United States
Environmental Protection
Jf lkAgency
EPA/600/R-20/012
April 2020
www.epa.gov/isa
Integrated Science Assessment for
Ozone and Related Photochemical
Oxidants
April 2020
Center for Public Health and Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Research Triangle Park, NC

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EXECUTIVE SUMMARY
ES.1 Purpose and Scope of the Integrated Science Assessment
This Integrated Science Assessment (ISA)1 is a comprehensive evaluation and synthesis of the
policy-relevant science aimed at characterizing the health and welfare2 effects caused by ozone. It
communicates critical science judgments of the health-based and welfare-based criteria for ozone and
related photochemical oxidants in ambient air. In 2015, the U.S. EPA lowered the health- and
welfare-based National Ambient Air Quality Standards (NAAQS) for ozone to 0.070 ppm (annual
fourth-highest daily max 8-hour concentration averaged over 3 years3). The health-based ozone NAAQS
is meant to protect public health, including at-risk populations such as children and people with asthma,
with an adequate margin of safety. The welfare-based ozone standard is intended to protect the public
welfare from known or anticipated adverse effects associated with the presence of ozone in ambient air.
The ISA identifies and critically evaluates the most policy-relevant scientific literature across
scientific disciplines, including epidemiology, controlled human exposure studies, animal toxicology,
atmospheric science, exposure science, vegetation studies, agricultural science, ecology, and
climate-related science. Key scientific conclusions (e.g., causality determinations; Section ES.4) are
presented and explained. These conclusions provide the scientific basis for developing risk and exposure
analyses, policy evaluations, and policy decisions for the review. This ISA draws conclusions about the
causal nature of the relationships between ozone exposure and health and welfare effects by integrating
recent evidence across scientific disciplines with the evidence base evaluated in previous reviews. U.S.
EPA engages the Clean Air Scientific Advisory Committee (CASAC) as an independent federal advisory
committee to conduct peer reviews of draft ISA and other materials. Peer review comments provided by
the CASAC and public comments about the external review draft were considered in the development of
this ISA (Section 10.4). The ISA thus provides the policy-relevant scientific information necessary to
conduct a review of the NAAQS.
This Executive Summary provides an overview of the important conclusions drawn in the ISA
across scientific disciplines, beginning with information on sources, concentrations, estimated
background concentrations of ozone and ozone exposure, followed by health and welfare effects. A more
detailed summary of the evidence is presented in the Integrated Synthesis, and individual Appendices for
1	The general process for developing an ISA, including the framework for evaluating weight of evidence and
drawing scientific conclusions and causality determinations, is described in a companion document, Preamble to the
Integrated Science Assessments (U.S. EPA. 20151. www.epa.gov/isa.
2	Under Clean Air Act section 302(h), effects on welfare include, but are not limited to, "effects on soils, water,
crops, vegetation, manmade materials, animals, wildlife, weather, visibility, and climate, damage to and
deterioration of property, and hazards to transportation, as well as effects on economic values and on personal
comfort and well-being."
3	Final rule signed October 1, 2015, and effective December 28, 2015 (80 FR 65291).
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each topic area include study-level information and an in-depth characterization of the weight-of-evidence
conclusions.
ES.2 Ozone in Ambient Air
The general photochemistry of tropospheric ozone is well-established. Ozone is produced in
urban areas and downwind of sources mainly by the reaction of volatile organic compounds (VOCs) with
oxides of nitrogen (NOx) in the presence of sunlight, and outside of polluted areas mainly by reactions of
carbon monoxide (CO) and methane (CH4) with NOx (Section 1.4). Recent developments in
understanding ozone chemistry include observations of higher ozone concentrations during the winter in
some western U.S. mountain basins (Section 1.4.1) and new research on the role of marine halogen
chemistry in suppressing coastal ozone concentrations (Section 1.4.2). Air monitoring data for the period
2015-2017 show that U.S. daily max 8-hour avg concentrations of ozone (MDA8) are higher in spring
and summer (median = 46 ppb) than in autumn (median = 38 ppb) and winter (median = 34 ppb).
Figure ES-1 shows the highest values of the 3-year avg of annual fourth-highest MDA8 ozone
concentrations (design values above 70 ppb) occur in central and southern California, Arizona, Colorado,
Utah, Texas, along the shore of Lake Michigan, and in the Northeast Corridor, typically during the ozone
season between May and September (Section 1.2.1.1).
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2015-2017 Ozone Design Values
• 43-60 ppb (179 sites) O 66 - 70 ppb (334 sites) • 76 -112 ppb (110 sites)
O 61-65 ppb (378 sites) © 71-75 ppb (136 sites)
Figure ES-1 Individual monitor ozone concentrations in terms of design
values (i.e., 3-year avg of annual fourth-highest max daily 8-hour
avg ozone concentration) for 2015-2017.
