Carcinogenicity of ambient air pollution: use of biomarkers,lessons learnt and future directions

The association between ambient air pollution (AAP) exposure and lung cancer risk has been investigated in prospective studies and the results are generally consistent, indicating that long-term exposure to air pollution can cause lung cancer. Biomarkers can enhance research on the health effects of air pollution by improving exposure assessment, increasing the understanding of mechanisms, and enabling the investigation of individual susceptibility. In this review, we assess DNA adducts as biomarkers of exposure to AAP and early biological effect, and DNA methylation as biomarker of early biological change and discuss critical issues arising from their incorporation in AAP health impact evaluations, such as confounding, individual susceptibilities, timing, intensity and duration of exposure, and investigated tissue. DNA adducts and DNA methylation are treated as paradigms. However, the lessons, learned from their use in the examination of AAP carcinogenicity, can be applied to investigations of other biomarkers involved in AAP carcinogenicity.     

Air pollution induces heritable DNA mutations

Hundreds of thousands of people worldwide live or work in close proximity to steel mills. Integrated steel production generates chemical pollution containing compounds that can induce genetic damage (1, 2). Previous investigations of herring gulls in the Great Lakes demonstrated elevated DNA mutation rates near steel mills (3, 4) but could not determine the importance of airborne or aquatic routes of contaminant exposure, or eliminate possible confounding factors such as nutritional status and disease burden. To address these issues experimentally, we exposed laboratory mice in situ to ambient air in a polluted industrial area near steel mills. Heritable mutation frequency at tandem-repeat DNA loci in mice exposed 1 km downwind from two integrated steel mills was 1.5- to 2.0-fold elevated compared with those at a reference site 30 km away. This statistically significant elevation was due primarily to an increase in mutations inherited through the paternal germline. Our results indicate that human and wildlife populations in proximity to integrated steel mills may be at risk of developing germline mutations more frequently because of the inhalation of airborne chemical mutagens.     

Outdoor air pollution: particulate matter health effects

Numerous investigations studying multiple populations across a variety of environmental settings have demonstrated a strong association between ambient air particulate matter and cardiopulmonary morbidity and mortality. In most studies, the effect size of ambient air particulate pollution on health outcomes is small. However, the exposed population worldwide is very large. Accordingly, particulate air pollution appears to be an important public health hazard that makes an important contribution to the total burden of disease and death in populations across the world. Much of the evidence linking ambient air particulates with adverse health effects is derived from population-based, observational research with potential unidentified confounding exposures, precluding definitive assessments about causation and providing limited mechanistic insights. A growing body of research suggests particulate-associated adverse health effects result from the induction of proinflammatory responses in the lower respiratory tract. Ambient air particulates may increase lung cancer risk.     

Acute effects of SO2 and particles from a power plant on respiratory symptoms of children, Thailand

Epidemiological studies to evaluate the acute effects of ambient SO2 on the respiratory health of children provide inconclusive results. A panel study to examine the association of short-term exposure to ambient SO2 and respiratory symptoms of 196 children for a period of 107 days was conducted in Thailand. Generalized Estimating Equations were used to examine the association of daily variation of air pollution with daily respiratory symptoms. During the study period, SO2 was not associated with respiratory symptoms in either asthmatics or non-asthmatics, whereas a 10 microg/m3 increase in PM10 was modestly associated with increases of lower respiratory symptom incidence (OR=1.03, 95%CI=0.98, 1.09) and cough (OR=1.04, 95% CI=1.00, 1.08) in asthmatics. At the low ambient air pollution concentrations observed, particulate matter rather than SO2 was associated on a microg/m3 basis with acute daily respiratory symptoms.     

