### Draft

– Do Not Cite or Quote 2

- 1 June 2012 

## 2 INTEGRATIVE SUMMAR Y

This Integrated Science Assessment (ISA) forms the scientific foundation for the review 

### 1

of the national ambient air quality standards (NAAQS) for ozone (O 3 ). The ISA is a 

### 2

concise evaluation and synthesis of the most policy

- relevant science

— and it 

### 3

communi cates critical science judgments relevant to the review of the NAAQS for O 3

. 

### 4

The ISA accurately reflects “the latest scientific knowledge useful in indicating the kind 

### 5

and extent of identifiable effects on public health or welfare which may be expected fro m 

### 6

the presence of [a] pollutant in ambient air” ( CAA, 1990a ) . Key information and 

### 7

judgments contained in prior Air Quality Criteria Documents (AQCD) for O 3 are 

### 8

incorporated into this assessment. Additional details of the pertinent scientific literature 

### 9

published since the last re view, as well as selected earlier studies of particular interest, 

### 10

are included. This ISA thus serves to update and revise the evalu ation of the scientific 

### 11

evidence available at the time of the completion of the 2006 O 3 AQCD. The current 

### 12

primary O 3 standard includes an 8

- hour (h) average (avg) standard set at 75 parts per 

### 13

billion (ppb). The secondary standard for O 3 is set equal to the primary standard. Further 

### 14

information on the legislative and historical background for the O 3 NAAQS is contained 

### 15

in the Preface to this ISA. 

### 16

This chapter summ arizes and synthesizes the available scientific evidence and is intended 

### 17

to provide a concise syn opsis of the ISA conclusions and findings that best inform 

### 18

consideration of the policy

- relevant questions that frame this assessment ( U.S. EPA, 

### 19

2009c ) . It includes: 

### 20

 An integration of the evidence on the health effects associated with short

- and 

### 21

long

- term exposure to O 3 , discussion of important uncertainties identified in 

### 22

the interpretation of the scientific evidence, and an integration of health 

### 23

evidence from the different scientific disciplines and exposure durations. 

### 24

 An integration of the evidence on the welfare effects associated with exposure 

### 25

to O 3 , including those associated with vegetation and ecosystems, and 

### 26

discussion of important uncertainties identified in the interpretation of the 

### 27

scientific evidence. 

### 28

 Discussion of policy

- relevant considerations, such as potentially at

- risk 

### 29

populations and concentration

- response relationships and how they inform 

### 30

selection of appropriate exposure metrics/indices. 

### 31

### Draft

– Do Not Cite or Quote 2

- 2 June 2012 

## 2.1 ISA Development and Scope

EPA has a developed a robust, consistent, and transparent process for evaluating the 

### 1

scientific evidence and drawing conclusions and causal judgments regarding air 

### 2

pollution

- related health and environmental effects. The ISA development process 

### 3

includes literature search strategies, criteria for selecting and evaluating studies, 

### 4

approaches for evaluating weight of the evidence, and a framework for making causality 

### 5

determinations. The process and causality framework are described in more detail in the 

### 6

Preamble to the ISA. This section provides a brief overview of the process for 

### 7

development of this ISA. 

### 8

EPA initiated the current review of the NAAQS for O 3 on September 29, 2008, with a 

### 9

call for information from the public ( U.S. EPA, 2008f ) . Literature searches were 

### 10

conducted routinely to identify studies published since the last review, focusing on 

### 11

studies published from 2005 (close of previous scientific assessment) through July 201 1. 

### 12

References that were considered for inclusion in this ISA can be found using the HERO 

### 13

website ( http://hero.epa.gov/ozone ). This site contains HERO links to lists of references 

### 14

that are cited in the ISA, as well as those that were considered for inclusion, but not cited 

### 15

in the ISA, with bibliographic information and abstracts. 

### 16

This review has endeavored to evaluate all relevant data published since the last review; 

### 17

this includes studies pertaining to the atmospheric science of O 3 , human exposure to 

### 18

ambient O 3 , and health, ecological, climate and UV

- B effects studies. These include 

### 19

studies that are related to concentration

- response relationships, mode(s) of action (MOA), 

### 20

and understanding of at

- risk populations for ef fects of O 3 exposure. Added to the body of 

### 21

research were EPA’s analyses of air quality and emissions data, studies on atmospheric 

### 22

chemistry, transport, and fate of these emissions. 

### 23

Previous AQCDs ( U.S. EPA, 2006b

, 1996a

, b

, 19 84

, 1978a ) have included an extensive 

### 24

body of evidence on both health and welfare effects of O 3 exposure, as well as an 

### 25

understanding of the atmospheric chemistry of O 3 ( U.S. EPA, 2006b ) . In this ISA, the 

### 26

conclusions and key findings from previous reviews are summarized at the beginning of 

### 27

each section, to provide the foundation for considerat ion of evidence from recent studies. 

### 28

Results of key studies from previous reviews are included in discussions or tables and 

### 29

figures, as appropriate, and conclusions are drawn based on the synthesis of evidence 

### 30

from recent studies with the extensive literat ure summarized in previous reviews. 

### 31

The Preamble discusses the general framework for conducting the science assessment 

### 32

and developing an ISA, including criteria for evaluating studies and developing scientific 

### 33

conclusions. For selection of epidemiologic s tudies in the O 3 ISA, particular emphasis is 

### 34

placed on those studies most relevant to the review of the NAAQS. Studies conducted in 

### 35

### Draft

– Do Not Cite or Quote 2

- 3 June 2012 the United States (U.S.) or Canada are discussed in more detail than those from other 

### 1

geographical regions, and in regard to human health, particular emphasis is placed on: 

### 2

(1) recent multicity studies that employ standardized analysis methods for evaluating 

### 3

effects of O 3 and that provide overall estimates for effects, based on combined analyses 

### 4

of information pooled across mul tiple cities; (2) studies that help understand quantitative 

### 5

relationships between exposure concentrations and effects; (3) new studies that provide 

### 6

evidence on effe cts in at

- risk populations; and (4) studies that consider and report O 3 as a 

### 7

component of a complex mixture of air pollutants. In evaluating toxicological and 

### 8

controlled human exposure studies, emphasis is placed on studies using concentrations 

### 9

that are within about an order of magnitude of ambient O 3 concentrations. Consideration 

### 10

of studies impo rtant for evaluation of human exposure to ambient O 3 places emphasis on 

### 11

those evaluating the relationship between O 3 measured at central site monitors and 

### 12

personal exposure to ambient O 3 . Important factors affecting this relationship include 

### 13

spatial and te mporal variations in ambient O 3 concentration , and time spent outdoors, 

### 14

since penetrations of O 3 into indoor environments may be limited. 

### 15

Epidemiologic studies generally present O 3 - related effect estimates for mortality and 

### 16

morbidity health outcomes based on an incremental change in exposure, traditionally 

### 17

equal to the interquartile range in O 3 concentrations or some other arbitrary value 

### 18

(e.g., 10 ppb). Additionally, various averaging times are used in O 3 epidemiologic studies, 

### 19

with the three most common being the maximum 1

- hour average within a 24

- hour period 

### 20

(1

- h max), the maximum 8

- hour average within a 24

- h period (8

- h max), and 24

- hour 

### 21

average (24

- h avg). For the purpose of presenting results from studies that use different 

### 22

exposure metrics, EPA consi stently applies the same O 3 increments to facilitate 

### 23

comparisons between the results of various studies that may use different indices. These 

### 24

increments were derived using the nationwide distributional data for O 3 monitors in U.S. 

### 25

Metropolitan Statistical Areas and are representative of a low

- to

- high change in O 3 

### 26

concentrations and were approximated on the basis of annual mean to 95th percentile 

### 27

differences ( Langstaff, 2003 ) . Therefore, throughout Chapter 6 , efforts were made to 

### 28

standardize O 3 - related effect estimates using the increments of 20 ppb for 24

- h avg, 

### 29

30 ppb for 8

- h max, and 40 ppb for 1

- h max O 3 concentrations, except as noted. In long



### 30

term exposure studies, typically, O 3 co ncentrations are lower and less variable when 

### 31

averaged across longer exposure periods, and differences due to the use of varying 

### 32

averaging times (e.g., 1

- h max, 24

- h avg) become less apparent. As such, in the long

- term 

### 33

exposure chapter (Chapter 7 ) an increment of 10 ppb was consistently applied across 

### 34

studies, regardless of averaging time, to facilitate comparisons between the results from 

### 35

these studi es. 

### 36

### Draft

– Do Not Cite or Quote 2

- 4 June 2012 This ISA uses a five

- level hierarchy that classifies the weight of evidence for causation: 

### 1

 Causal relationship 

### 2

 Likely to be a causal relationship 

### 3

 Suggestive of a causal relationship 

### 4

 Inadequate to infer a causal relationship 

### 5

 Not likely to be a cau sal relationship 

### 6

Beyond judgments regarding causality are questions relevant to quantifying health or 

### 7

environmental risks based on the understanding of the quantitative relationships between 

### 8

pollutant exposures and health or welfare effects. Once a determ ination is made regarding 

### 9

the causal relationship between the pollutant and outcome category, important questions 

### 10

regarding quantitative relationships include: 

### 11

 What is the concentration

- response , exposure

- response, or dose

- response 

### 12

relationship? 

### 13

 Under what exposure conditions (dose or concentration, duration and pattern) 

### 14

are effects observed? 

### 15

 What populations appear to be differentially affected i.e., at

- risk to effects? 

### 16

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

### 17

populations, functions, etc.) appear to be affected or are more sensitive to 

### 18

effects? 

### 19

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

### 20

informs consideration of the policy

- relevant questions that frame this assessment

. 

### 21

Section 2.2 discusses the trends in ambient concentrations and sources of O 3 and provides 

### 22

a brief summary of ambient air quality for short

- and l ong

- term exposure durations. 

### 23

Section 2.3 presents the evidence regarding personal exposure to ambient O 3 in outdoor 

### 24

and indoor microenvironments, an d it discusses the relationship between ambient O 3 

### 25

concentrations and personal exposure to ambient O 3 . Section 2.4 provides a discussion of 

### 26

the dosi metry and mode of action evidence for O 3 exposure. Section 2.5 integrates the 

### 27

evidence for studies that examine the health effects associated with s hort

- and long

- term 

### 28

exposure to O 3 and discusses important uncertainties identified in the interpretation of the 

### 29

scientific evidence. A discussion of policy

- relevant considerations, such as potentially at



### 30

risk populations, lag structure, and the O 3 concent ration

- response relationship is also 

### 31

included in Section 2.5 . Finally, Section 2.6 summarizes the evidence for welfare effects 

### 32

related to O 3 exposure, and Section 2.7 reviews the literature on the influence of 

### 33

tropospheric O 3 on climate and exposure to solar ultraviolet radiation. 

### 34

### Draft

– Do Not Cite or Quote 2

- 5 June 2012 

## 2.2 Atmospheric Chemistry and Ambient Concentrations

2.2.1 Physical and Chemical Proc esses

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

### 1

reactions of precursor gases and is not directly emitted from specific sources. Ozone 

### 2

precursor gases originate from both anthropogenic (i.e., man

- made) and natural sour ce 

### 3

categories. Ozone attributed to anthropogenic sources is formed in the atmosphere by 

### 4

photochemical reactions involving sunlight and precursor pollutants including volatile 

### 5

organic compounds (VOCs), nitrogen oxides (NO X ), and carbon monoxide (CO). Ozone 

### 6

attributed to natural sources is formed through similar photochemical reactions involving 

### 7

natural emissions of precursor pollutants from vegetation, microbes, animals, biomass 

### 8

burning, lightning, and geogenic sources. The distinction between natural and 

### 9

an thropogenic sources of O 3 precursors is often difficult to make in practice, as human 

### 10

activities affect directly or indirectly emissions from what would have been considered 

### 11

natural sources during the pre

- industrial era. A schematic overview of the major 

### 12

p hotochemical cycles influencing O 3 in the troposphere and the stratosphere is shown in 

### 13

Figure 2

- 1 . The processes depicted in this figure are fairly wel l understood, and were 

### 14

covered in detail in the previous O 3 AQCD. The formation of O 3 , other oxidants, and 

### 15

oxidation products from these precursors is a complex, nonlinear function of many 

### 16

factors including: (1) the intensity and spectral distribution of s unlight reaching the lower 

### 17

troposphere; (2) atmospheric mixing; (3) concentrations of precursors in the ambient air 

### 18

and the rates of chemical reactions of these precursors; and (4) processing on cloud and 

### 19

aerosol particles. 

### 20

### Draft

– Do Not Cite or Quote 2

- 6 June 2012 Figure 2

- 1 Schematic overview of photochemical processes influencing stratospheric and tropospheric ozone.

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

### 1

even in rem ote areas of the globe. Similar basic processes involving sunlight

- driven 

### 2

reactions of NO X , VOCs and CO contribute to O 3 formation throughout the troposphere. 

### 3

These processes also lead to the formation of other photochemical products, such as 

### 4

peroxyacetyl nitrate, nitric acid, and sulfur ic acid, and to other compounds, such as 

### 5

formaldehyde and other carbonyl compounds. In urban areas, NO X , VOCs, and CO are 

### 6

all important for O 3 formation. In non

- urban vegetated areas, biogenic VOCs emitted 

### 7

from vegetation tend to be the most important prec ursor to O 3 formation. In the remote 

### 8

troposphere, methane

— structurally the simplest VOC

— and CO are the main carbon



### 9

containing precursors to O 3 formation. Ozone is subsequently removed from the 

### 10

### Draft

– Do Not Cite or Quote 2

- 7 June 2012 troposphere through a number of gas phase reactions and deposition to surfaces as shown 

### 1

in Figure 2

- 1

. 

### 2

Convective processes and turbulence transport O 3 and other pollutants both upward and 

### 3

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

### 4

areas of the U.S., O 3 and its precursors can be transported over long distances, aided by 

### 5

vertical mixing. The transport of pollutants downwind of major urban centers is 

### 6

characterized by the development of urban plumes. Meteorological conditions, small



### 7

scale circulation patterns, localized chemistry, and mountain barriers can influence 

### 8

mixing on a smaller scale, resulting in frequent hete rogeneous O 3 concentrations across 

### 9

individual urban areas. 

### 10

Furthermore, because the mean tropospheric lifetime of O 3 is a few weeks, O 3 can be 

### 11

transported from continent to continent. The degree of influence from intercontinental 

### 12

transport varies greatly b y location and time. For instance, high elevation sites are most 

### 13

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

### 14

However, because the atmospheric chemistry of O 3 is quite complex and can be highly 

### 15

non

- linear in envir onments close to sources of precursors, isolating the influence of 

### 16

intercontinental transport of O 3 and O 3 precursors on urban air quality is particularly 

### 17

problematic. 

### 18

2.2.2 Atmospheric Modeling of Background Ozone Concentrations

A number of recent studies indic ate that natural sources such as wildfires and 

### 19

stratospheric intrusions and the intercontinental transport of pollution can affect O 3 air 

### 20

quality at specific times and in specific locations in the United States. These contributions 

### 21

are in addition to contr ibutions from dominant local pollution sources. To gain a broader 

### 22

perspective and to isolate the influence of natural or transported O 3 , estimates from 

### 23

chemical transport models (CTMs) must be used. This is because observations within the 

### 24

U.S.

— even at rela tively remote monitoring sites

— are impacted by transport from 

### 25

anthropogenic source regions within U.S. borders. 

### 26

In the context of a review of the NAAQS, it is useful to define background O 3 

### 27

concentrations in a way that distinguishes between concentrations that result from 

### 28

precursor emissions that are relatively less controllable from those that are relatively 

### 29

more controllable through U.S. policies. For this assessment, three definitions of 

### 30

background O 3 concentrations are considered , including (1) North Am erican (NA) 

### 31

background (simulated O 3 concentrations that would exist in the absence of 

### 32

anthropogenic emissions from the U.S., Canada and Mexico), (2) United States (U.S.) 

### 33

background (simulated O 3 concentrations that would exist in the absence of 

### 34

### Draft

– Do Not Cite or Quote 2

- 8 June 2012 anthropoge nic emissions from the U.S.), and (3) natural background (simulated O 3 

### 1

concentrations in the absence of all anthropogenic emissions globally). Each definition of 

### 2

background O 3 includes contributions resulting from emissions from natural sources 

### 3

(e.g., stra tospheric intrusion, wildfires, biogenic methane and more short

- lived VOC 

### 4

emissions) throughout the globe. There is no chemical difference between background O 3 

### 5

and O 3 attributable to U.S. or North American anthropogenic sources. However, to 

### 6

inform policy considerations regarding the current or potential alternative standards, it is 

### 7

useful to understand how total O 3 concentrations (i.e., O 3 from all sources) can be 

### 8

attributed to different sources. 

### 9

Since background O 3 concentrations as defined above are a co nstruct that cannot be 

### 10

directly measured, the range of background O 3 concentrations is estimated using CTMs. 

### 11

For the current assessment, the GEOS

- Chem model at 0.5°×0.667° (~50 km×50 km) 

### 12

horizontal resolution and a nested, hybrid GEOS

- Chem/CAMx model at fi ner horizontal 

### 13

resolution (12 km × 12 km) were used. Results from these two models represent the latest 

### 14

estimates for background O 3 concentrations documented in the peer

- reviewed literature 

### 15

and are shown in Table 2

- 1 . The R 2 for both models are generally <0.5, with CAMx 

### 16

showing generally higher values than GEOS

- Chem ( Table 3

- 1 ) . The GEOS

- Chem 

### 17

model

- predicted seasonal mean daily maximum 8

- h average O 3 concentrations for the 

### 18

base case (i.e., including all anthropogenic and natural sources globally), U.S. 

### 19

background, and NA background simulations during spring and summer 2006 are shown 

### 20

in Figure 2

- 2

. 

### 21

Table 2

- 1 Compariso n of seasonal mean MDA8 ozone concentrations simulated by the GEOS

- Chem and CAMx base case models for 2006, with measurements at CASTNET sites.

