] R. Pozzi, B.B. De Berardis, L. Paoletti, C. Guastadisegni, Inflammatory mediators induced by coarse (PM2.5–10) and fine (PM2.5) urban air particles in RAW 264.7 cells, Toxicology 183 (2003) 243–254. [168] A.K. Sharma, K.A. Jensen, J. Rank, P.A. White, S. Lundstedt, R. Gagne, N.R. Jacobsen, J. Kristiansen, U. Vogel, H. Wallin, Genotoxicity, inflammation and physico-chemical properties of fine particle samples from an incineration energy plant and urban air, Mutat. Res. 633 (2007) 95–111. [169] E. Alfaro-Moreno, L. Martinez, C. Garcia-Cuellar, J.C. Bonner, J.C. Murray, I. Rosas, S.P. Rosales, A.R. Osornio-Vargas, Biologic effects induced in vitro by PM10 from three different zones of Mexico City, Environ. Health Perspect. 110 (2002) 715–720. [170] R.M. Duvall, G.A. Norris, L.A. Dailey, J.M. Burke, J.K. McGee, M.I. Gilmour, T. Gordon, R.B. Devlin, Source apportionment of particulate matter in the U.S. and associations with lung inflammatory markers, Inhal. Toxicol. 20 (2008) 671–683. [171] D.W. Graff, M.T. Schmitt, L.A. Dailey, R.M. Duvall, E.D. Karoly, R.B. Devlin, Assessing the role of particulate matter size and composition on gene expression in pulmonary cells, Inhal. Toxicol. 19 (Suppl. 1) (2007) 23–28. [172] F.T. Lauer, L.A. Mitchell, E. Bedrick, J.D. McDonald, W.Y. Lee, W.W. Li, H. Olvera, M.A. Amaya, M. Berwick, M. Gonzales, R. Currey, N.E. Pingitore Jr., S.W. Burchiel, Temporal-spatial analysis of U.S.-Mexico border environmental fine and coarse PM air sample extract activity in human bronchial epithelial cells, Toxicol. Appl. Pharmacol. 238 (2009) 1–10. [173] Y. Ning, A. Imrich, C.A. Goldsmith, G. Qin, L. Kobzik, Alveolar macrophage cytokine production in response to air particles in vitro: role of endotoxin, J. Toxicol. Environ. Health A 59 (2000) 165–180. [174] T.L. Watterson, J. Sorensen, R. Martin, R.A. Coulombe Jr., Effects of PM2.5 collected from Cache Valley Utah on genes associated with the inflammatory response in human lung cells, J. Toxicol. Environ. Health A 70 (2007) 1731–1744. [175] S.L. Huang, M.K. Hsu, C.C. Chan, Effects of submicrometer particle compositions on cytokine production and lipid peroxidation of human bronchial epithelial cells, Environ. Health Perspect. 111 (2003) 478–482. [176] D. Dieme, M. Cabral-Ndior, G. Garcon, A. Verdin, S. Billet, F. Cazier, D. Courcot, A. Diouf, P. Shirali, Relationship between physicochemical characterization and toxicity of fine particulate matter (PM2.5) collected in Dakar city (Senegal), Environ. Res. 113 (2012) 1–13. [177] S. Val, C. Liousse, E.H. Doumbia, C. Galy-Lacaux, H. Cachier, N. Marchand, A. Badel, E. Gardrat, A. Sylvestre, A. Baeza-Squiban, Physico-chemical characterization of African urban aerosols (Bamako in Mali and Dakar in Senegal) and their toxic effects in human bronchial epithelial cells: description of a worrying situation, Part. Fibre Toxicol. 10 (2013) 10. [178] I. Bos, P. De Boever, J. Emmerechts, J. Buekers, J. Vanoirbeek, R. Meeusen, M. Van Poppel, B. Nemery, T. Nawrot, L.I. Panis, Changed gene expression in brains of mice exposed to traffic in a highway tunnel, Inhal. Toxicol. 24 (2012) 676–686. [179] F.R. Cassee, A.J. Boere, P.H. Fokkens, D.L. Leseman, C. Sioutas, I.M. Kooter, J.A. Dormans, Inhalation of concentrated particulate matter produces pulmonary inflammation and systemic biological effects in compromised rats, J. Toxicol. Environ. Health A 68 (2005) 773–796. [180] D.L. Costa, K.L. Dreher, Bioavailable transition metals in particulate matter mediate cardiopulmonary injury in healthy and compromised animal models, Environ. Health Perspect. 105 (Suppl. 5) (1997) 1053–1060. [181] P.H. Danielsen, S. Loft, N.R. Jacobsen, K.A. Jensen, H. Autrup, J.L. Ravanat, H. Wallin, P. Møller, Oxidative stress, inflammation and DNA damage in rats after intratracheal instillation or oral exposure to ambient air and wood smoke particulate matter, Toxicol. Sci. 118 (2010) 574–585. [182] J. Emmerechts, V. De Vooght, S. Haenen, S. Loyen, K.S. Van Kerckhoven, B. Hemmeryckx, J.A. Vanoirbeek, P.H. Hoet, B. Nemery, M.F. Hoylaerts, Thrombogenic changes in young and old mice upon subchronic exposure to air pollution in an urban roadside tunnel, Thromb. Haemost. 108 (2012) 756–768. [183] F. Farina, G. Sancini, P. Mantecca, D. Gallinotti, M. Camatini, P. Palestini, The acute toxic effects of particulate matter in mouse lung are related to size and season of collection, Toxicol. Lett. 202 (2011) 209–217. [184] M.E. Gerlofs-Nijland, J.A. Dormans, H.J. Bloemen, D.L. Leseman, A. John, F. Boere, F.J. Kelly, I.S. Mudway, A.A. Jimenez, K. Donaldson, C. Guastadisegni, N.A. Janssen, B. Brunekreef, T. Sandstrom, L. van Bree, F.R. Cassee, Toxicity of coarse and fine particulate matter from sites with contrasting traffic profiles, Inhal. Toxicol. 19 (2007) 1055–1069. [185] M.E. Gerlofs-Nijland, A.J. Boere, D.L. Leseman, J.A. Dormans, T. Sandstrom, R.O. Salonen, L. van Bree, F.R. Cassee, Effects of particulate matter on the pulmonary and vascular system: time course in spontaneously hypertensive rats, Part. Fibre Toxicol. 2 (2005) 2. [186] T. Halatek, M. Stepnik, J. Stetkiewicz, A. Krajnow, B. Kur, W. Szymczak, K. Rydzynski, E. Dybing, F.R. Cassee, The inflammatory response in lungs of rats exposed on the airborne particles collected during different seasons in four European cities, J. Environ. Sci. Health A: Tox. Hazard. Subst. Environ. Eng. 46 (2011) 1469–1481. [187] M.S. Happo, R.O. Salonen, A.I. Halinen, P.I. Jalava, A.S. Pennanen, V.M. Kosma, M. Sillanpaa, R. Hillamo, B. Brunekreef, K. Katsouyanni, J. Sunyer, M.R. Hirvonen,

[188]

[189]

[190]

[191]

[192]

[193]

[194]

[195]

[196]

[197]

[198]

[199]

[200]

[201]

[202]

[203]

[204]

[205]

[206]

[207]

[208]

Dose and time dependency of inflammatory responses in the mouse lung to urban air coarse, fine, and ultrafine particles from six European cities, Inhal. Toxicol. 19 (2007) 227–246. I.M. Kooter, A.J. Boere, P.H. Fokkens, D.L. Leseman, J.A. Dormans, F.R. Cassee, Response of spontaneously hypertensive rats to inhalation of fine and ultrafine particles from traffic: experimental controlled study, Part. Fibre Toxicol. 3 (2006) 7. X.Y. Li, P.S. Gilmour, K. Donaldson, W. MacNee, Free radical activity and proinflammatory effects of particulate air pollution (PM10) in vivo and in vitro, Thorax 51 (1996) 1216–1222. G.M. Mutlu, C. Snyder, A. Bellmeyer, H. Wang, K. Hawkins, S. Soberanes, L.C. Welch, A.J. Ghio, N.S. Chandel, D. Kamp, J.I. Sznajder, G.R. Budinger, Airborne particulate matter inhibits alveolar fluid reabsorption in mice via oxidant generation, Am. J. Respir. Cell Mol. Biol. 34 (2006) 670–676. S. Upadhyay, K. Ganguly, T. Stoeger, M. Semmler-Bhenke, S. Takenaka, W.G. Kreyling, M. Pitz, P. Reitmeir, A. Peters, O. Eickelberg, H.E. Wichmann, H. Schulz, Cardiovascular and inflammatory effects of intratracheally instilled ambient dust from Augsburg, Germany, in spontaneously hypertensive rats (SHRs), Part. Fibre Toxicol. 7 (2010) 27. G.R. Budinger, J.L. McKell, D. Urich, N. Foiles, I. Weiss, S.E. Chiarella, A. Gonzalez, S. Soberanes, A.J. Ghio, R. Nigdelioglu, E.A. Mutlu, K.A. Radigan, D. Green, H.C. Kwaan, G.M. Mutlu, Particulate matter-induced lung inflammation increases systemic levels of PAI-1 and activates coagulation through distinct mechanisms, PLoS ONE 6 (2011) e18525. R.W. Clarke, P.J. Catalano, P. Koutrakis, G.G. Murthy, C. Sioutas, J. Paulauskis, B. Coull, S. Ferguson, J.J. Godleski, Urban air particulate inhalation alters pulmonary function and induces pulmonary inflammation in a rodent model of chronic bronchitis, Inhal. Toxicol. 11 (1999) 637–656. R.W. Clarke, B. Coull, U. Reinisch, P. Catalano, C.R. Killingsworth, P. Koutrakis, I. Kavouras, G.G. Murthy, J. Lawrence, E. Lovett, J.M. Wolfson, R.L. Verrier, J.J. Godleski, Inhaled concentrated ambient particles are associated with hematologic and bronchoalveolar lavage changes in canines, Environ. Health Perspect. 108 (2000) 1179–1187. R.W. Clarke, P. Catalano, B. Coull, P. Koutrakis, G.G.K. Murthy, T. Rice, J.J. Godleski, Age-related responses in rats to concentrated urban air particles (CAPs), Inhal. Toxicol. 12 (2000) 73–84. C.A. Dick, P. Singh, M. Daniels, P. Evansky, S. Becker, M.I. Gilmour, Murine pulmonary inflammatory responses following instillation of size-fractionated ambient particulate matter, J. Toxicol. Environ. Health A 66 (2003) 2193–2207. S.H. Gavett, N. Haykal-Coates, J.W. Highfill, A.D. Ledbetter, L.C. Chen, M.D. Cohen, J.R. Harkema, J.G. Wagner, D.L. Costa, World Trade Center fine particulate matter causes respiratory tract hyperresponsiveness in mice, Environ. Health Perspect. 111 (2003) 981–991. M.I. Gilmour, J. McGee, R.M. Duvall, L. Dailey, M. Daniels, E. Boykin, S.H. Cho, D. Doerfler, T. Gordon, R.B. Devlin, Comparative toxicity of size-fractionated airborne particulate matter obtained from different cities in the United States, Inhal. Toxicol. 19 (Suppl. 1) (2007) 7–16. J.J. Godleski, R.W. Clarke, B. Coull, P.H. Saldiva, N.-F. Jiang, J. Lawrence, P. Koutrakis, Composition of inhaled urban air particles determines acute pulmonary responses, Ann. Occup. Hyg. 46 (2002) 419–424. T. Gordon, C. Nadziejko, R. Schlesinger, L.C. Chen, Pulmonary and cardiovascular effects of acute exposure to concentrated ambient particulate matter in rats, Toxicol. Lett. 96–97 (1998) 285–288. B.L. Heidenfelder, D.M. Reif, J.R. Harkema, E.A. Cohen Hubal, E.E. Hudgens, L.A. Bramble, J.G. Wagner, M. Morishita, G.J. Keeler, S.W. Edwards, J.E. Gallagher, Comparative microarray analysis and pulmonary changes in Brown Norway rats exposed to ovalbumin and concentrated air particulates, Toxicol. Sci. 108 (2009) 207–221. T. Ichinose, S. Yoshida, K. Sadakane, H. Takano, R. Yanagisawa, K. Inoue, M. Nishikawa, I. Mori, H. Kawazato, A. Yasuda, T. Shibamoto, Effects of Asian sand dust, Arizona sand dust, amorphous silica and aluminum oxide on allergic inflammation in the murine lung, Inhal. Toxicol. 20 (2008) 685–694. U.P. Kodavanti, R. Mebane, A. Ledbetter, T. Krantz, J. McGee, M.C. Jackson, L. Walsh, H. Hilliard, B.Y. Chen, J. Richards, D.L. Costa, Variable pulmonary responses from exposure to concentrated ambient air particles in a rat model of bronchitis, Toxicol. Sci. 54 (2000) 441–451. C. Quan, Q. Sun, M. Lippmann, L.C. Chen, Comparative effects of inhaled diesel exhaust and ambient fine particles on inflammation, atherosclerosis, and vascular dysfunction, Inhal. Toxicol. 22 (2010) 738–753. C.R. Rhoden, J. Lawrence, J.J. Godleski, B. Gonzalez-Flecha, N-acetylcysteine prevents lung inflammation after short-term inhalation exposure to concentrated ambient particles, Toxicol. Sci. 79 (2004) 296–303. P.H. Saldiva, R.W. Clarke, B.A. Coull, R.C. Stearns, J. Lawrence, G.G. Murthy, E. Diaz, P. Koutrakis, H. Suh, A. Tsuda, J.J. Godleski, Lung inflammation induced by concentrated ambient air particles is related to particle composition, Am. J. Respir. Crit. Care Med. 165 (2002) 1610–1617. J. Seagrave, J.D. McDonald, E. Bedrick, E.S. Edgerton, A.P. Gigliotti, J.J. Jansen, L. Ke, L.P. Naeher, S.K. Seilkop, M. Zheng, J.L. Mauderly, Lung toxicity of ambient particulate matter from southeastern U.S. sites with different contributing sources: relationships between composition and effects, Environ. Health Perspect. 114 (2006) 1387–1393. S. Sigaud, C.A. Goldsmith, H. Zhou, Z. Yang, A. Fedulov, A. Imrich, L. Kobzik, Air pollution particles diminish bacterial clearance in the primed lungs of mice, Toxicol. Appl. Pharmacol. 223 (2007) 1–9.

