Pediatric Pulmonology 51:94–108 (2016)

State of the Art

Respiratory Effects of Air Pollution on Children Fiona C. Goldizen,

1,2 MSc,

Peter D. Sly,

1,2 DSc, *

and Luke D. Knibbs,

3 PhD

Summary. A substantial proportion of the global burden of disease is directly or indirectly attributable to exposure to air pollution. Exposures occurring during the periods of organogenesis and rapid lung growth during fetal development and early post-natal life are especially damaging. In this State of the Art review, we discuss air toxicants impacting on children’s respiratory health, routes of exposure with an emphasis on unique pathways relevant to young children, methods of exposure assessment and their limitations and the adverse health consequences of exposures. Finally, we point out gaps in knowledge and research needs in this area. A greater understanding of the adverse health consequences of exposure to air pollution in early life is required to encourage policy makers to reduce such exposures and improve human health. Pediatr Pulmonol. 2016;51:94–108. ß 2015 Wiley Periodicals, Inc. Key words: indoor air pollution; ambient air pollution; biomass fuel; traffic; particulate matter; respiratory disease; respiratory infections; lung function; asthma; COPD; cancer; exposure assessment.

INTRODUCTION

Ambient outdoor and indoor air pollution contributed to the deaths of an estimated 7.7 million people in 2012, including over 660,000 children.1–3 Children in all regions are at particular risk because of their behavior, environment, and physiology. Despite general improvements in air quality in many parts of the world, the number of people exposed to dangerous levels of ambient and indoor air pollution is growing as global air pollution and the population rise.4 The health effects of air pollution have been studied extensively. Indoor and ambient air pollution exposure are associated with the development of, and increased severity of, childhood respiratory infections.5–8 Maternal and childhood exposure are associated with deficits in lung function and lung function growth.9–11 Air pollution may play a role in the development of childhood asthma.12,13 In adults, air pollution has been linked to chronic obstructive pulmonary disease (COPD) and respiratory cancer with ambient air pollution, particulate matter and the indoor combustion of coal classified as carcinogenic to humans.14–16 Early life respiratory effects from air pollution can persist in adulthood and may increase the risk of developing adult lung disease.17–19 This State of the Art examines published data on the effects of indoor and ambient air pollution on the prenatal ß 2015 Wiley Periodicals, Inc.

and childhood respiratory system, determines the current gaps in our knowledge and presents a way forward for future research. We provide an overview of air toxicants commonly present in air pollution, indoor and outdoor sources of air pollution and the pathways of exposure. However, it is outside the scope of this article to review

1 Queensland Children’s Medical Research Institute, Brisbane, Queensland, Australia. 2

Children’s Health and Environment Program, Children’s Health Research Centre, The University of Queensland, Brisbane, Queensland, Australia. 3 School of Public Health, The University of Queensland, Brisbane, Queensland, Australia.

Conflict of interest: None. Funding source: None.


Correspondence to: P.D. Sly, DSc, QCMRI, L4 Foundation Building, Royal Children’s Hospital, Herston Rd, Herston QLD 4029, Australia. E-mail: [email protected] Received 15 May 2015; Revised 25 June 2015; Accepted 3 July 2015. DOI 10.1002/ppul.23262 Published online 24 July 2015 in Wiley Online Library (wileyonlinelibrary.com).

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the respiratory effects of environmental tobacco smoke exposure in children as they have been reviewed extensively elsewhere.20–23 In addition, we describe the susceptibility of children to environmental exposures, the normal development of the respiratory system and critical windows of susceptibility. Advances in methods of exposure assessment are also discussed. It is outside the scope of this article to review all published literature on this topic.

compounds (VOCs), and semi-volatile organic compounds (SVOCs).26 Secondary pollutants are also produced by chemical interactions between air pollutants after they are released into the atmosphere. Ozone (O3), the most widely known secondary pollutant, is formed by a photochemical reaction between VOCs and NOx in the presence of sunlight.26

AIR TOXICANTS

Children are more susceptible than adults to the effects of air pollution because of environmental, behavioral, and physiological factors. Children spend more time outside engaged in physical activity, exposing them to larger doses of ambient air pollution.27 In some regions, mothers carry infants on their backs while cooking, exposing them to high concentrations of biomass fumes.28 Because children are shorter that adults they breathe air nearer to the ground, exposing them to higher concentrations of most air pollutants, as these toxicants settle towards the ground.29 Normal hand-to-mouth behavior and more extreme pica behaviors, which is the compulsive consumption of non-nutritive substances, increase exposure through non-nutritive ingestion, primarily of dust and soil.30 Higher rates of mouth breathing in children, further increasing by 20% during exercise,31 minute ventilation rates relative to body size, and ineffective particle filtering in the nasal passage facilitate the movement of particles into the lungs, increasing the dose received.27 Changes in lung function present earlier in children because they have smaller airways than adults and their breathing is further constricted by exposure to a similar level of pollution.29 Their underdeveloped detoxification systems can cause greater harm by preventing children from metabolizing hazardous compounds into less toxic components, or protect children, by limiting the absorption of hazardous toxins.27 During the growth and development of the respiratory system there are specific periods during which toxic exposures can interrupt normal development, causing long-term damage.

