Chapter 2. Integrative Health and Welfare Effects Overview 

1 The subsequent chapters of this ISA will present the most policy-relevant information related 

2 to this review of the NAAQS for O3. This chapter integrates the key findings from the disciplines 

3 evaluated in this current assessment of the O3 scientific literature, which includes the atmospheric 

4 sciences, ambient air data analyses, exposure assessment, dosimetry, health studies 

5 (e.g., toxicological, controlled human exposure, and epidemiologic), and welfare effects. The EPA 

6 framework for causal determinations described in Chapter 1 has been applied to the body of 

7 scientific evidence in order to collectively examine the health or welfare effects attributed to O3 

8 exposure in a two-step process. 

9 As described in Chapter 1, EPA assesses the results of recent relevant publications, building 

10 upon evidence available during the previous NAAQS review, to draw conclusions on the causal 

11 relationships between relevant pollutant exposures and health or environmental effects. This ISA 

12 uses a five-level hierarchy that classifies the weight of evidence for causation: 

13  Causal relationship 

14  Likely to be a causal relationship 

15  Suggestive of a causal relationship 

16  Inadequate to infer a causal relationship 

17  Not likely to be a causal relationship 

18 Beyond judgments regarding causality are questions relevant to quantifying health or 

19 environmental risks based on our understanding of the quantitative relationships between pollutant 

20 exposures and health or welfare effects. Once a determination is made regarding the causal 

21 relationship between the pollutant and outcome category, important questions regarding quantitative 

22 relationships include: 

23  What is the concentration-response or dose-response relationship? 

24  Under what exposure conditions (amount deposited, dose or concentration, duration and 

25 pattern) are effects observed? 

Note: Hyperlinks to the reference citations throughout this document will take you to the NCEA HERO database (Health and 

Environmental Research Online) at http://epa.gov/hero. HERO is a database of scientific literature used by U.S. EPA in the process of 

developing science assessments such as the Integrated Science Assessments (ISA) and the Integrated Risk Information System (IRIS). 

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1  What populations appear to be differentially affected i.e., more susceptible to effects? 

2  What elements of the ecosystem (e.g., types, regions, taxonomic groups, populations,
 

3 functions, etc.) appear to be affected or are more sensitive to effects?
 

4 To address these questions, in the second step of the EPA framework, the entirety of 

quantitative evidence is evaluated to identify and characterize potential concentration-response 

6 relationships. This requires evaluation of levels of pollutant and exposure durations at which effects 

7 were observed for exposed populations including potentially susceptible populations. 

8 This chapter summarizes and integrates the newly available scientific evidence that best 

9 informs consideration of the policy-relevant questions that frame this assessment, presented in 

Chapter 1. Section 2.1 discusses the trends in ambient concentrations and sources of O3 and provides 

11 a brief summary of ambient air quality for short- and long-term exposure durations. Section 2.2 

12 presents the evidence regarding personal exposure to ambient O3 in outdoor and indoor 

13 microenvironments, and it discusses the relationship between ambient O3 concentrations and 

14 exposure to O3 from ambient sources. Section 2.3 provides a discussion of the dosimetry and mode 

of action evidence for O3 exposure. Section 2.4 integrates the evidence for studies that examine the 

16 health effects associated with short- and long-term exposure to O3 and discusses important 

17 uncertainties identified in the interpretation of the scientific evidence. Section 2.5 provides a 

18 discussion of policy-relevant considerations, such as potentially susceptible populations, lag 

19 structure, and the O3 concentration-response relationship. Section 2.6 integrates the health evidence 

from the different scientific disciplines and exposure durations. Finally, Section 2.7 summarizes the 

21 evidence for welfare effects related to O3 exposure, and Section 2.8 reviews the literature on climate 

22 and UV-B. 

2.1. Atmos pheric Chemis try and Ambient Concentrations 

23 In the stratosphere, O3 serves the beneficial role of blocking the Sun's harmful ultraviolet 

24 radiation and preventing the majority of it from reaching the Earth's surface. In the troposphere, 

however, O3 and other photochemical oxidants are air pollutants with potentially harmful effects on 

26 living organisms and materials. Chapter 3 of this review addresses the atmospheric chemistry 

27 associated with tropospheric O3 and other related photochemical oxidants and provides a detailed 

28 analysis of recent surface-level concentrations. This material builds on information reported in the 

29 2006 O3 AQCD (U.S. EPA, 2006, 088089). Topics covered below and addressed in further detail in 

Chapter 3 include: (1) physical and chemical processes of O3 formation and removal; 

31 (2) atmospheric modeling; (3) policy relevant background concentrations; (4) monitoring techniques 

32 and networks; and (5) ambient concentrations. 

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2.1.1. Phys ical and Chemical Proces s es 

1 Ozone in the troposphere is a secondary pollutant; it is formed by photochemical reactions of 

2 precursor gasses and is not directly emitted from specific sources. Ozone and other oxidants, such as 

3 peroxyacetyl nitrate (PAN) and hydrogen peroxide (H2O2) form in polluted areas by atmospheric 

4 reactions involving two main classes of precursor pollutants: VOCs and NOX. Carbon monoxide 

(CO) is also important for O3 formation in polluted areas and in the remote troposphere. The 

6 formation of O3, other oxidants and oxidation products from these precursors is a complex, nonlinear 

7 function of many factors: (1) the intensity and spectral distribution of sunlight; (2) atmospheric 

8 mixing; (3) concentrations of precursors in the ambient air and the rates of chemical reactions of 

9 these precursors; and (4) processing on cloud and aerosol particles. 

Ozone is present not only in polluted urban atmospheres but throughout the troposphere, even 

11 in remote areas of the globe. The same basic processes involving sunlight-driven reactions of NOX, 

12 VOCs and CO contribute to O3 formation throughout the troposphere. These processes also lead to 

13 the formation of other photochemical products, such as PAN, nitric acid (HNO3), and sulfuric acid 

14 (H2SO4), and to other compounds, such as formaldehyde (HCHO) and other carbonyl compounds. 

2.1.1.1. Gas Phas e Reac tio ns Lea din g to Ozone Form atio n and Los s 

Photochemical processes involved in O3 formation are relatively well understood and were 

16 reviewed in detail in the 2006 O3 AQCD (U.S. EPA, 2006, 088089). The photochemical formation of 

17 O3 in the troposphere proceeds through the photolysis of nitrogen dioxide (NO2) to yield nitric oxide 

18 (NO) and a ground-state oxygen atom, O(3P), which then reacts with molecular oxygen (O2) to form 

19 O3. Free radicals formed in the atmosphere through the oxidation of VOCs and CO proceed to 

oxidize NO back to NO2, hence perpetuating the O3 forming cycle. In urban areas, VOCs and CO are 

21 both important for O3 formation. In nonurban vegetated areas, biogenic VOCs emitted from 

22 vegetation tend to be the most important. In the remote troposphere, methane (CH4) – structurally the 

23 simplest VOC – and CO are the main carbon-containing precursors to O3 formation. A schematic 

24 overview of the major photochemical cycles influencing O3 in the troposphere and the stratosphere is 

given in Figure 3-1. 

26 Ozone is lost through a number of gas phase reactions and deposition to surfaces. The reaction 

27 of O3 with NO to produce NO2 mainly results in the recycling of O3 downwind via the 

28 recombination of O(3P) with O2 to reform O3. By itself, this reaction does not lead to a net change in 

29 O3 unless the NO2 is converted to a stable end product such as HNO3 or a temporary reservoir 

product such as PAN. Ozone also reacts with unsaturated hydrocarbons and with hydrogen 

31 containing free radicals (OH, HO2). Recent field studies aimed at obtaining a better understanding of 

32 atmospheric chemical processes involved in O3 formation are discussed in Section 3.2. 

33 Convective processes and small scale turbulence transport O3 and other pollutants both upward 

34 and downward throughout the planetary boundary layer and the free troposphere. In many areas of 

the U.S., O3 and its precursors can be transported over long distances, aided by vertical mixing. The 

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1 transport of pollutants downwind of major urban centers is characterized by the development of 

2 urban plumes. Meteorological conditions, small-scale circulation patterns, localized chemistry, and 

3 mountain barriers can influence mixing on a smaller scale, resulting in frequent heterogeneous O3 

4 concentrations across an individual urban area. More details and observations of these processes are 

included in Section 3.2 and Section 3.6. 

2.1.1.2. Sourc e s of Pre c urs o rs Involve d in Ozone Formation 

6 Emissions of O3 precursor compounds (NOX, VOCs, and CO) can be divided into 

7 anthropogenic and natural source categories. Natural sources can be further divided into biogenic 

8 from vegetation, microbes, and animals, and abiotic from biomass burning, lightning, and geogenic 

9 sources. However, the distinction between natural sources and anthropogenic sources is often 

difficult to make in practice, as human activities affect directly or indirectly emissions from what 

11 would have been considered natural sources during the preindustrial era. The magnitudes of O3 

12 precursor sources are strongly location- and time-dependent and so average emission estimates 

13 should not be used to apportion sources of exposure. More details on O3 precursor emission 

14 inventories are included in Section 3.2. 

2.1.2. Atmo s ph e ric Mo delin g 

Chemistry-transport models (CTMs) have been widely used to compute the interactions 

16 among atmospheric pollutants and their transformation products, and the transport and deposition of 

17 pollutants. They have also been widely used to improve our basic understanding of atmospheric 

18 chemical processes and to develop control strategies. The main components of a comprehensive 

19 atmospheric chemistry modeling system are shown in Figure 3-5 and are discussed in more detail in 

Section 3.3. 

21 The domains of CTMs extend from a few hundred kilometers on a side to the entire globe. 

22 Most major regional (i.e., sub-continental) scale air-related modeling efforts at EPA rely on the 

23 Community Multi-scale Air Quality modeling system (CMAQ). CMAQ’s horizontal domain 

24 typically extends over North America with efforts underway to extend it over the entire Northern 

Hemisphere. The upper boundary for CMAQ is typically set at 100 hPa, which is located on average 

26 at about 16-km altitude. CMAQ is most often driven by the MM5 mesoscale meteorological model, 

27 though it may be driven by other meteorological models including the Weather Research Forecasting 

28 (WRF) model and the Regional Atmospheric Modeling System (RAMS). Other major air quality 

29 systems used for regional scale applications include The Comprehensive Air Quality Model with 

extensions (CAMx) and the Weather Research and Forecast model with Chemistry (WRF/Chem). 

31 Fine scale resolution is necessary to resolve features which can affect pollutant concentrations 

32 such as urban heat island circulation; sea breezes; mountain and valley breezes; and the nocturnal 

33 low-level jet. Horizontal domains are typically modeled by nesting a finer grid model within a larger 

34 domain model of coarser resolution. Caution must be exercised in using nested models because 

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1 certain parameterizations like those for convection might be valid on a relatively coarse grid scale 

2 but may not be valid on finer scales and because incompatibilities can occur at the model boundaries. 

3 The use of finer resolution in CTMs will require advanced parameterizations of meteorological 

4 processes such as boundary layer fluxes, deep convection, and clouds, and necessitate finer-scale 

inventories of land use, source locations, and emission inventories. 

6 Because of the large number of chemical species and reactions that are involved in the 

7 oxidation of realistic mixtures of anthropogenic and biogenic hydrocarbons, condensed mechanisms 

8 must be used to simplify atmospheric models. These mechanisms can be tested by comparison with 

9 smog chamber data. However, the existing chemical mechanisms often neglect many important 

processes such as the formation and subsequent reactions of long-lived carbonyl compounds, the 

11 incorporation of the most recent information about intermediate compounds, and heterogeneous 

12 reactions involving cloud droplets and aerosol particles. As a result, models such as CMAQ have had 

13 difficulties with capturing the regional nature of O3 episodes, in part because of uncertainty in the 

14 chemical pathways converting NOX to HNO3 and recycling of NOX. 

Each of the model components shown in Figure 3-5 has associated uncertainties and the 

16 relative importance of these uncertainties varies with the modeling application. The largest errors in 

17 photochemical modeling are still thought to arise from the meteorological and emissions inputs to 

18 the model. Algorithms must be used for simulating meteorological processes that occur on spatial 

19 scales smaller than the model's grid spacing and for calculating the dependence of emissions on 

meteorology and time. Significant errors in emissions can occur if inappropriate assumptions are 

21 used in these parameterizations. 

22 The performance of CTMs must be evaluated by comparison with field data as part of a cycle 

23 of model evaluations and subsequent improvements. Discrepancies between model predictions and 

24 observations can be used to point out gaps in current understanding of atmospheric chemistry and to 

spur improvements in parameterizations of atmospheric chemical and physical processes. 

2.1.3. Policy Relevant Background Concentrations 

26 The background concentrations of O3 that are useful for risk and policy assessments informing 

27 decisions about the NAAQS are referred to as policy-relevant background (PRB) concentrations. 

28 PRB concentrations have historically been defined by EPA as those concentrations that would occur 

29 in the U.S. in the absence of anthropogenic emissions in continental North America (CNA) defined 

here as the U.S., Canada, and Mexico. For this document, PRB concentrations include contributions 

31 from natural sources everywhere in the world and from anthropogenic sources outside CNA. 

32 Contributions to PRB O3 include photochemical reactions involving natural emissions of 

33 VOCs, NOX, and CO as well as the long-range transport of O3 and its precursors from outside CNA 

34 and the stratospheric-tropospheric exchange (STE) of O3. Natural sources of O3 precursors include 

biogenic emissions, wildfires, and lightning. Biogenic emissions from agricultural activities in CNA 

36 are not considered in the formation of PRB O3. PRB O3 sources and concentrations are summarized 

37 here with further details in Section 3.4. 

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2.1.3.1. Contributions from a n throp oge nic e mis s ions ou ts ide North Ame ric a 

1 Because the mean tropospheric lifetime of O3 is 30-35 days, O3 can be transported from 

2 continent to continent and around the globe in the Northern Hemisphere and O3 produced by U.S. 

3 emissions can be recirculated around northern mid-latitudes back to the U.S. High elevation sites are 

4 most susceptible to the intercontinental transport of pollution, particularly during spring. Surface 

PRB O3 contributions are much smaller than those derived in the free troposphere because of 

6 dilution and chemical destruction during downward transport to the surface. There are no instances 

7 where direct observation of PRB contributions from anthropogenic emissions outside North America 

8 are directly observable; careful screening of observations and application of photochemical models 

9 must be used instead to estimate anthropogenic contributions to PRB from sources outside North 

America. 

2.1.3.2. Contributions from the s tra tos phere 

11 Ozone is produced naturally by photochemical reactions in the stratosphere and some of this 

12 O3 is transported downward into the troposphere throughout the year in a process known as 

13 tropopause folding. Maximum stratospheric contributions occur during late winter and early spring, 

14 particularly behind cold fronts that mix tropospheric and stratospheric air. Stratospheric intrusions 

that reach the surface are rare. Much more common are intrusions which penetrate only to the middle 

16 and upper troposphere. However, O3 transported to the upper and middle troposphere can still affect 

17 surface concentrations through various exchange mechanisms that mix air from the free troposphere 

18 with air in the planetary boundary layer. There is considerable uncertainty in the magnitude and 

19 distribution of this potentially important source of tropospheric O3. 

2.1.3.3. Natural s o urces o f prec urs o rs to PRB Ozone forma tion 

Biogenic sources of VOC and CO emissions contribute to precursors to PRB O3 formation. 

21 These sources were discussed above in Section 2.1.1.1 with further details in Section 3.2. 

22 Biomass burning in the form of wildfires and prescribed fires contribute to NOX, CO and 

23 VOCs, precursors to PRB O3 formation. Biomass burning exhibits strong seasonality and interannual 

24 variability, with most biomass burned during the local dry season. There is considerable uncertainty 

in attributing the fraction of wildfire emissions to human activities because the emissions from 

26 naturally occurring fires that would have been present in the absence of fire suppression practices are 

27 not known. 

28 Lightning is also a source for NOX production. Although total column estimates of lightning 

29 produced NOX are substantial, this source does not contribute substantially to the NOX burden in the 

continental boundary layer. This is because only 2% of NOX production by lightning occurs within 

31 the boundary layer and most occurs in the free troposphere where much of the NOX produced is 

32 converted to more oxidized nitrogen species during downward transport. 

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2.1.3.4. Es tima ting PRB Concentra tions 

There are two approaches to estimating PRB concentrations that have been considered thus 

far. The first involves using measurements and the second the use of chemistry-transport models. 

The 2006 O3 AQCD (Section 3.9) (U.S. EPA, 2006, 088089) noted that estimates of PRB 

concentrations cannot be obtained solely by examining measurements of O3 obtained at relatively 

remote monitoring sites in the U.S. because of the long-range transport from anthropogenic source 

regions within North America. The 2006 AQCD also noted that it is impossible to determine sources 

of O3 without ancillary data that could be used as tracers of sources or to calculate photochemical 

production and loss rates. Furthermore, the use of monitoring data is limited to the edges of the 

domain of interest because PRB O3 entering from outside North America is destroyed over North 

America either through chemical reactions or by deposition. Within North America, PRB O3 is only 

produced by natural sources. Therefore, the current definition of PRB implies that only CTMs can be 

used to estimate the range of PRB values. A further advantage to using models is that the entire range 

of O3 concentrations in different environments can be used to evaluate model performance. 

However, there may be specific instances such as stratospheric intrusions that occur on spatial scales 

too fine to be resolved by the current generation of global CTMs. 

Estimates of PRB concentrations for April-May, 2001 (Figure 3-9) and June-August, 2001 

(Figure 3-10) from the GEOS-Chem model used in the 2006 O3 AQCD (U.S. EPA, 2006, 088089) 

are described in Section 3.4. These estimates indicated that PRB O3 concentrations in the U.S. 

surface air were generally 15-35 ppb from June through August. Concentrations decline from spring 

to summer and are generally <25 ppb under conditions conducive to high O3 episodes. PRB O3 

concentrations may be higher, especially at high altitude sites during the spring, due to enhanced 

contributions from (1) pollution sources outside North America; and (2) stratospheric O3 exchange. 

Simulated monthly mean concentrations in different quadrants of the U.S. are typically within 

5 ppbv of observations at remote CASTNET sites, with no significant bias, except in the Southeast 

in summer when the model is 8-12 ppbv too high. This bias might be due to excessive background 

O3 transported in from the Gulf of Mexico and the tropical Atlantic Ocean or to inaccuracies in 

emissions inventories within the U.S. The model reproduced the occurrences of relatively high O3 at 

remote sites, and shows that these can generally be explained by North American pollution. 

Although many of the features of the day-to-day variability of O3 at relatively remote 

monitoring sites in the U.S. are simulated reasonably well, uncertainties in the calculation of the 

temporal variability of O3 originating from different sources on shorter time scales must be 

recognized. The uncertainties stem in part from an underestimate in the seasonal variability in the 

STE of O3, the geographical variability of this exchange, and the variability in the exchange between 

the free troposphere and the planetary boundary layer in the model. In addition, the relatively coarse 

spatial resolution in the model (2°×2.5°) limited the ability to provide separate estimates for cities 

located close to each other, and so only regional estimates were provided for the 2006 O3 AQCD 

(U.S. EPA, 2006, 088089). 

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2.1.4. Mo nito rin g 

2.1.4.1. Ro utine Mo nitorin g Te c hnique s 

1 The Federal Reference Method (FRM) for O3 measurement is called the Chemiluminescence 

2 Method (CLM) and is based on the detection of chemiluminescence resulting from the reaction of O3 

3 with ethylene gas. The first ultraviolet (UV) absorption photometric analyzers were approved as 

4 Federal Equivalent Methods (FEMs) in 1977 and gained rapid acceptance for NAAQS compliance 

purposes due to ease of operation, relatively low cost, and reliability. Almost all of the state or local 

6 air monitoring stations (SLAMS) that reported data to EPA Air Quality System (AQS) from 2005 to 

7 2009 used UV absorption photometer FEMs and greater than 96% of O3 monitors met precision and 

8 bias goals during this period. The rationale, history, and calibration of O3 measurements were 

9 summarized in the 1996 O3 AQCD (U.S. EPA, 1996, 017831) and the 2006 O3 AQCD (U.S. EPA, 

2006, 088089) and focused on the state of ambient O3 measurements at that time as well as 

11 evaluation of interferences and new developments. Section 3.5 in this review includes the current 

12 state of O3 measurements, interferences, and new developments for the period 2005-2009. 

13 Satellite observations for O3 are growing as a resource for many purposes, including model 

14 evaluation, assessing emissions reductions, pollutant transport, and air quality management. Satellite 

remote sensing instruments do not directly measure the composition of the atmosphere. Satellite 

16 retrievals are conducted using the solar backscatter or thermal infrared emission spectra and a variety 

17 of algorithms. Most satellite measurement systems have been developed for stratospheric 

18 measurement of the total O3 column. Mathematical techniques have been developed and must be 

19 applied to derive information from these systems about tropospheric O3. 

2.1.4.2. Ambient Ozone Ne twork Des ign 

To support the NAAQS, state and local monitoring agencies must operate O3 monitors at 

21 various locations depending on the area size and typical peak concentrations (expressed in 

22 percentages below, or near the O3 NAAQS). SLAMS make up the ambient air quality monitoring 

23 sites that are primarily needed for NAAQS comparisons and include Photochemical Assessment 

24 Monitoring Stations (PAMS), National Core (NCore), and all other State or locally-operated stations 

except for the monitors designated as special purpose monitors (SPMs). 

26 In 2009, there were 1208 SLAMS O3 monitors reporting values to the EPA AQS database 

27 (Figure 3-16). Since O3 levels decrease significantly in the colder parts of the year in many areas, O3 

28 is required to be monitored at SLAMS monitoring sites only during the “O3 season.” PAMS provides 

29 more comprehensive data on O3 in areas classified as serious, severe, or extreme nonattainment for 

O3. There were a total of 119 PAMS reporting values to the EPA AQS database in 2009. NCore is a 

31 new multi-pollutant monitoring network currently being implemented to meet multiple monitoring 

32 objectives. Each state is required to operate at least one NCore site and the network will consist of 

33 about 60 urban and 20 rural sites nationwide. 

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1 The Clean Air Status and Trends Network (CASTNET) is a regional monitoring network 

2 established to assess trends in acidic deposition and also provides concentration measurements of O3. 

3 CASTNET O3 monitors operate year round and are primarily located in rural areas. At the beginning 

4 of 2010, there were 80 CASTNET sites located in, or near, rural areas. The NPS also operates a 

Portable Ozone Monitoring Systems (POMS) network. The POMS couples the small, low-power O3 

6 monitor with a data logger, meteorological measurements, and solar power in a self contained system 

7 for monitoring in remote locations. Twenty NPS POMS reported O3 data to AQS in 2010. A map of 

8 the current and proposed rural NCore sites, along with the CASTNET, and the NPS POMS sites is 

9 shown in Figure 3-17. 