A better understanding of the origins of ground-level U.S. background (USB) ozone and its
concentration trends has emerged since the 2013 Ozone ISA. USB ozone concentration is defined as the
ozone concentration that would occur if all U.S. anthropogenic ozone precursor emissions were removed
(Section IS.2.2). Major contributors to USB ozone concentrations are stratospheric exchange,
international transport, wildfires, lightning, global methane emissions, and natural biogenic and geogenic
precursor emissions. Ozone monitors cannot discern the portion of ambient ozone concentrations that
come from USB. Instead, USB concentrations are estimated using photochemistry and transport models.
The estimates of USB ozone concentrations include uncertainties of about 10 ppb for seasonal average
concentrations, with higher uncertainty for MDA8 concentrations. Models consistently estimate higher
USB ozone concentrations at higher elevations of the western U.S. than in the eastern U.S. or along the
Pacific coast. The estimated seasonal pattern in USB ozone concentrations tends to indicate lower USB in
the summer than during the rest of the year. Several modeling studies using different approaches indicate
that for MDA8 concentrations above 50-60 ppb, USB concentration estimates generally do not increase
with increasing total ozone concentration (i.e., USB ozone concentrations are no higher on high ozone
days than on low or moderate ozone days). The temporal trend in estimated USB ozone concentrations
indicates increasing concentrations at high elevation western U.S. sites through approximately 2010.
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Recently, however, this trend has shown signs of slowing or even reversing, possibly due to decreasing
East Asian precursor emissions.
ES.3 Exposure to Ozone
Ambient air ozone concentrations, either measured at fixed-site monitors or estimated by models,
are often used as surrogates for personal exposure in epidemiologic studies. Exposure measurement error
can lead to reduced precision and an underestimation of the association between short-term ambient
ozone exposure and a health effect (Section 2.6.1). For studies of long-term exposure, the true effect of
exposure to ambient ozone may be underestimated or overestimated when the exposure model
respectively overestimates or underestimates ozone exposure. It is much more common for the effect to
be underestimated, and bias in the effect estimate is typically small in magnitude (Section 2.6.2). The
availability and sophistication of models to predict ambient ozone concentrations to estimate exposure
have increased substantially in recent years (Section 2.3.2). For effects elicited by ozone, the use of
exposure estimates that do not account for population behavior and mobility (e.g., via use of time-activity
data) may result in underestimation of the true effect and reduced precision (Section 2.4.1).
Tropospheric ozone can cause plant damage, which can then have negative impacts on terrestrial
ecosystems as shown in observational and controlled exposure studies and in models using experimental
data to extrapolate to effects at the community and ecosystem scale. Robust exposure indices that quantify
exposure as it relates to measured plant response (e.g., growth) have been in use for decades and are
derived from hourly ozone concentrations. Exposure duration influences the degree of plant response, and
ozone effects on plants are cumulative. Cumulative indices summarize ozone concentrations overtime
and provide a consistent metric for reviewing and comparing exposure-response effects obtained from
various studies. Cumulative indices of exposure that differentially weight hourly concentrations have
been found to be best suited to characterize vegetation exposure to ozone with regard to reductions in
vegetation growth and yield (Section 8.1.2.1).
ES.4 Health and Welfare Effects of Ozone Exposure
Broad health and welfare effect categories are evaluated independently in the Appendices of this
ISA. Determinations are made about causation by evaluating evidence across scientific disciplines and are
based on judgments of consistency, coherence, and biological plausibility of observed effects, as well as
related uncertainties. The ISA uses a formal causality framework to classify the weight of evidence using
a five-level hierarchy described in Table II of the Preamble (U.S. EPA. 2015). The subsequent sections
characterize the evidence that forms the basis of causality determinations for health and welfare effect
categories of a "causal relationship" or a "likely to be causal relationship," or describe instances where a
causality determination has changed (i.e., "likely to be causal" changed to "suggestive of, but not
sufficient to infer, a causal relationship"). Other relationships between ozone and health effects are
"suggestive of but not sufficient to infer" and "inadequate to infer" a causal relationship. These causality
ES-4

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determinations appear in Table ES-1. and are more fully discussed in the respective health effects
Appendices.
ES.4.1 Health Effects of Ozone Exposure
Ozone-induced effects can occur through a variety of complex pathways within the body. After
inhalation, ozone reacts with lipids, proteins, and antioxidants in the epithelial lining fluid of the
respiratory tract, creating secondary oxidation products (Section 5.2.3). Initial ozone exposure leads to
physiological reactions that may induce a host of autonomic, endocrine, immune, and inflammatory
responses throughout the body at the cellular, tissue, and organ level. Recent evidence continues to
support ozone-induced effects on the respiratory system. In addition, recent evidence indicates that short-
term exposure to ozone is likely to induce metabolic effects, as shown in Figure ES-2. There is also some
evidence that ozone exposure can affect the cardiovascular and nervous systems, reproduction and
development, and mortality, although there are more uncertainties associated with interpretation of the
evidence for these effects.