Please cite this article in press as: P. Møller, et al., Oxidative stress and inflammation generated DNA damage by exposure to air pollution particles, Mutat. Res.: Rev. Mutat. Res. (2014), http://dx.doi.org/10.1016/j.mrrev.2014.09.001

G Model

MUTREV-8090; No. of Pages 34 P. Møller et al. / Mutation Research xxx (2014) xxx–xxx [209] J.T. Zelikoff, L.C. Chen, M.D. Cohen, K. Fang, T. Gordon, Y. Li, C. Nadziejko, R.B. Schlesinger, Effects of inhaled ambient particulate matter on pulmonary antimicrobial immune defense, Inhal. Toxicol. 15 (2003) 131–150. [210] T. Ichinose, M. Nishikawa, H. Takano, N. Sera, K. Sadakane, I. Mori, R. Yanagisawa, T. Oda, H. Tamura, K. Hiyoshi, H. Quan, S. Tomura, T. Shibamoto, Pulmonary toxicity induced by intratracheal instillation of Asian yellow dust (Kosa) in mice, Environ. Toxicol. Pharmacol. 20 (2005) 48–56. [211] T. Ito, T. Suzuki, K. Tamura, T. Nezu, K. Honda, T. Kobayashi, Examination of mRNA expression in rat hearts and lungs for analysis of effects of exposure to concentrated ambient particles on cardiovascular function, Toxicology 243 (2008) 271–283. [212] Y.C. Lei, M.C. Chen, C.C. Chan, P.Y. Wang, C.T. Lee, T.J. Cheng, Effects of concentrated ambient particles on airway responsiveness and pulmonary inflammation in pulmonary hypertensive rats, Inhal. Toxicol. 16 (2004) 785–792. [213] Y.C. Lei, J.S. Hwang, C.C. Chan, C.T. Lee, T.J. Cheng, Enhanced oxidative stress and endothelial dysfunction in streptozotocin-diabetic rats exposed to fine particles, Environ. Res. 99 (2005) 335–343. [214] W. Zhang, T.A. Lei, Z.Q. Lin, H.S. Zhang, D.F. Yang, Z.G. Xi, J.H. Chen, W. Wang, Pulmonary toxicity study in rats with PM10 and PM2.5: differential responses related to scale and composition, Atmos. Environ. 45 (2011) 1034–1041. [215] S. Martin, L. Dawidowski, P. Mandalunis, F. Cereceda-Balic, D.R. Tasat, Characterization and biological effect of Buenos Aires urban air particles on mice lungs, Environ. Res. 105 (2007) 340–349. [216] S. Martin, E. Fernandez-Alanis, V. Delfosse, P. Evelson, J.S. Yakisich, P.H. Saldiva, D.R. Tasat, Low doses of urban air particles from Buenos Aires promote oxidative stress and apoptosis in mice lungs, Inhal. Toxicol. 22 (2010) 1064–1071. [217] C.E. Pereira, T.G. Heck, P.H. Saldiva, C.R. Rhoden, Ambient particulate air pollution from vehicles promotes lipid peroxidation and inflammatory responses in rat lung, Braz. J. Med. Biol. Res. 40 (2007) 1353–1359. [218] D.R. Riva, C.B. Magalhaes, A.A. Lopes, T. Lancas, T. Mauad, O. Malm, S.S. Valenca, P.H. Saldiva, D.S. Faffe, W.A. Zin, Low dose of fine particulate matter (PM2.5) can induce acute oxidative stress, inflammation and pulmonary impairment in healthy mice, Inhal. Toxicol. 23 (2011) 257–267. [219] I.Y. Adamson, H. Prieditis, R. Vincent, Pulmonary toxicity of an atmospheric particulate sample is due to the soluble fraction, Toxicol. Appl. Pharmacol. 157 (1999) 43–50. [220] I.Y. Adamson, R. Vincent, S.G. Bjarnason, Cell injury and interstitial inflammation in rat lung after inhalation of ozone and urban particulates, Am. J. Respir. Cell Mol. Biol. 20 (1999) 1067–1072. [221] I.Y. Adamson, H. Prieditis, C. Hedgecock, R. Vincent, Zinc is the toxic factor in the lung response to an atmospheric particulate sample, Toxicol. Appl. Pharmacol. 166 (2000) 111–119. [222] R.L. Auten, E.N. Potts, S.N. Mason, B. Fischer, Y. Huang, W.M. Foster, Maternal exposure to particulate matter increases postnatal ozone-induced airway hyperreactivity in juvenile mice, Am. J. Respir. Crit. Care Med. 180 (2009) 1218–1226. [223] K. Bagate, J.J. Meiring, M.E. Gerlofs-Nijland, R. Vincent, F.R. Cassee, P.J. Borm, Vascular effects of ambient particulate matter instillation in spontaneous hypertensive rats, Toxicol. Appl. Pharmacol. 197 (2004) 29–39. [224] D.L. Costa, J.R. Lehmann, D. Winsett, J. Richards, A.D. Ledbetter, K.L. Dreher, Comparative pulmonary toxicological assessment of oil combustion particles following inhalation or instillation exposure, Toxicol. Sci. 91 (2006) 237–246. [225] A.J. Ghio, H.B. Suliman, J.D. Carter, A.M. Abushamaa, R.J. Folz, Overexpression of extracellular superoxide dismutase decreases lung injury after exposure to oil fly ash, Am. J. Physiol. Lung Cell Mol. Physiol. 283 (2002) L211–L218. [226] T.R. Nurkiewicz, D.W. Porter, M. Barger, L. Millecchia, K.M. Rao, P.J. Marvar, A.F. Hubbs, V. Castranova, M.A. Boegehold, Systemic microvascular dysfunction and inflammation after pulmonary particulate matter exposure, Environ. Health Perspect. 114 (2006) 412–419. [227] C.R. Rhoden, E. Ghelfi, B. Gonzalez-Flecha, Pulmonary inflammation by ambient air particles is mediated by superoxide anion, Inhal. Toxicol. 20 (2008) 11–15. [228] E.S. Roberts, J.H. Richards, R. Jaskot, K.L. Dreher, Oxidative stress mediates air pollution particle-induced acute lung injury and molecular pathology, Inhal. Toxicol. 15 (2003) 1327–1346. [229] K.R. Smith, J.M. Veranth, U.P. Kodavanti, A.E. Aust, K.E. Pinkerton, Acute pulmonary and systemic effects of inhaled coal fly ash in rats: comparison to ambient environmental particles, Toxicol. Sci. 93 (2006) 390–399. [230] E. Tamagawa, N. Bai, K. Morimoto, C. Gray, T. Mui, K. Yatera, X. Zhang, L. Xing, Y. Li, I. Laher, D.D. Sin, S.F. Man, S.F. van Eeden, Particulate matter exposure induces persistent lung inflammation and endothelial dysfunction, Am. J. Physiol. Lung Cell Mol. Physiol. 295 (2008) L79–L85. [231] E.M. Thomson, A. Williams, C.L. Yauk, R. Vincent, Toxicogenomic analysis of susceptibility to inhaled urban particulate matter in mice with chronic lung inflammation, Part. Fibre Toxicol. 6 (2009) 6. [232] M.M. Ulrich, G.M. Alink, P. Kumarathasan, R. Vincent, A.J. Boere, F.R. Cassee, Health effects and time course of particulate matter on the cardiopulmonary system in rats with lung inflammation, J. Toxicol. Environ. Health A 65 (2002) 1571–1595. [233] J.L. Mauderly, E.G. Barrett, A.P. Gigliotti, J.D. McDonald, M.D. Reed, J. Seagrave, L.A. Mitchell, S.K. Seilkop, Health effects of subchronic inhalation exposure to simulated downwind coal combustion emissions, Inhal. Toxicol. 23 (2011) 349–362. [234] E. Cozzi, S. Hazarika, H.W. Stallings III, W.E. Cascio, R.B. Devlin, R.M. Lust, C.J. Wingard, M.R. Van Scott, Ultrafine particulate matter exposure augments ischemia-reperfusion injury in mice, Am. J. Physiol. Heart Circ. Physiol. 291 (2006) H894–H903.