Region CASTNET GEOS

- Chem GEOS

- Chem/CAMx

Spring Summer Spring Summer Spring Summer

California (5) a 58 ± 12 b 69 ± 14 52 ± 11

38 ± 7 c 66 ± 18

37 ± 9 50 ± 10

39 ± 6 66 ± 13

42 ± 6

West (14) 54 ± 9 55 ± 11 53 ± 7

42 ± 6 55 ± 11

40 ± 9 49 ± 8

40 ± 7 57 ± 10

41 ± 8

North Central (6) 47 ± 10 50 ± 12 47 ± 8

33 ± 6 51 ± 14

27 ± 7 45 ± 11

30 ± 6 54 ± 13

31 ± 5

Northeast (5) 48 ± 10 45 ± 14 45 ± 7

33 ± 7 45 ± 13

24 ± 7 46 ± 11

30 ± 5 53 ± 14

27 ± 6

Southeast (9) 52 ± 11 52 ± 16 51 ± 7

32 ± 7 54 ± 9

29 ± 10 54 ± 9

33 ± 6 61 ± 12

30 ± 6

a Values in parentheses after each region name refer to the number of sites.

b Shown are seasonal (spring, summer) mean daily maximum 8

- h avg O 3 concentrations in ppb ± standard deviation.

c North American background mean daily maximum 8

- h avg O 3 concentrations (ppb ± standard deviation) are shown beneath the

### Draft

– Do Not Cite or Quote 2

- 9 June 2012 base case means.

Note: Mean daily average 8

- h O 3 concentrations were calculated by GEOS

- Chem for the base case (top, Base), United States background (middle, USB) and North American Background (lower, NAB). Values in parentheses (above each map) refer to continental U.S. m eans, and are shown in the color bar as black squares for summer and white squares for spring.

Source: Adapted from Zhang et al. (2011 )

.



### Figure 2

- 2 Mean daily average 8

- h our ozone concentrations in surface air , for spring and summer 2006.

### Draft

– Do Not Cite or Quote 2

- 10 June 2012 The main results from these modeling efforts can be summarized as follows. 

### 1

 Simulated regional and seasonal means of base

- case O 3 using both models 

### 2

generally agree to within a few ppb with observations throughout the western 

### 3

and central U.S., except in California; but GEOS

- Chem shows better 

### 4

agreement than CAMx in the eastern U.S. However, these results are likely to 

### 5

change with upda tes to model chemistry and physics. 

### 6

 Both models show background concentrations vary spatially and temporally. 

### 7

NA background concentrations are generally higher in spring than in summer 

### 8

across the U.S. Simulated mean NA background concentrations are h ighest in 

### 9

the Intermountain West (i.e., at high altitude) in spring and in the Southwest in 

### 10

summer. Lowest estimates of NA background occur in the East in the spring 

### 11

and the Northeast in summer. 

### 12

 NA background concentrations tend to increase with total (i.e., bas e case) O 3 

### 13

concentrations at high elevation, but that tendency is not as clear at low 

### 14

elevations. 

### 15

 Comparison of NA background and natural background indicate that methane 

### 16

is a major contributor to NA background O 3 , accounting for slightly less than 

### 17

half of the increase in background since the preindustrial era and whose 

### 18

relative contribution is projected to grow in the future. 

### 19

 U.S. background concentrations are on average 2.6 ppb higher than NA 

### 20

background concentrations during spring and 2.7 ppb during summ er across 

### 21

the U.S. with highest increases above NA background over the Northern Tier 

### 22

of New York State (19.1 ppb higher than NA background) in summer. High 

### 23

values for U.S. background are also found in other areas bordering Canada 

### 24

and Mexico. 

### 25

 Contributions to background O 3 can be episodic or non

- episodic; high 

### 26

background concentrations are driven primarily by the episodic events such as 

### 27

stratospheric intrusions and wildfires. The most pronounced differences 

### 28

between these model results and observations are at the upper end of the 

### 29

concentration distribution, particularly at high elevations. 

### 30

Note that the calculations of background concentrations presented in this chapter were 

### 31

formulated to answer the question, “what would O 3 concentrations be if there were no 

### 32

a nthropogenic sources”. This is different from asking, “how much of the O 3 measured or 

### 33

simulated in a given area is due to background contributions”. Because of potentially 

### 34

strong non

- linearities

— particularly in many urban areas

— these estimates should not b e 

### 35

used by themselves to answer the second question posed above. The extent of these non



### 36

linearities will generally depend on location and time, the strength of concentrated 

### 37

### Draft

– Do Not Cite or Quote 2

- 11 June 2012 sources, and the nature of the chemical regime. Further work is needed on how these 

### 1

estimates of background concentrations can be used to help determine the contributions 

### 2

of background sources of O 3 to urban concentrations. 

### 3

2.2.3 Monitoring

The federal reference method (FRM) for O 3 measurement is based on the detection of 

### 4

chemiluminescence res ulting from the reaction of O 3 with ethylene gas. However, almost 

### 5

all of the state and local air monitoring stations (SLAMS) that reported data to the EPA’s 

### 6

Air Quality System (AQS) database from 2005 to 2009 used the federal equivalence 

### 7

method (FEM) UV ab sorption photometer. More than 96% of O 3 monitors met precision 

### 8

and bias goals during this period. 

### 9

In 2010, there were 1250 SLAMS O 3 monitors reporting data to AQS. Ozone monitoring 

### 10

is required at SLAMS sites during the local “ozone season” which varies by state. In 

### 11

addition, National Core (NCore) is a new multipollutant monitoring network 

### 12

implemented to meet multiple monitoring objectives and each state is required to operate 

### 13

at least one NCore site. The NCore network consists of 60 urban and 20 rural site s 

### 14

nationwide (See Figure 3

- 21 and Figure 3

- 22 ). The densest concentrations of O 3 sites are 

### 15

located in California and the eastern half of the U.S. 

### 16

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

### 17

establis hed to assess trends in acidic deposition and also provides concentration 

### 18

measurements of O 3 . CASTNET O 3 monitors operate year round and are primarily 

### 19

located in rural areas; in 2010, there were 80 CASTNET sites reporting O 3 data to AQS. 

### 20

The National Park Service (NPS) operates 23 CASTNET sites in national parks and other 

### 21

Class

- i areas, and provided data to AQS from 20 additional Portable Ozone Monitoring 

### 22

Systems (POMS) in 2010 (See Figure 3

- 22 ). Compared to urban

- focused monitors, rural



### 23

focused monitors are relatively scarce across the U.S. 

### 24

2.2.4 Ambient Concentrations

Ozone is the only photochemical oxidant other than NO 2 that is routinely monitored and 

### 25

for which a comprehensive database exists. Other photochemical oxidants are typically 

### 26

only measured during special field studies. The concentration analyses in Chapter 3 are 

### 27

limited to widely available O 3 data obtained directly from AQS for the period from 2007 

### 28

to 2009. The median 24

- h average, 8

- h daily maximum, and 1

- h daily maximum O 3 

### 29

concentrations across all U.S. sites reporting data to AQS between 2007 and 2009 were 

### 30

29, 40, and 44 ppb, respectively. 

### 31

### Draft

– Do Not Cite or Quote 2

- 12 June 2012 To investigate O 3 variability in urban areas across the U.S., 20 combined statistical areas 

### 1

(CSAs) were selected for closer analysis based on their importance in O 3 epidemiology 

### 2

studies and on their loca tion. Several CSAs had relatively little spatial variability in 

### 3

8

- hour daily maximum O 3 concentrations (e.g., inter

- monitor correlations ranging from 

### 4

0.61 to 0.96 in the Atlanta CSA) while other CSAs exhibited considerably more 

### 5

variability in O 3 concentrat ions (e.g., inter

- monitor correlations ranging from

- 0.06 to 

### 6

0.97 in the Los Angeles CSA). Uncertainties resulting from the observed variability in O 3 

### 7

concentration fields should be considered when using data from the network of ambient 

### 8

O 3 monitors to appr oximate community

- scale exposures. 

### 9

To investigate O 3 variability in rural settings across the U.S., six focus areas were 

### 10

selected for closer analysis based on the impact of O 3 or O 3 precursor transport from 

### 11

upwind urban areas. The selected rural focus area with the largest number of available 

### 12

AQS monitors was Great Smoky Mountains National Park where the May

- September 

### 13

median 8

- h daily maximum O 3 concentration ranged from 47 ppb at the lowest elevation 

### 14

(564 m) site to 60 ppb at the highest elevation (2,021 m ) site. Correlations between sites 

### 15

within each rural focus area ranged from 0.78 to 0.92. Ozone in rural areas is produced 

### 16

from emissions of O 3 precursors emitted directly within the rural areas, from emissions in 

### 17

urban areas that are processed during tran sport, and from occasional stratospheric 

### 18

intrusions. Factors contributing to variations observed within these rural focus areas 

### 19

include proximity to local O 3 precursor emissions, local scale circulations related to 

### 20

topography, and possibly stratospheric intrusions as a function of elevation. In addition, 

### 21

O 3 tends to persist longer in rural than in urban areas as a result of less chemical 

### 22

scavenging. This resul ts in a more uniform O 3 concentration throughout the day and night 

### 23

without the typical nocturnal decrease in O 3 concentration observed in urban areas. 

### 24

Persistently high O 3 concentrations observed at many of the rural sites investigated here 

### 25

indicate that c umulative exposures for humans and vegetation in rural areas can 

### 26

frequently exceed cumulative exposures in urban areas. 

### 27

Nation

- wide surface level O 3 concentrations have declined over the last decade, with a 

### 28

particularly noticeable decrease between 2003 and 2004 coinciding with NO X emissions 

### 29

reductions resulting from implementation of the NO X SIP Call rule, which began in 2003 

### 30

and was fully implemented in 2004. This rule was designed to reduce NO X emissions 

### 31

from power plants and other large combustion source s in the eastern U.S. The largest 

### 32

density of individual monitors showing downward trends in O 3 concentrations over the 

### 33

last decade occur in the Northeast where this rule was focused. In addition to a downward 

### 34

trend, the nation

- wide surface level O 3 concent ration data also show a general tightening 

### 35

of the distribution across sites. In contrast to the majority of U.S. surface level monitors 

### 36

reporting downward trends, a few surface

- level monitors and elevated observations along 

### 37

the Pacific Coast have shown inc reases in O 3 concentrations in recent years, possibly 

### 38

### Draft

– Do Not Cite or Quote 2

- 13 June 2012 resulting from intercontinental transport from Asia. As noted in the 2006 O 3 AQCD, 

### 1

trends in national parks and rural areas are similar to nearby urban areas, reflecting the 

### 2

regional nature of O 3 pollut ion. 

### 3

Since O 3 is a secondary pollutant, it is not expected to be highly correlated with primary 

### 4

pollutants such as CO and NO X . Furthermore, O 3 formation is strongly influenced by 

### 5

meteorology, entrainment, and transport of both O 3 and O 3 precursors, resulti ng in a 

### 6

broad range in correlations with other pollutants which can vary substantially with 

### 7

season. Correlations between 8

- h daily maximum O 3 and other criteria pollutants exhibit 

### 8

mostly negative correlations in the winter and mostly positive correlations in the summer. 

### 9

The median seasonal correlations are modest at best with the highest positive correlation 

### 10

at 0.52 for PM 2.5 in the summer and the highest negative correlation at

- 0.38 for PM 2.5 in 

### 11

the winter. As a result, statistical analyses that may be se nsitive to correlations between 

### 12

copollutants need to take seasonality into consideration, especially when O 3 is being 

### 13

investigated. 

### 14



## 2.3 Human Exposure

The widespread presence of O 3 in the environment results in exposure as people 

### 15

participate in normal daily ac tivities. Personal exposure measurements have been found 

### 16

to be moderately associated with fixed

- site ambient O 3 concentrations, although a number 

### 17

of factors affect the relationship between ambient concentration and personal exposure. 

### 18

These include: infiltr ation of ambient O 3 into indoor microenvironments, which is driven 

### 19

by air exchange rate; time spent outdoors and activity pattern, which include s changes in 

### 20

personal behavior by some populations to avoid exposure to O 3 ; and the variation in O 3 

### 21

concentratio ns at various spatial and temporal scales. Personal exposure to O 3 is 

### 22

moderately correlated with ambient O 3 concentration, as indicated by studies reporting 

### 23

correlations generally in the range of 0.3

- 0.8 ( Table 4

- 2 ). This suggests that ambient 

### 24

monitor concentrations are representative of day

- to

- day changes in personal exposure to 

### 25

ambient O 3 . Some studies report lower personal

- ambient correlations, a result attributable 

### 26

in part to low building air exchange rates and O 3 concentrations below the personal 

### 27

sampler detection limit. Low correlations may also occur for individuals or populations 

### 28

spending increased time indoors. In contrast to correlation, whi ch represents the temporal 

### 29

association between exposure and concentration, the magnitude of exposure can be 

### 30

represented as the ratio between personal exposure and ambient concentration. This ratio 

### 31

varies widely depending on activity patterns, housing chara cteristics, and season. 

### 32

Personal

- ambient ratios are typically 0.1

- 0.3 for sampling durations of several hours to 

### 33

several days, although individuals spending substantial time outdoors (e.g., outdoor 

### 34

workers) have shown much higher ratios (0.5

- 0.9) ( Table 4

- 3 ). Since there are relatively 

### 35

### Draft

– Do Not Cite or Quote 2

- 14 June 2012 few indoor sources of O 3, and because of reactions of O 3 with indoor surfaces and 

### 1

airborne constituents, indoor O 3 conce ntrations are often substantially lower than outdoor 

### 2

concentrations (Section 4.3.2 ). The lack of indoor sources also suggests that fluctuations 

### 3

in a mbient O 3 may be primarily responsible for changes in personal exposure, even under 

### 4

low

- ventilation, low

- concentration conditions. 

### 5

Another factor that may influence the pattern of exposure is the tendency for people to 

### 6

avoid O 3 exposure by altering their behavior (e.g., reducing outdoor activity levels or 

### 7

time spent being active outdoors) on high

- O 3 days. Activity pattern has a substantial 

### 8

effect on ambient O 3 exposure, with time spent outdoors contributing to increased 

### 9

exposure (Section 4.4.2 ). Air quality alerts and public health recommendations induce 

### 10

reductions in time spent outdoors on high

- O 3 days among some populations, particularly 

### 11

for childr en, older adults, and people with respiratory problems. Such effects are less 

### 12

pronounced in the general population. Limited e vidence from a n epidemiologic study 

### 13

conducted in the 1990’s in Los Angeles, CA reports increased asthma hospital 

### 14

admissions among c hildren and older adults when O 3 alert days (1

- h max O 3 

### 15

concentration >200 ppb) were excluded from the analysis of daily hospital admissions 

### 16

and O 3 concentrations (presumably thereby eliminating averting behavior based on high 

### 17

O 3 forecasts). The lower rate of admissions observed when alert days were included in 

### 18

the analysis suggests that estimates of health effects based on concentration

- response 

### 19

functions that do not account for averting behavior may be biased towards the null. 

### 20

Variations in O 3 concentrati ons occur over multiple spatial and temporal scales. Near 

### 21

roadways, O 3 concentrations are reduced due to reaction with NO and other species 

### 22

(Section 4.3.4.2 ). Over spatial scales of a few kilometers and away from roads, O 3 may 

### 23

be somewhat more homogeneous due to its formation as a secondary pollutant, while 

### 24

over scales of tens of kilometers, addi tional atmospheric processing can result in higher 

### 25

concentrations downwind of an urban area. Although local

- scale variability impacts the 

### 26

magnitude of O 3 concentrations, O 3 formation rates are influenced by factors that vary 

### 27

over larger spatial scales, suc h as temperature (Section 3.2 ), suggesting that urban 

### 28

monitors may track one another temporally

, but miss small

- scale variability. This 

### 29

variation i n concentrations changes the pattern of exposure people experience as they 

### 30

move through different microenvironments and affects the magnitude of exposures in 

### 31

different locations within an urban area. The various factors affecting exposure patterns 

### 32

and quan tification of exposure result in uncertainty which may contribute to exposure 

### 33

measurement error in epidemiologic studies, which typically use fixed

- site monitor data 

### 34

as an indicator of exposure. Low personal

- ambient correlations are a source of exposure 

### 35

er ror for epidemiologic studies, tending to obscure the presence of potential thresholds

, 

### 36

bias effect estimates toward the null, and widen confidence intervals, and this impact may 

### 37

be more pronounced among populations spending substantial time indoors. The i mpact of 

### 38

### Draft

– Do Not Cite or Quote 2

- 15 June 2012 this exposure error may tend more toward widening confidence intervals than biasing 

### 1

effect estimates, since epidemiologic studies evaluating the influence of monitor selection 

### 2

indicate that effect estimates are similar across different spatial ave raging scales and 

### 3

monitoring sites. In addition, in examinations of respiratory endpoints in epidemiologic 

### 4

studies, associations were similar in magnitude across analyses using several different 

### 5

exposure assessment methods that likely vary in how well ambi ent O 3 concentrations 

### 6

represent personal exposures and between

- subject variability in exposures. Respiratory 

### 7

effects were observed with ambient O 3 concentrations found to have stronger personal



### 8

ambient relationships, including those measured on

- site during long periods of outdoor 

### 9

activity. However, such effects were also found with ambient O 3 measurements expected 

### 10

to have weaker personal

- ambient relationships, including those measured at home or 

### 11

school, measured at the closest site, averaged from multiple c ommunity sites, and 

### 12

measured at a single site. Overall, there was no clear indication that a particular method 

### 13

of exposure assessment produced stronger findings. 

### 14



## 2.4 Dosimetry and Mode of Action

Upon inspiration, O 3 uptake in the respiratory tract is affected by a number of factors 

### 15

including respiratory tract morphology, and breathing route, frequency, and volume. 

### 16

Additionally, physicochemical properties of O 3 itself and how it is transported, as well as 

### 17

the physical and chemical properties of the extracellular lining fluid (ELF) and tissue 

### 18

layers in the respiratory tract can influence O 3 uptake. Experimental studies and models 

### 19

have suggested that there are differences between the total absorption of O 3 from the 

### 20

inhaled air and the O 3 dose reaching the respirato ry tract tissues. The total O 3 absorption 

### 21

gradually decreases with distal progression into the respiratory tract. In contrast, the 

### 22

primary site of O 3 delivery to the lung epithelium is believed to be the centriacinar region 

### 23

or the junction of the conductin g airways with the gas exchange region. 