Diesel exhaust exposure enhances the expression of IL-13 in the bronchial epithelium of healthy subjects

Epidemiological studies have demonstrated adverse health effects of environmental pollution. Diesel exhaust (DE) is an important contributor to ambient particulate matter pollution. DE exposure has been shown to induce a pronounced inflammatory response in the airways, with an enhanced epithelial expression of IL-8, and Gro-alpha in healthy subjects. The present investigation was aimed to further characterise the epithelial response to DE in vivo, with particular reference to possible TH2 response, in non-atopic healthy subjects. To determine this response, 15 healthy, non-atopic non-smoking subjects with normal lung function were exposed to DE (PM10 300 microg/m3) and filtered air during 1 h on two separate randomised occasions. Bronchoscopy sampling of bronchial mucosal biopsies was performed 6 h after exposure. Immunohistochemical staining were performed using mAb for IL-10, IL-13 and IL-18 expression. DE exposure induced a significant increase in the expression of IL-13 in the bronchial epithelium cells, 2.1 (1.35-4.88) Md (Q1-Q3) vs. air 0.94 (0.53-1.23); P = 0.009. No significant changes were seen in IL-10 and IL-18 expression. This finding suggests an TH2-inflammatory response in the airways of non-atopic healthy individuals.     

Ultrafine particles in urban air and respiratory health among adult asthmatics.

Airborne particles are associated with adverse health effects and contribute to excess mortality in epidemiological studies. A recent hypothesis proposes that the high numbers of ultrafine (<0.1 microm diameter) particles in ambient air might provoke alveolar inflammation and subsequently cause exacerbations in pre-existing cardiopulmonary diseases. To test the hypothesis adult asthmatics were followed with daily peak expiratory flow (PEF) measurements and symptom and medication diaries for six months, while simultaneously monitoring particulate pollution in ambient air. The associations between daily health endpoints of 57 asthmatics and indicators of air pollution were examined by multivariate regression models. Daily mean number concentration of particles, but not particle mass (PM10 (particle mass <10 microm), PM2.5-10, PM2.5, PM1), was negatively associated with daily PEF deviations. The strongest effects were seen for particles in the ultrafine range. However, the effect of ultrafine particles could not definitely be separated from other traffic generated pollutants, namely nitric oxide, nitrogen dioxide and carbon monoxide. No associations were observed with respiratory symptoms or medication use. Particle mass measurements can be strongly influenced by mechanically produced, soil-derived particles, which may not be associated with adverse health effects. Therefore, air quality monitoring should include particle number concentrations, which mainly reflect ultrafine particles.     

Ambient particulate pollutants in the ultrafine range promote early atherosclerosis and systemic oxidative stress

Air pollution is associated with significant adverse health effects, including increased cardiovascular morbidity and mortality. Exposure to particulate matter with an aerodynamic diameter of <2.5 microm (PM(2.5)) increases ischemic cardiovascular events and promotes atherosclerosis. Moreover, there is increasing evidence that the smallest pollutant particles pose the greatest danger because of their high content of organic chemicals and prooxidative potential. To test this hypothesis, we compared the proatherogenic effects of ambient particles of <0.18 microm (ultrafine particles) with particles of <2.5 microm in genetically susceptible (apolipoprotein E-deficient) mice. These animals were exposed to concentrated ultrafine particles, concentrated particles of <2.5 microm, or filtered air in a mobile animal facility close to a Los Angeles freeway. Ultrafine particle-exposed mice exhibited significantly larger early atherosclerotic lesions than mice exposed to PM(2.5) or filtered air. Exposure to ultrafine particles also resulted in an inhibition of the antiinflammatory capacity of plasma high-density lipoprotein and greater systemic oxidative stress as evidenced by a significant increase in hepatic malondialdehyde levels and upregulation of Nrf2-regulated antioxidant genes. We conclude that ultrafine particles concentrate the proatherogenic effects of ambient PM and may constitute a significant cardiovascular risk factor.     

Diesel exhaust enhances airway responsiveness in asthmatic subjects.