2.1.5. Ambient Concentrations 

Ozone is the only photochemical oxidant other than NO2 that is routinely monitored and for 

11 which a comprehensive database exists. Data for other photochemical oxidants typically have been 

12 obtained only as part of special field studies. Most continuous O3 monitors report hourly average 

13 concentrations. This data can be used as reported 1-h avg, or reported as a daily metric such as: (1) 

14 the average of the hourly observations over a 24-h period (24-h avg); (2) the maximum hourly 

observation occurring in a 24-h period (1-h daily max); and (3) the maximum 8-h running average of 

16 the hourly observations occurring in a 24-h period (8-h daily max). 

17 Section 3.6.1 includes an analysis of U.S. O3 data reported to AQS between 2007 and 2009. 

18 The median 1-h daily max, 8-h daily max, and 24-h avg O3 concentrations across all sites were 44, 

19 40, and 29 ppb, respectively. The 98th percentiles of these same metrics across all sites were 86, 74, 

and 55 ppb, respectively. The 8-h daily max and 1-h daily max metrics were highly correlated 

21 (median r = 0.97, IQR = 0.96-0.98) while comparisons with the 24-h avg metric were lower (e.g., 

22 median r = 0.83, IQR = 0.78-0.88 for comparison between the 24-h avg and the 1-h daily max). The 

23 ratio and correlation between these metrics, however, can be very site-specific. 

2.1.5.1. Urba n -Foc us ed S patial Va riability 

24	 AQS O3 concentrations were used to investigate urban-focused spatial variability in 

Section 3.6.2. Figure 3-22 contains the county-scale 8-h daily max O3 concentrations from the 

26 highest monitor within each U.S. county for 2007-2009 (top map) with seasonal stratification 

27 (bottom 4 maps). This map is only meant to illustrate the general spatial and temporal distribution in 

28 nationwide O3 concentrations, and is limited by monitor availability, resulting in the majority of U.S. 

29 counties not having available data. Furthermore, this map is not representative of O3 concentrations 

at all locations or times within the counties shown; considerable spatial variability can and does exist 

31 within a county. 

32 The highest 3-yr avg (2007-2009) 8-h daily max O3 concentrations (≥ 50 ppb), shown in 

33 Figure 3-22, occur in counties in southern California, Arizona, Colorado and Tennessee. The lowest 

34 monitored 3-yr avg 8-h daily max O3 concentrations (<30 ppb) occur in Pacific Coast counties in 

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1 northern California and Washington, as well as in two northeastern counties in Pennsylvania and 

2 Massachusetts. The seasonally-stratified county-scale maps in the lower half of Figure 3-22 illustrate 

3 the strong seasonality in 8-h daily max O3 concentrations. 

4 To investigate urban-scale variability, 20 focus cities were selected for closer analysis here and 

in Section 3.6.2; these cities were selected based on their importance in O3 epidemiology studies and 

6 on their geographic distribution across the U.S. The warm season (May-September) distribution of 

7 the 8-h daily max O3 concentrations from 2007-2009 for the 20 focus cities is included in Table 3-10. 

8 Box plots of the distribution of 2007-2009 warm-season 8-h daily max O3 data from each 

9 individual monitor in the 20 focus cities were used in Section 3.6.2 to investigate individual city 

variability in O3 concentrations. Several cities had relatively little spatial variability in 8-h daily max 

11 O3 concentrations (e.g., correlations ranging from 0.61 to 0.96 in Atlanta) while other cities exhibited 

12 considerably more variability in O3 concentrations (e.g., correlations ranging from -0.06 to 0.97 for 

13 Los Angeles). The negative and near-zero correlations in Los Angeles were between monitors with a 

14 relatively large separation distance (>150 km), but even some of the closer monitor pairs were not 

very highly correlated. Similar to the correlation, the coefficient of divergence (COD) was found to 

16 be highly dependent on the urban area under investigation. As a result, caution should be observed in 

17 using data from a sparse network of ambient O3 monitors to approximate community-scale 

18 exposures. 

2.1.5.2. Rural-Focus e d Spa tial Variability 

19	 AQS O3 data for monitors located within six rural monitoring sites were used in Section 3.6.2 

to investigate rural-focused O3 concentration variability. These rural monitoring sites tend to be less 

21 directly affected by obvious anthropogenic pollution sources than urban sites. However, they can be 

22 regularly affected by transport of O3 or O3 precursors from upwind urban areas, or by local 

23 anthropogenic emissions within the rural areas such as emissions from motor vehicles, power 

24 generation, biomass combustion, or oil and gas operations. As a result, monitoring data from these 

rural locations are not unaffected by anthropogenic emissions. 

26 Box plots of 8-h daily max O3 concentrations measured at the 6 rural monitoring sites during 

27 the warm season (May-September) between 2007 and 2009 are shown in Figure 3-37. The sites 

28 include one in Adirondack State Park (ADSP) on Whiteface Mountain in Upstate NY, one in Mount 

29 Mitchell State Park (MMSP) in NC, five in Great Smoky Mountain National Park (SMNP) in NC 

and TN, one in Rocky Mountain National Park (RMNP) in CO, one in San Bernardino National 

31 Forest (SBNF), CA, and two in Sequoia National Park (SENP), CA. Within SMNP, the median 

32 warm-season 8-h daily max O3 concentration ranged from 47 ppb at the lowest elevation site 

33 (elevation = 564 m; site ID = 470090102) to 60 ppb at the highest elevation site (elevation = 2021 m; 

34 site ID = 471550102), with correlations between the 5 sites ranging from 0.78 to 0.92 and CODs 

ranging from 0.04 to 0.16. The correlation between the 2 sites in SENP was 0.86 and the COD was 

36 0.09. A host of factors may contribute to variations observed at these rural sites, including proximity 

37 to local O3 precursor emissions, variations in boundary-layer influences, meteorology and 

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1 stratospheric intrusion as a function of elevation, and differences in wind patterns and transport 

2 behavior due to local topography. Expanded analyses of O3 concentrations measured using the more 

3 rural-focused CASTNET monitoring network are included in Chapter 9. 

4 Since O3 produced from emissions in urban areas is transported to more rural downwind 

locations, elevated O3 concentrations can occur at considerable distances from urban centers. In 

6 addition, major sources of O3 precursors such as highways, power plants, biomass combustion, and 

7 oil and gas operations are commonly found in rural areas, adding to the O3 in these areas. Due to 

8 lower chemical scavenging in nonurban areas, O3 tends to persist longer in rural than in urban areas 

9 which tends to lead to higher cumulative exposures in rural areas influenced by anthropogenic 

precursor emissions. The persistently high O3 concentrations observed at many of these rural sites 

11 investigated here indicate that cumulative exposures for humans and vegetation in rural areas can be 

12 substantial and often higher than cumulative exposures in urban areas. 

2.1.5.3. Na tiona l Tre n ds 

13 Nationally, O3 concentrations have declined over the last decade, as shown in Figure 3-41 

14 from the 2010 National Air Quality Status and Trends report (U.S. EPA, 2010, 647278). The 

majority of this decline occurred before 2004 with national average concentrations remaining 

16 relatively flat between 2004 and 2008. The large decreases in 2003 and 2004 coincides with NOX 

17 emissions reductions resulting from implementation of the NOX State Implementation Plan (SIP) 

18 Call rule, which began in 2003 and was fully implemented in 2004. This rule was designed to reduce 

19 NOX emissions from power plants and other large combustion sources in the eastern U.S. 

As noted in the 2006 O3 AQCD (U.S. EPA, 2006, 088089), trends in national parks and rural 

21 areas are similar to nearby urban areas, reflecting the regional nature of O3 pollution. However, 

22 caution should be exercised in using trends calculated at national parks to infer contributions from 

23 distant sources either inside or outside of North America because of the influence of regional 

24 pollution. 

2.1.5.4. Ho urly Va ria tions 

Ozone concentrations show a strong degree of diel variability resulting from daily patterns in 

26 temperature, sunlight, and precursor emissions. Other factors, such as the relative importance of 

27 transport versus local photochemical production and loss rates, the timing for entrainment of air from 

28 the nocturnal residual boundary layer, and the diurnal variability in mixing layer height also play a 

29 role in daily O3 patterns. Urban diel variations investigated in Section 3.6.3.2 of this assessment 

show no substantial change in patterns since the 2006 O3 AQCD (U.S. EPA, 2006, 088089). The 1-h 

31 max concentrations tend to occur in mid-afternoon and 1-h min concentrations tend to occur in early 

32 morning, with more pronounced peaks in the warm months relative to the cold months. Diel patterns 

33 in O3 have remained stable over the last 20 years, with times of occurrence of the daily maxima 

34 varying by no more than an hour from year to year. There is city-to-city variability in these times, 

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1 however, and caution is raised in extrapolating results from one city to another in determining the
 

2 time of day for O3 maxima and minima.
 

2.1.5.5. As s ocia tions with Co -pollutants 

3 Since O3 is a secondary pollutant formed in the atmosphere from precursor emissions, it is not 

4 expected to be highly correlated with primary pollutants such as CO and NOX. Furthermore, O3 

5 formation is strongly influenced by meteorology, entrainment, and transport of both O3 and O3 

6 precursors, resulting in a broad range in correlations with other pollutants which can vary 

7 substantially with season. To investigate correlations with co-pollutants, 8-h daily max O3 was 

8 compared with co-located 24-h avg CO, SO2, NO2, PM2.5 and PM10 obtained from AQS for 

9 2007-2009. Figure 3-43 contains co-pollutant box plots of the correlation between co-located 

10 monitors for the year-round data set and broken down by season. 

11 The year-round 8-h daily max O3 data exhibited a very wide range in correlations with all the 

12 24-h avg co-pollutants. A clearer pattern emerged when the data are stratified by season with mostly 

13 negative correlations in the winter and mostly positive correlations in the summer for all co14 pollutants. The median seasonal correlations are modest at best with the highest positive correlation 

15 at 0.52 for PM2.5 in the summer and the highest negative correlation at -0.38 for PM2.5 in the winter. 

16 Spring and fall lie in between with spring having a slightly narrower distribution than fall for all co17 pollutants. Expanded discussion of co-pollutant correlation can be found in Section 3.6.4. 

2.2. Human Expos ure 

2.2.1. Expos ure Me as u re me n t 

2.2.1.1. Me a s ure me n t o f Ozone Exposure 

18 Passive badge samplers are the most widely used technique for measuring personal O3 

19 exposure. They operate on the nitrite-nitrate conversion principle, and are convenient since they 

20 require no pumps or wet chemistry in the field. They represent a cumulative (rather than continuous) 

21 sample, and their detection limit makes them suitable for monitoring periods of 24 hours or greater. 

22 This limits their applicability in measuring short-term daily fluctuations in personal exposure. Over a 

23 24-h period, the detection limit of the badges is approximately 5-10 ppb, which may result in an 

24 appreciable fraction of the samples being below the detection limit. An active sampler based on the 

25 nitrite-nitrate conversion reaction is also available, with a reported detection limit of 10 ppb-h, 

26 enabling measurement of sub-daily O3 concentrations. A portable continuous O3 monitor based on a 

27 different principle, UV absorption, has recently become available. Its size and weight make it 

28 suitable for use in a backpack configuration, although its use for personal exposure measurements 

29 has been limited. 

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Several studies described in the 2006 O3 AQCD, along with a few new studies published since, 

describe the relationship between indoor O3 concentration and the O3 concentration immediately 

outside the indoor microenvironment. These studies show that the indoor concentration is often 

substantially lower than the outdoor concentration unless indoor sources are present. Low indoor O3 

concentrations can be explained by reaction of O3 with surfaces and airborne constituents. However, 

the indoor-outdoor relationship is greatly affected by the air exchange rate; under conditions of high 

air exchange rate, such as open windows, the indoor O3 concentration may approach the outdoor 

concentration. In residential microenvironments, studies report indoor-outdoor ratios ranging from 

approximately 0.1-0.4, with the highest ratios observed in the summer O3 season and for homes with 

increased window ventilation. A correlation of 0.58 was reported between indoor and outdoor O3 

concentrations, indicating that variations in outdoor concentration may be reflected indoors, though 

the magnitude of the concentration is lower. Indoor-outdoor ratios at schools were similar, with 

higher ratios observed during the school day when opening doors and windows may lead to 

increased air exchange rates. In vehicles, high air exchange rates that would normally lead to high 

interior-exterior concentration ratios are offset by O3 scavenging through vehicle-emitted NO, 

resulting in reported in-vehicle concentrations that were approximately 50% of those measured at the 

roadside. 

The relationship between personal exposure and ambient O3 concentrations has been evaluated 

in several research studies, many of which were conducted prior to 2005 and are discussed in the 

2006 O3 AQCD. The results of these studies indicate that personal exposures are moderately well 

correlated with ambient concentrations, and that the ratio of personal exposure to ambient 

concentration is higher in outdoor microenvironments and during the summer season. In situations 

where a lack of correlation was observed, this may be due in part to a high proportion of personal 

measurements below the detection limit. Correlations reported for daily or multi-day measurements 

range from approximately 0.3-0.8, with the upper end of the range reflecting longer-duration (4-day) 

community average measurements that may limit the influence of inter-individual variability in 

exposure. Hourly measurements in specific microenvironments show greater variability in 

correlations between personal exposure and ambient concentration, with residential indoor 

correlations <0.1 and outdoor correlations of 0.7-0.9. Slopes from regression analyses of personal 

exposure on ambient concentration generally ranged from approximately 0.1-0.3. Higher slopes were 

observed in studies that either adjusted for activity pattern and air exchange rate (0.54) or focused on 

outdoor shoe cleaners (0.56), who may have increased exposure due to spending a substantial 

fraction of the day outdoors. Ratios of personal exposure to ambient concentration showed similar 

results, with a ratio of 0.3 reported for a year-round study in southern California, while ratios ranged 

from 0.28-0.96 for outdoor workers, increasing with time spent outdoors. 

Taken together, results from previous and recently published studies indicate that while the 

relationship between personal exposures and ambient concentrations varies due to a number of 

factors, such as activity patterns, housing characteristics, and season, O3 concentrations measured at 

central-site monitors are representative of day-to-day changes in average personal O3 exposure, 

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1 which is the important parameter for time-series epidemiologic studies. Another important finding is 

2 that the magnitude of personal exposures is smaller than concentrations reported at fixed-site 

3 monitors due to time spent indoors and the low indoor penetration of O3. 

2.2.1.2. Co-Exposure to Ozone a nd Othe r Polluta nts 

4	 Individuals may be exposed to other pollutants in conjunction with exposure to O3. Personal 

exposure to O3 shows variable association with personal exposure to other pollutants, with 

6 differences in association depending on factors such as season, city-specific characteristics, and 

7 spatial variability of the co-pollutant. For PM2.5, a rank correlation of 0.14 was reported between 

8 daily O3 and PM2.5 exposures during spring and fall in Atlanta. Positive slopes were reported during 

9 summer in both Baltimore and Boston, although the slopes were somewhat different (0.21 and 0.72, 

respectively). The summertime slope in Baltimore was higher for children (0.37) than for adults 

11 (0.07), which may be the result of different activity patterns and time spent outdoors. Additional 

12 evidence of variation by season and city is provided by the differing signs of the wintertime slopes, 

13 with Baltimore showing a negative slope and Boston showing a positive slope. Interindividual 

14 variability likely played a role as well, since both cities showed a wide range (including both 

negative and positive values) for individual-specific personal O3- PM2.5 slopes. For EC and NO2, 

16 near-zero correlations were reported with O3 during spring and fall in Atlanta. These extremely low 

17 correlations for the traffic-related and spatially variable pollutants EC and NO2 contrast with the 

18 higher correlation observed for PM2.5, a regional pollutant. 

19 In near-road and on-road microenvironments, correlations between O3 and traffic-related 

pollutants are moderately to strongly negative, with the most strongly negative correlations observed 

21 for NO2 (-0.8 to -0.9). This is consistent with the chemistry of NO oxidation, in which O3 is 

22 consumed to form NO2. The more moderate negative correlations observed for PM2.5, UFP, and VOC 

23 may reflect reduced concentrations of O3 in more polluted environments due to other scavenging 

24 reactions. A similar process occurs indoors, where infiltrated O3 reacts with airborne or surfaceassociated materials to form secondary compounds, such as formaldehyde. Although such reactions 

26 decrease indoor O3 exposure, they result in increasing exposure to other species which may 

27 themselves have health effects. 

2.2.2. Expos ure Modeling 

28 Exposures estimates in urban areas may be improved by constructing a concentration surface 

29 over a geographic domain using a model to compensate for missing data. The calculated 

concentration surface can then be used to estimate exposures outside residences, schools, 

31 workplaces, roadways, or other locations of interest. This technique does not estimate exposure 

32 directly because it does not account for activity patterns or concentrations in different 

33 microenvironments. Most such modeling efforts have focused on the less-reactive pollutants PM or 

34 NO2. In a study that extended CALINE4 NOX modeling results to evaluate the impact on residential 

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1 O3 concentrations, O3 concentrations were reduced by 0.51 ppb O3 per 1 ppb NOX. This intra-urban 

2 traffic-related variability in O3 concentrations suggests that differences in traffic density between the 

3 central site monitor and individual homes could result in either an overestimate or underestimate of 

4 residential O3. 

A separate class of models, known as microenvironmental models, estimate time-weighted 

6 exposure for modeled individuals by summing exposure in each microenvironment visited during the 

7 exposure period. Stochastic microenvironmental models, such as APEX and SHEDS, utilize 

8 distributions of pollutant-related and individual-level variables, such as ambient and local O3 

9 concentration contributions and breathing rate respectively, to compute the distribution of individual 

exposures across the modeled population. The models also have the capability to estimate received 

11 dose through a dosimetry model. Using distributions of input parameters in the model framework 

12 rather than point estimates allows the models to incorporate uncertainty and variability explicitly into 

13 exposure estimates. For the APEX model, an analysis has been conducted indicating that the 

14 uncertainty in model exposure estimates for asthmatic children during moderate exercise is small to 

moderate; however, APEX appears to substantially underestimate the frequency of multiple high16 exposure events for a single individual. Microenvironmental models, such as EMI, are also being 

17 developed to use individual-specific information derived from measurements or questionnaires, 

18 rather than population distributions, to estimate exposures. This approach is particularly suitable for 

19 panel health studies where information is available for each participant, and may reduce uncertainty 

in health effect estimates by improving exposure estimates. 

2.2.3. Implic a tio ns fo r Epide miolo gic Stu die s 

21 Exposure error can be an important contributor to variability in epidemiologic study results, 

22 although this may be less of an issue for O3 because it is a secondary pollutant with relatively low 

23 spatial variability across an urban area. For example, an epidemiologic study in Atlanta observed 

24 similar associations between heart rate variability (HRV) parameters and either ambient 

concentrations or personal exposures of O3 and PM2.5, another regional pollutant. The importance of 

26 exposure error varies with study design and is dependent on the spatial and temporal aspects of the 

27 design. Several factors that could influence exposure estimates include nonambient exposure, spatial 

28 and temporal variability, and the presence of O3 in a mixture of pollutants. Nonambient exposure is 

29 unlikely to influence health effect estimates because of the lack of indoor O3 sources and because 

indoor-generated O3 exposures are unlikely to be correlated with ambient O3 exposure. Compared 

31 with directly emitted pollutants such as CO and NOX, O3 exhibits relatively low spatial variability 

32 across urban areas, as discussed in Chapter 3. Averaging data from a large number of samplers will 

33 dampen intersampler variability, and use of multiple monitors over smaller land areas may allow for 

34 more variability to be incorporated into an epidemiologic analysis. Evidence from a study comparing 

the effect of spatial variability on effect estimates for O3, PM2.5, NO2, and CO suggests that choice of 

36 monitor for spatially homogenous pollutants such as O3 may have little impact on the results of 

37 epidemiologic studies. Season, however, may have a substantial effect due to much lower O3 

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1 concentrations during the winter, along with the higher correlations between ambient concentrations 

2 and personal exposures observed during the summer. Studies conducted during the O3 season or in 

3 periods when communities are likely to have high air exchange rates (e.g., during mild weather) may 

4 be less prone to exposure error than studies conducted only during winter. Year-round studies that 

include both the O3 and non-O3 seasons may have an intermediate level of exposure error. Exposure 

6 to mixtures of pollutants containing O3 also complicates interpretation of epidemiologic results. 

7 Moderate to strong negative correlations between O3 and traffic-related pollutants, particularly NO2, 

8 make it difficult to determine to what extent O3-based effect estimates quantitatively reflect the 

9 independent effect of O3 itself, or the effect of another pollutant or pollutants in the mixture. 

Interpretation of O3 effects in the presence of PM is additionally complicated by the highly variable 

11 correlations observed, which differ by city, season, and population characteristics (e.g., children 

12 versus adults). Although these sources of exposure error should be considered in evaluating 

13 epidemiologic results, previous and recently published exposure research indicate that O3 

14 concentrations measured at central-site monitors are indicative of day-to-day changes in average 

personal O3 exposure, making ambient concentrations a useful parameter for epidemiologic studies. 

2.3. Do s ime try a n d Mo d e o f Ac tio n 

16 Ozone is a highly reactive and poorly water soluble gas allowing it to penetrate into targets in 

17 the lower respiratory tract. The fact that it is so chemically reactive suggests that the effective dose at 

18 target sites exists in the form of secondary oxidation products such as aldehydes and peroxides. 

19 Reaction products are formed when O3 interacts with components of the extracellular lining fluid 

(ELF) such as lipids, proteins, and antioxidants. Ozone uptake relates directly to these ELF substrate 

21 reactions and is termed 'reactive absorption'. The level and type of antioxidants varies between 

22 species, regions of the respiratory tract itself, and can be altered by O3 exposure. ELF constituents 

23 appear in most cases to limit interaction of O3 with underlying tissues and to prevent penetration of 

24 O3 deeper into the lung. However, in some cases, the antioxidants and secondary oxidation products 

formed in the aqueous phase might penetrate into the cells and cause injury. Ozone toxicity is 

26 observed to some extent in the nasal cavity, however further toxicity exists in the deep lung where 

27 the ELF thickness narrows allowing O3 to react directly with the epithelial cells and surface 

28 macrophages. 

2.3.1. Hu ma n a nd Animal Ozone Dos imetry 

29 O3 uptake efficiency is chemical-reaction dependent, driven by the conversion of O3 to 

reaction products. The primary site of O3 uptake and greatest O3 dose in the lungs is the centriacinar 

31 region (CAR), containing the respiratory bronchioles. Recent studies have provided evidence for hot 

32 spots of O3 flux around bifurcations in the airways. Ozone uptake is 80-95% efficient in humans and 

33 approximately 54% efficient in rats. The nasopharyngeal region provides defense against O3 entering 

34 the lungs and removes ~50% of the absorbed O3 in both species. Ozone uptake efficiency is sensitive 

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1 to a number of factors. Fractional absorption will decrease with increased flow and increase 

2 proportional to tidal volume (VT). Increased breathing frequency (fB) and oronasal breathing, as 

3 occurs during exercise, will shift the O3 dose distribution deeper and lead to a greater dose to the 

4 pulmonary region, increasing the potential of damage to bronchiolar and alveolar tissues. Individual 

total airway O3 uptake efficiency is also sensitive to large changes in O3 concentration, exposure 

6 time, and minute ventilation (VE). Major sources of variability in absorption of O3 include O3 

7 concentration, exposure time, breathing frequency, minute volume, and tidal volume, but the 

8 interindividual variation is the greatest source of variability uptake efficiency. However, to date, no 

9 studies have shown that the large differences in biological response between subjects (forced 

expiratory volume in 1 sec [FEV1], bronchoalveolar lavage fluid [BAL], cell inflammatory response, 

11 etc.) are explainable by the differences in O3 uptake. 

