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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INTEGRATED SYNTHESIS
Overall Conclusions of the Ozone Integrated Science Assessment (ISA)
Human Health Effects
• Recent studies support and expand upon the strong body of evidence, which has been
accumulating over many decades, that short-term ozone exposure causes respiratory
effects. The strongest evidence comes from controlled human exposure studies
demonstrating ozone-induced decreases in lung function and inflammation in healthy,
exercising adults at concentrations as low as 60 ppb after 6.6 hours of exposure. In
addition, epidemiologic studies continue to provide strong evidence that ozone is
associated with respiratory effects, including asthma and chronic obstructive
pulmonary disease exacerbations, as well as hospital admissions and emergency
department visits for respiratory diseases. The results from toxicological studies
further characterize potential mechanistic pathways and provide continued support for
the biological plausibility of ozone-induced respiratory effects.
• There is emerging evidence that short-term ozone exposure contributes to metabolic
disease, including complications related to diabetes. Specifically, animal toxicological
studies demonstrate that ozone exposure impaired glucose tolerance, increased
triglycerides in serum, fasting hyperglycemia, and increased hepatic gluconeogenesis.
• The integration of recent evidence from controlled human exposure studies showing
inconsistent evidence of ozone-induced cardiovascular effects with the overall body of
evidence for an association of short-term ozone exposure with cardiovascular effects
and total (nonaccidental) mortality available in the 2013 Ozone ISA, results in a
change in the causality determinations for those outcome categories.
Welfare Effects
Ecological Effects
• A large body of scientific evidence spanning more than 60 years clearly demonstrates
that ozone affects vegetation and ecosystems. The strongest evidence comes from
vegetation-related endpoints; foliar injury, reduced growth, and decreased yield
resulting from ozone exposure are well characterized in a variety of crop and noncrop
species. Ecological effects of ozone are observed across several scales of biological
organization (i.e., from the cellular level through individual organisms to the level of
communities and ecosystems), ultimately affecting aboveground and belowground
processes including productivity, carbon sequestration, biogeochemical cycling and
hydrology. In most cases, new research strengthens the previously reached
conclusions in the 2013 Ozone ISA. New endpoints included in this review result from
emerging areas of study such as chemical ecology (e.g., plant-insect signaling) or new
evidence enabling further refinement of previously understood ozone effects
(e.g., plant reproduction, tree mortality, herbivore growth and reproduction, terrestrial
community composition).
Effects on Climate
• New research builds on the evidence in the 2013 Ozone ISA and continues to support
the previous findings of tropospheric ozone impacts on radiative forcing and climate
variables, including temperature and precipitation (referred to as "climate change" in
the 2013 Ozone ISA).
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IS.1
Introduction
IS.1.1 Purpose and Overview
The Integrated Science Assessment (ISA) serves as the scientific foundation of the National
Ambient Air Quality Standard (NAAQS) review process.1 The ISA is a comprehensive evaluation and
synthesis of the policy-relevant science "useful in indicating the kind and extent of all identifiable effects
on public health or welfare2 which may be expected from the presence of [a] pollutant in the ambient air,"
as described in Section 108 of the Clean Air Act (42 U.S. Code [U.S.C.] 7408).3 This ISA reviews and
synthesizes the air quality criteria for the health and welfare effects of ozone and related photochemical
oxidants in ambient air. It draws on the existing body of evidence to evaluate and describe the current
state of scientific knowledge on the most relevant issues pertinent to the current review of the ozone
NAAQS,4 to identify changes in the scientific evidence since the previous review, and to describe
remaining or newly identified uncertainties and limitations in the evidence. In 2015, the U.S. EPA
lowered the level of the primary and secondary ozone standards to 0.070 ppm and maintained the form of
the standard as the annual fourth-highest daily max 8-hour concentration averaged over 3 years.5 The
ozone primary NAAQS is established to protect public health, including at-risk populations such as
children and people with asthma, with an adequate margin of safety. The ozone secondary standard is
intended to protect the public welfare from known or anticipated adverse effects associated with the
presence of ozone and related photochemical oxidants in the ambient air.
This ISA identifies and critically evaluates the most policy-relevant current scientific literature
published since the 2013 Ozone ISA across scientific disciplines including epidemiology, controlled
human exposure studies, experimental animal toxicology, atmospheric science, exposure science,
vegetation studies, agricultural science, ecology, and climate-related science. Key scientific conclusions
(e.g., causality determinations; Section IS.1.2.4) are presented that provide the basis for developing risk
1 Section 109(d)(1) of the Clean Air Act requires periodic review and, if appropriate, revision of existing air quality
criteria to reflect advances in scientific knowledge on the effects of the pollutant on public health and welfare. Under
the same provision, U.S. EPA is also to periodically review and, if appropriate, revise the NAAQS, based on the
revised air quality criteria.
2 Under CAA 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 The general process for developing an ISA, including the framework for evaluating weight of evidence and
drawing scientific conclusions and causal judgments, is described in a companion document, Preamble to the
Integrated Science Assessments (U.S. EPA. 20151.
4 The "indicator" of a standard defines the chemical species or mixture that is to be measured in determining
whether an area attains the standard. The indicator of the current NAAQS for photochemical oxidants is ozone
5 Final rule signed October 1, 2015 and effective December 28, 2015 (80 FR 65291).
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and exposure analyses, evaluating policy, and making environmental health and welfare decisions. In
characterizing the evidence for each of the health and welfare effects categories evaluated, this ISA draws
conclusions about the causal nature of the relationships between ozone exposure and outcomes by
integrating information across scientific disciplines and synthesizing evidence from previous and recent
studies. As in previous reviews, the ISA for this review focuses mainly on the assessment of health and
welfare effects resulting from exposure to concentrations of tropospheric ozone. Ozone is currently the
NAAQS indicator for photochemical oxidants, and the primary literature evaluating the health and
ecological effects of photochemical oxidants includes ozone almost exclusively as an indicator of
photochemical oxidants.1 This ISA thus provides the policy-relevant scientific information that supports
the review of the current ozone NAAQS.
IS.1.2 Process and Development
Through iterative NAAQS reviews, ISAs build on evidence and conclusions from previous
assessments. The previous ozone ISA was published in 2013 (U.S. EPA. 2013b) and included
peer-reviewed literature published through July 2011. Prior assessments include the 2006 Air Quality
Criteria Document (AQCD) for Ozone and Related Photochemical Oxidants (U.S. EPA. 2006a'). the 1996
AQCD for Ozone (U.S. EPA. 1996a). the 1986 AQCD for Ozone (U.S. EPA. 1986). the 1978 Air Quality
Criteria for Ozone and Other Photochemical Oxidants (U.S. EPA. 1978). and the 1970 Criteria Document
(NAPCA. 1970). This ISA focuses on synthesizing and integrating the new evidence (i.e., studies
published between January 2011 and March 2018, as well as more recent studies identified during peer
review or by public comments) with the information and conclusions from previous assessments.
In the process of developing an ISA, systematic review methodologies are used to identify and
evaluate relevant scientific information, which is synthesized into text and figures for the purpose of
communicating the state of the science. The process begins with a "Call for Information" published in the
Federal Register that announces the start of the NAAQS review and invites the public to assist in this
process by identifying relevant research studies in the subject areas of concern. For this Ozone NAAQS
review, the Federal Register notice was published on June 26, 2018 (83 FR 29785). The subsequent ISA
development steps are described in greater detail in the Preamble to the Integrated Science Assessments
(U.S. EPA. 2015). which provides a general overview of the process. The Preamble describes the general
framework for evaluating scientific information, including criteria for assessing study quality and
developing scientific conclusions. The U.S. EPA uses a structured and transparent process to evaluate
scientific information and to determine the causal nature of relationships between air pollution and health
1 Ozone is the only photochemical oxidant other than nitrogen dioxide (NO2) that is routinely monitored in ambient
air (i.e., U.S. EPA's AQS database; https://www.epa.gov/ags). Data for other photochemical oxidants (e.g., PAN,
H2O2, etc.) typically have been obtained only as part of special field studies. Consequently, no data on nationwide
patterns of ambient air concentrations are available for these other photochemical oxidants; nor are extensive data
available on the relationships of concentrations and patterns of these photochemical oxidants to those of ozone.
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and welfare effects [see Preamble (U.S. EPA. 2015)1. Development of the ISA includes approaches for
literature searches, application of criteria for selecting and evaluating relevant studies, and application of
framework for evaluating the weight of evidence and forming causality determinations. As part of this
process, the ISA is reviewed by the public and by the Clean Air Scientific Advisory Committee
(CASAC), which is a formal, independent scientific committee (Section 10.4). The Preamble describes a
science and policy workshop that often occurs at the beginning of the NAAQS review process; such a
workshop was not convened for the current Ozone NAAQS review. Instead, the "Call for Information"
published in the Federal Register requested public input on science and polity issues pertinent to the
Ozone NAAQS review.
IS.1.2.1 Scope of the ISA and the Population, Exposure, Comparison, Outcome, and
Study Design (PECOS) Tools
The Ozone ISA includes research relevant to characterizing ozone in ambient air (hereafter
referred to as ambient ozone) and assessing the health and welfare effects of exposure to ambient ozone.
Health effects evidence evaluated in the ISA includes experimental controlled human exposure and
animal toxicological studies, and observational epidemiologic studies. Welfare-based evidence included
in the Ozone ISA focuses specifically on ecological effects and effects on climate. The evidence
connecting tropospheric ozone and UV-B (short-wave ultraviolet rays) shielding was evaluated in the
2013 Ozone ISA and determined to be inadequate to draw a causal conclusion. The current ISA concludes
there was no new evidence since the 2013 Ozone ISA relevant to the question of UV-B shielding by
tropospheric ozone, including the incremental effects of tropospheric ozone concentration changes on
UV-B. (Section 9.1.3.4). and this topic is not discussed further in this synthesis.
The scope of the health and welfare effects evidence evaluated in this ISA is further refined by
using the Population, Exposure, Comparison, Outcome, and Study Design (PECOS) tool. The PECOS
tools provide structured frameworks for defining the scope of the ISA. There are discipline-specific
PECOS tools for experimental and epidemiologic studies (Section 3.1.2. Section 3.2.2. Section 4.1.2.
Section 4.2.1.1. Section 5.1.1. Section 5.2.1. Section 6.1.1.1. Section 6.2.1.1. Section 7.1.1.1.
Section 7.2.1.1. Section 7.2.2.1. and Section 7.3.1.1). ecological studies (Table 8-2). and studies of the
effects of tropospheric ozone on climate (Table 9-1). These PECOS criteria were developed with
consideration of the evidence base available at the time of the last review (i.e., the causality
determinations from the 2013 Ozone ISA) and the uncertainties and limitations associated with that
evidence. The use of PECOS tools is a widely accepted and rapidly growing approach to systematic
review in risk assessment, and their use is consistent with recommendations by the National Academy of
Sciences for improving the design of risk assessment through planning, scoping, and problem formulation
to better meet the needs of decision makers (NRC. 2009). The PECOS tools serve as guides for the
inclusion or exclusion of studies in the ISA. Additional details on the development and use of these
PECOS tools can be found in Appendix 10 (Section 10.3.1).
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IS.1.2.2 Organization of the ISA
The ISA consists of the Preface (legislative requirements and history of the primary and
secondary ozone NAAQS; and purpose and overview of the ISA along with the overall scope, and
process for evaluating evidence), Executive Summary, Integrated Synthesis, and 10 Appendices. This
Integrated Synthesis provides the key information for each topic area, encompassing a description of
ozone concentrations in the U.S. (including background sources), conclusions regarding the health and
welfare effects associated with ozone exposure (including causality determinations for relationships
between exposure to ozone and specific types of health and welfare effects), identification of the human
lifestages and populations at increased risk of the effects of ozone, and a discussion of the key strengths,
limitations, and uncertainties inherent in this evidence base. The purpose of this Integrated Synthesis is
not to summarize each of the Appendices; rather it is to synthesize the key findings on each topic
considered in characterizing ozone exposure and relationships with health and welfare effects. This
Integrated Synthesis also discusses additional policy-relevant issues. These include exposure durations,
metrics, and concentrations eliciting health and welfare effects and the concentration-response (C-R)
relationships for specific effects, including their overall shapes and the evidence with regard to
discernibility of threshold exposures below which effects are unlikely to occur. Subsequent
Appendix 1-Appendix 10 are organized by subject area, with the detailed assessment of atmospheric
science (Appendix 1). exposure (Appendix 2). health (Appendix 3-Appendix 7). and welfare evidence
(Appendix 8-Appendix 9). Each of the Appendices contain an evaluation of results from recent studies
integrated with evidence from previous reviews. Appendices for each broad health effect category
(e.g., respiratory effects) discuss potential biological pathways and conclude with a causality
determination describing the strength of the evidence between exposure to ozone and the outcome(s)
under consideration. Likewise, the Appendices devoted to ecological (Appendix S) and climate evidence
(Appendix 9) for welfare effects include causality determinations for multiple effects on ecosystems and
climate, respectively. Appendix 10 describes the process of developing the ozone ISA, including aspects
related to systematic review of the literature, evaluation of study quality, and quality assurance (QA) and
quality control (QC) documentation.