29

[235] E. Cozzi, C.J. Wingard, W.E. Cascio, R.B. Devlin, J.J. Miles, A.R. Bofferding, R.M. Lust, M.R. Van Scott, R.A. Henriksen, Effect of ambient particulate matter exposure on hemostasis, Transl. Res. 149 (2007) 324–332. [236] R. Li, M. Navab, P. Pakbin, Z. Ning, K. Navab, G. Hough, T.E. Morgan, C.E. Finch, J.A. Araujo, A.M. Fogelman, C. Sioutas, T. Hsiai, Ambient ultrafine particles alter lipid metabolism and HDL anti-oxidant capacity in LDLR-null mice, J. Lipid Res. 54 (2013) 1608–1615. [237] J. Zhao, Y. Xie, X. Qian, R. Jiang, W. Song, Acute effects of fine particles on cardiovascular system: differences between the spontaneously hypertensive rats and Wistar Kyoto rats, Toxicol. Lett. 193 (2010) 50–60. [238] S.Y. Gardner, J.R. Lehmann, D.L. Costa, Oil fly ash-induced elevation of plasma fibrinogen levels in rats, Toxicol. Sci. 56 (2000) 175–180. [239] Y. Goto, J.C. Hogg, C.H. Shih, H. Ishii, R. Vincent, S.F. van Eeden, Exposure to ambient particles accelerates monocyte release from bone marrow in atherosclerotic rabbits, Am. J. Physiol. Lung Cell Mol. Physiol. 287 (2004) L79–L85. [240] R. Miyata, N. Bai, R. Vincent, D.D. Sin, S.F. van Eeden, Novel properties of statins: suppression of the systemic and bone marrow responses induced by exposure to ambient particulate matter (PM(10)) air pollution, Am. J. Physiol. Lung Cell Mol. Physiol. 303 (2012) L492–L499. [241] K. Yatera, J. Hsieh, J.C. Hogg, E. Tranfield, H. Suzuki, C.H. Shih, A.R. Behzad, R. Vincent, S.F. van Eeden, Particulate matter air pollution exposure promotes recruitment of monocytes into atherosclerotic plaques, Am. J. Physiol. Heart Circ. Physiol. 294 (2008) H944–H953. [242] G. Adamkiewicz, S. Ebelt, M. Syring, J. Slater, F.E. Speizer, J. Schwartz, H. Suh, D.R. Gold, Association between air pollution exposure and exhaled nitric oxide in an elderly population, Thorax 59 (2004) 204–209. [243] A. Barraza-Villarreal, J. Sunyer, L. Hernandez-Cadena, M.C. Escamilla-Nunez, J.J. Sienra-Monge, M. Ramirez-Aguilar, M. Cortez-Lugo, F. Holguin, D. Diaz-Sanchez, A.C. Olin, I. Romieu, Air pollution, airway inflammation, and lung function in a cohort study of Mexico City schoolchildren, Environ. Health Perspect. 116 (2008) 832–838. [244] I. Romieu, A. Barraza-Villarreal, C. Escamilla-Nunez, A.C. Almstrand, D. azSanchez, P.D. Sly, A.C. Olin, Exhaled breath malondialdehyde as a marker of effect of exposure to air pollution in children with asthma, J. Allergy Clin. Immunol. 121 (2008) 903–909. [245] R.J. Delfino, N. Staimer, D. Gillen, T. Tjoa, C. Sioutas, K. Fung, S.C. George, M.T. Kleinman, Personal and ambient air pollution is associated with increased exhaled nitric oxide in children with asthma, Environ. Health Perspect. 114 (2006) 1736–1743. [246] R.J. Delfino, N. Staimer, T. Tjoa, D.L. Gillen, J.J. Schauer, M.M. Shafer, Airway inflammation and oxidative potential of air pollutant particles in a pediatric asthma panel, J. Expo. Sci. Environ. Epidemiol. 23 (2013) 466–473. [247] R.J. Delfino, N. Staimer, T. Tjoa, M. Arhami, A. Polidori, D.L. Gillen, S.C. George, M.M. Shafer, J.J. Schauer, C. Sioutas, Associations of primary and secondary organic aerosols with airway and systemic inflammation in an elderly panel cohort, Epidemiology 21 (2010) 892–902. [248] A.J. Ghio, C. Kim, R.B. Devlin, Concentrated ambient air particles induce mild pulmonary inflammation in healthy human volunteers, Am. J. Respir. Crit. Care Med. 162 (2000) 981–988. [249] D.W. Graff, W.E. Cascio, A. Rappold, H. Zhou, Y.C. Huang, R.B. Devlin, Exposure to concentrated coarse air pollution particles causes mild cardiopulmonary effects in healthy young adults, Environ. Health Perspect. 117 (2009) 1089–1094. [250] K.L. Jansen, T.V. Larson, J.Q. Koenig, T.F. Mar, C. Fields, J. Stewart, M. Lippmann, Associations between health effects and particulate matter and black carbon in subjects with respiratory disease, Environ. Health Perspect. 113 (2005) 1741–1746. [251] J.Q. Koenig, T.F. Mar, R.W. Allen, K. Jansen, T. Lumley, J.H. Sullivan, C.A. Trenga, T. Larson, L.J. Liu, Pulmonary effects of indoor- and outdoor-generated particles in children with asthma, Environ. Health Perspect. 113 (2005) 499–503. [252] J.Q. Koenig, K. Jansen, T.F. Mar, T. Lumley, J. Kaufman, C.A. Trenga, J. Sullivan, L.J. Liu, G.G. Shapiro, T.V. Larson, Measurement of offline exhaled nitric oxide in a study of community exposure to air pollution, Environ. Health Perspect. 111 (2003) 1625–1629. [253] T.F. Mar, K. Jansen, K. Shepherd, T. Lumley, T.V. Larson, J.Q. Koenig, Exhaled nitric oxide in children with asthma and short-term PM2.5 exposure in Seattle, Environ. Health Perspect. 113 (2005) 1791–1794. [254] L. Liu, R. Poon, L. Chen, A.M. Frescura, P. Montuschi, G. Ciabattoni, A. Wheeler, R. Dales, Acute effects of air pollution on pulmonary function, airway inflammation, and oxidative stress in asthmatic children, Environ. Health Perspect. 117 (2009) 668–674. [255] K.W. Rundell, J.B. Slee, R. Caviston, A.M. Hollenbach, Decreased lung function after inhalation of ultrafine and fine particulate matter during exercise is related to decreased total nitrate in exhaled breath condensate, Inhal. Toxicol. 20 (2008) 1–9. [256] J.M. Samet, A. Rappold, D. Graff, W.E. Cascio, J.H. Berntsen, Y.C.T. Huang, M. Herbst, M. Bassett, T. Montilla, M.J. Hazucha, P.A. Bromberg, R.B. Devlin, Concentrated ambient ultrafine particle exposure induces cardiac changes in young healthy volunteers, Am. J. Respir. Crit. Care Med. 179 (2009) 1034–1042. [257] B. Urch, M. Speck, P. Corey, D. Wasserstein, M. Manno, K.Z. Lukic, J.R. Brook, L. Liu, B. Coull, J. Schwartz, D.R. Gold, F. Silverman, Concentrated ambient fine particles and not ozone induce a systemic interleukin-6 response in humans, Inhal. Toxicol. 22 (2010) 210–218. [258] B.M. Larsson, J. Grunewald, C.M. Skold, A. Lundin, T. Sandstrom, A. Eklund, M. Svartengren, Limited airway effects in mild asthmatics after exposure to air pollution in a road tunnel, Respir. Med. 104 (2010) 1912–1918.

Please cite this article in press as: P. Møller, et al., Oxidative stress and inflammation generated DNA damage by exposure to air pollution particles, Mutat. Res.: Rev. Mutat. Res. (2014), http://dx.doi.org/10.1016/j.mrrev.2014.09.001

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[259] S. Manney, C.M. Meddings, R.M. Harrison, A.H. Mansur, A. Karakatsani, A. Analitis, K. Katsouyanni, D. Perifanou, I.G. Kavouras, N. Kotronarou, J.J. de Hartog, J. Pekkanen, K. Hameri, B.H. ten, G. Hoek, J.G. Ayres, Association between exhaled breath condensate nitrate + nitrite levels with ambient coarse particle exposure in subjects with airways disease, Occup. Environ. Med. 69 (2012) 663–669. [260] J. McCreanor, P. Cullinan, M.J. Nieuwenhuijsen, J. Stewart-Evans, E. Malliarou, L. Jarup, R. Harrington, M. Svartengren, I.K. Han, P. Ohman-Strickland, K.F. Chung, J. Zhang, Respiratory effects of exposure to diesel traffic in persons with asthma, N. Engl. J. Med. 357 (2007) 2348–2358. [261] N.L. Mills, S.D. Robinson, P.H. Fokkens, D.L. Leseman, M.R. Miller, D. Anderson, E.J. Freney, M.R. Heal, R.J. Donovan, A. Blomberg, T. Sandstrom, W. MacNee, N.A. Boon, K. Donaldson, D.E. Newby, F.R. Cassee, Exposure to concentrated ambient particles does not affect vascular function in patients with coronary heart disease, Environ. Health Perspect. 116 (2008) 709–715. [262] M. Strak, N.A. Janssen, K.J. Godri, I. Gosens, I.S. Mudway, F.R. Cassee, E. Lebret, F.J. Kelly, R.M. Harrison, B. Brunekreef, M. Steenhof, G. Hoek, Respiratory health effects of airborne particulate matter: the role of particle size, composition, and oxidative potential-the RAPTES project, Environ, Health Perspect. 120 (2012) 1183–1189. [263] P.A. Steerenberg, S. Nierkens, P.H. Fischer, H. van Loveren, A. Opperhuizen, J.G. Vos, J.G. van Amsterdam, Traffic-related air pollution affects peak expiratory flow, exhaled nitric oxide, and inflammatory nasal markers, Arch. Environ. Health 56 (2001) 167–174. [264] W. Huang, G. Wang, S.E. Lu, H. Kipen, Y. Wang, M. Hu, W. Lin, D. Rich, P. OhmanStrickland, S.R. Diehl, P. Zhu, J. Tong, J. Gong, T. Zhu, J. Zhang, Inflammatory and oxidative stress responses of healthy young adults to changes in air quality during the Beijing Olympics, Am. J. Respir. Crit. Care Med. 186 (2012) 1150–1159. [265] A. Baccarelli, A. Zanobetti, I. Martinelli, P. Grillo, L. Hou, S. Giacomini, M. Bonzini, G. Lanzani, P.M. Mannucci, P.A. Bertazzi, J. Schwartz, Effects of exposure to air pollution on blood coagulation, J. Thromb. Haemost. 5 (2007) 252–260. [266] E.V. Bra¨uner, L. Forchhammer, P. Møller, L. Barregard, L. Gunnarsen, A. Afshari, P. Wahlin, M. Glasius, L.O. Dragsted, S. Basu, O. Raaschou-Nielsen, S. Loft, Indoor particles affect vascular function in the aged: an air filtration-based intervention study, Am. J. Respir. Crit. Care Med. 177 (2008) 419–425. [267] E.V. Bra¨uner, P. Møller, L. Barregard, L.O. Dragsted, M. Glasius, P. Wahlin, P. Vinzents, O. Raaschou-Nielsen, S. Loft, Exposure to ambient concentrations of particulate air pollution does not influence vascular function or inflammatory pathways in young healthy individuals, Part. Fibre Toxicol. 5 (2008) 13. [268] I. Bruske, R. Hampel, M.M. Socher, R. Ruckerl, A. Schneider, J. Heinrich, G. Oberdorster, H.E. Wichmann, A. Peters, Impact of ambient air pollution on the differential white blood cell count in patients with chronic pulmonary disease, Inhal. Toxicol. 22 (2010) 245–252. [269] J. Emmerechts, L. Jacobs, k.S. Van Kerckhoven, S. Loyen, C. Mathieu, F. Fierens, B. Nemery, T.S. Nawrot, M.F. Hoylaerts, Air pollution-associated procoagulant changes: the role of circulating microvesicles, J. Thromb. Haemost. 10 (2012) 96–106. [270] L.J. Forbes, M.D. Patel, A.R. Rudnicka, D.G. Cook, T. Bush, J.R. Stedman, P.H. Whincup, D.P. Strachan, R.H. Anderson, Chronic exposure to outdoor air pollution and markers of systemic inflammation, Epidemiology 20 (2009) 245–253. [271] S. Hertel, A. Viehmann, S. Moebus, K. Mann, M. Brocker-Preuss, S. Mohlenkamp, M. Nonnemacher, R. Erbel, H. Jakobs, M. Memmesheimer, K.H. Jockel, B. Hoffmann, Influence of short-term exposure to ultrafine and fine particles on systemic inflammation, Eur. J. Epidemiol. 25 (2010) 581–592. [272] K. Hildebrandt, R. Ruckerl, W. Koenig, A. Schneider, M. Pitz, J. Heinrich, V. Marder, M. Frampton, G. Oberdo¨rster, H.E. Wichmann, A. Peters, Short-term effects of air pollution: a panel study of blood markers in patients with chronic pulmonary disease, Part. Fibre Toxicol. 6 (2009) 25. [273] K. Huttunen, T. Siponen, I. Salonen, T. Yli-Tuomi, M. Aurela, H. Dufva, R. Hillamo, E. Linkola, J. Pekkanen, A. Pennanen, A. Peters, R.O. Salonen, A. Schneider, P. Tiittanen, M.R. Hirvonen, T. Lanki, Low-level exposure to ambient particulate matter is associated with systemic inflammation in ischemic heart disease patients, Environ. Res. 116 (2012) 44–51. [274] A. Iannuzzi, M.C. Verga, M. Renis, A. Schiavo, V. Salvatore, C. Santoriello, D. Pazzano, M.R. Licenziati, M. Polverino, Air pollution and carotid arterial stiffness in children, Cardiol. Young 20 (2010) 186–190. [275] G.S. Leonardi, D. Houthuijs, P.A. Steerenberg, T. Fletcher, B. Armstrong, T. Antova, I. Lochman, A. Lochmanova, P. Rudnai, E. Erdei, J. Musial, B. Jazwiec-Kanyion, E.M. Niciu, S. Durbaca, E. Fabianova, K. Koppova, E. Lebret, B. Brunekreef, H. van Loveren, Immune biomarkers in relation to exposure to particulate matter: a cross-sectional survey in 17 cities of Central Europe, Inhal. Toxicol. 12 (Suppl. 4) (2000) 1–14. [276] J. Pekkanen, E.J. Brunner, H.R. Anderson, P. Tiittanen, R.W. Atkinson, Daily concentrations of air pollution and plasma fibrinogen in London, Occup. Environ. Med. 57 (2000) 818–822. [277] A. Peters, M. Frohlich, A. Doring, T. Immervoll, H.E. Wichmann, W.L. Hutchinson, M.B. Pepys, W. Koenig, Particulate air pollution is associated with an acute phase response in men; results from the MONICA-Augsburg Study, Eur. Heart J. 22 (2001) 1198–1204. [278] R. Ruckerl, S. Greven, P. Ljungman, P. Aalto, C. Antoniades, T. Bellander, N. Berglind, C. Chrysohoou, F. Forastiere, B. Jacquemin, S. von Klot, W. Koenig, H. Kuchenhoff, T. Lanki, J. Pekkanen, C.A. Perucci, A. Schneider, J. Sunyer, A. Peters, Air pollution and inflammation (interleukin-6, C-reactive protein, fibrinogen) in myocardial infarction survivors, Environ. Health Perspect. 115 (2007) 1072–1080.

