Airborne Particulate Matter

CME AVAILABLE

FOR THIS

ARTICLE

AT

ACOEM.ORG

Airborne Particulate Matter Human Exposure and Health Effects Jonathan E. Thompson, PhD

Downloaded from https://journals.lww.com/joem by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3be73+7zLk/Sq+y6koaZl6Ep8oGuop87+8AoBvh7J400mYizg71tReg== on 05/15/2018

Objective: Exposure to airborne particulate matter (PM) is estimated to cause millions of premature deaths annually. This work conveys known routes of exposure to PM and resultant health effects. Methods: A review of available literature. Results: Estimates for daily PM exposure are provided. Known mechanisms by which insoluble particles are transported and removed from the body are discussed. Biological effects of PM, including immune response, cytotoxicity, and mutagenicity, are reported. Epidemiological studies that outline the systemic health effects of PM are presented. Conclusion: While the integrated, per capita, exposure of PM for a large fraction of the first-world may be less than 1 mg per day, links between several syndromes, including attention deficit hyperactivity disorder (ADHD), autism, loss of cognitive function, anxiety, asthma, chronic obstructive pulmonary disease (COPD), hypertension, stroke, and PM exposure have been suggested. This article reviews and summarizes such links reported in the literature. Keywords: aerosol, health effects of pollution, immune response, inflammation, particulate matter, PM10, PM2.5

A

cute exposure to large quantities of airborne particulate matter (PM a.k.a atmospheric aerosol) has long been recognized as being deleterious to human and animal health. Dramatic events, such as the 1952 London smog, 1948 Donora event, or the immediate aftermath of the World Trade Center building collapse create significant public awareness of the impact of particulate pollution on health.1 –5 However, while less obvious to citizen observers, recent research has suggested significant health impacts of chronic exposure to atmospheric PM.6– 9 For instance, Pope et al10 found that reducing the PM2.5 loading by 10 mg/m3 led to an increase of 0.61 0.20 year (P ¼ 0.004) in life expectancy in the United States during the 1980 to 1990s. Such a change in ambient concentration may barely be experientially noticeable to an average observer, however, more and more empirical evidence has suggested that such low-level chronic exposure to particulate pollution has profound human health effects contributing to a variety of ailments. This has led some investigators to suggest that there is no ‘‘safe’’ level of exposure to either PM10 or PM2.5 particulate pollution.11 Some estimates suggest a global burden of 4.2 million premature deaths due to particulate pollution for the year 2015.12 Future projections suggest outdoor air pollution could cause as many as 6 to 9 million premature deaths annually, and a financial cost of 1% of global GDP (approx. $2.6 trillion USD) by the year 2060.13 Atmospheric aerosols have long been of interest due to reduction of visibility in urban environments, and the aerosols role From the Department of Chemistry & Biochemistry, Texas Tech University, Lubbock, Texas. No sources of funding have been provided to prepare this specific work. The author’s research is currently not funded by any agency of a government or any private company. Author Thompson has no relationships/conditions/circumstances that present potential conflict of interest. The JOEM editorial board and planners have no financial interest related to this research. Address correspondence to: Jonathan E. Thompson, PhD, Department of Chemistry & Biochemistry, Texas Tech University, Lubbock, TX 79409-1061 ([email protected]). Copyright ß 2018 American College of Occupational and Environmental Medicine DOI: 10.1097/JOM.0000000000001277

392

Learning Objectives Become familiar with current understanding of the routes of human exposure to particulate pollutants and the mechanisms of their removal or excretion. Summarize emerging evidence on physiologic responses and systemic effects of particulate matter (PM). Discuss the evidence for associations between PM and various types of health conditions.