IS.1.2.3 Quality Assurance Summary
The use of QA and peer review helps ensure that the U.S. EPA conducts high-quality science
assessments that can be used to help policymakers, industry, and the public make informed decisions.
Quality assurance activities performed by the U.S. EPA ensure that environmental data are of sufficient
quantity and quality to support the Agency's intended use. The U.S. EPA has developed a detailed
Program-level QA Project Plan (PQAPP) for the ISA Program to describe the technical approach and
associated QA/QC procedures associated with the ISA Program. All QA objectives and measurement
criteria detailed in the PQAPP have been employed in developing this ISA. Furthermore, the Ozone ISA
is classified as a Highly Influential Scientific Assessment (HISA), which is defined by the Office of
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Management and Budget (OMB) as a scientific assessment that is novel, controversial, or
precedent-setting, or has significant interagency interest (OMB. 2004). OMB requires a HISA to be peer
reviewed before dissemination. To meet this requirement, the U.S. EPA engages the Clean Air Scientific
Advisory Committee (CASAC) as an independent federal advisory committee to conduct peer reviews.
Both peer-review comments provided by the CASAC panel and public comments submitted to the panel
during its deliberations about the external review draft were considered in the development of this ISA.
For a more detailed discussion of peer review and quality assurance, see Section 10.4 and Section 10.5.
respectively.
IS.1.2.4 Evaluation of the Evidence
This ISA draws conclusions about the causal nature of relationships between exposure to ozone
and categories of related health and welfare effects (e.g., respiratory effects) by integrating recent
evidence across scientific disciplines and building on the evidence from previous assessments.
Determinations are made about causation, not just association, and are based on judgments of
consistency, coherence, and biological plausibility of observed effects, and on related uncertainties. The
ISA uses a formal causal framework to classify the weight of evidence using a five-level hierarchy
[i.e., "causal relationship"; "likely to be causal relationship"; "suggestive of, but not sufficient to infer, a
causal relationship"; "inadequate to infer the presence or absence of a causal relationship"; or "not likely
to be a causal relationship" as described in Table II of the Preamble (U.S. EPA. 2015)1 that is based
largely on the aspects for causality proposed by Sir Austin Bradford Hill, as well as other frameworks to
assess causality developed by other organizations.
IS.1.3 New Evidence Evaluation and Causality Determinations
In the 2013 Ozone ISA, the causality determinations communicated the extent of the then current
knowledge of health and welfare effects. Updates to the causality determinations for ozone based on new
evidence in this review are summarized below and are described in greater detail in Section IS.4 (Health)
and Section IS.5 (Welfare).
IS.1.3.1 Human Health
The results from the health studies, supported by the evidence from atmospheric chemistry and
exposure assessment studies, contribute to the causality determinations made for the health outcomes. The
conclusions from the 2013 Ozone ISA and the causality determinations from this review are summarized
in Table IS-1.
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Table IS-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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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. Consistent with conclusions from the 2013
Ozone ISA, it is determined that there is a "causal relationship" between short-term ozone exposure and
respiratory effects, and there is a "likely to be causal relationship" between long-term ozone exposure and
respiratory effects. For short-term ozone exposure, controlled human exposure studies provide
experimental evidence for ozone-induced lung function decrements, respiratory symptoms, and
respiratory tract inflammation. Epidemiologic studies continue to provide evidence that increased ozone
concentrations are associated with a range of respiratory effects, including asthma exacerbation, chronic
obstructive pulmonary disease (COPD) exacerbation, respiratory infection, and hospital admissions and
ED visits for combined respiratory diseases. A large body of experimental animal toxicological studies
demonstrates ozone-induced changes in measures of lung function, inflammation, increased airway
responsiveness, and impaired lung host defense. These animal studies also inform the potential
mechanisms underlying downstream respiratory effects (e.g., respiratory tract inflammation) and thereby
provide strong support for 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, and respiratory symptoms in children with asthma. Furthermore, the experimental
evidence provides biologically plausible pathways through which long-term ozone exposure could lead to
the types of 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. Recent evidence from animal toxicological, controlled human exposure, and
epidemiologic studies support a "likely to be causal relationship" between short-term ozone exposure and
metabolic effects. The strongest evidence for this determination is provided by animal toxicological
studies that demonstrate impaired glucose tolerance, fasting hyperglycemia, and increased serum
triglycerides and free fatty acids 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 that trigger the
central neuroendocrine stress response, as indicated by increased corticosterone/cortisol and adrenaline
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 changes in liver biomarkers.
The strongest evidence for metabolic effects following long-term ozone exposure is provided by
epidemiologic studies. In prospective cohort studies in the U.S. and Europe, increased incidence of type 2
diabetes was observed with long-term ozone exposure. In a study conducted in China, long-term ozone
exposure was associated with the development and diagnosis of metabolic syndrome. Several long-term
ozone exposure studies in China, one in adults and one in children, observed increased odds of obesity (a
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risk factor for type 2 diabetes) in both adults and children. Positive associations between long-term
exposure to ozone and diabetes-related mortality were observed in well-established cohorts in the U.S.
and Canada. The results of mortality studies are supported by epidemiologic and experimental studies
reporting effects on glucose homeostasis and serum lipids, as well as other indicators of metabolic
function (e.g., peripheral inflammation and neuroendocrine activation). This evidence is "suggestive of,
but not sufficient to infer, a causal relationship" between long-term ozone exposure and metabolic effects.
Notably, compared with the 2013 Ozone ISA, there are changes in the causality determinations
for short-term ozone exposure and cardiovascular effects and total mortality. In both instances, the 2013
Ozone ISA concluded that the evidence was sufficient to conclude a "likely to be causal relationship," but
after integrating the previous evidence with recent evidence, the collective evidence is "suggestive of, but
not sufficient to infer, a causal relationship" in this ISA. The evidence that supports this change in the
causality determination includes (1) a growing body of controlled human exposure studies providing less
consistent evidence for an effect of short-term ozone exposure on cardiovascular health endpoints; (2) a
paucity of positive evidence from epidemiologic studies for more severe cardiovascular morbidity
endpoints (i.e., heart failure [HF], ischemic heart disease [IHD] and myocardial infarction [MI],
arrhythmia and cardiac arrest, and stroke); and (3) uncertainties due to few studies evaluating the potential
for confounding by copollutants in epidemiologic studies. Although there is consistent or generally
consistent evidence for several ozone-induced cardiovascular endpoints in animal toxicological studies
and for cardiovascular mortality in epidemiologic studies, these results are not coherent with those in
controlled human exposure and epidemiologic studies examining cardiovascular morbidity endpoints.
IS.1.3.2 Welfare: Ecological Effects
The 2013 Ozone ISA (U.S. EPA. 2013b) concluded that the responses to ozone exposure occur
across multiple biological scales and a broad array of ecological endpoints, with the strongest evidence
for effects on vegetation. The focus of the current ISA and literature evaluated herein are those effects
observed at the individual-organism level of biological organization and higher (e.g., population,
community, ecosystem). New research largely strengthens the previous conclusions on the ecological
effects of ozone. The types of ecological effects studies conducted since the 2013 Ozone ISA mostly fall
into three categories: (1) empirical research that has refined/reinforced earlier studies, in some cases using
new approaches, new species, or larger-scale systems; (2) meta-analyses that have provided a more
statistically based understanding of patterns compiled from existing literature; and (3) modeling
approaches that have increased in complexity and enabled examination of ozone effects at larger spatial
scales (e.g., regional, national). There are 12 causality determinations for ecological effects of ozone
(Table IS-2). generally organized from the individual-organism scale to the ecosystem scale. Similar to
the findings of the 2013 Ozone ISA, 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
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water cycling). One endpoint, alteration of terrestrial community composition, is now concluded to be a
causal relationship, whereas this endpoint was classified as likely to be causal in the 2013 Ozone ISA.
Three new endpoint categories (i.e., increased tree mortality, alteration of herbivore growth and
reproduction, and alteration of plant-insect signaling) not evaluated for causality in the 2013 Ozone ISA
all have a "likely to be causal relationship." Plant reproduction, previously considered as part of the
evidence for growth effects, is now a stand-alone causal relationship.
IS.1.3.3 Welfare: Effects on Climate
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 ITablc IS-31). The new evidence comes from the Intergovernmental Panel on Climate
Change (IPCC) Fifth Assessment Report [AR5; Mvhre et al. (2013)1 and its supporting references—in
addition to a few 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.
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Table IS-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.
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Table IS-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
climate variables
Likely to be causal relationship
Likely to be causal relationship
IS.2 Atmospheric Chemistry, Ambient Air Ozone Concentrations,
and Background Ozone
Scientific advances in atmospheric ozone research relevant to the Ozone NAAQS are reviewed in
this section, with a primary focus on understanding the relative contribution of precursor emissions to
ambient ozone concentrations from natural processes and anthropogenic activities. The section
summarizes recent developments in measurement and modeling methods, atmospheric chemistry, and
ambient air concentration trends (Section IS.2.1). The U.S. background (USB) ozone concentration is
defined as the ozone concentration that would occur if all U.S. anthropogenic ozone precursor emissions
were removed, as described in Section IS.2.2. This definition facilitates separate consideration of ozone
that results from anthropogenic precursor emissions within the U.S. and ozone originating from natural
and foreign precursor sources. This discussion is followed by a summary of recent observations and
research related to USB ozone, with an emphasis on major sources (Section IS.2.2.1). estimation methods
(Section IS.2.2.2). and geographic, seasonal, and long-term ozone concentration trends (Section IS.2.2.3).
IS.2.1 Ambient Air Ozone Anthropogenic Sources, Measurement, and
Concentrations
The general photochemistry of tropospheric ozone is described in detail in previous assessments
(U.S. EPA. 2013b. 2006a'). Anthropogenic ozone in urban settings is produced primarily by the reaction
of volatile organic compounds (VOCs) with oxides of nitrogen (NOx) in the presence of sunlight. Carbon
monoxide (CO) and methane (CH4) also react with NOx to form ozone in the absence of more reactive
organic compounds (Section 1.4). The most abundant national and global sources of VOCs are biogenic
(U.S. EPA. 2013b). and oxides of nitrogen are predominately emitted from a range of anthropogenic
sources, including automobile exhaust, off-road vehicles and engines, electric power generation,
industrial activities, and stationary fuel combustion (U.S. EPA. 2016). Recent developments in
understanding ozone chemistry include observations of high ozone concentrations during the winter in
some western U.S. mountain basins (Section 1.4.1V For example, wintertime ozone concentrations in the
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Uintah Basin of Utah and Upper Green River Basin of Wyoming have been measured as high as 150 ppb
(1-hour avg), with episodes driven by local concentrations of ozone precursor emissions from oil and gas
extraction coinciding with strong mountain valley temperature inversions on cold winter days with snow
cover. In addition, there is new research on the role of marine halogen chemistry in suppressing coastal
ozone concentrations (Section 1.4.2). Incorporating marine halogen chemistry into atmospheric modeling
methods for predicting ozone concentrations has improved agreement between model results and
observed ozone near marine environments.
Extensive air monitoring data are obtained from the state and local air monitoring site (SLAMS)
network for ozone, consisting of more than 1,300 monitors throughout the U.S. (Section 1.7). In the
SLAMS network, ozone is measured by ultraviolet spectroscopy using a Federal Equivalency Method
(FEM) at most sites (Section 1.6.1.1). A new Federal Reference Method (FRM) for ozone measurement
was adopted in 2015 (Section 1.6.1.1) based on chemiluminescence resulting from the reaction of ozone
with nitric oxide, and is used at some sites. In addition to network monitoring, satellite-based remote
sensing methods are increasingly used to measure the total ozone column in the atmosphere, and satellite
data are used to constrain model estimates of ground-level tropospheric ozone concentrations
(Section 1.6.1.2). Because tropospheric concentration estimates based on satellite measurements can have
much greater uncertainty than total column ozone measurements, these technologies are most suitable for
investigating trends in total column ozone or in the upper troposphere. The 2013 Ozone ISA provided an
overview of chemical transport models (CTMs), including the relevant processes, numerical approaches,
relevant spatial scales, and methods for evaluation (U.S. EPA. 2013b). Since the 2013 Ozone ISA,
numerous improvements to these models have been made. These include: the addition of a halogen
chemistry mechanism; improvements in the representation of land cover and near surface meteorology;
the inclusion of dry deposition and stomatal uptake, stratosphere-troposphere exchange, and biogenic
emissions; and, the integration of meteorological models and CTMs (Section 1.6.2).