Particulate matter (PM) pollution has been associated with negative health effects, including exacerbations of asthma following exposure to PM peaks. The aim of the present study was to investigate the effects of short-term exposure to diesel exhaust (DE) in asthmatics, by specifically addressing the effects on airway hyperresponsiveness, lung function and airway inflammation. Fourteen nonsmoking, atopic asthmatics with stable disease, on continuous treatment with inhaled corticosteroids, were included. All were hyperresponsive to methacholine. Each subject was exposed to DE (particles with a 50% cut-off aerodynamic diameter of 10 microm (PM10) 300 microg x m(-3)) and air during 1 h on two separate occasions. Lung function was measured before and immediately after the exposures. Sputum induction was performed 6 h, and methacholine inhalation test 24 h, after each exposure. Exposure to DE was associated with a significant increase in the degree of hyperresponsiveness, as compared to after air, of 0.97 doubling concentrations at 24 h after exposure (p < 0.001). DE also induced a significant increase in airway resistance (p=0.004) and in sputum levels of interleukin (IL)-6 (p=0.048). No changes were detected in sputum levels of methyl-histamine, eosinophil cationic protein, myeloperoxidase and IL-8. This study indicated that short-term exposure to diesel exhaust, equal to high ambient levels of particulate matter, is associated with adverse effects in asthmatic airways, even in the presence of inhaled corticosteroid therapy. The increase in airway responsiveness may provide an important link to epidemiological findings of exacerbations of asthma following exposure to particulate matter.     

Respiratory survey of North American Indian children living in proximity to an aluminum smelter

We explored the relationship of respiratory symptoms and lung function to exposure to ambient air pollution consisting of particulate and gaseous fluorides. The subjects were 253 North American Indian children 11 to 17 yr of age living on the Akwasasne reserve, which is adjacent to an aluminum smelter. Among boys, closing volume (CV/VC%) was increased in those raised closest to the smelter as opposed to those having lived most of their lives farthest from this source of air pollution. In both sexes, there was a significant linear relationship between increasing CV/VC% and the amount of fluoride contained in a spot urine sample. We conclude that exposure to fluoride air pollution in the community may be associated with abnormalities in small airways. The implication of these abnormalities for future respiratory health is unknown.     

Air pollution and health

The health effects of air pollution have been subject to intense study in recent years. Exposure to pollutants such as airborne particulate matter and ozone has been associated with increases in mortality and hospital admissions due to respiratory and cardiovascular disease. These effects have been found in short-term studies, which relate day-to-day variations in air pollution and health, and long-term studies, which have followed cohorts of exposed individuals over time. Effects have been seen at very low levels of exposure, and it is unclear whether a threshold concentration exists for particulate matter and ozone below which no effects on health are likely. In this review, we discuss the evidence for adverse effects on health of selected air pollutants.     

Investigating air pollution and atherosclerosis in humans: concepts and outlook

Although ambient particulate matter contributes to atherosclerosis in animal models, its role in atherogenesis in humans needs to be established. This article discusses concepts, study design, and choice of health outcomes to efficiently investigate the atherogenic role of ambient air pollution, with an emphasis on early preclinical biomarkers of atherosclerosis that are unaffected by short-term exposure to air pollution (eg, carotid intima-media thickness [CIMT] and functional performance of the vessel). Air pollution studies using these end points are summarized. The CIMT is currently the most frequently used outcome in this field (6 studies). The continuous nature of CIMT, the lack of short-term variation, its relationship to atherosclerotic changes in the artery wall, its predictive value for coronary heart disease, and the noninvasiveness of the assessment make it a useful candidate for cross-sectional and longitudinal studies investigating the role of air pollution in atherogenesis.     

Endothelial function and chronic exposure to air pollution in normal male subjects