[279] R. Ruckerl, A. Ibald-Mulli, W. Koenig, A. Schneider, G. Woelke, J. Cyrys, J. Heinrich, V. Marder, M. Frampton, H.E. Wichmann, A. Peters, Air pollution and markers of inflammation and coagulation in patients with coronary heart disease, Am. J. Respir. Crit. Care Med. 173 (2006) 432–441. [280] G. Rudez, N.A. Janssen, E. Kilinc, F.W. Leebeek, M.E. Gerlofs-Nijland, H.M. Spronk, C.H. ten, F.R. Cassee, M.P. de Maat, Effects of ambient air pollution on hemostasis and inflammation, Environ. Health Perspect. 117 (2009) 995–1001. [281] A. Seaton, A. Soutar, V. Crawford, R. Elton, S. McNerlan, J. Cherrie, M. Watt, R. Agius, R. Stout, Particulate air pollution and the blood, Thorax 54 (1999) 1027–1032. [282] M. Sørensen, B. Daneshvar, M. Hansen, L.O. Dragsted, O. Hertel, L. Knudsen, S. Loft, Personal PM2.5 exposure and markers of oxidative stress in blood, Environ. Health Perspect. 111 (2003) 161–166. [283] M. Strak, G. Hoek, K.J. Godri, I. Gosens, I.S. Mudway, R. van Oerle, H.M. Spronk, F.R. Cassee, E. Lebret, F.J. Kelly, R.M. Harrison, B. Brunekreef, M. Steenhof, N.A. Janssen, Composition of PM affects acute vascular inflammatory and coagulative markers – The RAPTES Project, PLoS ONE 8 (2013) e58944. [284] D.H. Tsai, N. Amyai, P. Marques-Vidal, J.L. Wang, M. Riediker, V. Mooser, F. Paccaud, G. Waeber, P. Vollenweider, M. Bochud, Effects of particulate matter on inflammatory markers in the general adult population, Part. Fibre Toxicol. 9 (2012) 24. [285] E.H. van den Hooven, Y. de Kluizenaar, F.H. Pierik, A. Hofman, S.W. van Ratingen, P.Y. Zandveld, J. Lindemans, H. Russcher, E.A. Steegers, H.M. Miedema, V.W. Jaddoe, Chronic air pollution exposure during pregnancy and maternal and fetal C-reactive protein levels: the Generation R Study, Environ. Health Perspect. 120 (2012) 746–751. [286] A. Vujovic, J. Kotur-Stevuljevic, D. Kornic, S. Spasic, V. Spasojevic-Kalimanovska, N. Bogavac-Stanojevic, A. Stefanovic, M. Deanovic, S. Babka, B. Aleksic, Z. JelicIvanovic, Oxidative stress and anti-oxidative defense in schoolchildren residing in a petrochemical industry environment, Indian Pediatr. 47 (2010) 233–239. [287] W. Yue, A. Schneider, M. Stolzel, R. Ruckerl, J. Cyrys, X. Pan, W. Zareba, W. Koenig, H.E. Wichmann, A. Peters, Ambient source-specific particles are associated with prolonged repolarization and increased levels of inflammation in male coronary artery disease patients, Mutat. Res. 621 (2007) 50–60. [288] M. Zuurbier, G. Hoek, M. Oldenwening, K. Meliefste, E. Krop, P. van den Hazel, B. Brunekreef, In-traffic air pollution exposure and CC16, blood coagulation, and inflammation markers in healthy adults, Environ. Health Perspect. 119 (2011) 1384–1389. [289] R.W. Allen, C. Carlsten, B. Karlen, S. Leckie, S.F. van Eeden, S. Vedal, I. Wong, M. Brauer, An air filter intervention study of endothelial function among healthy adults in a woodsmoke-impacted community, Am. J. Respir. Crit. Care Med. 183 (2011) 1222–1230. [290] R.D. Brook, B. Urch, J.T. Dvonch, R.L. Bard, M. Speck, G. Keeler, M. Morishita, F.J. Marsik, A.S. Kamal, N. Kaciroti, J. Harkema, P. Corey, F. Silverman, D.R. Gold, G. Wellenius, M.A. Mittleman, S. Rajagopalan, J.R. Brook, Insights into the mechanisms and mediators of the effects of air pollution exposure on blood pressure and vascular function in healthy humans, Hypertension 54 (2009) 659–667. [291] L. Calderon-Garciduenas, R. Villarreal-Calderon, G. Valencia-Salazar, C. Henriquez-Roldan, P. Gutierrez-Castrellon, R. Torres-Jardon, N. Osnaya-Brizuela, L. Romero, R. Torres-Jardon, A. Solt, W. Reed, Systemic inflammation, endothelial dysfunction, and activation in clinically healthy children exposed to air pollutants, Inhal. Toxicol. 20 (2008) 499–506. [292] R.J. Delfino, N. Staimer, T. Tjoa, A. Polidori, M. Arhami, D.L. Gillen, M.T. Kleinman, N.D. Vaziri, J. Longhurst, F. Zaldivar, C. Sioutas, Circulating biomarkers of inflammation, antioxidant activity, and platelet activation are associated with primary combustion aerosols in subjects with coronary artery disease, Environ. Health Perspect. 116 (2008) 898–906. [293] R.J. Delfino, N. Staimer, T. Tjoa, D.L. Gillen, A. Polidori, M. Arhami, M.T. Kleinman, N.D. Vaziri, J. Longhurst, C. Sioutas, Air pollution exposures and circulating biomarkers of effect in a susceptible population: clues to potential causal component mixtures and mechanisms, Environ. Health Perspect. 117 (2009) 1232–1238. [294] R.J. Delfino, N. Staimer, T. Tjoa, M. Arhami, A. Polidori, D.L. Gillen, M.T. Kleinman, J.J. Schauer, C. Sioutas, Association of biomarkers of systemic inflammation with organic components and source tracers in quasi-ultrafine particles, Environ. Health Perspect. 118 (2010) 756–762. [295] A.V. Diez Roux, A.H. Auchincloss, B. Astor, R.G. Barr, M. Cushman, T. Dvonch, D.R. Jacobs Jr., J. Kaufman, X. Lin, P. Samson, Recent exposure to particulate matter and C-reactive protein concentration in the multi-ethnic study of atherosclerosis, Am. J. Epidemiol. 164 (2006) 437–448. [296] S.D. Dubowsky, H. Suh, J. Schwartz, B.A. Coull, D.R. Gold, Diabetes, obesity, and hypertension may enhance associations between air pollution and markers of systemic inflammation, Environ. Health Perspect. 114 (2006) 992–998. [297] A.J. Ghio, A. Hall, M.A. Bassett, W.E. Cascio, R.B. Devlin, Exposure to concentrated ambient air particles alters hematologic indices in humans, Inhal. Toxicol. 15 (2003) 1465–1478. [298] D. Liao, G. Heiss, V.M. Chinchilli, Y. Duan, A.R. Folsom, H.M. Lin, V. Salomaa, Association of criteria pollutants with plasma hemostatic/inflammatory markers: a population-based study, J. Expo. Anal. Environ. Epidemiol. 15 (2005) 319–328. [299] L. Liu, T.D. Ruddy, M. Dalipaj, M. Szyszkowicz, H. You, R. Poon, A. Wheeler, R. Dales, Influence of personal exposure to particulate air pollution on cardiovascular physiology and biomarkers of inflammation and oxidative stress in subjects with diabetes, J. Occup. Environ. Med. 49 (2007) 258–265. [300] L. Liu, T. Ruddy, M. Dalipaj, R. Poon, M. Szyszkowicz, H. You, R.E. Dales, A.J. Wheeler, Effects of indoor, outdoor, and personal exposure to particulate air

Please cite this article in press as: P. Møller, et al., Oxidative stress and inflammation generated DNA damage by exposure to air pollution particles, Mutat. Res.: Rev. Mutat. Res. (2014), http://dx.doi.org/10.1016/j.mrrev.2014.09.001

G Model

MUTREV-8090; No. of Pages 34 P. Møller et al. / Mutation Research xxx (2014) xxx–xxx

[301]

[302]

[303]

[304]

[305] [306]

[307]

[308]

[309]

[310]

[311]

[312]

[313]

[314]

[315]

[316]

[317]

[318]

[319]

[320]

[321]

[322]

[323]

[324]

[325]

pollution on cardiovascular physiology and systemic mediators in seniors, J. Occup. Environ. Med. 51 (2009) 1088–1098. M.S. O’Neill, A. Veves, J.A. Sarnat, A. Zanobetti, D.R. Gold, P.A. Economides, E.S. Horton, J. Schwartz, Air pollution and inflammation in type 2 diabetes: a mechanism for susceptibility, Occup. Environ. Med. 64 (2007) 373–379. T.E. O’Toole, J. Hellmann, L. Wheat, P. Haberzettl, J. Lee, D.J. Conklin, A. Bhatnagar, C.A. Pope III, Episodic exposure to fine particulate air pollution decreases circulating levels of endothelial progenitor cells, Circ. Res. 107 (2010) 200–203. C.A. Pope III, M.L. Hansen, R.W. Long, K.R. Nielsen, N.L. Eatough, W.E. Wilson, D.J. Eatough, Ambient particulate air pollution, heart rate variability, and blood markers of inflammation in a panel of elderly subjects, Environ. Health Perspect. 112 (2004) 339–345. M. Riediker, R.B. Devlin, T.R. Griggs, M.C. Herbst, P.A. Bromberg, R.W. Williams, W.E. Cascio, Cardiovascular effects in patrol officers are associated with fine particulate matter from brake wear and engine emissions, Part. Fibre Toxicol. 1 (2004) 2. J. Schwartz, Air pollution and blood markers of cardiovascular risk, Environ. Health Perspect. 109 (Suppl. 3) (2001) 405–409. S. Wittkopp, N. Staimer, T. Tjoa, D. Gillen, N. Daher, M. Shafer, J.J. Schauer, C. Sioutas, R.J. Delfino, Mitochondrial genetic background modifies the relationship between traffic-related air pollution exposure and systemic biomarkers of inflammation, PLoS ONE 8 (2013) e64444. K. Yeatts, E. Svendsen, J. Creason, N. Alexis, M. Herbst, J. Scott, L. Kupper, R. Williams, L. Neas, W. Cascio, R.B. Devlin, D.B. Peden, Coarse particulate matter (PM2.5–10) affects heart rate variability, blood lipids, and circulating eosinophils in adults with asthma, Environ. Health Perspect. 115 (2007) 709–714. A. Zeka, J.R. Sullivan, P.S. Vokonas, D. Sparrow, J. Schwartz, Inflammatory markers and particulate air pollution: characterizing the pathway to disease, Int. J. Epidemiol. 35 (2006) 1347–1354. K.J. Chuang, C.C. Chan, T.C. Su, C.T. Lee, C.S. Tang, The effect of urban air pollution on inflammation, oxidative stress, coagulation, and autonomic dysfunction in young adults, Am. J. Respir. Crit. Care Med. 176 (2007) 370–376. R. Kelishadi, N. Mirghaffari, P. Poursafa, S.S. Gidding, Lifestyle and environmental factors associated with inflammation, oxidative stress and insulin resistance in children, Atherosclerosis 203 (2009) 311–319. M.A. Khafaie, S.S. Salvi, A. Ojha, B. Khafaie, S.S. Gore, C.S. Yajnik, Systemic inflammation (C-reactive protein) in type 2 diabetic patients is associated with ambient air pollution in Pune City, India, Diabetes Care 36 (2013) 625–630. C.H. Lai, S.H. Liou, H.C. Lin, T.S. Shih, P.J. Tsai, J.S. Chen, T. Yang, J.J. Jaakkola, P.T. Strickland, Exposure to traffic exhausts and oxidative DNA damage, Occup. Environ. Med. 62 (2005) 216–222. D.Q. Rich, H.M. Kipen, W. Huang, G. Wang, Y. Wang, P. Zhu, P. Ohman-Strickland, M. Hu, C. Philipp, S.R. Diehl, S.E. Lu, J. Tong, J. Gong, D. Thomas, T. Zhu, J.J. Zhang, Association between changes in air pollution levels during the Beijing Olympics and biomarkers of inflammation and thrombosis in healthy young adults, JAMA 307 (2012) 2068–2078. A. Steinvil, L. Kordova-Biezuner, I. Shapira, S. Berliner, O. Rogowski, Short-term exposure to air pollution and inflammation-sensitive biomarkers, Environ. Res. 106 (2008) 51–61. W.C. Tan, D. Qiu, B.L. Liam, T.P. Ng, S.H. Lee, S.F. van Eeden, Y. D’Yachkova, J.C. Hogg, The human bone marrow response to acute air pollution caused by forest fires, Am. J. Respir. Crit. Care Med. 161 (2000) 1213–1217. S.W. Wu, F.R. Deng, H.Y. Wei, J. Huang, H.Y. Wang, M. Shima, X. Wang, Y. Qin, C.J. Zheng, Y. Hao, X.B. Guo, Chemical constituents of ambient particulate air pollution and biomarkers of inflammation, coagulation and homocysteine in healthy adults: a prospective panel study, Part. Fibre Toxicol. 9 (49) (2012). Z. Yuan, Y. Chen, Y. Zhang, H. Liu, Q. Liu, J. Zhao, M. Hu, W. Huang, G. Wang, T. Zhu, J. Zhang, P. Zhu, Changes of plasma vWF level in response to the improvement of air quality: an observation of 114 healthy young adults, Ann. Hematol. 92 (2013) 543–548. R.J. Delfino, C. Sioutas, S. Malik, Potential role of ultrafine particles in associations between airborne particle mass and cardiovascular health, Environ. Health Perspect. 113 (2005) 934–946. C.Y. Chuang, C.C. Lee, Y.K. Chang, F.C. Sung, Oxidative DNA damage estimated by urinary 8-hydroxydeoxyguanosine: influence of taxi driving, smoking and areca chewing, Chemosphere 52 (2003) 1163–1171. P. Møller, N.R. Jacobsen, J.K. Folkmann, P.H. Danielsen, L. Mikkelsen, J.G. Hemmingsen, L.K. Vesterdal, L. Forchhammer, H. Wallin, S. Loft, Role of oxidative damage in toxicity of particulates, Free Radic. Res. 44 (2010) 1–46. M.S. Cooke, S. Loft, R. Olinski, M.D. Evans, K. Bialkowski, J.R. Wagner, P.C. Dedon, P. Møller, M.M. Greenberg, J. Cadet. Recommendations for standardized description of and nomenclature concerning oxidatively damaged nucleobases in DNA, Chem. Res. Toxicol. 23 (2010) 705–707. J. Cadet, S. Loft, R. Olinski, M.D. Evans, K. Bialkowski, W.J. Richard, P.C. Dedon, P. Møller, M.M. Greenberg, M.S. Cooke, Biologically relevant oxidants and terminology, classification and nomenclature of oxidatively generated damage to nucleobases and 2-deoxyribose in nucleic acids, Free Radic. Res. 46 (2012) 367–381. P. Hainaut, G.P. Pfeifer, Patterns of p53 G–>T transversions in lung cancers reflect the primary mutagenic signature of DNA-damage by tobacco smoke, Carcinogenesis 22 (2001) 367–374. S. Loft, P. Danielsen, M. Løhr, K. Jantzen, J.G. Hemmingsen, M. Roursgaard, D.G. Karotki, P. Møller, Urinary excretion of 8-oxo-7,8-dihydroguanine as biomarker of oxidative damage to DNA, Arch. Biochem. Biophys. 518 (2012) 142–150. S. Loft, P.H. Danielsen, L. Mikkelsen, L. Risom, L. Forchhammer, P. Møller, Biomarkers of oxidative damage to DNA and repair, Biochem. Soc. Trans. 36 (2008) 1071–1076.