SLAMS network data for the period 2015-2017 show higher nationwide median "max daily
8-hour avg" (MDA8) ozone concentrations across all monitoring sites in spring (median = 46 ppb) and
summer (median = 46 ppb) than in autumn (median = 38 ppb) and winter (median = 34 ppb). The highest
values of annual 4th-highest MDA8 ozone concentration (>75 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 warm season between May and September (Section 1.2.1.1). These results
are similar to those reported in the 2013 Ozone ISA (U.S. EPA. 2013b). The highest values of W126, an
example of a cumulative index of plant exposure (Section IS. 3.2 and Section 1.2.1.2). occurred in
California and the southwestern U.S.
Several recent studies have documented a long-term decreasing trend in nationwide average
ambient air MDA8 ozone concentration over several decades and a faster decline in the magnitude and
frequency of high MDA8 ozone episodes (Section 1.7). Comparison of the difference between 5th and
95th percentile concentrations indicates a compression of the MDA8 ozone concentration distribution
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occurring widely across the U.S. This compression results from a decrease in 95th percentile
concentrations together with a general increase in 5th percentile concentrations. This is consistent with
observed reductions in NOx emissions (Section 1.3.1). because there is less NO available to react with
ozone at low ozone concentrations, as well as less NO2 available to form ozone at high ozone
concentrations.
IS.2.2 Background Ozone
Use of the term "background ozone" varies within the air pollution research community. It has
generally been used to describe ozone levels that would exist in the absence of anthropogenic emissions
within a particular area and has been broadly applied to every geospatial scale: local, regional, national,
continental, or global. For instance, on a local scale, ozone that originates from precursor emissions
outside of a locality's municipal boundaries could be considered background ozone for that locality.
Similarly, on a national scale, background ozone could be defined as ozone that is not formed from
anthropogenic emissions within national boundaries.
The USB concentration is defined as the ozone concentration that would occur if all U.S.
anthropogenic ozone precursor emissions were removed. It is a hypothetical construct that cannot be
measured. The 2006 Ozone AQCD (U.S. EPA. 2006a) and 2013 Ozone ISA (U.S. EPA. 2013b)
concluded that background ozone concentrations could not be determined solely from ozone
measurements, even at the most remote monitoring sites, because of long-range transport of ozone
originating from U.S. anthropogenic precursors. Since then, chemical transport models have been used as
the primary tool for estimating USB ozone concentrations.
IS.2.2.1 Sources of U.S. Background Ozone
Major contributors to ground-level USB ozone concentrations are stratospheric exchange,
international transport, wildfires, lightning, global methane emissions, and natural biogenic and geogenic
precursor emissions. As the USB literature has evolved, much of the discussion has focused on the
relative importance of stratospheric ozone and intercontinental transport as major sources.
Tropospheric ozone derived from stratosphere-troposphere dynamics was described in detail in
the 2013 Ozone ISA (U.S. EPA. 2013b). Stratospheric air naturally rich in ozone can be transported into
the troposphere under certain meteorological circumstances, with maximum contributions observed at
midlatitudes during the late winter and early spring. This process, known as "tropopause folding," is
characterized by episodic events typically lasting a few days from late winter through spring when deep
stratospheric intrusions rich in ozone can quickly and directly well into the troposphere and, more rarely,
reach ground level (U.S. EPA. 2013b). The 2013 Ozone ISA (U.S. EPA. 2013b) also discussed the
potential importance of deep convection, another form of stratosphere-troposphere exchange that occurs
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mainly in summer, as a mechanism for transporting stratospheric ozone into the upper troposphere.
Stratospheric ozone contributions from deep intrusion between 17 and 40 ppb have been estimated at
ground level for springtime model simulations in the western U.S. (Section 1.3.2.1). Stratospheric
intrusion events related to frontal passage and tropopause folding that reach the surface have less
influence on surface ozone during the summer months when total ground-level ozone concentrations tend
to be highest.
Intercontinental transport from Asia has also been identified as a major source of precursors that
can contribute 5 to 7 ppb to USB ozone concentrations over the western U.S. (U.S. EPA. 2013b. 2006a.
b). Ozone precursor emissions from China and other Asian countries have been estimated to have more
than doubled in the period 1990-2010 (Section 1.3.1.2). and an estimated increase of 0.3 to 0.5 ppb/year
of midtropospheric ozone USB in spring over the western U.S. in the two decades after 1990 was largely
attributed to a tripling of Asian NOx emissions (Section 1.3.1). However, after this period, trends in NOx
emissions from China, the largest ozone precursor source in Asia, have declined as confirmed by rapidly
decreasing satellite-derived tropospheric NO2 column measurements over China since 2012. Stringent air
quality standards implemented in 2013 within China have markedly reduced national emissions of NOx
(Section 1.3.1.2).
Other contributors to USB are either smaller or more uncertain than stratospheric and
intercontinental contributions. Wildfires have been estimated to contribute a few ppb to seasonal mean
ozone concentrations in the U.S., but episodic contributions may be as high as 30 ppb (Section 1.3.1.2).
However, estimates of the magnitude of ozone formation from wildfires is highly uncertain with some
work showing large overpredictions of modeled wildfire contributions (Section 1.3.1.3). Lightning was
estimated to contribute 2 to 3 ppb to ground level ozone concentrations in the southeastern U.S. in the
summer (U.S. EPA. 2013b). Eighty percent of the NOx present in the upper troposphere is generated by
lightning where it can have a longer atmospheric residence time than NOx derived from ground sources
(Section 1.3.1.3). There is an approximately linear relationship between anthropogenic methane emissions
and tropospheric ozone, which is consistent with the contribution of anthropogenic methane emissions to
global annual mean ozone concentration of -4-5 ppb reported in the 2013 Ozone ISA (U.S. EPA. 2013b).
Biogenic emissions of NOx are estimated to contribute 0.3 Tg N/year, or about 7.5% of total NOx
emissions (Section 1.3.1.3).
IS.2.2.2 Methods for Estimating U.S. Background Ozone
Large uncertainties are associated with estimating USB ozone concentrations. Approaches for
estimating USB ozone are described in Section 1.8.1. USB ozone is estimated using either zero-out
simulations or source apportionment simulations. The most widely used approach to measuring USB or
other measures of background ozone is the zero-out method, in which anthropogenic U.S. or other areas
emissions are set to zero in a model simulation to estimate these ozone measures (Section 1.8.1.1). As an
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alternative to model sensitivity approaches, source apportionment techniques track source contributions to
ozone formation without perturbing emissions (Section 1.8.1.2). Tracking techniques use reactive tracer
species to tag specific emissions source categories or source regions and then track the ozone produced by
emissions from those source groups. Both approaches are essential and complementary for understanding
and estimating USB ozone. The zero out approach is suited for estimating what ozone levels would have
existed in recent modeled years in the absence of all U.S. emissions, while the source apportionment
approach is suited for estimating the fraction of current ozone originating from background sources in
recent modeled years. The difference between estimates from these approaches is small in remote areas
that are most strongly affected by USB sources. However, the differences in the estimates given by these
methods can be substantial in urban areas strongly affected by anthropogenic sources that influence both
production and destruction of ozone.
USB ozone concentrations vary daily and by location and are a function of season, meteorology,
and elevation. Quantification of USB ozone on days when MDA8 ozone concentrations exceed 70 ppb is
more relevant to understanding USB ozone contributions on those days than are seasonal mean USB
ozone estimates, but also more uncertain (Jaffc et al.. 2018). Jaffe et al. (2018) reviewed recent modeling
results and reported that USB ozone estimates contain uncertainties of about 10 ppb for seasonal average
concentrations and 15 ppb for MDA8 avg concentrations on individual days. Because of uncertainty in
model predictions of USB, model results are often adjusted using simple bias correction approaches.
Because such approaches might not be reliable if the model has diverging errors in USB ozone and
locally produced ozone, however, days with poor model performance have sometimes been excluded
when using model results to estimate USB or other measures of background ozone. There have been
continued efforts to improve model performance and better understand biases and uncertainties involved
in the application of CTMs to estimating USB or other measures of background ozone (Section 1.8.1.5).
IS.2.2.3 U.S. Background Concentrations and Trends
A greater variety of approaches for estimating USB concentrations and other measures of
background ozone used in recent years have led to a wider range of USB estimates than reported in the
2013 Ozone ISA (U.S. EPA. 2013b). although some of the basic patterns remain consistent. For example,
higher USB concentrations (and related measures of background ozone) were estimated in the western
U.S. than in the eastern U.S. in the 2013 Ozone ISA (U.S. EPA. 2013b). especially in the intermountain
West and Southwest. Higher USB concentrations were also estimated at elevations higher than 1,500 m
than at lower elevations (U.S. EPA. 2013b). New studies since the 2013 Ozone ISA confirm these
findings (Section 1.8.2.1).
USB concentrations are relatively constant with increasing total ozone concentration, indicating
that days with higher ozone concentrations generally occur because of higher U.S. anthropogenic
contributions (Section 1.8.2.3). In the eastern U.S. and in urban and low-elevation areas of the western
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U.S., there is consistent evidence across several studies that daily USB ozone concentrations are similar to
or smaller than seasonal mean USB ozone concentrations on most high ozone concentration days
(i.e., days with MDA8 ozone greater than 60 ppb). In contrast, for high elevation locations in the western
U.S., USB concentration estimates have been consistently predicted to increase with total ozone
concentration, consistent with a larger background contribution. Lower USB contributions on days of
high ozone concentration can result from meteorological conditions that favor large ozone production
from U.S. anthropogenic sources relative to USB sources (Section 1.5.2). The highest ozone
concentrations observed in the U.S. have historically occurred during stagnant conditions when an air
mass remains stationary over a region abundant in anthropogenic ozone precursor sources (U.S. EPA.
2013b. 2006a. 1996a). while the largest USB contributions often occur under the opposite conditions,
when the atmosphere is well mixed and transport of USB ozone generated in the stratosphere or during
long-range transport of Asian or natural precursors in the upper troposphere more readily occurs
(Section 1.5.2).
Characterizing long-term trends in USB presents numerous challenges (Section 1.8.2.4). Research
has mainly focused on high elevation sites in the western U.S. or measurements made aloft, where, until
recently, increasing midtropospheric ozone was reported. The most recent analyses suggest that this trend
has now slowed or reversed, and there is no evidence to suggest that USB is still increasing, even in the
western U.S. (Section 1.8.2.4).
IS.3 Exposure to Ambient Ozone
IS.3.1 Human Exposure Assessment in Epidemiologic Studies
With regard to exposure assessment relevant to human health effects, the 2013 Ozone ISA (U.S.
EPA. 2013b) primarily discussed personal exposure to ozone and its relationship to ambient air
concentrations.
Its primary conclusions were that personal exposure to ozone is moderately correlated with
ambient air concentration (Pearson R = 0.3-0.8) and indoor ozone concentrations were roughly 10-30%
of ambient air concentrations. In addition, ozone exposure minimization efforts through public messaging
(e.g., ozone action days) were effective in reducing exposures for people younger than 20 years old but
did not make an appreciable difference in exposure among those ages 20-64 years old. The 2013 Ozone
ISA noted that urban scale ozone concentrations often have low spatial variability except in the vicinity of
roadways, where nitrogen oxides emitted from motor vehicles tend to scavenge ozone.
The 2013 Ozone ISA also found that exposure measurement error can bias epidemiologic
associations between ambient ozone concentrations and health outcomes and widen confidence intervals
around effect estimates. Recently published studies agree with these previous findings. Although ozone
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concentrations measured at fixed-site ambient air monitors are still widely used as surrogates for ozone
exposure in epidemiologic studies (Section 2.3.1.1). the availability and sophistication of models to
predict ambient ozone concentrations for this purpose have increased substantially in recent years
(Section 2.3.2). The greatest expansion in modeling capability has occurred in chemical transport
modeling (CTM; Section 2.3.2.3). especially when incorporated into a hybrid spatiotemporal framework
that integrates modeling output with monitoring and satellite data over time and space (Section 2.3.2.4).