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Table ES-1 Summary of causality determinations by exposure duration and
health outcome.
Health Outcome3
Conclusions from
2013 Ozone ISA
Conclusions in the 2020 ISA
Short-term exposure to ozone
Respiratory effects
Causal relationship
Causal relationship
Cardiovascular effects
Likely to be causal relationship
Suggestive of, but not sufficient to infer, a causal
relationship0
Metabolic effects
No determination made
Likely to be causal relationship15
Total mortality
Likely to be causal relationship
Suggestive of, but not sufficient to infer, a causal
relationship0
Central nervous system
effects
Suggestive of a causal relationship11
Suggestive of, but not sufficient to infer, a causal
relationship
Long-term exposure to ozone
Respiratory effects
Likely to be causal relationship
Likely to be causal relationship
Cardiovascular effects
Suggestive of a causal relationship11
Suggestive of, but not sufficient to infer, a causal
relationship
Metabolic effects
No determination made
Suggestive of, but not sufficient to infer, a causal
relationship15
Total mortality
Suggestive of a causal relationship11
Suggestive of, but not sufficient to infer, a causal
relationship
Reproductive effects
Suggestive of a causal relationship11
Effects on fertility and reproduction: suggestive of, but
not sufficient to infer, a causal relationship15
Effects on pregnancy and birth outcomes: suggestive of,
but not sufficient to infer, a causal relationship15
Central nervous system
effects
Suggestive of a causal relationship11
Suggestive of, but not sufficient to infer, a causal
relationship
Cancer
Inadequate to infer a causal
relationship
Inadequate to infer the presence or absence of a causal
relationship®
aHealth effects (e.g., respiratory effects, cardiovascular effects) include the spectrum of outcomes, from measurable subclinical effects
(e.g., decrements in lung function, blood pressure) to observable effects (e.g., medication use, hospital admissions) and cause-specific mortality.
Total mortality includes all-cause (nonaccidental) mortality, as well as cause-specific mortality.
bDenotes new causality determination.
°Denotes change in causality determination from 2013 Ozone ISA.
dSince the 2013 Ozone ISA, the causality determination language has been updated and this category is now stated as suggestive of, but not
sufficient to infer, a causal relationship.
eSince the 2013 Ozone ISA, the causality determination language has been updated and this category is now stated as inadequate to infer the
presence or absence of a causal relationship.
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Causality Determinations for Health Effects of Ozone

2020 Ozone ISA



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Ozone ISA
Figure ES-2 Causality determinations for health effects of short- and
long-term exposure to ozone.
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The strongest evidence for health effects due to ozone exposure continues to come from studies
of short- and long-term ozone exposure and respiratory health, and this evidence is detailed in
Appendix 3. Consistent with conclusions from the 2013 Ozone ISA (Table ES-1). there is a "causal
relationship" between short-term ozone exposure and respiratory effects (Section 3.1.11). and there
is a "likely to be causal relationship" between long-term ozone exposure and respiratory effects
(Section 3.2.6).
For short-term ozone exposure, controlled human exposure studies conducted over many decades
provide experimental evidence for ozone-induced lung function decrements (Figure ES-3). airway
responsiveness, respiratory symptoms, and respiratory tract inflammation. Epidemiologic studies continue
to provide evidence that ozone concentrations in ambient air are associated with a range of respiratory
effects, including asthma exacerbation, chronic obstructive pulmonary disease (COPD) exacerbation,
respiratory infection, and hospital admissions and emergency department (ED) visits for combined
respiratory diseases.
A large body of animal toxicological studies demonstrate ozone-induced alterations in lung
function, inflammation, increased airway responsiveness, and impaired lung host defense. These animal
toxicological studies also aid in our understanding of potential mechanisms underlying respiratory effects
at the population level and the biological plausibility of epidemiologic associations between short-term
ozone exposure and respiratory-related ED visits and hospital admissions.
With respect to long-term ozone exposure, there is strong coherence between animal
toxicological studies of changes in lung morphology and epidemiologic studies reporting positive
associations between long-term ozone exposure and new-onset asthma, respiratory symptoms in children
with asthma, and respiratory mortality. Furthermore, the experimental evidence provides biologically
plausible pathways through which long-term ozone exposure could lead to respiratory effects reported in
epidemiologic studies.