31

[326] S. Loft, P. Svoboda, K. Kawai, H. Kasai, M. Sørensen, A. Tjonneland, U. Vogel, P. Møller, K. Overvad, O. Raaschou-Nielsen, Association between 8-oxo-7,8-dihydroguanine excretion and risk of lung cancer in a prospective study, Free Radic. Biol. Med. 52 (2012) 167–172. [327] S. Loft, P. Svoboda, H. Kasai, A. Tjonneland, U. Vogel, P. Møller, K. Overvad, O. Raaschou-Nielsen, Prospective study of 8-oxo-7,8-dihydro-20 -deoxyguanosine excretion and the risk of lung cancer, Carcinogenesis 27 (2006) 1245–1250. [328] S. Loft, A. Olsen, P. Møller, H.E. Poulsen, A. Tjonneland, Association between 8oxo-7,8-dihydro-20 -deoxyguanosine excretion and risk of postmenopausal breast cancer: nested case-control study, Cancer Epidemiol. Biomarkers Prev. 22 (2013) 1289–1296. [329] H.L. Karlsson, The comet assay in nanotoxicology research, Anal. Bioanal. Chem. 398 (2010) 651–666. [330] R. Landsiedel, M.D. Kapp, M. Schulz, K. Wiench, F. Oesch, Genotoxicity investigations on nanomaterials: methods, preparation and characterization of test material, potential artifacts and limitations – many questions, some answers, Mutat. Res. 681 (2009) 241–258. [331] P. Møller, L.E. Knudsen, S. Loft, H. Wallin, The comet assay as a rapid test in biomonitoring occupational exposure to DNA-damaging agents and effect of confounding factors, Cancer Epidemiol. Biomarkers Prev. 9 (2000) 1005–1015. [332] A. Collins, G. Koppen, V. Valdiglesias, M. Dusinska, M. Kruszewski, P. Møller, E. Rojas, A. Dhawan, I. Benzie, E. Coskun, M. Moretti, G. Speit, S. Bonassi, The comet assay as a tool for human biomonitoring studies: The ComNet Project, Mutat. Res. 759 (2014) 27–39. [333] K. Jantzen, M. Roursgaard, C.D. Madsen, S. Loft, L.J. Rasmussen, P. Møller, Oxidative damage to DNA by diesel exhaust particle exposure in co-cultures f human lung epithelial cells and macrophages, Mutagenesis 27 (2012) 693–701. [334] M.D. Evans, M. Dizdaroglu, M.S. Cooke, Oxidative DNA damage and disease: induction, repair and significance, Mutat. Res. 567 (2004) 1–61. [335] ESCODD (European Standards Committee on Oxidative DNA Damage), Comparative analysis of baseline 8-oxo-7,8-dihydroguanine in mammalian cell DNA, by different methods in different laboratories: an approach to consensus, Carcinogenesis 23 (2003) 2129–2133. [336] ESCODD (European Standards Committee on Oxidative DNA Damage), Measurement of DNA oxidation in human cells by chromatographic and enzymic methods, Free Radic. Biol. Med. 34 (2003) 1089–1099. [337] P. Møller, M. Løhr, J.K. Folkmann, L. Mikkelsen, S. Loft, Aging and oxidatively damaged nuclear DNA in animal organs, Free Radic. Biol. Med. 48 (2010) 1275–1285. [338] P. Møller, L. Moller, R.W. Godschalk, G.D. Jones, Assessment and reduction of comet assay variation in relation to DNA damage: studies from the European Comet Assay Validation Group, Mutagenesis 25 (2010) 109–111. [339] L. Forchhammer, C. Johansson, S. Loft, L. Mo¨ller, R.W. Godschalk, S.A. Langie, G.D. Jones, R.W. Kwok, A.R. Collins, A. Azqueta, D.H. Phillips, O. Sozeri, M. Stepnik, J. Palus, U. Vogel, H. Wallin, M.N. Routledge, C. Handforth, A. Allione, G. Matullo, J.P. Teixeira, S. Costa, P. Riso, M. Porrini, P. Møller, Variation in the measurement of DNA damage by comet assay measured by the ECVAG inter-laboratory validation trial, Mutagenesis 25 (2010) 113–123. [340] C. Johansson, P. Møller, L. Forchhammer, S. Loft, R.W. Godschalk, S.A. Langie, S. Lumeij, G.D. Jones, R.W. Kwok, A. Azqueta, D.H. Phillips, O. Sozeri, M.N. Routledge, A.J. Charlton, P. Riso, M. Porrini, A. Allione, G. Matullo, J. Palus, M. Stepnik, A.R. Collins, L. Mo¨ller, An ECVAG trial on assessment of oxidative damage to DNA measured by the comet assay, Mutagenesis 25 (2010) 125–132. [341] L. Forchhammer, C. Ersson, S. Loft, L. Mo¨ller, R.W. Godschalk, F.J. van Schooten, G.D. Jones, J.A. Higgins, M. Cooke, V. Mistry, M. Karbaschi, A.R. Collins, A. Azqueta, D.H. Phillips, O. Sozeri, M.N. Routledge, K. Nelson-Smith, P. Riso, M. Porrini, G. Matullo, A. Allione, M. Steepnik, M. Komorowska, J.P. Teixeira, S. Costa, L.A. Corcuera, A.L. de Cerain, B. Laffon, V. Valdiglesias, P. Møller, Inter-laboratory variation in DNA damage using a standard comet assay protocol, Mutagenesis 27 (2012) 665–672. [342] C. Ersson, P. Møller, L. Forchhammer, S. Loft, A. Azqueta, R.W.L. Godschalk, F.J. van Schooten, G.D.D. Jones, J.A. Higgins, M.S. Cooke, V. Mistry, M. Karbaschi, D.H. Phillips, O. Sozeri, M.N. Routledge, K. Nelson-Smith, P. Riso, M. Porrini, G. Matullo, A. Allione, M. Stepnik, M. Ferlinska, J.P. Teixeira, S. Costa, L.A. Corcuera, A.L. de Cerain, B. Laffon, V. Valdiglesias, A.R. Collins, L. Moller, An ECVAG interlaboratory validation study of the comet assay: inter- and intra-laboratory variation of DNA strand breaks and FPG-sensitive sites in human mononuclear cells, Mutagenesis 28 (2013) 279–286. [343] R.W. Godschalk, C. Ersson, M. Stepnik, M. Ferlilska, J. Palus, J.P. Teixeira, S. Costa, G.D. Jones, J.A. Higgins, J. Kain, L. Moller, L. Forchhammer, S. Loft, Y. Lorenzo, A.R. Collins, F.J. van Schooten, B. Laffon, V. Valdiglesias, M. Cooke, V. Mistry, M. Karbaschi, D.H. Phillips, O. Sozeri, M.N. Routledge, K. Nelson-Smith, P. Riso, M. Porrini, C.A. Lopez de, A. Azqueta, G. Matullo, A. Allione, P. Moller, Variation of DNA damage levels in peripheral blood mononuclear cells isolated in different laboratories, Mutagenesis 29 (2014) 241–249. [344] P. Møller, M.S. Cooke, A. Collins, R. Olinski, R. Rozalski, S. Loft, Harmonising measurements of 8-oxo-7,8-dihydro-20 -deoxyguanosine in cellular DNA and urine, Free Radic. Res. 46 (2012) 541–553. [345] P. Rossner Jr., R.J. Sram, Immunochemical detection of oxidatively damaged DNA, Free Radic. Res. 46 (2012) 492–522. [346] M.S. Cooke, L. Barregard, V. Mistry, N. Potdar, R. Rozalski, D. Gackowski, A. Siomek, M. Foksinski, P. Svoboda, H. Kasai, J.C. Konje, G. Sallsten, M.D. Evans, R. Olinski, Interlaboratory comparison of methodologies for the measurement of urinary 8-oxo-7,8-dihydro-20 -deoxyguanosine, Biomarkers 14 (2009) 103–110. [347] J. Cadet, H. Poulsen, Measurement of oxidatively generated base damage in cellular DNA and urine, Free Radic. Biol. Med. 48 (2010) 1457–1459.

