Aerosol Health Effects from Molecular to Global Scales

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Critical Review

Aerosol health effects from molecular to global scales Manabu Shiraiwa, Kayo Ueda, Andrea Pozzer, Gerhard Lammel, Christopher J. Kampf, Akihiro Fushimi, Shinichi Enami, Andrea M. Arangio, Janine Fröhlich-Nowoisky, Yuji Fujitani, Akiko Furuyama, Pascale Sylvie Jeanne Lakey, Jos Lelieveld, Kurt Lucas, Yu Morino, Ulrich Pöschl, Satoshi Takahama, Akinori Takami, Haijie Tong, Bettina Weber, Ayako Yoshino, and Kei Sato Environ. Sci. Technol., Just Accepted Manuscript • DOI: 10.1021/acs.est.7b04417 • Publication Date (Web): 07 Nov 2017 Downloaded from http://pubs.acs.org on November 8, 2017

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Environmental Science & Technology

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Aerosol health effects from molecular to global scales

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Manabu Shiraiwa1,2,*, Kayo Ueda3, Andrea Pozzer4, Gerhard Lammel2,5, Christopher J.

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Kampf2,6, Akihiro Fushimi7, Shinichi Enami7, Andrea M. Arangio2,8, Janine Fröhlich-

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Nowoisky2, Yuji Fujitani7, Akiko Furuyama7, Pascale S. J. Lakey1,2, Jos Lelieveld4, Kurt

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Lucas2, Yu Morino7, Ulrich Pöschl2, Satoshi Takahama8, Akinori Takami7, Haijie Tong2,

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Bettina Weber2, Ayako Yoshino7, Kei Sato7

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1. Department of Chemistry, University of California, Irvine, CA, USA.

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2. Multiphase Chemistry Department, Max Planck Institute for Chemistry, Mainz, Germany

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3. Kyoto University, Kyoto, Japan

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4. Atmospheric Chemistry Department, Max Planck Institute for Chemistry, Mainz,

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Germany

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5. Research Centre for Toxic Compounds in the Environment, Masaryk University, Brno,

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Czech Republic

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6. Institute for Organic Chemistry, Johannes Gutenberg University, Mainz, Germany

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7. National Institute for Environmental Studies, Tsukuba, Japan

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8. EPFL, Lausanne, Switzerland

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* Correspondence to M. Shiraiwa ([email protected])

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Submitted to Environmental Science & Technology

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Article type: Critical Review

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ACS Paragon Plus Environment


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Abstract.

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Poor air quality is the globally largest environmental health risk. Epidemiological studies

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have uncovered clear relationships of gaseous pollutants and particulate matter (PM) with

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adverse health outcomes, including mortality by cardiovascular and respiratory diseases.

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Studies of health impacts by aerosols are highly multidisciplinary with a broad range of

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scales in space and time. We assess recent advances and future challenges regarding

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aerosol effects on health from molecular to global scales, through epidemiological studies,

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field measurements, health-related properties of PM, and multiphase interactions of

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oxidants and PM upon respiratory deposition. Global modeling combined with

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epidemiological exposure-response functions indicates that ambient air pollution causes

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more than four million premature deaths per year. Epidemiological studies usually refer to

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PM mass concentrations, but some health effects may relate to specific constituents such as

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bioaerosols, polycyclic aromatic compounds, and transition metals. Various analytical

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techniques, cellular and molecular assays are applied to assess the redox activity of PM and

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the formation of reactive oxygen species. Multiphase chemical interactions of lung

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antioxidants with atmospheric pollutants are crucial to the mechanistic and molecular

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understanding of oxidative stress upon respiratory deposition. The role of distinct PM

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components in health impacts and mortality needs to be clarified by integrated research on

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various spatiotemporal scales for better evaluation and mitigation of aerosol effects on

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public health in the Anthropocene.

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1. Introduction

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A strong increase of air pollutants has been observed on local, regional, and global

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scales since the industrial revolution during the period known as the Anthropocene.1-4 High

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concentrations of gaseous pollutants such as ozone and nitrogen oxides are a threat to

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public health, as they cause adverse health effects such as respiratory, allergic and

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cardiovascular diseases.5-11 Particulate matter with a diameter less than 2.5 μm (PM2.5) can

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be deposited deep into the lungs, inducing oxidative stress and respiratory diseases.

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Epidemiological studies have shown that air pollution can elevate mortality12 and global

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analyses have estimated that about 3.3 million people died due to air pollution in 2010,5, 13

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which has been recently updated to about 4.3 million per year.14, 15 The most prominent

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risk factors for the global burden of disease were identified to be ambient and indoor air

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pollution by air particulate matter and ozone.

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The causes of aerosol health effects are highly complex and interdisciplinary studies

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are required to address a wide range of length and time scales, as depicted in Figure 1.

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Regional and global modeling studies address long-term and large-scale health impacts of

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aerosols. Epidemiological studies are the basis of such modeling studies and foundation of

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relations between air pollution and local health impacts. Long-term field measurements of

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PM2.5 and oxidants in urban air pollution are not only critical for evaluating air quality, but

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also essential for conducting epidemiological studies and validating regional and global

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modeling. For the mechanistic understanding of aerosol health effects, cellular studies

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investigate how PM2.5 components can induce inflammation and oxidative stress. Acellular

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studies are also often conducted to quantify oxidative potential and redox activity of PM2.5.

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Chemical interactions between air pollutants and lung antioxidants are investigated by

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laboratory experiments to reveal mechanistic and molecular-level understanding. In this

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article, we provide an overview of aerosol health effects from the molecular level to global

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perspectives and the connection between them.

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2. Epidemiological studies and related field studies

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The design of epidemiological studies can focus on short-term or long-term health

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outcomes depending on the time duration of exposure. Previous epidemiological studies

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focusing on short-term exposure generally compare the daily temporal variation in air 3



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pollution and occurrence of specific health events using time-series methods. On the other

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hand, epidemiological studies for long-term exposure to air pollution generally compare

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spatial variations in air pollution levels and the occurrence of health events. Historically,

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the epidemiological studies evaluating the effect of long-term exposure to particulate

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matter on mortality have relied on cohort studies, which follow a group of people

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longitudinally and compare the individual exposure to particulate air pollutants and the

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occurrence of death.

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It is considered that smaller particles are more hazardous than larger particles

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because they penetrate deeply into the lungs. Recently, a number of cohort studies

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examined the effects of PM2.5 in Europe16-18 and North America19-23 as well as Asia.24, 25

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Previous cohort studies used observational PM2.5 values representing the community-

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average exposure of the study area as a proxy of individual exposure and subsequently

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were restricted to the areas surrounding monitoring stations. Recent advances in exposure

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assessment, which includes geostatistical methods, land-use regression, dispersion models,

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chemical transport model and utilization of satellite data, have considerably improved the

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spatiotemporal resolution and coverage22 and have allowed estimations of individual

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exposure based on the subjects’ addresses. In this review, we describe the state of

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epidemiological studies and measurements of air pollution used in North America and

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Europe, and Asian countries.

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2.1 Assessing health effects from epidemiological studies

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The integrated exposure-response (IER) functions estimated from epidemiological

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cohort studies are a critical part of the assessment of the global burden of disease. Although

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previous cohort studies have contributed to the identification of IERs for PM, there remains

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substantial uncertainty. One of the sources of uncertainty is the relationship at relatively

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high levels of PM. Most of the published cohort studies investigating the association

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between long-term exposure to PM2.5 and mortality were from North America and Europe.

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The annual mean PM2.5 concentrations for these areas are typically less than 30 μg m-3 and

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there are only a few studies from other areas with high PM levels, most of which are

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developing countries. Burnett, et al.

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developed non-linear IER functions by integrating

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the evidence from epidemiological studies from ambient air pollution, firsthand and

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secondhand tobacco smoke and household cooking smoke.

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Another source of uncertainty pertains to possible variations in toxicity of PM

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constituents. PM is emitted from a wide range of sources and contains various chemical

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constituents. Previous studies focused mainly on health effects of particles from

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anthropogenic sources. It is of large interest to identify the most harmful particle

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constituents and emission sources from the perspective of health risk assessment.

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Although several recent studies found both short- and long-term exposure to specific

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constituents such as organic carbon, elemental carbon, sulfate, nitrate, and sulfur,

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associated with mortality,18, 27, 28 the results were inconclusive due to spatiotemporally

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sparse data for PM constituents.29 A high correlation between constituents also makes it

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difficult to assess the health effect of a single constituent. Developing a multi-pollutant

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approach, which focuses on health effects of simultaneous exposure to multiple pollutants

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may be the key solution for future studies.

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2.2 Estimation of PM characteristics for epidemiological studies

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North America and Europe

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The measurement of gravimetric mass of PM10 and PM2.5 are specified by the Code of

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Federal Regulations (40 CFR 50 and 53) in the US and European Committee for

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Standardization (CEN) standard EN 12341:2014 in Europe (regulatory limits are listed in

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Table 1). As these or equivalent methods are used in routine air quality monitoring

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networks, they have formed the basis of numerous epidemiological studies.9, 12, 31 The

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monitoring stations are often situated in locations isolated from the influence of any

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specific source to provide representative concentrations experienced by the population.

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Driven by the previously mentioned hypothesis that a subclass of sizes or chemical

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constituents are responsible for health effects, size stratification, chemical speciation, and

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source apportionment have been investigated using physical or statistical separation of the

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total mass. Chemical analysis is often conducted within monitoring networks, particularly

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with X-ray fluorescence and thermal optical analysis for organic and elemental carbon.32, 33

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There are additional efforts to directly measure parameters linked with biological

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responses by in vitro assays.34-36 Source apportionment and land use regression models are 5



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used to further define links with source classes,37 which may further be interpreted as

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indicators for unidentified, toxic constituents.

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In addition, modern efforts have moved toward obtaining spatially and temporally

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resolved fields of various aerosol metrics for better exposure assessment.38-40 These

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strategies may require a combination of high-precision measurements by established

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methods with low-cost devices that can be placed in multiple micro-environments, mobile

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platforms, or on individuals (personal monitors). These instruments employ miniaturized

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technologies of their more established counterparts, or use different principles altogether.