Air pollution is a dynamic mixture of individual toxicants from natural and anthropogenic sources. Many studies of air pollution focus on the so-called “criteria pollutants”, particulate matter (PM), ozone (O3), carbon monoxide (CO), sulfur dioxide (SO2), nitrogen oxides (NOx), and lead, for which the United States Environmental Protection Agency (US EPA) and many other regulators have set ambient air quality and emissions standards.24 However, the US EPA is required to regulate emissions of 188 air pollutants24 and more have been identified. There are numerous sources of indoor air pollution including biomass, gas and other fuels for cooking and heating, tobacco smoke, plastic furnishings, composite wood products, textiles, building materials, insulation, carpet, paint, cleaning products, dust, mold, mites, and viruses. Less commonly recognized sources include: combustion sources such as candles, incense, and mosquito coils; aerosolized products, such as personal care products, air fresheners and insecticides; and household dust, which contains many chemicals such as flame retardants, plasticizers, phthalates and other endocrine-disrupting chemicals. Traffic-related air pollution (TRAP), a mixture of gasoline exhaust and diesel exhaust, is a major source of ambient air pollution. Fossil fuel extraction, mining, chemical production, agriculture, waste disposal, and incineration, construction, industrial accidents, bush fires, and volcanic eruptions contribute to ambient air pollution, which can enter the indoor environment. A more comprehensive list of the hazardous components of common sources of ambient and indoor air pollution is shown in the online supplement (Table E1, E2). A single source can release dozens of harmful pollutants. The International Agency for Research on Cancer (IARC) identifies 35 compounds in diesel and gasoline exhaust that are known or probable human carcinogens including the Group 1 carcinogens arsenic, beryllium, cadmium, chromium, 1, 3-Butadiene, benzene, formaldehyde, dioxin/dibenzofurans (TCDD), and benzo[a]pyrene.25 Controlled studies of one mixture of diesel fuel exhaust also identified elevated levels of PM, NO2, NOx, SO2, polycyclic aromatic hydrocarbons (PAHs), sodium, calcium, zinc, hafnium, volatile organic

SUSCEPTIBILITY OF CHILDREN TO ENVIRONMENTAL EXPOSURES

NORMAL GROWTH AND DEVELOPMENT OF THE RESPIRATORY SYSTEM

The human respiratory system develops in five stages from early gestation to early adulthood. Table 1 outlines the five stages of human respiratory system development. During these periods of development the respiratory system is especially vulnerable to environmental exposures. WINDOWS OF DEVELOPMENTAL SUSCEPTIBILITY

Children are most susceptible to the effects of environmental exposures during certain developmental Pediatric Pulmonology

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TABLE 1— Stages Development Stages Embryonic

of

Human

Gestational age32,33

Respiratory

System

Physiological process32–34

0–7 weeks

Formation of laryngotracheal groove. Trachea development. Development of the main, lobar and segmental bronchi. Beginning of vasculogenesis. Pseudo-glandular 7–17 weeks Branching of segmental airways and formation of terminal bronchioles. Blood vessel development. Differentiation of epithelial cells. Canalicular 17–27 weeks Development of the respiratory bronchioles, alveolar ducts and alveoli. Development of the alveolar-capillary barrier. Saccular 27–36 weeks Development of saccules. Thinning of alveolar walls and increased gas exchange. Alveolar 37 weeks – 18–20 Alveolar and pulmonary years (end date of microvasculature growth not known) development.

windows. It is well established that the effects of a toxic exposure depend on timing and the dose absorbed,35 but the exact timing and effects of exposures during these windows are not conclusively defined. Pinkerton and Joad34 have singled out the respiratory system, suggesting the timing of a hazardous exposure alters its effect on the developing lungs.34 Many assumptions about the timing of critical windows of exposure are based on the known timing of prenatal organ system development.35 Calogeo and Sly33 infer that due to the timing of respiratory development in utero, exposure to certain toxicants before 18 weeks could impact the growth of the tracheobronchial tree and large blood vessels, whereas the development of pulmonary capillaries and lung capacity may be affected by later prenatal exposures.33 Exposures during infancy and childhood could impact the development of alveoli and lung growth.33 Longitudinal studies have shown small reductions in fetal growth depending on the timing and quantities of individual pollutants.36,37 Although these studies do not prove causation, they suggest exposures during particular windows of development will have different effects on the prenatal development of organ systems. Little is known about the post-natal windows of development.35 Our limited understanding of the pre and postnatal windows of developmental Pediatric Pulmonology

susceptibility hinders accurate calculations of the true burden of environmental exposures. ROUTES OF EXPOSURE