Please cite this article in press as: P. Møller, et al., Oxidative stress and inflammation generated DNA damage by exposure to air pollution particles, Mutat. Res.: Rev. Mutat. Res. (2014), http://dx.doi.org/10.1016/j.mrrev.2014.09.001

G Model

MUTREV-8090; No. of Pages 34 32

P. Møller et al. / Mutation Research xxx (2014) xxx–xxx

[348] J. Cadet, T. Douki, J.L. Ravanat, Measurement of oxidatively generated base damage in cellular DNA, Mutat. Res. 711 (2011) 12. [349] M.D. Evans, R. Olinski, S. Loft, M.S. Cooke, Toward consensus in the analysis of urinary 8-oxo-7,8-dihydro-20 -deoxyguanosine as a noninvasive biomarker of oxidative stress, FASEB J. 24 (2010) 1249–1260. [350] L. Barregard, P. Møller, T. Henriksen, V. Mistry, G. Koppen, P. Rossner, R. Sram, A. Weimann, H. Poulsen, R. Nataf, R. Andreolli, P. Manini, T.H. Marczylo, P. Lam, M.D. Evans, H. Kasai, K. Kawai, Y.S. Li, K. Sakai, R. Singh, F. Teichert, P. Farmer, R. Rozalski, D. Gackowski, A. Siomek, G. Saez, C. Cerda, K. Broberg, C. Lund, M. Hossain, S. Haghdoost, C.W. Hu, M.R. Chao, K.Y. Wu, N. Senduran, H. Orhan, R.J. Smith, R. Santella, Y. Su, C. Cortez, S. Yeh, R. Olinski, S. Loft, M.S. Cooke, Human and methodological sources of variability in the measurement of urinary 8-oxo7,8-dihydro-20 -deoxyguanosine, Antioxid. Redox Signal. 18 (2013) 2377–2391. [351] P.S. Gilmour, D.M. Brown, T.G. Lindsay, P.H. Beswick, W. MacNee, K. Donaldson, Adverse health effects of PM10 particles: involvement of iron in generation of hydroxyl radical, Occup. Environ. Med. 53 (1996) 817–822. [352] L.L. Greenwell, T. Moreno, T.P. Jones, R.J. Richards, Particle-induced oxidative damage is ameliorated by pulmonary antioxidants, Free Radic. Biol. Med. 32 (2002) 898–905. [353] K. Healey, J.J. Lingard, A.S. Tomlin, A. Hughes, K.L. White, C.P. Wild, M.N. Routledge, Genotoxicity of size-fractionated samples of urban particulate matter, Environ. Mol. Mutagen. 45 (2005) 380–387. [354] L. Koshy, T. Jones, K. BeruBe, Characterization and bioreactivity of respirable airborne particles from a municipal landfill, Biomarkers 14 (2009) 49–53. [355] J.J.N. Lingard, A.S. Tomlin, A.G. Clarke, K. Healey, A.W.M. Hay, C.P. Wild, M.N. Routledge, A study of trace metal concentration of urban airborne particulate matter and its role in free radical activity as measured by plasmid strand break assay, Atmos. Environ. 39 (2005) 2377–2384. [356] T. Moreno, L. Merolla, W. Gibbons, L. Greenwell, T. Jones, R. Richards, Variations in the source, metal content and bioreactivity of technogenic aerosols: a case study from Port Talbot, Wales, UK, Sci. Total Environ. 333 (2004) 59–73. [357] C. Reche, T. Moreno, F. Amato, M. Viana, B.L. van Drooge, H.C. Chuang, K. BeruBe, T. Jones, A. Alastuey, X. Querol, A multidisciplinary approach to characterise exposure risk and toxicological effects of PM10 and PM2.5 samples in urban environments, Ecotoxicol. Environ. Saf. 78 (2012) 327–335. [358] A. Whittaker, K. BeruBe, T. Jones, R. Maynard, R. Richards, Killer smog of London, 50 years on: particle properties and oxidative capacity, Sci. Total Environ. 334 (2004) 435–445. [359] L. Senlin, Z. Yao, X. Chen, M. Wu, G. Sheng, F. Jiamo, P. Daly, The relationship between physicochemical characterization and the potential toxicity of fine particulates (PM2.5) in Shanghai atmosphere, Atmos. Environ. 42 (2008) 7205–7214. [360] L. Shao, Z. Shi, T.P. Jones, J. Li, A.G. Whittaker, K.A. Berube, Bioreactivity of particulate matter in Beijing air: results from plasmid DNA assay, Sci. Total Environ. 367 (2006) 261–272. [361] K.R. Smith, A.E. Aust, Mobilization of iron from urban particulates leads to generation of reactive oxygen species in vitro and induction of ferritin synthesis in human lung epithelial cells, Chem. Res. Toxicol. 10 (1997) 828–834. [362] O.R. Abou Chakra, M. Joyeux, E. Nerriere, M.P. Strub, D. Zmirou-Navier, Genotoxicity of organic extracts of urban airborne particulate matter: an assessment within a personal exposure study, Chemosphere 66 (2007) 1375–1381. [363] S. Bonetta, V. Gianotti, S. Bonetta, F. Gosetti, M. Oddone, M.C. Gennaro, E. Carraro, DNA damage in A549 cells exposed to different extracts of PM(2.5) from industrial, urban and highway sites, Chemosphere 77 (2009) 1030–1034. [364] E. Brits, G. Schoeters, L. Verschaeve, Genotoxicity of PM(10) and extracted organics collected in an industrial, urban and rural area in Flanders, Belgium, Environ. Res. 96 (2004) 109–118. [365] A. Buschini, F. Cassoni, E. Anceschi, L. Pasini, P. Poli, C. Rossi, Urban airborne particulate: genotoxicity evaluation of different size fractions by mutagenesis tests on microorganisms and comet assay, Chemosphere 44 (2001) 1723–1736. [366] P.H. Danielsen, S. Loft, P. Møller, DNA damage and cytotoxicity in type II lung epithelial (A549) cell cultures after exposure to diesel exhaust and urban street particles, Part. Fibre Toxicol. 5 (2008) 6. [367] P.H. Danielsen, S. Loft, A. Kocbach, P.E. Schwarze, P. Møller, Oxidative damage to DNA and repair induced by Norwegian wood smoke particles in human A549 and THP-1 cell lines, Mutat. Res. 674 (2009) 116–122. [368] R. Fabiani, A. De Bartolomeo, P. Rosignoli, G. Morozzi, A. Cecinato, C. Balducci, Chemical and toxicological characterization of airborne total suspended particulate (TSP) and PM10 organic extracts, Polycyclic Aromat. Compd. 28 (2008) 486–499. [369] A. Gabelova, Z. Valovicova, E. Horvathova, D. Slamenova, B. Binkova, R.J. Sram, P.B. Farmer, Genotoxicity of environmental air pollution in three European cities: Prague, Kosice and Sofia, Mutat. Res. 563 (2004) 49–59. [370] A. Gabelova, Z. Valovicova, J. Labaj, G. Bacova, B. Binkova, P.B. Farmer, Assessment of oxidative DNA damage formation by organic complex mixtures from airborne particles PM(10), Mutat. Res. 620 (2007) 35–144. [371] M. Gualtieri, J. Ovrevik, S. Mollerup, N. Asare, E. Longhin, H.J. Dahlman, M. Camatini, J.A. Holme, Airborne urban particles (Milan winter-PM2.5) cause mitotic arrest and cell death: effects on DNA, mitochondria, AhR binding and spindle organization, Mutat. Res. 713 (2011) 18–31. [372] H.L. Karlsson, L. Nilsson, L. Moller, Subway particles are more genotoxic than street particles and induce oxidative stress in cultured human lung cells, Chem. Res. Toxicol. 18 (2005) 19–23. [373] M. Lazarova, D. Slamenova, Genotoxic effects of a complex mixture adsorbed onto ambient air particles on human cells in vitro; the effects of vitamins E and C, Mutat. Res. 557 (2004) 167–175.

[374] A. Tarantini, A. Maitre, E. Lefebvre, M. Marques, C. Marie, J.L. Ravanat, T. Douki, Relative contribution of DNA strand breaks and DNA adducts to the genotoxicity of benzo[a]pyrene as a pure compound and in complex mixtures, Mutat. Res. 671 (2009) 67–75. [375] D. Upadhyay, V. Panduri, A. Ghio, D.W. Kamp, Particulate matter induces alveolar epithelial cell DNA damage and apoptosis: role of free radicals and the mitochondria, Am. J. Respir. Cell Mol. Biol. 29 (2003) 180–187. [376] S.M. Elassouli, M.H. Alqahtani, W. Milaat, Genotoxicity of air borne particulates assessed by comet and the Salmonella mutagenicity test in Jeddah, Saudi Arabia, Int. J. Environ. Res. Public Health 4 (2007) 216–233. [377] T. Jayasekher, Aerosols near by a coal fired thermal power plant: chemical composition and toxic evaluation, Chemosphere 75 (2009) 1525–1530. [378] Z. Meng, Q. Zhang, Damage effects of dust storm PM2.5 on DNA in alveolar macrophages and lung cells of rats, Food Chem. Toxicol. 45 (2007) 1368–1374. [379] S.M. Oh, H.R. Kim, Y.J. Park, S.Y. Lee, K.H. Chung, Organic extracts of urban air pollution particulate matter (PM2.5)-induced genotoxicity and oxidative stress in human lung bronchial epithelial cells (BEAS-2B cells), Mutat. Res. 723 (2011) 142–151. [380] D.Q. Xu, W.L. Zhang, Monitoring of pollution of air fine particles (PM2.5) and study on their genetic toxicity, Biomed. Environ. Sci. 17 (2004) 452–458. [381] W.L. Wendy Hsiao, Z.-Y. Mo, M. Fang, X.M. Shi, F. Wang, Cytotoxicity of PM2.5 and PM2.5–10 ambient air pollutants assessed by the MTT and the comet assays, Mutat. Res. 471 (2000) 45–55. [382] H. Xu, X. Wang, U. Poschl, S. Feng, D. Wu, L. Yang, S. Li, W. Song, G. Sheng, J. Fu, Genotoxicity of total and fractionated extractable organic matter in fine air particulate matter from urban Guangzhou: comparison between haze and nonhaze episodes, Environ. Toxicol. Chem. 27 (2008) 206–212. [383] M.E. Gutierrez-Castillo, D.A. Roubicek, M.E. Cebrian-Garcia, A. De Vizcaya-Ruiz, M. Sordo-Cedeno, P. Ostrosky-Wegman, Effect of chemical composition on the induction of DNA damage by urban airborne particulate matter, Environ. Mol. Mutagen. 47 (2006) 199–211. [384] H.A. Carreras, M.E. Calderon-Segura, S. Gomez-Arroyo, M.A. Murillo-Tovar, O. Amador-Munoz, Composition and mutagenicity of PAHs associated with urban airborne particles in Cordoba, Argentina, Environ. Pollut. 178 (2013) 403–410. [385] H.L. Karlsson, J. Nygren, L. Moller, Genotoxicity of airborne particulate matter: the role of cell-particle interaction and of substances with adduct-forming and oxidizing capacity, Mutat. Res. 565 (2004) 1–10. [386] A. Don Porto Carero, P.H.M. Hoet, L. Verschaeve, G. Schoeters, B. Nemery, Genotoxic effects of carbon black particles, diesel exhaust particles, and urban air particulates and their extracts on a human alveolar epithelial cell line (A549) and a human monocytic cell line (THP-1), Environ. Health Perspect. 37 (2001) 155–163. [387] R.M. Mroz, R.P. Schins, H. Li, L.A. Jimenez, E.M. Drost, A. Holownia, W. MacNee, K. Donaldson, Nanoparticle-driven DNA damage mimics irradiation-related carcinogenesis pathways, Eur. Respir. J. 31 (2008) 241–251. [388] Z.Q. Lin, Z.G. Xi, D.F. Yang, F.H. Chao, H.S. Zhang, W. Zhang, H.L. Liu, Z.M. Yang, R.B. Sun, Oxidative damage to lung tissue and peripheral blood in endotracheal PM2.5-treated rats, Biomed. Environ. Sci. 22 (2009) 223–228. [389] L.K. Vesterdal, K. Jantzen, M. Sheykhzade, M. Roursgaard, J.K. Folkmann, S. Loft, P. Møller, Pulmonary exposure to particles from diesel exhaust, urban dust or single-walled carbon nanotubes and oxidatively damaged DNA and vascular function in apoE(/) mice, Nanotoxicology 8 (2014) 61–71. [390] Y. Bagryantseva, B. Novotna, P. Rossner Jr., I. Chvatalova, A. Milcova, V. Svecova, Z. Lnenickova, I. Solansky, R.J. Sram, Oxidative damage to biological macromolecules in Prague bus drivers and garagemen: impact of air pollution and genetic polymorphisms, Toxicol. Lett. 199 (2010) 60–68. [391] B. Bincova, J. Lewtas, I. Miskova, P. Ro¨ssner, M. Cerna´, G. Mra´ckova, K. Peterkova´, J. Mumford, S. Meyer, R. Sram, Biomarker studies in Northern Bohemia, Environ. Health Perspect. 4 (Suppl. 3) (1996) 591–597. [392] E.V. Bra¨uner, L. Forchhammer, P. Møller, J. Simonsen, M. Glasius, P. Wa˚hlin, O. Raaschou-Nielsen, S. Loft, Exposure to ultrafine particles from ambient air and oxidative stress-induced DNA damage, Environ. Health Perspect. 115 (2007) 1177–1182. [393] A. Carere, C. Andreoli, R. Galati, P. Leopardi, F. Marcon, M.V. Rosati, S. Rossi, F. Tomei, A. Verdena, A. Zijno, R. Crebelli, Biomonitoring of exposure to urban pollutants: analysis of sister chromatid exchanges and DNA lesions in peripheral lymphocytes of traffic policemen, Mutat. Res. 518 (2002) 215–224. [394] A. Cebulska-Wasilewska, A. Wiechec, A. Panek, B. Binkova, R.J. Sram, P.B. Farmer, Influence of environmental exposure to PAHs on the susceptibility of lymphocytes to DNA-damage induction and on their repair capacity, Mutat. Res. 588 (2005) 73–81. [395] S. De Coster, G. Koppen, M. Bracke, C. Schroijen, H.E. Den, V. Nelen, E. Van de Mieroop, L. Bruckers, M. Bilau, W. Baeyens, G. Schoeters, N.A. van Larebeke, Pollutant effects on genotoxic parameters and tumor-associated protein levels in adults: a cross sectional study, Environ. Health 7 (2008) 26. [396] H.B. Ketelslegers, R.W. Gottschalk, G. Koppen, G. Schoeters, W.F. Baeyens, N.A. van Larebeke, J.H. van Delft, J.C. Kleinjans, Multiplex genotyping as a biomarker for susceptibility to carcinogenic exposure in the FLEHS biomonitoring study, Cancer Epidemiol. Biomarkers Prev. 17 (2008) 1902–1912. [397] L. Giovannelli, V. Pitozzi, S. Moretti, V. Boddi, P. Dolara, Seasonal variations of DNA damage in human lymphocytes: correlation with different environmental variables, Mutat. Res. 593 (2006) 143–152. [398] G. Koppen, G. Verheyen, A. Maes, U. Van Gorp, G. Schoeters, E.D. Hond, J. Staessen, T. Nawrot, H.A. Roels, R. Vlietinck, L. Verschaeve, A battery of DNA effect biomarkers to evaluate environmental exposure of Flemish adolescents, J. Appl. Toxicol. 27 (2007) 238–246.