12 Interspecies differences limit quantitative comparison between species; however, the acute and 

13 chronic functional responses of laboratory animals to O3 appear qualitatively homologous to that of 

14 the human making them a useful tool in determining mechanistic and cause-effect relationships with 

O3 exposure. Recent studies have shown that varied O3 response in different mouse strains was not 

16 due to differences in delivered dose of O3 to the lung but more likely genetic sensitivity. Dose 

17 comparison between humans and rats shows that exercising humans accumulated 4-5 times higher 

18 O3 reactants in BAL compared to similarly exposed resting rats and it was necessary to expose 

19 resting rats to 2 ppm O3 to achieve increases in BAL protein and polymorphonuclear cells [PMNs] 

similar to those of the 0.4 ppm exposed humans. 

2.3.2. Po s s ible Pa thwa ys /Mo de s o f Ac tio n 

21 Three distinct short-term responses have been well-characterized in humans challenged with 

22 O3: decreased pulmonary function, airways inflammation, and increased bronchial reactivity. In 

23 addition, evidence has been accumulating that O3 exposure exacerbates, and possibly causes, asthma 

24 and allergic airways disease in humans. Effects on the nasal airways and distal lung of humans, 

including inflammation and injury, have also been described. Animal studies have demonstrated a 

26 wide range of respiratory system effects. While the respiratory tract is the primary target tissue, 

27 cardiovascular and other organ effects occur following short- and long-term exposures of animals to 

28 O3. Mechanisms responsible for these effects are incompletely understood. 

29 The initial key event in the O3 toxicity pathway is the formation of secondary oxidation 

products in the respiratory tract. Pathways for the removal of those products are also of great 

31 importance. Due to the highly reactive nature of O3, direct reactions most likely involve components 

32 of the ELF and/or plasma membranes of surface macrophages which extend beyond the ELF. 

33 Reaction products likely mediate O3 effects on respiratory tract epithelium. 

34 Another key event in the O3 toxicity pathway is the activation of neural reflexes which leads to 

decrements in pulmonary function. Evidence is accumulating that secondary oxidation products are 

36 responsible for this effect. Eicosanoids have been implicated in humans while eicosanoids and 

37 aldehydes are effective in animal models. Different receptors on bronchial C-fibers have been shown 

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to mediate separate effects of O3 on pulmonary function. Nociceptor sensory nerves are involved in 

the involuntary truncation of respiration which results in decreases in forced vital capacity (FVC), 

FEV1, tidal volume and an increase in respiratory frequency and pain upon deep inspiration. Opioids 

block these responses while atropine does not. New evidence in an animal model suggests that 

TRPA1 receptors on bronchial C-fibers mediate this pathway. Ozone exposure also results in 

activation of vagal sensory nerves and a mild increase in airways obstruction measured as increased 

specific airway resistance (sRaw). Atropine and beta-adrenergic agonists blocked this response in 

one study indicating that the airway obstruction was due to bronchoconstriction. Other studies in 

humans implicated SP release from bronchial C-fibers resulting in airway narrowing due to either 

neurogenic edema or bronchoconstriction. New evidence in an animal model suggests that the SPNK receptor pathway caused bronchoconstriction following O3 exposure. Considerable interindividual variability exists in O3 responsiveness measured by decrements in pulmonary function. 

Further, attenuation of these pulmonary function decrements occurs following O3 exposure for 

several consecutive days. Mechanisms responsible for these effects are not known but may be related 

to inherent differences in neural sensitivity. 

Injury and inflammation are additional key events in the O3 toxicity pathway. Secondary 

oxidation products have been implicated in a number of these processes. Although there may be 

inter-species differences with respect to specific mediators, mechanisms involved in the acute 

responses to O3 include epithelial injury and airways neutrophilia. Longer-term exposures may result 

in mucus cell metaplasia of nasal epithelium or airways remodeling and fibrosis. Work from several 

laboratories in humans and animal models suggest that O3 triggers the release of tachykinins such as 

SP from airway sensory nerves which could contribute to downstream effects including injury and 

inflammation. New investigations show that O3 exposure leads to the generation of hyaluronan 

fragments which activate TLR4 and CD44-dependent signaling pathways in macrophages and result 

in a greater turnover of macrophage populations in the lung. Activation of these pathways occurs 

later than the acute neutrophilic response suggesting that they may contribute to longer-term effects 

of O3. The mechanisms involved in clearing O3-provoked inflammation remain to be clarified. 

Similar to the pulmonary function responses, considerable inter-individual variability exists in O3 

responsiveness as measured by airways neutrophilia. Further, attenuation of the inflammatory 

response occurs following O3 exposure for several consecutive days. However evidence suggests 

that injury may continue despite the dampening of the inflammatory response during repeated 

exposures. Mechanisms responsible for inter-individual variability and response attenuation, or the 

lack thereof, are not known. It should be noted that inflammation, as measured by airways 

neutrophilia, is not correlated with decrements in pulmonary function as measured by spirometry. 

Consequently, spirometric measures are not a good surrogate for the degree of inflammation in any 

given individual following O3 exposure. Furthermore, airways neutrophilia may not be a good 

indicator of O3-mediated lung injury. 

Increased bronchial reactivity is a key event in the toxicity pathway of O3. It can be both a 

rapidly occurring and persistent response, although adaptation can also occur during multi-day 

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exposures. Both direct effects on smooth muscle and neurally-mediated effects on smooth muscle 

have been proposed to contribute to airway hyperresponsiveness (AHR) following O3 exposure. 

Currently, more evidence has accumulated for the latter mechanism. In humans exposed to O3, 

atropine was found to block the early AHR response indicating the involvement of cholinergic 

postganglionic pathways. Inhibition of arachidonic acid metabolism was ineffective in blocking this 

response in humans while mixed results were found in animal models. Studies in O3-exposed 

animals have demonstrated a role for SP release from bronchial C fibers in mediating neurallymediated effects on smooth muscle. Later phases of increased bronchial reactivity may involve the 

induction of interleukin (IL)-1beta which in turn upregulates SP production. In guinea pigs, 

eosinophil-derived major basic protein contributed to the stimulation of cholinergic postganglionic 

pathways. A novel role for hyaluronan in mediating the later phase effects of O3 has recently been 

demonstrated. High molecular weight polymers of hyaluronan normally found in the ELF were 

degraded following O3 exposure in mice. The resulting hyaluronan fragments stimulated AHR in a 

toll-like receptor (TLR4) and CD44 receptor-dependent manner. Previous work has shown that O3­

mediated increases in lung permeability required a functioning TLR4 suggesting a possible 

relationship between increased epithelial permeability and AHR in this model. Other cytokines and 

chemokines have been implicated in the AHR response to O3 in animal models. 

Both older and more recent studies provide insight into the ability of O3 to provoke asthma 

exacerbations in humans. Greater airways inflammation and/or greater bronchial reactivity have 

been demonstrated in asthmatics compared to non-asthmatics. This pre-existing inflammation and 

altered baseline bronchial reactivity may contribute to the enhanced bronchoconstriction seen in 

asthmatics exposed to O3. Furthermore inflammation may contribute to O3-mediated AHR. Animal 

studies have demonstrated a role for eosinophil-derived proteins in mediating these effects. Since 

airways eosinophilia occurs in both allergic humans and allergic animal models, this pathway may 

underlie the exacerbation of allergic asthma by O3. In addition, differences have been noted in 

epithelial cytokine expression in bronchial biopsy samples of healthy and asthmatic subjects. A Th2 

phenotype, indicative of adaptive immune system activation and enhanced allergic responses, was 

observed before O3 exposure and was increased by O3 exposure in asthmatics. Since eosinophilia is a 

hallmark of a Th2 phenotype, these findings support links between allergic asthma, sensitivity to O3 

and adaptive immunity. Studies in humans and animal models also provide evidence for activation of 

innate immunity by O3. In humans, O3 exposure resulted in increased numbers of airways monocytes 

and dendritic-like cells. Altered expression of cell surface markers characteristic of innate immunity 

and antigen presentation was observed on monocytes and macrophages. Recruitment of these 

activated immune cells could lead to activation of allergen-specific memory T cells in allergic 

individuals and result in the exacerbation of existing asthma in response to an allergen trigger. In 

animal studies, O3 exposure primed the innate immune system and led to increased endotoxininduced AHR by a mechanism involving hyaluronan and TLR4. The exaggerated immune response 

to O3 + endotoxin could lead to a more pronounced lung injury response to a bacterial trigger. 

Enhanced bronchial reactivity, airways eosinophilia, Th2 phenotype, recruitment of activated innate 

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immune cells, and enhanced responsiveness to endotoxin all provide biological plausibility for 

epidemiologic evidence of asthma exacerbations associated with exposure to O3. Thus, the influx of 

immunomodulatory cells and the activation of innate and adaptive immunity leads to the 

exacerbation of asthma and allergic responses which is emerging as a key event in the toxicity 

pathway of O3. 

Recent studies in humans and animal models also provide evidence that O3 exposure causes 

induction of AHR and allergic responses. Both activation of innate immunity and promotion of 

adaptive immunity have been implicated. In humans, O3 exposure resulted in increased numbers of 

dendritic-like cells and levels of a cytokine associated with dendritic cell activation in the sputum, 

suggesting the presence of a population of activated dendritic cells which could stimulate naïve 

T-cells to promote the development of asthma. Evidence for activated dendritic cells was also found 

in glutathione S transferase M1 (GSTM1) null human subjects (Section 5.2.9.1) and in allergensensitized animals exposed to O3. In the latter study, O3 acted as an adjuvant for allergic sensitization 

and the development of AHR by a mechanism involving TLR4. In a different animal model, O3­

induced AHR required the presence of NKT cells and IL-17, both of which indicate innate immune 

system activation. Ozone-induced goblet cell metaplasia has also been demonstrated. These findings 

suggest that O3 may be capable of causing new onset asthma and allergic responses in humans. Thus, 

promotion of adaptive immunity and activation of innate immunity leads to the induction of AHR 

and allergic responses which is emerging as a key event in the toxicity pathway of O3. 

Both older and more recent studies in animal models provide several mechanisms by which O3 

exposure could enhance susceptibility to lung infections. Both decreased mucociliary particle 

clearance and decreased numbers and function of alveolar macrophage have been implicated. Recent 

studies suggest that O3-mediated oxidation of SP-A oxidation and priming of the innate immune 

system may contribute to decreased pathogen clearance. Immune dysfunction outside of the lung has 

also been demonstrated. Thus, immune system modulation is emerging as a key event in the O3 

toxicity pathway. 

Studies in animals provide evidence for extrapulmonary effects of O3. Although it was 

suggested that these effects are directly mediated by secondary oxidation products formed in the lung 

as a result of O3 exposure, there is no evidence that these species enter the circulation. Alternatively, 

extrapulmonary effects may be due to activation of neural reflexes or to release of diffusible 

mediators which may initiate or propagate inflammatory responses in the vascular or systemic 

compartments. Recent studies suggest that oxidative/nitrosative stress contributes to O3-induced 

cardiovascular effects. Thus, systemic inflammation and vascular oxidative/nitrosative stress are 

emerging as key events in the toxicity pathway of O3. 

Collectively, older and more recent studies provide evidence for mechanisms which may 

underlie the variability in responsiveness seen among individuals. Certain functional genetic 

polymorphisms, pre-existing conditions and diseases, lifestages and co-exposures contribute to 

enhanced susceptibility to O3. Adaptation may also be important, but it is incompletely understood ­

both in terms of the pathways involved and the resulting consequences. 

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1 Overall, key events in the toxicity pathway of O3 have been identified in humans and animal 

2 models. They include the formation of secondary oxidation products in the lung, activation of neural 

3 reflexes, pulmonary injury and inflammation and increased bronchial reactivity. In addition, 

4 evidence is accumulating that immune system modulation may lead to impaired host defense and the 

5 exacerbation and/or induction of asthma and allergic responses. Systemic inflammation and vascular 

6 oxidative/nitrosative stress may be critical to the extrapulmonary effects of O3. 

2.4. Health Effects 

7 This section evaluates the evidence from toxicological, controlled human exposure, and 

8 epidemiologic studies that examined the health effects associated with short- and long-term exposure 

9 to O3. The results from the health studies evaluated in combination with the evidence from 

10 atmospheric chemistry and exposure assessment studies contribute to the causal determinations made 

11 for the health outcomes discussed in this assessment (Section 1.6.4). In the following sections a 

12 discussion of the causal determinations will be presented by exposure duration (i.e., short- or long13 term exposure) for the health effects for which sufficient evidence was available to conclude a 

14 causal, likely to be causal or suggestive relationship. Although not presented in depth in this chapter, 

15 a detailed discussion of the underlying evidence used to formulate each causal determination can be 

16 found in Chapters 6 and 7. 

2.4.1. Effe cts o f S ho rt-Te rm Expo s ure to Ozone 

Table 2-1. Summary of causal determinations for short-term exposure to ozone 

Outcome Causality Determination 

Respiratory Effects Causal Relationship 

Cardiovascular Effects Suggestive of a Causal Relationship 

Central Nervous System Effects Suggestive of a Causal Relationship 

Mortality Likely to be a Causal Relationship 

2.4.1.1. Re s pira tory Effe c ts 

17 The 2006 O3 AQCD concluded that there was clear, consistent evidence of a causal 

18 relationship between short-term exposure to O3 and respiratory health effects (U.S. EPA, 2006, 

19 088089). This causal association was substantiated by the coherence of effects observed across 

20 controlled human exposure, epidemiologic, and toxicological studies indicating associations of 

21 short-term O3 exposures with a range of respiratory health endpoints from respiratory tract 

22 inflammation to respiratory hospital admissions (HA) and ED visits. Across disciplines, acute O3 

23 exposures induced or were associated with statistically significant declines in lung function. An 

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equally strong body of evidence from controlled human exposure and toxicological studies 

demonstrated O3-induced inflammatory responses, increased epithelial permeability, and airway 

hyperresponsiveness (both specific and nonspecific). Toxicological studies provided additional 

evidence for O3-induced impairment of host defenses. Coherent with inflammation and airway 

hyperresponsiveness, epidemiologic studies consistently demonstrated positive associations of 

increases in ambient O3 concentrations with increases in respiratory symptoms and asthma 

medication use in asthmatic children and with respiratory-related hospital admissions and asthmarelated emergency department (ED) visits. Although O3 was consistently associated with 

nonaccidental and cardiopulmonary mortality, the contribution of respiratory causes to these findings 

was uncertain. 

Building on the strong body of evidence presented in the 2006 AQCD, recent studies continue 

to support associations between short-term O3 exposure and respiratory effects. In young healthy 

adults exposed to O3 for 6.6 hours, studies demonstrate mean FEV1 decrements of about 3% at 

60 ppb, 5% at 70 ppb, and 6-8% at 80 ppb (Section 6.2.1.2). These studies also show considerable 

intersubject variability in responsiveness to O3, with the percentage of subjects with >10% 

decrement in FEV1 increasing with increasing concentration of O3 exposure. The proportion 

(uncorrected for filtered air [FA] responses) of individuals with >10% FEV1 decrements ranges from 

3 to 20% at an average O3 exposure level of 60 ppb and from 17 to 29% at 80 ppb. 

The collective body of epidemiologic evidence demonstrates associations between ambient O3 

and decrements in lung function, although recent studies contributed more mixed evidence. A 

notable difference among newer studies is the limited investigation of populations engaged in 

outdoor recreation, exercise, or work, which contributed to the strength of evidence in previous 

AQCDs (U.S. EPA, 1996, 017831; U.S. EPA, 2006, 088089). Some recent evidence suggests that 

public attention to daily AQI may be reducing exposures of some groups. Recent epidemiologic 

studies contributed insight into susceptibility factors for O3-associated respiratory morbidity. Among 

subjects with atopy, asthmatics with concurrent respiratory infection, elderly with AHR or obesity, or 

groups with diminished antioxidant enzyme activity, lung function responses to ambient O3 

exposures generally were exacerbated. The susceptibility of these populations is supported by 

extensive laboratory evidence (human and animal) for O3-induced exacerbation of allergic 

inflammation, increased susceptibility to bacterial and viral infections, exacerbation of O3-induced 

AHR by obesity, and modulation of O3 effects by the oxidative stress/antioxidant balance. In recent 

controlled human exposure studies, lung function responses to O3 are enhanced in subjects with 

higher body mass index (BMI). 

As with lung function, recent controlled human exposure studies demonstrate increases in 

respiratory symptoms in healthy, young adults following 5.6- to 6.6-h exposure to O3 at levels 

<80 ppb. The collective body of epidemiologic studies strongly demonstrates positive associations of 

ambient O3 exposure with respiratory symptoms and asthma medication use among asthmatic 

subjects, especially in populations with additional susceptibility factors such as asthmatics with 

atopy, asthmatics with diminished antioxidant enzyme activity, or infants with asthmatic mothers. 

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1 Recent studies in animals and in vitro models also continue to demonstrate O3-induced lung 

2 injury and inflammatory responses. Building on the extensive experimental evidence, new 

3 epidemiologic evidence emerged for ambient O3-associated increases in mediators of inflammation 

4 measured in upper and lower airway samples, including eNO, cytokines such as IL-6 or IL-8, and 

inflammatory cells such as eosinophils. Epidemiologic studies also report associations of increases in 

6 ambient O3 with decreased levels of glutathione and increased levels of malondialdehyde in airways. 

7 At the time of the 2006 O3 AQCD, controlled human studies of dietary antioxidant supplementation 

8 had shown some protective effects of alpha-tocopherol and ascorbate on lung function from O3 

9 exposure, but not on the intensity of subjective symptoms and inflammatory response. More recent 

evidence indicates that diminished activity of oxidant metabolizing enzymes (e.g., GSTM1, GSTP1) 

11 or intake of antioxidant vitamins influences inflammatory responses to O3 exposure. Across all three 

12 disciplines, evidence suggests a role antioxidant defenses in modulating responses to O3. 

13 Recent epidemiologic studies build upon the strong body of evidence that demonstrated 

14 consistent positive associations between daily changes in O3 exposure and respiratory-related 

hospital admissions and ED visits by demonstrating associations in diverse populations across the 

16 U.S., Canada, and Europe. In all-year analyses, recent multicity studies and a multicontinent study 

17 found an approximate 1.6-5.4% increase in all respiratory-related hospital admissions and ED visits 

18 for standardized increases in ambient O3 concentrations 1. Positive associations persisted in analyses 

19 restricted to the summer season, but the magnitude varied depending on the study location. 

Compared with studies reviewed in the 2006 O3 AQCD, more recent studies examine associations 

21 between short-term O3 exposure and specific respiratory outcomes. Although still limited in number, 

22 both single- and multicity studies found consistent, positive associations of daily changes in O3 

23 concentrations with asthma and chronic obstructive pulmonary disease (COPD) hospital admissions 

24 and ED visits. Evidence was more limited for pneumonia. Consistent with the conclusions of the 

2006 O3 AQCD (U.S. EPA, 2006, 088089), in studies that conducted seasonal analyses, larger effects 

26 were estimated for the warm season or summer months than for the cold season or for all seasons, 

27 particularly for asthma and COPD. Although the current body of evidence did not include detailed 

28 age-stratified results, the increased risk of asthma hospital admissions observed for children provided 

29 additional support for the conclusion from the 2006 O3 AQCD that children are particularly 

susceptible to O3-induced respiratory effects (U.S. EPA, 2006, 088089). Among studies that 

31 evaluated the potential confounding effects of co-pollutants, O3 effect estimates for respiratory32 related hospital admissions and ED visits remained relatively robust upon the inclusion of PM and 

33 gaseous pollutants in two-pollutant models. Although the concentration-response relationship 

34 between short-term O3 exposure and respiratory-related hospital admissions and ED visits has not 

been extensively examined, preliminary examinations found no evidence of a threshold between 

36 short-term O3 exposure and asthma hospital admissions and pediatric asthma ED visits. 

1 Effect estimates were standardized to a 20-ppb increase for 24-h avg O3, a 30-ppb increase for 8-h max O3, and a 40 ppb increase for 1-h 

max O3. 

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New evidence extends the potential continuum of well-established O3-associated respiratory 

effects (e.g., airway inflammation; impaired host defense; lung function decrements; and respiratory 

symptoms, ED visits, and hospital admissions) by demonstrating associations between ambient O3 

exposure and respiratory-related mortality. The multicontinent APHENA study reported primarily 

positive associations with respiratory mortality in all-year analyses, with stronger associations 

observed in analyses restricted to the summer season. These findings were supported by U.S. and 

European multicity studies, in which a majority of respiratory mortality effect estimates ranged from 

a 2.3 to 6.8% increase per standardized increase in ambient O3 concentrations. Although co-pollutant 

confounding was not extensively examined, the O3-respiratory mortality relationship was moderately 

to substantially sensitive (e.g., increased or attenuated) to inclusion of PM10 in co-pollutant models. 

However, interpretation of these results requires caution due to the limited PM datasets used in these 

studies. 

In summary, new studies evaluated in the current review support or expand upon the strong 

body of evidence presented in the 2006 O3 AQCD that short-term O3 exposure is causally associated 

with respiratory health effects. Recent controlled human exposure studies demonstrate decreases in 

FEV1 in the range of 2.8 to 3.6% with prolonged O3 exposures (6.6 hours) as low as 60 ppb in 

concentration. By demonstrating O3-induced airway hyperresponsiveness, activation of neural 

reflexes, allergic responses, lung injury, impaired host defense, and airway inflammation, 

toxicological studies have characterized O3 modes of action and provided biological plausibility for 

epidemiologic observations of associations of ambient O3 exposure with decreases in lung function 

and increases in respiratory symptoms. The coherence of results across studies for O3-associated 

changes in lung function, airway inflammation, and respiratory symptoms, in turn, provides the 

biological plausibility for epidemiologic findings of consistently positive associations of ambient O3 

exposure with respiratory hospital admissions and ED visits in diverse populations across the U.S., 

Europe, and Canada. Additionally, a multicontinent study and several multicity studies reported 

positive associations between ambient O3 exposures and respiratory mortality. New epidemiologic 

studies provide evidence for associations of ambient O3 exposure with biological markers of airway 

inflammation and oxidative stress and indicated that groups with diminished antioxidant capacity or 

comorbidities such as atopy, AHR, or obesity may have increased susceptibility to respiratory 

morbidity associated with O3 exposure. This new information is consistent with previously available 

toxicological and clinical evidence as well as current information on modes of action. A common 

observation among epidemiologic studies of respiratory morbidity and mortality was stronger 

associations in analyses restricted to warm seasons compared to cold seasons. Additionally, although 

co-pollutant confounding was evaluated infrequently, O3 effect estimates generally remained 

statistically significant in co-pollutant models with PM2.5, PM10, or NO2. Collectively, the evidence 

integrated across controlled human exposure, epidemiologic, and toxicological studies as well as 

across the spectrum of respiratory health endpoints continues to demonstrate that there is a causal 

relationship between short-term O3 exposure and respiratory health effects. 