Children are exposed to pollutants through unique and dynamic routes of exposure. In utero, the placental transport of some compounds, like lead, exposes fetuses to concentrations of toxicants similar to those of the mother.38 Infants are exposed through inhalation, breast milk, and dermal absorption.39 Young children are also exposed through non-nutritive ingestion via oral contact with dust-covered objects and surfaces.39 Children exhibiting pica ingest larger doses of pollutant containing dust.30 Like adults, older children are exposed through inhalation, dermal absorption, and endogenous exposures, when toxins stored in tissue are released as a result of physiological changes such as eating disorders, pregnancy, lactation, osteoporosis, menopause, or calcium deficiency.30,39 Of these, transplacental exposure, exposure through breast milk, and most non-nutritive ingestion are unique to children.39 These unique characteristics of childhood exposure and dose change the timing and quantity of toxins absorbed by the body. For example, compounds transferred transplacentally have passed through a mother’s body before reaching the infant.34,40 There is evidence that, like tobacco smoke, alcohol, prescription medicine, and recreational drugs, maternal exposure to air pollution causes different effects in the fetus to the mother.39 Tables 2 and 3 show the routes of exposure of common air pollutants. EXPOSURE ASSESSMENT

Exposure assessment seeks to determine the concentrations of pollutants a child comes into contact with and the duration for which this contact occurs. Concentrations and durations, and thus exposures, can vary markedly across the locations children occupy throughout the day (e.g., home, in-transit, school, outdoors). Exposure assessment involves determining a child’s (or mother’s) exposure to multiple pollutants, whose individual effects can then be adjusted for other pollutants, or a single pollutant may be used as an indicator of the wider mixture of anthropogenic pollution. Ideally, direct measurements of exposure are used to quantify the effects of one or more pollutants on respiratory health. Continuous measurement of personal exposure to air pollutants is the gold standard for exposure assessment.52,53 Often, however, it is impractical to measure exposures for the large numbers of participants required to satisfy statistical power requirements, and exposures need to be estimated or a proxy used instead. A variety of methods have been used to assess air pollution in studies of children’s respiratory health. Some of the

Respiratory Effects of Air Pollution on Children TABLE 2— Routes of Exposure of Common Ambient Air Pollutants Ambient air pollutants Ambient air pollution–global exposure

Particulate matter (PM2.5, PM10) Lead (Pb)

Nitrogen dioxide (NO2)

Carbon monoxide (CO)

Routes of exposure Prenatal–trans-placental39 Young child–inhalation,39 non-nutritive ingestion,39 dermal absorption39 Adolescent and adult–inhalation,39 dermal absorption39 Prenatal – Young child–inhalation41 Adolescent and adult–inhalation41 Prenatal–trans-placental,30 breast milk30 Young child–ingestion,30 non-nutritive ingestion,30 inhalation30 dermal exposure30 Adolescent and adult–inhalation,30 dermal exposure,30 endogenous exposure30 Prenatal– Young child–inhalation42 Adolescent and adult–inhalation42 Prenatal–trans-placental43 Young child–inhalation43,44 Adolescent and adult–inhalation,43,44 endogenous exposure43,44

Adapted from: Sly P. Environmental Pollutants and Postnatal Growth. In Preedy VR, editor. Handbook of Growth and Growth Monitoring in Health and Disease. Volume 1. London, United Kingdom: Springer Science þ Business Media; 2012. p 757–768.

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most common methods are described in the following section. Proxy Methods

A simple proxy for exposure to TRAP is the distance from a child’s home or school to the nearest road. Distance is readily determined using a geographic information system (GIS) if the residential or school address is known.54–56 The advantages of this approach are its low cost, straightforward calculation, and ability to estimate exposures for large numbers of participants at their current address or historically. However, it does not consider traffic composition (i.e., petrol vs. diesel) or volume (i.e., vehicles/day) on roads, both of which can affect exposure to air pollutants. Likewise, the effects of prevailing winds and obstructions to pollutant transport (e.g., roadside barriers) are not considered. Traffic density is another proxy for TRAP and is derived by counting the numbers and types of vehicles on roads within a specified distance of an address and the length of those roads.55Traffic density can offer an improved ability to capture variability in TRAP compared with distance to road estimates.57 However, it is dependent on the availability of relevant traffic volume data for all subjects, which is often difficult to acquire across large areas. Measurement Methods

TABLE 3— Routes of Exposure of Common Indoor Air Pollutants Indoor air pollutants Routes of exposure Prenatal–trans-placental39 Young child–inhalation,39 non-nutritive ingestion,39 dermal absorption39 Adolescent and adult– inhalation,39 dermal absorption39 Second-hand Prenatal–trans-placental39,45 Young child–inhalation,39 non-nutritive tobacco ingestion,39 dermal absorption,46 breast milk39 smoke Adolescent and adult–inhalation,39 dermal absorption39 Formaldehyde Prenatal–trans-placental (suggested from animals studies)47,48 Young child–inhalation,49 dermal absorption49 Adolescent and adult–ingestion,49 inhalation,49 dermal absorption,49 blood transfusions49 PAHs (also a Prenatal–trans-placental44,45 component of Young child–inhalation,44 non-nutritive ingestion,44 ingestion,44 breast milk50,51 ambient air Adolescent and adult–inhalation,44 ingestion44 pollution) Indoor air pollution – global exposure