### 24

Ozone uptake is sensitive to a number of factors including tidal volume, breathing 

### 25

frequency, O 3 concentration, and exposure time. Interindividual variability also accounts 

### 26

for a large amount of the variability in l ocal dose due to differences in pulmonary 

### 27

physiology, anatomy, and biochemistry. An increase in tidal volume and breathing 

### 28

frequency are both associated with increased physical activity. These changes and a 

### 29

switch to oronasal breathing during exercise resu lt in deeper penetration of O 3 into the 

### 30

lower respiratory tract in part due to less oral versus nasal uptake efficiency. For these 

### 31

reasons, increased physical activity acts to move the maximum tissue dose of O 3 distally 

### 32

in the respiratory tract and more in to the alveolar region. 

### 33

### Draft

– Do Not Cite or Quote 2

- 16 June 2012 The ELF is a complex mixture of lipids, proteins, and antioxidants that serves as the first 

### 1

barrier and target for inhaled O 3 (see Figure 5

- 7 ). Distinct products with diverse reactivity 

### 2

(i.e., secondary oxidation products), are mainly formed by reactions of O 3 with soluble 

### 3

ELF components. The thickness of the ELF and that of the mucus layer, within the ELF, 

### 4

are important determinants of the dose of O 3 to the tissues; a thicker ELF generally 

### 5

results in a lower dose of O 3 to the tissues. Additionally, the quenchi ng ability and the 

### 6

concentrations of antioxidants and other ELF components are determinants of the 

### 7

formation of secondary oxidation products. These reactions appear to limit interaction of 

### 8

O 3 with underlying tissues and to reduce penetration of O 3 distally into the respiratory 

### 9

tract. 

### 10

In addition to contributing to the driving force for O 3 uptake, formation of secondary 

### 11

oxidation products contributes to oxidative stress which may lead to cellular injury and 

### 12

altered cell signaling in the respiratory tract. S econdary oxidation products initiate 

### 13

pathways (See Figure 5

- 8 ) that provide the mechanistic basis for short

- and long

- term 

### 14

health effects described in detail in Chapters 6 and 7. Other key events involved in the 

### 15

mode of action of O 3 in the respiratory tract include the activation of neural reflexes, 

### 16

initiation of inflammation, alterations of epithelial barrier function, sensitization of 

### 17

bronchial smooth muscle, modification of innate and adaptive immunity, and airways 

### 18

remodeling. Another key event, systemic inflammation and vascular oxidative/nitrosative 

### 19

stress, may be critical to the extrapulmonary effects of O 3

. 

### 20

Secondary oxidation products can transmit signals to respiratory tract cells resulting in 

### 21

the activation of neural reflexes. Nociceptive sensory nerves mediate the involuntary 

### 22

truncation of respiration, resulting in decreases in lung function (i.e., FVC, FEV 1 , and 

### 23

tidal volume), and pain upon dee p inspiration. Studies implicate TRPA1 receptors on 

### 24

bronchial C

- fibers in this reflex. Another neural reflex involves vagal sensory nerves, 

### 25

which mediate a mild increase in airways obstruction (i.e., bronchoconstriction) 

### 26

following exposure to O 3 via parasy mpathetic pathways. Substance P release from 

### 27

bronchial C

- fibers and the SP

- NK receptor pathway may also contribute to this response. 

### 28

Secondary oxidation products also initiate the inflammatory cascade following exposure 

### 29

to O 3 . Studies have implicated eico sanoids, chemokines and cytokines, vascular 

### 30

endothelial adhesion molecules, and tachykinins in mediating this response. 

### 31

Inflammation is characterized by airways neutrophilia as well as the influx of other 

### 32

inflammatory cell types. Recent studies demonstrate a later phase of inflammation 

### 33

characterized by increased numbers of macrophages, which is mediated by hyaluronan. 

### 34

Inflammation further contributes to O 3 - induced oxidative stress. 

### 35

Alteration of the epithelial barrier function of the respiratory tract also occurs as a result 

### 36

of O 3 - induced secondary oxidation product formation. Increased epithelial permeability 

### 37

### Draft

– Do Not Cite or Quote 2

- 17 June 2012 may lead to enhanced sensitization of bronchial smooth muscle, resulting in airways 

### 1

hyperresponsiveness (AHR). Neurally

- mediated sensitization also o ccurs and is mediated 

### 2

by cholinergic postganglionic pathways and bronchial C

- fiber release of substance P. 

### 3

Recent studies implicate hyaluronan and Toll

- like receptor 4 (TLR4) signaling in 

### 4

bronchial smooth m uscle sensitization, while earlier studies demonst rate roles for 

### 5

eicosanoids, cytokines, and chemokines. 

### 6

Evidence is accumulating that exposure to O 3 modifies innate and adaptive immunity 

### 7

through effects on macrophages, monocytes, and dendritic cells. Enhanced antigen 

### 8

presentation, adjuvant activity, and altered responses to endotoxin have been 

### 9

demonstrated. TLR4 signaling contributes to some of these responses. Effects on innate 

### 10

and adaptive immunity may result in both short

- and longer

- term consequences related to 

### 11

the exacerbation and/or induction of as thma and to alterations in host defense. 

### 12

Airways remodeling has been demonstrated following chronic and/or intermittent 

### 13

exposure to O 3 by mechanisms that are not well understood. However, the TGF

- β 

### 14

signaling pathway has recently been implicated in O 3 - indu ced deposition of collagen in 

### 15

the airways wall. These studies were conducted in adult animal models and their 

### 16

relevance to effects in humans is unknown. 

### 17

Evidence is also accumulating that O 3 exposure results in systemic inflammation and 

### 18

vascular oxidative /nitrosative stress. The release of diffusible mediators from the 

### 19

O 3 - exposed lung into the circulation may initiate or propagate inflammatory responses in 

### 20

the vascular or in systemic compartments. This may provide a mechanistic basis for 

### 21

extrapulmonary eff ects, such as vascular dysfunction. 

### 22

Both dosimetric and mechanistic factors contribute to the understanding of 

### 23

inter

- individual variability in response. Inter

- individual variability is influenced by 

### 24

variability in respiratory tract volume and thus surface area, breathing route, certain 

### 25

genetic polymorphisms, pre

- existing conditions and disease, nutritional status, lifestages, 

### 26

attenuation, and co

- exposures. In particular, very young individuals may be sensitive to 

### 27

developmental effects of O 3 since studies i n animal models demonstrated altered 

### 28

development of lung and immune system. 

### 29

Some of these factors are also influential in understanding species homology and 

### 30

sensitivity. Qualitatively, animal models exhibit a similar pattern of tissue dose 

### 31

distribution fo r O 3 with the largest tissue dose delivered to the centriacinar region. 

### 32

However, due to anatomical and biochemical respiratory tract differences, the actual O 3 

### 33

dose delivered differs between humans and animal models. Animal data obtained in 

### 34

resting conditi ons underestimates the dose to the respiratory tract tissue relative to 

### 35

exercising humans. Further, it should be noted that, with the exception of airways 

### 36

### Draft

– Do Not Cite or Quote 2

- 18 June 2012 remodeling, the mechanistic pathways discussed above have been demonstrated in both 

### 1

animals and human subjects in response to the inhalation of O 3 . Even though interspecies 

### 2

differences limit quantitative comparison between species, the short

- and long

- term 

### 3

functional responses of laboratory animals to O 3 appear qualitatively homologous to 

### 4

those of the hum an making them a useful tool in determining mechanistic and 

### 5

cause

- effect relationships with O 3 exposure. Furthermore, animal studies add to a better 

### 6

understanding of the full range of potential O 3 - mediated effects. 

### 7



## 2.5 Integration of Ozone Health Effects

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

### 8

epidemiologic studies (which examined the health effects associated with short

- and 

### 9

long

- term exposure to O 3 , ) and summarizes the main conclusions of this assessment 

### 10

regardin g the health effects of O 3 and the concentrations at which those effects are 

### 11

observed. The results from the health studies, supported by the synthesis of atmospheric 

### 12

chemistry (See Section 2.2 ) and exposure assessment (See Section 2.3 ) studies, contribute 

### 13

to the causal determinations made for the health outcomes discussed in this assessment 

### 14

(See Preamble to this document for details on the causal framework). 

### 15

2.5.1 Conclusions fr om Previous Ozone AQCDs

The 2006 O 3 AQCD concluded that there was clear, consistent evidence of a causal 

### 16

relationship between short

- term O 3 exposure and respiratory health effects ( U.S. EPA, 

### 17

2006b ) . The causal relationship for respiratory health effects was substantiated by the 

### 18

coherence of effects observed across co ntrolled human exposure, epidemiologic, and 

### 19

toxicological studies indicating effects of short

- term O 3 exposures on a range of 

### 20

respiratory health endpoints from respiratory tract inflammation to respiratory

- related 

### 21

emergency department (ED) visits and hospi tal admissions. 

### 22

Across disciplines, short

- term O 3 exposures induced or were associated with statistically 

### 23

significa nt declines in lung function. An equally strong body of evidence from controlled 

### 24

human exposure and toxicological studies demonstrated O 3 - ind uced inflammatory 

### 25

responses, increased epithelial permeability, and airway hyperresponsiveness (both 

### 26

specific and nonspecific). Toxicological studies provided additional evidence for 

### 27

O 3 - induced impairment of host defenses. Combined, these findings from exp erimental 

### 28

studies provided support for epidemiologic evidence, in which short

- term increases in 

### 29

ambient O 3 concentration were consistently associated with increases in respiratory 

### 30

symptoms and asthma medication use in children with asthma, respiratory

- rela ted 

### 31

### Draft

– Do Not Cite or Quote 2

- 19 June 2012 hospital admissions, and asthma

- related ED visits. Although O 3 was consistently 

### 1

associated with nonaccidental and cardiopulmonary mortality, the contribution of 

### 2

respiratory causes to these findings was uncertain. 

### 3

Collectively, there is a vast amount o f evidence spanning several decades that 

### 4

demonstrated that exposure to O 3 induces a range of respiratory effects . The majority of 

### 5

this evidence was derived from studies investigating short

- term exposure (i.e., hours to 

### 6

weeks) to O 3 . The combined evidence a cross disciplines led to the causal relationship 

### 7

between short

- term O 3 exposure and respiratory effects reported in the 2006 O 3 AQCD. 

### 8

Mechanistic evidence for the effects of O 3 on the respiratory system was characterized in 

### 9

the 1996 O 3 AQCD, which identif ied O 3 - induced changes in a variety of lung lipid 

### 10

species whose numerous biologically active metabolites, in turn, can affect host defenses, 

### 11

lung function, and the immune system. As summarized in Section 2.4 and fully 

### 12

characterized in Chapter 5 , key events in the toxicity pathway of O 3 have been identified 

### 13

in humans and animal models. They include formation of secondary oxidation products, 

### 14

activation of neural reflexes, initiation o f inflammation, alteration of epithelial barrier 

### 15

function, sensitization of bronchial smooth muscle, modification of innate/adaptive 

### 16

immunity, airways remodeling, and systemic inflammation and oxidative/nitrosative 

### 17

stress. 

### 18

2.5.2 Summary of Causal Determinations

Recent studies support or build upon the strong body of evidence presented in the 1996 

### 19

and 2006 O 3 AQCDs that short

- term O 3 exposure is causally associated with respiratory 

### 20

health effects . Recent controlled human exposure studies demonstrate statistically 

### 21

significa nt group mean decreases in pulmonary function to exposures as low as 

### 22

60

- 70 ppb O 3 in young, healthy adults, and are supported by the strong, cumulative 

### 23

evidence from epidemiologic studies. Equally strong evidence demonstrated associations 

### 24

of ambi ent O 3 with respiratory hospital admissions and ED visits across the U.S., Europe, 

### 25

and Canada. Most effect estimates ranged from a 1.6 to 5.4% increase in daily all 

### 26

respiratory

- related ED visits or hospital admissions in all

- year analyses for unit increase s 1 

### 27

in ambient O 3 concentrations. Several multicity studies and a multicontinent study 

### 28

reported associations between short

- term increases in ambient O 3 concentrations and 

### 29

increases in respiratory mortality. This evidence is supported by a large body of 

### 30

indi vidual

- level epidemiologic panel studies that demonstrate associations of ambient O 3 

### 31

with respiratory symptoms in children with asthma. Further support is provided by recent 

### 32

studies that found O 3 - associated increases in indicators of airway inflammation an d 

### 33

1 Effect estimates were standardized to a 40

- , 30

- , and 20

- ppb unit increase for 1

- h max, 8

- h max, and 24

- h avg O 3

.

### Draft

– Do Not Cite or Quote 2

- 20 June 2012 oxidative stress in children with asthma. Across respiratory endpoints, evidence indicates 

### 1

antioxidant capacity may modify the risk of respiratory morbidity associated with O 3 

### 2

exposure. The potentially elevated risk of populations with diminished antioxi dant 

### 3

capacity and the reduced risk of populations with enhanced antioxidant capacity 

### 4

identified in epidemiologic studies is strongly supported by similar findings from 

### 5

controlled human exposure studies and by evidence that characterizes O 3 - induced 

### 6

decrease s in intracellular antioxidant levels as a mode of action for downstream effects. 

### 7

By demonstrating O 3 - induced airway hyperresponsiveness, decreased pulmonary 

### 8

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

### 9

toxicol ogical studies have characterized O 3 modes of action and provided biological 

### 10

plausibility for epidemiologic associations of ambient O 3 concentrations with lung 

### 11

function and respiratory symptoms, hospital admissions, ED visits, and mortality. 

### 12

Together, the evidence integrated across controlled human exposure, epidemiologic, and 

### 13

toxicological studies and across the spectrum of respiratory health endpoints continues to 

### 14

demonstrate that there is a causal relationship between short

- term O 3 exposure and 

### 15

respirato ry health effects

. 

### 16

The strongest evidence for a relationship between long

- term O 3 exposure and respiratory 

### 17

health effects (including respiratory symptoms, new

- onset asthma, and repiratory 

### 18

mortality) is contributed by recent studies that demonstrated associations between long



### 19

term measures of O 3 exposure and both new

- onset asthma in children and increased 

### 20

respiratory symptom effects in individuals with asthma. While the evidence is limited, a 

### 21

U.S. multicommunity prospective cohort demonstrates that ast hma risk is affected by 

### 22

interactions among genetic variability, environmental O 3 exposure, and behavior. The 

### 23

evidence relating new

- onset asthma to long

- term O 3 exposure is supported by 

### 24

toxicological studies of asthma in monkeys. This nonhuman primate evide nce of 

### 25

O 3 - induced changes supports the biologic plausibility of long

- term exposure to O 3 

### 26

contributing to the effects of asthma in children. Early life O 3 exposure may alter airway 

### 27

development and lead to the development of asthma. Other recent epidemiologi c studies 

### 28

provide coherent evidence for long

- term O 3 exposure and respiratory effects such as first 

### 29

asthma hospitalization, respiratory symptoms in asthmatics, and respiratory mortality. 

### 30

Generally, the epidemiologic and toxicological evidence provides a co mpelling case that 

### 31

supports the hypothesis that a relationship exists between long

- term exposure to ambient 

### 32

O 3 and measures of respiratory health effects and mortality. The evidence for short

- term 

### 33

exposure to O 3 and effects on respiratory endpoints provide s coherence and biological 

### 34

plausibility for the effects of long

- term exposure to O 3

. Building upon that evidence, the 

### 35

more recent epidemiologic evidence, combined with toxicological studies in rodents and 

### 36

nonhuman primates, provides biologically plausible evidence that there is likely to be a 

### 37

causal relationship between long

- term exposure to O 3 and respiratory health 

### 38

effects. 

### 39

### Draft

– Do Not Cite or Quote 2

- 21 June 2012 The 2006 O 3 AQCD concluded that the overall body of evidence was highly suggestive 

### 1

that short

- term exposure to O 3 directly or indirec tly contributes to nonaccidental and 

### 2

cardiopulmonary

- related mortality, but additional research was needed to more fully 

### 3

establish underlying mechanisms by which such effects occur. The evaluation of recent 

### 4

multicity studies and a multicontinent study that examined the association between short



### 5

term increases in ambient O 3 concentration and mortality found evidence that supports 

### 6

the conclusions of the 2006 O 3 AQCD. These recent studies reported consistent positive 

### 7

associations between short

- term increases in ambient O 3 concentration and total 

### 8

(nonaccidental) mortality, with associations being stronger during the warm season, as 

### 9

well as provided additional supp ort for associations between O 3 concentrations and 

### 10

cardiovascular mortality being similar or larger in magnitude compared to respiratory 

### 11

mortality. Additionally, these new studies examined previously identified areas of 

### 12

uncertainty in the O 3 - mortality rela tionship, and provide additional evidence supporting 

### 13

an association between short

- term O 3 exposure and mortality. Taken together, the body of 

### 14

evidence indicates that there is likely to be a causal relationship between short

- term 

### 15

O 3 exposures and total mort ality. 

### 16

The 2006 O 3 AQCD concluded that an insufficient amount of evidence existed to suggest 

### 17

a causal relationship between long

- term O 3 exposure and mortality ( U.S. EPA, 2006b )

. 

### 18

A synthesis of the recent and earlier evidence reveals that the strongest evidence for an 

### 19

association between long

- term exposure to ambient O 3 concentrations and mortality is 

### 20

derived from associations for respiratory mortality that remained robust after adjusting 

### 21

for PM 2.5 concentrations. There is inconsistent evidence for an association between long



### 22

term exposure to ambient O 3 and cardiopulom ary mortality, with several analyses from 

### 23

the ACS cohort reporting some positive associations, while other studies reported no 

### 24

association. There is generally limited evidence for an association with long

- term 

### 25

exposure to ambient O 3 and total mortality.The findings for respiratory mortality are 

### 26

consistent and coherent with the evidence from epidemiologic, controlled human 

### 27

exposure, and animal toxicological studies for the effects of short

- and long

- term 

### 28

exposure to O 3 on respiratory effects. Respiratory mortality is a relatively small portion 

### 29

of total mortality [about 7.6% of all deaths in 2010 were due to respiratory causes 

### 30

( Murphy et al., 2012 ) ], thus it is not surprising that the respiratory mortality signal may 

### 31

be difficult to detect in studies of cardiopulmonary or total morta l ity. Based on the recent 

### 32

evidence for respiratory mortality along with limited evidence for total and 

### 33

cardiopulmonary mortality, the evidence is suggestive of a causal relationship 

### 34

between long

- term O3 exposures and total mortality. 