Metabolic effects related to ozone exposure are evaluated as a separate health endpoint category
for the first time in this ISA (Appendix 5). Recent evidence from animal toxicological, controlled human
exposure, and epidemiologic studies indicate that there is a "likely to be causal relationship" between
short-term ozone exposure and metabolic effects (Section 5.1.8). The strongest evidence for this
determination is provided by animal toxicological studies that demonstrate impaired glucose tolerance,
increased serum triglycerides, fasting hyperglycemia, and increased hepatic gluconeogenesis in various
stocks/strains of animals across multiple laboratories. Biological plausibility is provided by results from
controlled human exposure and animal toxicological studies that demonstrate activation of sensory nerve
pathways following ozone exposure triggers the central neuroendocrine stress response, which includes
increased corticosterone, Cortisol, and epinephrine production. These findings are coherent with
epidemiologic studies that report associations between ozone exposure and perturbations in glucose and
insulin homeostasis. In addition, these pathophysiological changes are often accompanied by increased
inflammatory markers in peripheral tissues and by activation of the neuroendocrine system.
ES-8

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All responses at and above 70 ppb (targeted concentration) were statistically significant (p < 0.05). Adams (2006) found statistically
significant responses to square-wave chamber exposures at 60 ppb based on the analysis of Brown et al. (2008) and Kim et al.
(2011). During each hour of the exposures, subjects were engaged in moderate quasi-continuous exercise (20 L/minute per m2
BSA) for 50 minutes and rest for 10 minutes. Following the 3rd hour, subjects had an additional 35-minute rest period for lunch. The
data at 60 and 80 ppb have been offset on the x axis for illustrative purposes. The solid line illustrates the predicted FE\A
decrements using Model 3 coefficients at 6.6 hours as a function of ozone concentration for a 23.8-year-old with a BMI of 23.1 kg/m2
from McDonnell et al. (2013).
*80 ppb data for 30 health subjects were collected as part of the Kim et al. (2011) study, but only published in Figure 5 of McDonnell
et al. (2012).
Adapted from Figure 6-1 of 2013 Ozone ISA (U.S. EPA. 2013). Studies appearing in the figure legend are: Adams (2006). Adams
(2003). Adams (2002). Horstman et al. (1990). Kim et al. (2011). McDonnell et al. (2013). McDonnell et al. (1991). and Schelegle et
al. (2009).
Figure ES-3
Cross-study comparisons of mean decrements in ozone-induced
forced expiratory volume in 1 second (FEVi) in young, healthy
adults following 6.6 hours of exposure to ozone.
Notably, there are changes in the causality determinations for short-term ozone exposure and
cardiovascular effects (Appendix 4). as well as for total mortality (Appendix 6). In both instances, the
evidence synthesized in the 2013 Ozone ISA was sufficient to conclude a "likely to be causal
relationship," but after integrating the previous evidence with recent data, the collective evidence is
"suggestive of, but not sufficient to infer, a causal relationship" between short-term ozone exposure
and cardiovascular effects (Section 4.1.17) or total mortality (Section 6.1.8) in this ISA. The evidence
that supports this change in the causality determinations includes: (1) a growing body of controlled
human exposure studies providing less consistent evidence for an effect of short-term ozone exposure on
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cardiovascular health endpoints; (2) a paucity of positive evidence from epidemiologic studies for more
severe cardiovascular morbidity endpoints (i.e., heart failure, ischemic heart disease and myocardial
infarction, arrhythmia and cardiac arrest, and stroke); and (3) uncertainties due to a lack of control for
potential confounding by copollutants in epidemiologic studies. Although there is generally consistent
evidence for a limited number of ozone-induced cardiovascular endpoints in animal toxicological studies
and for cardiovascular mortality in epidemiologic studies, these results are not coherent with results from
controlled human exposure and epidemiologic studies examining cardiovascular morbidity endpoints.
There remains evidence for ozone-induced cardiovascular mortality from epidemiologic studies.
However, inconsistent results from a larger number of recent controlled human exposure studies that do
not provide evidence of cardiovascular effects in response to short-term ozone exposure introduce
additional uncertainties.
ES.4.2 Ozone Exposure and Welfare Effects
The scientific evidence for welfare effects of ozone consists mainly of effects on vegetation and
ecosystems (Appendix S) and effects on climate (Appendix 9). For ecological effects, damage to
terrestrial ecosystems as evaluated through controlled exposure studies, observational studies and
modeling based on experimental data, is largely a function of uptake of ozone into the leaf via stomata
(gas exchange openings on leaves). Subsequent reactions with plant tissues alter whole-plant responses
that cascade up to effects at higher levels of biological organization (i.e., from the cellular and subcellular
level to the individual organism up to ecosystem level processes and services; Figure ES-4). At the leaf
level, ozone uptake produces reactive oxygen species that affect cellular function (Section 8.1.3 and
Figure 8-2). Reduced photosynthesis, altered carbon allocation, and impaired stomatal function lead to
observable responses in plants. Observed vegetation responses to ozone include visible foliar injury
(Section IS.5.1.1). and whole-plant level responses (Section IS.5.1.2). which encompass reduction in
aboveground and belowground growth, reproduction and yield. Plant-fauna linkages affected by ozone
include herbivores that feed on ozone-damaged vegetation and interactions of ozone with compounds
emitted by plants that can alter attraction of pollinators to plants (Section IS.5.1.3). A combination of
observational and experimental data, and modeling output provides evidence for broad changes in
ecosystems such as decreased productivity and carbon sequestration (Section IS.5.1.4). altered
belowground processes (Section IS.5.1.5). terrestrial community composition (Section IS.5.1.6). and
water cycling (Section IS.5.1.7).