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2.4.1.2. Ca rdiova s c ula r Effe c ts 

1 In past O3 AQCDs, the effects of O3 to the cardiovascular system could not be thoroughly 

2 evaluated due to the paucity of information available. However, in recent years, investigation of O3­

3 induced cardiovascular events has advanced. In general, compared with the epidemiologic evidence, 

4 the toxicological evidence is more supportive of an O3-induced cardiovascular effect. Epidemiologic 

evidence does not consistently demonstrate a positive relationship between short-term O3 exposure 

6 and cardiovascular morbidity. However, most epidemiologic studies have not extensively 

7 investigated the cardiovascular effects of O3 exposure in susceptible populations, which may further 

8 support the toxicological findings. Although the epidemiologic evidence is limited, single-city 

9 studies reviewed in the 2006 O3 AQCD (U.S. EPA, 2006, 088089), recent multicity studies, and the 

multicontinent APHENA study provide evidence of consistent positive associations between short11 term O3 exposure and cardiovascular mortality. However, in contrast with respiratory effects, there is 

12 weak coherence between the associations for cardiovascular morbidity and mortality. Further, there 

13 is no apparent biological mechanism to explain the association observed between short-term O3 

14 exposure and cardiovascular mortality and not for cardiovascular morbidity. 

Animal toxicological studies (O3 concentration 0.5-0.8 ppm) provide evidence for O3-induced 

16 cardiovascular effects, specifically enhanced ischemia/reperfusion injury, disrupted NO-induced 

17 vascular reactivity, decreased cardiac function, and increased HRV. The observed increase in HRV is 

18 supported by a recent controlled human exposure study that also finds increased high frequency 

19 HRV, but not altered blood pressure, following O3 exposure. Toxicological studies investigating the 

role of O3 in heart rate regulation are mixed with both bradycardic and tachycardic responses 

21 observed. These changes in cardiac function provide evidence for O3-induced alterations in the 

22 autonomic nervous system leading to cardiovascular complications. Epidemiologic studies showing 

23 positive associations between O3 and arrhythmias confirm the development of autonomic 

24 dysfunction following O3 exposure. It is still uncertain how O3 inhalation may cause systemic 

toxicity, however the cardiovascular effects of O3 found in animals correspond to the development 

26 and maintenance of a extrapulmonary oxidative, proinflammatory environment. 

27 Overall, animal toxicological studies provide stronger evidence for O3 exposure leading to 

28 cardiovascular morbidity than epidemiologic evidence which observed a lack of coherent evidence. 

29 Based on the relatively strong body of toxicological evidence, and the consistent evidence of an 

association between O3 and cardiovascular mortality, but weak coherence and biological plausibility 

31 for O3-induced cardiovascular morbidity, the generally limited body of evidence is suggestive of a 

32 causal relationship between relevant short-term exposures to O3 and cardiovascular effects. 

2.4.1.3. Ce n tra l Ne rvo us Sys te m Effe c ts 

33 In rodents, O3 exposure has been shown to cause physicochemical changes in the brain 

34 indicative of oxidative stress and inflammation. Recent toxicological studies add to earlier evidence 

that acute exposures to O3 can produce a range of effects on the central nervous system (CNS) and 

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1 behavior. Previously observed effects, including neurodegeneration, alterations in neurotransmitters, 

2 short- and long-term memory, and sleep patterns, have been further supported by recent studies. In 

3 instances where pathology and behavior are both examined, animals exhibit decrements in behaviors 

4 tied to the brain regions or chemicals found to be affected or damaged. For example, damage in the 

hippocampus, which is important for memory acquisition, was correlated with impaired performance 

6 in tests designed to assess memory. Thus the brain is functionally affected by O3 exposure. The 

7 single epidemiologic study conducted showed that O3 affects memory in humans as well, albeit on a 

8 long-term exposure basis. Notably, exposure to O3 levels as low as 0.25 ppm has resulted in 

9 progressive neurodegeneration and deficits in both short- and long-term memory in rodents. 

Additionally, changes in the CNS, including biochemical, cellular, and behavioral effects, have been 

11 observed in animals whose sole exposure occurred in utero, at levels as a low as 0.3 ppm. Although 

12 evidence from epidemiologic and controlled human exposure studies is lacking, the toxicological 

13 evidence for the impact of O3 on the brain and behavior is strong, and is suggestive of a causal 

14 relationship between O3 exposure and adverse CNS effects. 

2.4.1.4. Mo rtality 

The 2006 O3 AQCD concluded that the overall body of evidence was highly suggestive that O3 

16 directly or indirectly contributes to non-accidental and cardiopulmonary-related mortality, but 

17 additional research was needed to more fully establish underlying mechanisms by which such effects 

18 occur. The evaluation of new multicity studies that examined the association between short-term O3 

19 exposure and mortality found evidence which supports the conclusions of the 2006 O3 AQCD. These 

new studies reported consistent positive associations between short-term O3 exposure and total 

21 (nonaccidental) mortality, with associations being stronger during the warm season, as well as 

22 additional support for associations between O3 exposure and cardiovascular mortality being similar 

23 or larger in magnitude compared to respiratory mortality. Additionally, these new studies examined 

24 previously identified areas of uncertainty in the O3-mortality relationship. 

Recent studies further examined potential confounders (i.e., co-pollutants and seasonality) of 

26 the O3-mortality relationship (Section 6.6.2.1). Unlike previous studies that were limited to primarily 

27 examining the confounding effects of PM10, these studies expanded their analyses to include multiple 

28 PM indices (i.e., PM10, PM2.5, and PM components). Co-pollutant models found evidence that 

29 associations between O3 and total mortality were robust to the inclusion of PM10 or PM2.5, while 

other studies found evidence for a modest reduction (~20-30%) when examining PM10 and by age 

31 group or cause-specific mortality (i.e., cardiovascular). Additional reductions in O3-mortality risk 

32 estimates were also observed when examining PM components, specifically sulfate, in co-pollutant 

33 models. Overall, the impact of PM indices on O3-mortality risk estimates was found to be much 

34 smaller than the variation in O3-mortality risk estimates across cities. Although some studies suggest 

that O3-mortality risk estimates may be confounded by PM or its chemical components, the 

36 interpretation of these results requires caution due to the limited datasets used in these studies. When 

37 examining the potential for seasonal confounding of the O3-mortality relationship it was observed 

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that the extent of smoothing or the methods used for adjustment can influence O3 risk estimates 

because of the opposing seasonal trends of O3 and mortality when not instituting enough degrees of 

freedom (df) to control for temporal/seasonal trends. 

The multicity studies evaluated in this review also examined the potential regional 

heterogeneity in O3-mortality risk estimates (Section 6.6.2.2). These studies provide evidence which 

suggests generally higher O3-mortality risk estimates in northeastern U.S. cities with some regions 

showing no associations between O3 exposure and mortality (e.g., Southwest, urban Midwest). 

Multicity studies that examined individual- and community-level characteristics identified factors 

that may explain the observed regional heterogeneity in O3-mortality risk estimates as well as 

characteristics of populations potentially susceptible to O3-related health effects. An examination of 

community-level characteristics found an increase in the O3-mortality risk estimates in cities with 

higher unemployment, percentage of the population Black/African-American, percentage of the 

working population that uses public transportation, lower temperatures, and lower prevalence of 

central air conditioning. 

Additional studies were evaluated that examined factors, such as multi-day effects, mortality 

displacement, adaptation, and whether a threshold exists in the O3-mortality relationship, which may 

influence the shape of the O3-mortality concentration-response (C-R) curve. An examination of 

multiday effects in a U.S. and European multicity study found conflicting evidence for mortality 

displacement, but the evidence suggests that the positive associations between O3 and mortality are 

observed mainly in the first few days after exposure. Additionally, a U.S. multicity study found 

evidence of an adaptive response to O3 exposure, with the highest risk estimates earlier in the O3 

season (i.e., July) and diminished effects later (i.e., August). However, the evidence of adaptive 

effects has an implication for the interpretation of multi-day effects, and requires further analysis. 

Analyses that specifically focused on the O3-mortality C-R relationship found no evidence of a 

threshold, but did observe evidence for potential differences in the C-R relationship across cities. 

Overall, this evidence supports the 2006 O3 AQCD which concluded that “if a population threshold 

level exists in O3 health effects, it is likely near the lower limit of ambient O3 concentrations in the 

U.S.” (U.S. EPA, 2006, 088089). Taken together, the body of evidence indicates that there is likely 

to be a causal relationship between short-term exposures to O3 and all-cause mortality. 

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2.4.2. Effe cts o f Lon g-Te rm Expo s ure to Ozone
 

Table 2-2. Summary of causal determinations for long-term exposure to ozone 

Outcome Causality Determination 

Respiratory Effects Likely to be a Causal Relationship 

Cardiovascular Effects Suggestive of a Causal Relationship 

Mortality Suggestive of a Causal Relationship 

Reproductive and Developmental Suggestive of a Causal Relationship 

Central Nervous System Effects Suggestive of a Causal Relationship 

Cancer, Mutagenicity, and Genotoxicity Inadequate to Infer a Causal Relationship 

2.4.2.1. Re s pira tory Effe c ts 

1 The epidemiologic studies reviewed in the 2006 O3 AQCD detected no associations between 

2 long-term O3 exposures and asthma-related symptoms, asthma prevalence or allergy to common 

3 aeroallergens among children after controlling for covariates. Little evidence was available to relate 

4 long-term exposure to current ambient O3 concentrations to deficits in the growth of lung function in 

5 children. Additionally, limited evidence was available evaluating the relationship between long-term 

6 O3 levels and pulmonary inflammation and other endpoints. 

7 Recent studies examine the relationship between long-term O3 exposure and new onset asthma 

8 in children (Section 7.2.1). Studies have provided evidence for a relationship between different 

9 genetic variants (e.g., heme oxygenase [HMOX], GSTs, arginase [ARG]) that, in combination with 

10 O3 exposure, are related to new onset asthma. Studies using a cross-sectional design provide support 

11 for a relationship between long-term O3 exposure and health effects in asthmatics, including 

12 bronchitic symptoms and respiratory-related school absences. Additionally, chronic O3 exposure was 

13 related to childhood asthma hospital admissions. 

14 Studies of long-term exposure to O3 and pulmonary function effects are inconclusive, with 

15 some new epidemiologic studies relating effects at higher exposure levels. Information from 

16 toxicological studies in adult and infant non-human primates indicates that long-term exposure to O3 

17 during development can result in irreversible morphological changes in the lung along with changes 

18 in pulmonary function. 

19 The strongest evidence for a relationship between long-term O3 exposure and respiratory 

20 morbidity in recent studies demonstrates associations between long-term measures of O3 exposure 

21 and new-onset asthma in children and increased respiratory symptom effects in asthmatics. While the 

22 evidence may be limited, these U.S. multi-community prospective cohort studies demonstrate that 

23 asthma risk is associated with the important relationships between genetic variability, environmental 

24 O3 exposure, and behavior. These relationships are complex. The genes evaluated in these studies are 

25 both key candidates in the oxidative stress pathway and have been shown to play an important role in 

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1 asthma development. Reduced risk for asthma development is reported in some studies in children 

2 living in low-O3 communities. Other recent studies provide coherent evidence for long-term O3 

3 exposure and respiratory morbidity effects such as first asthma hospitalization and respiratory 

4 symptoms in asthmatics. Studies considering other pollutants provide data supporting the notion that 

the effects related to O3 are independent from potential effects of the other pollutants. Some studies 

6 provide evidence for a positive concentration-response relationship. Generally, the epidemiologic 

7 and toxicological evidence provides a compelling case that supports the hypothesis that a 

8 relationship exists between long-term exposure to ambient O3 and measures of respiratory morbidity. 

9 The 2006 O3 AQCD concluded the evidence was suggestive but inconclusive at that time. Building 

upon that evidence, the more recent epidemiologic evidence, combined with toxicological studies in 

11 rodents and non-human primates, provides biologically plausible evidence that there is likely to be 

12 a causal relationship between long-term exposure to O3 and respiratory morbidity. 

2.4.2.2. Cardiovas cular Effec ts 

13 Previous AQCDs did not address the cardiovascular effects of long-term O3 exposure. The 

14 evidence remains limited; however the emerging data is supportive of a role for O3 in chronic 

cardiovascular diseases. Two epidemiologic studies have investigated cardiovascular morbidity after 

16 long-term O3 exposure and both assessed cardiovascular disease related biomarkers. A study of the 

17 relationship between O3 and cardiovascular mortality reported no association after adjustment for 

18 PM2.5 levels. Additional epidemiologic studies on cardiovascular morbidity and mortality after long19 term exposure have not been published. 

Toxicological evidence of long-term O3 exposure is also limited but three strong toxicological 

21 studies have been published since the previous AQCD. These studies provide evidence for O3 

22 enhanced atherosclerosis and ischemia/reperfusion injury, corresponding with development of a 

23 systemic oxidative, proinflammatory environment (Section 7.3.1.2). Although questions exist for 

24 how O3 inhalation causes systemic effects, a recent study proposes a mechanism for development of 

vascular pathology that involves activation of LOX-1 by O3 oxidized lipids. This activation may also 

26 be responsible for O3 induced changes in genes involved in proteolysis, thrombosis, and 

27 vasoconstriction. Taking into consideration the positive toxicological studies reported, the generally 

28 limited body of evidence is suggestive of a causal relationship between relevant long-term 

29 exposures to O3 and cardiovascular effects. 

2.4.2.3. Re prod uc tive a nd De ve lo pme nta l Effe c ts 

The 2006 O3 AQCD concluded that the limited number of studies that investigated O3 

31 demonstrated no associations between O3 and birth outcomes, with the possible exception of birth 

32 defects. The current review included an expanded body of evidence of the associations between O3 

33 and reproductive and developmental effects. Recent toxicological studies provide evidence for an 

34 effect of prenatal exposure to O3 on ultrastructural changes in bronchiole development, alterations in 

placental and offspring cytokines, and increased offspring airway hyper-reactivity (Section 7.4.7). 

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1 Also, there is limited toxicological evidence for an effect of prenatal and early life exposure on 

2 central nervous system effects, including laterality, brain morphology, neurobehavioral 

3 abnormalities, and sleep aberration (Section 7.4.8). Recent epidemiologic studies have begun to 

4 explore the effects of O3 on sperm quality, and provide limited evidence for decrements in sperm 

concentration, while there is limited toxicological evidence for testicular degeneration caused by O3 

6 (Section 7.4.2). There is no evidence that prenatal or early life O3 concentrations are associated with 

7 infant mortality. 

8 Collectively, there is limited though positive toxicological evidence for O3-induced 

9 developmental effects, including effects on pulmonary structure and function and central nervous 

system effects. Limited epidemiologic evidence exists for an association with O3 concentration and 

11 decreased sperm concentration. A recent toxicological study provides limited evidence for a possible 

12 biological mechanism (histopathology showing impaired spermatogenesis) for such an association. 

13 Additionally, though the evidence for an association between O3 concentrations and adverse birth 

14 outcomes is generally inconsistent, there are several influential studies that indicate an association 

with reduced birth weight and restricted fetal growth. Taking into consideration the positive evidence 

16 for developmental and reproductive outcomes from toxicological and epidemiological studies, and 

17 the few influential birth outcome studies, the evidence is suggestive of a causal relationship 

18 between long-term exposures to O3 and reproductive and developmental effects. 

2.4.2.4. Ce n tra l Ne rvo us Sys te m Effe c ts 

19	 Recent research in the area of O3-induced neurotoxicity has included several long-term 

exposure studies. Notably, the first epidemiologic study to examine the relationship between O3 

21 exposure and neurobehavioral effects observed an association between annual O3 levels and an 

22 aging-related cognitive performance decline in tests measuring coding ability and attention/short23 term memory. This observation is supported by studies in rodents which demonstrate oxidative stress 

24 in the brain and associated decrements in behavioral tests, including those measuring memory, after 

subchronic exposure to 0.25 ppm O3. Additionally, neurobehavioral changes are evident in animals 

26 whose only exposure to O3 occurred in utero. Collectively, the limited epidemiologic and 

27 toxicological evidence is coherent and is suggestive of a causal relationship between O3 exposure 

28 and adverse CNS effects. 

2.4.2.5. Ca nc e r, Muta ge nic ity a nd Ge n otoxic ity 

29	 The 2006 O3 AQCD (U.S. EPA, 2006, 088089) reported that evidence did not support ambient 

O3 as a pulmonary carcinogen. Since the 2006 AQCD, very few epidemiologic and toxicological 

31 studies have been published that examine O3 as a carcinogen, but collectively, study results indicate 

32 that O3 may contribute to DNA damage. Overall, the evidence is inadequate to determine if a 

33 causal relationship exists between ambient O3 exposures and cancer. 

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2.4.2.6. Mo rtality 

1 The 2006 O3 AQCD concluded that an insufficient amount of evidence existed “to suggest a 

2 causal relationship between chronic O3 exposure and increased risk for mortality in humans” 

3 (U.S. EPA, 2006, 088089). Two additional studies have been conducted since the last review, an 

4 ecologic study that finds no association between mortality and O3, and a reanalysis of the ACS 

5 cohort that specifically points to a relationship between long-term O3 exposure and an increased risk 

6 of respiratory mortality (Section 7.7.1). The findings from the reanalysis of the ACS cohort are
 

7 consistent and coherent with the evidence from epidemiologic, controlled human exposure, and 

8 animal toxicological studies for the effects of short- and long-term exposure to O3 on respiratory 

9 effects. Additionally, the evidence for short- and long-term respiratory morbidity provides biological 

10 plausibility for mortality due to respiratory disease. Collectively, the evidence is suggestive of a 

11 causal relationship between long-term O3 exposures and all-cause mortality. 

2.5. P olicy Relevant Cons iderations 

2.5.1. Potentially Sus ceptible Populations 

12 Upon evaluating the association between short- and long-term exposure to O3 and various 

13 health outcomes, studies also attempted to identify populations that are more susceptible1 to O3. 

14 These studies did so by conducting stratified epidemiologic analyses; by examining individuals with 

15 an underlying health condition in controlled human exposure studies; or by developing animal 

16 models that mimic the pathophysiological conditions associated with an adverse health effect. These 

17 studies identified a multitude of factors that could potentially contribute to whether an individual is 

18 susceptible to O3 (Table 8-1). The examination of susceptible populations to O3 exposure allows for 

19 the NAAQS to provide an adequate margin of safety for both the general population and for sensitive 

20 populations. 

21 The populations identified in Chapter 8 that are most susceptible to O3-related health effects 

22 are individuals with influenza/infection, individuals with asthma, and older age groups. There were a 

23 small number of studies on influenza/infection but both reported influenza/infection to modify the 

24 association between O3 exposure and respiratory effects, with individuals having influenza or an 

25 infection being at increased susceptibility. Asthma as a susceptibility factor was supported by 

26 controlled human exposure and toxicological studies, as well as some evidence from epidemiologic 

27 studies. Most studies comparing age groups reported greater effects of short-term O3 exposure on 

28 mortality among older adults. Diet and obesity are also both likely susceptibility factors. Multiple 

29 epidemiologic, controlled human exposure, and toxicological studies reported that diets deficient in 

1 Populations that have a greater likelihood of experiencing health effects related to exposure to an air pollutant (e.g., O3) due to a variety 

of factors including, but not limited to: genetic background, birth outcomes (e.g., low birth weight, birth defects), race, sex, lifestage, 

lifestyle (e.g., smoking status, nutrition), preexisting disease, SES (e.g., educational attainment, reduced access to health care), and 

characteristics that may modify exposure to O3 (e.g., time spent outdoors) 

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1 Vitamins E and C are associated with susceptibility to O3 -related health effects. Similarly, studies of 

2 effect measure modification by BMI observed greater O3 -related respiratory decrements for 

3 individuals who were obese. 

4 Other potential factors [pre-existing conditions (such as COPD and CVD) young age, sex, and 

multiple genes (such as GSTM1, GSTP1, HMOX-1, NQO1, and TNF-α)] provided some evidence 

6 of susceptibility, but further evidence is needed. In addition, examination of modification of the 

7 associations between O3 exposure and health effects by SES and race were available in a limited 

8 number of studies, and demonstrated possible increased odds of health effects related to O3 exposure 

9 among those with low SES and Blacks. 

Individuals involved in outdoor activities were examined in a recent study but no effect 

11 modification was observed. However, previous evidence along with biological plausibility from 

12 toxicological and controlled human studies has shown this population to be susceptible to O3-related 

13 health effects. The only studies examining effect measure modification by diabetes examined O3 

14 exposure and cardiovascular outcomes, but none of the studies reported any change in the 

association by diabetes. 

16 Studies of air conditioning use, physical conditioning, and smoking were conducted but not 

17 much evidence was available to determine whether susceptibility to O3-related health effects is 

18 present for these factors. Toxicological studies also identified hyperthyroidism and the lifestage of 

19 gestation to be factors warranting further examination. Future research on these will provide 

additional insight into whether these factors affect susceptibility to O3-related health effects. 

2.5.2. La g Stru c tu re o f Ozone -Morbidity and Ozone-Mo rtality As s o cia tion s 

21 Epidemiologic studies have attempted to identify the time-frame in which exposure to O3 can 

22 impart a health effect. Although O3 exposure-response relationships have traditionally been 

23 examined using air quality data for a defined lag period (e.g., 1 day or average of 0-1 days), the 

24 relationship can potentially be influenced by a multitude of factors, such as the underlying 

susceptibility of an individual (e.g., age, pre-existing diseases), which could increase or decrease the 

26 lag times observed. 

27 An attempt has been made to identify whether certain lag periods are more strongly associated 

28 with specific health outcomes. The epidemiologic evidence evaluated in the 2006 O3 AQCD 

29 indicated that one of the remaining uncertainties in characterizing the O3-mortality relationship was 

identifying the appropriate lag structure (e.g., single-day lags versus distributed lag model). 

31 Currently, many investigators have chosen to examine the lag structure of associations between O3 

32 concentration and health outcome instead of focusing on a priori lag times. This approach is 

33 informative because if effects are cumulative, higher overall risks may exist than would be observed 

34 for any given single day lag. An examination of lag times used in the epidemiologic studies 

evaluated in this assessment can provide further insight on the relationship between O3 exposure and 

36 morbidity and mortality outcomes. 