### 35

In past O 3 AQCDs the ef fects of short

- and long

- term exposure to O 3 on the 

### 36

cardiovascular system could not be thoroughly evaluated due to the paucity of 

### 37

information available. However, studies investigating O 3 - induced cardiovascular events 

### 38

### Draft

– Do Not Cite or Quote 2

- 22 June 2012 have advanced in the last two decades. Animal toxicological studies provide evidence for 

### 1

both short

- and long

- term O 3 exposure leading to cardiovascular morbidity. The 

### 2

toxicological studies demonstrate O 3 - induced cardiovascular effects, specifically 

### 3

enhanced atherosclerosis and ischemia/reperfu sion injury with or without the 

### 4

corresponding development of a systemic oxidative, pro

- inflammatory environment, 

### 5

disrupted NO

- induced vascular reactivity, decreased cardiac function, and increased heart 

### 6

rate variability (HRV). The observed increase in HRV is supported by a recent controlled 

### 7

human exposure study that also found increased high frequency HRV, but not altered 

### 8

blood pressure, following O 3 exposure. It is still uncertain how O 3 inhalation may cause 

### 9

systemic toxicity; however the cardiovascular ef fects of O 3 found in animals correspond 

### 10

to the development and maintenance of an extrapulmonary oxidative, proinflammatory 

### 11

environment that may result from pulmonary inflammation. 

### 12

There is limited, inconsistent evidence for cardiovascular morbidity in epid emiologic 

### 13

studies examining both short

- and long

- term exposure to O 3 . This is highlighted by the 

### 14

multiple studies that examined the association between short

- term increases in ambient 

### 15

O 3 concentration and cardiovascular

- related hospital admissions and ED v isits and other 

### 16

various cardiovascular effects and found no evidence of a consistent relationship with O 3 

### 17

exposure. Positive associations between short

- term increases in O 3 concentration and 

### 18

cardiovascular mortality have been consistently reported in multi ple epidemiologic 

### 19

studies. However, the lack of coherence between the results from studies that examined 

### 20

associations between short

- term increases in O 3 concentration and cardiovascular 

### 21

morbidity and subsequently cardiovascular mortality, complicate the in terpretation of the 

### 22

evidence for O 3 - induced cardiovascular mortality. 

### 23

Overall, animal toxicological studies provide some evidence for O 3 - induced 

### 24

cardiovascular effects, but the effects observed were not consistently supported by 

### 25

controlled human exposure studies or epidemiologic studies. Although the toxicological 

### 26

evidence provides initial support to the relatively strong body of evidence indicating 

### 27

O 3 - induced cardiovascular mortality, there is a lack of coherence with controlled human 

### 28

exposure and epidemiologic studies of cardiovascular morbidity which together do not 

### 29

support O 3 - induced cardiovascular effects. Thus, the overall body of evidence across 

### 30

disciplines is suggestive of a causal relationship for both relevant short

- and long



### 31

term exposures to O 3 and cardiovascular effects. 

### 32

In the 2006 O 3 AQCD, there were a number of health effects for which an insufficient 

### 33

amount of evidence existed to adequately characterize the relationships with exposure to 

### 34

O 3 . However, recent evidence suggests that O 3 m ay impart health effects through 

### 35

exposure durations and biological mechanisms not previously considered. For example, 

### 36

recent toxicological studies add to earlier evidence that short

- and long

- term exposures to 

### 37

O 3 can produce a range of effects on the centr al nervous system and behavior

. 

### 38

### Draft

– Do Not Cite or Quote 2

- 23 June 2012 Additionally, an epidemiologic study demonstrated that long

- term exposure to O 3 affects 

### 1

memory in humans as well

. Together the evidence from studies of short

- and long

- term 

### 2

exposure to O 3 is suggestive of a causal relationsh ip between O 3 exposure and 

### 3

central nervous system effects. There is also limited though positive toxicological 

### 4

evidence for O 3 - induced developmental effects . Limited epidemiologic evidence exists 

### 5

for an association of O 3 concentration with decreased sperm concentration and 

### 6

associations with reduced birth weight and restricted fetal growth. Overall, the evidence 

### 7

is suggestive of a causal relationship between long

- term exposures to O 3 and 

### 8

reproductive and developmental effects. 

### 9

These causal determinations are summarized in Table 2

- 2, along with the conclusions 

### 10

from the previous NAAQS review. Special emphasis and additional details are provided 

### 11

in Table 2

- 2 for respiratory health outcomes, for which there is the strongest body of 

### 12

evidence. 

### 13

Table 2

- 2 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 O 3 AQCD Conclusions from 2012 3rd Draft ISA

Short

- Term Exposure to O 3

Respiratory effects The overall evidence supports a causal relationship between acute ambient O 3 exposures and increased respiratory morbidity

outcomes. Evidence integrated across controlled human exposure, epidemiologic, and toxicological studies and across the spectrum of respiratory health endpoints continues to demonstrate that there is a causal relationship between short

- term O 3 exposure and respiratory health effects.

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)

O 3 exposure and relatively small, but statistically significa nt declines in lu ng 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 demonstrate group mean decreases in FEV 1 in the range of 2 to 3% with 6.6 hour exposures to as low

as 60 ppb O 3 . The collective body of epidemiologic

evidence demonstrates associations between short

term ambient O 3 exposure and decrements in lung function, particularly in children with asthm a, children, and adults who work or exercise outdoors.

Airway

hyperresponsiveness Evidence from human clinical and animal toxicological studies clearly indicate that acute exposure to O 3 can induce airway hyperreactivity, thus likely placing atopic

asthma tics 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 gu inea pigs after exposure to less than 300 ppb O 3 . As previously reported in the 2006 O 3 AQCD, increased airway responsiveness has been

demonstrated at 80 ppb in young, healthy adults,

and at 50 ppb in certain strains of rats

.

### Draft

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- 24 June 2012 Health Outcome Conclusions from 2006 O 3 AQCD Conclusions from 2012 3rd Draft ISA

Pulmonary inflammation, inju ry 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 O 3 in inflammatory responses in the airways. Epidemiologic studie s provided new evidence for

associations of ambient O 3 with mediators of airway

inflammation and oxidative stress and indicate that higher antioxidant levels may reduce pulmonary

inflammation associated with O 3 exposure. Generally, these studies had mean 8

- h max O 3 concentrations less than 73 ppb . Recent controlled human exposure studies show O 3 - induced inflammatory responses at 60 ppb, the lowest

concentration evaluated.

Respiratory symptoms

and medication use Young healthy adult subjects exposed in

clini cal studies to O 3 concentrations ≥ 80 ppb for 6 to 8 h during moderate exercise exhibit symptoms of cough and pain on deep inspiration. The epidemiologic evidence shows significa nt associations between acute exposure to ambient O 3 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 short

term exposure to ambient O 3 and respiratory symptoms (e.g., cough, wheeze, and shortness of breath) in children with asthma. Generally, these

studies had mean 8

- h max O 3 concentrations less

than 69 ppb

.

Lung host defenses Toxicological studies provided extensive

evidence that acute O 3 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 al v eolar macrophages to phagocytize microorganisms upon exposure to 80 to 100 ppb O 3

. Recent controlled human exposure studies demonstrate the increased expression of cell surface markers and alterations in sputum leukocyte markers related to innate adaptive immunity with short

- term O 3 exposures of

80

- 400 ppb . Recent studies demonstrating altered immune responses and natural killer cell function build on prior evidence that O 3 can affect multiple aspects of innate and acquired immunity with short

term O 3 expo sures as low as 80 ppb

.

Allergic and asthma related responses Previous toxicological evidence indicated that

O 3 exposure skews immune responses toward an allergic phenotype, and enhances the development and severity of asthma

- related responses such as AHR

. Recent controlled human exposure studies demonstrate enhanced allergic cytokine production in atopic individuals and asthmatics, increased IgE receptors in atopic asthmatics, and enhanced markers of innate immunity and antigen presentation in health sub jects or atopic asthmatics

with short

- term exposure to 80

- 400 ppb O 3 , all of which may enhance allergy and/or asthma. Further

evidence for O 3 - induced allergic skewing is provided by a few recent studies in rodents using exposure concentrations as low as 20 0 ppb

.

Respiratory Hospital admissions, ED visits, and physician

visits Aggregate population time

- series studies

observed that ambient O 3 concentrations are positively and robustly associated with respiratory

- related hospitalizations and asthma

ED visits during the warm season. Consistent, positive associations of ambient O 3 with respiratory hospital admissions and ED visits in the U.S., Europe, and Canada with supporting evidence from single city studies. Generally, these studies

had mean 8

- h max O 3 conc entrations less than

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 O 3 exposure and respiratory mortality. Recent multicity time

- series studies and a multicontinent study consistently demonstrated

associations between ambient O 3 and respiratory

related mortality visits across the U.S., Europe, and Canada with supporting evidence from single city studies. Generally, these studies had mean 8

- h max O 3 concentrations less than 63 ppb

.

Cardiovascular effects The limited evidence is highly suggestive that

O 3 directly and/or indirectly contributes to

cardiovascular

- related morbidity, but much remains to be done to more fully substantiate

the association. The overall body of evidence across disciplines is suggestive of a causal relationship for relevant

short

- t erm exposures to O 3 and cardiovascular

effects.

### Draft

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- 25 June 2012 Health Outcome Conclusions from 2006 O 3 AQCD Conclusions from 2012 3rd Draft ISA

Central nervous system

effects Toxicological studies report that acute exposures to O 3 are associated with alterations in neurotransmitters, motor activity,

short

- and long

- term memory, sleep patterns, and histological signs of neurodegeneration. Together the evidence from studies of short

- term exposure to O 3 is suggestive of a causal

relat ionship between O 3 exposure and CNS

effects.

Total Mortality The evidence is highly suggestive that O 3 directly or indirectly contributes to non

accidental and cardiopulmonary

- related mortality. Taken together, the body of evidence indicates that

there is likely to be a causal relationship

between short

- term exposures to O 3 and all

cause total mortality.

Long

- term Exposure to O 3

Respiratory effects The current evidence is suggestive but inconclusive for respiratory health effects from long

- term O 3 exposure. Recent epidemiologic evidence, combined with toxicological studies in rodents and non

- human primates, provides biologically plausible evidence

that there is likely to be a causal relationship between long

- term exposure to O 3 and respiratory heal th effects.

New onset asthma No studies examining this outcome were

evaluated in the 2006 O 3 AQCD. Evidence that different genetic variants (HMOX, GST, ARG), in combination with O 3 exposure, are
related to new onset asthma. These associations were observed when subjects living in areas where

the mean annual 8

- h max O 3 concentration was

55.2 ppb , compared to those who lived where it

was 38.4 ppb

.

Asthma hospital

admissions No studie s examining this outcome were

evaluated in the 2006 O 3 AQCD. Chronic O 3 exposure was related to first childhood asthma hospital admissions in a positive

concentration

- response relationship. Generally,

these studies had mean annual 8

- h max O 3 concentrations less than 41 ppb

.

Pulmonary structure and

function Epidemiologic studies observed that reduced lung function growth in children was associated with seasonal exposure to O 3 ; however, cohort studies of annual or multiyear

O 3 exposure observed little clear evidence for impacts of longer

- term, relatively low

- level O 3 exposure on lung function development in children. Animal toxicological studies reported

chronic O 3 - induced structural alterations , some of which were irreversible, in several regions of the resp iratory 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 observing positive associations (mean annual

8

- h max O 3 concentrations less than 65 ppb ). Information from toxicological studies indicates that long

- term maternal exposure during gestation ( 100 ppb ) or development ( 500 ppb ) 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 O 3 in inflammatory responses in the airways. Several epidemiologic studies (mean 8

- h max O 3 concentrations less than 69 ppb ) and toxicology studies (as low as 500 ppb ) add t o observations of

O 3 - induced inflammation and injury.

Lung host defenses Toxicological studies provided evidence that

chronic O 3 exposure as low as 100 ppb can cause increases in susceptibility to infectious diseases due to modulation of lung host

defense s, but do not cause greater effects on infectivity than short exposures. Consistent with decrements in host defenses observed in rodents exposed to 100 ppb O 3 , recent evidence demonstrates a decreased ability to respond to pathogenic signals in infant mon keys exposed to 500 ppb O 3

.

Allergic responses Limited epidemiologic evidence supported an

association between ambient O 3 and allergic symptoms. Little if any information was available from toxicological studies. Evidence relates positive outcomes of alle rgic response and O 3 exposure but with variable strength for the effect estimates; exposure to O 3 may increase total IgE in adult asthmatics. Allergic indicators in monkeys were increased by exposure

to O 3 concentrations of 500 ppb

.

### Draft

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- 26 June 2012 Health Outcome Conclusions from 2006 O 3 AQCD Conclusions from 2012 3rd Draft ISA

Respiratory mortality Studies of cardio

- pulmonary mortality were insufficient to suggest a causal relationship

between chronic O 3 exposure and increased risk for mortality in humans. A single study demonstrated that exposure to O 3 (long

- term mean O 3 less than 104 ppb ) elevated the risk of death from respiratory causes and this

effect was robust to the inclusion of PM 2.5

.

Cardiovascular Effects No studies examining this outcome were

evaluated in the 2006 O 3 AQCD. The overall body of evidence across disciplines is suggestive of a causal relationship for relevant long

- term exposures to O 3 and cardiovascular

effects.

Reproductive and developmental effects Limited evidence for a relationship between air pollution and birth

- related health outcomes, including mortality, premature birt hs, low birth weights, and birth defects, with little evidence being found for O 3 effects. Overall, the evidence is suggestive of a causal relationship between long

- term exposures to O 3 and reproductive and developmental effects.

Central nervous system

ef fects Toxicological studies reported that acute exposures to O 3 are associated with alterations in neurotransmitters, motor activity, short and long term memory, sleep patterns, and histological signs of neurodegeneration. Evidence regarding chronic exposu re and

neurobehavioral effects was not available. Together the evidence from studies of long

- term exposure to O 3 is suggestive of a causal relationship between O 3 exposure and CNS

effects.

Cancer Little evidence for a relationship between

chronic O 3 expos ure and increased risk of lung

cancer. Overall, the evidence is inadequate to determine if a causal relationship exists between ambient

O 3 exposures and cancer.

Total Mortality There is little evidence to suggest a causal relationship between chronic O 3 exposure and increased risk for mortality in humans. Collectively, the evidence is suggestive of a causal relationship between long

- term O 3 exposures and total mortality.



### 2.5.3 Integrated Synthesis of Evidence for Health Effects

Building off that evaluated in previous O 3 AQCDs, recent evidence demonstrates that O 3 

### 1

is associated with a broad range of respiratory effects, including altered development of 

### 2

the respiratory tract . Recent animal toxicological studies of long

- term exposure to O 3 

### 3

occurring throughout va rious lifestages in monkeys , beginning with prenatal and early 

### 4

life exposures, provide novel evidence for effects on the development of the respiratory 

### 5

system, including ultrastructural changes in bronchiole development, effects on the 

### 6

developing immune sy stem, and increased offspring airway hyper

- reactivity 

### 7

(Section 7.4.7 ). The strongest evidence for O 3 - induced effects on the developing lung 

### 8

comes fr om a series of experiments using infant rhesus monkeys episodically exposed to 

### 9

500 ppb O 3 for approximately 5 months, starting at one month of age. Functional changes 

### 10

in the conducting airways of infant rhesus monkeys exposed to either O 3 alone or O 3 + 

### 11

ant igen were accompanied by a number of cellular and morphological changes. In 

### 12

addition to these functional and cellular changes, substantial structural changes in the 

### 13

respiratory tract were observed. Importantly, the O 3 - induced structural pathway changes 

### 14

persisted after recovery in filtered air for six months after cessation of the O 3 exposures. 

### 15

Exposure to O 3 has also been associated with similar types of alterations in pulmonary 

### 16

structure, including airways remodeling and pulmonary injury and increased 

### 17

### Draft

– Do Not Cite or Quote 2

- 27 June 2012 p ermeability, in all adult laboratory animal species studied, from rats to monkeys ( U.S. 

### 1

EPA, 1996a )

. 

### 2

In addition to effects on the development and structure of the r espiratory tract, there is 

### 3

extensive evidence for the effects of short

- term exposure to O 3 on pulmonary 

### 4

inflammation and oxidative stress . Previous evidence from controlled human exposure 

### 5

studies indicated that O 3 causes an inflammatory response in the lun gs ( U.S. EPA, 

### 6

1996a ) . This inflammatory response to O 3 was detected after a single 1

- h exposure with 

### 7

exercise to O 3 concentrations of 300 ppb; the increased levels of some inflammatory cells 

### 8

and mediators persisted for at least 18 hours. Toxicological studies provided additional 

### 9

evidence for increases in permeability and inflammation in rabbits at levels as low as 

### 10

100 ppb O 3 . Evidence summarized in the 2006 O 3 AQCD dem onstrated that 

### 11

inflammatory responses were observed subsequent to 6.6 hours O 3 exposure to the lowest 

### 12

tested level of 80 ppb in healthy human adults, while toxicological studies provided 

### 13

extensive evidence that short

- term (1

- 3 hours) O 3 exposure in the ran ge of 100

- 500 ppb 

### 14

could cause lung inflammatory responses. The limited epidemiologic evidence reviewed 

### 15

in the 2006 O 3 AQCD demonstrated an association between short

- term increases in 

### 16

ambient O 3 concentration and airways inflammation in children (1

- h max O 3 of 

### 17

approximately 100 ppb). Recent studies in animals and in vitro models described 

### 18

inflammatory and injury responses mediated by Toll

- like receptors (e.g., TLR4, TLR2), 

### 19

receptors for TNF or IL

- 1, multiple signaling pathways (e.g., p38, JNK, NFκB, 

### 20

MAPK/AP

- 1), and oxidative stress (Section 6.2.3.3 ). Recent epidemiologic studies 

### 21

provide additional supporting evidence by demonstrating associations of am bient O 3 with 

### 22

mediators of airways inflammation and oxidative stress. 