Please cite this article in press as: P. Møller, et al., Oxidative stress and inflammation generated DNA damage by exposure to air pollution particles, Mutat. Res.: Rev. Mutat. Res. (2014), http://dx.doi.org/10.1016/j.mrrev.2014.09.001

G Model

MUTREV-8090; No. of Pages 34 P. Møller et al. / Mutation Research xxx (2014) xxx–xxx [399] B. Novotna, J. Topinka, I. Solansky, I. Chvatalova, Z. Lnenickova, R.J. Sram, Impact of air pollution and genotype variability on DNA damage in Prague policemen, Toxicol. Lett. 172 (2007) 37–47. [400] S. Pacini, L. Giovannelli, M. Gulisano, B. Peruzzi, G. Polli, V. Boddi, M. Ruggiero, C. Bozzo, F. Stomeo, G. Fenu, S. Pezzatini, V. Pitozzi, P. Dolara, Association between atmospheric ozone levels and damage to human nasal mucosa in Florence, Italy, Environ. Mol. Mutagen. 42 (2003) 127–135. [401] S.M. Piperakis, E. Petrakou, S. Tsilimigaki, Effects of air pollution and smoking on DNA damage of human lymphocytes, Environ. Mol. Mutagen. 36 (2000) 243–249. [402] R.J. Sram, K. Podrazilova, J. Dejmek, G. Mrackova, T. Pilcik, Single cell gel electrophoresis assay: sensitivity of peripheral white blood cells in human population studies, Mutagenesis 13 (1998) 99–103. [403] J.A. Staessen, T. Nawrot, E.D. Hond, L. Thijs, R. Fagard, K. Hoppenbrouwers, G. Koppen, V. Nelen, G. Schoeters, D. Vanderschueren, E. Van Hecke, L. Verschaeve, R. Vlietinck, H.A. Roels, Renal function, cytogenetic measurements, and sexual development in adolescents in relation to environmental pollutants: a feasibility study of biomarkers, Lancet, 357 (2001) 1660–1669. [404] M. Sørensen, H. Skov, H. Autrup, O. Hertel, S. Loft, Urban benzene exposure and oxidative DNA damage: influence of genetic polymorphisms in metabolic genes, Sci. Total Environ. 309 (2003) 69–80. [405] M. Sørensen, R.P. Schins, O. Hertel, S. Loft, Transition metals in personal samples of PM2.5 and oxidative stress in human volunteers, Cancer Epidemiol. Biomarkers Prev. 14 (2005) 1340–1343. [406] P. Vinzents, P. Møller, M. Sørensen, L.E. Knudsen, O. Hertel, F. Palmgren, B. Schibye, S. Loft, Personal exposure to ultrafine particles and oxidative DNA damage, Environ. Health Perspect. 113 (2005) 1485–1490. [407] M. Arayasiri, C. Mahidol, P. Navasumrit, H. Autrup, M. Ruchirawat, Biomonitoring of benzene and 1, 3-butadiene exposure and early biological effects in traffic policemen, Sci. Total Environ. 408 (2010) 4855–4862. [408] N. Buthbumrung, C. Mahidol, P. Navasumrit, J. Promvijit, P. Hunsonti, H. Autrup, M. Ruchirawat, Oxidative DNA damage and influence of genetic polymorphisms among urban and rural schoolchildren exposed to benzene, Chem. Biol. Interact. 172 (2008) 185–194. [409] M. Ruchirawat, P. Navasumrit, D. Settachan, H. Autrup, Environmental impacts on children’s health in Southeast Asia: genotoxic compounds in urban air, Ann. N. Y. Acad. Sci. 1076 (2006) 678–690. [410] M. Ruchirawat, D. Settachan, P. Navasumrit, J. Tuntawiroon, H. Autrup, Assessment of potential cancer risk in children exposed to urban air pollution in Bangkok, Thailand, Toxicol. Lett. 168 (2007) 200–209. [411] J. Tuntawiroon, C. Mahidol, P. Navasumrit, H. Autrup, M. Ruchirawat, Increased health risk in Bangkok children exposed to polycyclic aromatic hydrocarbons from traffic-related sources, Carcinogenesis 28 (2007) 816–822. [412] P.H. Avogbe, L. Ayi-Fanou, H. Autrup, S. Loft, B. Fayomi, A. Sanni, P. Vinzents, P. Møller, Ultrafine particulate matter and high-level benzene urban air pollution in relation to oxidative DNA damage, Carcinogenesis 26 (2005) 613–620. [413] M.V. Coronas, T.S. Pereira, J.A. Rocha, A.T. Lemos, J.M. Fachel, D.M. Salvadori, V.M. Vargas, Genetic biomonitoring of an urban population exposed to mutagenic airborne pollutants, Environ. Int. 35 (2009) 1023–1029. [414] T.S. Pereira, L.S. Beltrami, J.A.V. Rocha, F.P. Broto, L.R. Comellas, D.M.F. Salvadori, V.M.F. Vargas, Toxicogenetic monitoring in urban cities exposed to different airborne contaminants, Ecotoxicol. Environ. Saf. 90 (2013) 174–182. [415] L. Calderon-Garciduen˜as, N. Osnaya-Brizuela, L. Ramirez-Martinez, A. VillarealCalderon, DNA strand breaks in human nasal respiratory epithelium are induced upon exposure to urban pollution, Environ. Health Perspect. 104 (1996) 160–168. [416] L. Calderon-Garciduen˜as, N. Osnaya, A. Rodriguez-Alcaraz, C.A. Villareal, DNA damage in nasal respiratory epithelium from children exposed to urban pollution, Environ. Mol. Mutagen. 30 (1997) 11–20. [417] L. Calderon-Garciduenas, L. Wen-Wang, Y.J. Zhang, A. Rodriguez-Alcaraz, N. Osnaya, A. Villarreal-Calderon, Santella.F R.M., 8-Hydroxy-20 -deoxyguanosine, a major mutagenic oxidative DNA lesion, and DNA strand breaks in nasal respiratory epithelium of children exposed to urban pollution, Environ. Health Perspect. 107 (1999) 469–474. [418] T.I. Fortoul, M. Valverde, M.C. Lopez, M.R. Avila-Costa, M.C. Avila-Casado, P. Mussali-Galante, A. Gonzalez-Villalva, E. Rojas, P. Ostrosky-Shejet, Genotoxic differences by sex in nasal epithelium and blood leukocytes in subjects residing in a highly polluted area, Environ. Res. 94 (2004) 243–248. [419] T.I. Fortoul, M. Rojas-Lemus, M.C. Avila-Casado, V. Rodriguez-Lara, L.F. Montano, A. Munoz-Comonfort, L.S. Lopez-Zepeda, Endogenous antioxidants and nasal human epithelium response to air pollutants: genotoxic and inmmuno-cytochemical evaluation, J. Appl. Toxicol. 30 (2010) 661–665. [420] E. Rojas, M. Valverde, M.C. Lopez, I. Naufal, I. Sanchez, P. Bizarro, I. Lopez, T.I. Fortoul, P. Ostrosky-Wegman, Evaluation of DNA damage in exfoliated tear duct epithelial cells from individuals exposed to air pollution assessed by single cell gel electrophoresis, Mutat. Res. 468 (2000) 11–17. [421] R.J. Sram, I. Benes, B. Binkova, J. Dejmek, D. Horstman, F. Kotesovec, D. Otto, S.D. Perreault, J. Rubes, S.G. Selevan, I. Skalik, R.K. Stevens, J. Lewtas, Teplice program – the impact of air pollution on human health, Environ. Health Perspect. 104 (Suppl. 4) (1996) 699–714. [422] R.J. Sram, B. Binkova, P. Rossner, J. Rubes, J. Topinka, J. Dejmek, Adverse reproductive outcomes from exposure to environmental mutagens, Mutat. Res. 428 (1999) 203–215. [423] T.M. de Kok, J.G. Hogervorst, J.J. Briede, M.H. van Herwijnen, L.M. Maas, E.J. Moonen, H.A. Driece, J.C. Kleinjans, Genotoxicity and physicochemical characteristics of traffic-related ambient particulate matter, Environ. Mol. Mutagen. 46 (2005) 71–80.