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Mass measurements may be provided with sensitive microbalances, or reconstructed from

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size distributions obtained by electrostatic or optical size classification.41, 42 However, given

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the non-specificity of measured parameters for estimation of mass concentrations, the

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latter may have to be calibrated for typical aerosols in different environments

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devices can be combined together in a distributed sensor network, and the data

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incorporated into statistical models to extend estimates of concentrations over a wider

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space or time (e.g., as demonstrated in two Swiss cities46, 47).

43-45.

Such

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Processed estimates from remote sensing observations and computer models are also

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used to extend concentration fields to locations where ground-based measurements are

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unavailable. Aerosol optical depth from satellite combined with ground-based PM or

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meteorological variables can provide hourly to daily concentrations at horizontal

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resolutions of one to several km.48, 49 Chemical transport models can provide relevant

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information for exposure analysis including high time resolution, long time series, and wide

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spatial coverage for multiple pollutant concentrations and PM characteristics that are often

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unavailable.16, 50, 51 Machine learning algorithms trained on a diverse set of data sources

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(e.g., land type, monitoring network measurements, and chemical transport model

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predictions) have been constructed to provide high spatial resolution (1 km grid) over the

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US on a daily basis for better resolution.52-54

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Tradeoffs among these estimates must be taken into account as some methods

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provide a subset of relevant aerosol parameters, lack sufficient spatial or temporal

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coverage, or suffer biases through measurement artifacts, prediction, or calibration. Even

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standardized gravimetric mass measurements can contain biases due to losses of semi-

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volatile compounds or retention of water.55 As novel approaches are introduced and used

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for exposure assessment, comparability between studies will face challenges.

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Asia

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Long-term monitoring of PM has been carried out in East Asia; Japan, Korea and China

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have their own national air quality standards (Table 1), and these countries measure PM

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accordingly. These observations are aimed at understanding trans-boundary and/or local

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air pollution, but are often not well designed for epidemiological studies. Because a death is

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a rare health event, studies examining the effects of PM2.5 and mortality need a large

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number of subjects and longer follow-up time. Although it is well recognized that

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conducting epidemiological studies for PM2.5 is necessary in Asian countries, the history of

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PM2.5 monitoring is relatively short compared to PM10 and suspended particulate matter

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(SPM, equivalent to PM7) and thus only a few epidemiological studies are available.25, 56

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Japan started SPM monitoring in 1974 and PM2.5 monitoring started in about 30

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stations in 2010 and the data have accumulated for 7 years, which may be just enough time

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for epidemiological studies. The 38% of 672 monitoring stations achieved the standards for

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PM2.5 in 2014.57 In Korea, the PM10 data since 2003 was published and the PM10 annual

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standards achieved in 2013 although PM2.5 data was not reported (Environmental Statistics

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Yearbook 2014). Recently, Kim, et al. 58 reported the association between long-term PM2.5

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exposure and major depressive disorder, in which they reported that the annual average

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PM2.5 concentration in Seoul declined from 29.8 μg m-3 in 2007 to 24.9 μg m-3 in 2010. In

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China, the national standard of PM2.5 was set and PM2.5 measurements on the national scale

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was introduced in 2012.59 The Class 1 standards apply for the special regions such as

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national parks, and the Class 2 standards apply for all other areas, including urban and

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industrial areas. The annual average of PM2.5 at Class 2 areas was 62 μg m-3 in 2014 and

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11% of 161 cities achieved the Class 2 air quality standard.57

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The chemical composition of PM receives attention since specific chemicals may play

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an important role in PM toxicity. Recent continuous measurements of aerosol chemical

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composition have shown that the Kyushu area in the west side of Japan is influenced by

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long-range transport from the Asian continent.60-62 They found that SO2 and VOC are

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oxidized and converted to sulfate and low volatile oxygenated organic aerosols, 7



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respectively, during transport from the Asian continent. The ongoing efforts including PM

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sampling and its chemical analysis will be used for further epidemiological studies to

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characterize the health effects of PM composition.

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An epidemiological study conducted in Xi’an suggested that secondary components,

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combustion species, and transition metals were most responsible for increased risk to

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health particularly in winter.63 The observation network called EANET was organized to

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measure some pollutants including SO2, NOx, ozone and PM in East Asia, but there are a

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limited number of observation sites in the South East Asian countries due to limited

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resources (human and budget for operating and maintenance). Therefore, both satellite

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and ground-based observations are necessary in this region.

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3. Modeling perspective on aerosol health effects

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Due to extensive epidemiological cohort studies as described above, it has become

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possible to establish relationships between air pollution concentrations and long-term

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health outcomes that lead to mortality, i.e., reduced life expectancy, though cardiovascular

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and respiratory diseases. From these studies, two major atmospheric components have

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been identified that most likely contribute to mortality: ozone and PM2.5. Long-term

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exposure to these species has been associated with cerebrovascular and ischemic heart

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disease, leading to strokes and heart attacks, chronic obstructive pulmonary disease, lung

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cancer and acute lower respiratory illness among infants.5, 64-70 As a consequence, the WHO

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has proposed an air quality guideline by maintaining the annual PM2.5 level below 10 μg

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m−3, while regulatory limits imposed by different political entities are shown in Table 1. As

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the impact of PM2.5 on mortality has been estimated to be around a factor of 20 higher than

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of O3,5 here we focus on premature mortality attributable to PM2.5.

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The calculation of mortality attributable to air pollution follows a procedure

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proposed by Anenberg et al.50, by defining IER functions based on epidemiological cohort

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studies, similarly applied by the Global Burden of Disease:5

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DM= y0 × AF × Pop

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where y0 is the baseline mortality rate (BMR) for a given population; AF is the attributable

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fraction of mortality due to PM2.5 and Pop is the population within the age range of interest.

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The largest source of uncertainty in equation (1) is the AF term, which is calculated as: 8


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AF = (RR-1)/RR

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with RR being the relative risk for the pollutant, i.e., PM2.5 and O3, and for the different

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disease categories. Several studies have investigated the relative risk, and different

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formulations have been derived, of which three are the most widely used. The first follows

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a linear relationship:64, 65, 67

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RR = exp[B(X-X0)]

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where X is the concentration of PM2.5 and X0 is the threshold where the pollutant is

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considered as not being harmful. However, this formulation yields unrealistic results at

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very high pollutant concentrations, and for long-term exposure a log-linear relationship

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has been developed:71, 72 RR = [(X+1)/(X0+1)]B

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Finally, Burnett et al.26 and Cohen et al.15 derived IERs that also take into account

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observations of very high PM2.5 concentrations, e.g., from tobacco smoking and indoor air

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pollution:

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RR = 1 + α [1 – exp[– γ (X – X0)δ]],

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Unknown parameters (α, γ, δ) were estimated by nonlinear regression methods based on a

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collection of epidemiological studies.26 With the same estimation method for the unknown

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parameters, also the lowest “safe” threshold of PM2.5 is calculated between 5.8 and 8.8 μg

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m-3, whereas convincing evidence showing that mortality is absent for concentrations

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below the threshold is lacking. Recently, the concentration range below which adverse

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health outcomes are not expected, reduced to 2.4 – 5.9 µg m-3.15 Thus, the annual mean

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“safe” threshold, below which PM2.5 does not contribute to mortality is 2.4 µg m-3, which is

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much below the air quality standards presented in Table 1.

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Implementing the revised IERs by Cohen et al.15, Lelieveld

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updated the global

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estimate of mortality attributable to air pollution to 4.3 million per year, of which 4.04

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million are due to PM2.5, being higher than previous estimates, mostly related to the

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downward revision of the “safe” threshold for PM2.5. The estimated uncertainty range is

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±25% (95% confidence interval). More than 70% occurs in Asia, and more than 50% in

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China and India alone (Fig. 2). The associated global, annual mean number of years of life

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lost is 122 million (PM2.5 + O3), which means that the average person who dies prematurely

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due to air pollution loses about 28 years of one’s life. With a global population of about 7

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billion, and an average life expectancy of about 70 years, it is implicated that the life

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expectancy reduction of the average person on the planet is about 1.2 years (15 months).

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While the total number of deaths is highest in China and India, the per capita mortality is

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highest in Eastern Europe (Fig. 2), e.g., in Russia, where the life expectancy reduction is 2.5

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years. To put the mortality attributable to air pollution into context, the 4.3 million per year

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are nearly four times the annual number by HIV/AIDS and about 15 times the number of

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deaths through violence. According to GBD (2016), particulate air pollution is among the

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seven largest health risk factors, together with high blood pressure, tobacco smoking,

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diabetes, childhood undernutrition, high body mass index and high cholesterol.

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Despite the implementation of improved parameterizations for the IER functions in

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recent years, many open questions remain. Most of the data from epidemiological cohort

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studies on which the response function is based have been collected in Europe and North

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America. Although Burnett et al.26 extended the analysis to high PM2.5 levels that are

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characteristic for some parts of Asia, dedicated cohort studies will need to be performed in

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many other regions of the world. As mentioned by Lelieveld, et al.