in affecting Earth’s climate by scattering or absorbing solar radiation.14–16 These impacts have driven considerable research into delineation of the chemical composition and size distribution of atmospheric PM.17 PM is often classified into categories based upon size.18 Particles greater than 2.5 mm aerodynamic diameter are called coarse mode particles. Particles between 0.1 and 2.5 mm are referred to as accumulation mode particles, given their tendency to grow larger during their atmospheric lifetime owing to deposition of materials that have undergone gas-phase reactions that reduced volatility of the parent compound. Ultrafine particles are those that take the form of molecular clusters up to about 100 nm in aerodynamic diameter. The chemical composition of the aerosol strongly depends upon location and distance from sources. The global aerosol consists of both natural and anthropogenic sources. A significant mass burden of wind-dispersed crustal material (wind blown dust) and sea-salt spray that forms when white-caps break or from escaping bubbles, are examples of natural sources. Inorganic ammonium sulfates or nitrates, and organic aerosol are largely thought to be pollution derived, although natural precursors do exist. Derived from incomplete combustion, black carbon or soot aerosol also has both natural and anthropogenic sources. One overarching characteristic of PM is its relative chemical complexity. Atmospheric particles are typically internally mixed, with hundreds or thousands of chemical compounds potentially being present within a single particle.19– 21 Many chemical components to PM are toxic, carcinogenic, or able to generate reactive oxygen species (ROS) that are deleterious to health.22,23 Given the broad social impact, the routes of human exposure to particulate pollution are summarized within this review article. In addition, I review existing knowledge of mechanisms with which particles are removed or excreted from mammals, the associated immunological responses that have been observed following exposure to particles within experimental animals, and emerging evidence of systemic health effects of particulate pollution. Thus, the manuscript serves to chronicle recent developments as the field of research continues to evolve.

DISCUSSION Routes of Exposure to Particulate Matter As with any chemical contaminant, components of PM may enter the human body through four mechanisms, including inhalation, dermal absorption, injection, and ingestion. Inhalation and dermal absorption present clear and often recognized routes to exposure. In addition, ingestion should be recognized as a very JOEM Volume 60, Number 5, May 2018

Copyright © 2018 American College of Occupational and Environmental Medicine. Unauthorized reproduction of this article is prohibited

JOEM Volume 60, Number 5, May 2018

important mechanism by which PM may enter the body. However, the author is unaware of any mechanism through which direct injection of aerosol materials through skin is encountered, and this route of exposure will not be considered further.

Ingestion Particulate matter can be ingested through the direct consumption of contaminated beverages and food24 and through clearance of particles removed from the lungs via mucociliary transport. Interestingly, roughly 50% of micron-sized aerosol inhaled by experimental animals is rapidly removed from the tracheobronchial (TCB) airways within the first few hours after inhalation, with mucociliary transport being the major mechanism of removal.25,26 Much smaller particles penetrate deeper into the lungs where mucosal transport may not be as an effective removal mechanism.27 Experiments with sub-100 nm particles also showed very rapid clearance of a similar fraction of particles that was consistent with mucociliary transport.28 If not removed from the body through other mechanisms, the expunged mucus may be introduced into the gastrointestinal (GI) tract through swallowing, creating an indirect route to ingestion of aerosol. While the exact mass fraction of particulate material that reaches the intestinal tract is unclear and very likely variable, roughly 50% of the inhaled dose appears to be a reasonable estimate. Clearly, this represents a significant fraction of total exposure, and ingestion should be recognized as an important route of human exposure to particulate pollution. Additional research on both the mechanisms of ingestion and constraints on ingested dose by each is required. An emerging research theme within this area is a potential link between ingestion of aerosol materials and a broad array of digestive conditions such as Crohn disease, inflammatory bowel disease, ulcerative colitis, appendicitis, and even cancer.29–32 Several groups have found that direct ingestion (gavage) of PM leads to inflammatory responses and increased oxidative stress in the gut of experimental animals. Mutlu et al33 found increased levels of the immune stimulating interleukin-6 hormone, increased intestinal permeability, and increased apoptosis in the colon of mice after gavage administration of 200 mg of PM collected from Washington, DC. Kish et al34 also found increased permeability, inflammatory cytokine secretion, and colitis in mice that were either gavaged at 18 mg/g/day or fed PM laced chow at 0.09 g/kg. While the does used in these studies are considered very high, such results are of physiological interest, as Arrieta et al35 note that abnormal gut permeability may play important roles in diabetes, Crohn disease, coeliac disease, multiple sclerosis, and irritable bowel syndrome.