Hybrid methods have produced lower error predictions of ozone concentration compared with
spatiotemporal models using land use and other geospatial data alone (Section 2.3.2.2) but may be subject
to overfitting given the many different sources of data incorporated into the hybrid framework.
Use of an exposure surrogate in epidemiologic studies generally leads to underestimation of any
association between short-term exposure to ozone and a health effect, with reduced precision. Although
the magnitude of an association between ambient ozone and a health effect is uncertain, the evidence
indicates that the true effect is typically larger than the effect estimate in these cases. Epidemiologic
studies evaluating short-term ozone exposure examine how short-term (e.g., hourly, daily, weekly)
changes in health effects are associated with short-term changes in exposure (Section 2.6.1). Accurate
characterization of temporal variability is more important than accurate characterization of spatial
variability for these studies. Use of an exposure surrogate may produce bias when temporal variability in
the concentration at the location of the measurement or model prediction differs from temporal variability
of the true exposure concentration. As a result, the correlation between the exposure surrogate and the
incidence of the effect would decrease due to the additional scatter in that relationship, and the reduced
correlation would also likely flatten the slope of the relationship between the effect and exposure
surrogate.
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 underestimate the true effect and have
reduced precision. Although the magnitude of association between ozone and such health effects are
uncertain, the evidence suggests that the true effect of ambient ozone exposure is larger than the effect
estimate when time-activity data are not considered in the analysis. Uncharacterized exposure variability
due to omission of time-activity data for short-term studies (Section 2.4.1) creates uncertainty in the
exposure estimate that could reduce the correlation between the exposure estimate and the health effect.
Depending on the exposure model and scenario being modeled for application in epidemiology
studies, the true effect of long-term 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 the bias is typically small in magnitude. Long-term
epidemiologic studies examine the association between the health effect endpoint and long-term average
ambient ozone exposure (Section 2.6.2). For cohort studies of long-term ambient ozone exposure,
ambient ozone concentration measured at monitors or estimated by a model is often used as a surrogate
for ambient ozone exposure. These studies typically examine differences among cohorts in different
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locations, at the scale of neighborhoods, cities, or states. Uncharacterized spatial variability in ozone
exposure across the study area could lead to bias in the effect estimate if modeled or measured ambient
concentration is not representative of ambient exposure. Bias can occur in either direction but more often
has been reported to be towards the null in exposure measurement error studies. Uncertainties in time
activity and residential patterns of exposed individuals and surface losses of ozone can reduce precision in
the effect estimates.
IS.3.2 Ecological Exposure
The key conclusions from the 1996 and 2006 Ozone AQCDs, and the 2013 Ozone ISA regarding
ozone exposure to vegetation, highlighted below, are still valid and most effects observed for
nonvegetation biota are mediated through ozone effects on vegetation. Absorption of ozone from the
atmosphere into leaves is controlled by the leaf boundary layer and stomatal conductance. Stomata
provide the principal pathway for ozone to enter and affect plants, with subsequent oxidative injury to leaf
tissue triggering a cascade of physical, biogeochemical, and physiological events that may scale up to
responses at the whole-plant scale.
As described in previous ozone assessments, ozone-related injury is a function of flux (i.e., the
amount of ozone taken up by the plant overtime). Ozone flux is affected by modifying factors such as
temperature, vapor pressure deficit, light, soil moisture, and plant growth stage (U.S. EPA. 2013b). Flux
is very difficult to measure directly, requiring quantification of stomatal or canopy conductance. While
some efforts have been made in the U.S. to calculate ozone flux into leaves and canopies, little
information has been published relating these fluxes to effects on vegetation. The scarcity of flux data in
the U.S. and lack of understanding of plant detoxification processes have made this technique less viable
for risk assessments in the U.S. (U.S. EPA. 2013b). An alternative to flux-based exposure estimates are
exposure indices. Exposure indices quantify exposure as it relates to measured plant response
(e.g., growth) and only require ambient air quality data rather than more complex indirect calculations of
dose to the plant. Cumulative indices summarize ozone concentrations over time to provide a consistent
metric for reviewing and comparing exposure-response effects obtained from various studies. For
ecological studies in this ISA, emphasis is placed on studies that characterize exposures at concentrations
occurring in the environment or experimental ozone concentrations within an order of magnitude of
recent concentrations observed in the U.S. (Appendix 1).
It is well established that exposure duration influences the degree of plant response and that
ozone effects on plants are cumulative. In previous ozone assessments, effects are clearly demonstrated to
be related to the cumulative exposure over the growing season for crops and herbaceous plant species. For
long-lived plants, such as trees, exposures occur over multiple seasons and years. Cumulative indices of
exposure are, therefore, best suited to assess exposure. Since the 1980s, cumulative-type indices such as
threshold weighted (e.g., SUM06, AOTx) and continuous weighted (e.g., W126) functions have been
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applied to evaluate ozone exposure in plants (U.S. EPA. 2013b). The 2013 Ozone ISA primarily
discussed SUM06, AOTx, and W126 exposure metrics. Below are the definitions of the three cumulative
index forms:
• SUM06: Sum of all hourly ozone concentrations greater than or equal to 60 ppb observed during
a specified daily and seasonal time window (U.S. EPA. 2013b).
• AOTx: Sum of the differences between hourly ozone concentrations greater than a specified
threshold during a specified daily and seasonal time window. For example, AOT40 is the sum of
the differences between hourly concentrations above 40 ppb during a specified period (U.S. EPA.
2013b).
• W126: Sigmoidally weighted sum of all hourly ozone concentrations observed during a specified
daily and seasonal time window (Lefohn et al.. 1988; Lefohn and Runeckles. 1987).
IS.4 Evaluation of the Health Effects of Ozone
IS.4.1 Connections among Health Effects
Broad health effect categories are evaluated separately in the Appendices of this ISA, though the
mechanisms underlying disease progression may overlap and not be restricted to a single organ system.
This section provides a brief overview of how the relationship between ozone and a variety of health
outcomes may be related or affect one another.
Ozone-induced injuries can take place via complex pathways within the body. After inhalation,
ozone reacts with lipids, proteins, and antioxidants in the respiratory tract epithelial lining fluid to create
secondary oxidation products ITJ.S. EPA (2013b); Section 5.2.31. The first steps (i.e., initial events) in the
cascade of physiological events includes activation of sensory nerves in the respiratory tract and
respiratory tract inflammation. These early physiological reactions to ozone may trigger a host of
autonomic, endocrine, immune, and inflammatory responses throughout the body at the cellular, tissue,
and organ level. Because the circulatory system is connected to all body systems, insults to multiple organ
systems may contribute to a single health effect. The 2006 Ozone AQCD RJ.S. EPA (2006a); Chapter 4]
and the 2013 Ozone ISA rU.S. EPA (2013b); Section 5.31 provide extensive background on dosimetry
and potential pathways underlying health effects for these responses.
Modulations of the autonomic nervous system, which consists of the sympathetic and
parasympathetic systems, provide inhibitory or excitatory inputs to tissues to generate organ responses.
Some examples of responses from alterations of the autonomic nervous system include changes to heart
rate, bronchodilation/bronchoconstriction, altered blood glucose, glycogenolysis/gluconeogenesis,
hormone release, and other organ functions (McCorrv. 2007). Endocrine, immune, and inflammatory
responses can send signals capable of altering multiple pathways and eliciting cardiovascular, respiratory,
and metabolic health effects.
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While all systems of the body are connected intrinsically, most research presented in the field of
air quality examines specific health endpoints resulting from exposure to a pollutant. In an effort to bring
together the scientific body of evidence in an easily understandable and relatable way, this document has
separated the supporting Appendices into Respiratory (Appendix 3). Cardiovascular (Appendix 4).
Metabolic (Appendix 5). Mortality (Appendix 6). and Other Health Effects (Appendix 7).
IS.4.2 Biological Plausibility
New to this Ozone ISA are biological plausibility sections for the broad health outcome
categories that are included in the human health Appendices (Appendix 3-Appendix 7). These sections
outline potential pathways along the exposure to outcome continuum and provide plausible links between
inhalation of ozone and health outcomes at the population level. Biological plausibility can strengthen the
basis for causal inference (U.S. EPA. 2015). In this ISA, biological plausibility is part of the weight-of-
evidence analysis that considers the totality of the health effects evidence, including consistency and
coherence of effects described in experimental and observational studies. Although there is some overlap
in the potential pathways between the Appendices, each biological plausibility section is tailored to the
specific broad health outcome category and exposure duration for which causality determinations are
made.
Each of the biological plausibility sections includes a figure depicting potential biological
pathways that is accompanied by text. The figures illustrate possible pathways related to ozone exposure
that are based on evidence evaluated in previous assessments, both AQCDs and ISAs, as well as evidence
from more recent studies. The text characterizes the evidence upon which the figures are based, including
results of studies demonstrating specific effects related to ozone exposure and considerations of
physiology and pathophysiology. Together, the figure and text portray the available evidence that
supports the biological plausibility of ozone exposure leading to specific health outcomes. Gaps in the
evidence base (e.g., health endpoints for which studies have not been conducted) are represented by
corresponding gaps in the figures and are identified in the accompanying text.
In the model figure below (Figure IS-1). each box represents evidence that has been demonstrated
in a study or group of studies for a particular effect related to ozone exposure. While most of the studies
used to develop the figures are experimental studies (i.e., animal toxicological and controlled human
exposure studies), some observational epidemiologic studies also contribute to the pathways. These
epidemiologic studies are generally (1) panel studies that measure the same or similar effects as the
experimental studies (and thus provide supportive evidence) or (2) emergency department and hospital
admission studies or studies of mortality, which are effects observed at the population level. The boxes
are arranged horizontally, with boxes on the left side representing initial effects that reflect early
biological responses and boxes to the right representing intermediate (i.e., subclinical or clinical) effects
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and effects at the population level. The boxes are color-coded according to their position in the exposure
to outcome continuum.
Key Clinical Effect
Ozone
Exposure
V.
Intermediate
Effect 2
r ^
/ ^
Effect at Population
Level
r, ^
"4"*
Effect 5
Intermediate
Effect 3
Note: The boxes above represent the effects for which there is experimental or epidemiologic evidence related to ozone exposure,
and the arrows indicate a proposed relationship between those effects. Solid arrows denote evidence of essentiality as provided, for
example, by an inhibitor of the pathway or a genetic knockout model used in an experimental study involving ozone exposure.
Shading around multiple boxes is used to denote a grouping of these effects. Arrows may connect individual boxes, groupings of
boxes, and individual boxes within groupings of boxes. Progression of effects is generally depicted from left to right and color coded
(white, exposure; green, initial effect; blue, intermediate effect; orange, effect at the population level or a key clinical effect). Here,
population-level effects generally reflect results of epidemiologic studies. When there are gaps in the evidence base, there are
complementary gaps in the figure and the accompanying text below.
Figure IS-1 Illustrative figure for potential biological pathways for health
effects following ozone exposure.
The arrows that connect the boxes indicate a progression of effects resulting from ozone
exposure. In most cases, arrows are dotted (arrow 1), denoting a possible relationship between the effects.
While most arrows point from left to right, some arrows point from right to left, reflecting progression of
effects in the opposite direction or a feedback loop (arrow 2). In a few cases, the arrows are solid
(arrow 2), indicating that progression from the upstream to downstream effect occurs as a direct result of
ozone exposure. This relationship between the boxes, where the upstream effect is necessary for
progression to the downstream effect, is termed essentiality (OECD. 2016). Evidence supporting
essentiality is generally provided by experimental studies using pharmacologic agents (i.e., inhibitors) or
animal models that are genetic knockouts. The use of solid lines, as opposed to dotted lines, reflects the
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availability of specific experimental evidence that ozone exposure results in an upstream effect which is
necessary for progression to a downstream effect.
In the figures, upstream effects are sometimes linked to multiple downstream effects. In order to
illustrate this proposed relationship using a minimum number of arrows, downstream boxes are grouped
together within a larger shaded box and a single arrow (arrow 3) connects the upstream single box to the
outside of the downstream shaded box containing the multiple boxes. Multiple upstream effects may
similarly be linked to a single downstream effect using an arrow (arrow 4) that connects the outside of a
shaded box, which contains multiple boxes, to an individual box. In addition, arrows sometimes connect
one individual box to another individual box that is contained within a larger shaded box (arrow 2) or two
individual boxes both contained within larger shaded boxes (arrow 5). Thus, arrows may connect
individual boxes, groupings of boxes, and individual boxes within groupings of boxes depending on the
proposed relationships between effects represented by the boxes.