Exposure to urban air pollution, ultrafine particles or gases, is associated with acute cardiovascular mortality and morbidity. We investigated the effect of ambient air pollution on endothelial function in 40 healthy white male nonsmokers spontaneously breathing ambient air in Paris, France. Air pollutant levels (nitrogen, sulfur and carbon oxides, and particulate matter) were averaged during the 5 days preceding arterial measurements. Brachial artery endothelium-dependent flow-mediated dilatation and reactive hyperemia induced by hand ischemia and endothelium-independent glyceryl trinitrate dilatation were measured using a radiofrequency-based echo-tracking device at 2-week intervals. Flow-mediated dilatation was independently and negatively correlated with the average levels of sulfur dioxide (P<0.001) and nitrogen monoxide (P<0.01). Sulfur dioxide levels explained 19% of the variance of flow-mediated dilatation. An increase in gaseous pollutants, 2 weeks apart, was significantly associated with a decreased in flow-mediated dilatation. No association was found between air pollutants and glyceryl trinitrate-induced vasodilatation. Reactive hyperemia was significantly and positively correlated with particulate matter with aerodynamic diameters <10 microm and <2.5 microm (P<0.0001 and P<0.001, respectively) and nitrogen dioxide (P<0.01). An increase in particulate matter, 2 weeks apart, was significantly correlated with an increase in reactive hyperemia. Endothelial function was impaired by ordinary levels of pollution in healthy young males, in an urban area, and may be reduced by 50% between the least and the most polluted day. Gaseous pollutants affect large artery endothelial function, whereas particulate matter exaggerates the dilatory response of small arteries to ischemia.     

Immediate effects of particulate air pollutants on heart rate and respiratory rate in hypertensive rats

Time-series studies have shown that the lag time between elevated particulate air pollution (PM) and increases in cardiovascular-related hospital admissions and death is very short 1 d or less. If PM does cause serious cardiovascular effects shortly after exposure, one would expect to see some physiological change during exposure. In this study, spontaneously hypertensive rats (SHRs) with surgically implanted blood pressure transmitters were exposed to concentrated ambient PM (CAPS) for 4 h to determine whether CAPS inhalation causes immediate effects. The rats were also exposed to sulfuric acid aerosols because acid is one of the components of PM that could potentially activate irritant receptors and cause effects during exposure. Exposure to CAPS caused a striking decrease in respiratory rate that was apparent soon after the start of exposure and stopped when exposure to CAPS ceased. The decrease in respiratory rate was accompanied by a decrease in heart rate. Exposure of the same rats to fine-particle-size sulfuric acid aerosol also caused a significant decrease in respiratory rate similar to the effects of CAPS. Ultrafine acid had the opposite effect on respiratory rate compared to CAPS. Because acids have been shown to evoke sensory irritant responses in rodents, the similarity between the effects of fine acid aerosol and CAPS suggests that CAPS activates airway-irritant receptors during exposure.     

A Quasi-Experimental Analysis of Elementary School Absences and Fine Particulate Air Pollution

Fine particulate air pollution (PM_2.5) has been associated with many adverse health outcomes including school absences. Specifically, a previous study in the Utah Valley area, conducted during a time with relatively high air pollution exposure, found significant positive correlations between school absences and air pollution.We examined the hypothesis that ambient PM_2.5 exposures are associated with elementary school absences using a quasi-natural experiment to help control for observed and unobserved structural factors that influence school absences. The Alpine, Provo, and Salt Lake City school districts are located in valleys subject to daily mean PM_2.5 concentrations almost twice as high as those in the Park City School District. We used seminonparametric generalized additive Poisson regression models to evaluate associations between absences and daily PM_2.5 levels in the 3 districts that were exposed to the most pollution while using Park City absences as a quasi-control. The study covered 3 school years (2011/12-2013/14).School absences were most strongly associated with observed structural factors such as seasonal trends across school years, day-of-week effects, holiday effects, weather, etc. However, after controlling for these structural factors directly and using a control district, a 10 μg/m³ increase in PM_2.5 was associated with an approximately 1.7% increase in daily elementary school absences.Exposure to ambient air pollution can contribute to elementary school absences, although this effect is difficult to disentangle from various other factors.     

Nasal heat exchange in a northern ungulate, the reindeer (Rangifer tarandus)

When reindeer were exposed to low ambient temperatures, heat and water were recovered from the exhaled air by a nasal counter-current heat exchanger. Measurements of respiratory frequency, minute volume, exhaled air temperature and metabolic rate were made over a range of ambient air temperatures extending from -5.5 degrees C to 27.2 degrees C. At ambient air temperatures less than 10 degrees C the exhaled air temperatures were an average of 21 degrees C less than body temperature. The reduction of the exhaled air temperature at the lowest ambient air temperatures used in this study resulted in the recovery of 75% of the heat added and 80% of the water added to the inspired air on its way to the lungs. The heat and water recovered by the nasal temporal counter-current heat exchanger in reindeer significantly reduced the metabolic cost of survival during cold exposure.     