Airborne Particulate Matter

In terms of the effects of ambient aerosol on digestive health, at present, conclusive data leading to definitive evidence of health effects in humans are elusive.36 Ananthakrishnan et al37 have reported observing a 40% increase in the rate of hospitalizations for inflammatory bowel disease associated with a 1-log increase in the density of total criteria pollutant emissions for a limited study of 72 counties in the state of Wisconsin. However, Opstelten et al38 did not find consistent links between air pollution and the digestive disorders in a study carried out in Europe. While not immediately obvious, ingestion of aerosol material may prove to be an important route of human exposure. Further research is needed to better quantitate the fraction of inhaled aerosol that becomes ingested, the relative importance/magnitude of aerosol ingested from food, and the related health effects following ingestion.

Inhalation The inhalation of aerosol particles is a rather obvious route of exposure. To further understand the risks posed by this route of exposure, the anatomy of the human airway, patterns of particle size-dependent deposition, and the fate of particles that have been inhaled are considered in this section.

The Human Airway The human airway is often described by three regions, the head airways (nose, mouth, pharynx, and larynx), the TCB region, and the pulmonary or aveolar region as illustrated in Fig. 1A. Air containing particles is initially warmed and humidified upon inhalation in the head airways. The airstream then passes into the trachea, bifurcated into left and right primary bronchus at the carina, and finally divided into the many bronchioles. As such, the TCB region is often described as an inverted tree. The head airways and TCB regions are very important to raise the temperature and relative humidity of the airstream to 378C and saturation (relative humidity approx. 100%). For most adults, this condition occurs near the carina.39 This fact is of significance to aerosol deposition and removal within the lungs because it is well-known that certain aerosol components can undergo deliquescence and hygroscopic growth at high relative humidity.16,40,41 Growth will significantly alter the size distribution of particles (compared to that inhaled) and possibly increase deposition into mucus within the TCB region. The surfaces of the head airways and TCB region are covered with mucus upon which particles can deposit and rapidly be removed to the pharynx through action of cilia.25 However, small, nonhygroscopic particles, such as fresh soot42–44 may be able to

FIGURE 1. (A) Anatomy of human lung showing the three regions. (B) Anatomy of human skin. Hair follicles and sweat glands create shunts through which deposited particulate matter may permeate skin through the stratum corneum (epidermis). Figures are adapted with minor labeling changes from W.C. Hinds62 and the National Institute of General Medical Sciences with permission.

ß

2018 American College of Occupational and Environmental Medicine

393



Thompson

escape this protective mechanism and penetrate further into the lungs. After the TCB region, exchange of gases between the air and blood occurs in the pulmonary region. This occurs within hollow sacs called alveoli. Interestingly, while the linear velocity of air streams within the head airways and TCB region can be quite high during inhalation, the flow velocity within the alveolar region is believed to be much slower as residual gases within the alveolar sacs compress ahead of the incoming breath. For instance, the model of Weibel45 suggests particle residence times of 200 ms within the entire TCB region and approx. 700 ms or more in the alveolar region during an inhalation modeled at a high respiratory rate of 3.6 m3/h.46 An important consequence is at such low flow velocity, the diffusion of gases and particles becomes the predominant mechanism of translation through the alveolar space. Due to the increased residence times, both diffusion and gravitational settling affect retention and removal of particles from the airstream in the pulmonary region.