### 23

The normal inflammatory response in lung tissue is part of host defense that aids in 

### 24

removing microorganisms or particles that have reached the distal airways and alveolar 

### 25

surface. The 1996 O 3 AQCD concluded that short

- term exposure to elevated 

### 26

concentrations of O 3 resulted in alterations in these host defense mechanisms in the 

### 27

respiratory system. Specifically, toxicological studies of short

- term exposures as low as 

### 28

100 ppb O 3 for 2 hour s were shown to decrease the ability of alveolar macrophages to 

### 29

ingest particles, and short

- term exposures as low as 80 ppb for 3 hours prevented mice 

### 30

from resisting infection with streptococcal bacteria and resulted in infection

- related 

### 31

mortality. Similar ly, alveolar macrophages removed from the lungs of human subjects 

### 32

after 6.6 hours of exposure to 80 and 100 ppb O 3 had decreased ability to ingest 

### 33

microorganisms, indicating some impairment of host defense capability. These altered 

### 34

host defense mechanisms can lead to increased risk of respiratory infections, which can 

### 35

often predispose individuals to developing asthma when occurring in early life. Despite 

### 36

the strong toxicological evidence, in the limited body of epidemiologic evidence, ambient 

### 37

O 3 concentrations have not been consistently associated with hospital admissions or ED 

### 38

### Draft

– Do Not Cite or Quote 2

- 28 June 2012 visits for respiratory infection, pneumon ia, or influenza (Section 6.2.7.2 and 

### 1

Section 6.2.7.3 ). 

### 2

The most commonly observed and strongest evidence for respiratory effects associated 

### 3

with short

- term exposure to O 3 is transient decrements in pulmonary function . Controlled 

### 4

human exposure studies reviewed in previous assessments demonstra ted O 3 - induced 

### 5

decrements in pulmonary function, characterized by alterations in lung volumes and flow 

### 6

and airway resistance and responsiveness for multihour exposures (up to 8 hours) to O 3 

### 7

concentrations as low as 80 ppb ( U.S. EPA, 1996a ) . A series of mobile laboratory studies 

### 8

of lung function and respiratory symptoms reported pulmonary function decrements at 

### 9

mean ambient O 3 concentrations of 140 ppb in exercising hea lthy adolescents and 

### 10

increased respiratory symptoms and pulmonary function decrements at 150 ppb in 

### 11

heavily exercising athletes and at 170 ppb in lightly exercising healthy and asthmatic 

### 12

subjects. Epidemiologic and animal toxicological evidence is coherent with the results of 

### 13

the controlled human exposure studies, both indicating decrements in lung function upon 

### 14

O 3 exposure. A combined statistical analysis of epidemiologic studies in children at 

### 15

summer camp with particularly strong exposure assessment demon strated decrements in 

### 16

FEV 1 of 0.50 mL/ppb with an increase in previous hour O 3 concentration. For 

### 17

preadolescent children exposed to 120 ppb ambient O 3 , this estimated volume decrease 

### 18

corresponded to an average decrement of 2.4

- 3.0% in FEV 1 . Key studies of lung function 

### 19

(FEV 1 ) measured before and after well

- defined outdoor exercise events in adults yielded 

### 20

concentration

- response slopes of 0.40 and 1.35 mL/ppb ambient O 3 after exposure for up 

### 21

to 1 hour. Animal toxicological studies reported similar respirator y effects in rats at 

### 22

exposures as low as 200 ppb O 3 for 3 hours. The 2006 O 3 AQCD characterized the 

### 23

controlled human exposure and animal toxicological studies as providing clear evidence 

### 24

of causality for the associations observed between short

- term (≤ 24 h ours) increases in O 3 

### 25

concentration and relatively small, but statistically significa nt declines in lung function 

### 26

observed in numerous recent epidemiologic studies. In epidemiologic studies, declines in 

### 27

lung function were particularly noted in children wit h and without asthma, and adults 

### 28

who work or exercise outdoors. 

### 29

Recent controlled human exposure studies examined lower concentration O 3 exposures 

### 30

(40

- 80 ppb) and demonstrated that FEV 1 , respiratory symptoms, and inflammatory 

### 31

responses were affected by O 3 exposures of 6.6 hours as low as 60 to 70 ppb 

### 32

(Section 6.2.1.1 and Section 6.2.3.1 ). These studies demonstrated average O 3 - induced 

### 33

decreases in FEV 1 in the range of 2.8 to 3.6% with O 3 exposures to 60 ppb for 6.6 hours. 

### 34

Further, in the controlled human exposure studies evaluating effects of 60 ppb O 3 , on 

### 35

average, 10% of the exposed individuals experienced >10% FEV 1 decrements following 

### 36

6.6 hours of exposure. Considerable intersubject variability has also been reported in 

### 37

studies at higher exposure concentrations (≥ 70 ppb) with some subjects ex periencing 

### 38

### Draft

– Do Not Cite or Quote 2

- 29 June 2012 considerably greater decrements than average. Recent epidemiologic studies provide 

### 1

greater insight into individual

- and population

- level factors that may increase for the risk 

### 2

of O 3 - associated respiratory morbidity. In addition to lung function decrements 

### 3

consistently reported in healthy children at summer camp, O 3 - associated decreases in 

### 4

lung function were consistently observed in epidemiologic studies that included 

### 5

potentially at

- risk populations (e.g., individuals with asthma with concurrent r espiratory 

### 6

infection, older adults with AHR or elevated body mass index, or groups with diminished 

### 7

antioxidant capacity). 

### 8

Exposure to O 3 may also result in respiratory symptoms (e.g., coughing, wheezing, 

### 9

shortness of breath). The 1996 O 3 AQCD identified an association between respiratory 

### 10

symptoms and increasing ambient O 3 , particularly among children with asthma. In the 

### 11

2006 O 3 AQCD, symptoms of cough and pain on deep inspiration were well documented 

### 12

in young healthy adult subjects after exposure of ≥ 80 ppb O 3 for 6

- 8 hours during 

### 13

moderate exercise. Limited data suggested an increase in respiratory symptoms down to 

### 14

60 ppb. More recently, these effects have been observed at 70 ppb in healthy adults. 

### 15

Controlled human exposure studies of hea lthy adults, have also reported an increased 

### 16

incidence of cough with O 3 exposures as low as 120 ppb and 1

- 3 hours in duration with 

### 17

very heavy exercise. The controlled human exposure studies also demonstrated lesser 

### 18

respiratory symptom responses in children and older adults relative to young healthy 

### 19

adults. Cumulative epidemiologic evidence adds to the findings from controlled human 

### 20

exposure studies for healthy adults by demonstrating the effects of ambient O 3 exposure 

### 21

on respiratory symptoms in children wit h asthma. Increases in ambient O 3 concentration 

### 22

were associated with a wide variety of respiratory symptoms (e.g., cough, wheeze, and 

### 23

shortness of breath) in children with asthma. Epidemiologic studies also indicated that 

### 24

short

- term increases in O 3 concent ration are likely associated with increased asthma 

### 25

medication use in children with asthma. Additionally, epidemiologic studies provide 

### 26

evidence for an association between long

- term exposure to O 3 and respiratory symptoms 

### 27

(Section 7.2.2 ). 

### 28

Ozone exposure has been shown to result in both specific and non

- specific airway 

### 29

hyperresponsiveness (AHR) . Increased AHR is an important consequence of exposure to 

### 30

O 3 because its presence represents a change in airway smooth muscle reactivity and 

### 31

implies that the airways are predisposed to narrowing on inhalation of a variety of stimuli 

### 32

(e.g., specific allergens, SO 2 , cold air). Specifically, short

- term (2 or 3 hours ) exposure to 

### 33

250 or 400 ppb O 3 was found to cause increases in AHR in response to allergen 

### 34

challenges among allergic asthmatic subjects who characteristically already had 

### 35

somewhat increased AHR at baseline. Increased non

- specific AHR has been 

### 36

demonstrated in healthy young adults down to 80 ppb O 3 following 6.6 hours of exposure 

### 37

during moderate exercise. While AHR has not been widely examined in epidemiologic 

### 38

### Draft

– Do Not Cite or Quote 2

- 30 June 2012 studies, findings for O 3 - induced increases in AHR in controlled human exposure 

### 1

(Section 6.2.2.1 ) and toxicological (Section 6.2.2.2 ) studies provide biological 

### 2

plausibility for associations observed between increases in ambient O 3 concentration and 

### 3

increases in respiratory symptoms in subjects with asthma. 

### 4

In addition to asthma exacerbations, recent epidemiologic evidence has indica ted that 

### 5

long

- term ambient O 3 concentrations may contribute to new onset asthma (Section 7.2.1

, 

### 6

Table 7

- 2 ). The new epidemiologic evidence base consists of studies using a variety of 

### 7

designs and analysis methods evaluating the relationship between long

- term annual 

### 8

measures of exposure to ambient O 3 and measures of respiratory morbidity. Studies from 

### 9

two California cohorts have provided evidence for different variants in genes related to 

### 10

oxidative or nitrosative stress (e.g., HMOX, GSTs, ARG ) that, depending on community 

### 11

long

- term O 3 concentrations, are related to new onset asthma. This is the first time that 

### 12

evidence has extended beyond the association of short

- term exposure to O 3 and asthma 

### 13

exacerbations to suggest that long

- term exposure to O 3 may play a role in the 

### 14

development of the disease and c ontribute to incident cases of asthma. 

### 15

The frequency of ED visits and hospital admissions due to respiratory symptoms, asthma 

### 16

exacerbations and other respiratory diseases is associated with short

- and long

- term 

### 17

exposure to ambient O 3 concentrations . Summer time daily hospital admissions for 

### 18

respiratory causes in various locations of eastern North America were consistently 

### 19

associated with ambient concentrations of O 3 in studies reviewed in the 1996 O 3 AQCD. 

### 20

This association remained even with examination of o nly concentrations below 120 ppb 

### 21

O 3 . The 2006 O 3 AQCD concluded that aggregate population time

- series studies 

### 22

demonstrate a positive and robust association between ambient O 3 concentrations and 

### 23

respiratory

- related hospitalizations and asthma ED visits during the warm season. Recent 

### 24

epidemiologic time

- series studies that include additional multicity studies and a 

### 25

multicontinent study further demonstrate that short

- term exposure s to ambient O 3 

### 26

concentrations are consistently associated with increases in respiratory hospital 

### 27

admissions and ED visits specifically during the warm/summer months across a range of 

### 28

O 3 concentrations (Section 6 .2.7 ). There is also recent evidence for an association 

### 29

between respiratory hospital admissions and long

- term exposure to O 3 (Section 7.2.2 ). 

### 30

Finally, O 3 exposure may contribute to death from respiratory causes . Recent evidence 

### 31

from several multicity studies and a multicontinent study demonstrate consistent positive 

### 32

associations between short

- term exposure to ambient O 3 concentrations and increases in 

### 33

respiratory mortality (Section 6.6.2.5 ). Similarly, a study of long

- term exposure to 

### 34

ambient O 3 concentrations also demonstrated an association between O 3 and increases in 

### 35

respiratory mortality (Section 7.7.1 ). Evidence from these recent mortality studies is 

### 36

consistent and coherent with the evidence from epidemiologic, controlled human 

### 37

### Draft

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- 31 June 2012 exposure, and animal toxicological studies for the effects of short

- and long

- term 

### 1

exposure to O 3 on respiratory effects. Additionally, the evidence for respiratory morbidity 

### 2

after short

- and long

- term exposure provides biological plausibility for mortality due to 

### 3

respiratory disease. 

### 4

There is similar evidence for a positive association between short

- term exposure to O 3 

### 5

and mortality. This evidence h as been substantiated by single

- city studies reviewed in the 

### 6

2006 O 3 AQCD and recent multicity and multicontinent studies. When examining 

### 7

mortality due to cardiovascular disease, epidemiologic studies consistently observe 

### 8

positive associations with short

- t erm exposure to O 3 . Additionally, there is some 

### 9

evidence for an association between long

- term exposure to O 3 and mortality. However, 

### 10

the association between long

- term ambient O 3 concentrations and cardiovascular 

### 11

mortality may be confounded by other polluta nts as evident by a study of cardiovascular 

### 12

mortality that reported no association after adjustment for PM 2.5 concentrations. The lack 

### 13

of coherence between the results from studies that examined associations between short



### 14

and long

- term O 3 concentrations a nd cardiovascular morbidity, and results from studies of 

### 15

cardiovascular mortality, complicate the interpretation of the evidence for O 3 - induced 

### 16

cardiovascular mortality. 

### 17

Epidemiologic studies evaluating cardiovascular morbidity and short

- and long

- term 

### 18

ex posure to O 3 provide no consistent evidence for an association. This is highlighted by 

### 19

the multiple studies that examined the association between short

- and long

- term O 3 

### 20

concentrations and cardiovascular

- related hospital admissions and ED visits and 

### 21

cardio vascular disease

- related biomarkers. Additionally, a single controlled human 

### 22

exposure study reported no statistically significa nt O 3 - induced differences in 

### 23

electrocardiogram (ECG), heart rate, or blood pressure in normal or hypertensive subjects 

### 24

(0.3 ppm for 3 h with intermittent exercise), however an overall increase in myocardial 

### 25

work and impairment in pulmonary gas exchange was obser ved. 

### 26

There is an emerging body of animal toxicological evidence suggesting that autonomic 

### 27

nervous system alterations (in heart rate and/or heart rate variability) and 

### 28

proinflammatory signals may mediate cardiovascular effects. Interactions of O 3 with ELF 

### 29

components result in secondary oxidation products and inflammatory mediators that have 

### 30

the potential to penetrate the epithelial barrier and to initiate toxic effects on the 

### 31

cardiovascular system. Animal toxicological studies of long

- term exposure to O 3 pr ovide 

### 32

evidence enhanced atherosclerosis and ischemia/reperfusion (I/R) injury, corresponding 

### 33

with development of a systemic oxidative, proinflammatory environment. 

### 34

Overall, animal toxicological studies provide some evidence for O 3 - induced 

### 35

cardiovascular ef fects, but the effects were not consistently supported by controlled 

### 36

human exposure studies or epidemiologic evidence. Although the toxicological evidence 

### 37

### Draft

– Do Not Cite or Quote 2

- 32 June 2012 provides initial support to the body of evidence indicating an association between short



### 1

term exposur e to O 3 and cardiovascular mortality, there is a lack of coherence with 

### 2

controlled human exposure and epidemiologic studies of cardiovascular morbidity. 

### 3

Together, these findings are suggestive of O 3 - induced cardiovascular effects. 

### 4

2.5.4 Policy Relevant Considera tions

2.5.4.1 Populations Potentially at Increased Risk

Studies were conducted to identify populations that are at increased risk for O 3 - related 

### 5

health effects. These studies have investigated factors that can cause populations to be at 

### 6

increased risk for O 3 - relat ed health effects by conducting stratified epidemiologic 

### 7

analyses; by examining individuals with an underlying health condition, genetic 

### 8

polymorphism, or categorized by age, race, or sex in controlled human exposure studies; 

### 9

or by developing animal models that mimic the pathophysiological conditions associated 

### 10

with a health effect. These studies have identified a multitude of factors that could 

### 11

potentially contribute to whether a population is at increased risk for O 3 - related health 

### 12

effects. 

### 13

The population s identified in Chapter 8 that were examined for their potential for 

### 14

increased risk of O 3 - related health effects are listed in Table 8

- 5 and are classified as 

### 15

providing adequate, suggestive, inadequate, or no evidence of being an at

- risk factor. The 

### 16

factors that have adequate evidence to be classi fied as an at

- risk factor for O 3 - related 

### 17

health effects are individuals with asthma, younger and older age groups, individuals with 

### 18

reduced intake of certain nutrients (i.e., vitamins C and E), and outdoor workers, based 

### 19

on consistency in findings across s tudies and evidence of coherence in results from 

### 20

different scientific disciplines. Asthma as a factor affecting risk was supported by 

### 21

controlled human exposure and toxicological studies, as well as some evidence from 

### 22

epidemiologic studies. Generally, studi es comparing age groups also reported greater 

### 23

associations for respiratory hospital admissions and ED visits among children than for 

### 24

adults. Biological plausibility for this increased risk is supported by toxicological and 

### 25

controlled human exposure studies . Also, children have higher exposure and dose due to 

### 26

increased time spent outdoors and ventilation rate, and childrens’ respiratory systems are 

### 27

also still undergrowing lung growth. Most studies comparing age groups reported greater 

### 28

effects of short

- term O 3 exposure on mortality among older adults, although studies of 

### 29

other health outcomes had inconsistent findings regarding whether older adults were at 

### 30

increased risk. Multiple epidemiologic, controlled human exposure, and toxicological 

### 31

studies reported tha t diets lower in vitamins E and C are associated with increased risk of 

### 32

### Draft

– Do Not Cite or Quote 2

- 33 June 2012 O 3 - related health effects. Previous studies have shown that increased exposure to O 3 due 

### 1

to outdoor work leads to increased risk of O 3 - related health effects and it is clear that 

### 2

outd oor workers have higher exposures, and possibly greater internal doses, of O 3 , which 

### 3

may lead to increased risk of O 3 - related health effects. 

### 4

Other potential factors [genetic variants (such as those in GSTM1, HMOX

- 1, NQO1, and 

### 5

TNF

- α ), obesity, sex, and SE S] provided some suggestive evidence of increased risk, but 

### 6

further investigation is needed. Similarly, many factors had inadequate evidence to 

### 7

determine if they increased the risk of O 3 - related health effects, including 

### 8

influenza/infection, COPD, CVD, dia betes, hyperthyroidism, smoking, race/ethnicity, 

### 9

and air conditioning use. 