Adapted from: Sly P. Environmental Pollutants and Postnatal Growth. In Preedy VR, editor. Handbook of Growth and Growth Monitoring in

Regulatory outdoor air monitoring data has been used extensively to estimate exposures to ambient air pollution. Monitoring is undertaken by government agencies to determine compliance with air quality goals or standards in many economically developed countries. A child’s exposure can be estimated by using the monitor nearest to their home or school58 or taking the average of all monitors within the study area.9,59,60 Because ambient monitoring is performed using standard reference methods and is subject to quality assurance, the data are of high quality. Data are available freely or at low cost to researchers. Ambient monitoring is able to capture the influence of multiple air pollution sources (e.g., industry, vegetation fires) and is not specific to just traffic emissions. However, monitoring sites are typically sparse, tend to be located in cities, are not set up to capture localized (i.e., non-ambient) pollution sources. Missing data can also be problematic. Ambient monitoring sites are unlikely to measure unregulated pollutants (e.g., ultrafine particles). Placing pollutant monitors at a child’s school or outside their home provides exposure estimates that are more representative than those obtained from ambient monitors. This approach offers the advantages of ambient pollution monitoring while also removing most assumptions about pollutant homogeneity that need to be made Pediatric Pulmonology

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when using ambient data to estimate exposures. It also allows additional pollutants to be measured beyond the standard suite measured at ambient sites. It is time and cost-intensive, however, and as a result is generally only used for relatively small numbers of children.61,62 Residential or school-based outdoor measurements are not able to capture indoor sources of exposure. Measuring children’s personal exposure to air pollutants by equipping them with monitors that are carried or worn is the benchmark for exposure assessment. This captures exposures that occur indoors, outdoors, and elsewhere. Offline sampling methods provide average concentrations over a specified time period, such as passive (i.e., not using a pump) diffusion tubes for 7-day average NO2 concentrations or active (i.e., using a pump) sampling using 24 hr gravimetric PM2.5 concentrations.63,64 These methods do not provide any information about peak exposures. Conversely, real-time sampling methods provide continuous monitoring at a time resolution of up to 1 sec. This enables peaks and other temporal fluctuations to be detected.65 Real-time personal sampling is the ideal approach to determine exposures, with offline sampling running a close second. Both methods are costly and require some level of user training and active sampling can be noisy, affected by battery life, and cumbersome for children to carry. The laboratory analyses required for offline sampling can be timeconsuming. Because of these limitations, personal sampling is only feasible for small numbers of children (usually < 100). Experimental exposure studies performed in controlled chambers have proven useful for understanding effects of short-term exposures in adults and longer-term exposures in animals. They can be used to replicate concentrations of pollutants in ambient air. Controlled exposures have been used historically to assess acute effects on children.66,67 However, ethical constraints have precluded its wider use in the present day, and as such we do not discuss it further in this article. Modeling Methods

Two of the most frequently encountered modeling methods in the literature are land use regression (LUR) and dispersion modeling. LUR uses features of the environment (e.g., road density, vegetation cover) to predict spatial variation in pollutants via multivariable linear regression.68 LUR models are developed using measured pollutant levels as the dependent variable, and once built the models can be applied to estimate levels at any location within the model’s spatial extent.69 Dispersion models use input data on pollutant emissions, meteorology, topography, and other parameters to estimate pollutant concentrations based on equations that describe the transport and dynamics within a Pediatric Pulmonology

pollutant plume.70 A recent study found the two methods gave predictions that were well-correlated for PM2.5 and NO2 and led to similar effect estimates for forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and peak expiratory flow (PEF).71 Both LUR and dispersion models offer the ability to estimate residential or school exposures across large areas and for large numbers of children. However, they are dependent on the availability and quality of input data, need to be carefully validated before they are used, and may not adequately capture pollution hot-spots. While continuous personal monitoring is the ideal approach, in practice the “best” exposure assessment method depends on the study design, aims, and resources (e.g, ambient monitoring data may be scarce or absent in many countries). Regardless of the method used, all approaches are associated with some degree of exposure misclassification and this should be considered when planning or interpreting the results of studies. Misclassification tends to bias results towards the null and can reduce precision. Assessing the likely implications of exposure misclassification on the findings of a given study is important. It is worth noting that children spend the vast majority of their time indoors at home (70%), at least in industrialized countries72. Most of the methods described here deal with outdoor air pollution. While they can capture some exposure variability that occurs indoors for certain pollutants, an expansive exposure assessment would ideally measure or model indoor exposures by taking account of both indoor sources and outdoor to indoor transport.68,73 If this is not feasible, then questionnaire information can be used to control for indoor exposure sources like gas stoves, gas or wood-fired heaters, and environmental tobacco smoke.74,75 HEALTH EFFECTS