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2.5.2.1. Ozone -Res pira tory Effe c t As s oc ia tio ns 

1 Collectively, recent epidemiologic studies of lung function, respiratory symptoms, and 

2 biological markers of airway inflammation and oxidative stress examined associations with single3 day ambient O3 exposures lagged from 0 to 7 days as well as concentrations averaged over 2 to 19 

4 days. Lag 0 and 1 ambient O3 exposures were associated with decreases in lung function and 

increases in respiratory symptoms, airway inflammation, and oxidative stress. In several studies, 

6 multiday averages of O3 exposure were associated with these endpoints, indicating that exposures 

7 accumulated over several days may be important or may be subject to less measurement error. 

8 Studies have suggested that O3-related respiratory morbidity may occur via multiple 

9 mechanisms with varying time courses of action. Many epidemiologic studies simultaneously 

examined associations of short-term ambient O3 exposure with lung function, respiratory symptoms, 

11 and biological markers of airway inflammation and oxidative stress and found inconsistent 

12 associations among endpoints whether evaluated at the same or different lags of O3 exposure. In 

13 most cases, investigators examined a limited number of O3 exposure lags and did not assign different 

14 O3 exposure lags for each endpoint based on hypothesized mechanisms of action. These limitations 

may explain some of the inconsistencies in associations of O3 with different respiratory health 

16 endpoints and may contribute to uncertainty over the important lags of ambient O3 exposure for 

17 particular respiratory endpoints. 

18 In studies of respiratory hospital admissions and ED visits, results were somewhat sensitive to 

19 the lag day selected (i.e., reduced when using a single-day lag and increased when using a distributed 

lag, up to 0-3 days), though when analyses were restricted to summer months only, the lag period 

21 tended to influence the results much less. Overall, among studies that examined a range of single-day 

22 lags and multiday averages, evidence did not overwhelmingly point to stronger immediate, delayed, 

23 or cumulative effects of O3 exposure on respiratory effects. 

2.5.2.2. Ozone -Morta lity As s oc ia tions 

24	 Epidemiologic studies that focused on the association between short-term O3 exposure and 

mortality (i.e., all-cause, respiratory and cardiovascular) mostly examined a priori lag structures of 

26 either 1 or 0-1 days. Although mortality studies do not often examine alternative lag structures, 

27 several recent studies have conducted more extensive analysis of lag structure to investigate 

28 “mortality displacement” (i.e., deaths are occurring in frail individuals and exposure is only moving 

29 the day of death to a day slightly earlier), with varying results (Section 6.6.2.4). An examination of 

multi-day effects in a U.S. and European multicity study found conflicting evidence for mortality 

31 displacement, but the evidence suggests that the positive associations between O3 and mortality are 

32 observed mainly in the first few days after exposure. A study conducted in 48 U.S. cities during the 

33 warm season (i.e., June-August) for the years 1989-2000 found that larger risk estimates were 

34 observed for distributed lag models compared to the lag 0 day estimates; however, larger risk 

estimates at lag 0-3 compared to 0-20 provide additional support for O3-induced mortality effects 

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1 occurring within the first few days after exposure. Although not a traditional mortality displacement 

2 study, the APHENA study found no indication that a distributed lag model with up to a 2-day lag 

3 yielded meaningfully larger O3 mortality risk estimates than the lag 0-1 and lag 1 results. Finally, a 

4 study conducted in 21 European cities reports that using single-day exposures may overestimate the 

5 effects on all-cause and cardiovascular mortality, but underestimated the effects on respiratory 

6 mortality. Thus, the results in part suggest evidence of mortality displacement for all-cause and 

7 cardiovascular mortality. However, it should be noted that the difference in results observed across 

8 studies may be due to the different model specifications used. Collectively, these studies suggest that 

9 the positive associations between O3 and mortality are observed mainly in the first few days after 

10 exposure. Overall, the evidence suggests that estimating the mortality risk using a single day of O3 

11 exposure may underestimate the public health impact, but the extent of multi-day effects appear to be 

12 limited to a few days. 

2.5.3. Ozone Concentration -Res pons e Relations hip 

13 An important consideration in characterizing the O3-morbidity and mortality association is 

14 whether the C-R relationship is linear across the full concentration range that is encountered or if 

15 there are concentration ranges where there are departures from linearity (i.e., nonlinearity). In this 

16 ISA studies have been identified that attempt to characterize the shape of the O3 C-R curve along 

17 with possible O3 “thresholds” (i.e., O3 levels which must be exceeded in order to elicit a health 

18 response). The controlled human exposure and epidemiologic studies that examined the shape of the 

19 C-R curve and the potential presence of a threshold have indicated a generally linear C-R function 

20 with no indication of a threshold for O3 concentrations greater than 30 or 40 ppb, which corresponds 

21 with PRB and the lower bound of O3 concentrations included in the C-R functions. 

2.5.3.1.	 Concentration -Re s p ons e Re la tions hip Cha ra c te rize d by Co ntrolle d Hu ma n 

Expos ure Studies 

22 Controlled human exposure studies have provided strong and quantifiable C-R data on the 

23 human health effects of O3. The magnitude of respiratory effects in these studies is generally a 

24 function of O3 exposure, i.e., the product of concentration (C), minute ventilation (VE), and exposure 

25 duration. Recent studies provide evidence for a smooth C-R curve without indication of a threshold 

26 in young healthy adults, exposed during moderate exercise for 6.6 hours to O3 concentrations of 

27 between 40 and 120 ppb (Figure 6-1). 

2.5.3.2.	 Concentration -Res pons e Relations hip Charac terized by Epidemiologic 

Studies 

28 A study examining the C-R relationship found no evidence of a threshold between short-term 

29 O3 exposure and pediatric asthma ED visits. One study reports that both quintile and loess dose30 response analyses (Figure 6-11) suggest that there are elevated associations with O3 at relatively low 

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1 concentrations, between 30 and 40 ppb, with stronger evidence at concentrations of 40 ppb and 

2 above. In an additional analysis, using a smooth function the authors examined whether the shape of 

3 the C-R curve for short-term exposure to O3 and asthma hospital admissions (i.e., both general and 

4 ICU for all ages) is linear. When comparing the curve to a linear fit line the authors found that the 

linear fit is a reasonable approximation of the C-R relationship between O3 and asthma hospital 

6 admissions around and below the current NAAQS (Figure 6-9). Although the C-R relationship 

7 between short-term O3 exposure and respiratory-related hospital admissions and ED visits has not 

8 been extensively examined, preliminary examinations found no evidence of a threshold between 

9 short-term O3 exposure and pediatric asthma ED visits. 

Evidence associating long-term O3 exposure to first asthma hospital admission in a C-R 

11 relationship is provided in a retrospective cohort study (Figure 7.3). 

12 Evaluation of the short-term exposure to O3-mortality C-R relationship is difficult due to the 

13 highly heterogeneous O3-mortality associations among regions in multicity studies (using log-linear 

14 models). In addition, there are numerous issues that may influence the shape of the O3-mortality C-R 

relationship that warrant examination including: multi-day effects (distributed lags), potential 

16 adaptation and mortality displacement (i.e., hastening of death by a short period). Several recent 

17 studies applied a variety of statistical approaches to examine the shape of the O3-mortality C-R 

18 relationship and whether a threshold exists. These studies did not find any evidence that supports a 

19 threshold for the association between short-term exposure to O3 and mortality. It was also 

demonstrated that the heterogeneity in the O3-mortality relationship across cities (or regions) 

21 complicates the interpretation of a combined C-R curve and threshold analysis. Additionally, given 

22 the effect modifiers identified in the mortality analyses that are also expected to vary regionally (e.g., 

23 temperature, air conditioning prevalence), a national or combined analysis may not be appropriate to 

24 identify whether a threshold exists in the O3-mortality C-R relationship. 

Additionally, several studies of long-term exposure to O3 and birth outcomes have 

26 characterized the C-R relationship. Evidence from the southern California Children's Health Study 

27 identified a C-R relationship of birth weight with 24-h avg O3 concentrations averaged over the 

28 entire pregnancy that was clearest above the 30 ppb level (Figure 7-4). Relative to the lowest decile 

29 of 24-h avg O3, estimates for the next 5 lowest deciles were approximately -40 g to -50 g, with no 

clear trend and with 95% confidence bounds that included zero. The highest four deciles of O3 

31 exposure showed an approximately linear decrease in birth weight, and all four 95% CIs excluded 

32 zero, and ranged from mean decreases of 74 grams to decreases of 148 grams. Another study 

33 conducted in southern California reported increased risks for cardiac birth defects in a dose-response 

34 manner with second-month O3 exposure. 

2.6. In te g ra tio n o f Ozone Health Effects 

This section summarizes the main conclusions of this assessment regarding the health effects 

36 of O3 and the concentrations at which those effects are observed. The conclusions from the previous 

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1 NAAQS review and the causality determinations from this review are summarized in Table 2-3. This 

2 section also integrates the evidence from short- and long-term exposure studies across scientific 

3 disciplines (i.e., controlled human exposure studies, toxicology, and epidemiology) in interpreting 

4 the health effects evidence that spans from prenatal development to death. The clearest evidence for 

5 health effects associated with short-term exposure to O3 is provided by studies of respiratory effects. 

6 The combined health effects evidence supports a causal relationship for this outcome. The evidence 

7 is also sufficient to infer a relationship that is likely to be causal for short-term exposure to O3 and 

8 mortality and long-term exposure to O3 and respiratory effects. 

Table 2-3. Summary of evidence from epidemiologic, controlled human exposure, and animal

toxicological studies on the health effects associated with short- and long-term exposure to 

ozone 

Health Outcome Conclusions from 2006 O3 AQCD Conclusions from 2011 1st Draft ISA 

Respiratory effects 

Short-Term Exposure to O3 

The overall evidence supports a causal

relationship between acute ambient O3 

exposures and increased respiratory morbidity 

outcomes. 

Causal relationship 

Lung function 

Results from controlled human exposure 

studies and animal toxicological studies

provide clear evidence of causality for the

associations observed between acute (≤ 24 h) 

O3 exposure and relatively small, but

statistically significant declines in lung function 

observed in numerous recent epidemiologic

studies. Declines in lung function are 

particularly noted in children, asthmatics, and

adults who work or exercise outdoors. 

Recent controlled human exposure studies

demonstrated decreases in FEV1 in the range of 

2.8 to 3.6% with O3 exposures 6.6 h in duration 

and as low as 60 ppb in concentration. The 

collective body of epidemiologic evidence 

demonstrates associations between acute 

ambient O3 exposure and decrements in lung 

function, particularly in asthmatics, children, and 

adults who work or exercise outdoors. 

Airway 

hyperresponsiveness 

Evidence from human clinical and animal 

toxicological studies clearly indicate that acute 

exposure to O3 can induce airway

hyperreactivity, thus likely placing atopic

asthmatics at greater risk for more prolonged 

bouts of breathing difficulties due to airway

constriction in response to various airborne 

allergens or other triggering stimuli. 

A limited number of studies have observed 

airway hyperresponsiveness in rodents and 

guinea pigs after exposure to less than 300 ppb

O3. As previously reported in the 2006 O3 AQCD, 

50 ppb O3 induced airway hyperresponsiveness

in certain strains of rats, suggesting a genetic 

component. 

Pulmonary

inflammation, injury

and oxidative stress 

The extensive human clinical and animal 

toxicological evidence, together with the limited

available epidemiologic evidence, is clearly

indicative of a causal role for O3 in 

inflammatory responses in the airways. 

Epidemiologic studies provided new evidence for

associations of ambient O3 with mediators of 

airway inflammation and oxidative stress and 

indicated that groups with diminished antioxidant

capacity or comorbidities such as atopy, AHR, or

obesity may have increased susceptibility to 

respiratory morbidity associated with O3 

exposure. Generally, these studies were

conducted in locations where the 8-h max O3 

concentration ranged from 31 to 66 ppb. 

Respiratory symptoms

and medication use 

Young healthy adult subjects exposed in 

clinical studies to O3 concentrations ≥ 80 ppb

for 6 to 8 h during moderate exercise exhibit

symptoms of cough and pain on deep

inspiration. The epidemiologic evidence shows

significant associations between acute 

exposure to ambient O3 and increases in a 

wide variety of respiratory symptoms (e.g.,

cough, wheeze, production of phlegm, and 

shortness of breath) and medication use in 

asthmatic children. 

The collective body of epidemiologic evidence

demonstrates positive associations between 

acute exposure to ambient O3 and respiratory

symptoms (e.g., cough, wheeze, production of

phlegm, and shortness of breath) in asthmatic

children. Generally, these studies were 

conducted in locations where the 8-h max O3 

concentration ranged from 17 to 66 ppb. 

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Health Outcome Conclusions from 2006 O3 AQCD Conclusions from 2011 1st Draft ISA 

Lung host defenses 

Toxicological studies provided extensive 

evidence that acute O3 exposures as low as 80

to 500 ppb can cause increases in 

susceptibility to infectious diseases due to 

modulation of lung host defenses. A single 

controlled human exposure study found 

decrements in the ability of alveolar

macrophages to phagocytose microorganisms

upon exposure to 80 to 100 ppb O3. 

Recent studies build on prior evidence that O3 

can affect multiple aspects of innate and 

acquired immunity, including macrophage 

function, immune cell proliferation, and natural

killer cell function with acute O3 exposures as 

low as 80 ppb. 

Previous toxicological evidence indicated that Further evidence for O3-induced allergic skewing O3 exposure skews immune responses toward Allergic and asthma is provided by a few recent studies in rodents an allergic phenotype, and enhances the related responses	 using exposure concentrations as low as development and severity of asthma-related 200 ppb. responses such as AHR. 

Aggregate population time-series studies

Hospital admissions, observed that ambient O3 concentrations are 

ED visits, and positively and robustly associated with

physician visits respiratory-related hospitalizations and asthma 

ED visits during the warm season. 

Strong evidence demonstrated associations of

ambient O3 with respiratory hospital admissions

and ED visits in diverse populations across the 

U.S., Europe, and Canada. Generally, these 

studies were conducted in locations where the 

8-h max O3 concentration ranged from 18 to 

60 ppb. 

Respiratory Mortality 

Aggregate population time-series studies

specifically examining mortality from

respiratory causes were limited in number and 

showed inconsistent associations between 

acute exposure to ambient O3 exposure and 

respiratory mortality. 

Recent multicity time-series studies and a multicontinent study consistently demonstrated 

associations between ambient O3 and 

respiratory-related mortality visits in diverse

populations across the U.S., Europe, and 

Canada. Generally, these studies were 

conducted in locations where the 8-h max O3 

concentration ranged from 20 to 63 ppb. 

The limited evidence is highly suggestive that

O3 directly and/or indirectly contributes to

Cardiovascular effects	 cardiovascular-related morbidity, but much Suggestive of a Causal Relationship 

remains to be done to more fully substantiate

the association. 

Toxicological studies report that acute 

exposures to O3 are associated with alterations Central nervous system in neurotransmitters, motor activity, short- and Suggestive of a Causal Relationship effects long-term memory, sleep patterns, and

histological signs of neurodegeneration. 

The evidence is highly suggestive that O3 

directly or indirectly contributes to non- All-cause mortality	 Likely to be a Causal Relationship accidental and cardiopulmonary-related 

mortality. 

Long-term Exposure to O3 

The current evidence is suggestive but

Respiratory effects	 inconclusive for respiratory health effects from Likely to be a Causal Relationship 

long-term O3 exposure. 

New onset asthma No Studies 

Evidence for a relationship between different 

genetic variants (HMOX, GST, ARG) that, in

combination with O3 exposure, are related to 

new onset asthma. These results were observed 

when subjects living in areas where the mean

annual 8-h max O3 concentration was 55.2 ppb, 

compared to those who lived where it was

38.4 ppb. 

Chronic O3 exposure was related to first

childhood asthma hospital admissions in a 

Asthma hospital positive concentration-response relationship. No Studies admissions	 Generally, these studies were conducted in 

locations where the 8-h max O3 concentration 

ranged from 30 to 41 ppb. 

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Health Outcome Conclusions from 2006 O3 AQCD Conclusions from 2011 1st Draft ISA 

Pulmonary structure

and function 

Epidemiologic studies observed that reduced

lung function growth in children was associated 

with seasonal exposure to O3; however, cohort 

studies of annual or multiyear O3 exposure

observed little clear evidence for impacts of

longer-term, relatively low-level O3 exposure on

lung function development in children. Animal

toxicological studies reported chronic O3­

induced structural alterations in several regions

of the respiratory tract including the 

centriacinar region. Morphologic evidence from

studies using exposure regimens that mimic

seasonal exposure patterns report increased 

lung injury compared to conventional chronic

stable exposures. 

Evidence for pulmonary function effects is

inconclusive, with some new epidemiologic

studies relating effects at exposure levels from

30 to 65 ppb. Information from toxicological

studies indicates that long-term exposure

(500 ppb) during gestation or development can 

result in irreversible morphological changes in 

the lung, which in turn can influence pulmonary

function. 

Pulmonary

inflammation, injury

and oxidative stress 

Extensive human clinical and animal 

toxicological evidence, together with limited 

epidemiologic evidence available, suggests a

causal role for O3 in inflammatory responses in 

the airways 

Several epidemiologic and toxicology studies (as

low as 500 ppb) add to observations of 

O3-induced inflammation and injury. 

Allergic responses 

Limited epidemiologic evidence supported an 

association between ambient O3 and allergic

symptoms. Little if any information was

available from toxicological studies. 

Evidence relates positive outcomes of allergic

response and O3 exposure but with variable 

strength for the effect estimates; exposure to O3 

may increase total IgE in adult asthmatics.

Allergic antibody levels in rodents were 

increased by exposure to O3 concentrations as 

low as 200 ppb 

Respiratory mortality 

Studies of cardio-pulmonary mortality were 

insufficient to suggest a causal relationship 

between chronic O3 exposure and increased 

risk for mortality in humans 

A single study demonstrated that exposure to O3 

(1-h max 45 to 60 ppb) elevated the risk of

death from respiratory causes and this effect

was robust to the inclusion of PM2.5 

Cardiovascular Effects No studies from previous review Suggestive of a Causal Relationship 

Limited evidence for a relationship between air

pollution and birth-related health outcomes, Reproductive and including mortality, premature births, low birth Suggestive of a Causal Relationship developmental effects weights, and birth defects, with little evidence

being found for O3 effects. 

Toxicological studies report that acute 

exposures to O3 are associated with alterations Central nervous system in neurotransmitters, motor activity, short and Suggestive of a Causal Relationship effects long term memory, sleep patterns, and 

histological signs of neurodegeneration. 

Little evidence for a relationship between

Cancer	 chronic O3 exposure and increased risk of lung Inadequate to infer a Causal Relationship 

cancer. 

There is little evidence to suggest a causal

All-cause mortality	 relationship between chronic O3 exposure and Suggestive of a Causal Relationship 

increased risk for mortality in humans. 

2.6.1. Respirato ry He alth Effe cts 

1 Collectively, there is a vast amount of evidence spanning several decades that supports a 

2 causal association between exposure to O3 and a spectrum of respiratory effects, including 

3 development of the respiratory system; pulmonary structure, inflammation, injury and function; 

4 changes in host defense; new onset asthma and asthma exacerbations; respiratory symptoms; ED 

5 visits and hospital admissions for respiratory diseases; and even death attributable to respiratory 

6 disease (Figure 2-1). The majority of this evidence is derived from studies investigating short-term 

7 exposure (i.e., days to weeks) to O3, although more recent evidence demonstrates that long-term 

8 exposure (i.e., months to years) may also be detrimental to the respiratory system. 

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Figure 2-1. Snapshot of evidence for the spectrum of respiratory health effects associated with

short- and long-term exposure to ozone. 

Green=Animal Toxicological Studies; Blue=Controlled Human Exposure Studies;

Purple=Epidemiologic Studies; AM=Alveolar Macrophage. ﷒

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1 Mechanistic evidence for the effect of O3 on the respiratory system was initially characterized 

2 in the 1996 O3 AQCD, and identified a variety of lung lipid changes which may be further 

3 metabolized to produce numerous biologically active mediators that can affect host defenses, lung 

4 function, the immune system and other functions. As summarized in Section 2.3 and fully 

5 characterized in Chapter 5 key events in the toxicity pathway of O3 have been identified in humans 

6 and animal models. They include the formation of secondary oxidation products in the lung, 

7 activation of neural reflexes, pulmonary injury and inflammation and increased bronchial reactivity. 

8 In addition, evidence is accumulating that influx of immunomodulatory cells, activation of innate 

9 and adaptive immunity, induction of AHR and allergic responses, impairment of host defense, 

10 systemic inflammation and vascular oxidative/nitrosative stress may also be critical to the O3 

11 toxicity pathway (Figure 2-2). 

Figure 2-2. Schematic depicting key events in the ozone toxicity pathway. ﷒Solid arrows denote 

pathways for which there is greater certainty. Broken arrows represent pathways of

emerging interest. 

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Recent toxicological studies of long-term exposure to O3 occurring throughout various 

lifestages, beginning with prenatal and early life exposures, provide novel evidence for effects on 

development of the respiratory system, including ultrastructural changes in bronchiole development, 

alterations in placental and offspring cytokines, and increased offspring airway hyper-reactivity 

(Section 7.4.7). The strongest evidence for O3-induced effects on the developing lung comes from a 

series of experiments using infant rhesus monkeys repeatedly exposed to 0.5 ppm O3 starting at 

one month of age. Functional changes in the conducting airways of infant rhesus monkeys exposed 

to either O3 alone or O3 + antigen were accompanied by a number of cellular and morphological 

changes. In addition to these functional and cellular changes, significant structural changes in the 

respiratory tract were observed. Importantly, the O3-induced structural pathway changes persisted 

after recovery in filtered air for six months after cessation of the O3 exposures. Exposure to O3 has 

also been associated with similar types of alterations in pulmonary structure in all adult laboratory 

animal species studied, from rats to monkeys (U.S. EPA, 1996, 017831). 

In addition to effects on the development and structure of the respiratory tract, there is 

extensive evidence for the effect of short-term exposure to O3 on pulmonary inflammation. Previous 

evidence from controlled human exposure studies indicated that O3 causes an inflammatory response 

in the lungs (U.S. EPA, 1996, 017831). This inflammatory response to O3 was detected after a single 

1-h exposure with exercise to O3 concentrations of 0.3 ppm; the increased levels of some 

inflammatory cells and mediators persisted for at least 18 hours. Toxicological studies provided 

additional evidence for increases in permeability and inflammation in rabbits at levels as low as 

0.1 ppm O3. Evidence summarized in the 2006 O3 AQCD demonstrated that inflammatory responses 

were observed subsequent to 6.6 h O3 exposure to the lowest tested level of 0.08 ppm in healthy 

human adults, while animal toxicological studies provided extensive evidence that short-term 

(1-3 hours) O3 exposure as low as 0.1-0.5 ppm could cause lung inflammatory responses. The 

limited epidemiologic evidence demonstrated an association between short-term ambient O3 

exposure and airway inflammation in children (1-h max O3 of approximately 0.1 ppm). The most 

recent epidemiologic studies provide additional supporting evidence by demonstrating associations 

of ambient O3 with mediators of airway inflammation and indicating that groups with diminished 

antioxidant capacity or comorbidities such as atopy, AHR, or obesity may have increased 

susceptibility to respiratory morbidity associated with O3 exposure (Sections 6.2.4 and 8.1). 