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observed in the western hemisphere do not necessarily characterize conditions in other

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countries, for which such information is not available. For example, the toxicity of

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particulates in different parts of the world is not necessarily the same, which might be most

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relevant for black and organic carbon compounds from combustion processes, including

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biomass burning and biofuel use for cooking and heating.74 Nevertheless, first cohort

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studies in China suggest that the relationships between fine particulate matter,

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cardiopulmonary diseases and lung cancer are consistent with studies in North America

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and Europe.75, 76

73,

the conditions

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In addition to expanding epidemiological studies to Asia and Africa, for example, it

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would also be helpful to associate IER functions to emission categories and measurements

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of specific aerosol components described in the previous section: nitrate, sulfate, ammonia,

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primary and secondary organics, black carbon and mineral compounds, and possibly also

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aerosols that are smaller than PM2.5, e.g., PM1 and ultrafine particles (PM0.1), as the latter

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not only penetrate deeply into the lungs but can be transferred into the bloodstream,

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traveling into other organs, including the brain, liver, spleen, kidney, and testis.77 This 10


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would provide a basis for more comprehensive and representative IER functions that could

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be used independently from locations, but rather based on observations and calculations of

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PM2.5 composition. Although this has been attempted in recent years by estimating health

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effects of short-time exposure to air pollution,78, 79 further study is needed regarding the

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effects of individual components through long-term exposure.80, 81

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While the IER functions used are a main source of uncertainty in premature

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mortality estimations, another important uncertainty is associated with the PM2.5

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concentration. Different methods have been applied to estimate representative annual

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mean PM2.5 concentrations worldwide, e.g., extrapolations from observations,82 model

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simulations13, 50, 73 or a combination of the two.83-85 Advantages of using an atmospheric

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chemistry model are that the particle composition can be consistently calculated for the

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entire globe, i.e., including areas and time periods for which measurements are not

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available, and that vertical distributions and surface concentrations of aerosols can be

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explicitly calculated, and that PM2.5 concentrations can be unambiguously attributed to

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source categories. For example, Pozzer et al. (2017)86 computed that a 50% reduction of

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agricultural ammonia emissions could avoid 250,000 deaths globally, while a theoretical

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elimination of such emissions would reduce the air pollution related mortality by 800,000

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persons per year. Nevertheless, the latter advantage cannot yet be fully exploited since the

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differential toxicity of the different compounds is largely unknown. Moreover, accurate

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predictions of formation and chemical aging of secondary organic aerosols are still

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challenging, even though major efforts and progress have been made in recent years.87-91

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While satellite remote sensing aerosol products have the advantage of a relatively

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fine spatial resolution, they suffer from a lack of continuous temporal coverage, e.g., due to

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clouds and during the night, and the need of a priori information from model simulations,

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e.g., to estimate vertical concentration profiles. Therefore, both model simulations and

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remote sensing derived data yield comparable uncertainty in estimating PM2.5. Lelieveld et

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al.13 pursued the philosophy of applying model calculations to derive global PM2.5

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concentration distributions, and use ground-based in situ and remote sensing data to

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evaluate and improve the results. They demonstrated that the level of (dis)agreement

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between their model results and different remote sensing data products is practically the

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same. A main limitation of applying remote sensing data is that source attribution is not 11



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possible, while models can be used to evaluate emission scenarios in support of policy

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making, the development of optimal control strategies and accounting for natural sources.

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For example, Giannadaki, et al. 92 estimated that by applying the EU air quality standard of

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25 µg m-3 (annual average) worldwide, mortality attributable to PM2.5 may be reduced by

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17%, while implementation of the US standard of 12 µg m-3 would lead to a global

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reduction of 46%.

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Using the above mentioned methodology with different data products and IER

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functions, a series of studies of mortality attributable to air pollution have been

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performed,93, 94 as summarized in Fig. 3. It should be noted that the studies by Anenberg, et

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al. 50 and Lelieveld, et al. 73 only reported results for anthropogenic PM2.5 and ozone, while

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the Global Burden of Disease95 and Lelieveld, et al. 13 accounted for some portion of natural

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PM2.5 such as atmospheric desert dust by applying low concentration thresholds. This

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explains why the estimates of the former studies are systematically lower. The latter two

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studies as well as Apte, et al.

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approximately 3.3 million premature deaths per year with an uncertainty range of about

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±25%. The recent GBD Study94 revised the number upward, estimating 4.2 million deaths

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per year due to particulate matter pollution, close to the most recent estimate of 4.04

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million per year by Lelieveld (2017). The differences from the previous estimates are due

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to application of different coefficients in the IER functions (Burnett, personal. comm.;

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Cohen et al. 2017), and updated calculations of global PM2.5 concentrations.

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conclude that outdoor air pollution is associated with

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Recently, more attention has been paid to health effects of particles from natural

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events, such as desert dust,97 wildfires,98 and volcanic eruptions. Health outcomes include

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mortality, respiratory endpoints, cardiovascular endpoints and birth outcomes. Studies

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showed that exposure to long-range transported dust particles from desert areas may lead

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to mortality and hospitalization due to cardiovascular and respiratory diseases.99, 100 In

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addition, extremely high levels of PM10 from haze were associated with an increase in all-

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cause mortality and hospitalization for ischemic heart diseases in Malaysia during the 1997

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Southeast Asian forest fires.98 Giannadaki, et al.

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premature mortality attributable to natural dust is between 400 and 500 thousand per

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year, contributing ~18% to the total premature mortality attributable to air pollution.

12

101

and Lelieveld et al.13 estimated that


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Locally, the contribution of natural dust can reach up to 90% of the total premature

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mortality due to air pollution, mostly in countries located in and around the dust belt zone

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in Africa, the Middle East and Asia. From the perspective of preventing natural-event

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related diseases, it is necessary to determine the exposure-response relationship to

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characterize particle constituents originating from natural events.

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To assess regional air pollution impacts on human health, a number of limited area

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models have been used to achieve relatively higher spatial resolution, which can be

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relevant to more realistically represent urban atmospheres compared to the coarser grid

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global models (examples for N. America, Europe, and Asia are shown in Table 2).

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Furthermore, several regional models apply dedicated emission inventories that have been

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developed specifically for the regions under study. Thus, it is expected that results by

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regional models better reflect the conditions of the target regions or countries, while it is

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generally less straightforward to inter-compare different regions due to the diverse

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methodologies used.

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4. Carcinogens and allergens

368

While epidemiological studies have shown that PM2.5 mass concentrations correlate

369

well with adverse health effects, certain types of chemical composition are known to have

370

specific health effects. In this section, we focus on polycyclic aromatic compounds acting as

371

carcinogens and mutagens, as well as bioaerosols that among other effects may cause

372

allergies.

373 374

4.1 Polycyclic aromatic compounds

375

Among pathogenic characteristics of PM, the particular carcinogenicity and

376

mutagenicity of polycyclic aromatic compounds have been known since 1940s.102, 103 Two

377

mechanisms of carcinogenic action have been identified, i.e., formation of DNA adducts by

378

PAHs and their derivatives, and induction of oxidative DNA damage by particle-mediated

379

oxidative stress.104 Apart from tumor-initiating activity, tumor-promoting activity has been

380

identified for at least some of these compounds.105

381

The mutagenic potential of benzo[a]pyrene (BaP) in PM has been known for a long

382

time, as well as the fact that BaP during collection on a filter is converted into oxygenated 13



Page 14 of 62

383

products of direct mutagenicity (bacterial mutagenicity/ Ames test106). 26 out of 39 tested

384

PAHs were found mutagenic, including dibenzo[a,l]pyrene, cyclopental[c,d]pyrene,

385

naphtho[2,1-a]pyrene,

386

oxygenated PAHs and quinones that have been shown to possess dioxin-like potency.108, 109

387

Among 19 oxygenated PAHs, seven OPAHs were found mutagenic: phenalenone, 7H-

388

benz[d,e]anthracen-7-one,

389

3(4H)-one, 6H-benzo[c,d]pyren-6-one, anthanthrenequinone,107 and benz[a]anthracene-

390

7,12-dione.110 Quantitative toxicity assessment of mixtures can be based on toxic

391

equivalency factors (TEFs) and the cancer potency of the mixture of toxic PM components

392

is commonly quantified relative to that of BaP.111 This approach implies the assumption of

393

additivity, reflecting similar action of the substances. Deviations from additivity are found

394

to be rare, even so dissimilar action and other endpoints may be relevant for the toxic

395

components of PM.112

dibenzo[a,e]pyrene

and

1-methylbenzo[a]pyrene.107

3-nitro-6H-dibenzo[b,d]pyran-6-one,

Some

cyclopenta[c,d]pyren-

396

Nitration of PAHs tends to increase the mutagenic potency. Nitro-PAHs usually

397

contribute more to toxicity of ambient PM than parent PAHs.113 For example, in organic

398

extracts of PM samples, approximately half of the mutagenic activity was found in the most

399

polar sub-fractions and were most likely nitro-substituted polar aromatic compounds

400

(bacterial mutagenicity114). Among 9 nitro-PAHs, 9-nitroanthracene, 1-nitropyrene, 2-

401

nitrofluoranthene, 3-nitrofluoranthene, 1,3-dinitropyrene, 1,6-dinitropyrene and 1,8-

402

dinitropyrene were found to be mutagenic, but much less mutagenic than BaP

403

substance with the highest mutagenicity found in ambient air is an oxygenated nitro-PAH,

404

3-nitrobenzanthrone, which seems to be emitted from diesel exhausts.115 Nitro-PAHs are

405

emitted from diesel engines, but also, to a lesser extent, from gasoline engines, industries

406

(coal fired power, aluminum smelters, carbon black production, and coal stoves.116-118

407

Possible artifact formation of nitro-PAH on filters may cause an overestimation of primary

408

emitted nitro- and oxygenated PAHs.119, 120

107.