Rapid changes occurring in physiology and cell function during prenatal development and childhood suggest that studies in adults should not be used to determine the effect of environmental exposures during early life.34,40 In addition, children are more vulnerable to the effects of oxidative stress due to less mature antioxidant defense systems. When adult studies are used to suggest the possibility of harm, they will be clearly identified. An overview of the respiratory health effects of air pollution exposure is shown in Table 4. The mechanisms responsible for the adverse health effects are complex and a full discussion is beyond the scope of this article. The effects are likely to vary with factors associated with the toxicant, including the water solubility, the size and composition, especially of particulates, and the source of the toxicant. Highly water soluble toxicants, such as SO2 are likely to cause short-

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TABLE 4— Respiratory Health Effects of Air Pollution Health Effect Short term effects Mucosal irritation (adult) Cough, wheeze, shortness of breath (adult) Growth Reduced fetal growth, premature birth, low birth weight, intra-uterine growth restriction (prenatal) Growth (child) Respiratory infections Respiratory infections (prenatal) Respiratory infections (child) Lung function Lung function growth (prenatal) Lung function growth (child) Asthma Asthma exacerbation (child) Asthma development (child) Chronic Obstructive Pulmonary Disease COPD development (childhood exposure, adult development) COPD exacerbation (adult) COPD (adult) Respiratory Cancers Lung cancer (childhood exposure, adult development) Lung cancer (adult)

Nasopharyngeal cancer (adult) Sinonasal cancer (adult)

Pollutant with established or suggested health effect PM, NO2, NOx, Benzene, 1, 3-Butadiene, Fungal spores O3, 1, 3-Butadiene, PAHs

Ambient air pollution, TRAP, Maternal tobacco smoking, Environmental tobacco smoke, BMF, Wood combustion

Ambient air pollution, Biomass fuel emissions PM2.5 Ambient air pollution, TRAP, PM10, PM2.5, NO2, Indoor air pollution, Fungal spores Ambient air pollution, PM2.5, PM10, NO Ambient air pollution, TRAP, PM2.5, PM10, NO2, O3, BMF Ambient air pollution, TRAP, PM2.5,PM10, NO2, O3, Black carbon, Fungal spores Ambient air pollution, O3, BMF, Fungal spores Ambient air pollution, Indoor air pollution Ambient air pollution, TRAP Ambient air pollution, TRAP, Environmental tobacco smoke, Tobacco smoke, Biomass fuel emissions Environmental tobacco smoke Ambient air pollution, Diesel exhaust, Gasoline exhaust, Particulate matter, Benzo[a]pyrene, Trichloroethylene, Radon, Asbestos, Formaldehyde, Black carbon, Styrene, Asphalt, Environmental tobacco smoke, Coal combustion, Wood combustion, High temperature frying Formaldehyde Formaldehyde

term effects by irritating mucous membranes. The toxicity of PM is influenced by the source and by compounds adsorbed by the particle’s surface, such as transitional metals. Many components of TRAP are strong oxidants and likely to induce oxidative stress, especially in individuals more susceptible due their age or genetic variations in anti-oxidant defenses. Air toxicants may also induce DNA damage directly or via oxidative stress, underlying the carcinogenicity of air pollution. Evidence is increasing that epigenetic changes induced by air toxicants are likely to be involved in many of the adverse health effects of exposure to air pollution, especially during fetal development and early post-natal life. This is an expanding area of research interest.

mucosa of the nose and throat.80 In high doses benzene irritates the mucosa of the nose and throat81 and 1, 3Butadiene causes coughing, and irritation to the lungs and nasal passages.82 Fungal spores and pollutants from biological sources have been reported to cause rhinitis and hypersensitivity pneumonitis.83,84 Workers exposed to high concentrations of PAH’s have recorded breathing difficulties, respiratory tract irritation, chest irritation, and chest x-ray abnormalities.85 These observations have been described mostly in adults and in occupational studies. Prenatal exposure to PAH’s, during the second trimester, has been shown to increase the risk of infection, cough, breathing difficulties, and “nasal symptoms” in infants.86

Short-Term Effects

Growth

The short-term respiratory effects of air pollution are well established. O3 is known to cause shortness of breath, cough and wheezing,76,77 PM causes nose and throat irritation,78 SO2 can cause breathing difficulties and cough,79 and NO2 and other NOx cause irritation to the

Maternal air pollution, environmental tobacco smoke, and BMF exposure have been positively associated with intrauterine growth restriction (IUGR),87,88 low birth weight,87,89–92and premature birth,87,89,93–96 although meta-analyses and combined cohort studies reduced the Pediatric Pulmonology

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power of this evidence.97,98 Despite evidence of windows of developmental susceptibility, air pollution, and traffic pollution in particular, may cause negative respiratory effects at any stage of gestation.99 It is debated whether impaired fetal growth causes lower lung function and poorer respiratory outcomes in children100–104and adults.105–108 Despite the inconsistency of these results, there is evidence prenatal air pollution exposure is associated with impaired fetal growth, and that this contributes to lung function deficits in later life. Exposure to ambient air pollution109–111 and indoor biomass fuel combustion110,112,113 during childhood may reduce somatic and skeletal growth. Jedrychowski and colleagues’ 2002 study of Polish children reported a height deficit of 1.5 cm in exposed preadolescent children, when compared to less exposed children residing in the same city.111 Ambient air pollution accounted for 3.1% of the total growth rate variability.111 It is biologically plausible that air pollution negatively effects childhood growth through the genotoxicity of chemical air pollutants, the effect of low birth weight or IUGR on later development, or the negative effects of lung function deficits and frequent respiratory infections.109,111 The small number of studies, inadequate controlling for socio-economic factors in some studies, and selection bias in some studies prevents an association from being confirmed. Respiratory Tract Infections