The normal inflammatory response in lung tissue is part of host defense that aids in removing 

microorganisms or particles that have reached the distal airways and alveolar surface. The 1996 O3 

AQCD concluded that short-term exposure to elevated concentrations of O3 resulted in alterations in 

these host defense mechanisms in the respiratory system. Specifically, toxicological studies of shortterm exposures as low as 0.1 ppm O3 were shown to decrease the ability of alveolar macrophages to 

ingest particles, and short-term exposures as low as 0.08 ppm for 3 hours prevented mice from 

resisting infection with streptococcal bacteria, resulting in mortality. Similarly, alveolar macrophages 

removed from the lungs of human subjects after 6.6 hours of exposure to 0.08 and 0.10 ppm O3 

resulted in a decreased ability to ingest microorganisms, indicating some impairment of host defense 

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capability. These altered host defense mechanisms can lead to susceptibility to respiratory infections, 

which are associated with increased risk of asthma when occurring in early life. 

In addition to pulmonary inflammation and host defenses, recent epidemiologic evidence has 

revealed an association between long-term exposure to O3 and new onset asthma (Section 7.2.1). 

Studies have provided evidence for a relationship between different genetic variants (e.g., HMOX, 

GST, ARG) that, in combination with O3 exposure, are related to new onset asthma. This is the first 

time that evidence has extended beyond the association of exposure to O3 and asthma exacerbations 

to suggest that long-term exposure to O3 may play a role in the development of the disease and 

contribute to incident cases of asthma. 

The most commonly observed and strongest evidence for respiratory effects associated with 

short-term exposure to O3 are increased frequency of breathing and decreased tidal volume (i.e., 

rapid, shallow breathing). Previous controlled human exposure studies demonstrated O3-induced 

decrements in pulmonary function, characterized by alterations in lung volumes and flow and airway 

resistance and responsiveness for multihour exposures (up to 7 hours) to O3 concentrations as low as 

0.08 ppm (U.S. EPA, 1996, 017831). A series of mobile laboratory studies of lung function and 

respiratory symptoms reported pulmonary function decrements at mean ambient O3 concentrations 

of 0.14 ppm in exercising healthy adolescents and increased respiratory symptoms and pulmonary 

function decrements at 0.15 ppm in heavily exercising athletes and at 0.17 ppm in lightly exercising 

healthy and asthmatic subjects. Epidemiologic and animal toxicological evidence is coherent with 

the results of the controlled human exposure studies, both indicating decrements in lung function 

upon O3 exposure. Combined statistical analysis of six epidemiologic studies in children at summer 

camp demonstrated decrements in FEV1 of 0.50 mL/ppb with previous hour O3 concentration. For 

preadolescent children exposed to 120 ppb (0.12 ppm) ambient O3, this amounted to an average 

decrement of 2.4-3.0% in FEV1. Two key studies of lung function measurements before and after 

well-defined outdoor exercise events in adults yielded exposure-response slopes of 0.40 and 

1.35 mL/ppb. Animal toxicological studies reported similar respiratory effects in rats at exposures as 

low as 0.2 ppm O3 for 3 hours. The 2006 O3 AQCD characterized the controlled human exposure 

and animal toxicological studies as providing clear evidence of causality for the associations 

observed between acute (≤ 24 hours) O3 exposure and relatively small, but statistically significant 

declines in lung function observed in numerous recent epidemiologic studies. Declines in lung 

function were particularly noted in children, asthmatics, and adults who work or exercise outdoors. 

Recent studies in animals and in vitro models described inflammatory and injury responses mediated 

by toll-like receptors (e.g., TLR4, TL2), receptors for TNF or IL-1, multiple signaling pathways 

(e.g., p38, JNK, NFκB, MAPK/AP-1), and oxidative stress (Section 6.2.3.3). Recent controlled 

human exposure studies examined lower concentration O3 exposures (40-80 ppb) and demonstrated 

that FEV1, respiratory symptoms, and inflammatory responses were affected by O3 exposures of 

6.6 hours and in the range of 60 to 80 ppb (Section 6.2.1.2). These studies demonstrated decreases in 

FEV1 in the range of 2.8 to 3.6% with O3 exposures 6.6 h in duration and as low as 60 ppb in 

concentration. Recent epidemiologic studies provide greater insight into subject factors that may 

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increase susceptibility for O3-associated respiratory morbidity. It was in these potentially susceptible 

populations (e.g., asthmatics with atopy or concurrent respiratory infection, infants with asthmatic 

mothers, elderly with AHR or obesity, or groups with diminished antioxidant capacity) that O3­

associated decreases in lung function tended to be observed. 

Ozone exposure has been shown to result in airway hyperresponsiveness (both specific and 

non-specific), epithelial permeability, and respiratory tract inflammation. Increased airway 

responsiveness is an important consequence of exposure to O3 because its presence means a change 

in airway smooth muscle reactivity and implies that the airways are predisposed to narrowing on 

inhalation of a variety of stimuli (e.g., specific allergens, SO2, cold air). Specifically, acute (2 or 

3 hours) exposure to 0.25 or 0.4 ppm O3 was found to cause increases in airway responsiveness in 

response to allergen challenges among allergic asthmatic subjects who characteristically already had 

somewhat increased airway responsiveness at baseline. 

In addition to alterations in lung volumes and flow, changes in pulmonary function due to 

exposure to O3 may be elicited as respiratory symptoms (e.g., coughing, wheezing, shortness of 

breath). The 1996 O3 AQCD identified an association between respiratory symptoms and increasing 

ambient O3, particularly among asthmatic children. In the 2006 O3 AQCD, the evidence was 

extended to include young healthy adult subjects that exhibited symptoms of cough and pain on deep 

inspiration after exposure to 0.08 ppm O3 for 6-8 hours during moderate exercise. The increase in the 

incidence of cough was found in controlled human exposure studies as low as 0.12 ppm in healthy 

adults during 1-3 hours with very heavy exercise and other respiratory symptoms, such as pain on 

deep inspiration and shortness of breath, were observed at 0.16-0.18 ppm with heavy and very heavy 

exercise. Previous epidemiologic evidence showed significant associations between acute exposure 

to ambient O3 and increases in a wide variety of respiratory symptoms (e.g., cough, wheeze, 

production of phlegm, and shortness of breath) in asthmatic children (U.S. EPA, 2006, 088089). 

Epidemiologic studies also indicated that acute O3 exposure is likely associated with increased 

asthma medication use in asthmatic children. Similar to what was observed for pulmonary function, 

recent epidemiologic studies provided greater insight into subject factors that may increase 

susceptibility for O3-associated respiratory symptoms. It was in these potentially susceptible 

populations (e.g., asthmatics with atopy or concurrent respiratory infection, infants with asthmatic 

mothers, elderly with AHR or obesity, or groups with diminished antioxidant capacity) that O3­

associated increases in respiratory symptoms tended to be observed. Additionally, recent evidence 

provides evidence for an association between long-term exposure to O3 and respiratory symptoms 

(Section 7.2.2). 

When respiratory symptoms, asthma exacerbations, or other respiratory diseases become too 

serious to be cared for at home, they can result in visits to hospital emergency departments (ED) or 

hospital admissions. The frequency of these types of ED visits and hospital admissions is associated 

with ambient O3 concentrations. Summertime daily hospital admissions for respiratory causes in 

various locations of eastern North America consistently reported a relationship with ambient levels 

of O3 in studies reviewed in the 1996 O3 AQCD. This association remained even when considering 

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only concentrations below 0.12 ppm O3. The 2006 O3 AQCD concluded that aggregate population 

time-series studies demonstrate a positive and robust association between ambient O3 concentrations 

and respiratory-related hospitalizations and asthma ED visits during the warm season. Recent 

epidemiologic time-series studies included additional multicity and multicontinent studies in which 

short-term increases in ambient O3 concentrations were consistently associated with increases in 

respiratory hospital admissions and ED visits across diverse populations, geographic locations, and 

range of O3 concentrations (Section 6.2.7). There is also recent evidence for an association between 

respiratory hospital admissions and long-term exposure to O3 (Section 7.2.2). 

Finally, in very serious cases, O3 exposure may contribute to death from respiratory causes. 

Recent evidence from several multicity and multicontinent studies demonstrated associations 

between increases in short-term exposure to ambient O3 concentrations and increases in respiratory 

mortality (Section 6.6.2.5). Similarly, a study of long-term exposure to ambient O3 concentrations 

also demonstrated an association between O3 and increases in respiratory mortality (Section 7.7.1). 

Evidence from these new mortality studies is consistent and coherent with the evidence from 

epidemiologic, controlled human exposure, and animal toxicological studies for the effects of shortand long-term exposure to O3 on respiratory effects. Additionally, the evidence for short- and longterm respiratory morbidity provides biological plausibility for mortality due to respiratory disease. 

In summary, recent studies support or build upon the strong body of evidence presented in the 

1996 and 2006 O3 AQCDs that short-term O3 exposure is causally associated with adverse 

respiratory health effects. Recent controlled human exposure studies demonstrated decreases in 

FEV1 in the range of 2.8 to 3.6% with O3 exposures 6.6 hours in duration and as low as 60 ppb in 

concentration. Equally strong evidence demonstrated associations of ambient O3 with respiratory 

hospital admissions and ED visits in diverse populations across the U.S., Europe, and Canada. Most 

effect estimates ranged from a 1.4 to 2.9% increase in daily ED visits or hospital admissions and 

were observed in locations with mean 1-h max O3 concentrations between 11 and 60 ppb. Several 

multicity and multicontinent studies reported associations between increases in ambient O3 

concentrations and increases in respiratory mortality. Individual-level epidemiologic studies 

provided new evidence for associations of ambient O3 with mediators of airway inflammation and 

oxidative stress and indicated that groups with diminished antioxidant capacity or comorbidities such 

as atopy, AHR, or obesity may have increased susceptibility to respiratory morbidity associated with 

O3 exposure. These recent epidemiologic findings provided support for ambient O3 exposure having 

similar effects and modes of action as those observed in studies with experimental exposures. By 

demonstrating O3-induced airway hyperresponsiveness, activation of neural reflexes (indicative of 

decreased pulmonary function), allergic responses, lung injury, impaired host defense, and airway 

inflammation, toxicological studies have characterized O3 modes of action and have provided 

biological plausibility for epidemiologic associations of ambient O3 exposure with lung function and 

respiratory symptoms, hospital admissions, ED visits, and mortality. Together, the evidence 

integrated across controlled human exposure, epidemiologic, and toxicological studies and across the 

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1 spectrum of respiratory health endpoints continues to demonstrate that there is a causal 

2 relationship between short-term O3 exposure and respiratory health effects. 

3 The strongest evidence for a relationship between long-term O3 exposure and respiratory 

4 morbidity in recent studies demonstrates associations between long-term measures of O3 exposure 

and new-onset asthma in children and increased respiratory symptom effects in asthmatics. While the 

6 evidence may be limited, these U.S. multi-community prospective cohort studies demonstrate that 

7 asthma risk is associated with the important relationships between genetic variability, environmental 

8 O3 exposure, and behavior. Other recent studies provide coherent evidence for long-term O3 

9 exposure and respiratory morbidity effects such as first asthma hospitalization and respiratory 

symptoms in asthmatics. Generally, the epidemiologic and toxicological evidence provides a 

11 compelling case that supports the hypothesis that a relationship exists between long-term exposure to 

12 ambient O3 and measures of respiratory morbidity. Building upon that evidence, the more recent 

13 epidemiologic evidence, combined with toxicological studies in rodents and non-human primates, 

14 provides biologically plausible evidence that there is likely to be a causal relationship between 

long-term exposure to O3 and respiratory morbidity. 

2.6.2. Mortality Effects 

16 The 2006 O3 AQCD concluded that the overall body of evidence was highly suggestive that 

17 short-term exposure to O3 directly or indirectly contributes to non-accidental and cardiopulmonary18 related mortality, but additional research was needed to more fully establish underlying mechanisms 

19 by which such effects occur. The evaluation of new multicity studies that examined the association 

between short-term O3 exposure and mortality found evidence which supports the conclusions of the 

21 2006 O3 AQCD. These new studies reported consistent positive associations between short-term O3 

22 exposure and total (nonaccidental) mortality, with associations being stronger during the warm 

23 season, as well as additional support for associations between O3 exposure and cardiovascular 

24 mortality being similar or larger in magnitude compared to respiratory mortality. Additionally, these 

new studies examined previously identified areas of uncertainty in the O3-mortality relationship. 

26 Taken together, the body of evidence indicates that there is likely to be a causal relationship 

27 between short-term exposures to O3 and all-cause mortality. 

28 The 2006 O3 AQCD concluded that an insufficient amount of evidence existed “to suggest a 

29 causal relationship between chronic O3 exposure and increased risk for mortality in humans” 

(U.S. EPA, 2006, 088089). Two additional studies have been conducted since the last review, an 

31 ecologic study that finds no association between mortality and O3, and a reanalysis of the ACS 

32 cohort that specifically points to a relationship between long-term O3 exposure and an increased risk 

33 of respiratory mortality. The findings from the reanalysis of the ACS study are consistent and 

34 coherent with the evidence from epidemiologic, controlled human exposure, and animal 

toxicological studies for the effects of short- and long-term exposure to O3 on respiratory effects. 

36 Additionally, the evidence for short- and long-term respiratory morbidity provides biological 

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1 plausibility for mortality due to respiratory disease. Collectively, the evidence is suggestive of a
 

2 causal relationship between long-term O3 exposures and mortality.
 

2.6.3. Ca rdio va s cular He alth Effec ts 

3 In past O3 AQCDs the effects of short- and long-term exposure to O3 on the cardiovascular 

4 system could not be thoroughly evaluated due to the paucity of information available. However, 

studies investigating O3-induced cardiovascular events have advanced in the last two decades. 

6 Overall, there is limited, mixed evidence for cardiovascular effects in epidemiologic studies. Animal 

7 toxicological studies provide more evidence for O3 exposure leading to cardiovascular morbidity. 

8 The toxicological studies demonstrate O3-induced cardiovascular effects, specifically enhanced 

9 ischemia/reperfusion injury with or without the corresponding development of a systemic oxidative, 

proinflammatory environment, disrupted NO-induced vascular reactivity, decreased cardiac function, 

11 and increased HRV. Taking into consideration the positive toxicological studies reported, the 

12 generally limited body of evidence is suggestive of a causal relationship for both relevant short13 and long-term exposures to O3 and cardiovascular effects. 

2.6.4. Central Nervous Sys tem Effects 

14 In rodents, O3 exposure has been shown to cause physicochemical changes in the brain 

indicative of oxidative stress and inflammation. Recent toxicological studies add to earlier evidence 

16 that short- and long-term exposures to O3 can produce a range of effects on the central nervous 

17 system and behavior. Previously observed effects, including neurodegeneration, alterations in 

18 neurotransmitters, short- and long-term memory, and sleep patterns, have been further supported by 

19 recent studies. In instances where pathology and behavior are both examined, animals exhibit 

decrements in behaviors tied to the brain regions or chemicals found to be affected or damaged. The 

21 single epidemiologic study conducted showed that long-term exposure to O3 affects memory in 

22 humans as well. Notably, exposure to O3 levels as low as 0.25 ppm has resulted in progressive 

23 neurodegeneration and deficits in both short- and long-term memory in rodents. Additionally, 

24 changes in the CNS, including biochemical, cellular, and behavioral effects, have been observed in 

animals whose sole exposure occurred in utero, at levels as a low as 0.3 ppm. Together the evidence 

26 from studies of short- and long-term exposure to O3 is suggestive of a causal relationship between 

27 O3 exposure and adverse CNS effects. 

2.6.5. Re p ro du c tive a n d Develo p me ntal Effe cts 

28 There is limited though positive toxicological evidence for O3-induced developmental effects, 

29 including effects on pulmonary structure and function and central nervous system effects. Limited 

epidemiologic evidence exists for an association with O3 concentration and decreased sperm 

31 concentration. A recent toxicological study provides limited evidence for a possible biological 

32 mechanism (histopathology showing impaired spermatogenesis) for such an association. 

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1 Additionally, though the evidence for an association between O3 concentrations and adverse birth 

2 outcomes is generally inconsistent, there are several influential studies that indicate an association 

3 with reduced birth weight and restricted fetal growth. Overall, the evidence is suggestive of a causal 

4 relationship between long-term exposures to O3 and reproductive and developmental effects. 

2.6.6. Cancer and Mutagenicity and Genotoxicity 

The 2006 O3 AQCD (U.S. EPA, 2006, 088089) reported that evidence did not support ambient 

6 O3 as a pulmonary carcinogen. Since the 2006 AQCD, very few epidemiologic and toxicological 

7 studies have been published that examine O3 as a carcinogen, but collectively, study results indicate 

8 that O3 may contribute to DNA damage. Overall, the evidence is inadequate to determine if a 

9 causal relationship exists between ambient O3 exposures and cancer. 

2.7. Effe c ts o n Ve g e ta tio n a n d Eco s ys te m s 

Chapter 9 presents the most policy-relevant information related to this review of the NAAQS 

11 for the effects of O3 on vegetation and ecosystems. This section integrates the key findings from the 

12 disciplines evaluated in this current assessment of the O3 scientific literature, which includes plant 

13 physiology, biochemistry, whole plant biology, ecosystems and exposure-response. 

14 Ozone effects at small scales, such as the leaf of an individual plant, can result in effects at a 

continuum of larger scales. Figure 2-3 is a simplified diagram of the major pathway through which 

16 O3 enters plants and the major endpoints O3 may affect from small to large scales. The sections of 

17 Chapter 9 are organized around this paradigm of effects at the cellular and subcellular level followed 

18 by consideration of the whole plant and finally, O3 impacts on ecosystem-level processes. Ozone 

19 enters leaves through stomata, and can alter stomatal conductance and disrupt CO2 fixation (Section 

9.4). These effects can change rates of leaf gas exchange, growth and reproduction at the individual 

21 plant level (Section 9.5). Those O3-induced effects can translate from the individual plant level to the 

22 ecosystem level, and cause changes in ecosystem services, such as C storage, water production, 

23 nutrient cycling, and community composition (Section 9.6). The EPA framework for causal 

24 determinations described in Chapter 1 has been applied to the body of scientific evidence to 

collectively examine effects attributed to O3 exposure (Table 2-4). 

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Figure 2-3. The effects of ozone at leaf, plant and ecosystem scales. 

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Table 2-4. Summary of ozone causal determinations for vegetation and ecosystem effects 

Vegetation and Ecosystem Effects Causality Determination 

Reduced Vegetation Growth Causal 

Alteration of Vegetation Reproduction Causal 

Visible Foliar Injury Effects on Vegetation Causal 

Alteration of Leaf Gas Exchange in Vegetation Causal 

Reduced Yield and Quality of Agricultural Crops Causal 

Reduced Productivity in Terrestrial Ecosystems Causal 

Reduced Carbon (C) Sequestration in Terrestrial Ecosystems Likely Causal 

Alteration of Terrestrial Ecosystem Water Cycling Likely Causal 

Alteration of Below-ground Biogeochemical Cycles Causal 

Alteration of Terrestrial Community Composition Likely Causal 

2.7.1. Me ch a nis ms Go ve rnin g Res p on s e 

1 Section 9.4 focuses on the effects of O3 stress on plants and their responses to that stress on the 

2 molecular, biochemical and physiological levels. Many of the studies focus on the molecular 

3 mechanisms that underlie the observed biochemical and physiological changes observed in many 

4 plant species in response to O3 exposure. The results support and strengthen those reported in the 

5 2006 O3 AQCD. The most significant change in this section from the 2006 O3 AQCD is the emphasis 

6 on molecular mechanisms as new techniques, such as those used in evaluating transcriptomes (total 

7 set of RNA transcripts in a particular cell at a particular time) and proteomes (total set of proteins 

8 expressed in a particular cell at a particular time), have been utilized to perform very comprehensive 

9 analyses of changes in gene transcription and protein expression in plants exposed to O3. These 

10 newer molecular studies not only provide very important and wide-ranging information regarding 

11 the many mechanisms of plant responses to O3, they also allow for the analysis of interactions 

12 between various biochemical pathways which are induced in response to O3. However, many of 

13 these studies are conducted in artificial conditions with model plants which are typically exposed to 

14 very high, short doses of O3. Therefore, additional work remains to elucidate whether these plant 

15 responses are transferable to other plant species exposed to more realistic ambient conditions. 

16 Ozone is taken up into leaves through open stomata. Once inside the substomatal cavity, O3 is 

17 thought to rapidly react with the aqueous layer surrounding the cell (apoplast) to form breakdown 

). These • ) and peroxy radicals (HO 2 • ), hydroxyl radicals (HO ־ 18 products such as H2O2, superoxide (O2 

19 radicals may play a role in signaling processes and may also interact with sensitive molecules both 

20 outside and inside the cell to cause damage. This process was very comprehensively described in the 

21 2006 O3 AQCD and is only summarized in this document in Section 9.4.2. 

22 As plants have been shown to respond to O3 exposure very rapidly, this response must result 

23 from a plant's ability to sense the presence of O3 and/or its breakdown products and then 

24 communicate that information to the nucleus to initiate changes in gene expression. While it remains 

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unclear what the exact mechanism is by which the plant senses the presence of O3, whether there are 

multiple simultaneous mechanisms by which O3 can be sensed, and how much variation exists in O3 

sensing between species and exposure conditions, some progress has been made in the understanding 

of this process since the 2006 O3 AQCD. Experimental evidence described in Section 9.4.3.1 

suggests that O3 and/or its breakdown products may be directly sensed by apoplastic receptor 

proteins (although they have not yet been identified). Additionally, a change in cellular redox state 

due to plant exposure to O3 could be the manner in which plants sense the presence of the pollutant. 

Once the plant has sensed the presence of the pollutant, there is much evidence to suggest that 

mitogen-activated protein kinases (MAPK) play an important role in communicating signals to the 

nucleus that result in gene expression changes in response to O3. Calcium has also been implicated to 

play a role in the signal transduction processes. To summarize, the evidence to date suggests there 

may be several mechanisms by which plants sense the presence of O3 and then communicate this 

signal to the nucleus to induce changes in gene expression. 