The

409

As nitro-PAHs are mostly semi-volatile, a substantial fraction of the mutagenicity

410

may reside in the gas-phase.121 The mass fraction of nitro-PAHs in the gas-phase can be up

411

to 90% in summer.122, 123 The mutagenicity of PM may be partly not bioavailable, because at

412

least in most particle size fractions part of (or all) molecular carriers of mutagenicity

413

cannot dissolve in, and ultimately penetrate the air/blood interface. The ultrafine particles 14


Page 15 of 62


414

may penetrate the interface as a whole. However, the fraction of constituents of ambient

415

PM mobilized by lung fluids has hardly been addressed so far. While the leaching of heavy

416

metals and mineral fibers in PM by simulated lung fluids was studied in very limited

417

studies,124, 125 the dissolution of organic substances has not been addressed. Extraction

418

methods using aqueous solutions and simulated lung fluids can better address the

419

bioavailable fraction. Carriers of mutagenicity may also be depleted during storage

420

(freezing) or by ultrasonic extraction.126

421 422

4.2. Bioaerosols

423

Primary biological aerosols (bioaerosols) are a subset of atmospheric PM, which are

424

emitted directly from the biosphere into the atmosphere. They comprise living and dead

425

microorganisms (e.g., bacteria and archaea), dispersal units (e.g., fungal spores and plant

426

pollen), and further cellular material from plants and animals.127-130 Bioaerosols can be

427

infectious, allergenic or toxic for living organisms, impacting public health and agriculture

428

on local, regional, and global scales.131 Many plant, animal, and human pathogens are

429

dispersed through the air and sometimes travel long distances, spreading diseases across

430

and even between continents.132, 133 The inhalation of viruses and viable airborne fungi or

431

bacteria can cause infectious diseases in humans and animals (e.g., foot-and-mouth disease,

432

tuberculosis, Legionnaire’s disease, influenza and measles).134-139 In particular for indoor

433

environments like hospitals, these bioparticles, emitted by humans or re-suspended from

434

surfaces, are challenging for infection control and safety.140-146 Recently it was estimated

435

that humans emit approximately 106 particles per hour into the surrounding air per hour

436

under seated conditions.141

437

Bioaerosols can cause toxic responses in humans and animals upon inhalation.147, 148

438

Toxic substances transported with bioaerosols include secondary metabolites of fungi

439

(mycotoxins), cell wall components of bacteria (endotoxins)

440

and hepatotoxins by cyanobacteria.150-152 Mycotoxins can cause acute and chronic health

441

effects in humans and animals, as discussed in recent review articles.153-155 Endotoxins, e.g.,

442

bacterial lipopolysaccharides (LPS), which are compounds of the outer cell membrane of

443

gram-negative bacteria, can induce strong inflammation and other adverse symptoms.148,

444

149, 156, 157

149,

as well as endo-, neuro-,

Cyanobacterial neurotoxins inhibit neurotransmission by variable mechanisms, 15



Page 16 of 62

445

whereas hepatotoxins cause severe health effects for domestic and wild animals as well as

446

for humans.158 Both neurotoxins and hepatotoxins are produced by aquatic cyanobacteria,

447

but hepatotoxins are also produced by a variety of terrestrial lichens with cyanobacterial

448

photobionts.151 One neurotoxin produced by cyanobacteria, β-methylamino-ʟ-alanine, is

449

suspected to contribute to human neurodegenerative diseases, as this same substance has

450

been identified in the brain and cerebrospinal fluid of amyotrophic lateral sclerosis (ALS)

451

and Alzheimer’s disease victims159-161 and has been shown to cause neuronal changes in

452

animal experiments.162-164 Apart from ingestion and skin contact, uptake of BMAA may

453

happen via aerosolization in cooling towers.165

454

Moreover, plant pollen, fungal spores, cyanobacteria, animal dander, and house-dust

455

mite excretions are important carriers of allergenic proteins and allergen-associated

456

immunomodulators such as pollen-associated lipid mediators (PALM), β-glucan, toll-like

457

receptor ligands, phycocyanin, and LPS.131,

458

corresponding bioparticles deposit in different depths of the respiratory tract,170 inducing a

459

variety of adverse health effects ranging from mild nasal or ocular symptoms to asthmatic

460

shock.171-173 Free allergens and related compounds derived from bioaerosols can bind to

461

fine particulate matter, such as diesel exhaust particles, leading to the generation of

462

allergen-containing aerosols in the submicrometer range that can be transported deep into

463

the human airways.174-177 Recently, a functional interaction between cyanobacterial toxins

464

and allergens has been observed, revealing a toxin dose-dependent decrease of

465

allergenicity.178 Allergies and associated respiratory diseases represent a serious health

466

challenge of increasing importance in many countries and affect large proportions of the

467

population in industrialized countries with increasing global trends.167, 168, 179

166-169

Depending on their size, the

468

Gaseous and particulate air pollutants like O3, NO2, SO2, diesel exhaust particles

469

(DEP), and other nanoparticles can lead to modifications of allergenic proteins and

470

potentially also allergen-associated immunomodulators in bioaerosols and bioaerosol

471

fragments, thus altering their allergenic potential.74, 174, 180-183 In a recent study, in vivo

472

fumigation of ragweed pollen resulted in an altered proteomic pattern including

473

nitrosylation products and the treated pollen showed higher IgE recognition in

474

immunoblots.184 Another study also confirmed a higher allergenic potential for Betula

475

pendula, Ostrya carpinifolia and Carpinus betulus pollen after NO2 exposure.185 Chemical 16


Page 17 of 62


476

modification of allergenic proteins by air pollutants can lead to changes in the protein

477

structure (conformational changes, cross-linking), and affect protein stability and other

478

properties such as hydrophobicity and affinity of binding sites, e.g., by nitration of tyrosine

479

residues.186-189 Proteins can be efficiently nitrated and cross-linked at atmospherically

480

relevant concentrations of O3 and NO2,190-195 providing a potential molecular rational for

481

modulated immune responses to allergens exposed to air pollution.

482

Bioaerosols are complex mixtures of particles, which also comprise toxins,

483

allergenic proteins and allergen-associated immunomodulators.196 Upon skin contact,

484

ingestion, and inhalation, humans are co-exposed to different types of bioparticles,

485

providing additional immune-stimulatory signals that need to be studied together in

486

realistic and relevant mixtures to assess the whole health-related potential of bioaerosols

487

and elucidate their role in allergy development.

488 489

5. Oxidative potential of PM

490

In addition to carcinogenicity and allergenicity, oxidative potential is an important

491

property of PM, which has gained growing attention in recent studies. Oxidative potential

492

of PM is related to the redox activity and the formation of reactive oxygen species (ROS)

493

and there are several commonly applied assays and techniques for its quantification,

494

including a macrophage-based assay, dithiothreitol (DTT) and ascorbic acid assays, as well

495

as

496

spectrometry, which are reviewed in this section as below. Oxidative potential has been

497

suggested to be a more health-relevant metric than PM mass.197-199 Short-term exposures

498

to traffic-related air pollutants with high oxidative potential are found to be major

499

components contributing to microvascular dysfunction.200 There are a number of studies

500

suggesting that the DTT activity can be a good indicator of oxidative stress and

501

inflammation.201-205 DTT activity was also shown to be strongly associated with emergency

502

department visits for asthma/wheezing and congestive heart failure.206 However, some

503

studies found limited207, 208 or little evidence to support the hypothesis that short-term

504

exposure to PM oxidative potential is associated with adverse health effects.209-211

505

Ascorbate-related oxidative burden was found not to be associated with mortality and

506

respiratory outcomes, while glutathione-related oxidative potential may be more

iodometric

spectrophotometry

and

17

electron

paramagnetic/spin


resonance


Page 18 of 62

507

relevant.212, 213 Thus, further studies are required to elucidate the exact mechanism and

508

connection of PM oxidative potential and health endpoints.210

509 510

5.1 ROS and DTT activities

511

The macrophage-based assay has been developed to assess the ROS activity of

512

particles.214 This biological assay is a rapid, inexpensive cell-based method that is

513

performed with rat alveolar macrophages and uses 2’,7’-dichlorodihydrofluorescein

514

diacetate (DCFH-DA) as the redox-sensitive fluorescence probe. In this method, a rat

515

alveolar cell line is exposed to water extracts of aerosols and a fluorescence probe. The ROS

516

activity is quantified by measuring the fluorescence intensity, which reflects the amount of

517

ROS generated from alveolar macrophages. The ROS activity is usually expressed as

518

equivalent to zymosan (β-1,3 polysaccharide of D-glucose), which is recognized by the toll-

519

like receptor 2 on macrophage cells, activating a strong immuno-chemical response.214

520

The macrophage-based ROS assay has been applied to ambient PM collected in

521

various places in the world, showing that the ROS activities among the sites differ by more

522

than one order of magnitude.215 A greater PM redox activity was observed in developing

523

areas of the world, which may be due to stronger emissions of fuel oil combustion, vehicle

524

exhaust and biomass burning.216 ROS activity levels were generally higher close to sources

525

and urban sites compared to rural locations, except in summer when comparable ROS

526

activity was observed at rural sites.217 In the Los Angeles basin, it was found that both

527

water-soluble and water-insoluble organic carbon as emitted by vehicular sources

528

contribute substantially to the ROS activity of PM,217, 218 Biomass burning can enhance ROS

529

activity of ambient PM and a positive correlation between ROS activity and biomass

530

burning tracers was observed,217, 219 although its activity per particulate mass is in the

531

lower range of vehicle exhaust.220

532

Smaller size fractions are found to be generally associated with higher intrinsic ROS

533

activity, which may be due to higher abundance of water-soluble metals or organics.

534

Concentrations of water-soluble transition metals (e.g. Fe, Ni, Cu, Cr, Mn, Zn and V) showed

535

positive correlations with the ROS activity of airborne PM across different urban areas and

536

size ranges.217, 221, 222 Removal of metal ions by chelation removed a large fraction of the

537

water-soluble ROS-activity.216, 222 A multivariate linear regression model incorporating Fe, 18


Page 19 of 62


538

Cr and Co explained 90% of variability in ROS levels, with Fe accounting for the highest

539

fraction of the variance. Dust containing soluble metals have been shown to generate ROS,

540

causing oxidative stress.223, 224

541

The DTT assay is widely used as an acellular method to assess the oxidative potential

542

of redox active species contained in PM.225 In this assay, PM water extracts are mixed with

543

DTT and incubated at 37°C simulating the environment in the human body. During this

544

process, the redox-active compounds can catalyze the transfer of electrons from DTT to

545

oxygen molecules and generate superoxide radicals. DTT can be measured by using 5,5’-

546

ditiobis-2-nitrobenzoic acid (DTNB) as the thiol reagent. Results are most commonly

547

expressed as the DTT decay rate normalized by the reaction time and PM mass [pmol μg-1

548

min-1]. The DTT activity was shown to have a positive correlate with H2O2 formation, but

549

not with OH formation.226

550

Table 3 summarizes the reported DTT activity of PM from different sources

551

including chamber experiments, diesel exhausts and field measurements. Among different

552

types of secondary organic aerosols (SOA), naphthalene SOA shows the highest DTT decay

553

rates due to high abundance of quinones with high redox activity.227, 228 There have been

554

extensive measurements of diesel exhaust particles and DTT decay rates were in the wide

555

range of 1 – 138 pmol μg-1 min-1, depending on vehicle types. Ambient PM have typical DTT

556

decay rates of 20 – 100 pmol μg-1 min-1.