Evidence suggests some components of ambient air pollution increase the severity of respiratory infections, particularly in children with asthma.114,115 A metaanalysis of 10 European cohort studies involved in the European Study of Cohorts for Air Pollution Effects (ESCAPE) reported a strong positive association between PM10 and pneumonia (adjusted OR; PM10 1.76, 95%CI 1.00 to 3.90, P ¼ 0.051).6 The same meta-analysis found no significant association between PM2.5 and childhood respiratory infections (adjusted OR 2.58, 95%CI (0.91, 7.27).6A 2013 Bayesian meta-analysis reported a 1.12 increase in risk of acute lower respiratory tract infections per 10 mg/m2 increase in PM2.5 in children.7 A metaanalysis of 16,059 children involved in the ESCAPE cohorts found an increased risk of pneumonia due to NO2 (1.30, 95% CI 1.02–1.65, P ¼ 0.024).6 A birth cohort study found increased susceptibility to infections in children exposed to PM2.5 during pregnancy.116 A relatively small number of studies have measured the effect of TRAP on children’s respiratory infections. A series of studies on the same cohort of children in the Netherlands reported non-significant associations between exposure to traffic pollution (measured by PM2.5, NO2, and soot) and self-reported upper respiratory tract infections.117,118 Otitis media and other respiratory illnesses were associated with exposure to traffic related Pediatric Pulmonology

air pollution in a pooled analysis of the same Dutch cohort and a German cohort.119 Indoor air pollution has been repeatedly and consistently linked to childhood respiratory infections.5 There is consensus that biomass fuel used for cooking and heating, is associated with respiratory infections in children.8,28,83,120–122 A widely referenced review by Po and colleagues8 reported a threefold increase in risk of acute respiratory infections in children (OR 3.52, 95%CI 1.94– 6.43). In an extensive review, Dherani and colleages122 found the risk of developing pneumonia in children under five increased 80% with exposure to biomass fuel.122 Lung Function

Maternal exposure to air pollution has been consistently associated with respiratory deficits in infancy and childhood.11,123,124 A cohort study in Bern, Switzerland, reported higher minute ventilation in infants prenatally exposed to elevated PM10 (24.9 ml  min1 per mg  m3 PM10) and increased exhaled nitric oxide (NO) in infants prenatally exposed to elevated NO2 (0.98 ppb per mg  m3 NO2).124 A cohort study in Krakow, Poland, measured maternal exposure to ambient air pollution (measured by PM2.5) and used spirometry to measure respiratory function at age five.123 The authors found large reductions in FVC in children with the largest PM2.5 exposure, and deficits in FEV1 in exposed children.123 Using modeled exposure estimates, a Spanish prospective study reported associations between TRAP related benzene and NO2 exposure during the second trimester and lung function deficits in preschool aged children.11 One of the most extensive studies of lung function in communities with relatively high ambient air pollution is the Southern California Children’s Health Study, a prospective study that followed the lung function of four cohorts of school age children, beginning in 1994.9,125 High ambient air pollution, measured by PM10, PM2.5, NO2, and inorganic acid vapor, was repeatedly associated with significant deficits in lung function growth.9,126–130 Children who spent more time outside experienced larger deficits in lung function, suggesting a dose-response relationship.126 Children involved in the Southern California cohort who moved to communities with lower particulate matter (PM10) showed improvements in lung function, while children who moved to more polluted communities experienced reductions in lung function growth.131 Improvements in overall ambient air quality in Southern California were associated with significant improvements in lung function growth over a 13 year period.9 Cohort studies in Manchester and Mexico City reported smaller but still significant reductions in lung function in exposed children.132,133 Ghering and colleagues134 measured ambient air pollution and TRAP exposure in children from five

Respiratory Effects of Air Pollution on Children

cohorts (n ¼ 5,921) in the ESCAPE project and authors reported minor decreases in lung function in children exposed at their current address.134 Other studies have reported similar results and concluded there may be a risk of reduced lung function with exposure to TRAP.135,136 Investigations of elevated O3 exposure and reduced lung function have found non-significant126 and weak associations137 in school age children. However, studies of modeled childhood exposure to O3 show long-term lung function deficits in college students.138,139 In a 2008 review G€otschi and colleagues argue that although there is evidence of a positive association between ambient air pollution and lung function deficits in children, cohort study participants have never been followed up long term.10 The role of individual pollutants and the windows of developmental susceptibility also require more study.10 The impact of studies is reduced because of the extensive heterogeneity in study types, differences in pollutants assessed, exposure assessment, measurement of lung function, and short follow-up periods.10,134 Asthma