IS.4.3 Summary of Health Effects Evidence
This ISA evaluates the relationships between an array of health effects and short- and long-term
exposure to ozone in epidemiologic, controlled human exposure, and animal toxicological studies.
Short-term exposures are defined as those with durations of hours up to 1 month, with most studies
examining effects related to exposures in the range of several hours to 1 week. Long-term exposures are
defined as those with durations of more than 1 month, with many studies spanning a period of years. As
detailed in the Preface, the evaluation of the health effects evidence from animal toxicological studies
focuses on exposures conducted at concentrations of ozone that are relevant to the range of human
exposures associated with ambient air (up to 2 ppm, which is one to two orders of magnitude above recent
ambient air concentrations in the U.S.). Drawing from evidence related to the discussion of biological
plausibility of ozone-related health effects and the broader health effects evidence spanning scientific
disciplines described in detail in Appendix 3-Appendix 7. as well as issues regarding exposure
assessment and potential confounding described in Appendix 2. the subsequent sections characterize the
evidence that forms the basis of the causality determinations for health effect categories of a "causal
relationship" or a "likely to be causal relationship," or describe instances where a causality determination
has been changed (i.e., "likely to be causal" changed to "suggestive of, but not sufficient to infer a causal
relationship"). The evidence that supports these causality determinations builds upon the potential
biological pathways, which provide evidence of biological plausibility, as well as the broader health
effects evidence spanning scientific disciplines for each health effects category, as well as issues related
to dosimetry, exposure assessment, and potential confounding. Other relationships between ozone and
health effects where the causality determinations are "suggestive of but not sufficient to infer a causal
relationship " or "inadequate to infer the presence or absence of a causal relationship" are noted in
Table IS-1. and more fully discussed in the respective health effects Appendices.
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IS.4.3.1 Short-Term Exposure and Respiratory Health Effects
The 2013 Ozone ISA concluded that there is a "causal relationship" between short-term ozone
exposure and respiratory health effects (U.S. EPA. 2013b). This conclusion was based largely on
controlled human exposure studies demonstrating ozone-related respiratory effects in healthy individuals
(Table IS-4V Specifically, statistically significant decreases in group mean pulmonary function in
response to 6.6-hour ozone exposures (which included six 50-minutes periods of moderate exertion) to
concentrations as low as 60 ppb1 were observed in young, healthy adults (Figure IS-2). Additionally,
controlled human exposure and experimental animal studies demonstrated ozone-induced increases in
respiratory symptoms, lung inflammation, airway permeability, and airway responsiveness. The
experimental evidence was supported by strong evidence from epidemiologic studies demonstrating
associations between ambient ozone concentrations and respiratory hospital admissions and ED visits
across the U.S., Europe, and Canada. This evidence was further supported by a large body of
individual-level epidemiologic panel studies that demonstrated associations of short-term ozone
concentrations with respiratory symptoms in children with asthma. Additional support for a causal
relationship was provided by epidemiologic studies that observed ozone-associated increases in indicators
of airway inflammation and oxidative stress in children with asthma. Additionally, several multicity
studies and a multicontinent study reported associations between short-term increases in ozone
concentrations and increases in respiratory mortality.
Table IS-4 Summary of evidence from epidemiologic, controlled human
exposure, and animal toxicological studies on the respiratory effects
of short-term exposure to ozone.
1 Concentrations from controlled human exposure studies are target concentrations, unadjusted for study-specific
measurement information.
Conclusions from 2013 Ozone ISA Results and Conclusions from 2020 ISAa
Respiratory effects Evidence integrated across controlled
Recent evidence from controlled human
exposure, epidemiologic, and animal
toxicological studies support and extend the
conclusions from the 2013 Ozone ISA that
there is a causal relationship between
short-term ozone exposure and respiratory
effects.
human exposure, epidemiologic, and
animal toxicological studies and across
the spectrum of respiratory health
endpoints demonstrated that there was a
causal relationship between
short-term ozone exposure and
respiratory health effects.
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Table IS-4 (Continued): Summary of evidence from epidemiologic, controlled
human exposure, and animal toxicological studies on the
respiratory effects of short-term exposure to ozone.
Conclusions from 2013 Ozone ISA
Results and Conclusions from 2020 ISAa
Lung function
Controlled human exposure studies of
young, healthy adults demonstrate group
mean decreases in FEVi in the range of
2 to 3% with 6.6-h exposures, while
exercising, from concentrations as low as
60 ppb ozone. The collective body of
epidemiologic evidence demonstrate
associations between short-term ambient
ozone concentrations and decrements in
lung function, particularly in children with
asthma, children, and adults who work or
exercise outdoors.
Controlled human exposure studies of young,
healthy adults demonstrate ozone-induced
decreases in FEVi at concentrations as low as
60 ppb and the combination of FEVi
decrements and respiratory symptoms at
ozone concentrations 70 ppb or greater
following 6.6-h exposures while exercising.
Studies show interindividual variability with
some individuals being intrinsically more
responsive. Results from recent epidemiologic
studies are consistent with evidence from the
2013 Ozone ISA of an association with lung
function decrements as low as 33 ppb (mean
8-h avg ozone concentrations).
Airway responsiveness
A limited number of studies observe
increased airway responsiveness in
rodents and guinea pigs after being
exposed for 72 h to ozone concentrations
ranging from less than 300 ppb up to
1,000 ppb. As previously reported in the
2006 63 AQCD, increased airway
responsiveness demonstrated at 80 ppb
in young, healthy adults, and at 50 ppb in
certain strains of rats.
Controlled human exposure studies provide
evidence of increased airway responsiveness
with exposures as low as 80 ppb. Baseline
airway responsiveness does not appear
predictive of changes in lung function following
ozone exposure. Recent animal toxicological
studies demonstrate increases in airway
responsiveness following ozone exposures as
low as 800 ppb. A recent animal toxicological
study showed increased airway
responsiveness to a greater degree in allergic
mice than in naive mice at 1,000 ppb for 8 h.
Pulmonary
inflammation, injury,
and oxidative stress
Epidemiologic studies provide evidence
for associations of ambient ozone with
mediators of airway inflammation and
oxidative stress and indicated that higher
antioxidant levels may reduce pulmonary
inflammation associated with ozone
exposure. Generally, these studies had
mean 8-h daily max ozone concentrations
less than 66 ppb. Controlled human
exposure studies show ozone-induced
inflammatory responses at 60 ppb, the
lowest concentration evaluated.
Controlled human exposure studies
demonstrate ozone-induced increases in
pulmonary inflammation at concentrations as
low as 60 ppb after 6.6 h of exposure. Studies
show interindividual variability in inflammatory
responses with some individuals reproducibly
experiencing intrinsically greater responses
than average. Animal toxicological studies
demonstrate inflammation, injury, and
oxidative stress following ozone exposures as
low as 300 ppb for up to 72 h. Epidemiologic
studies observe associations with pulmonary
inflammation in studies of healthy children
(mean 8-h daily max ozone concentrations as
low as 53 ppb).
Respiratory symptoms
and medication use
The collective body of epidemiologic
evidence demonstrate positive
associations between short-term
exposure to ambient ozone and
respiratory symptoms (e.g., cough,
wheeze, and shortness of breath) in
children with asthma. Generally, these
studies had mean 8-h daily max ozone
concentrations less than 69 ppb.
Controlled human exposure studies provide
evidence of increased respiratory symptoms
following 6.6-h exposures to 70 ppb and
greater. Limited data suggests that lung
function responses to ozone in individuals with
asthma may depend on baseline lung function
and medication use. The large body of
epidemiologic evidence from the 2013 Ozone
ISA continues to provide the strongest support
for these outcomes.
IS-25
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Table IS-4 (Continued): Summary of evidence from epidemiologic, controlled
human exposure, and animal toxicological studies on the
respiratory effects of short-term exposure to ozone.
Conclusions from 2013 Ozone ISA
Results and Conclusions from 2020 ISAa
Lung host defenses
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
ozone exposures of 80-400 ppb. Animal
toxicological studies demonstrate
increased susceptibility to infectious
disease with short-term ozone exposures
as low as 80 ppb. Altered macrophage
function was reported with exposures as
low as 100 ppb. Other effects on the
immune system (i.e., adaptive immunity
and natural killer cells) are seen with
exposures as low as 500 ppb.
A limited number of recent controlled human
exposure studies report results that are
consistent with studies evaluated in the 2013
Ozone ISA that demonstrated impaired lung
host defense following acute ozone exposure.
A limited number of recent animal toxicological
studies demonstrate susceptibility to infectious
disease at 2,000 ppb ozone for 3 h. Recent
epidemiologic studies of ED visits for
respiratory infection provide the strong support
for these outcomes.
Allergic and Controlled human exposure studies in
asthma-related atopic individuals with asthma
responses demonstrate increased airway
eosinophils, enhanced allergic cytokine
production, increased IgE receptors, and
enhanced markers of innate immunity
and antigen presentation with short-term
exposure to 80-400 ppb ozone, all of
which may enhance allergy and/or
asthma. Increased airway
responsiveness is seen in atopic
individuals with asthma at 120-250 ppb
ozone. In allergic rodents, enhanced
goblet cell metaplasia is seen using
exposure concentrations as low as
100 ppb, and enhanced responses to
allergen challenge is seen with
short-term exposure to 1,000 ppm
ozone.
A limited number of recent controlled human
exposure and animal toxicological studies
demonstrate enhanced type 2 immune
responses following acute ozone exposures as
low as 200 ppb in atopic adults with asthma
and 800 ppb (8 h a day for 3 days) in healthy
rodents. Exacerbated bronchoconstriction
(airway resistance) and lung injury is seen in
allergic rodents at 1,000 ppb. These results
support and expand upon evidence from the
2013 Ozone ISA that ozone enhances allergic
and asthma related responses.
Respiratory hospital
admissions, ED visits,
and physician visits
Consistent, positive associations of
ambient ozone concentrations with
respiratory hospital admissions and ED
visits in the U.S., Europe, and Canada
are observed with supporting evidence
from single-city studies. Generally, these
studies had mean 8-h max ozone
concentrations less than 60 ppb.
Evidence from many recent, large multicity
epidemiologic studies provide further support
for an association between ozone and ED
visits and hospital admissions for asthma;
associations are generally strongest in
magnitude for children between the ages of 5
and 18 years in studies with mean 8-h daily
max ozone concentrations between 31 and
54 ppb. Additional epidemiologic evidence for
associations between ozone and hospital
admissions and ED visits for combinations of
respiratory diseases (31 to 50 ppb as the
study mean 8-h daily max), ED visits for COPD
(33 to 55 ppb as the study mean daily 1-h
max), and ED visits for respiratory infection
(33 to 55 ppb as the study mean daily 1-h
max).
IS-26
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Table IS-4 (Continued): Summary of evidence from epidemiologic, controlled
human exposure, and animal toxicological studies on the
respiratory effects of short-term exposure to ozone.
Conclusions from 2013 Ozone ISA Results and Conclusions from 2020 ISAa
Respiratory mortality
Multicity time-series studies and a
multicontinent study consistently
demonstrated associations between
ambient ozone concentrations and
respiratory-related mortality across the
U.S., Europe, and Canada with
supporting evidence from single-city
studies. Generally, these studies had
mean 8-h max ozone concentrations less
than 63 ppb.
Recent epidemiologic evidence for respiratory
mortality is limited, but there remains evidence
of consistent, positive associations, specifically
in the summer months, with mean daily
8-h max ozone concentrations between
8.7 and 63 ppb. When recent evidence is
considered in the context of the larger number
of studies evaluated in the 2013 Ozone ISA,
there remains consistent evidence of an
association between short-term ozone
exposure and respiratory mortality.
Conclusions from the 2020 ISA include evidence from recent studies integrated with evidence included in previous Ozone ISAs
and AQCDs.
Evidence from recent controlled human exposure studies augment the evidence from previously
available studies. There are, however, no new 6.6-hour ozone exposure studies since the 2013 Ozone ISA.
Evidence in the 2013 Ozone ISA demonstrated increases in FEVi decrements, respiratory symptoms, and
inflammation following ozone exposures of 6.6 hours, with exercise, as low as 60 to 70 ppb
(Section 3.1.4). Evidence from recent epidemiologic studies of short-term ozone exposure and hospital
admission or emergency department visits observed associations at concentrations as low as 31 ppb.