557

WIOC often showed higher DTT activity than the water-soluble organic

558

compounds.229-233 Furthermore, it has also been found that the DTT activity depends on

559

particle size,201, 234-239 chemical composition,240-243 and emission source.228, 233, 237, 240, 244-249

560

These studies have shown that ultrafine particles contain more DTT-active components

561

including water-soluble organic compounds and soot,201, 234-237 while the DTT activity of

562

coarse particles are mainly associated with transition metal ions.239 A recent study has

563

suggested that sulfate plays a key role in producing highly acidic fine aerosols capable of

564

dissolving primary transition metals that contribute to DTT activity.238 Biomass burning

565

aerosols and soil dusts are reported to also have high DTT activity.245, 247, 250 It was found

566

that chemical aging can enhance the DTT activity.229-233, 251-255

567

The ascorbic acid assay250, 256-258 and the profluorescent nitroxides assay257 have

568

also been applied to assess the oxidation potential of PM. These assays were found to be 19



Page 20 of 62

569

sensitive to transition metals258-261 and provide consistent results with the DTT assay.242,

570

262

571

obtained by different assays. There are only a few studies that simultaneously conduct

572

multiple assays.230, 262, 263 The DTT assay was found to have lower sensitivity to elemental

573

carbon and transition metals, which are known to generate ROS efficiently.234, 264-267 A

574

recent study suggests that extraction of PM in simulated lung fluid may be necessary for

575

relevant measurements of PM oxidative potential to account for the effect of ligands and

576

complexation in lining fluids.268

It should be noted, however, that there are still challenges for comparing the results

577 578

5.2 Particle-associated ROS

579

Organic hydroperoxides and peroxides are main components of extremely low

580

volatility compounds (ELVOC) or highly oxidized molecules (HOM), which play a key role in

581

nucleation and SOA formation and growth.269, 270 They are formed via multigenerational

582

oxidation and autoxidation271, 272 as well as heterogeneous oxidation of aqueous organic

583

species initiated by gas-phase OH radicals.273-275 It has been shown that ambient and

584

laboratory-generated SOA are associated with ROS including H2O2 and organic radicals.276-

585

280

586

substantial amounts of OH radicals upon interaction with liquid water, which can be

587

enhanced by Fenton-like reactions with transition metals281, 282 or UV exposure.283

Furthermore, the decomposition of organic hydroperoxides in SOA could form

588

The total amount of organic peroxides contained in PM can be quantified by an

589

iodometric spectrophotometric method. The basis for this method is that one peroxide

590

molecule oxidizes 2I- to I2 in the presence of acid. The I2 complexes with I- to form I3-,

591

whose absorbance is measured spectrophotometrically.284 Molecular weights of organic

592

peroxides need to be assumed to estimate weight fractions. This method has often been

593

applied to laboratory chamber SOA rather than ambient particles mainly to avoid

594

interference from iron ions or inorganic ions that are often present in ambient PM. Table 4

595

summarizes the measured total organic peroxide content in SOA. The organic peroxide

596

content has been well investigated for α-pinene SOA. The peroxide content in SOA was

597

reported to be 12-65 w/w% for α-pinene ozonolysis,284-286 whereas it was reported to be 6-

598

18 w/w% for α-pinene photooxidation and decreased with increasing initial NOx level.287

599

The peroxide content in SOA was reported to decrease with UV exposure time.285 The total 20


Page 21 of 62


600

peroxide content for monoterpenes with an exocyclic double bond (i.e., β-pinene and

601

sabinene; 73-120%) was higher than that reported for those with an endocyclic double

602

bond (i.e., α-pinene, Δ3-carene, and limonene; 2-65%).284, 288 The peroxide content depends

603

strongly on precursors, oxidants and NOx level.289-291

604

Continuous wave electron paramagnetic resonance (cw-EPR) spectroscopy is a

605

versatile and sensitive technique for detecting and quantifying a wide range of particle-

606

associated radicals. Direct EPR measurements of aerosol particles collected on a filter are

607

used to quantify stable radicals such as environmentally persistent free radicals (EPFR),

608

which have an e-folding life time exceeding one day.292 The chemical identity of EPFR is

609

suggested to be semiquinone radicals.293 EPFR are formed by combustion processes, during

610

which decomposition of aromatic compounds is followed by the formation of radical

611

intermediates that can be chemically stabilized by metal oxides.294-297 Thus, EPFR are often

612

associated with soot or black carbon particles. EPFR concentrations contained in ambient

613

PM were reported to be in the range of ~1010 - 1012 spins μg-1 (the number of spins per

614

mass of particles).298-301 Particles in the accumulation mode were observed to contain

615

higher EPFR concentrations compared to coarse particles.298 Stable radicals may also be

616

formed via heterogeneous chemistry and some studies have shown the formation of long-

617

lived reactive oxygen intermediates from heterogeneous ozonolysis of PAHs.302, 303

618

Although EPR spectroscopy is highly sensitive, radicals with a short lifetime such as

619

OH radicals cannot be directly detected, as their concentrations are usually below the

620

detection limit. To overcome this limitation, a spin-trapping technique is widely used to

621

detect short-lived radicals in liquid solutions. It is based on the reaction between a target

622

radical and a molecular probe containing a nitrone or nitroso functional group, leading to

623

the generation of a long-lived nitroxide radical adduct that can be detected by EPR.304 By

624

applying this technique, EPFR or semiquinone radicals were shown to be capable of

625

generating hydroxyl radicals by redox reactions.299, 305, 306 Ambient particles were found to

626

release a wide range of ROS including OH, superoxide, and carbon- and oxygen-centered

627

organic radicals driven by interactions of SOA, EPFR, and transition metals.282, 298

628 629

6. Multiphase processes of ROS in the lung

21



Page 22 of 62

630

Inhalation and deposition of air pollutants in the human respiratory tract is the first

631

step in adverse aerosol health effects. Our lungs are covered and protected by a 0.1 – 0.5

632

μm epithelium lining fluid (ELF), which contains low molecular weight antioxidants such as

633

ascorbic acid (vitamin C, AH2), uric acid (UA), glutathione (GSH) and α-tocopherol (vitamin

634

E, α-Toc) with concentrations in the range of ~1 – 500 μM.307, 308 As shown in Fig. 4(a),

635

these antioxidants can react with inhaled atmospheric oxidants such as OH and O3

636

protecting underlying tissues and cells. Reactions of antioxidants with redox-active

637

components contained in PM2.5 can lead to the formation of ROS within ELF that may cause

638

oxidative stress. This section summarizes the recent progress in our understanding of

639

these multiphase chemical processes,2 which is essential for molecular-level understanding

640

of aerosol health effects.

641 642

Ozone, OH, and NOx

643

A recent modeling study has shown that inhaled OH radicals are expected to be

644

reacted away very efficiently by antioxidants due to high reaction rate coefficients, whereas

645

inhalation of O3 can lead to a significant decrease in antioxidant concentrations.309 An

646

increase in O3 concentrations from ~ 30 ppb to 100 ppb leads to a decrease in the chemical

647

half-life of antioxidants from days to hours. Recently, Enami, et al. 310 reported that in acidic

648

(pH ≤ 5) ELF, GSH is oxidized by OH radicals forming sulfenic, sulfinic and sulfonic acids.

649

The exceptional specificity of the OH radical on the surface of water versus its lack of

650

selectivity in bulk water implicates a previously overlooked molecular recognition process

651

during [OH···GSH] interfacial encounter.310, 311 These results suggest that the redox balance

652

and signal transduction by ELF glutathione may involve sulfur oxoacids (e.g., GSH-sulfenic

653

acid) rather than the previously assumed GSSG disulfide.312, 313

654

O3 oxidative aggression can also be transduced across the ELF by deleterious

655

secondary oxidants generated by the rapid ozonolysis of sacrificial antioxidants.314 These

656

secondary oxidants require a lifetime of only a few μs in order to diffuse through ELF. A

657

previous study revealed that these secondary oxidants are not O2-, H2O2, OH radicals, or Fe–

658

O complexes.314 It is also known that the ascorbate anion reacts with O3 to produce the

659

non-toxic dehydroascorbic acid (DHA) at pH 7.315 However, Enami, et al. 316 demonstrated

660

that a previously unreported ascorbic ozonide (AOZ) is produced from the heterogeneous 22


Page 23 of 62


661

ozonolysis of ascorbic acid, specifically at the air-water interface. It is proposed that O3

662

adds to the C=C bond of AH2 under acidic conditions and generates an unstable primary

663

ozonide (POZ) that will open up to a Criegee intermediate (CI), followed by ring-reclosure

664

into a secondary AOZ; while DHA is dominantly formed at pH of 7 – 8.316 This interface-

665

specific mechanism would stem from the rapid ring reclosure of the CI rather than the

666

reaction with H2O at the air-water interface, where the water density is sharply decreasing.

667

These experimental results imply that the combination of inhaled O3, NO2 and PM2.5

668

may synergistically promote harmful effects, which is observed in an epidemiological

669

study,317 by an enhanced formation of AOZ, as PM2.5 is often highly acidic with pH as low as

670

~1 - 2318, 319 and inhalation of NO2 can also acidify the lung ELF.320 Furthermore, these

671

results emphasize the importance of interfacial chemistry and acidity, which may also

672

explain why asthmatic patients, whose lungs are known to be acidified to pH values as low

673

at 4.5, are more sensitive towards O3 than healthy people.321 Interfacial ozonolysis of other

674

components of the ELF, e.g., UA, GSH, α-Toc, also show unique mechanisms including

675

hitherto unreported interface-specific intermediates (e.g., UA-epoxide).322-325

676

Inhalation of NOx leads to the formation of reactive nitrogen species (RNS) including

677

nitrotyrosine, nitrite (NO2-) and nitrate (NO3-) that may cause nitrative stress to the lung

678

leading to disruptions in normal mechanisms of cellular signaling.326, 327 These species are

679

associated with allergic sensitization and lower pulmonary function.328 While NO2 can react

680

directly with antioxidants, lipids and proteins within the ELF, NO will react with O2- radicals

681

forming the highly reactive peroxynitrite molecule (ONOO-). Although ONOO- is itself a

682

strong oxidant, in the presence of carbon dioxide it has an extremely short half-life and

683

most of its effects are likely to be due to the formation of secondary oxidants such as

684

carbonate and nitrogen dioxide radicals.329 However, there remains uncertainty in the

685

effects and interactions of inhaled NOx with antioxidants and other ELF components and

686

further studies are warranted.2, 330-332

687 688

Reactive oxygen species from PM2.5

689

As reviewed in Sect. 4, PM2.5 contains particle associated ROS as well as redox-active

690

components that can lead to the production and transformation of ROS upon respiratory

691

deposition. As shown in Fig. 4(a), transition metal ions and quinones can react with 23



Page 24 of 62

692

antioxidants and oxygen forming superoxide, which can be converted to hydrogen peroxide

693

(H2O2) by the superoxide dismutase enzyme (SOD). H2O2 can be destroyed by Fenton

694

reactions forming the highly reactive OH radical.333-335 Copper and three different quinones

695

have previously been observed to lead to H2O2 formation, while both copper and iron have

696

been shown to lead to a significant production of OH radicals in surrogate lung fluid.335, 336

697

Recent studies have shown that quinones contained in humic-like substances (HULIS) may

698

form complexes with iron ions, promoting the formation of superoxide and OH radicals.337,

699

338

700

inflammatory and oxidative stress parameters.224, 267, 339

701

Other metal ions, such as Zn, As, Mn and Ni, have also been observed to impact

Lakey, et al.