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03 exposure
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Antioxidant metabolism upregulated
Decreased photosynthesis
Decreased stomatal conductance
or sluggish stomatal response
Effects on leaves
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•Altered leaf chemical composition
Plant growth
•Decreased biomass accumulation
•Altered root growth
•Altered carbon allocation
•Altered reproduction
1 -Altered crop quality
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•Altered forest products
Source: Adapted from U.S. EPA (2013).
Figure ES-4
Illustrative diagram of ozone effects cascading from the cellular
level to plants and ecosystems.
There are 12 causality determinations for ecological effects of ozone generally organized from
the individual-organism scale to the ecosystem scale in Figure ES-5. Like the findings of the 2013 Ozone
ISA (Table E'S-2). five are causal relationships (i.e., visible foliar injury, reduced vegetation growth,
reduced crop yield, reduced productivity, and altered belowground biogeochemical cycles) and two are
likely to be causal relationships (i.e., reduced carbon sequestration, altered ecosystem water cycling). One
of the endpoints, alteration of terrestrial community composition, is now concluded to be a causal
relationship whereas in the 2013 Ozone ISA this endpoint was classified as a likely to be causal
relationship. Three new endpoint categories (i.e., increased tree mortality, alteration of herbivore growth
and reproduction, alteration of plant-insect signaling) not evaluated in the 2013 Ozone ISA, are all
determined to have a likely to be causal relationship with ozone. Plant reproduction, previously
considered as part of the evidence for growth effects, is now a stand-alone causal relationship.
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Causality Determinations for Ecological Effects of Ozone



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Figure ES-5 Causality determinations for ozone across biological scales of
organization and taxonomic groups.
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Table ES-2 Summary of causality determinations for ecological effects.
Endpoint
Conclusions from
2013 Ozone ISA
Conclusions in the 2020 ISA
Visible foliar injury
Causal relationship
Causal relationship
Reduced vegetation growth
Causal relationship
Causal relationship
Reduced plant reproduction
No separate causality
determination; included with plant
growth
Causal relationship3
Increased tree mortality
Causality not assessed
Likely to be causal relationship3
Reduced yield and quality of agricultural
crops
Causal relationship
Causal relationship
Alteration of herbivore growth and
reproduction
Causality not assessed
Likely to be causal relationship3
Alteration of plant-insect signaling
Causality not assessed
Likely to be causal relationship3
Reduced productivity in terrestrial
ecosystems
Causal relationship
Causal relationship
Reduced carbon sequestration in terrestrial
ecosystems
Likely to be causal relationship
Likely to be causal relationship
Alteration of belowground biogeochemical
cycles
Causal relationship
Causal relationship
Alteration of terrestrial community
composition
Likely to be causal relationship
Causal relationship15
Alteration of ecosystem water cycling
Likely to be causal relationship
Likely to be causal relationship
aDenotes new causality determination.
bDenotes change in causality determination from 2013 Ozone ISA.
Visible foliar injury resulting from exposure to ozone has been well characterized and
documented in over six decades of controlled experimental research involving many tree, shrub,
herbaceous, and crop species and using both long-term field studies and laboratory approaches. Recent
experimental evidence (Section 8.2) continues to show a consistent association between visible injury and
ozone exposure supporting the conclusion of the 2013 Ozone ISA that, there is a "causal relationship"
between ozone and visible foliar injury. Measured changes in photosynthesis and carbon allocation in
ozone-exposed plants scale up to reduced growth documented in natural and managed (e.g., agriculture,
forestry, landscaping) species (Section 8.3). as well as impaired reproduction in individual plants
(Section 8.4.1). Consistent with the conclusions in the 2013 Ozone ISA, there is a "causal relationship"
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between ozone and reduced plant growth and a "causal relationship" between ozone and reduced
crop yield and quality. In the 2013 Ozone ISA, reproduction was considered in the same category with
plant growth. Increased information on metrics of plant reproduction (e.g., observed flower number, fruit
number, fruit weight, seed number, rate of seed germination) and evidence for direct negative effects on
reproductive tissues as well as for indirect negative effects (resulting from decreased photosynthesis and
other whole-plant physiological changes) warrants a separate causality determination of a "causal
relationship" between ozone exposure and reduced plant reproduction. Since the 2013 Ozone ISA, a
large-scale multivariate analysis of factors contributing to tree mortality (1971-2005) concluded that
county-level ozone concentrations averaged over the study period significantly increased tree mortality in
7 out of 10 plant functional types in the eastern and central U.S. (Section 8.4.3). This evidence, combined
with observations of long-term declines of conifer forests in several high ozone regions and new
experimental evidence that sensitive genotypes of aspen have increased mortality with ozone exposure,
supports a "likely to be causal relationship" between ozone exposure and tree mortality.