Controlled human exposure studies also provide consistent evidence of ozone-induced increases in airway
responsiveness (Section 3.1.4.3 and Section 3.1.5.5) and inflammation in the respiratory tract
(Section 3.1.4.4 and Section 3.1.5.6). Recent animal toxicological studies are consistent with evidence
summarized in the 2013 Ozone ISA (U.S. EPA. 2013b); these studies support the evidence observed in
healthy humans.
Evidence from epidemiologic studies of healthy populations is generally coherent with
experimental evidence, with most of the evidence coming from panel studies that were previously
evaluated in the 2013 Ozone ISA (U.S. EPA. 2013b). Several panel studies of healthy children reported
decreases in FEVi and increases in markers of pulmonary inflammation associated with increases in
short-term ozone exposure. While there is coherence between epidemiologic and experimental evidence
of ozone-induced lung function decrements and pulmonary inflammation, respiratory symptoms were not
associated with ozone exposure in a limited number of epidemiologic studies. However, these studies
generally relied on parent-reported outcomes that may have resulted in under- or over-reporting of
respiratory symptoms.
IS-27
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~
A
X
~
O
o
~
~ (S)
I T I I I I t
30 40 50 60 70 80 90
Ozone (ppb)
Note: All studies used constant exposure concentrations in a chamber unless designated as stepwise (S) and/or facemask (m)
exposures. All responses at and above 70 ppb (targeted concentration) were statistically significant. 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 along the x-axis for illustrative purposes. The curved solid line from McDonnell et al. (2013)
illustrates the predicted FEVi 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.
*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).
Source: Adapted from Figure 6-1 of 2013 Ozone ISA (U.S. EPA. 2013b). 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
Scheleale et al. (2009).
Figure IS-2 Cross-study comparisons of mean ozone-induced forced
expiratory volume in 1 second (FEVi) decrements in young
healthy adults following 6.6 hours of exposure to ozone.
= !
T3 E
= Si
i O 4
= Ł
O ^
N -
o >
LU 2
Evidence from numerous recent, large, multicity epidemiologic studies conducted in the U.S.
among people of all ages also expands upon evidence from the 2013 Ozone ISA (U.S. EPA. 2013b) to
further support an association between ozone exposure and ED visits and hospital admissions for asthma
(Section 3.1.5.1 and Section 3.1.5.2). Reported associations were generally highest for children between
the ages of 5 and 18 at mean daily 8-hour concentrations of 31-54 ppb. Additionally, consistent, positive
associations were reported across models implementing measured and modeled ozone concentrations. A
large body of evidence from the 2013 Ozone ISA (U.S. EPA. 2013b) reported ozone associations with
markers of asthma exacerbation (e.g., respiratory symptoms, medication use, lung function) that support
the ozone-related increases in asthma hospital admissions and ED visits observed in recent studies. Few
Adams (2006)
Adams (2003)
Adams (2002)
Horstman et al. (1990)
Kim et al. (2011)*
McDonnell et al. (1991)
Schelegle et al. (2009)
McDonnell et al. (2013)
IS-28
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recent epidemiologic studies in the U.S. or Canada have examined respiratory symptoms and medication
use, lung function, and subclinical effects in people with asthma. Recent experimental studies in animals,
along with similar studies summarized in the 2013 Ozone ISA (U.S. EPA. 2013b). provide coherence
with and biological plausibility for the epidemiologic evidence of asthma exacerbation, indicating
respiratory tract inflammation, oxidative stress, injury, allergic skewing, goblet cell metaplasia, and
upregulation of mucus synthesis and storage in allergic mice exposed to ozone (Section 3.1.5.4.
Section 3.1.5.5. and Section 3.1.5.6).
In addition to epidemiologic evidence of asthma exacerbation, a number of recent epidemiologic
studies continue to provide evidence of an association of ozone concentrations with hospital admissions
and ED visits for combined respiratory diseases (Section 3.1.8). ED visits for respiratory infection
(Section 3.1.7.1). and ED visits for COPD (Section 3.1.6.1.1). Recent epidemiologic evidence for
respiratory mortality is limited, but there remains evidence of consistent, positive associations,
specifically in the summer months (Section 3.1.9). A limited number of recent controlled human exposure
and animal toxicological studies are consistent with studies evaluated in the 2013 Ozone ISA (U.S. EPA.
2013b) that demonstrate altered immunity and impaired lung host defense following acute ozone
exposure (Section 3.1.7.3). These findings support the epidemiologic evidence of an association between
ozone concentrations and respiratory infection. Additionally, results from recent animal toxicological
studies provide new evidence that chronic inflammation enhances sensitivity to ozone exposure,
providing coherence for ozone-related increases in ED visits for COPD (Section 3.1.6.2.1.2).
Copollutant analyses were limited in epidemiologic studies evaluated in the 2013 Ozone ISA, but
they did not indicate that associations between ozone concentrations and respiratory effects were
confounded by copollutants or aeroallergens. Copollutant analyses have been more prevalent in recent
studies and continue to suggest that observed associations are independent of coexposures to correlated
pollutants or aeroallergens (Section 3.1.10.1 and Section 3.1.10.2). Despite expanded copollutant analyses
in recent studies, determining the independent effects of ozone in epidemiologic studies is complicated by
the high copollutant correlations observed in some studies and the possibility for effect estimates to be
overestimated for the better measured pollutant in copollutant models (Section 2.5). Nonetheless, the
consistency of associations observed across studies with different copollutant correlations, the generally
robust associations observed in copollutant models, and evidence from controlled human exposure studies
demonstrating respiratory effects in response to ozone exposure in the absence of other pollutants,
provide compelling evidence for the independent effect of short-term ozone exposure on respiratory
symptoms.
Several controlled human exposure studies provided evidence on the C-R relationship for FEVi
decrements in young healthy adults exposed during moderate exercise for 6.6. hours to ozone
concentrations between 40 and 120 ppb. The lack of any studies at lower ozone concentrations and the
small decrements observed at 40 ppb preclude characterization of the C-R relationship at lower
concentrations. A model-predicted C-R function is described in a recent study presenting a mechanistic
IS-29
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model based on these [and other controlled human exposure data; McDonnell et al. (2013); Figure IS-1;
Section 3.1.4.1.11.
Epidemiologic studies examining the shape of the relationship between ambient air
concentrations and the studied health outcome and/or the presence of a threshold in this relationship have
been inconsistent (Section 3.1.10.1.4). While most studies assume a no-threshold, log-linear C-R shape, a
limited number of studies have used more flexible models to test this assumption. Results from some of
these studies indicate approximately linear associations between ozone concentrations and hospital
admissions for asthma, while others indicate the presence of a threshold ranging from 20 to 40 ppb 8-hour
max ozone concentrations.
Most epidemiologic studies that examine the relationship between short-term concentrations of
ozone in ambient air and health effects rely primarily on a 1-hour max, 8-hour max, or 24-hour avg
averaging times. Epidemiologic time-series and panel studies evaluated in the 2013 Ozone ISA do not
provide any evidence to indicate that any one averaging time is more consistently or strongly associated
with respiratory-related health effects (U.S. EPA. 2013b). Recent epidemiologic studies examining
respiratory effects continue to show evidence of positive associations for each of these averaging times
(see Figure 3-4. Figure 3-5. Figure 3-6. and Figure 3-7). For example, Darrow et al. (2011). as detailed in
the 2013 Ozone ISA, demonstrated a similar pattern of associations between short-term ozone exposure
and respiratory-related ED visits for 1-hour max, 8-hour max, and 24-hour avg exposure metrics
(Section 3.1.10.3.2). Similarly, a recent panel study focusing on respiratory symptoms in children
reported positive associations when using both a 1-hour max and 8-hour max averaging time rLewis et al.
(2013); Section 3.1.5.3.21. The combination of evidence from studies evaluated in the 2013 Ozone ISA,
along with the results across recent studies that demonstrate positive associations using either a 1-hour
max, 8-hour max, or 24-hour avg averaging time, further supports the conclusion that no one averaging
time is more consistently or strongly associated with respiratory effects and that each of these averaging
times could be surrogates for the exposure conditions that elicit respiratory health effects.
The evaluation of the lag structure of associations is an important consideration when examining
the relationship between short-term ozone exposure and respiratory effects. With respect to ozone
exposure, epidemiologic studies often examine associations between short-term exposure and health
effects over a series of single-day lags, multiday lags, or by selecting lags a priori (Section 3.1.10.3). For
respiratory health effects, when examining more overt effects, such as respiratory-related hospital
admissions and ED visits (i.e., asthma, COPD, and all respiratory outcomes), epidemiologic studies
reported strongest associations occurring within the 1st few days of exposure (i.e., in the range of 0 to
3 days). The effects of ozone exposure on subclinical respiratory endpoints, including lung function,
respiratory symptoms, and markers of airway inflammation, similarly occur at lags of 0 and 1 day. This
finding is consistent with the evidence from controlled human exposure and experimental animal studies
of respiratory effects occurring relatively soon after ozone exposures.
IS-30
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In summary, recent studies evaluated since the completion of the 2013 Ozone ISA (U.S. EPA.
2013b) support and expand upon the strong body of evidence indicating a "causal relationship" between
short-term ozone exposure and respiratory effects. Controlled human exposure studies demonstrate
ozone-induced FEVi decrements and respiratory tract inflammation at concentrations as low as 60 ppb
after 6.6 hours of exposure with exercise among young, healthy adults. The combination of lung function
decrements and respiratory symptoms has been observed following exposure to 70 ppb and greater ozone
concentrations over 6.6-hours and combined with exercise. Epidemiologic studies continue to provide
evidence that increased ozone concentrations are associated with a range of respiratory effects, including
asthma exacerbation, COPD exacerbation, respiratory infection, and hospital admissions and ED visits for
combined respiratory diseases. A large body of animal toxicological studies demonstrate ozone-induced
changes in lung function measures, inflammation, increased airway responsiveness, and impaired lung
host defense. Additionally, mouse models indicate enhanced ozone-induced inflammation, oxidative
stress, injury, allergic skewing, goblet cell metaplasia, and upregulation of mucus synthesis and storage in
allergic mice compared with naive mice. These toxicological results provide further information on the
potential mechanistic pathways that underlie downstream respiratory effects. They also provide continued
support for the biological plausibility of the observed epidemiologic results. Thus, the recent evidence
integrated across disciplines, along with the total body of evidence evaluated in previous assessments, is
sufficient to conclude that there is a "causal relationship" between short-term ozone exposure and
respiratory effects.
IS.4.3.2 Long-Term Exposure and Respiratory Effects
The 2013 Ozone ISA concluded that there was "likely to be causal relationship" between
long-term exposure to ozone and respiratory health effects (U.S. EPA. 2013b). The epidemiologic
evidence for a relationship between long-term ozone exposure and respiratory effects in the 2013 Ozone
ISA was provided by epidemiologic studies that typically evaluated the association between the annual
average of daily ozone concentrations and new-onset asthma, respiratory symptoms in children with
asthma, and respiratory mortality. Notably, associations of long-term ozone concentrations with
new-onset asthma in children and increased respiratory symptoms in individuals with asthma were
primarily observed in studies that examined interactions between ozone and exercise or different genetic
variants. The evidence relating new-onset asthma to long-term ozone exposure was supported by
toxicological studies of allergic airways disease in infant monkeys exposed to biweekly cycles of
alternating filtered air and ozone (i.e., 9 consecutive days of filtered air and 5 consecutive days of 0.5 ppm
ozone, 8 hours/day). This evidence from a nonhuman primate study of ozone-induced changes in the
airways provided biological plausibility for early-life exposure to ozone contributing to asthma
development in children. Generally, the consistent evidence from epidemiologic and animal toxicological
studies formed the basis of the conclusions that there is "likely to be causal relationship" between
long-term exposure to ambient ozone and respiratory effects. Uncertainties in the evidence base included
limited assessment of potential copollutant confounding and the potential for exposure measurement error
IS-31
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relating to exposure assignment from fixed site monitors in epidemiologic studies. Although potential
copolluant confounding was examined in a limited number of epidemiologic studies, results suggested
that the reported associations were robust to adjustment for other pollutants, including PM2 5. Building
upon the evidence from the 2013 Ozone ISA, more recent epidemiologic evidence, combined with
toxicological studies in rodents and nonhuman primates, provides coherence and biological plausibility to
support that there is a "likely to be causal relationship" between long-term exposure to ozone and
respiratory effects.