309

modeled the ROS production rates and concentrations in the ELF

702

upon inhalation of PM2.5 for different locations and cities around the world. The model

703

contained over 50 known reactions and was constrained by experimental measurements

704

performed in surrogate ELF.335, 336 The chemical exposure-response relationship shown in

705

Fig. 4(b) provides a quantitative basis for assessing the importance of specific air pollutants

706

(such as transition metal ions, SOA and quinones) and for different regions of the world.

707

The green horizontal line represents the typical ROS concentrations in the ELF of healthy

708

people. In clean air, with low PM2.5 concentrations (< 10 μg m-3), all points fall below this

709

line indicating that the PM2.5 will have a negligible impact on oxidative stress. In

710

moderately polluted air the composition of the PM2.5, particularly copper and iron,

711

determines ROS concentrations. In highly polluted air (PM2.5 > 50 μg m-3) the calculated

712

ROS concentrations are similar to those found in the ELF of patients suffering from

713

respiratory diseases (100 – 250 nmol L-1),340, 341 strongly indicating that PM2.5 can cause

714

oxidative stress to lungs.

715

The generated ROS may trigger inflammation by interacting with pattern

716

recognition receptors, for example, the toll-like receptor 4 (TLR4). TLR4 consists of four

717

steps.342 Step 1 is the activation of the receptor of the innate immune system expressed on

718

and in leucocytes, epithelial cells and fibroblasts. In step 2, the triggered cells release pro-

719

inflammatory signal molecules like Tumor necrosis factor (TNFα) and Interleukin 1 (IL-1).

720

In step 3, these cell-cell communication molecules induce the release of cellular ROS and

721

RNS. This biological or endogenous ROS are actively produced by cells and usually secreted

722

to kill invading microbes. Endogenous molecules become oxidized or degraded (step 4) and 24


Page 25 of 62


723

some of these damaged molecules (damage associated molecular patterns, DAMPs) have

724

the ability to activate receptors (step 1 again). In this way the molecular loop closes. This

725

TLR4 radical cycle can become autonomous, self-amplifying and chronic.

726

PM may trigger the TLR radical cycle by inducing cytokine secretion or exogenous

727

ROS formation.343 It has been reported that a broad variety of species present in

728

nanoparticles (silica, iron, cobalt oxide, silver, nickel, copper ferrite, titanium dioxide)

729

induce ROS production in animal and plant tissue due to the generation of free chemical

730

radicals causing inflammation.344-350 Pathogens and other bio-molecules may act as DAMPs,

731

activating the receptors. Nickel and cobalt, which may be contained in ambient PM, can

732

directly dimerize the TLR4 receptors351 causing hypersensitivity to these bivalent

733

metals.352, 353 Recent studies suggest that SOA can influence gene expression in human

734

airway epithelial cells.354, 355 The common mechanism of many nanoparticles seems to be

735

the generation of chemical radicals and ROS/RNS, but further studies are clearly required

736

for a better mechanistic understanding and for elucidation of biological effects and cellular

737

responses.

738 739

7. Outlook

740

Active research over the last decades has made good progress toward

741

understanding aerosol health effects from global to molecular scales as reviewed in the

742

above sections. Nevertheless, because of the complex and interdisciplinary nature of

743

aerosol – health relationships, there remain many open questions that should be

744

addressed, and further studies are warranted to improve our comprehension in the

745

direction of therapies, and provide a basis for the targeted and optimal control of air

746

pollution emissions. Knowledge obtained in studies that cover different space and time

747

scales (e.g., Fig. 1) needs to be synthesized and integrated. Such integrated knowledge will

748

be useful and indispensable for public health planners, policymakers and regulators to

749

improve air quality.

750 751 752 753

For epidemiological studies and global modeling studies, we prioritize the following points for an improved assessment of mortality caused by air pollution:

Epidemiological studies clarifying the health effects of specific PM components and sources. The role of different components and oxidative potential of PM2.5 on health 25



754

impacts and premature mortality, e.g., the differential toxicity of organic and

755

inorganic pollutants, needs to be investigated.

756

Improvement of IER functions, especially by epidemiological cohort studies in

757

regions where such studies have not yet been performed, especially in Asia and

758

Africa. Improved quantification of PM2.5 concentrations, and the associated chemical

759

composition and related source categories are required.

760

Page 26 of 62

IER functions of natural PM should be identified, including biogenic and Aeolian dust

761

PM, and contrasted with anthropogenic PM (including anthropogenic bioaerosols).

762

Integration of personal exposure assessments using novel and low-cost devices.

763 764 765 766

For better understanding of PM health-related properties such as toxicity, redox activity and oxidative potential, we propose that the following aspects are addressed:

A consensus on redox-activity and oxidative potential of PM components (e.g.,

767

metals, SOA, soot, diesel exhaust particles) as measured by different assays is

768

currently lacking. To resolve it, concurrent studies of multiple assays (i.e.,

769

macrophage-based and DTT assays, iodometric spectrophotometry, EPR) as well as

770

measurements of physical and chemical properties of PM are needed. Consolidation

771

of unified methodological approaches in sample preparation and treatment may be

772

required.

773

Identification and characterization of the major contributors (i.e. specific organic

774

compounds or elements) to the toxicity and allergenicity as well as quantification of

775

their abundance in ambient air and spatial distribution.

776 777

To advance mechanistic and molecular-level understanding of aerosol health effects

778

upon respiratory deposition, we need to acquire deeper insight into multiphase chemical

779

processes in lungs and cellular responses upon PM interactions:

780

•

Interactions of lung surfactants and antioxidants with atmospheric oxidants and PM

781

components need to be better understood. ROS formation efficiency of different PM

782

components should be quantified under different conditions (i.e., pH, antioxidant

783

and PM concentrations). Synergistic effects of co-deposition of atmospheric oxidants

784

and PM are poorly understood. 26


Page 27 of 62

785


•

Relative importance of different ROS (OH, O2-, H2O2, organic species and radicals) on

786

inflammation and cellular response is still unclear. The type of ROS that plays a

787

critical role in causing oxidative stress needs to be identified.

788

•

Interactions and effects of PM components and formed ROS with toll-like receptors

789

are largely unknown. PM components may also trigger cytokine formation and alter

790

gene expression. The combination and integration of chemical and biochemical

791

approaches are essential for in-depth understanding of the underlying processes.

792 793

Acknowledgements: This work is funded by DFG (No. SH 941/1-1) and JSPS (No.

794

15045811-000041). We thank participants of the workshop “Physicochemical Properties

795

of Atmospheric Aerosols and their Effects on Air Quality and Public Health” for active

796

discussions. MS thanks Kaori Shiraiwa for her help in managing references.