New technologies have allowed for the evaluation of changes in the entire transcriptome and 

proteome, rather than analyzing the modification of the expression of individual genes and proteins; 

the results of these studies are presented in Section 9.4.3.2. While transcriptome and proteome 

analyses per se were not previously addressed, the 2006 O3 AQCD did provide much information 

regarding changes in gene expression and protein quantity of individual genes and proteins in 

O3-treated plants. In the transcriptome and proteome studies described here, O3 exposure conditions 

(concentration, duration of exposure), plant species and sampling times vary significantly; however, 

functional classification of the genes and proteins that are either up- or down-regulated by plant 

exposure to O3 exhibit common trends. In summary, genes involved in plant defense, signaling, and 

those associated with the synthesis of plant hormones and secondary metabolism are generally upregulated in plants exposed to O3, while those related to photosynthesis and general metabolism are 

typically down-regulated. Proteome studies support these results by demonstrating concomitant 

increases or decreases in the proteins encoded by these genes. The transcriptome and proteome 

results support and enhance the findings of the 2006 O3 AQCD. 

The 2006 O3 AQCD included a discussion on the role of phytohormones, including salicylic 

acid, ethylene and jasmonic acid, in plant response to O3. Many additional studies using microarray 

technology (used to determine changes in the transcriptome) and a variety of Arabidopsis mutants 

are described in Section 9.4.3.3 and support the conclusions from the 2006 O3 AQCD. Transcriptome 

analysis has also illuminated the complex interactions that exist between these hormones to better 

define plant response to O3. To summarize, the results indicate that while ethylene and salicylic acid 

are needed to develop O3-induced leaf lesions, jasmonic acid acts antagonistically to ethylene and 

salicylic acid to limit the spread of the lesions. Abscisic acid, in addition to its role in regulating 

stomatal aperture, may also act antagonistically to the jasmonic acid signaling pathway. Nitric oxide 

has also been proposed to play a role in regulating O3-induced changes in gene expression; however, 

its role is not yet well defined. Changes in phytohormones and the interactions between them reveal 

some of the complexity of plant responses to an oxidative stressor such as O3. 

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Antioxidant metabolites, such as ascorbate and glutathione, and the enzymes that regenerate 

them are a critical part of plant defense responses to oxidative stress. The role of ascorbate, which is 

located in several cellular compartments and also in the apoplast, was comprehensively evaluated in 

the 2006 O3 AQCD as a first line of defense (due to its location in the apoplast) against oxidative 

stress. Ascorbate has also been the focus of studies investigating differences in O3 tolerance between 

plant species or cultivars/genotypes within one species. While the studies evaluated for the current 

document support the important role of ascorbate, several studies suggest that ascorbate quantity, 

especially in the apoplast, is not the primary factor in determining plant tolerance to O3. In summary, 

antioxidant metabolites and enzymes increase in quantity in plants exposed to O3. In most cases, 

there is a correlation between the degree to which these defensive systems are induced and the 

ability of the plant to tolerate exposure to O3. This up-regulation of antioxidant defenses and the 

need to keep antioxidant metabolites in a reduced state requires a significant shift in C metabolism 

away from growth and reproduction to sustain the energy needs of the plant for defense. 

While declines in C fixation as a result of plant exposure to O3 were extensively described in 

the 2006 O3 AQCD, some recent studies (described in Section 9.4.5.1) of O3-induced declines in 

photosynthesis have focused also on O3 effects on the light reactions. Declines in the Fv/Fm ratio (a 

measure of the maximum efficiency of the light reactions of photosynthesis) were observed in 

several studies using a variety of plant species and exposure conditions. Additionally, O3 increased 

the coefficient of non-photochemical quenching in several species, an indication that defense and 

repair mechanisms of a non-photochemical nature are activated in these plants while less absorbed 

light is being used to drive photosynthesis. This indicates a shift away from photosynthesis to 

defense, resulting in negative impacts on growth and reproduction. 

Section 9.4.5.2 evaluates the effects of O3 on respiration. While C assimilation declines in O3 

exposed plants, respiration is generally up-regulated. These increases in respiration are thought to 

result from a plant's greater energy needs for defense (maintaining its antioxidant metabolites in a 

reduced state) and repair. The increased energy needs will negatively impact plant growth and 

reproduction. 

Secondary metabolism is most often up-regulated in a variety of species exposed to either 

acute or chronic O3 exposures as a part of a generalized plant defense mechanism. Changes in gene 

expression, quantity and activity of enzymes associated with secondary metabolism and alterations 

in secondary metabolite quantity have been documented in plants exposed to O3. Some secondary 

metabolites, such as flavonoids and polyamines, are of particular interest as they are known to have 

antioxidant properties. Investigations on the importance of isoprenes in plant response to O3 have 

revealed conflicting results; however, there is some evidence to suggest that they may play a 

protective role. In summary, secondary metabolites increase in quantity in O3-treated plants as part of 

a generalized plant defense response. Some secondary metabolites are of particular importance in 

O3-treated plants as they may have antioxidant functions. Increased synthesis of secondary 

metabolites represents a large energy investment of the plant into defense responses and away from 

growth and reproduction. 

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1 Section 9.4.6 focuses on O3-induced changes in stomatal function. Stomata play a critical role 

2 in limiting O3 uptake into the plant by reducing stomatal aperture. Declines in stomatal conductance 

3 in response to O3 have been documented for many plant species, and much evidence suggests that 

4 this results from increases in intercellular CO2 concentration due to reductions in C fixation. 

Additionally, sensitivity of some plants to O3 has been related to a sluggish stomatal response, in 

6 which plants are unable to close their stomata rapidly in response to O3. To summarize, stomatal 

7 response to O3 can help to determine plant sensitivity to the pollutant, and the decreases in stomatal 

8 conductance are thought to be related to declines in C fixation rates. Reduced stomatal conductance 

9 will decrease rates of C assimilation and lead to diminished growth and reproduction in plants. 

2.7.2. Na ture o f Effec ts on Veg eta tio n 

Ambient O3 concentrations have long been known to cause visible foliar injury, decreases in 

11 photosynthetic rate, decreases in growth, and decreases in the quality and yield of some plant species 

12 (U.S. EPA, 1978, 040586; U.S. EPA, 1984, 029711; U.S. EPA, 1996, 080827; U.S. EPA, 2006, 

13 088089). Numerous studies have related O3 exposure to plant responses, with most research effort 

14 focused on the growth of tree seedlings and the yield of crops as endpoints. The response of a plant 

species to O3 exposure depends upon many factors, including genetic characteristics, biochemical 

16 and physiological status, and previous and current exposure to other stressors. The associated 

17 sections in Section 9.5 focus mainly on studies published since the release of the 2006 O3 AQCD 

18 (U.S. EPA, 2006, 088089). However, because much O3 research was conducted prior to the 2006 O3 

19 AQCD, the conclusions presented below are collectively based on this ISA as well as the 1978, 

1986, 1996, and 2006 AQCDs (U.S. EPA, 1978, 040586; U.S. EPA, 1984, 029711; U.S. EPA, 1996, 

21 080827; U.S. EPA, 2006, 088089). 

2.7.2.1. Effe c ts o n Wo ody a nd He rba c e ous Ve ge ta tio n 

Growth and Biomass Allocation 

22 The previous O3 AQCDs concluded that there is strong and consistent evidence that ambient 

23 concentrations of O3 decrease growth in numerous plant species across the U.S. Studies published 

24 since the last review continue to support that conclusion (Section 9.5.2.1). 

A recently published meta-analysis of 263 studies reported that current ambient O3 

26 concentrations (~40 ppb) significantly decreased annual total biomass growth of forest species by an 

27 average of 7%, with potentially greater decreases (11 to 17%) in areas that have higher O3 

28 concentrations and as background O3 increases in the future. This meta-analysis demonstrates the 

29 coherence of O3 effects across numerous studies and species using a variety of experimental 

techniques. A study conducted on mature forest trees reported that the cumulative effects of ambient 

31 levels of O3 decreased seasonal stem growth by 30-50% for most of the species in a high O3-year in 

32 comparison to a low O3-year. 

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1 Since the 2006 O3 AQCD, several studies were published based on the Aspen free-air carbon2 dioxide/O3 enrichment (FACE) experiment using “free air,” O3, and CO2 exposures in a forest in 

3 Wisconsin. It was found that O3 caused reductions in total biomass relative to the control in aspen, 

4 paper birch, and sugar maple communities during the first seven years of stand development. 

Overall, the studies at the Aspen FACE experiment were consistent with many of the open-top 

6 chamber (OTC) studies that were the foundation of previous O3 NAAQS reviews. These results 

7 strengthen our understanding of O3 effects on forests and demonstrate the relevance of the 

8 knowledge gained from trees grown in open-top chamber studies. 

9 In recent studies, O3 was shown to have either negative, non-significant, or positive effects on 

root biomass and root:shoot ratio. While the findings of individual studies were mixed, recent meta11 analyses have generally indicated that O3 reduced C allocated to roots. 

12 For some annual species, particularly crops, the endpoint for an assessment of the risk of O3 

13 exposure can be defined as yield or growth, e.g., production of grain. For plants grown in mixtures 

14 such as hayfields, and natural or semi-natural grasslands (including native nonagricultural species), 

endpoints other than production of biomass may be important. Such endpoints include biodiversity 

16 or species composition, and measures of plant quality. Effects may also result from competitive 

17 interactions among plants in mixed-species communities. Most of the available data on non-crop 

18 herbaceous species are for grasslands with many of the recent studies conducted in Europe. 

19 Evidence is sufficient to conclude that there is a causal relationship between O3 exposure 

and reduced growth of woody and herbaceous vegetation. 

Reproduction 

21 Studies during recent decades have demonstrated O3 effects on different stages of plant 

22 reproduction (Section 9.5.2.2). Several recent studies published since the 2006 O3 AQCD further 

23 demonstrate the effects of O3 on reproductive processes in herbaceous and woody plant species. 

24 The impacts of O3 on reproductive development can occur by influencing (1) age at time of 

initial flowering, particularly in long-lived trees that often have long juvenile periods of early growth 

26 without flower and seed production; (2) flower bud initiation and development; (3) pollen 

27 germination and pollen tube growth; and (4) seed, fruit, or cone yields and seed quality. 

28 Evidence is sufficient to conclude that there is a causal relationship between O3 exposure 

29 and changes in reproduction of vegetation. 

Visible Foliar Injury 

Visible foliar injury resulting from exposure to O3 has been well characterized and 

31 documented over several decades of research on many tree, shrub, herbaceous, and crop species 

32 (U.S. EPA, 1978, 040586; U.S. EPA, 1984, 029711; U.S. EPA, 1996, 080827; U.S. EPA, 2006, 

33 088089) (Section 9.5.2.3). Ozone-induced visible foliar injury symptoms on certain bioindicator 

34 plant species are considered diagnostic as they have been verified experimentally in exposureresponse studies, using exposure methodologies such as continuous stirred tank reactors (CSTRs), 

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1 OTCs, and free-air fumigation. Experimental evidence has clearly established a consistent 

2 association of visible injury with O3 exposure, with greater exposure often resulting in greater and 

3 more prevalent injury. Since the 2006 O3 AQCD, several multiple-year field surveys of O3-induced 

4 visible foliar injury have been conducted at National Wildlife Refuges in Maine, Michigan, New 

Jersey, and South Carolina. New sensitive species showing visible foliar injury continue to be 

6 identified from field surveys and verified in controlled exposure studies. 

7 The use of biological indicators in field surveys to detect phytotoxic levels of O3 is a 

8 longstanding and effective methodology. The USDA Forest Service through the Forest Health 

9 Monitoring (FHM) Program (1990-2001) and currently the Forest Inventory and Analysis (FIA) 

Program has been collecting data regarding the incidence and severity of visible foliar injury on a 

11 variety of O3 sensitive plant species throughout the U.S. The network has provided evidence that O3 

12 concentrations were high enough to induce visible symptoms on sensitive vegetation. From repeated 

13 observations and measurements made over a number of years, specific patterns of areas experiencing 

14 visible O3 injury symptoms can be identified. 

In addition, a study assessed the risk of O3-induced visible foliar injury on bioindicator plants 

16 in 244 national parks in support of the National Park Service's Vital Signs Monitoring Network. The 

17 results of the study demonstrated that the risk of visible foliar injury was high in 65 parks (27%), 

18 moderate in 46 parks (19%), and low in 131 parks (54%). Some of the well-known parks with a high 

19 risk of O3-induced visible foliar injury include: Gettysburg, Valley Forge, Delaware Water Gap, Cape 

Cod, Fire Island, Antietam, Harpers Ferry, Manassas, Wolf Trap Farm Park, Mammoth Cave, Shiloh, 

21 Sleeping Bear Dunes, Great Smoky Mountains, Joshua Tree, Sequoia and Kings Canyon, and 

22 Yosemite. 

23 Evidence is sufficient to conclude that there is a causal relationship between ambient O3 

24 exposure and the occurrence of O3-induced visible foliar injury on sensitive vegetation across 

the U.S. 

Gas Exchange 

26 There is strong experimental evidence over several decades of research that exposure to O3 

27 reduces photosynthesis and alters stomatal conductance in a wide variety of plant species. The mode 

28 of action, as characterized in Section 9.4 and in previous reviews, provides biological plausibility for 

29 O3 effects on leaf gas exchange. 

In compiling more than 55 studies, a meta-analysis reported that current O3 concentrations in 

31 the northern hemisphere are decreasing photosynthesis (11%) and stomatal conductance (13%) 

32 across tree species. It was also found that younger trees less than four years old) were affected less 

33 by O3 than older trees. Further, the authors also found that decreases in photosynthesis are consistent 

34 with the cumulative uptake of O3 into the leaf. In contrast, several studies reported that O3 exposure 

may result in loss of stomatal control, incomplete stomatal closure at night and a decoupling of 

36 photosynthesis and stomatal conductance, which may have implications for whole-plant water use 

37 (Section 9.6.3). 

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1 Evidence is sufficient to conclude that there is a causal relationship between O3 exposure 

2 and the alteration of leaf gas exchange in vegetation. 

2.7.2.2. Agric ultura l Cro ps 

Yield and Crop Quality 

3 The detrimental effect of O3 on crop production has been recognized since the 1960s and a 

4 large body of research has subsequently stemmed from those initial findings. Previous O3 AQCDs 

have extensively reviewed this body of literature (U.S. EPA, 2006, 088089). Recent experimental 

6 studies of O3 effects on crops are discussed in Section 9.5.3 and summarized in Tables 9-3 and 9-16. 

7 Current O3 concentrations across the U.S. are high enough to cause yield loss for a variety of 

8 agricultural crops including, but not limited to, soybean, wheat, cotton, potato, watermelon, beans, 

9 turnip, onion, lettuce, and tomato. Continued increases in O3 concentration may further decrease 

yield in these sensitive crops while also initiating yield losses in less sensitive crops. Despite the 

11 well-documented yield losses due to increasing O3 concentration, there is still a knowledge gap 

12 pertaining to the exact mechanism of O3-induced yield loss. Research has linked increasing O3 

13 concentration to decreased photosynthetic rates and accelerated senescence, which are related to 

14 yield. 

Recent modeling research has correlated satellite air-column observations with direct air16 sampling O3 data and modeled the yield-loss due to O3 over the continuous tri-state area of Illinois, 

17 Iowa and Wisconsin. This modeling data correlates well with the previous results from FACE-type 

18 experiments and OTC experiments. 

19 New research is beginning to consider the mechanism of damage caused by long, lower O3 

concentration (so-called chronic exposure) compared to short, very high O3 concentration (so-called 

21 acute exposure). Both types of O3 exposure cause damage to agricultural crops, but through very 

22 different mechanisms. Until recently, most research on the mechanism of O3 damage has used acute 

23 exposure studies. It has become clear that the same cellular and biochemical processes involved in 

24 the response to acute O3 exposure are not involved in response to chronic O3 exposure, yet both 

cause yield-loss in agriculturally important crops. 

26 In addition, new research has highlighted the effects of O3 on crop quality. Increasing O3 

27 concentration decreases nutritive quality of grasses, decreases macro- and micro-nutrient 

28 concentrations in fruits and vegetable crops, and decreases cotton fiber quality. These areas of 

29 research require further investigation to determine the mechanism and dose-responses. 

Evidence is sufficient to conclude that there is a causal relationship between O3 exposure 

31 and reduced yield and quality of agricultural crops. 

2.7.2.3. Fa c tors Tha t Mo dify Fu nc tio na l a nd Gro wth Re s pons e 

32 Many biotic and abiotic factors, including insects, pathogens, root microbes and fungi, 

33 temperature, water and nutrient availability, and other air pollutants, as well as elevated CO2, 

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1 influence or alter plant response to O3. These modifying factors were comprehensively reviewed in 

2 the 2006 O3 AQCD. A limited number of studies published since 2006 provide further support for 

3 our understanding of the role of these interactions in modifying O3-induced plant responses and are 

4 discussed in Section 9.5.4. 

2.7.3. Ecos ys tems and Services 

Ozone has been found to alter plant physiological processes such as growth, biomass 

6 allocation, reproduction and gas exchange (Section 9.5). Those O3-induced effects at the individual 

7 plant scale have the potential to translate to effects at the ecosystem level, and cause changes in 

8 biogeochemical cycling and community composition. Information presented in the associated section 

9 (Section 9.6) was collected at multiple scales, ranging from responses at the population level to the 

ecosystem level. The effects of O3 on ecosystem productivity, C sequestration, water cycling, 

11 nutrient cycling, and community composition are reviewed. 

2.7.3.1. Productivity and Carbon Se ques tration 

12 During the previous NAAQS reviews, there were very few studies that investigated the effect 

13 of O3 exposure on ecosystem productivity and C sequestration. Recent studies from long-term FACE 

14 experiments provided evidence of the association of O3 exposure and reduced productivity at the 

ecosystem level. Elevated O3 reduced stand-level biomass by 13-23% at Aspen FACE after 7 years 

16 of O3 exposure, and annual volume growth by 9.5 m3/ha at the Kranzberg Forest (Germany) FACE. 

17 Studies at the leaf and plant scales showed that O3 reduced photosynthesis and plant growth, which 

18 provided coherence and biological plausibility for the decrease in ecosystem productivity. Results 

19 across different ecosystem models were consistent with the FACE experimental evidence, which 

showed that O3 reduced ecosystem productivity. 

21 Although O3 generally causes negative effects on plant growth, the magnitude of the response 

22 varies among plant communities. For example, O3 had little impact on white fir, but greatly reduced 

23 growth of ponderosa pine in southern California. Ozone decreased net primary production (NPP) of 

24 most forest types by 7-8% in Mid-Atlantic region, but had small impacts on spruce-fir forest, which 

was decreased by only 1%. Among crop species, the estimated yield loss for wheat (7-12%) and 

26 soybean (6-16%) were higher than rice (3-4%) and maize (3-5%). 

27 In addition to plant growth, other indicators that are typically estimated by model studies 

28 include net ecosystem CO2 exchange (NEE), C sequestration, and crop yield. Model simulations 

29 consistently found that O3 exposure caused negative impacts on those indicators (Section 9.6.2, 

Table 9-5), but the severity of these impacts was influenced by multiple interactions of biological 

31 and environmental factors. For example, the largest O3-induced crop yield losses occurred in high32 production areas exposed to high O3 concentrations, such the Midwest and the Mississippi Valley 

33 regions of the U.S. 

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1 The suppression of ecosystem C sinks results in more CO2 accumulation in the atmosphere. 

2 Globally, the indirect radiative forcing, reported in Watts/square meter (W/m2), caused by O3 

3 exposure through lowering ecosystem C sink (0.62-1.09 W/m2 ) could have an even greater impact 

4 on global warming than the direct radiative forcing of O3 (0.89 W/m2). Ozone could also affect 

regional C budgets through interacting with multiple factors, such as N deposition, elevated CO2 and 

6 land use history. Model simulations suggested that O3 partially offset the growth stimulation caused 

7 by elevated CO2 and N deposition in both Northeast- and Mid Atlantic-region forest ecosystems of 

8 the U.S. 

9 The evidence is sufficient to infer that there is a causal relationship between O3 exposure 

and reduced productivity, and there is likely to be causal relationship between O3 exposure and 

11 reduced carbon sequestration in terrestrial ecosystems. 

2.7.3.2. Wa te r Cyc ling 

12 Although the evidence was from a limited number of field and modeling studies, these 

13 findings showed an association of O3 exposure and the alteration of water cycle at the ecosystem 

14 level. Field studies suggested that peak hourly O3 exposure increased the rate of water loss from 

several tree species, and led to a reduction in the late-season modeled stream flow in three forested 

16 watersheds in eastern Tennessee. Evidence of sluggish stomatal responses during O3 exposure was 

17 found in their study and several other studies (Section 9.6.3), which provided biological plausibility 

18 for the observed higher water loss at the ecosystem level. However, many experiments, mostly based 

19 on short-term O3 exposure, found that O3 generally reduced stomatal conductance. The O3-induced 

reduction in stomatal aperture is the biological assumption for most process-based models. 

21 Therefore, results of those models normally found that O3 reduced water loss. For example, one 

22 study found that O3 damage and N limitation together reduced evapotranspiration and increase 

23 runoff. 

24 Although the direction of the response differed among studies, the evidence is sufficient to 

conclude that there is likely to be a causal relationship between O3 exposure and the alteration 

26 of ecosystem water production. 

2.7.3.3. Below-Ground Processes 

27 Since the 2006 O3 AQCD, more evidence has shown that although the responses are often 

28 species specific, O3 altered the quality and quantity of C input to soil, microbial community 

29 composition, and C and nutrient cycling. Biogeochemical cycling of below-ground processes is 

driven by C input from plants. Studies at the leaf and plant level have provided biologically plausible 

31 mechanisms, such as reduced photosynthetic rates, increased metabolic cost, and reduced root C 

32 allocation (Section 9.6.4) for the association of O3 exposure and the alteration of below-ground 

33 processes. 

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1 Results from Aspen FACE and other experimental studies consistently found that O3 reduced 

2 litter production and altered C chemistry, such as soluble sugars, soluble phenolics, condensed 

3 tannins, lignin, and macro/micro nutrient concentration in litter. The changes in substrate quality and 

4 quantity could alter microbial metabolism under elevated O3, and therefore soil C and nutrient 

cycling. Several studies indicated that O3 generally suppressed soil enzyme activities. However, the 

6 impact of O3 on litter decomposition was inconsistent and varied among species, sites and exposure 

7 length. Ozone had small impact on dynamics of micro and macro nutrients, except for N. Ozone was 

8 found to reduce N release from leaf litter and decrease gross N mineralization, which could 

9 potentially decrease N availability to plants. 

Studies from the Aspen FACE experiment suggested that the response of below-ground 

11 C cycle to O3 exposure, such as litter decomposition, soil respiration and soil C content, changed 

12 over time. For example, in the early part of the experiment (1998-2003), O3 had no impact on soil 

13 respiration but reduced the formation rates of total soil C under elevated CO2. However, after 10­

14 11 years of exposure, O3 was found to increase soil respiration but have no significant impact on soil 

C formation under elevated CO2 (Section 9.6.4.1). 

16 The evidence is sufficient to infer that there is a causal relationship between O3 exposure 

17 and the alteration of below-ground biogeochemical cycles. 