Adverse effects of outdoor pollution in the elderly

With fewer newborns and people living longer, older people are making up an increasing fraction of the total population. Epidemiological evidence shows that older-age-related health problems affect a wide and expanding proportion of the world population. One of the major epidemiological trends of this century is the rise of chronic diseases that affect more elderly than younger people. A total of 3.7 million premature deaths worldwide in 2012 are attributable to outdoor air pollution; the susceptibility to adverse effects of air pollution is expected to differ widely between people and within the same person, and also over time. Frailty history, a measure of multi-system decline, modifies cumulative associations between air pollution and lung function. Moreover, pre-existing diseases may determine susceptibility. In the elderly, due to comorbidity, exposure to air pollutants may even be fatal. Rapid and not-well-planned urbanization is associated with high level of ambient air pollution, mainly caused by vehicular exhausts. In general, there is sufficient evidence of the adverse effects related to short-term exposure, while fewer studies have addressed the longer-term health effects. Increased pollution exposures have been associated with increased mortality, hospital admissions/emergency-room visits, mainly due to exacerbations of chronic diseases or to respiratory tract infections (e.g., pneumonia). These effects may also be modulated by ambient temperature and many studies show that the elderly are mostly vulnerable to heat waves. The association between heat and mortality in the elderly is well-documented, while less is known regarding the associations with hospital admissions. Chronic exposure to elevated levels of air pollution has been related to the incidence of chronic obstructive pulmonary disease (COPD), chronic bronchitis (CB), asthma, and emphysema. There is also growing evidence suggesting adverse effects on lung function related to long-term exposure to ambient air pollution. Few studies have assessed long-term mortality in the elderly. It is still unclear what are the pollutants most damaging to the health of the elderly. It seems that elderly subjects are more vulnerable to particulate matter (PM) than to other pollutants, with particular effect on daily cardio-respiratory mortality and acute hospital admissions. Not many studies have targeted elderly people specifically, as well as specific respiratory morbidity. Most data have shown higher risks in the elderly compared to the rest of the population. Future epidemiological cohort studies need to keep investigating the health effects of air pollutants (mainly cardiopulmonary diseases) on the elderly.     

Exposure to ambient air particulate matter and non-alcoholic fatty liver disease

The present study was designed to alert the public opinion and policy makers on the supposed enhancing effects of exposure to ambient air particulate matter with aerodynamic diameters < 2.5 mm (PM 2.5 ) on non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease in Western countries. For far too long literature data have been fixated on pulmonary diseases and/or cardiovascular disease, as consequence of particulate exposure, ignoring the link between the explosion of obesity with related syndromes such as NAFLD and air pollution, the worst characteristics of nowadays civilization. In order to delineate a clear picture of this major health problem, further studies should investigate whether and at what extent cigarette smoking and exposure to ambient air PM 2.5 impact the natural history of patients with obesity-related NAFLD,i.e. , development of non alcoholic steatohepatitis, disease characterized by a worse prognosis due its progression towards fibrosis and hepatocarcinoma.     

Air pollution

Despite progress in improving ambient air quality and reducing personal exposures to air pollutants in indoor settings, population exposures to air pollutants remain widespread and are an important public health concern. Many air pollutants are associated with adverse health effects; the most serious include development and exacerbation of asthma, loss of lung function, impaired neurobehavioral development, and death. These outcomes are the focus of current health effects research on environmental tobacco smoke and radon in indoor settings, and lead, ozone, and particulate matter outdoors. Advances in methods to measure exposures to specific pollutants and the identification of markers of individual susceptibility are providing improved data on the relation of exposure and disease, and, in turn, will improve efforts to protect public health.