### 10

2.5.4.2 Exposure Metrics in Epidemiologic Studies

Some epidemiologic studies have conducted analyses between O 3 concentration and 

### 11

health effects (i.e., mortality, respiratory or cardiovascular) using various exposure 

### 12

metrics (i.e., 1

- h max, 8

- h max, and 24

- h avg). No studies of long

- term exposure 

### 13

(i.e., months to years) to O 3 have compared the use of different expo sure metrics on risk 

### 14

estimation. 

### 15

Among time

- series studies, the limited evidence suggests comparable risk estimates 

### 16

across exposure metrics with some evidence for smaller O 3 risk estimates when using a 

### 17

24

- hour average exposure metric. Several panel studies examined whether associations of 

### 18

lung function and respiratory symptoms varied depending on the O 3 exposure metric 

### 19

used. Although differences in effect estimates across exposure metrics were found within 

### 20

some studies, collectively, there was no indication that the consistency or magnitude of 

### 21

the observed association was stronger for a particular O 3 exposure metric. Comparisons 

### 22

of lung function decrements among O 3 exposure metrics were similarly inconsistent in 

### 23

populations without increased outdoor exposure s. It is important to note in these studies, 

### 24

the degree of exposure measurement error associated with use of central site ambient O 3 

### 25

concentrations may vary among O 3 averaging times, depending on time spent outdoors. 

### 26

Among studies that examined association s of multiple respiratory symptoms in children 

### 27

with multiple O 3 exposure metrics, most did not find higher odds ratios for any particular 

### 28

exposure metric. Overall, the evidence from time

- series and panel epidemiologic studies 

### 29

does not indicate that one exp osure metric is more consistently or strongly associated 

### 30

with mortality or respiratory

- related health effects. 

### 31

### Draft

– Do Not Cite or Quote 2

- 34 June 2012 2.5.4.3 Lag Structure in Epidemiologic Studies

Epidemiologic studies have attempted to identify the time

- frame in which exposure to O 3 

### 1

can impart a healt h effect. The time period between O 3 exposure and health effects can 

### 2

potentially be influenced by a multitude of factors, such as age or existence of 

### 3

pre

- existing diseases. Different lag times have been evaluated for specific health 

### 4

outcomes. 

### 5

The epidemio logic evidence evaluated in the 2006 O 3 AQCD indicated that one of the 

### 6

remaining uncertainties in characterizing the O 3 - mortality relationship was identifying 

### 7

the appropriate lag structure (e.g., single

- day lags versus distributed lag model). An 

### 8

examinatio n of lag times used in the epidemiologic studies evaluated in this assessment 

### 9

can provide further insight on the characterization of the relationship between O 3 

### 10

exposure and morbidity and mortality outcomes from epidemiologic studies. 

### 11

The majority of epid emiologic studies that focused on the association between short

- term 

### 12

O 3 exposure and mortality (i.e., all

- cause, respiratory and cardiovascular) examined the 

### 13

average of multiday lags with some studies examining single

- day lags. Across a range of 

### 14

multiday l ags (i.e., average of 0

- 1 to 0

- 6 days), the studies evaluated consistently 

### 15

demonstrate that the O 3 effects on mortality occur within a few days of exposure 

### 16

( Figure 6

- 28 ). 

### 17

Epidemiologic studies of lung function, respiratory symptoms, and biological markers of 

### 18

airway inflammation and oxidative stress examined associations with single

- day ambient 

### 19

O 3 concentrations (using various averaging times) lagged fr om 0 to 7 days as well as 

### 20

concentrations averaged over 2 to 19 days. Lags of 0 and 1 day ambient O 3 

### 21

concentrations were associated with decreases in lung function and increases in 

### 22

respiratory symptoms, airway inflammation, and oxidative stress. Additionall y, several 

### 23

studies found that multiday averages of O 3 concentration were associated with these 

### 24

endpoints, indicating that not only single day, but exposures accumulated over several 

### 25

days led to a respiratory health effect. In studies of respiratory hospita l admissions and 

### 26

ED visits, investigators either examined the lag structure of associations by including 

### 27

both single

- day and the average of multiday lags, or selecting lags a priori. The collective 

### 28

evidence indicates a rather immediate response within the first few days of O 3 exposure 

### 29

(i.e., for lags days averaged at 0

- 1, 0

- 2, and 0

- 3 days) for hospital admissions and ED 

### 30

visits for all respiratory outcomes, asthma, and chronic obstructive pulmonary disease in 

### 31

all

- year and seasonal analyses. 

### 32

### Draft

– Do Not Cite or Quote 2

- 35 June 2012 2.5.4.4 Ozone Concentra tion

- Response Relationship

An important consideration in characterizing the O 3 - morbidity and mortality association 

### 1

is whether the concentration

- response (C

- R) relationship is linear across the full 

### 2

concentration range that is encountered or if there are co ncentration ranges where there 

### 3

are departures from linearity (i.e., nonlinearity). In this ISA studies have been identified 

### 4

that attempt to characterize the shape of the O 3 C

- R curve along with possible O 3 

### 5

“thresholds” (i.e., O 3 concentrations which must b e exceeded in order to elicit an 

### 6

observable health response). The controlled human exposure and epidemiologic studies 

### 7

that examined the shape of the C

- R curve and the potential presence of a threshold have 

### 8

indicated a generally linear C

- R function with no indication of a threshold in analyses 

### 9

that have examined 8

- h max and 24

- h avg O 3 concentrations. However, there is less 

### 10

certainty in the shape of the C

- R curve at the lower end of the distribution of O 3 

### 11

concentrations due to the low density of data in this range. 

### 12

Controlled human exposure studies have provided strong and quantifiable C

- R data on 

### 13

the human health effects of O 3 . The magnitude of respiratory effects in these studies is 

### 14

generally a function of O 3 exposure, i.e., the product of concentration (C), minute 

### 15

ventilation ( V ̇ E ), and exposure duration. Several studies provide evidence for a smooth 

### 16

C

- R curve without indication of a threshold in young healthy adults exposed during 

### 17

moderate exercise for 6 .6 hours to O 3 concentrations between 40 and 120 ppb 

### 18

( Figure 6

- 1 ). It is difficult to characterize the C

- R relationship below 40 ppb due to 

### 19

uncertaint y associated with the sparse data at these lower concentrations. 

### 20

Although relatively few epidemiologic studies have examined the O 3 - health effects C

- R 

### 21

relationship, the C

- R relationship has been examined across multiple health endpoints 

### 22

and exposure durati ons. Some studies of populations engaged in outdoor activity found 

### 23

that associations between O 3 and lung function decrements persisted at lower O 3 

### 24

concentrations with some studies showing larger negative associations in analyses limited 

### 25

to lower O 3 concent rations (e.g., 60

- 80 ppb; Table 6

- 6 ) and shorter exposure durations 

### 26

(i.e., in the range of 30 minutes to less than 8 hours; Table 6

- 6 ). A study examining the 

### 27

C

- R relationship between short

- term O 3 exposure and pediatric asthma ED visits found 

### 28

no evidence of a threshold with a linear relationship evid ent down to 8

- h max O 3 

### 29

concentrations as low as 30 ppb ( Figure 6

- 17 ). In an additional study, authors used a 

### 30

smooth function while also accounting for the potential confounding effects of PM 2.5 , to 

### 31

examine whether the shape of the C

- R curve for short

- term exposure to O 3 and asthma 

### 32

hospital admissions is linear. When comparing the curve to a linear fit, the authors found 

### 33

that the linear fit is a reasonabl e approximation of the C

- R relationship between O 3 and 

### 34

asthma hospital admissions in the mid

- range of the data though it can be seen that there is 

### 35

### Draft

– Do Not Cite or Quote 2

- 36 June 2012 greater uncertainty at the lower end of the distribution of ambient O 3 concentrations, 

### 1

generally below 20 ppb ( Figure 6

- 15 ) due to sparse data at these lower concentrations. 

### 2

Several recent studies applied a variety of s tatistical approaches to examine the shape of 

### 3

the O 3 - mortality C

- R relationship and existence of a threshold (Section 6.6.2.4 ). These 

### 4

studies sugge st that the shape of the O 3 - mortality C

- R curve is linear across the range of 

### 5

O 3 concentrations though uncertainty in the relationship increases at the lower end of the 

### 6

distribution ( Figure 6

- 35 ). Generally, the epidemiologic studies that examined the 

### 7

O 3 - mortality C

- R relationship do not provide evidence for the existence of a threshold 

### 8

within the range of 24

- h average (24

- h avg) O 3 concentrations most commonly observed 

### 9

in the U.S. during the O 3 season (i.e., above 20 ppb). It should be noted that the 

### 10

evaluation of the C

- R relationship for short

- term exposure to O 3 and mortality is difficult 

### 11

due to the evidence from multicity studies indicating highly he terogeneous O 3 - mortality 

### 12

associations across regions of the U.S. In addition, there are numerous issues that may 

### 13

influence the shape of the O 3 - mortality C

- R relationship that need to be taken into 

### 14

consideration including: multiday effects (distributed lags ), and potential adaptation and 

### 15

mortality displacement (i.e., hastening of death by a short period). Additionally, given the 

### 16

effect modifiers identified in mortality analyses that are also expected to vary regionally 

### 17

(e.g., temperature, air conditioning pr evalence), a national or combined analysis may not 

### 18

be appropriate to identify whether a threshold exists in the O 3 - mortality C

- R relationship. 

### 19

In addition, the C

- R relationship of long

- term exposure to O 3 and birth outcomes has 

### 20

been evaluated. Evidence from the southern California Children’s Health Study identified 

### 21

a C

- R relationship of birth weight with 24

- h avg O 3 concentrations averaged over the 

### 22

entire pregnancy that was clearest above the 30 ppb level ( Figure 7

- 4 ). 

### 23

Generally, both short

- and long

- term exposure studies indicate a linear, no threshold C

- R 

### 24

relationship when examining the association be tween O 3 exposure and multiple health 

### 25

effects across the range of 8

- h max and 24

- h avg O 3 concentrations most commonly 

### 26

observed in the U.S. during the O 3 season (i.e., greater than 20 ppb). However, evidence 

### 27

from studies of respiratory health effects and m ortality indicates less certainty in the 

### 28

shape of the C

- R curve at the lower end of the distribution of O 3 data, which corresponds 

### 29

to 8

- h max and 24

- h avg O 3 concentrations generally below 20 ppb. 

### 30

2.5.4.5 Regional Heterogeneity in Risk Estimates

Multicity epidemiologic studies that have examined the relationship between short

- term 

### 31

O 3 exposures and mortality have provided evidence of city

- to

- city and regional 

### 32

heterogeneity in O 3 - mortality risk estimates. A possible explanation for this heterogeneity 

### 33

may be d ifferences in community characteristics (individual

- or community

- level) across 

### 34

### Draft

– Do Not Cite or Quote 2

- 37 June 2012 cities that could modify the O 3 effect. Another possible explanation for the observed 

### 1

heterogeneity could be effect modification by concentrations of other air pollutants or 

### 2

in teractions with temperature or other meteorological factors that vary regionally in the 

### 3

U.S. 

### 4

An examination of community characteristics measured at the individual level that may 

### 5

contribute to the observed heterogeneity in O 3 - mortality risk estimates indic ates increased 

### 6

risk in older adults (i.e., ≥ 65 years of age), women, African American individuals, 

### 7

individuals with pre

- existing diseases/conditions (e.g., diabetes, atrial fibrillation), and 

### 8

lower SES. Furthermore, studies have examined community charac teristics measured at 

### 9

the community level and found that higher O 3 - mortality risk estimates were associated 

### 10

with higher: percent unemployment, fraction of the population Black/African

- American, 

### 11

percent of the population that take public transportation to w ork; and with lower: 

### 12

temperatures and percent of households with central air conditioning. There is also 

### 13

evidence of greater effects in cities with lower mean O 3 concentrations. Additionally, 

### 14

there is evidence of increased risk of O 3 - related mortality as p ercentage unemployed 

### 15

increases and a reduction in O 3 - related mortality as mean temperature increased (i.e., a 

### 16

surrogate for air conditioning rate) in the U.S. The lack of a consistent reduction in 

### 17

O 3 - risk estimates in cities with a higher percentage of cen tral air conditioning across 

### 18

health outcomes complicates the interpretation of the potential modifying effects of air 

### 19

conditioning use. 

### 20

Overall, the epidemiologic studies that have examined the city

- to

- city and regional 

### 21

heterogeneity observed in multicity studies have identified a variety of factors that may 

### 22

modify the O 3 - mortality or

- respiratory hospital admission relationship. Some studies 

### 23

have also examined the correlation with other air pollutants or the potential interactive 

### 24

effects between O 3 and te mperature to explain city

- to

- city heterogeneity in O 3 - mortality 

### 25

risk estimates. This includes evidence that O 3 - mortality risk estimates in the U.S. varied 

### 26

by mean SO 2 concentrations, the ratio between mean NO 2 /PM 10 concentrations, and 

### 27

temperatures. However , studies have not consistently identified specific community 

### 28

characteristics that explain the observed heterogeneity. 

### 29



## 2.6 Integration of Effects on Vegetation and Ecosystems

Chapter 9 presents the most policy

- relevant information related to this review of the 

### 30

NAAQS for the welfare effects of O 3 on vegetation and ecosystems. This section 

### 31

integrates the key findings from the disciplines evaluated in this assessment of the O 3 

### 32

scientific literature, which includes plant physiology, whole plant biology, ecosystems, 

### 33

and exposure

- response. 

### 34

### Draft

– Do Not Cite or Quote 2

- 38 June 2012 Overall, exposure to O 3 is causally related or likely to be causally related to effects 

### 1

observed on vegetation and ecosys tems. These effects are observed across the entire 

### 2

conti nuum of biological organization; from the cellular and subcellular level to the whole 

### 3

plant level, and up to ecosystem

- level processes. Furthermore, there is evidence that the 

### 4

effects observed across this continuum are related to one another; effects of O 3 at lower 

### 5

levels of organization, such as the leaf of an individual plant, can result in effects at 

### 6

higher levels. Ozone enters leaves through stomata, and can alter stomatal conductance 

### 7

and disrupt C O 2 fixation (Section 9.3 ). These effects can change rates of leaf gas 

### 8

exchange, growth and reproduction at the individual plant level and result in changes in 

### 9

ecosystems, such as productivity, C storage, water cycling, nutrient cycling, and 

### 10

community composition (Section 9.4 ). Figure 2

- 3 is a simplified illustrative diagram of 

### 11

the major pathway through which O 3 enters leaves and the major endpoints O 3 may affect 

### 12

in vegetation and ecosystems. 

### 13

The framework for causal determinations (see Preamble) has been applied to the body of 

### 14

scientific evidence to examine effects attributed to O 3 exposure ( Table 2

- 3 ). The 

### 15

summary below provides brief integrated summaries of the evidence that supports the 

### 16

causal determinations. The detailed discussion of the underlying evidence used to 

### 17

formulate each causal determination can be found in Chapter 9 . This summary ends with 

### 18

a short discussion of policy relevant considerations. 

### 19

2.6.1 Visible Foliar Injury

Visible foliar injury resulting from exposure to O 3 has b een well characterized and 

### 20

documented over several decades of research on many tree, shrub, herbaceous, and crop 

### 21

species ( U.S. EPA, 2006b

, 1996b

, 1984

, 1978a ) (Section 9.4.2 ). Ozone

- induced visible 

### 22

foliar injury symptoms on certain bioindicator plant species are considered diagnostic as 

### 23

they have been verified experimentally in exposure

- response studies, using exposure 

### 24

methodologies such as continu ous stirred tank reactors (CSTRs), open

- top chambers 

### 25

(OTCs), and free

- air fumigation. Experimental evidence has clearly established a 

### 26

consistent association of visible injury with O 3 exposure, with greater exposure often 

### 27

resulting in greater and more preva lent injury. Since publication of the 2006 O 3 AQCD, 

### 28

the results of several multiple

- year field surveys of O 3 - induced visible foliar injury at 

### 29

National Wildlife Refuges in Maine, Michigan, New Jersey, and South Carolina have 

### 30

been published. New sensitive sp ecies showing visible foliar injury continue to be 

### 31

identified from field surveys and verified in controlled exposure studies. 

### 32

### Draft

– Do Not Cite or Quote 2

- 39 June 2012 Figure 2

- 3 An illustrative diagram of the major pathway through which ozone enters leaves and the major endpoints that ozone may affect in plants and ecosystems.

O 3 

### exposure

O 3 

### uptake & physiology (Fig 9

- 2)

• Antioxidant metabolism up

- regulated

• Decreased photosynthesis

• Decreased stomatal conductance or sluggish stomatal response



### Effects on leaves

• Visible leaf injury

• Altered leaf production

• Altered leaf chemical composition



### Plant growth (Fig 9

- 8)

• Decreased biomass accumulation

• Altered reproduction

• Altered carbon allocation

• Altered crop quality



### Belowground processes (Fig 9

- 8)

• Altered litter production and decomposition

• Altered soil carbon and nutrient cycling

• Altered soil fauna and microbial communitiesDifferential O3sensitivity



### Affected ecosystem services

• Decreased productivity

• Decreased C sequestration

• Altered water cycling (Fig 9

- 7)

• Altered community composition (i.e., plant, insect & microbe)

### Draft

– Do Not Cite or Quote 2

- 40 June 2012 Table 2

- 3 Summary of ozone causal determinations for vegetation and ecosystem effects.