33

[424] A.K. Prahalad, J. Inmon, L.A. Dailey, M.C. Madden, A.J. Ghio, J.E. Gallagher, Air pollution particles mediated oxidative DNA base damage in a cell free system and in human airway epithelial cells in relation to particulate metal content and bioreactivity, Chem. Res. Toxicol. 14 (2001) 879–887. [425] P. Rossner Jr., J. Topinka, J. Hovorka, A. Milcova, J. Schmuczerova, J. Krouzek, R.J. Sram, An acellular assay to assess the genotoxicity of complex mixtures of organic pollutants bound on size segregated aerosol. Part II: oxidative damage to DNA, Toxicol. Lett. 198 (2010) 312–316. [426] J. Topinka, P. Rossner Jr., A. Milcova, J. Schmuczerova, V. Svecova, R.J. Sram, DNA adducts and oxidative DNA damage induced by organic extracts from PM2.5 in an acellular assay, Toxicol. Lett. 202 (2011) 186–192. [427] A.K. Prahalad, J. Inmon, A.J. Ghio, J.E. Gallagher, Enhancement of 20 -deoxyguanosine hydroxylation and DNA damage by coal and oil fly ash in relation to particulate metal content and availability, Chem. Res. Toxicol. 13 (2000) 1011–1019. [428] V. Andre, S. Billet, D. Pottier, G.J. Le, I. Pottier, G. Garcon, P. Shirali, F. Sichel, Mutagenicity and genotoxicity of PM2.5 issued from an urbano-industrialized area of Dunkerque (France), J. Appl. Toxicol. 31 (2011) 131–138. [429] K. Hanzalova, P. Rossner Jr., R.J. Sram, Oxidative damage induced by carcinogenic polycyclic aromatic hydrocarbons and organic extracts from urban air particulate matter, Mutat. Res. 696 (2010) 114–121. [430] Y.J. Hwang, Y.S. Jeung, M.H. Seo, J.Y. Yoon, D.Y. Kim, J.W. Park, J.H. Han, S.H. Jeong, Asian dust and titanium dioxide particles-induced inflammation and oxidative DNA damage in C57BL/6 mice, Inhal. Toxicol. 22 (2010) 1127–1133. [431] Y. Tsurudome, T. Hirano, H. Yamato, I. Tanaka, M. Sagai, H. Hirano, N. Nagata, H. Itoh, H. Kasai, Changes in levels of 8-hydroxyguanine in DNA, its repair and OGG1 mRNA in rat lungs after intratracheal administration of diesel exhaust particles, Carcinogenesis 20 (1999) 1573–1576. [432] L. Risom, M. Dybdahl, J. Bornholdt, U. Vogel, H. Wallin, P. Møller, S. Loft, Oxidative DNA damage and defence gene expression in the mouse lung after short-term exposure to diesel exhaust particles by inhalation, Carcinogenesis 24 (2003) 1847–1852. [433] P. Møller, B. Daneshvar, S. Loft, H. Wallin, H.E. Poulsen, H. Autrup, G. Ravn-Haren, L.O. Dragsted, Oxidative DNA damage in vitamin C supplemented guinea pigs after intratracheal instillation of diesel exhaust particles, Toxicol. Appl. Pharmacol. 189 (2003) 39–44. [434] L. Risom, M. Dybdahl, P. Møller, H. Wallin, T. Haun, U. Vogel, A. Klungland, S. Loft, Repeated inhalations of diesel exhaust particles and oxidatively damaged DNA in young oxoguanine DNA glycosylase (OGG1) deficient mice, Free Radic. Res. 41 (2007) 172–181. [435] D. Palli, F. Sera, L. Giovannelli, G. Masala, D. Grechi, B. Bendinelli, S. Caini, P. Dolara, C. Saieva, Environmental ozone exposure and oxidative DNA damage in adult residents of Florence, Italy, Environ. Pollut. 157 (2009) 1521–1525. [436] P. Rossner Jr., N. Tabashidze, M. Dostal, Z. Novakova, I. Chvatalova, M. Spatova, R.J. Sram, Genetic, biochemical, and environmental factors associated with pregnancy outcomes in newborns from the Czech Republic, Environ. Health Perspect. 119 (2011) 265–271. [437] R. Singh, B. Kaur, I. Kalina, T.A. Popov, T. Georgieva, S. Garte, B. Binkova, R.J. Sram, E. Taioli, P.B. Farmer, Effects of environmental air pollution on endogenous oxidative DNA damage in humans, Mutat. Res. 620 (2007) 71–82. [438] M. Peluso, P. Srivatanakul, A. Munnia, A. Jedpiyawongse, M. Ceppi, S. Sangrajrang, S. Piro, P. Boffetta, Malondialdehyde-deoxyguanosine adducts among workers of a Thai industrial estate and nearby residents, Environ. Health Perspect. 118 (2010) 55–59. [439] M. Peluso, V. Bollati, A. Munnia, P. Srivatanakul, A. Jedpiyawongse, S. Sangrajrang, S. Piro, M. Ceppi, P.A. Bertazzi, P. Boffetta, A.A. Baccarelli, DNA methylation differences in exposed workers and nearby residents of the Ma Ta Phut industrial estate, Rayong, Thailand, Int. J. Epidemiol. 41 (2012) 1753–1760. [440] U. Vattanasit, P. Navasumrit, M.B. Khadka, J. Kanitwithayanun, J. Promvijit, H. Autrup, M. Ruchirawat, Oxidative DNA damage and inflammatory responses in cultured human cells and in humans exposed to traffic-related particles, Int. J. Hyg. Environ. Health (2013). [441] L.A. Fanou, T.A. Mobio, E.E. Creppy, B. Fayomi, S. Fustoni, P. Møller, S. Kyrtopoulos, P. Georgiades, S. Loft, A. Sanni, H. Skov, S. Ovrebo, H. Autrup, Survey of air pollution in Cotonou, Benin – air monitoring and biomarkers, Sci. Total Environ. 358 (2006) 85–96. [442] E. Taioli, R.J. Sram, S. Garte, I. Kalina, T.A. Popov, P.B. Farmer, Effects of polycyclic aromatic hydrocarbons (PAHs) in environmental pollution on exogenous and oxidative DNA damage (EXPAH project): description of the population under study, Mutat. Res. 620 (2007) 1–6. [443] R. Andreoli, C. Protano, P. Manini, P.G. De, M. Goldoni, M. Petyx, B.M. Rondinone, M. Vitali, A. Mutti, Association between environmental exposure to benzene and oxidative damage to nucleic acids in children, Med. Lav. 103 (2012) 324–337. [444] H. Autrup, B. Daneshvar, L.O. Dragsted, M. Gamborg, A˚.M. Hansen, S. Loft, H. Okkels, F. Nielsen, P.S. Nielsen, E. Raffn, H. Wallin, L.E. Knudsen, Biomarkers for exposure to ambient air pollution – comparison of carcinogen-DNA adduct levels with other exposure markers and markers for oxidative stress, Environ. Health Perspect. 107 (1999) 233–238. [445] S. Loft, H.E. Poulsen, K. Vistisen, L.E. Knudsen, Increased urinary excretion of 8oxo-20 -deoxyguanosine, a biomarker of oxidative DNA damage, in urban bus drivers, Mutat. Res. 441 (1999) 11–19. [446] P. Rossner Jr., V. Svecova, A. Milcova, Z. Lnenickova, I. Solansky, R.M. Santella, R.J. Sram, Oxidative and nitrosative stress markers in bus drivers, Mutat. Res. 617 (2007) 23–32.

Please cite this article in press as: P. Møller, et al., Oxidative stress and inflammation generated DNA damage by exposure to air pollution particles, Mutat. Res.: Rev. Mutat. Res. (2014), http://dx.doi.org/10.1016/j.mrrev.2014.09.001

G Model

MUTREV-8090; No. of Pages 34 34

P. Møller et al. / Mutation Research xxx (2014) xxx–xxx

[447] P. Rossner Jr., V. Svecova, A. Milcova, Z. Lnenickova, I. Solansky, R.J. Sram, Seasonal variability of oxidative stress markers in city bus drivers. Part I. Oxidative damage to DNA, Mutat. Res. 642 (2008) 14–20. [448] P. Rossner Jr., A. Rossnerova, R.J. Sram, Oxidative stress and chromosomal aberrations in an environmentally exposed population, Mutat. Res. 707 (2011) 34–41. [449] P. Rossner Jr., K. Uhlirova, O. Beskid, A. Rossnerova, V. Svecova, R.J. Sram, Expression of XRCC5 in peripheral blood lymphocytes is upregulated in subjects from a heavily polluted region in the Czech Republic, Mutat. Res. 713 (2011) 76–82. [450] P. Rossner Jr., A. Rossnerova, M. Spatova, O. Beskid, K. Uhlirova, H. Libalova, I. Solansky, J. Topinka, R.J. Sram, Analysis of biomarkers in a Czech population exposed to heavy air pollution. Part II: Chromosomal aberrations and oxidative stress, Mutagenesis 28 (2013) 97–106. [451] V. Svecova, P. Rossner Jr., M. Dostal, J. Topinka, I. Solansky, R.J. Sram, Urinary 8oxodeoxyguanosine levels in children exposed to air pollutants, Mutat. Res. 662 (2009) 37–43. [452] R. Fan, D. Wang, C. Mao, S. Ou, Z. Lian, S. Huang, Q. Lin, R. Ding, J. She, Preliminary study of children’s exposure to PAHs and its association with 8-hydroxy-20 deoxyguanosine in Guangzhou, China, Environ. Int. 42 (2012) 53–58. [453] Y.Y. Han, M. Donovan, F.C. Sung, Increased urinary 8-hydroxy-20 -deoxyguanosine excretion in long-distance bus drivers in Taiwan, Chemosphere 79 (2010) 942–948. [454] H.B. Huang, G.W. Chen, C.J. Wang, Y.Y. Lin, S.H. Liou, C.H. Lai, S.L. Wang, Exposure to heavy metals and polycyclic aromatic hydrocarbons and DNA damage in Taiwanese traffic conductors, Cancer Epidemiol. Biomarkers Prev. 22 (2013) 102–108. [455] H.B. Huang, C.H. Lai, G.W. Chen, Y.Y. Lin, J.J. Jaakkola, S.H. Liou, S.L. Wang, Trafficrelated air pollution and DNA damage: a longitudinal study in Taiwanese traffic conductors, PLoS ONE 7 (2012) e37412. [456] T. Mori, J. Yoshinaga, K. Suzuki, M. Mizoi, S. Adachi, H. Tao, T. Nakazato, Y.S. Li, K. Kawai, H. Kasai, Exposure to polycyclic aromatic hydrocarbons, arsenic and environmental tobacco smoke, nutrient intake, and oxidative stress in Japanese preschool children, Sci. Total Environ. 409 (2011) 2881–2887. [457] S.B. Prasad, P. Vidyullatha, G.T. Vani, R.P. Devi, U.P. Rani, P.P. Reddy, H.M. Prasad, Association of gene polymorphism in detoxification enzymes and urinary 8OHdG levels in traffic policemen exposed to vehicular exhaust, Inhal. Toxicol. 25 (2013) 1–8. [458] J. Suzuki, Y. Inoue, S. Suzuki, Changes in the urinary excretion level of 8hydroxyguanine by exposure to reactive oxygen-generating substances, Free Radic. Biol. Med. 18 (1995) 431–436. [459] Y. Wei, I.K. Han, M. Shao, M. Hu, O.J. Zhang, X. Tang, PM2.5 constituents and oxidative DNA damage in humans, Environ. Sci. Technol. 43 (2009) 4757–4762. [460] Y. Wei, I.K. Han, M. Hu, M. Shao, J.J. Zhang, X. Tang, Personal exposure to particulate PAHs and anthraquinone and oxidative DNA damages in humans, Chemosphere 81 (2010) 1280–1285.

[461] R.H. Wong, C.Y. Kuo, M.L. Hsu, T.Y. Wang, P.I. Chang, T.H. Wu, S. Huang, Increased levels of 8-hydroxy-2-deoxyguanosine attributable to carcinogenic metal exposure among schoolchildren, Environ. Health Perspect. 113 (2005) 1386–1390. [462] J.Y. Kim, L.A. Prouty, S.C. Fang, E.G. Rodrigues, S.R. Magari, G.A. Modest, D.C. Christiani, Association between fine particulate matter and oxidative DNA damage may be modified in individuals with hypertension, J. Occup. Environ. Med. 51 (2009) 1158–1166. [463] C. Ren, P.S. Vokonas, H. Suh, S. Fang, D.C. Christiani, J. Schwartz, Effect modification of air pollution on urinary 8-hydroxy-20 -deoxyguanosine by genotypes: an application of the multiple testing procedure to identify significant SNP interactions, Environ. Health 9 (2010) 78. [464] C. Ren, S. Fang, R.O. Wright, H. Suh, J. Schwartz, Urinary 8-hydroxy-20 -deoxyguanosine as a biomarker of oxidative DNA damage induced by ambient pollution in the Normative Aging Study, Occup. Environ. Med. 68 (2011) 562–569. [465] K.J. Godri, R.M. Harrison, T. Evans, T. Baker, C. Dunster, I.S. Mudway, F.J. Kelly, Increased oxidative burden associated with traffic component of ambient particulate matter at roadside and urban background schools sites in London, PLoS ONE 6 (2011) e21961. [466] O.P. Kurmi, C. Dunster, J.G. Ayres, F.J. Kelly, Oxidative potential of smoke from burning wood and mixed biomass fuels, Free Radic. Res. 47 (2013) 829–835. [467] A.B. Knol, J.J. de Hartog, H. Boogaard, P. Slottje, J.P. van der Sluijs, E. Lebret, F.R. Cassee, J.A. Wardekker, J.G. Ayres, P.J. Borm, B. Brunekreef, K. Donaldson, F. Forastiere, S.T. Holgate, W.G. Kreyling, B. Nemery, J. Pekkanen, V. Stone, H.E. Wichmann, G. Hoek, Expert elicitation on ultrafine particles: likelihood of health effects and causal pathways, Part. Fibre Toxicol. 6 (2009) 19. [468] R. Duffin, L. Tran, D. Brown, V. Stone, K. Donaldson, Proinflammogenic effects of low-toxicity and metal nanoparticles in vivo and in vitro: highlighting the role of particle surface area and surface reactivity, Inhal. Toxicol. 19 (2007) 849–856. [469] T. Stoeger, C. Reinhard, S. Takenaka, A. Schroeppel, E. Karg, B. Ritter, J. Heyder, H. Schulz, Instillation of six different ultrafine carbon particles indicates a surface area threshold dose for acute lung inflammation in mice, Environ. Health Perspect. 114 (2006) 328–333. [470] V. Stone, J. Shaw, D.M. Brown, W. MacNee, S.P. Faux, K. Donaldson, The role of oxidative stress in the prolonged inhibitory effect of ultrafine carbon black on epithelial cell function, Toxicol. In Vitro 12 (1998) 649–659. [471] C. Monteiller, L. Tran, W. MacNee, S. Faux, A. Jones, B. Miller, K. Donaldson, The pro-inflammatory effects of low-toxicity low-solubility particles, nanoparticles and fine particles, on epithelial cells in vitro: the role of surface area, Occup. Environ. Med. 64 (2007) 609–615. [472] P.E. Schwarze, J. Ovrevik, R.B. Hetland, R. Becher, F.R. Cassee, M. Lag, M. Lovik, E. Dybing, M. Refsnes, Importance of size and composition of particles for effects on cells in vitro, Inhal. Toxicol. 19 (Suppl. 1) (2007) 17–22. [473] L.A. Hansen, O.M. Poulsen, H. Wu¨rtz, Endotoxin potency in the A549 lung epithelial cell bioassay and the limulus amebocyte lysate assay, J. Immunol. Methods 226 (1999) 49–58.

Please cite this article in press as: P. Møller, et al., Oxidative stress and inflammation generated DNA damage by exposure to air pollution particles, Mutat. Res.: Rev. Mutat. Res. (2014), http://dx.doi.org/10.1016/j.mrrev.2014.09.001