Deposition Within the Airway The study of deposition within the human respiratory tract is, of course, complicated by the lack of suitable experimental subjects. Historically, this challenge has been met through computational modeling of deposition within airway compartments with validation through experiments in animal models. According to Rostami,47 computational models fall into two general categories. The first class is those models that consider the entire airway from oronasal cavity to the alveolar region. These models generally treat airway deposition from a classical viewpoint of aerosol impaction, Brownian diffusion, settling, and filtration based upon the airway model of E.R. Weibel or an extension thereof.45–51 Over time, these models have been enhanced through the use of empirical airway deposition data, so the models are often referred as semi-empirical. These models have the advantages of being relatively easy to use and having the ability to estimate deposition throughout the entire airway as demonstrated in Fig. 2A. Conversely, caveats are related to the general inflexibility of the model, the inability to treat special circumstances or details of aerosol administration or physiological differences in airway dimensions or airway performance.

For end-users, several models are available for community use. The Respiratory Deposition Calculator52– 54 of the Aerosol Research Laboratory of Alberta (http://www.mece.ualberta.ca/arla/ deposition_calculator.html) offers a simple online interface to estimate deposition in a variety of airway compartments. The multiplepath-particle-deposition model (MPPD)55,56 can also be obtained free of charge online (https://www.ara.com/products/multiplepath-particle-dosimetry-model-mppd-v-304). The MPPD model considers airway deposition of particles between 0.01 and 20 mm and has modules to consider particle deposition in murine models as well as in human children and adults from 3 months of age to 21 years. While such models are commonly employed in the literature and often yield acceptable results when averaged over many experimental subjects, recent conventions of model users have concluded that future efforts should focus on wider access to detailed anatomical data on the mammalian respiratory tract and intersubject variability as a means to improve the existing models further.57 This need is highlighted by the recent work of Jakobsson et al58 who have described an experimental apparatus for measurement of the total recovery of inhaled, monodisperse polystyrene nanospheres with diameters of 100 nm or less. In this work, the authors made measurements on seven human volunteers and successfully characterized recoveries of 50, 75, and 100 nm particles after inhalation. The authors found that person-to-person variability was quite large, some 26 to 50 times larger than measurement imprecision. However, on average, the results for 75, and 100 nm polystyrene particles agreed very well with the MPPD deposition model. Of note is that data presented for the average recovery of 50 nm spheres were only approx. 50% of the MPPD model’s prediction. It is not clear whether the underestimate of deposition of very small ultrafine particles should be attributed to the model, the limited number of experimental subjects, or limitations of the apparatus. The second type of model is computational fluid dynamics (CFD) models. CFD models aim to discretely describe aerosol particle deposition within airways through consideration of the Navier–Stokes equations governing fluid flow and transport of the particles.59 In this approach, 3D airway geometries are often FIGURE 2. (A) Modeled deposition of inhaled particles in the upper and lower human respiratory tract as a function of particle size for nose breathing. A, alveolar; NPL, nasal, pharynx, larynx; TB, tracheobronchial. Figure A reproduced from Oberdorster with permission.333 (B) In vivo inhalation experiments using baboons. Representative scintigraphic images of head airways, trachea, and lungs obtained for the three polydisperse aerosol samples. All images are for the same baboon. Relative aerosol depositions (%) for the extrathoracic (ET) and thoracic (TH) regions are indicated. Activity median aerodynamic diameter (AMAD) and [d16, d84] were noticed for each aerosol sample generated. It is observed that aerosol particles with Dp < 500 nm more effectively accumulate within the lungs, while larger micrometer sized particles deposit in head airways. Figure B is reproduced from Albuquerque-Silva et al under CCBY license.61