Vegetation and Ecosystem Effects Co nclusions from 2006 O 3 AQCD Conclusions from

2011 2nd Draft ISA

Visible Foliar Injury Effects on Vegetation Data published since the 1996 O 3 AQCD strengthen previous conclusions that there is strong evidence that current ambient O 3 concentrations cause impaired aesthetic quality of many native plants and trees by increasing foliar injury. Causal Relationship

Reduced Vegetation Growth Data published since the 1996 O 3 AQCD strengthen previous conclusions that there is strong evidence that current ambient O 3 concentrations cause decreased growth and biomass accumulation in annual, perennial and woody plants, including agronomic crops, annuals, shrubs, grasses, and trees. Causal Relationship

Reduced Productivity in

Terrestrial Ecosystems There is evidence that O 3 is an important stressor of ecosystems and

that the effects of O 3 on individual plants and processes are scaled up through the ecosystem, affecting net primary productivity. Causal Relationship

Reduced Carbon (C) Seque stration in Terrestrial Ecosystems Limited studies from previous review Likely to be a Causal Relationship

Reduced Yield and Quality of Agricultural Crops Data published since the 1996 O 3 AQCD strengthen previous conclusions that there is strong evidence that current ambient O 3 concentrations cause decreased yield and/or nutritive quality in a large number of agronomic and forage crops. Causal Relationship

Alteration of Terrestrial Ecosystem Water Cycling Ecosystem water quantity may be affected by O 3 exp osure at the landscape level. Likely to be a Causal Relationship

Alteration of Below

- ground Biogeochemical Cycles Ozone

- sensitive species have well known responses to O 3 exposure, including altered C allocation to below

- ground tissues, and altered rates

o f 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 and inorganic C and N. Causal Relationship

Alteration of Terrestrial Community Composition Ozone may be affecting above

- and below

- ground community composition through impacts on both growth and reproduction. Significa nt changes in plant community composition resulting directly

from O 3 exposure h ave been demonstrated. Likely to be a Causal Relationship

The use of biological indicators in field surveys to detect phytotoxic levels of O 3 is a 

### 1

longstanding and effective methodology. The USDA Forest Service through the Forest 

### 2

Health Monitoring (FHM) Program (1990

- 2001) and currently the Forest Inventory and 

### 3

Analysis (FIA) Program has been collecting data regarding the incidence and severity of 

### 4

visible foliar injury on a variety of O 3 sensitive plant species throughout the U.S. The 

### 5

network has provided evidence that O 3 concentrations were high enough to induce visible 

### 6

symptoms on sensitive vegetation. From repeated observations and measuremen ts made 

### 7

over a number of years, specific geographical patterns of visible O 3 injury symptoms can 

### 8

be identified. In addition, a study assessed the risk of O 3 - induced visible foliar injury on 

### 9

bioindicator plants in 244 national parks in support of the Nation al Park Service’s Vital 

### 10

Signs Monitoring Network. The results of the study demonstrated that the estimated risk 

### 11

of visible foliar injury was high in 65 parks (27%), moderate in 46 parks (19%), and low 

### 12

in 131 parks (54%). Some of the well

- known parks with a high risk of O 3 - induced visible 

### 13

foliar injury include Gettysburg, Valley Forge, Delaware Water Gap, Cape Cod, Fire 

### 14

### Draft

– Do Not Cite or Quote 2

- 41 June 2012 Island, Antietam, Harpers Ferry, Manassas, Wolf Trap Farm Park, Mammoth Cave, 

### 1

Shiloh, Sleeping Bear Dunes, Great Smoky Mountains, Joshua Tre e, Sequoia and Kings 

### 2

Canyon, and Yosemite. Overall, evidence is sufficient to conclude that there is a causal 

### 3

relationship between ambient O 3 exposure and the occurrence of O 3 - induced 

### 4

visible foliar injury on sensitive vegetation across the U.S. 

### 5

2.6.2 Growth, Pr oductivity, Carbon Storage and Agriculture

Ambient O 3 concentrations have long been known to cause decreases in photosynthetic 

### 6

rates and plant growth. The O 3 - induced damages at the plant scale may translate to 

### 7

damages at the stand, then ecosystem scales, a nd cause changes in productivity and C 

### 8

storage. The effects of O 3 exposure on photosynthesis, growth, biomass allocation, 

### 9

ecosystem production, and ecosystem C sequestration were reviewed for the natural 

### 10

ecosystems, and crop productivity and crop quality w ere reviewed for the agricultural 

### 11

ecosystems. 

### 12

2.6.2.1 Natural Ecosystems

The previous O 3 AQCDs concluded that there is strong and consistent evidence that 

### 13

ambient concentrations of O 3 decrease plant photosynthesis and growth in numerous 

### 14

plant species across the U.S. Studies published since the last review continue to support 

### 15

that conclusion (Section 9.4.3.1 ). Recent studies, based on the Aspen free

- air carbon



### 16

dioxide/ozone enrichment (FACE) experiment, found that O 3 caused reductions in total 

### 17

biomass relative to the control in aspen, paper birch, and sugar maple communities 

### 18

during the first seven years of stand development. Overall, the studies at the Aspen FACE 

### 19

experiment were consistent with the open

- top chamber (OTC) studies that were the 

### 20

foundation of previous O 3 NAAQS reviews. These results strengthen the understanding 

### 21

of O 3 e ffects on forests and demonstrate the relevance of the knowledge gained from 

### 22

trees grown in OTC studies. 

### 23

A set of meta

- analyses assessed the effects of O 3 on plant photosynthesis and growth 

### 24

across different species and fumigation methods (such as OTC and FACE). Those studies 

### 25

reported that current O 3 concentrations in the northern hemisphere are decreasing 

### 26

photosynthesis (~11%) across tree species, and the decreases in photosynthesis are 

### 27

consistent with cumulative uptake of O 3 into the leaf. The current amb ient O 3 

### 28

concentrations (~40 ppb averaged across all hours of exposure) decreased annual total 

### 29

biomass growth of forest species by an average of 7%, with potentially greater decreases 

### 30

(11

- 17%) with elevated O 3 exposures (Section 9.4.3.1 ). The meta

- analyses further 

### 31

### Draft

– Do Not Cite or Quote 2

- 42 June 2012 confirmed that reduction of plant photosynthesis and growth under O 3 exposure are 

### 1

coherent across numerous species and various experimental techniques. 

### 2

Studies during recent decades have also demonstrated O 3 alters biomass allocation and 

### 3

plant reproduction (Section 9.4.3 ). Recent meta

- analyses have generally indicated that O 3 

### 4

reduced C allocated to roots. Several recent studies published since the 2006 O 3 AQCD 

### 5

further demonstrate that O 3 altered reproductive processes, such as timing of flowering, 

### 6

number of flowers, fruits and seeds, in herbaceous and woody plant species. However, a 

### 7

knowledge gap still exists pertaining to the exact mechanism of the responses of 

### 8

reproductive processes to O 3 exposure (Section 9.4.3.3 ). 

### 9

Studies at the leaf and plant scales show that O 3 decreased photosynthesis and plant 

### 10

growth, providing coherence and biological plausibili ty for the reported decreases in 

### 11

ecosystem productivity. During the previous NAAQS reviews, there were very few 

### 12

studies that investigated the effect of O 3 exposure on ecosystem productivity and 

### 13

C sequestration. Recent studies from long

- term FACE experiment s and ecosystem 

### 14

models provided evidence of the association of O 3 exposure and reduced productivity at 

### 15

the ecosystem scale. Elevated O 3 reduced stand biomass at Aspen FACE after 7 years of 

### 16

O 3 exposure, and annual volume growth at the Kranzberg Forest in Ge rmany. Results 

### 17

across different ecosystem models were consistent with the FACE experimental 

### 18

evidence, which showed that O 3 reduced ecosystem productivity (Section 9.4.3.4 ). In 

### 19

addition to primary productivity, other indicators such as net ecosystem productivity 

### 20

(NEP), net ecosystem CO 2 exchange (NEE) and C sequestration were often assessed by 

### 21

model studies. Model simulations consistently found that O 3 exposure caused negative 

### 22

impacts on these indicators (Section 9.4.3.4

, Table 9

- 3 ), but the severity of these impacts 

### 23

was influenced by multiple interactions of biological and environmental factors. The 

### 24

suppression of ecosystem C sinks results in more CO 2 accumulation in the atmosphere. A 

### 25

recent st udy suggested that the indirect radiative forcing caused by O 3 exposure through 

### 26

lowering the ecosystem C sink could have an even greater impact on global warming than 

### 27

the direct radiative forcing of O 3

. 

### 28

Although O 3 generally causes negative effects on ecosystem productivity, the magnitude 

### 29

of the response varies among plant communities (Section 9.4.3.4 ). For e xample, O 3 had 

### 30

little impact on white fir, but greatly reduced growth of ponderosa pine in southern 

### 31

California. Ozone decreased net primary production (NPP) of most forest types in the 

### 32

Mid

- Atlantic region, but had small impacts on spruce

- fir forest. Ozone could also affect 

### 33

regional C budgets through interacting with multiple factors, such as N deposition, 

### 34

elevated CO 2 and land use history. Model simulations suggested that O 3 partially offset 

### 35

the growth stimulation caused by elevated CO 2 and N deposition in both Northeast

- and 

### 36

Mid

- Atlantic

- region forest ecosystems of the U.S. 

### 37

### Draft

– Do Not Cite or Quote 2

- 43 June 2012 Overall, evidence is sufficient to conclude that there is a causal relationship between 

### 1

ambient O 3 exposure and reduced native plant growth and productivity, and a likely 

### 2

causal relation ship between O 3 exposure and reduced carbon sequestration in 

### 3

terrestrial ecosystems. 

### 4

2.6.2.2 Agricultural Crops

The detrimental effect of O 3 on crop production has been recognized since the 1960’s and 

### 5

a large body of research has subsequently stemmed from those in itial findings. Previous 

### 6

O 3 AQCDs have extensively reviewed this body of literature. Current O 3 concentrations 

### 7

across the U.S. are high enough to cause yield loss for a variety of agricultural crops 

### 8

including, but not limited to, soybean, wheat, potato, wa termelon, beans, turnip, onion, 

### 9

lettuce, and tomato (Section 9.4.4.1 ). Continued increases in O 3 concentration may 

### 10

further decrease yield in these s ensitive crops. Despite the well

- documented yield losses 

### 11

due to increasing O 3 concentration, there is still a knowledge gap pertaining to the exact 

### 12

mechanism of O 3 - induced yield loss. Research has linked increasing O 3 concentration to 

### 13

decreased photosynthe tic rates and accelerated senescence, which are related to yield. 

### 14

In addition, recent research has highlighted the effects of O 3 on crop quality. Increasing 

### 15

O 3 concentration decreases nutritive quality of grasses, decreases macro

- and micro



### 16

nutrient concen trations in fruits and vegetable crops, and decreases cotton fiber quality. 

### 17

These areas of research require further investigation to determine the mechanism and 

### 18

dose

- responses (Section 9.4.4.2 ). 

### 19

During the previous NAAQS reviews, there were very few studies that estimated O 3 

### 20

impacts on crop yields at large geographical scales (i.e., regional, national or global). 

### 21

Recent modeling studies found that O 3 generally reduced crop yield, but the impacts 

### 22

varied across regions and crop species (Section 9.4.4.1 ). For example, the largest 

### 23

O 3 - induced crop yi eld losses occurred in high

- production areas exposed to high O 3 

### 24

concentrations, such as the Midwest and the Mississippi Valley regions of the U.S. 

### 25

Among crop species, the estimated yield loss for wheat and soybean were higher than 

### 26

rice and maize. Satellite and ground

- based O 3 measurements have been used to assess 

### 27

yield loss caused by O 3 over the continuous tri

- state area of Illinois, Iowa, and 

### 28

Wisconsin. The results showed that O 3 concentrations reduced soybean yield, which 

### 29

correlates well with the previous results from FACE

- and OTC

- type experiments 

### 30

(Section 9.4.4.1 ). 

### 31

Evidence is sufficient to conclude that there is a causal relationship between O 3 

### 32

exposure and reduced yield and quality of agricultural crops. 

### 33

### Draft

– Do Not Cite or Quote 2

- 44 June 2012 2.6.3 Water Cycling

Ozone can affect water use in plants and ecosystems through several mechanisms 

### 1

including damage to stomatal functioning and loss of leaf area. Section 9.3.6 reviewed 

### 2

possible mechanisms for O 3 exposure effects on stomatal functioning. Regardless of the 

### 3

mechanism, O 3 exposure has been shown to alter stomatal performance, which may affect 

### 4

plant and stand transpiration and therefore possibly affecting hydrological cycling. 

### 5

Although the evidence was from a limited number of field and modeling studies, these 

### 6

findings showed an association of O 3 exposure and the alteration of water use and cycling 

### 7

in vegetation and ecosystems (Section 9.4.5 ). There is not a clear consensus on the nature 

### 8

of leaf

- level stomatal conductance response to O 3 exposure. When measured at steady



### 9

state high light conditions, leaf

- level stomatal conductance is often found to be reduced 

### 10

when exposed to O 3 . However, measurements of stomatal conductance under dynamic 

### 11

light and vapor pressure deficit cond itions indicate sluggish responses under elevated O 3 

### 12

exposure which could potentially lead to increased water loss from vegetation. In 

### 13

situations where stomata fail to close under low light or water stressed conditions water 

### 14

loss may be greater over time. In other situations it is possible that sluggish stomata may 

### 15

fail to completely open in response to environmental stimuli and result in decreased water 

### 16

loss. Field studies suggested that peak hourly O 3 exposure increased the rate of water loss 

### 17

from several tree species, and led to a reduction in the late

- season modeled stream flow in 

### 18

three forested watersheds in eastern Tennessee. Sluggish stomatal responses during O 3 

### 19

exposure was suggested as a possible mechanism for increased water loss during peak O 3 

### 20

exp osure. Currently, the O 3 - induced reduction in stomatal aperture is the biological 

### 21

assumption for most process

- based models. Therefore, results of those models normally 

### 22

found that O 3 reduced water loss. For example, one study found that O 3 damage and 

### 23

N limi tation together reduced evapotranspiration and increase runoff. 

### 24

Although the direction of the response differed among studies, the evidence is sufficient 

### 25

to conclude that there is likely to be a causal relationship between O 3 exposure and 

### 26

the alteration of ecosystem water cycling. 

### 27

2.6.4 Below

- Ground Processes

Below

- ground processes are tightly linked with aboveground processes. The responses of 

### 28

aboveground process to O 3 exposure, such as reduced photosynthetic rates, increased 

### 29

metabolic cost, and reduced root C a llocation, have provided biologically plausible 

### 30

mechanisms for the alteration of below

- ground processes. Since the 2006 O 3 AQCD, 

### 31

more evidence has shown that although the responses are often species specific, O 3 

### 32

### Draft

– Do Not Cite or Quote 2

- 45 June 2012 altered the quality and quantity of C input to soil, microbial community composition, and 

### 1

C and nutrient cycling. 

### 2

Results from Aspen FACE and other experimental studies consistently found that O 3 

### 3

reduced litter production and altered C chemistry, such as soluble sugars, soluble 

### 4

phenolics, condensed tannins, lignin, and macro/micro nutrient concentration in litter 

### 5

(Section 9.4.6.1 ). Under elevated O 3 , the changes in substrate quality and quant ity could 

### 6

alter microbial metabolism, and therefore soil C and nutrient cycling. Several studies 

### 7

indicated that O 3 generally suppressed soil enzyme activities (Section 9.4.6.2 ). However, 

### 8

the impact of O 3 on litter decomposition was inconsistent and varied among species, 

### 9

sites, and exposure length. Similarly, O 3 had inconsistent impacts on dynamics of micro 

### 10

and macro nutrients (Section 9.4.6.4 ). 

### 11

Studies from the Aspen FACE experiment suggested that the response of below

- ground 

### 12

C cycle to O 3 exposure, such as litter decomposition, soil respiration , and soil C content, 

### 13

changed over time. For example, in the early part of the experiment (1998

- 2003), O 3 had 

### 14

no impact on soil respiration but reduced the formation rates of total soil C under 

### 15

eleva ted CO 2 . However, after 10 to 11 years of exposure, O 3 was found to increase soil 

### 16

respiration but have no substantial impact on soil C formation under elevated CO 2 

### 17

(Section 9.4.6.3 ). 

### 18

The evidence is sufficient to infer that there is a causal relationship between O 3 

### 19

exposure and the alteration of below

- ground biogeochemical cycles. 

### 20

2.6.5 Community Composition

In the 2006 O 3 AQCD, the impact of O 3 exposure o n species competition and community 

### 21

composition was assessed. Ozone was found to be one of the dominant factors causing a 

### 22

decline in ponderosa and Jeffrey pine in the San Bernardino Mountains in southern 

### 23

California. Ozone exposure also tended to shift the grass

- legume mixtures in favor of 

### 24

grass species. Since the 2006 O 3 AQCD, more evidence has shown that O 3 exposure 

### 25

changed the competitive interactions and led to loss of O 3 sensitive species or genotypes. 

### 26

Studies found that the severity of O 3 damage on gro wth, reproduction and foliar injury 

### 27

varied among species (Section 9.4.3 ), which provided the biological plausibility for the 

### 28

alteration of communit y composition. Additionally, research since the last review has 

### 29

shown that O 3 can alter community composition and diversity of soil microbial 

### 30

communities. 

### 31

The decline of conifer forests under O 3 exposure was continually observed in several 

### 32

regions. Ozone d amage was believed to be an important causal factor in the dramatic 

### 33

### Draft

– Do Not Cite or Quote 2

- 46 June 2012 decline of sacred fir in the valley of Mexico, a s well as cembran pine in southern France 

### 1

and the Carpathian Mountains, although several factors, such as drought, insect outbreak 

### 2

and fores t management, may also contribute to or even be the dominant factors causing 

### 3

the mortality of the conifer trees. Results from the Aspen FACE site indicated that O 3 

### 4

could alter community composition of broadleaf forests as well. At the Aspen FACE site, 

### 5

O 3 reduced growth and increased mortality of a sensitive aspen clone, while the O 3 

### 6

tolerant clone emerged as the dominant clone in the pure aspen community. In the mixed 

### 7

aspen

- birch and aspen

- maple communities, O 3 reduced the competitive capacity of aspen 

### 8

co mpared to birch and maple (Section 9.4.7.1 ). 

### 9

The tendency for O 3 - exposure to shift the biomass of grass

- legume mixtures in favor of 

### 10

grass species wa s reported in the 2006 O 3 AQCD and has been generally confirmed by 

### 11

recent studies. However, in a high elevation mature/species

- rich grass

- legume pasture, O 3 

### 12

fumigation showed no substantial impact on community composition (Section 9.4.7.2 ). 