797 798

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348. Grassian, V. H.; O'Shaughnessy, P. T.; Adamcakova-Dodd, A.; Pettibone, J. M.; Thorne, P. S., Inhalation exposure study of titanium dioxide nanoparticles with a primary particle size of 2 to 5 nm. Environ. Health Perspect. 2007, 115, (3), 397-402. 349. Sundarraj, K.; Manickam, V.; Raghunath, A.; Periyasamy, M.; Viswanathan, M. P.; Perumal, E., Repeated exposure to iron oxide nanoparticles causes testicular toxicity in mice. Environ. Toxicol. 2017, 32, (2), 594-608. 350. Sies, H.; Berndt, C.; Jones, D. P., Oxidative Stress. Annual Review of Biochemistry 2017, 86, (1), 715-748. 351. Schmidt, M., et al., Crucial role for human Toll-like receptor 4 in the development of contact allergy to nickel. Nature immunology 2010, 11, (9), 814-9. 352. Raghavan, D.; Jain, R., Increasing awareness of sex differences in airway diseases. Respirology (Carlton, Vic.) 2016, 21, (3), 449-59. 353. Raghavan, B.; Martin, S. F.; Esser, P. R.; Goebeler, M.; Schmidt, M., Metal allergens nickel and cobalt facilitate TLR4 homodimerization independently of MD2. EMBO reports 2012, 13, (12), 1109-15. 354. Lin, Y.-H., et al., Gene Expression Profiling in Human Lung Cells Exposed to Isoprene-Derived Secondary Organic Aerosol. Environ. Sci. Technol. 2017, 51, (14), 8166-8175. 355. Lin, Y. H., et al., Isoprene-Derived Secondary Organic Aerosol Induces the Expression of Oxidative Stress Response Genes in Human Lung Cells. Environmental Science & Technology Letters 2016, 3, (6), 250-254. 356. Amann, M., et al., Cost-effective control of air quality and greenhouse gases in Europe: Modeling and policy applications. Environmental Modelling & Software 2011, 26, (12), 1489-1501. 357. Andersson, C.; Bergström, R.; Johansson, C., Population exposure and mortality due to regional background PM in Europe–Long-term simulations of source region and shipping contributions. Atmos. Environ. 2009, 43, (22), 3614-3620. 358. Kiesewetter, G.; Schoepp, W.; Heyes, C.; Amann, M., Modelling PM 2.5 impact indicators in Europe: Health effects and legal compliance. Environmental Modelling & Software 2015, 74, 201-211. 359. Boldo, E., et al., Health impact assessment of a reduction in ambient PM 2.5 levels in Spain. Environment International 2011, 37, (2), 342-348. 360. Fann, N.; Lamson, A. D.; Anenberg, S. C.; Wesson, K.; Risley, D.; Hubbell, B. J., Estimating the national public health burden associated with exposure to ambient PM2. 5 and ozone. Risk analysis 2012, 32, (1), 81-95. 361. Thompson, T. M.; Saari, R. K.; Selin, N. E., Air quality resolution for health impact assessment: influence of regional characteristics. Atmos. Chem. Phys. 2014, 14, (2), 969-978. 362. Nawahda, A.; Yamashita, K.; Ohara, T.; Kurokawa, J.; Yamaji, K., Evaluation of premature mortality caused by exposure to PM2. 5 and ozone in East Asia: 2000, 2005, 2020. Water, Air, & Soil Pollution 2012, 223, (6), 3445-3459. 363. Wang, J., et al., Assessment of short-term PM 2.5-related mortality due to different emission sources in the Yangtze River Delta, China. Atmos. Environ. 2015, 123, 440-448. 364. Ghude, S. D., et al., Premature mortality in India due to PM2. 5 and ozone exposure. Geophys. Res. Lett. 2016, 43, (9), 4650-4658. 365. Wang, M.; Xiao, G. G.; Li, N.; Xie, Y.; Loo, J. A.; Nel, A. E., Use of a fluorescent phosphoprotein dye to characterize oxidative stress‐induced signaling pathway components in macrophage and epithelial cultures exposed to diesel exhaust particle chemicals. Electrophoresis 2005, 26, (11), 2092-2108. 366. Geller, M. D.; Ntziachristos, L.; Mamakos, A.; Samaras, Z.; Schmitz, D. A.; Froines, J. R.; Sioutas, C., Physicochemical and redox characteristics of particulate matter (PM) emitted from gasoline and diesel passenger cars. Atmos. Environ. 2006, 40, (36), 6988-7004. 367. Biswas, S.; Verma, V.; Schauer, J. J.; Cassee, F. R.; Cho, A. K.; Sioutas, C., Oxidative potential of semi-volatile and non volatile particulate matter (PM) from heavy-duty vehicles retrofitted with emission control technologies. Environ. Sci. Technol. 2009, 43, (10), 3905-3912.

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368. Cheung, K. L., et al., Chemical characteristics and oxidative potential of particulate matter emissions from gasoline, diesel, and biodiesel cars. Environ. Sci. Technol. 2009, 43, (16), 6334-6340. 369. Gerlofs-Nijland, M. E., et al., Cell toxicity and oxidative potential of engine exhaust particles: impact of using particulate filter or biodiesel fuel blend. Environ. Sci. Technol. 2013, 47, (11), 5931-5938. 370. Dou, J.; Lin, P.; Kuang, B.-Y.; Yu, J. Z., Reactive Oxygen Species Production Mediated by Humic-like Substances in Atmospheric Aerosols: Enhancement Effects by Pyridine, Imidazole, and Their Derivatives. Environ. Sci. Technol. 2015, 49, (11), 6457-6465. 371. De Vizcaya-Ruiz, A., et al., Characterization and in vitro biological effects of concentrated particulate matter from Mexico City. Atmos. Environ. 2006, 40, 583-592. 372. Verma, V.; Polidori, A.; Schauer, J. J.; Shafer, M. M.; Cassee, F. R.; Sioutas, C., Physicochemical and toxicological profiles of particulate matter in Los Angeles during the October 2007 southern California wildfires. Environ. Sci. Technol. 2009, 43, (3), 954-960. 373. Chan, J. K., et al., Combustion-derived flame generated ultrafine soot generates reactive oxygen species and activates Nrf2 antioxidants differently in neonatal and adult rat lungs. Part. Fibre Toxicol. 2013, 10, (1), 1. 374. Verma, V.; Rico-Martinez, R.; Kotra, N.; King, L.; Liu, J.; Snell, T. W.; Weber, R. J., Contribution of water-soluble and insoluble components and their hydrophobic/hydrophilic subfractions to the reactive oxygen species-generating potential of fine ambient aerosols. Environ. Sci. Technol. 2012, 46, (20), 11384-11392. 375. Ntziachristos, L.; Froines, J. R.; Cho, A. K.; Sioutas, C., Relationship between redox activity and chemical speciation of size-fractionated particulate matter. Part. Fibre Toxicol. 2007, 4, (1), 1. 376. Wang, B., et al., Properties and inflammatory effects of various size fractions of ambient particulate matter from Beijing on A549 and J774A. 1 cells. Environ. Sci. Technol. 2013, 47, (18), 1058310590. 377. Fang, T.; Verma, V.; Guo, H.; King, L. E.; Edgerton, E. S.; Weber, R. J., A semi-automated system for quantifying the oxidative potential of ambient particles in aqueous extracts using the dithiothreitol (DTT) assay: results from the Southeastern Center for Air Pollution and Epidemiology (SCAPE). Atmos. Meas. Tech. 2015, 8, (1), 471-482. 378. Li, H.; Chen, Z. M.; Huang, L. B.; Huang, D., Organic peroxides' gas-particle partitioning and rapid heterogeneous decomposition on secondary organic aerosol. Atmos. Chem. Phys. 2016, 16, (3), 1837-1848. 379. Ng, N. L., et al., Secondary organic aerosol (SOA) formation from reaction of isoprene with nitrate radicals (NO3). Atmos. Chem. Phys. 2008, 8, (14), 4117-4140. 380. Nguyen, T. B.; Bateman, A. P.; Bones, D. L.; Nizkorodov, S. A.; Laskin, J.; Laskin, A., Highresolution mass spectrometry analysis of secondary organic aerosol generated by ozonolysis of isoprene. Atmos. Environ. 2010, 44, (8), 1032-1042. 381. Ziemann, P. J., Aerosol products, mechanisms, and kinetics of heterogeneous reactions of ozone with oleic acid in pure and mixed particles. Faraday Discuss. 2005, 130, 469-490. 382. Sato, K., et al., AMS and LC/MS analyses of SOA from the photooxidation of benzene and 1,3,5trimethylbenzene in the presence of NOx: effects of chemical structure on SOA aging. Atmos. Chem. Phys. 2012, 12, (10), 4667-4682.

46


Page 46 of 62

Page 47 of 62


1774

Table 1. National Environmental Standards for different size ranges of particulate matter

1775

(PM2.5, PM10, TSP). Political

United States

European Union

bodies PM2.5

PM10

PM2.5

PM10

µg m-3

µg m-3

µg m-3

µg m-3

–

–

–

–

Daily

35

150

Annual

12

PM Hourly

50 25

40

1776 Countries

Korea

China*

PM2.5

SPM

PM2.5

PM10

PM2.5

PM10

TSP

µg m-3

µg m-3

µg m-3

µg m-3

µg m-3

µg m-3

µg m-3

–

200

–

–

–

–

–

Daily

35

100

50

100

75

150

300

Annual

15

–

25

50

35

70

200

PM Hourly

1777

Japan

* Class 2 to be applied for urban and industrial areas.

1778

47



Page 48 of 62

1779

Table 2. Overview of recent studies that have applied regional atmospheric models for the

1780

assessment of premature mortality due to PM2.5 exposure. Regions

Models

Grid size Period

Threshold

References

(PM2.5) #1 Europe Europe

EMEP

50 km

2005, 2020 No threshold

Amann, et al. 356

0.4º

1997-2003

Andersson, et al.

(Eulerian) Europe

MATCH

No threshold

357

Europe

CHIMERE

7 km

2010, 2030

Kiesewetter, et al. 358

Spain

CMAQ/

18 km

2004, 2011 No assumption

Boldo, et al. 359

12km

2005

Fann, et al. 360

BenMAP USA

Asia

Continental CMAQ

No threshold

USA

/BenMAP

Eastern

CAMx

36/12/4 2005, 2014 No threshold

Thompson, et al.

USA

/BenMAP

km

361

East Asia

CMAQ

80 km

2000,

10 μg m-3

Nawahda, et al. 362

Wang, et al. 363

2005, 2020 YRD, China

CMAQ

4 km

2010

No threshold

36 km

2011

Burnett, et al. 26 Ghude, et al. 364

/BenMAP India

WRFChem

1781

#1

1782

Abbreviations: BenMAP, Benefits Mapping and Analysis Program; CAMx, Comprehensive

1783

Air Quality Model with Extensions; CMAQ, Community Multiscale Air Quality; C-R function,

1784

concentration-response function; EMEP, European Monitoring and Evaluation Programme;

1785

EU, European Union; MATCH, Multi-scale Atmospheric Transport and Chemistry; SIA,

1786

secondary inorganic aerosol; USA, United States of America; WRF-Chem, Weather Research

1787

and Forecasting model coupled with chemistry; YRD, Yangtze River Delta;

threshold PM2.5 concentration for mortality impacts.