In addition to effects on plants, ozone can alter ecological interactions between plants and other
species including herbivores consuming ozone-exposed vegetation. Studies of insect herbivores in
previous ozone assessments and newer experimental studies covering a range of species at varying levels
of ozone exposure frequently show statistically significant effects; however, effects on growth and
reproduction are highly context- and species-specific, and not all species tested show a response
(Section 8.6). The collective evidence supports "a likely to be causal relationship" between ozone
exposure and altered herbivore growth and reproduction. Many plant-insect interactions are mediated
through volatile plant signaling compounds which plants use to signal other community members. In the
2013 Ozone ISA, a few experimental and modeling studies reported altered insect-plant interactions that
are mediated through chemical signaling. New evidence from multiple studies show altered/degraded
emissions of chemical signals from plants and reduced detection of volatile plant signaling compounds by
insects, including pollinators, in the presence of ozone (Section 8.7). The collective evidence supports
"a likely to be causal relationship" between ozone exposure and alteration of plant-insect signaling.
At the ecosystem scale, ozone-caused decreases in plant photosynthesis can lead to reduced
ecosystem carbon content. Changes in patterns of aboveground and belowground carbon allocation
associated with ozone effects on plants can alter ecosystem properties of storage (e.g., productivity,
carbon sequestration) and cycling (e.g., biogeochemistry) through both experimental and modeling
studies. Consistent with the conclusions of the 2013 Ozone ISA, there is a "causal relationship"
between ozone exposure and reduced productivity and a "likely to be causal relationship" between
ozone and reduced carbon sequestration (Section 8.8). As described in the 2013 Ozone ISA and new
experimental studies, processes such as carbon and nitrogen cycling and decomposition in soils are
indirectly affected via ozone effects on the quality and quantity of carbon supply from plants and leaf
litter (Section 8.9). Recent evidence continues to support a "causal relationship" between ozone
exposure and the alteration of belowground biogeochemical cycles. Ozone can affect water use in
plants through several mechanisms including damage to stomatal functioning, loss of leaf area, and
ES-14

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changes in wood anatomy (e.g., vessel size and density) that can affect plant and stand evapotranspiration
and may lead, in turn, to possible effects on hydrological cycling as shown through a combination of
experimental data and modeling (Section 8.11). Evidence continues to support the conclusion of the 2013
Ozone ISA that, there is a "likely to be causal relationship" between ozone and alteration of
ecosystem water cycling. In terrestrial ecosystems, ozone may alter community composition by uneven
effects on co-occurring species, decreasing the abundance of sensitive species, and giving tolerant species
a competitive advantage. Alteration of community composition of some ecosystems including conifer
forests, broadleaf forests, and grasslands and altered fungal and bacterial communities in soils reported in
the 2013 Ozone ISA is augmented by additional experimental and modeling evidence for effects in forest
and grassland communities (Section 8.10); collective evidence indicates a change in the causality
determination to a "causal relationship" between ozone exposure and altered terrestrial community
composition of some ecosystems.
For effects on climate, changes in the abundance of tropospheric ozone perturb the radiative
balance of the atmosphere by interacting with incoming solar radiation and outgoing longwave radiation.
This effect is quantified by radiative forcing.1 Through this effect on the Earth's radiation balance,
tropospheric ozone plays a major role in the climate system and increases in tropospheric ozone
abundance contribute to climate change. Recent evidence continues to support a "causal relationship"
between tropospheric ozone and radiative forcing and a 'likely to be causal relationship," via
radiative forcing, between tropospheric ozone and temperature, precipitation, and related climate
variables (referred to as "climate change" in the 2013 Ozone ISA; the revised title for this causality
determination provides a more accurate reflection of the available evidence; Table ES-3). The new
evidence comes from the Intergovernmental Panel on Climate Change (IPCC) Fifth Assessment Report
(AR5) and its supporting references, as well as a limited number of more recent studies, and builds on
evidence presented in the 2013 Ozone ISA. The new studies further support the causality determinations
included in the 2013 Ozone ISA.
Table ES-3 Summary of causality determinations for tropospheric ozone effects
on climate.