There is a consensus that air pollution can trigger and exacerbate the symptoms of asthma but the role of air pollution in the development of asthma is debated. A 2005 World Health Organization (WHO) review140 concluded that the symptoms of asthma are exacerbated by exposure to TRAP. Currently, there is sufficient evidence to conclude that traffic pollution exacerbates asthma but insufficient evidence to conclude that it causes the development of asthma. WHO also concluded in 2009 that there is sufficient evidence that exposure to the microorganisms in damp buildings exacerbate the symptoms of asthma and respiratory symptoms and almost sufficient evidence that they cause asthma, but insufficient evidence to identify the effects of individual species.141 Despite heterogeneity of study types, a 2011 review of the role of ambient air pollution in asthma exacerbation, found that all 27 studies showed a positive association.142 The authors concluded, despite study limitations, that air pollution increases the symptoms of asthma in children with a prior diagnosis.142 There is continued debate about the role of ambient air pollution in the development of asthma. As Gowers13 suggests, the results of many studies are in conflict. It is biologically plausible that asthma, in partnership with genetic and epigenetic factors, plays a role in the initiation of asthma, through structural changes to the respiratory system, increased sensitization to allergens, or immune responses triggered by inflammation.13,143 There is suggestive evidence of a correlation between TRAP and asthma inception. The first birth cohort study of

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childhood asthma initiation and traffic related air pollution exposure was published in 2014. Analysing single pollutants, Bowatte and colleagues144 found positive associations between PM2.5, black carbon and asthma in four cohort studies of asthma incidence, and weak positive associations between NO2 and asthma. Overall, exposure to traffic related air pollution in early childhood was determined to increase the risk of asthma initiation until age 12.144 However, a 2009 systematic review145 found exposure to transport related air pollution was only weakly correlated with increased childhood asthma. There are conflicting reports about the relationship between ozone exposure and childhood asthma prevalence.83 Some studies have reported a positive association146–148 but others, no association.130 These differences may have been caused by age and sex specific physiological responses to ozone exposure. A recent study on New York children found that the effects of O3 exposure differed depending on the age and sex of children.149 In addition, Buchdahl and colleagues150 suggest the dose-response curve for ozone may be Ushaped, which may be partly explained by an adjuvant effect of hydrocarbons and other air pollutants at low ozone levels. Reviews of evidence of a relationship between indoor biomass fuel use and asthma risk in children reported inconsistent results. Belanger and colleagues12 found eight studies showing positive associations and two studies showing negative associations between indoor biomass fuel exposure and asthma prevalence. In a review of studies on women, Laumbach and colleagues28 reported two studies with a positive association, two statistically insignificant associations, and two negative associations, although all studies had significant limitations. A meta-analysis by Po and colleagues8 found no statistically significant associations between the risk of asthma in children and exposure to biomass fuel, when compared to cleaner fuel (pooled OR 0.50 95%CI 0.12– 1.98). Chronic Obstructive Pulmonary Disease (COPD)

Most studies of COPD development are in adults as COPD does not usually present clinical symptoms until adulthood. Poor early life lung function and respiratory illness may increase the risk of developing COPD.17 The mechanisms through which early life respiratory infections, asthma, and wheeze impact adult development of COPD are debated but evidence suggests prenatal and childhood exposure to environmental toxicants, in combination with genetic predisposition, contributes to adult respiratory disease and COPD.19 In the European Community Respiratory Health Survey “childhood disadvantage factors”, including parental smoking during Pediatric Pulmonology

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early life and childhood asthma, increased the odds ratio for COPD in adult life to a similar degree as personal smoking.151 There is suggestive evidence that reduced lung function, asthma and increased respiratory symptoms in childhood cause COPD development in adulthood.18,152 In 2010 the American Thoracic Society stated the evidence was sufficient to confirm a positive association between biomass fuel exposure and COPD development in women.153 Three influential meta-analyses published between 2010 and 2011 support this decision.8,121,154 Biomass fuel increases fibrosis in the lung parenchyma and small airways,155 which is different from damage caused by cigarette smoking.152,155 These data in women, together with the known effects of biomass smoke exposure on respiratory infections in children suggest that early life exposure is likely to increase the life-long risk of COPD. Despite the large amount of data from crosssectional and case-control studies, there is insufficient evidence to confirm a causal relationship because of a lack of longitudinal studies,152 the dearth of studies investigating a dose-response and little use of objective exposure measurements.28 Cancer