1788

48


Page 49 of 62


1789

Table 3. Overview of measured DTT decay rates (pmol min-1 μg-1) that applied DTT assays

1790

for the assessment of the oxidation potential of particulate matter (PM) normalized by PM

1791

mass. Sampling site PM Source

Coarse

Fine

Ultrafine

2.5-10 μm

≤2.5 μm

≤1.0 μm

Sampling site Isoprene SOA

Chamber

Methacrolein SOA

2.10 ± 0.22

Chamber

Isoprene epoxydiol SOA

2.30 ± 0.27

Chamber

Methacrylic acid epoxide SOA

1.79 ± 0.16

Chamber

Toluene SOA

3.13 ± 0.30

Chamber

1,3,5-trimethylbenzene SOA

24.8±6.4

Chamber

Isoprene SOA

20.8±3.0

Chamber

α-pinene SOA

57.5±3.6

Chamber

Wood smoke

5.5±2.5

Chamber

Isoprene SOA

25.2±0.9

Chamber

α-pinene SOA

11.1±0.5

Chamber

β-caryophyllene SOA

25.4±5.4

Chamber

Pentadecane SOA

18.3±3.3

Chamber

m-xylene SOA

14.5±1.4

Chamber

Naphthalene SOA

30.7±10.3

Chamber

Diesel exhaust SOA

153.4±49.2

Chamber

DEP-Crude extract DEP-Aliphatic fraction

102±5

DEP

DEP-Aromatic fraction

0

DEP

DEP-Polar fraction

1

DEP

Diesel transient

53±11

DEP

Diesel steady state

39±50

DEP

Cat. DPF transient

34

DEP

Gasoline transient Vehicle baseline-different run conditions-Avg Vehicle with the Horizon trapdifferent run conditions-Avg Vehicle with continuously regenerating technologydifferent run conditions-Avg

110±20

Accord diesel

58±11

DEP DEP

DEP

Kramer, et al. 252

Jiang, et al. 254

Tuet, et al. 228

Fujitani, et al. 249

49.3±18.9

DEP

DEP

References

Wang, et al. 365

Geller, et al. 366

25±30 17±8 138±65

49


Biswas, et al. 367


DEP

Accord diesel with DPF

23±2

DEP

Corolla gasoline

19±2

DEP

Golf diesel

12±1

DEP

Golf biodiesel

18±3

DEP

Diesel vehicles without DPF

25±3

DEP

Diesel vehicles-with DPF 50% v/v biodiesel blend vehicles without DPF 50% v/v biodiesel blend vehicles-with DPF

DEP DEP

Cheung, et al. 368

32.1±41.4 41.4±13.8 Gerlofs-Nijland, et al. 369

11.0±1.4

DEP

High engine load

10.8±3.0

DEP

Medium engine load

61±12

DEP

Low engine load

23±15

DEP DEP

Coarse Avg Fine Avg Ship emissions-Nansha and Guangzhou-Avg

46±15 1±1

DEP

Page 50 of 62

McWhinney, et al. 232

6±4

DEP

Steady state at high idling

7.1±0.2

DEP

Japanese transient mode JC08

25.9±2.6

Dou, et al. 370

Gasoline direct injection particles

Secondary process-Nansha and Guangzhou-Avg

21.5±8.7

Field

Biomass burning emissionsGuangzhou

5.9±0.3

Field

USC-Avg

5.2±0.2

field

Claremont-Avg

9.7±6.5

24.3±19.0

314.7±324.9

field

USC campus

9.5±4.3

19.9±4.3

95.0±56.6

field

USC-morning samples

13±4

19±4

39±10

field

USC-afternoon

52±20

field

Mexico City-May

90±21

field

Mexico City-November

14.5±1.1

30.8±4.7

field

Los Angeles-During Fire

9.0±1.9

18.5±1.6

field field Field Field Field

Los Angeles-Post Fire Los Angeles-morning Los Angeles-afternoon Los Angeles-night Fresno, CA-summer Avg


Dou, et al. 370

26.8±1.4 24.5±1.8

50


Li, et al. 201 Hu, et al. 235

Verma, et al. 230

De Vizcaya-Ruiz, et al. 371 17±0.9 7.3±1.6 19.6±7.4 30.7±2.5 28.0±0.5

Verma, et al. 372

Saffari, et al. 262

Page 51 of 62


Field Field

Field Field Field Field

Fresno, CA-winter Avg Los Angeles west-annual Avg Los Angeles central -annual Avg Los Angeles east-annual Avg North of Los Angeles -annual Avg Ambient-Fresno, CA Urban site of Fresno, CA Rural site of Westside, CA Atlanta-water extract

23.3±1.0 44±17 22.5±2.5

Field Field

Atlanta-methanol extract Riverside of Downey-Avg

23.3±4.7 35.9±3.0

field

Peking University campus

23±8.0

38±21

Field

Urban Jefferson Street-Avg

8.1±1.0

11±0.6

Field Field

34 36

Field

Urban site of Birmingham-Avg Rural site of Yorkville-Avg Rural site of Centervillemedian Georgia Tech-Avg

Field

Tunnel-Avg

28±8

Field

Depot-Avg

Field Field

Isoprene-derived OA More-oxidized oxygenated OA

10.1±2.0 8.8±21

Field

Biomass burning OA

36±22

Field

Cooking OA

151±20

Field

Ambient PM

90±51

Field

Traffic intersection, Japan

10-70

Field Field Field

Field

80 50

48 39

Charrier, et al. 237

46.0±16.5 78.5±8.0

Saffari, et al. 253

66.7±18.5 62.5±11.6

30

Chan, et al. 373

Verma, et al. 374

82±46

Ntziachristos, et al. 375 Wang, et al. 376

Fang, et al. 377

40 10.3±2.1

1792 1793

51


Sauvain, et al. 255

Verma, et al. 233



Page 52 of 62

1794

Table 4. Overview of studies reporting the total organic peroxide content of laboratory-

1795

generated secondary organic aerosols (SOA). Peroxide in

assumed

SOA (w/w%)

MW

Ozonolysis Ozonolysis Photooxidation (low NOx) Photooxidation (high NOx) Ozonolysis Ozonolysis Ozonolysis Ozonolysis Ozonolysis Ozonolysis Photooxidation (low NOx) Photooxidation (high NOx) NO3 reaction Ozonolysis Ozonolysis Photooxidation (high NOx)

28-65 12-34 5-18 6 22 16-25 24-43 73-120 93-103 2 25-61 Not detected 17-32 ~30 68 16-18

300 300 300 300 273 300 300 300 300 200 242 242 433 300 330 242

Docherty, et al. 284 Mertes, et al. 287 Mertes, et al. 287 Mertes, et al. 287 Epstein, et al. 285 Li, et al. 378 Docherty, et al. 284 Docherty, et al. 284 Docherty, et al. 284 Bateman, et al. 288 Surratt, et al. 289 Surratt, et al. 289 Ng, et al. 379 Nguyen, et al. 380 Ziemann 381 Sato, et al. 290

Photooxidation (high NOx)

12

242

Sato, et al. 382

Photooxidation (low NOx) Photooxidation (high NOx)

26 28

172 172

Kautzman, et al. 291 Kautzman, et al. 291

SOA precursor

Oxidation condition

α-Pinene α-Pinene α-Pinene α-Pinene α-Pinene α-Pinene Δ3-Carene β-Pinene Sabinene Limonene Isoprene Isoprene Isoprene Isoprene Oleic acid Toluene 1,3,5Trimethylbenzene Naphthalene Naphthalene 1796

52


Reference

Page 53 of 62

1797


Figure

1798 1799

Figure 1. Studies on aerosol health effects cover a wide range of length and time scales.

1800

Different physico-chemical and biomedical approaches (colored boxes) are needed to

1801

address the multi-faceted aspects of aerosol health effects (italic font).

1802

53



Total mortality

E-Europe (non-EU)

67%

Per capita mortality

N-America 1.6

3%

China

6% 7% 30%

21%

per 1,000 person-years

Europe (EU-28)

Page 54 of 62

1.4 1.2 1.0 0.8 0.6 0.4 0.2 0

India

E-Europe (non-EU)

1803

China

India

Europe N-America (EU-28)

1804

Figure 2. About two thirds of the global mortality attributable to air pollution of 4.3

1805

million/year occur in China, India, Europe and N-America (left). While China and India lead

1806

in terms of total mortality, the per capita mortality is highest in Eastern Europe (right).

1807

Adapted from Lelieveld 14.

1808

54


Page 55 of 62


1809 1810

Figure 3. Literature estimates of global premature mortality attributed to outdoor air

1811

pollution by fine particulate matter (PM2.5). Red color indicates Global Burden of Disease

1812

review articles.

1813 1814

55



1815 1816

Figure 4. (a) Interaction of air pollutants and reactive oxygen species in the epithelial

1817

lining fluid (ELF) of human lungs. (b)Predicted ROS concentrations in the ELF upon

1818

inhalation and deposition of fine particulate matter (PM2.5). The data points reflect

1819

characteristic levels and variabilities of PM2.5 concentration and chemical composition for

1820

different geographic locations ranging from pristine rainforest to polluted megacities. The

1821

dashed green horizontal bar indicates the ROS level characteristic for healthy humans.

1822

Reproduced from Lakey, et al. 309.

1823

56


Page 56 of 62

Page 57 of 62


1824 1825

TOC figure

57



Page 58 of 62

Global & long-term health impacts

Distance

km

Respiratory diseases Oxidative stress

m Molecular μm interactions

nm

ns

seconds

Epidemiological studies

Field measurements (oxidants, PM2.5)

Cellular & acellular assays

Kinetic experiments Chemical analysis

Regional & Global Modeling

Local & short-term health impacts

Urban air pollution

Inflammation

hours

days Time


months

years

Page 59 of 62


Total mortality

E-Europe (non-EU)

Per capita mortality

N-America

1.6

3%

China

6% 7% 30%

21%

India

per 1,000 person-years

Europe (EU-28)

67%

1.4 1.2 1.0 0.8 0.6 0.4 0.2 0

E-Europe (non-EU)


China

India

Europe N-America (EU-28)



Page 60 of 62

O3 OH NOx

Redox-active components in PM2.5 quinones SOA transition metals proteins

lipids

Fe2+, Cu+ antioxidants Asc, UA, GSH, α-Toc secondary oxidants (POZ)

O2

.

O2-

H2O2

(b) -1

(a) Atmospheric ROS/RNS


ROS concentration (nmol L )

Page 61 of 62

OH

Physiological ROS/RNS ONOONO

oxidative stress, inflammation, interactions with receptors

300 250 200 150 100 50 0 1

2

4

6 8

10

2

4

6 8

100

2

4 -3

PM 2.5 concentration (μg m )

lung cells, tissue


6 8

1000

Environmental Science & Technology Page 62&of 62 Regional Global Modeling

Distance

km Epidemiological studies Field measurements (oxidants, PM2.5)

m

Cellular & acellular assays

μm nm


Kinetic experiments Chemical analysis

ns

seconds

hours

days Time

months

years

Aerosol Health Effects from Molecular to Global Scales

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