Recent studies continue to examine the relationship between long-term exposure to ozone and
respiratory effects. Key evidence supporting the causality determination is presented in Table IS-5. A
limited number of recent epidemiologic studies provide generally consistent evidence that long-term
ozone exposure is associated with the development of asthma in children (Section 3.2.4.1.1). In addition
to investigating the development of asthma, epidemiologic studies have evaluated the relationship
between ozone exposure and asthma severity (Section 3.2.4.5). Like the studies described in the 2013
Ozone ISA (U.S. EPA. 2013b). recent studies provide evidence of consistent positive associations
between long-term exposure to ozone and hospital admissions and ED visits for asthma and prevalence of
bronchitic symptoms in children with asthma. Notably, some uncertainty remains about the validity of the
results from studies examining long-term ozone exposure and hospital admissions and ED visits for
asthma, because most of these studies do not adjust for short-term ozone concentrations, despite the
causal relationship between short-term exposure and asthma exacerbation (Section 3.1.4.2).
Table IS-5 Summary of evidence from epidemiologic and animal toxicological
studies on the respiratory effects associated with long-term ozone
exposure.
Conclusions from 2013 Ozone ISA Conclusions from 2020 ISA3
Respiratory effects Epidemiologic evidence, combined with
toxicological studies in rodents and nonhuman
primates, provided biologically plausible
evidence that there is likely to be causal
relationship between long-term exposure to
ozone and respiratory effects.
Epidemiologic evidence, combined with
toxicological studies in rodents and
nonhuman primates, continue to provide
biologically plausible evidence for respiratory
effects due to long-term ozone exposure.
Overall, the collective evidence is
sufficient to conclude that there is a likely
to be causal relationship between
long-term ozone exposure and
respiratory effects.
IS-32
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Table IS-5 (Continued): Summary of evidence from epidemiologic and animal
toxicological studies on the respiratory effects
associated with long-term ozone exposure.
Conclusions from 2013 Ozone ISA
Conclusions from 2020 ISA3
New onset asthma Animal toxicological studies provided evidence
that perinatal exposure to ozone compromises
airway growth and development in infant
monkeys (500 ppb; 6 h a day, 5 days a week for
20 weeks). Animal toxicological studies also
demonstrate increased airway responsiveness,
allergic airways responses, and persistent
effects on the immune system, which may lead
to the development of asthma. There is
evidence that different genetic variants (HMOX,
GST, ARG), in combination with ozone
exposure, are related to new-onset asthma.
These associations were observed when
subjects living in areas where the mean annual
8-h daily max ozone concentration was
55.2 ppb, compared with those who lived in
areas with a mean of 38.4 ppb.
Recent epidemiologic studies provide
generally consistent evidence for
associations of long-term ozone exposure
with the development of asthma in children.
Associations observed in locations with
mean annual concentrations of 32.1 ppb in
one study that reported study mean
concentrations (community-specific annual
average concentrations ranged from 26 to
76 ppb). Recent animal toxicological studies
demonstrate effects on airway development
in rodents (500 ppb; 6 h a day for
3-22 weeks) and build on and expand the
evidence for long-term ozone
exposure-induced effects that may lead to
asthma development.
Asthma hospital Epidemiologic studies provided evidence that
admissions long-term ozone exposure is related to
increased hospital admissions in children and
adults, and first childhood asthma hospital
admissions in a linear concentration-response
relationship. Generally, these studies had mean
annual 8-h daily max ozone concentrations less
than 41 ppb.
Long-term exposure is associated with
hospital admissions and ED visits for asthma
in study locations with mean annual ozone
concentrations between 30.6 and 47.7 ppb,
although uncertainties remain because most
studies do not adjust for short-term ozone
concentrations.
Pulmonary Evidence for pulmonary function effects was
structure and inconsistent, with some epidemiologic studies
function observing positive associations (mean annual
8-h daily max ozone concentrations less than
65 ppb). Results from toxicological studies
demonstrated that long-term exposure of adult
monkeys and rodents (>120 ppb; 6 h a day,
5 days a week for 20 weeks) can result in
irreversible morphological changes in the lung,
which in turn can influence pulmonary function.
Recent animal toxicological studies provide
evidence that postnatal ozone exposure may
affect processes in the developing lung,
including impaired alveolar morphogenesis,
a key step in lung development, in infant
monkeys (500 ppb; 6 h a day for
3-22 weeks). Notably, the impairments in
alveolar morphogenesis were reversible
(reversibility of the other effects was not
studied). A limited number of recent
epidemiologic studies continue to provide
inconsistent support for an association
between long-term ozone exposure and lung
function development in children.
Pulmonary Several epidemiologic studies (mean 8-h max
inflammation, ozone concentrations less than 69 ppb) and
injury, and animal toxicological studies (as low as 500 ppb)
oxidative stress added to existing evidence of ozone-induced
inflammation and injury.
Recent experimental studies in animals
provide evidence that postnatal ozone
exposure may affect the developing lung
(500 ppb). Results from studies of neonatal
rodents demonstrate ozone-induced
changes in injury and inflammatory and
oxidative stress responses during lung
development (1,000 ppb).
Lung host Evidence demonstrated a decreased ability to
defenses respond to pathogenic signals in infant monkeys
exposed to 500 ppb ozone and an increase in
severity of post-influenza alveolitis in rodents
exposed to 500 ppb.
A recent study demonstrates decreased
ability to respond to pathogenic signals in
infant monkeys exposed to 500 ppb.
IS-33
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Table IS-5 (Continued): Summary of evidence from epidemiologic and animal
toxicological studies on the respiratory effects
associated with long-term ozone exposure.
Conclusions from 2013 Ozone ISA
Conclusions from 2020 ISA3
Allergic responses
Evidence demonstrated a positive association
between allergic response and ozone exposure,
but the magnitude of the association varied
across studies; exposure to ozone may increase
total IgE in adult asthmatics. Allergic indicators
in infant monkeys and adult rodents were
increased by exposure to ozone concentrations
of 500 ppb.
Cross-sectional epidemiologic studies
provide generally consistent evidence that
ozone concentrations (mean annual
concentration less than 51.5 ppb) are
associated with hay fever/rhinitis and
serum-markers of allergic response,
although uncertainties related to study
design and potential confounding by pollen
remain. A recent animal toxicological study
provides evidence of ozone-induced airway
eosinophilia in a mouse model of allergic
sensitization (100 ppb; 0.33 h per day for
5 days per week for 2 weeks and once
weekly for 12 weeks).
Development of Animal toxicological studies provided evidence
COPD that long-term ozone exposure could lead to
persistent inflammation and interstitial
remodeling in adult rodents and monkeys,
potentially contributing to the development of
chronic lung disease such as COPD. The 2013
Ozone ISA did not evaluate any epidemiologic
studies that examined the relationship between
long-term exposure to ozone and the
development of COPD.
One recent epidemiologic study provides
evidence of an association between
long-term ozone concentrations and incident
COPD hospitalizations (mean annual
concentrations 39.3 ppb). Recent animal
toxicological studies provide consistent
evidence that subchronic ozone exposure
(500-1,000 ppb) can lead to airway injury
and inflammation. In adult animals, these
changes may underlie the progression and
development of chronic lung disease and
provide biological plausibility for
ozone-induced development of COPD.
Respiratory A single study demonstrated that exposure to
mortality ozone (long-term mean ozone less than
104 ppb) elevated the risk of death from
respiratory causes. This effect was robust to the
inclusion of PM2.5 in a copollutant model.
Recent epidemiologic studies provide some
evidence of an association with respiratory
mortality, but the evidence is not consistent
(mean annual ozone concentrations
25.9-57.5 ppb). New evidence from one
study reports an association with COPD
mortality.
Conclusions from the 2020 ISA include evidence from recent studies integrated with evidence included in previous Ozone ISAs
and AQCDs.
In support of evidence from recent epidemiologic studies, a number of recent animal
toxicological studies expand the evidence base for long-term ozone exposure-induced effects leading to
asthma development (Section 3.2.4.1.2). Specifically, both older and more recent long-term ozone
exposure studies in nonhuman primates show that postnatal ozone exposure can compromise airway
growth and development, promote the development of an allergic phenotype, and cause persistent
alterations to the immune system (Section 3.2.4.6.2). In addition, findings that ozone exposure enhances
injury, inflammation, and allergic responses in allergic rodents provide biological plausibility for the
relationship between ozone exposure and the exacerbation of allergic asthma.
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In addition to studies of asthma, several new or expanded lines of evidence from epidemiologic
and animal toxicological studies published since the completion of the 2013 Ozone ISA provide evidence
of associations between long-term ozone exposure and the development of COPD (Section 3.2.4.3) and
allergic responses (Section 3.2.4.6). A recently available epidemiologic study provides limited evidence
that long-term ozone exposure is associated with incident COPD hospitalizations in adults with asthma.
This finding is supported by recent animal toxicological studies that provide consistent evidence of
airway injury and inflammation resulting from subchronic ozone exposures. These results are coherent
with animal toxicological studies reviewed in the 2013 Ozone ISA, which demonstrated that chronic
ozone exposure damages distal airways and proximal alveoli, resulting in persistent inflammation and
lung tissue remodeling that leads to irreversible changes including fibrotic- and emphysematous-like
changes in the lung. Respiratory tract inflammation and morphologic and immune system-related changes
may underlie the progression and development of chronic lung disease like COPD.
A larger body of epidemiologic studies also supports an association between long-term ozone
exposure and allergic responses, including hay fever/rhinitis and serum allergen-specific IgE. While
recent studies demonstrate generally consistent results, potential confounding by pollen exposure remains
an uncertainty. However, there is supporting evidence from animal toxicological studies demonstrating
enhanced allergic responses in allergic rodents (Section 3.2.4.6.2). In addition, animal toxicological
studies reviewed in the short-term exposure section show type 2 immune responses in nasal airways of
rodents exposed repeatedly to ozone, indicating that ozone exposure can trigger allergic responses
(Section 3.1.4.4.2). These findings are characteristic of induced nonatopic asthma and rhinitis and provide
biological plausibility for the observed epidemiologic associations with hay fever/rhinitis.
Taken together, previous and more recent animal toxicological studies of long-term exposure to
ozone provide biological plausibility for the associations reported in the recent epidemiologic studies.
Specifically, there is strong evidence of ozone-induced inflammation, injury, and oxidative stress in adult
animals. These effects represent initial events through which ozone may lead to a number of downstream
respiratory effects, including altered morphology in the lower respiratory tract and the development of
COPD. Furthermore, there is evidence of a range of ozone-induced effects on lung development in
neonatal rodents and infant monkeys, including altered airway architecture, airway sensory nerve
innervation, airway cell death pathways, increased serotonin-positive airway cells, and
immunomodulation. An infant monkey model of allergic airway disease also demonstrated effects on lung
development, including compromised airway growth, impaired alveolar morphogenesis, airway smooth
muscle hyperreactivity, an enhanced allergic phenotype, priming of responses to oxidant stress, and
persistent effects on the immune system. These various upstream effects provide a plausible pathway
through which ozone may act on downstream events. These events include altered immune function
leading to altered host defense and allergic responses, as well as morphologic changes leading to the
development of asthma. A more thorough discussion of the biological pathways that potentially underlie
respiratory health effects resulting from long-term exposure to ozone can be found in Section 3.2.3.
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Recent epidemiologic studies provide some evidence that long-term ozone exposure is associated
with respiratory mortality, but the evidence is not consistent across studies (Section 3.2.4.9). A recent
nationwide study in the U.S. reported associations between ozone and the underlying causes of respiratory
mortality, including COPD. This finding is supported by the new lines of evidence from animal
toxicological and epidemiologic studies on the development of COPD, as discussed previously. Results
from epidemiologic studies of ozone-related respiratory mortality in populations outside the U.S. are
inconsistent.
A notable source of uncertainty across the reviewed epidemiologic studies is the lack of
examination of potential copollutant confounding. A limited number of studies that include results from
copollutant models suggest that ozone associations may be attenuated but still positive after adjustment
for NO2 or PM2 5. However, the few studies that include copollutant models examine different outcomes,
making it difficult to draw strong conclusions about the nature of potential copollutant confounding for
any given outcome. Importantly, in addition to studies that explicitly address potential copollutant
confounding through modeling adjustments, many studies report modest copollutant correlations,
suggesting that strong confounding due to copollutants is unlikely. Another source of uncertainty
common to epidemiologic studies of air pollution is the potential for exposure measurement error. The
majority of recent epidemiologic studies of long-term ozone exposure use concentrations from fixed-site
monitors as exposure surrogates. Exposure measurement error relating to exposure assignment from
fixed-site monitors has the potential to bias effect estimates in either direction, although it is more
common that effect estimates are underestimated, and the magnitude of the bias is likely small relative to
the magnitude of the effect estimate, given that ozone concentrations do not vary over space as much as
other criteria pollutants, such as NO2 or SO2 (Section 2.3.1.1).