### 13

Ozone exposure not only altered community composition of plant species, but also 

### 14

microorganisms. The shift in community composition of bacteria and fungi has been 

### 15

observed in both natural and agricultural ecosystems, although no general patterns could 

### 16

be identified (Section 9.4.7.3 ). 

### 17

The evidence is sufficie nt to conclude that there is likely to be a causal relationship 

### 18

between O 3 exposure and the alteration of community composition of some 

### 19

ecosystems. 

### 20

2.6.6 Policy Relevant Considerations

2.6.6.1 Air Quality Indices

Exposure indices are metrics that quantify exposure as it relates to measured plant injury 

### 21

(e.g., reduced growth). They are summary measures of monitored ambient O 3 

### 22

concentrations over time intended to provide a consistent metric for reviewing and 

### 23

comparing exposure

- response effects obtained from various studies . No recent 

### 24

information is available since 2006 that alters the basic conclusions put forth in the 2006 

### 25

and 1996 O 3 AQCDs. These AQCDs focused on the research used to develop various 

### 26

exposure indices to help quantify effects on growth and yield in crops, p erennials, and 

### 27

trees (primarily seedlings). The performance of indices was compared through regression 

### 28

analyses of earlier studies designed to support the estimation of predictive O 3 exposure



### 29

response models for growth and/or yield of crops and tree (seedl ing) species. 

### 30

### Draft

– Do Not Cite or Quote 2

- 47 June 2012 Another approach for improving risk assessment of vegetation response to ambient O 3 is 

### 1

based on determining the O 3 concentration from the atmosphere that enters the leaf 

### 2

(i.e., flux or deposition). Interest has been increasing in recent years , particularly in 

### 3

Europe, in using mathematically tractable flux models for O 3 assessments at the regional, 

### 4

national, and European scale. While some efforts have been made in the U.S. to calculate 

### 5

O 3 flux into leaves and canopies, little information has be en published relating these 

### 6

fluxes to effects on vegetation. There is also concern that not all O 3 stomatal uptake 

### 7

results in a yield reduction, which depends to some degree on the amount of internal 

### 8

detoxification occurring with each particular species. Species having high detoxification 

### 9

capacity may show little relationship between O 3 stomatal uptake and plant response. The 

### 10

lack of data in the U.S. and the lack of understanding of detoxification processes have 

### 11

made this technique less viable for vulnerability and risk assessments in the U.S. 

### 12

The main conclusions from the 1996 and 2006 O 3 AQCDs regard ing indices based on 

### 13

ambient exposure remain valid. These key conclusions can be restated as follows: 

### 14

 O 3 effects in plants are cumulative; 

### 15

 higher O 3 concentrations appear to be more important than lower 

### 16

concentrations in eliciting a response; 

### 17

 plant sensiti vity to O 3 varies with time of day and plant development stage; 

### 18

and 

### 19

 quantifying exposure with indices that cumulate hourly O 3 concentrations and 

### 20

preferentially weight the higher concentrations improves the explanatory 

### 21

power of exposure/response models for growth and yield, over using indices 

### 22

based on mean and peak exposure values. 

### 23

Various weighting functions have been used, including threshold

- weighted 

### 24

(e.g., SUM06) and continuous sigmoid

- weighted (e.g., W126) functions. Based on 

### 25

statistical goodness

- of

- fit tests, these cumulative, concentration

- weighted indices could 

### 26

not be differentiated from one another using data from previous exposure studies. 

### 27

Additional statistical forms for O 3 exposure indices are summarized in Section 9.5 of this 

### 28

ISA. The majority of studies published since the 2006 O 3 AQCD do not change earlier 

### 29

conclusions, including the importance of peak concentrations, and the duration and 

### 30

occurrence of O 3 exposures in altering plant growth and yield. 

### 31

Given the current state of knowledge and the best available data, exposure indices that 

### 32

cumulate and differentially weight the higher hourly average concentrations and also 

### 33

include the mid

- leve l values continue to offer the most defensible approach for use in 

### 34

developing response functions and comparing studies, as well as for defining future 

### 35

indices for vegetation protection. 

### 36

### Draft

– Do Not Cite or Quote 2

- 48 June 2012 2.6.6.2 Exposure

- Response

None of the information on effects of O 3 on vegetati on published since the 2006 O 3 

### 1

AQCD has modified the assessment of quantitative exposure

- response relationships that 

### 2

was presented in that document ( U.S. EPA, 2006b ) . This assessment updates the 2006 

### 3

exposure

- response models by computing them using the W126 metric, cumulated over 

### 4

90 days. Almost all of the experiment al research on the effects of O 3 on growth or yield 

### 5

of plants published since 2006 used only two levels of exposure. In addition, hourly O 3 

### 6

concentration data that would allow calculations of exposure using the W126 metric are 

### 7

generally unavailable. Howeve r, two long

- term experiments, one with a crop species 

### 8

(soybean), one with a tree species (aspen), have produced data that are used in 

### 9

Section 9.6 t o validate the exposure

- response models presented in the 2006 O 3 AQCD, 

### 10

and the methodology used to derive them. EPA compared predictions from the models 

### 11

presented in the 2006 O 3 AQCD, updated to use the 90 day 12hr W126 metric, with more 

### 12

recent observation s for yield of soybean and biomass growth of trembling aspen. The 

### 13

models were parameterized using data from the National Crop Loss Assessment Network 

### 14

(NCLAN) and EPA’s National Health and Environmental Effects Research Laboratory

– 

### 15

Western Ecology Division (NHEERL

- WED) projects, which were conducted in OTCs. 

### 16

The more recent observations were from experiments using FACE technology, which is 

### 17

intended to provide conditions closer to natural environments than OTC. Observations 

### 18

from these new experiments were ex ceptionally close to predictions from the models. 

### 19

The accuracy of model predictions for two widely different plant species, grown under 

### 20

very different conditions, provides support for the validity of the models for crops and 

### 21

trees developed using the same methodology and data for other species. However, 

### 22

variability observed among species in the NCLAN and NHEERL

- WED projects indicates 

### 23

that the range of sensitivity between and among species is likely quite wide. 

### 24

Results from several meta

- analyses have provided approximate values for responses of 

### 25

yield of soybean, wheat, rice and other crops under broad categories of exposure, relative 

### 26

to charcoal

- filtered air. Additional reports have summarized yield data for six crop 

### 27

species under various broad comparative exposure categories, and reviewed 263 studies 

### 28

that reported effects on tree biomass. However, these analyses have proved difficult to 

### 29

compare with exposure

- response models, especially given that exposure was not 

### 30

expressed using a common metric (i.e., W126). 

### 31

### Draft

– Do Not Cite or Quote 2

- 49 June 2012 

## 2.7 The Role of Tropospheric Ozone in Climate Change and UV

- B

Effects

Atmospheric O 3 plays an important role in the Earth’s energy budget by interacting with 

### 1

incoming solar radiation and outgoing infrared radiati on. Tropospheric O 3 makes up only 

### 2

a small portion of the total column of O 3 , but it has important incremental effects on the 

### 3

overall radiation budget. Chapter 10 assesses the specific role of tropospheric O 3 in the 

### 4

earth’s radiation budget and how perturbations in tropospheric O 3 might affect (1) climate 

### 5

through its role as a greenhouse gas, and (2) health, ecology and welfare through its role 

### 6

in shi elding the earth’s surface from solar ultraviolet (UV) radiation. 

### 7

2.7.1 Tropospheric Ozone as a Greenhouse Gas

Ozone is an important greenhouse gas, and increases in its abundance in the troposphere 

### 8

may contribute to climate change according to the 2007 climate assessment by the 

### 9

Intergovernmental Panel on Climate Change (IPCC). Models calculate that the global 

### 10

burden of tropospheric O 3 has doubled since the pre

- industrial era, while observations 

### 11

indicate that in some regions O 3 may have increased by factors as gr eat as 4 or 5. These 

### 12

increases are tied to the rise in emissions of O 3 precursors from human activity, mainly 

### 13

fossil fuel consumption and agricultural processes. 

### 14

Figure 2

- 4 shows the main steps involved in the influence of tropospheric O 3 on climate. 

### 15

Emissions of O 3 precursors including CO, VOCs, CH 4 , and NO X lead to production of 

### 16

tropospheric O 3 . A change in the abundance of tropospheric O 3 perturbs th e radiative 

### 17

balance of the atmosphere, an effect quantified by the radiative forcing (RF) metric. The 

### 18

earth

- atmosphere

- ocean system responds to the forcing with a climate response, typically 

### 19

expressed as a change in surface temperature. Finally, the climat e response causes 

### 20

downstream climate

- related health and ecosystem impacts, such as redistribution of 

### 21

diseases or ecosystem characteristics due to temperature changes. Feedbacks from both 

### 22

the climate response and downstream impacts can, in turn, affect the abundance of 

### 23

tropospheric O 3 and O 3 precursors through multiple feedback mechanisms as indicated in 

### 24

Figure 2

- 4 . Direct feedbacks are discussed in Sect ion 10.3.2.4 while downstream climate 

### 25

impacts and their feedbacks are extremely complex and outside the scope of this 

### 26

assessment. 

### 27

### Draft

– Do Not Cite or Quote 2

- 50 June 2012 Note: Units shown are those typical for each quantity illustrated. Feedb acks from both the climate response and climate impacts can, in turn, affect the abundance of tropospheric O 3 and O 3 precursors through multiple feedback mechanisms. Climate impacts are deemphasized in the figure since these downstream effects are extremel y complex and outside the scope of this assessment.



### Figure 2

- 4 Schematic illustrating the effects of tropospheric ozone on climate ; including the relationship between precursor emissions, tropospheric ozone abundance, radiative forcing, climate response, and climate impacts. Tropospheric Ozone and UV

- B related effects

The impact of the tropospheric O 3 change since pre

- industrial times on climate has been 

### 1

estimated to be about 25

- 40% of the anthropogenic CO 2 impact and about 75% of the 

### 2

anthropogenic CH 4 impact according to the IPCC, ranking it third in importance among 

### 3

the greenhouse gases. There are large uncertainties in the RF estimate attributed to 

### 4

tropospheric O 3 , making the impact of tropospheric O 3 on c limate more uncertain than 

### 5

the impact of the long

- lived greenhouse gases. Overall, the evidence supports a causal 

### 6

relationship between changes in tropospheric O 3 concentrations and radiative 

### 7

forcing. 

### 8

RF does not take into account the climate feedbacks that could amplify or dampen the 

### 9

actual surface temperature response. Quantifying the change in surface temperature 

### 10

requires a complex climate simulation in which all important feedbacks and interactions 

### 11

are accounted for. As these processes are not well under stood or easily modeled, the 

### 12

surface temperature response to a given RF is highly uncertain and can vary greatly 

### 13

among models and from region to region within the same model. In light of these 

### 14

uncertainties, the evidence indicates that there is likely to b e a causal relationship 

### 15

between changes in tropospheric O 3 concentrations and effects on climate. 

### 16

### Draft

– Do Not Cite or Quote 2

- 51 June 2012 2.7.3 Tropospheric Ozone and UV

- B Related Effects

UV radiation emitted from the Sun contains sufficient energy when it reaches the Earth to 

### 1

break (photolyze) chemical bonds in molecules, thereby leading to damaging effects on 

### 2

living organisms and materials. Atmospheric O 3 plays a crucial role in reducing exposure 

### 3

to solar UV radiation at the Earth’s surface. Ozone in the stratosphere is responsible for 

### 4

the majo rity of this shielding effect, as approximately 90% of total atmospheric O 3 is 

### 5

located there over mid

- latitudes. Ozone in the troposphere provides supplemental 

### 6

shielding of radiation in the wavelength band from 280

- 315 nm, referred to as UV

- B 

### 7

radiation. UV

- B radiation has important effects on human health and ecosystems, and is 

### 8

associated with materials damage. 

### 9

H uman health effects associated with solar UV

- B radiation exposure include erythema, 

### 10

skin cancer, ocular damage, and immune system suppression. A po tential human health 

### 11

benefit of increased UV

- B exposure involves the UV

- induced production of vitamin D 

### 12

which may help reduce the risk of metabolic bone disease, type I diabetes, mellitus, and 

### 13

rheumatoid arthritis, and may provide beneficial immunomodulato ry effects on multiple 

### 14

sclerosis, insulin

- dependent diabetes mellitus, and rheumatoid arthritis. E cosystem and 

### 15

materials damage effects associated with solar UV

- B radiation exposure include 

### 16

terrestrial and aquatic ecosystem impacts, alteration of biogeoche mical cycles, and 

### 17

degradation of man

- made materials. 

### 18

There is a lack of published studies that critically examine the incremental health or 

### 19

welfare effects (adverse or beneficial) attributable specifically to changes in UV

- B 

### 20

exposure resulting from pertur bations in tropospheric O 3 concentrations. The effects are 

### 21

expected to be small and they cannot yet be critically assessed within reasonable 

### 22

uncertainty. Overall, the evidence is inadequate to determine if a causal relationship 

### 23

exists between changes in tr opospheric O 3 concentrations and effects on health 

### 24

and welfare related to UV

- B shieldin g

. 

### 25



## 2.8 Summary of Causal Determinations for Health Effects and

Welfare Effects

This chapter has provided an overview of the underlying evidence used in making the 

### 26

causal det erminations for the health and welfare effects of O 3 . This review builds upon 

### 27

the conclusions of the previous AQCDs for O 3

. 

### 28

The evaluation of the epidemiologic, toxicological, and controlled human exposure 

### 29

studies published since the completion of the 200 6 O 3 AQCD have provided additional 

### 30

evidence for O 3 - related health outcomes. Table 2

- 4 provides an overview of the causal 

### 31

### Draft

– Do Not Cite or Quote 2

- 52 June 2012 determinations for all of the health outcomes evaluated. Causal determinations for O 3 and 

### 1

welfare effects are included in Table 2

- 5 , while causal determinations for climate change 

### 2

and UV

- B effects are in Table 2

- 6 . Detailed discussions of the scientific evidence and 

### 3

rationale for these causal determinations are provided in subsequent chapters of this ISA. 

### 4

Table 2

- 4 Summary of ozone causal determinations by exposure duration

and health outcome.

Health Outcome Conclusions from 2006 O 3 AQCD Conclusions from

2012 3rd Draft ISA

Short

- Term Exposure to O 3

Respiratory effects The overall evidence supports a causal relationship between acute ambient

O 3 exposures and increased respiratory morbidity outcomes. Causal Relationship

Cardiovascular effects The limited evidence is highly suggestive that O 3 directly and/or indirectly

contributes to cardiovascular

- related morbidity, but much remains to be done

t o more fully substantiate the association. Suggestive of a Causal Relationship

Central nervous system effects Toxicological studies report that acute exposures to O 3 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

Total Mortality The evidence is highly suggestive that O 3 directly or indirectly contributes to

non

- accidental and cardiopulmonary

- related mortality. Likely to be a Causal Relationship

Long

- term Exposure to O 3

Respiratory effects The current evidence is suggestive but inconclusive for respiratory health effects from long

- term O 3 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 O 3 effects. Suggestive of a Causal Relationship

Central nervous system effects Evidence regarding chronic exposure and neurobehavioral effects was not

available. Suggestive of a Causal Relationship

Cancer Little evidence for a relationship between chronic O 3 exposure and increased risk of lung cancer. Inadequate to infer a Causal Relationship

Total Mortality There is little evidence to suggest a causal relationship between chronic O 3 exposure and i ncreased risk for mortality in humans. Suggestive of a Causal Relationship

### Draft

– Do Not Cite or Quote 2

- 53 June 2012 Table 2

- 5 Summary of ozone causal determination for welfare effects.

Vegetation and Ecosystem Effects Conclusions from 2006 O 3 AQCD Conclusions from

2012 3rd Draft ISA

Visible Foliar Injury Effects on Vegetation Data published since the 1996 O 3 AQCD strengthen previous conclusions that there is strong evidence that current ambient O 3 concentrations cause impaired aesthetic quality o f many native plants and trees by increasing foliar injury. Causal Relationship

Reduced Vegetation Growth Data published since the 1996 O 3 AQCD strengthen previous conclusions that there is strong evidence that current ambient O 3 concentrations cause decr eased growth and biomass accumulation in annual, perennial and woody plants, including agronomic crops, annuals, shrubs, grasses, and trees. Causal Relationship

Reduced Productivity in Terrestrial Ecosystems There is evidence that O 3 is an important stres sor of ecosystems and

that the effects of O 3 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

Reduced Yield and Quality of Agricultural Crops Data published since the 1996 O 3 AQCD strengthen previous conclusions that there is strong evidence that current ambient O 3 concentrations cause decreased y ield and/or nutritive quality in a large number of agronomic and forage crops. Causal Relationship

Alteration of Terrestrial Ecosystem Water Cycling Ecosystem water quantity may be affected by O 3 exposure at the landscape level. Likely to be a Causal

Rela tionship

Alteration of Below

- ground Biogeochemical Cycles Ozone

- sensitive species have well known responses to O 3 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 and inorganic C and N. Causal Relationship

Alteration of Terrestrial Community Composition Ozone may be affecting above

- and be low

- ground community composition through impacts on both growth and reproduction. Significa nt changes in plant community composition resulting directly

from O 3 exposure have been demonstrated. Likely to be a Causal Relationship



### Table 2

- 6 Summary of ozone causal determination for climate and UV

- B

effects.

Effects Conclusions from 2006 O 3 AQCD Conclusions from

2012 3rd Draft ISA

Radiative Forcing Climate forcing by O 3 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 O 3 await further advances in monitoring and chemical transport modeling, the overall body of scientific evidence suggests that high

concentrations of O 3 on the regional scale could have a discernible influence on climate, leading to surface temperature and hydrological cycle changes. Likely to be a Causal

Re lationship

Health and Welfare

Effects Related to UV

- B Shielding 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 O 3 concentrations on UV

- induced health outcomes cannot yet be critically assessed within reasonable uncertainty. Inadequate to

Determine if a Causal Relationship Exists

### Draft

– Do Not Cite or Quote 2

- 54 June 2012 

### References

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