Conclusions in 2013 Ozone ISA
Conclusions in the 2020 ISA
Radiative forcing
Causal relationship
Causal relationship
Temperature, precipitation, and related Likely to be causal relationship Likely to be causal relationship
climate variables
1 Radiative forcing is the perturbation in net radiative flux at the tropopause (or top of the atmosphere) caused by a
change in radiatively active forcing agent(s) after stratospheric temperatures have readjusted to radiative equilibrium
[stratospherically adjusted radiative forcing; Mvhre et al. (2013)1.
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ES.5 Key Aspects of Health and Welfare Effects Evidence
There is extensive scientific evidence that demonstrates health and welfare effects from exposure
to ozone. As documented by the evaluation of evidence throughout the subsequent Appendices to this
ISA, the U.S. EPA carefully considers uncertainties in the evidence, the extent to which recent studies
have addressed or reduced uncertainties from previous assessments, and the strengths of the evidence.
Uncertainties do not necessarily change the fundamental conclusions of the literature base. In fact, some
conclusions are robust to such uncertainties. Where there is clear evidence linking ozone with health and
welfare effects—with or despite remaining uncertainties—the U.S. EPA makes a determination of a
causal or likely to be causal relationship. The identification of the strengths and limitations in the
evidence will help in the prioritization of research efforts to support future ozone NAAQS reviews.
ES.5.1 Health Effects Evidence: Key Findings
A large body of scientific evidence spanning many decades clearly demonstrates there are health
effects related to both short- and long-term exposure to ozone. The strongest evidence supports a
relationship between ozone exposure and respiratory health effects. The collective body of evidence for
each health outcome category evaluated in this ISA is considered systematically and assessed; this
assessment includes evaluation of the inherent strengths, limitations, and uncertainties in the overall body
of evidence for the health outcome, resulting in the causality determinations detailed in Table ES-1.
An inherent strength of the evidence integration in this ISA is the extensive amount (in both
breadth and depth) of available evidence resulting from decades of scientific research that describes the
relationship between both short- and long-term ozone exposure and health effects. The breadth of the
enormous database is illustrated by the different scientific disciplines that provide evidence
(e.g., controlled human exposure, epidemiologic, animal toxicological studies), the range of health
outcomes examined (e.g., respiratory, cardiovascular, metabolic, reproductive, and nervous system
effects, cancer and mortality), and the large number of studies within several of these outcome categories.
The depth of the literature base is exemplified by the examination of effects that range from biomarkers
of exposure, to subclinical effects, to overt clinical effects, and even mortality.
There is strong and consistent experimental evidence linking short- and long-term ozone exposure
with respiratory effects and short-term ozone exposure with metabolic health effects. However, several
uncertainties should be considered when evaluating and synthesizing evidence from these studies.
Experimental animal studies are often conducted at ozone concentrations higher than those observed in
ambient air (i.e., 250 to >1,000 ppb) to evoke a response within a short time period. These studies are
informative and the conduct of studies at these concentrations is commonly used for identifying potential
human hazards. There are also substantial differences in exposure concentrations and exposure durations
between animal toxicological and controlled human exposure studies. Additionally, a number of animal
toxicological studies are performed in rodent models of disease states, while controlled human exposure
studies generally are conducted in healthy individuals. Controlled human exposure studies do not
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typically include unhealthy or diseased individuals for ethical reasons; therefore, this exclusion represents
an important uncertainty to consider in interpreting the results of these studies (i.e., that other individuals
may be more sensitive and at risk to ozone than those in the study groups). Additional factors that differ
between human and experimental animal exposures include: exposure concentration and disease status;
differences in physiology (e.g., rodents are obligate nose breathers); differences in the duration and timing
of exposure (e.g., rodents are exposed typically during the day, during their resting cycle, while humans
are exposed during the day when they are normally active); and differences in the temperature at which
the exposure was conducted. These factors may contribute to any lack of coherence between results of
experimental animal and human studies. Despite these factors, there is consistent and coherent evidence
that spans scientific disciplines for respiratory and metabolic health effects.
Epidemiologic studies contribute important evidence supporting the relationship between short-
and long-term ozone exposure with respiratory effects. Although susceptible to chance, bias, and other
potential confounding due to their observational nature, epidemiologic studies have the benefit of
evaluating real-world exposure scenarios and can include sensitive populations that cannot typically be
included in controlled human exposure studies. Innovations in epidemiologic study designs and methods
have substantially reduced the role of chance, bias, and other potential confounders in well-designed,
well-conducted epidemiologic studies. The most common source of uncertainty in epidemiologic studies
of ozone is exposure measurement error. The exposure assignment methods used in short- and long-term
ozone exposure epidemiologic studies have inherent strengths and limitations, and exposure measurement
errors associated with those methods contribute bias and uncertainty to health effect estimates. For
short-term exposure studies, exposure measurement error generally leads to underestimation and reduced
precision of the association, whereas in long-term exposure studies exposure measurement error has the
potential to bias effect estimates in either direction, although it is more common that they are
underestimated. Furthermore, disentangling the effects of short-term ozone exposure from those of
long-term ozone exposure (and vice versa) is an inherent uncertainty in the evidence base. When
combined with coherent evidence from animal toxicological and controlled human exposure studies, the
epidemiologic evidence can support and strengthen determinations of the causal nature of the relationship
between health effects and exposure to ozone at relevant ambient air concentrations.