394

ß

2018 American College of Occupational and Environmental Medicine



described accurately through computed tomographic (CT) scans and equations of motion governing particle behavior rigorously solved from first principles. Owing to its exacting nature, CFD has the ability to consider more complex conditions for particle initial velocity, trajectory, and particle dynamics (eg, airspeed, sprays, use of inhalers, hygroscopic growth, etc), but solving the equations for particle motion in a complex system is computationally intense. Consequently, the CFD model is typically applied to certain regions or sections of the airway rather than the entire respiratory system. So, while more exact conditions can be considered, a significant limitation of CFD is the inability to model the integrated airway. Regardless of the exact model used, the focus of the current section of this review is exposure to PM via inhalation. Considering Fig. 2A and 2B, we see that deposition within the head airways, TCB region, and pulmonary region is particle size dependent. Figure 2A illustrates that deposition is high within the head airways (labeled NPL in figure) for particles which are more than 1 mm or less than 10 nm. Super-micron particles tend to deposit onto airway surfaces via impaction or settling, while the smallest ultrafine fraction can diffuse very rapidly and be removed. The TCB region also provides additional surface area for the smallest ultrafine particles to diffuse into and be removed. However, particles between about 20 nm and several hundred nanometer aerodynamic diameter are not removed effectively within the head or TCB regions and can penetrate into the pulmonary region. This fraction of particles is often believed to present the largest health risk, as particle removal kinetics are not as rapid from the deep lung for insoluble materials, and the particles may interfere with gas-exchange at alveolar junctions. For instance, Anderson et al60 report that at least one-third of 20 or 110 nm silver particles administered intranasally to rats were retained within the lungs 56 days after dosing, with silver accumulations at the terminal bronchial/alveolar duct junctions noted. Size-dependent, post-inhalation deposition within baboon airways is illustrated in Fig. 2B.61 In this work, the authors generated polydisperse aerosols using three different nebulizers from a solution that was laced with 74 MBq of technetium 99m (99mTc). The resulting aerosols from different nebulizers featured different particle size distributions. The aerosol was administered to anesthesized baboons during normal breathing and the deposition patterns within the animal airways studied by acquiring a posterior static view with a gamma camera. As expected, the authors found deposition of particles was strongly influenced by particle size. For the smallest size range tested, the activity median aerodynamic diameter (AMAD) was 230 nm. These particles preferentially accumulated within the lungs (84% in thoracic region) compared with only 16% depositing within the head airways. Deposition within the trachea was minimal. Particles from a nebulizer producing much larger particles (AMAD ¼ 2.8 mm) preferentially deposited within the head airways of the baboons, with only 28% reaching the lungs. For an intermediate size range (AMAD ¼ 550 nm), nearly equal deposition was found in lungs and head airways. Given an average adult tidal volume is 0.5 to 1.5 L and about 12 breaths per minute, an average adult will inhale a volume of 10 to 20 m3 of air daily. The ambient concentration of PM is highly variable, but if we consider the range of 10 to 300 mg/m3, we can estimate a range of 100 to 6000 mg of aerosol material being inhaled daily. It is noted that a concentration of 300 mg/m3 is exceedingly high, double the current US EPA National Ambient Air Quality Standard for 24-hour exposure. A typical atmospheric aerosol particle mass distribution exhibits large peaks in both the accumulation mode (0.1 to 1 mm) and coarse modes (>1 mm), but very little mass is typically present in the ultrafine (despite very large number concs.) mode owing to the miniscule mass of these particles.62 Figure 1A suggests accumulation mode particles are often captured at approx. 20% to 40% total efficiency, primarily in the alveolar and head airways. Supermicron, coarse mode particles ß

Airborne Particulate Matter

can be deposited in airways at efficiencies of 50% to 80%, with the majority of deposition occurring in the head airways. If the rough estimate of 40% to 50% of the total mass is retained in airways, a daily deposition of 50 to 3000 mg may be expected as a range of daily dose of PM to the respiratory system. Of course, individual exposure is likely to vary significantly due to circumstantial events such as occupation, time spent indoors versus outdoors, place of residency, time spent near cooking operations, even the mode of transport or route taken during a daily commute. This underscores the need for the development and implementation of portable sensors to better constrain and understand human exposure to airborne pollution sources.63-70

Fate of Inhaled Particulate Matter Several routes of particle removal from the airway after inhalation have been identified. After deposition of particles onto the airway epithelium, the particles will be wetted by epithelial lining fluid.71,72 Soluble fractions can dissolve in this fluid, and surfactants or biomolecules may adsorb to the surfaces of insoluble matter. The major route of removal (approx. 50% of deposited particles) in the upper airways and TCB region appears to be a rapid clearance (