2.7.3.4. Community Compos ition 

18 In the 2006 O3 AQCD, the impact of O3 exposure on species competition and community 

19 composition was assessed. Ozone was found to cause a significant decline in ponderosa and Jeffrey 

pine in the San Bernardino Mountains in southern California. Ozone-exposure also tended to shift 

21 the grass-legume mixtures in favor of grass species (U.S. EPA, 2006, 088089). Since the 2006 O3 

22 AQCD, more evidence has shown that O3 exposure changed the competitive interactions and led to 

23 loss of O3 sensitive species or genotypes. Studies at plant level found that the severity of O3 damage 

24 on growth, reproduction and foliar injury varied among species (Section 9.6.5), which provided the 

biological plausibility for the alteration of community composition. Additionally, research since the 

26 last review has shown that O3 can alter community composition and diversity of soil microbial 

27 communities. 

28 The decline of conifer forests under O3 exposure was continually observed in several regions. 

29 Ozone damage was believed to be an important causal factor in the dramatic decline of sacred fir in 

the valley of Mexico, as well as cembran pine in southern France and Carpathian Mountains. Results 

31 from the Aspen FACE site indicated that O3 could alter community composition of broadleaf forests 

32 as well. At the Aspen FACE site, O3 reduced growth and increased mortality of a sensitive aspen 

33 clone, while the O3 tolerant clone emerged as the dominant clone in the pure aspen community. In 

34 the mixed aspen-birch and aspen-maple communities, O3 reduced the competitive capacity of aspen 

compared to birch and maple. 

36 The tendency for O3-exposure to shift the biomass of grass-legume mixtures in favor of grass 

37 species, was reported in the 2006 O3 AQCD (U.S. EPA, 2006, 088089) and has been generally 

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1 confirmed by recent studies. However, in a high elevation mature/species-rich grass-legume pasture, 

2 O3 fumigation showed no significant impact on community composition. 

3 Ozone exposure not only altered community composition of plant species, but also 

4 microorganisms. The shift in community composition of bacteria and fungi has been observed in 

both natural and agricultural ecosystems, although no general patterns could be identified. 

6 The evidence is sufficient to conclude that there is likely to be a causal relationship between 

7 O3 exposure and the alteration of community composition. 

2.7.4. Air Qu ality Indic es 

8 Exposure indices are metrics that quantify exposure as it relates to measured plant damage 

9 (i.e., reduced growth). They are summary measures of monitored ambient O3 concentrations over 

time intended to provide a consistent metric for reviewing and comparing exposure-response effects 

11 obtained from various studies. No new information is available since 2006 that alters the basic 

12 conclusions put forth in the 2006 and 1996 O3 AQCDs (U.S. EPA, 1996, 080827; U.S. EPA, 2006, 

13 088089). These AQCDs focused on the research used to develop various exposure indices to help 

14 quantify effects on growth and yield in crops, perennials, and trees (primarily seedlings). The 

performance of indices was compared through regression analyses of earlier studies designed to 

16 support the estimation of predictive O3 exposure-response models for growth and/or yield of crops 

17 and tree (seedling) species. 

18 The main conclusions from the 1996 and 2006 O3 AQCDs (U.S. EPA, 1996, 080827; 

19 U.S. EPA, 2006, 088089) regarding an index based on ambient exposure are still valid. These key 

conclusions can be restated as follows: 

21  O3 effects in plants are cumulative; 

22  higher O3 concentrations appear to be more important than lower concentrations in 

23 eliciting a response; 

24  plant sensitivity to O3 varies with time of day and plant development stage; and 

 exposure indices that cumulate hourly O3 concentrations and preferentially weight the 

26 higher concentrations have better statistical fits to growth/yield response data than do the 

27 mean and peak indices. 

28 Various weighting functions have been used, including threshold-weighted (e.g., SUM06) and 

29 continuous sigmoid-weighted (e.g., W126) functions. Based on statistical goodness-of-fit tests, these 

cumulative, concentration-weighted indices could not be differentiated from one another using data 

31 from previous exposure studies. Additional statistical forms for O3 exposure indices are summarized 

32 in Section 9.7 of this ISA. The majority of studies published since the 2006 O3 AQCD (2006, 

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1 088089) do not change earlier conclusions, including the importance of peak concentrations, and the 

2 duration and occurrence of O3 exposures in altering plant growth and yield. 

3 Given the current state of knowledge and the best available data, exposure indices that 

4 cumulate and differentially weight the higher hourly average concentrations and also include the 

mid-level values continue to offer the most defensible approach for use in developing response 

6 functions and comparing studies, as well as for defining future indices for vegetation protection. 

2.7.4.1. Mo de le d Ozone De p os ition or "Flux" 

7 Another approach for improving risk assessment of vegetation response to ambient O3 is based 

8 on determining the O3 concentration from the atmosphere that enters the leaf (i.e., flux or 

9 deposition). Interest has been increasing in recent years, particularly in Europe, in using 

mathematically tractable flux models for O3 assessments at the regional, national, and European 

11 scale. While some efforts have been made in the U.S. to calculate O3 flux into leaves and canopies, 

12 little information has been published relating these fluxes to effects on vegetation. There is also 

13 concern that not all O3 stomatal uptake results in a yield reduction, which depends to some degree on 

14 the amount of internal detoxification occurring with each particular species. Those species having 

high amounts of detoxification potential may, in fact, show little relationship between O3 stomatal 

16 uptake and plant response. The lack of data in the U.S. and the lack of understanding of 

17 detoxification processes have made this technique less viable for vulnerability and risk assessments 

18 in the U.S. 

2.7.4.2. Night-Time Exp os ures 

19	 A 12-h (8:00 a.m. to 8:00 p.m.) daylight period for a W126 cumulating exposure was proposed 

in 2007 and 2009 following the release of the 2006 O3 AQCD and was based primarily on evidence 

21 that the conditions for uptake of O3 into the plant occur mainly during the daytime hours. Plants have 

22 the highest stomatal conductance during the daytime and atmospheric turbulent mixing is greatest 

23 then as well (U.S. EPA, 2006, 088089). Recent reviews of the literature reported that a large number 

24 of species had varying degrees of nocturnal stomatal conductance. In general, stomatal conductance 

at night is at a much lower rate compared to daytime conductance. For significant nocturnal stomatal 

26 flux and O3 effects to occur, specific conditions must exist. A susceptible plant with nocturnal 

27 stomatal conductance and low defense must be growing in an area with relatively high night-time O3 

28 and appreciable nocturnal turbulence. It is unclear how many areas there are in the U.S. where these 

29 conditions occur. More information is needed in these locations in order to assess the local O3 

patterns, micrometeorology and responses of potentially vulnerable plant species. 

2.7.5. Expos ure -Response 

31 None of the information on effects of O3 on vegetation published since the 2006 O3 AQCD has 

32 modified the assessment of quantitative exposure-response relationships that was presented in that 

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document (U.S. EPA, 2006, 088089). This assessment updates the 2006 exposure-response models 

by computing them using the W126 metric, cumulated over 90 days. Almost all of the experimental 

research on the effects of O3 on growth or yield of plants published since 2006 used only two levels 

of exposure. In addition, hourly O3 concentration data that would allow calculations of exposure 

using the W126 scale are generally unavailable. However, two long-term experiments, one with a 

crop species (soybean), one with a tree species (aspen), have produced data that can be used to 

validate the exposure-response models presented in the 2006 O3 AQCD, and methodology used to 

derive them. 

Quantitative characterization of exposure-response in the 2006 O3 AQCD was based on 

experimental data generated for that purpose by the National Crop Loss Assessment Network 

(NCLAN) and EPA National Health and Environmental Effects Research Laboratory, Western 

Ecology Division (NHEERL-WED) projects, using OTCs to expose crops and trees seedling to O3. 

In recent years, yield and growth results for two of the species that had provided extensive exposureresponse information in those projects have become available from studies that used FACE 

technology, which is intended to provide conditions much closer to natural environments. The robust 

methods that were used previously with exposure measured as SUM06 were applied to the NCLAN 

and NHEERL-WED data with exposure measured as W126, in order to derive single-species median 

models for soybean and aspen from studies involving different genotypes, years, and locations. The 

resulting models were used to predict the change in yield of soybean and biomass of aspen between 

the two levels of exposure reported in current FACE experiments. Results from these new 

experiments were exceptionally close to predictions from the models. The accuracy of model 

predictions for two widely different plant species provides support for the validity of the 

corresponding multiple-species models for crops and trees in the NCLAN and NHEERL-WED 

projects. However, variability among species in those projects indicates that the range of sensitivity 

is likely quite wide. This was confirmed by a recent experiment with cottonwood in a naturally 

occurring gradient of exposure, which established the occurrence of species with responses 

substantially more severe under currently existing conditions than are predicted by the median model 

for multiple species. 

Results from several meta-analyses have provided approximate values for responses of yield 

of soybean, wheat, rice and other crops under broad categories of exposure, relative to charcoalfiltered air. Additional reports have summarized yield data for six crop species under various broad 

comparative exposure categories, and reviewed 263 studies that reported effects on tree biomass. 

However, these analyses have proved difficult to compare with exposure-response models, especially 

given that exposure was not expressed on the same W126 scale. 

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2.8.	 Th e Role o f Tro p o s ph e ric Ozone in Climate Change

and UV-B Effects 

1 Atmospheric O3 plays an important role in the Earth's energy budget by interacting with 

2 incoming solar radiation and outgoing infrared radiation. Tropospheric O3 makes up only a small 

3 portion of the total column of O3, but it has important incremental effects on the overall radiation 

4 budget. Chapter 10 assesses the specific role of tropospheric O3 in the earth's radiation budget and 

how perturbations in tropospheric O3 might affect climate through its role as a greenhouse gas 

6 (Section 10.2), and health, ecology and welfare through its role in shielding the earth’s surface from 

7 solar ultraviolet radiation (Section 10.3). 

2.8.1.	 Tro po s p h eric Ozo n e as a Greenhouse Gas 

8 Tropospheric O3 is a major greenhouse gas, and increases in its abundance may contribute to 

9 climate change according to the 2007 climate assessment by the Intergovernmental Panel on Climate 

Change (IPCC). Models calculate that the global burden of tropospheric O3 has doubled since the 

11 preindustrial era, while observations indicate that in some regions O3 may have increased by factors 

12 as great as 4 or 5. These increases are tied to the rise in emissions of O3 precursors from human 

13 activity, mainly fossil fuel consumption and agricultural processes. The impact on climate of the O3 

14 change since preindustrial times has been estimated to be about 25-40% of anthropogenic CO2 

impact and about 75% of anthropogenic CH4 impact according to the IPCC, ranking it third in 

16 importance among the greenhouse gases. 

17 The metric frequently used to estimate the potential climate impact of O3 is called radiative 

18 forcing (RF). RF is a change in the radiative balance at the tropopause or at the top of the 

19 atmosphere when a perturbation is introduced in the earth-atmosphere-ocean system. The units of RF 

are energy flux per unit area, or W/m2

, and positive values indicate warming while negative values 

21 indicate cooling. The IPCC estimates a radiative forcing of 0.35 W/m2 for the change in tropospheric 

22 O3 since the preindustrial era, compared to 1.66 W/m2 for CO2 and 0.48 W/m2 for CH4. The error 

23 bars encompassing the tropospheric O3 radiative forcing estimate range from 0.25 to 0.65 W/m2, 

24 making it relatively more uncertain than the long-lived greenhouse gases. Despite these 

uncertainties, there is a causal relationship between tropospheric O3 and radiative forcing. 

26 RF does not take into account the climate feedbacks that could amplify or dampen the actual 

27 surface temperature response. Quantifying the change in surface temperature requires a complex 

28 climate simulation in which all important feedbacks are accounted for. As these processes are not 

29 well understood or easily modeled, the surface temperature response to a given RF is highly 

uncertain and can vary greatly among models and from region to region within the same model. 

31 Despite these uncertainties, there is likely to be a causal relationship between tropospheric O3 

32 and climate change. 

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2.8.2. Tro po s p h eric Ozo n e a nd UV-B rela ted e ffe cts 

Ultraviolet (UV) radiation emitted from the Sun contains sufficient energy when it reaches the 

Earth to break (photolyze) chemical bonds in molecules, thereby leading to damaging effects on 

living organisms and materials. Atmospheric O3 plays a crucial role in reducing exposure to solar 

UV radiation at the Earth's surface. Ozone in the stratosphere is responsible for the majority of this 

shielding effect, as approximately 90% of total atmospheric O3 is located there over mid-latitudes. 

Ozone in the troposphere provides supplemental shielding of radiation in the wavelength band from 

280-315 nm, UV-B radiation. UV-B radiation has important effects on human health and ecosystems, 

and is associated with materials damage. 

Adverse human health effects associated with solar UV-B radiation exposure include 

erythema, skin cancer, ocular damage, and immune system suppression. A potential human health 

benefit of increased UV-B exposure involves the UV-induced production of vitamin D which may 

help reduce the risk of metabolic bone disease, type I diabetes, mellitus, and rheumatoid arthritis, 

and may provide beneficial immunomodulatory effects on multiple sclerosis, insulin-dependent 

diabetes mellitus, and rheumatoid arthritis. 

Adverse ecosystem and materials damage effects are also associated with solar UV-B radiation 

exposure. Terrestrial ecosystem effects from increased UV-B radiation include reduced plant 

productivity and plant cover, changes in biodiversity, susceptibility to infection, and increases in 

natural UV protective responses. In general, however, these effects are small for moderate UV-B 

increases at mid-latitudes. Aquatic ecosystem effects from increased UV-B radiation include 

sensitivity in growth, immune response, and behavioral patterns of aquatic organisms. 

Biogeochemical cycles, particularly the carbon cycle, can also be influenced by increased UV-B 

radiation with effects ranging from UV-induced increases in CO2 uptake through soil respiration to 

UV-induced release of CO2 through photodegradation of above-ground plant litter. Changes in solar 

UV radiation may also have effects on carbon cycling and CO2 uptake in the oceans as well as 

release of dissolved organic matter from sediment and algae. Finally, materials damage from 

increased UV-B radiation include UV-induced photodegradation of wood and plastics. 

There is a lack of published studies that critically examine the incremental health or welfare 

effects (adverse or beneficial) attributable specifically to changes in UV-B exposure resulting from 

perturbations in tropospheric O3 concentrations. While the effects are expected to be small, they 

cannot yet be critically assessed within reasonable uncertainty. Overall, the evidence is inadequate 

to determine if a causal relationship exists between tropospheric O3 and UV-B related health 

and welfare effects. 

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2.9.	 Summary of Caus al Determinations for Health Effects

an d Welfare Effects 

1	 This chapter has provided an overview of the underlying evidence used in making the causal 

2 determinations for the health and welfare effects of O3. This review builds upon the conclusions of 

3 the previous AQCDs for O3 (U.S. EPA, 1978, 040586; U.S. EPA, 1984, 029711; U.S. EPA, 1996, 

4 017831; U.S. EPA, 1996, 080827; U.S. EPA, 2006, 088089). 

5	 The evaluation of the epidemiologic, toxicological, and controlled human exposure studies 

6 published since the completion of the 2006 O3 AQCD have provided additional evidence for O3­

7 related health outcomes. Table 2-5 provides an overview of the causal determinations for all of the 

8 health outcomes evaluated. Causal determinations for O3 and welfare effects are included in 

9 Table 2-6, while causal determinations for climate change and UV-B effects are in Table 2-7. 

10 Detailed discussions of the scientific evidence and rationale for these causal determinations are 

11 provided in subsequent chapters of this ISA. 

Table 2-5. Summary of ozone causal determinations by exposure duration and health outcome 

Health Outcome Conclusions from 2006 O3 AQCD Conclusions from 

2011 1st Draft ISA 

Short-Term Exposure to O3 

Respiratory effects The overall evidence supports a causal relationship between acute ambient O3 exposures and 

increased respiratory morbidity outcomes. Causal Relationship 

Cardiovascular effects 

The limited evidence is highly suggestive that O3 directly and/or indirectly contributes to 

cardiovascular-related morbidity, but much remains to be done to more fully substantiate the 

association. 

Suggestive of a Causal 

Relationship 

Central nervous system

effects 

Toxicological studies report that acute exposures to O3 are associated with alterations in 

neurotransmitters, motor activity, short and long term memory, sleep patterns, and histological signs of 

neurodegeneration. 

Suggestive of a Causal 

Relationship 

All-cause mortality The evidence is highly suggestive that O3 directly or indirectly contributes to non-accidental and 

cardiopulmonary-related mortality. 

Likely to be a Causal

Relationship 

Long-term Exposure to O3 

Respiratory effects The current evidence is suggestive but inconclusive for respiratory health effects from long-term O3 

exposure. 

Likely to be a Causal

Relationship 

Cardiovascular Effects No studies from previous review Suggestive of a Causal 

Relationship 

Reproductive and 

developmental effects 

Limited evidence for a relationship between air pollution and birth-related health outcomes, including 

mortality, premature births, low birth weights, and birth defects, with little evidence being found for O3 

effects. 

Suggestive of a Causal 

Relationship 

Central nervous system

effects 

Toxicological studies report that acute exposures to O3 are associated with alterations in 

neurotransmitters, motor activity, short and long term memory, sleep patterns, and histological signs of 

neurodegeneration. 

Suggestive of a Causal 

Relationship 

Cancer Little evidence for a relationship between chronic O3 exposure and increased risk of lung cancer. Inadequate to infer a 

Causal Relationship 

Mortality There is little evidence to suggest a causal relationship between chronic O3 exposure and 

increased risk for mortality in humans. 

Suggestive of a Causal 

Relationship 

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Table 2-6. Summary of ozone causal determination for welfare effects 

Vegetation and Ecosystem 

Effects Conclusions from 2006 O3 AQCD Conclusions from 2011 1st Draft ISA 

Reduced Vegetation Growth 

Data published since the 1996 AQCD strengthen previous conclusions that there is 

strong evidence that current ambient O3 concentrations cause decreased growth and 

biomass accumulation in annual, perennial and woody plants, including agronomic 

crops, annuals, shrubs, grasses, and trees. 

Causal Relationship 

Alteration of Vegetation 

Reproduction 

For several decades, studies have demonstrated O3 effects on different stages of 

reproduction. Causal Relationship 

Visible Foliar Injury Effects on 

Vegetation 

Data published since the 1996 AQCD strengthen previous conclusions that there is 

strong evidence that current ambient O3 concentrations cause impaired aesthetic 

quality of many native plants and trees by increasing foliar injury. 

Causal Relationship 

Alteration of Leaf Gas Exchange in 

Vegetation 

Ozone exposure reduces photosynthesis, and the mechanisms of this reduction 

are better understood as a result of the research since the 1996 AQCD. Causal Relationship 

Reduced Yield and Quality of 

Agricultural Crops 

Data published since the 1996 AQCD strengthen previous conclusions that there is 

strong evidence that current ambient O3 concentrations cause decreased yield 

and/or nutritive quality in a large number of agronomic and forage crops. 

Causal Relationship 

Reduced Productivity in Terrestrial 

Ecosystems 

There is evidence that O3 is an important stressor of ecosystems and that the 

effects of O3 on individual plants and processes are scaled up through the 

ecosystem, affecting net primary productivity. 

Causal Relationship 

Reduced Carbon (C) 

Sequestration in Terrestrial 

Ecosystems 

Limited studies from previous review Likely to be a Causal 

Relationship 

Alteration of Terrestrial Ecosystem 

Water Cycling Ecosystem water quantity may be affected by O3 exposure at the landscape level. Likely to be a Causal Relationship 

Alteration of Below-ground 

Biogeochemical Cycles 

Ozone-sensitive species have well known responses to O3 exposure, including 

altered C allocation to below-ground tissues, and altered rates of leaf and root 

production, turnover, and decomposition. These shifts can affect overall C and N loss 

from the ecosystem in terms of respired C, and leached aqueous dissolved organic 

Causal Relationship 

and inorganic C and N. 

Alteration of Terrestrial Community 

Composition 

Ozone may be affecting above- and below -ground community composition through 

impacts on both growth and reproduction. Significant changes in plant 

community composition resulting directly from O3 exposure have been 

demonstrated. 

Likely to be a Causal 

Relationship 

Table 2-7. Summary of ozone causal determination for climate change and UV-B effects 

Effects Conclusions from 2006 O3 AQCD Conclusions from 2011 1st 

Draft ISA 

Radiative Forcing Climate forcing by O3 at the regional scale may be its most important impact on climate. Causal Relationship 

Climate Change 

While more certain estimates of the overall importance of global-scale forcing due to 

tropospheric O3 await further advances in monitoring and chemical transport modeling, the 

overall body of scientific evidence suggests that high concentrations of O3 on the regional 

scale could have a discernable influence on climate, leading to surface temperature and 

hydrological cycle changes. 

Likely to be a Causal 

Relationship 

UV-B Related Health and 

Welfare Effects 

UV-B has not been studied in sufficient detail to allow for a credible health benefits 

assessment. In conclusion, the effect of changes in surface-level O3 concentrations on UVinduced health outcomes cannot yet be critically assessed within reasonable uncertainty. 

Inadequate to Determine if a 

Causal Relationship Exists 

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References
 

U.S. EPA (1978). Air quality criteria for ozone and other photochemical oxidants (Report No. EPA/600/8-78/004). 

Washington, DC: U.S. Environmental Protection Agency, Office of Research and Development. 040586 

U.S. EPA (1984). Air quality criteria for ozone and other photochemical oxidants, v 3 (Report No. EPA/600/8-84/020A). 

Research Triangle Park, NC: U.S. Environmental Protection Agency, Office of Research and Development. 

http://nepis.epa.gov/Exe/ZyPURL.cgi?Dockey=2000AVEV.txt. 029711 

U.S. EPA (1996). Air quality criteria for ozone and related photochemical oxidants (Report No. EPA/600/P-93/004AF). 

Research Triangle Park, NC: U.S. Environmental Protection Agency, Office of Research and Development. (NTIS 

No. PB94173127) 017831 

U.S. EPA (1996). Air quality criteria for ozone and related photochemical oxidants Volume II of III (Report No. 

EPA/600/P-93/004BF). Research Triangle Park, NC: U.S. Environmental Protection Agency, Office of Research 

and Development. 080827 

U.S. EPA (2006). Air quality criteria for ozone and related photochemical oxidants (Report No. EPA/600/R-05/004AF). 

Research Triangle Park, NC: U.S. Environmental Protection Agency, Office of Research and Development. 

http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=149923. 088089 

U.S. EPA (2010). Our nation's air: Status and trends through 2008 (Report No. EPA/454/R-09/002). Research Triangle 

Park, NC: U.S. Environmental Protection Agency, Office of Air Quality Planning and Standards. 

http://www.epa.gov/airtrends/2010/report/fullreport.pdf. 647278 

Note: Hyperlinks to the reference citations throughout this document will take you to the NCEA HERO database (Health and 

Environmental Research Online) at http://epa.gov/hero. HERO is a database of scientific literature used by U.S. EPA in the process of 

developing science assessments such as the Integrated Science Assessments (ISAs) and the Integrated Risk Information System (IRIS). 

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