ES.5.2 Welfare Effects Evidence: Key Findings
The collective body of evidence for each welfare endpoint evaluated in this ISA was carefully
considered and assessed, including the inherent strengths, limitations, and uncertainties in the overall
body of evidence, resulting in the causality determinations for ecological effects detailed in Table ES-2
and effects on climate in Table ES-3. A large body of scientific evidence spanning more than 60 years
clearly shows effects on vegetation due to ozone exposure. Decades of research on many plant species
confirm effects on visible foliar injury, plant growth, reproduction and yield. The use of visible foliar
injury to identify phytotoxic levels of ozone is an established and widely used methodology. There are
robust exposure-response functions for reduced growth and yield (i.e., from carefully controlled
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experimental conditions, involving multiple concentrations and based on multiple studies) for about a
dozen important tree species and a dozen major commodity crop species. Newer evidence supports a role
for ozone in tree mortality and shifts in community composition of forest tree and grassland species.
While the effect of ozone on vegetation is well established in general, there are some knowledge gaps
regarding precisely which species are sensitive, what exposures elicit adverse responses for many species
and how plant response changes with age and size.
There is high certainty in ozone effects on impairment to leaf physiology as mechanisms for
effects at higher levels of biological organization (i.e., from the cellular level through individual
organisms to the level of communities and ecosystems) and how those can ultimately affect aboveground
and belowground processes such as productivity, carbon sequestration, biogeochemical cycling, and
hydrology. However, ecosystems are inherently complex, and it is difficult to partition observed
responses within a suite of multiple stressors. Scaling ozone effects to the ecosystem level remains a
challenge, but there is a large body of knowledge of how ecosystems work through ecological
observations and models. Interactive effects in natural ecosystems with multiple stressors (e.g., drought,
disease) are difficult to study, but some have been investigated using different statistical methods.
Although models and methods for characterizing ecosystem-level responses to ozone are accompanied by
inherent uncertainties, more research will strengthen understanding of scaling across different levels of
biological organization.
There are multiple pathways in which ozone can affect plant-insect interactions. Studies that
characterize volatile plant signaling compounds in ozone-enriched environments and assess insect
response to altered chemical signals suggest that ozone alters scent-mediated interactions in ecological
communities. A relatively small number of insect species and plant-insect associations have been
assessed, and there are knowledge gaps in the mechanisms and consequences of modulation of signaling
by ozone. There are multiple studies demonstrating ozone effects on fecundity and growth in insects that
feed on ozone-exposed vegetation. However, no consistent directionality of response is observed across
studies and uncertainties remain in regard to different plant consumption methods across species and the
exposure conditions associated with particular severities of effects.
Changes in the abundance of tropospheric ozone affect radiative forcing, and thus tropospheric
ozone is considered an important greenhouse gas. The recent IPCC AR5 estimates global tropospheric
ozone radiative forcing to be 0.40 (0.20 to 0.60) W/m2 and recent studies reinforce the AR5 estimates.
Consistent with previous estimates, the effect of global, total tropospheric ozone increases on global mean
surface temperature, through its impact on radiative forcing, continues to be estimated at roughly 0.1 to
0.3°C since preindustrial times with larger effects regionally. Some new research has explored certain
additional aspects of the climate response to ozone radiative forcing beyond global and regional
temperature change. Specifically, ozone changes are understood to have impacts on other climate metrics
such as precipitation and atmospheric circulation patterns, and new evidence has continued to support and
further quantify this understanding.
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While the warming effect of tropospheric ozone in the climate system is well established in
general, precisely quantifying changes in surface temperature due to tropospheric ozone changes, along
with related climate effects, requires complex climate simulations that include all relevant feedbacks and
interactions. For example, trends in free tropospheric ozone and upper tropospheric ozone (where
radiative forcing is particularly sensitive to changes in ozone concentrations) are not captured well by
models. In addition, substantial variation exists across models. Such modeling uncertainties make it
especially difficult to provide precise quantitative estimates of the climate effects of regional-scale ozone
changes. Uncertainties in estimates of preindustrial ozone concentrations represent another important
source of uncertainty in climate effects resulting from long-term ozone concentration changes.
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ES.6 References
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