Many components of air pollution have been known to be human carcinogens for a considerable time. IARC has classified benzene, benzo[a]pyrene, asbestos, formaldehyde, radon, and secondhand smoke as Group 1 carcinogens.156,157 Diesel fuel exhaust, some PAHs, 1, 3-Butadiene, and Trichloroethylene have been classified as Group 2A carcinogens, probably carcinogenic to humans based on limited evidence in humans and sufficient evidence in animals.157 Gasoline exhaust, some PAHs, carbon black, styrene, and asphalt are classified as Group 2B carcinogens and possibly carcinogenic to humans.157 In 2013 an IARC working Group determined there was sufficient evidence from adult, animal, and mechanisms of action studies to confirm that ambient air pollution and particulate matter are Group 1 carcinogens.14,16 The most influential studies used, were a large cohort study in the United States and a study of pooled results from European cohorts.16,158,159 Raaschou–Nielsen and colleagues propose that particulate matter is the crucial carcinogenic component of ambient air pollution.158 An IARC associated metaanalysis found the relative risk of lung cancer associated with PM2.5 was 1.09 (95%CI: 1.04, 1.14) and a relative risk of 1.08 (95%CI: 1.00, 1.17) was associated with PM10.14 The estimated risks of adenocarcinoma associated with PM2.5 and PM10 exposure were 1.40 (95%CI: 1.07, 1.83) and 1.29 (95%CI: 1.02, 1.63),14 respectively. The IARC working group concluded there is sufficient evidence that indoor combustion of coal causes lung Pediatric Pulmonology

cancer in humans (Group 1),15,160,161 limited evidence that indoor combustion of biomass fuel, particularly wood, causes lung cancer in humans160,161 and sufficient evidence of wood smoke as a carcinogen in experimental animals.160,161 High-temperature frying, a practice particularly common in East Asia, was classified as a Group 2A carcinogen.160 There has been limited research into the effects of childhood air pollution exposure and later respiratory cancer risk. Most studied have focused on second-hand tobacco smoke and concluded that environmental tobacco smoke either had no significant effect162–164 or only a minor effect on later lung cancer development.165,166 Olivo–Marston and colleagues167 reported significant positive associations between retrospective studies of childhood exposure to environmental tobacco smoke and lung cancer development, especially among people with polymorphisms of the mannose binding lectin-2 gene (MBL2). Vineis and colleagues168 reported significant associations (HR 3.63,1.19–11.11) in children exposed to ETS for several hours each day. Exposure to second-hand smoke, diesel exhaust, and gasoline exhaust have been associated with several non-respiratory childhood cancers, in particular, leukaemia, lymphoma, brain tumors, Wilms tumours, acute lymphatic leukaemia, and central nervous systems cancers.25,165 GAPS AND CONCLUSIONS

Despite the large volume of research there are significant gaps in our understanding of the role childhood air pollution exposure plays on the development of respiratory disease. In particular, there is a pressing need to understand how exposures occurring during the periods of rapid lung development, especially during fetal development and the first 2 years of postnatal life, reduce lung function and lung function growth and increase the life-long risk of acute and chronic lung disease. Knowledge Gaps and Research Needs:

 Early origins of disease: what is the true nature of the link between early life air pollution exposure and longterm disease risk? Studies with the exposure and outcome separated by many decades are challenging, however, improved methods for assessing exposures during fetal development and early post-natal life coupled with early outcome markers, for example better measurements of lung function in infants and young children and biomarkers of effect, that track with known long-term disease risks would make longitudinal studies more feasible.  Asthma inception: while biologically plausible there is insufficient evidence to clearly demonstrate the role, if any, air pollution exposure has on asthma inception. Studies to investigate this issue are feasible but will

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require a large sample size to have sufficient statistical power. In addition, accurate exposure estimates, using state of the art modeling and measurements, that span the peri-conception period, fetal development and early post-natal life and improved objective, methods for diagnosing asthma will be required. Developing a standardized methodology and several studies using harmonized protocols are the most likely way this aim could be achieved.  Intervention studies in the form of regional air pollution reductions: effective reductions of ambient air pollution (i.e., Southern California) provide an opportunity for new data on the health effects of exposures and the therapeutic effects of reduced exposure. Positive legislative changes can contribute, for example China has committed to drastically reducing coal use and urban air pollution and the USEPA is poised to reduce “allowable” levels of criteria air pollutants; a move that could prevent as many as 3,500 premature deaths in the USA.169 High quality data on the links between current air quality and health outcomes are currently available for some but not most parts of the world. Efforts to improve current data will allow the benefits of policy changes that reduce pollution exposure to be documented, encouraging further action. New Insights

The literature reviewed in this article allows an expanded view of the adverse health effects of exposure to air pollution in children. The “medical model” tends to concentrate of health outcomes; however, a broader approach is needed to understand how such effects can be prevented. We chose to include sections on the limitations of exposure assessment in the developing fetus and young children and on extrapolating data from assessments of exposure in adults to alert the pediatric audience to these issues. A “life-stage” approach is not foreign to pediatrics; however it is less common in environmental and exposure sciences. Combing literature from diverse fields allows new insights for all. We hope that this article will stimulate research with an expanded vision to address the knowledge gaps highlighted above. CONCLUSIONS

While there are considerable data linking early life exposure to air pollution to both short- and long-term adverse health effects, important knowledge gaps still exist. A substantial component of the global burden of disease is attributable either directly or indirectly to air pollution exposure. Ambient air quality can be improved through regulation and technology to reduce vehicle and industrial emissions. Indoor air pollution, especially from

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