Strong coherence from animal toxicological studies supports the observed epidemiologic
associations related to respiratory morbidity. Experimental evidence also provides biologically plausible
pathways through which long-term ozone exposure may lead to respiratory effects. Overall, the
collective evidence supports a "likely to be causal relationship" between long-term ozone exposure
and respiratory effects.
IS.4.3.3 Short-Term Exposure and Metabolic Effects
The metabolic effects reviewed in this ISA include the risk factors and related endpoints for
metabolic syndrome, complications due to diabetes, and indicators of metabolic function. Metabolic
syndrome is a clinical diagnosis used to describe a collection of risk factors that include high blood
pressure (elevated systolic and/or diastolic blood pressure), dyslipidemia (elevated triglycerides and low
levels of high-density lipoprotein [HDL] cholesterol), obesity (central obesity), and increased fasting
blood glucose (Alberti et al.. 2009). Diagnosis of metabolic syndrome in humans is based on the presence
of three of these five risk factors (Alberti et al.. 2009). The presence of these risk factors may predispose
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individuals to an increased risk of type 2 diabetes and cardiovascular disease. Diabetes is characterized by
hyperglycemia (i.e., elevated glucose level) resulting from defects in insulin signaling, secretion, or both.
Indicators of metabolic function include adipose tissue inflammation, altered liver function, and
alterations in adrenal hormones, among other endpoints.
The evidence was not sufficient to evaluate metabolic effects as a separate health effect category
in the 2013 Ozone ISA. As a result, there were no causality determinations for metabolic effects in the
2013 Ozone ISA (U.S. EPA. 2013b). Since the completion of the 2013 Ozone ISA, the number of studies
examining the relationship between short-term ozone exposure and metabolic effects has expanded
substantially (Table IS-6). This recent evidence, primarily from experimental animal studies,
demonstrates that short-term ozone exposure triggers a stress response that leads to a cascade of transient
metabolic effects. Consistent animal toxicological evidence from multiple laboratories demonstrates that
short-term ozone exposure increases circulating levels of adrenaline and corticosterone, released from the
adrenal medulla and adrenal cortex, respectively (Section 5.1.5.3.2). This evidence is coherent with
results of a controlled human exposure study demonstrating that short-term ozone exposure to 300 ppb
resulted in increased circulating Cortisol and corticosterone. In animals, the metabolic effects that follow
short-term ozone exposure are similar to those that are used in the clinical diagnosis of metabolic
syndrome in humans. The strongest and most consistent evidence is for glucose and insulin homeostasis.
Several high-quality animal toxicological studies from multiple laboratories demonstrate that short-term
ozone exposure impairs glucose tolerance and causes insulin resistance (Section 5.1.3). Some but not all
animal toxicological studies show ozone-induced fasting hyperglycemia, with inconsistencies between
studies potentially caused by differences in rodent stock, strain, sex, or diet. Multiple animal toxicological
studies in several rodent strains demonstrate that short-term ozone exposure increases serum levels of
triglycerides and free fatty acids, results that are consistent with the mobilization of energy stores and
increased glucose (Section 5.1.3.2). Coherent with results in animal models, the controlled human
exposure study reported increases in medium- and long-chain circulating free fatty acids following
short-term exposure to 300 ppb ozone. However, this study did not find ozone-induced changes in serum
insulin, nonfasting glucose, insulin resistance, or triglyceride levels. Some epidemiologic studies
examining changes in glucose and lipids provide support for effects associated with short-term ozone
exposure.
There is additional evidence for ozone-induced metabolic effects from experimental animal
toxicological studies that are the same effects used for the clinical diagnosis of metabolic syndrome in
humans. This generally consistent evidence demonstrates that short-term ozone exposure affects
obesity-relevant endpoints and causes adipose tissue inflammation. Some, but not all, animal
toxicological studies reported that short-term ozone exposure reduces body-weight gain1 in rodent models
of diabetes and of spontaneous hypertension (Section 5.1.5). In addition, multiple animal toxicological
studies from different laboratories consistently reported that short-term ozone exposure affected levels of
1 Reductions or increases in body-weight gain can indicate altered metabolic function in animal models of disease,
such as those used in these studies.
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leptin, a hormone that regulates food intake. In coherence with these results, an epidemiologic study
reported trends for an association between short-term ozone exposure and changes in the obesity-related
hormones. In addition to changes in hormone levels, multiple animal toxicological studies in both healthy
and disease-prone rodent models showed that short-term ozone exposure can induce adipose tissue
inflammation (Section 5.1.5.IV Furthermore, while several studies reported null effects, others reported
that short-term ozone exposure can affect levels of HDL, LDL, and total cholesterol, with the
directionality of the effect varying by the rodent model and exposure duration (Section 5.1.5.1). Finally,
some animal toxicological studies provide evidence that short-term ozone exposure affects blood pressure
(Section 5.1.3.5).
Table IS-6 Summary of evidence from epidemiologic, controlled human
exposure, and animal toxicological studies on the metabolic effects
of short-term exposure to ozone.
Results and Conclusions from 2020 ISA
Metabolic effects
Recent evidence from controlled human exposure, epidemiologic, and animal
toxicological studies support a likely to be causal relationship between short-term
ozone exposure and metabolic effects.
Effects contributing to
the clinical diagnosis of
metabolic syndrome in
humans
Animal toxicological studies provide evidence for elevated triglycerides and fasting
hyperglycemia. Evidence is present, though less consistent, for low HDL cholesterol, high
blood pressure, and central adiposity.
Complications from
diabetes
An epidemiologic study provides evidence of associations between increases in
short-term ozone exposure and hospital admissions for diabetic ketoacidosis and diabetic
coma in older population subgroups.
Other indicators of
metabolic function
Multiple metabolic indicators provide evidence that ozone exposure induces changes
within the liver, affecting glucose homeostasis. Healthy volunteers who exercised with
ozone exposure in controlled human exposure studies had increased ketone body
formation. In animal toxicological studies, ozone exposure induced changes to the liver,
including hepatic gluconeogenesis, altered bile acid profile, alterations to (3-oxidation, and
alterations to proteins in hepatic metabolic pathways. In addition, elevated circulating
stress hormones were consistently observed in animal models and in a single controlled
human exposure study. Removal of the adrenal glands prevented the release of
adrenaline and corticosterone, and furthermore, prevented ozone-induced metabolic
effects in animal toxicological studies. Thus, neuroendocrine stress activation may be a
primary mechanism through which adverse metabolic outcomes develop from short-term
ozone exposure.
Recent studies of short-term ozone exposure and metabolic effects evaluated associations
between different age groups. One epidemiologic study observed increased risk among older adults
(e.g., 75-84 years and 85+ years) compared with other age groups (<65 years) for hospital admissions for
diabetic coma (Section 5.1.7.1) with a 24-hour avg ozone concentration across study areas of 64.4 ppb. In
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addition, an animal toxicological study demonstrated increases in metabolic indicators (i.e., increased
triglycerides and serum insulin) in aged animals.
Despite limited controlled human exposure and epidemiologic evidence, the expanding body of
animal toxicological studies shows robust evidence for short-term ozone exposure contributing to an array
of metabolic effects. These outcomes follow a biologically plausible pathway whereby ozone exposure
results in release of adrenaline and cortisol/corticosterone from the adrenal glands. These hormones act on
multiple organs and tissues of the metabolic system to mobilize energy reserves, including glucose and
lipids. In summary, based on evidence from animal toxicological and epidemiologic studies, as well as
some support from one controlled human exposure study, short-term ozone exposure consistently impairs
glucose and insulin homeostasis and increases triglycerides and fatty acids. In line with this, animal
toxicological studies show that inhibiting adrenaline and/or corticosterone, through either removal of the
adrenal glands or adrenal medulla, or by blocking the synthesis of corticosterone, prevents ozone-induced
metabolic effects, including hyperglycemia, glucose intolerance, and elevated circulating triglycerides. In
addition, there are generally consistent effects from animal toxicological studies showing that short-term
ozone exposure affects obesity-relevant endpoints and causes inflammation in adipose tissue. Further
supporting evidence comes from a limited number of animal toxicological studies providing some
evidence for alterations in HDL, LDL, and total cholesterol and changes in blood pressure following
short-term ozone exposure. Overall, the collective evidence is sufficient to conclude that the
relationship between short-term ozone exposure and metabolic effects is likely to be causal.
IS.4.3.4 Short-Term Exposure and Cardiovascular Effects
The 2013 Ozone ISA concluded that there is a "likely to be causal" relationship between relevant
short-term exposures and cardiovascular effects, but it also identified important uncertainties (U.S. EPA.
2013b). The available animal toxicological studies demonstrated ozone-induced impaired vascular and
cardiac function, as well as changes in heart rate (HR) and heart rate variability (HRV). The controlled
human exposure studies provided additional evidence but had limited coherence with the evidence from
animal studies. The epidemiologic evidence, while reporting associations between short-term ozone
exposure and cardiovascular mortality, did not show associations between short-term ozone exposure and
cardiovascular morbidity. This lack of coherence between the results for studies investigating associations
of cardiovascular morbidity with cardiovascular mortality was recognized as a complication in
interpreting the overall evidence for ozone-induced cardiovascular effects.
More recent animal toxicological studies published since the 2013 Ozone ISA provide generally
consistent evidence for impaired heart function and endothelial dysfunction, but limited evidence for
indicators of arrhythmia, HRV, and markers of oxidative stress and inflammation in response to ozone
exposure. Additional controlled human exposure studies have been published in recent years, although
they show little evidence for ozone-induced effects on cardiovascular endpoints. Specifically, some recent
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studies do not indicate an effect of ozone on cardiac function, ST segment, endothelial dysfunction, or
HR, while some evidence from a small number of controlled human exposure studies indicates ozone
exposure can result in changes in blood pressure, indicators of arrhythmia, HRV, markers of coagulation,
and inflammatory markers. The number of epidemiologic studies evaluating short-term ozone
concentrations and cardiovascular effects has grown somewhat, but overall, remains limited and continues
to provide little, if any, evidence for associations with heart failure, heart attack, arrhythmia and cardiac
arrest, or stroke. Recent epidemiologic evidence for short-term ozone exposure and cardiovascular
mortality is limited to one multicity study, but the collective body of evidence spanning multicity studies
evaluated in the 2013 Ozone ISA provides evidence of consistent positive associations. Overall, many of
the same limitations and uncertainties that existed in the body of evidence in the 2013 Ozone ISA
continue to exist. However, the number of controlled human exposure studies evaluating short-term ozone
exposure and cardiovascular endpoints has grown, and now includes studies at concentrations closer to
those likely to be encountered in U.S. ambient air. When evaluated in the context of the studies available
for the 2013 Ozone ISA, the controlled human exposure study evidence, overall, is less consistent and
less indicative of a relationship (Table IS-7).
Table IS-7 Summary of evidence from epidemiologic, controlled human
exposure, and animal toxicological studies on the cardiovascular
effects of short-term ozone exposure.
Conclusions from 2013 Ozone ISA
Conclusions from 2020 ISA
Cardiovascular effects
Evidence from animal toxicological
studies demonstrated ozone-induced
impaired vascular and cardiac function,
as well as changes in HR and HRV. This
evidence was supported from a limited
number of controlled human exposure
studies in healthy adults demonstrating
changes in HRV, as well as in blood
markers associated with an increase in
coagulation. There was limited or no
evidence from epidemiologic studies for
short-term ozone exposure and
cardiovascular morbidity, such as effects
related to HF, IHD, and Ml, arrhythmia
and cardiac arrest, or thromboembolic
disease. There was consistent evidence
from epidemiologic studies reporting
positive associations between short-term
ozone exposure and
cardiovascular-related mortality. Overall,
there is likely to be causal relationship
between long-term exposure to ozone
and cardiovascular effects.
Recent animal toxicological studies continue to
provide evidence for impaired heart function
and endothelial dysfunction, with limited
evidence from a small number of studies for
indicators of arrhythmia, HRV, and markers of
oxidative stress and inflammation in response
to ozone exposure. Recent controlled human
exposure studies provide little evidence for
ozone-induced effects on a number of
cardiovascular endpoints. No effect of ozone
was reported for indicators of cardiac function,
IHD, endothelial dysfunction, or changes in
HR. There is limited or inconsistent evidence
from a small number of studies for changes in
cardiac electrophysiology, HRV, blood
pressure, markers of coagulation, and
inflammatory markers. Epidemiologic studies
remain few and continue to provide little, if any,
evidence for associations with HF, IHD, and
Ml, arrhythmia and cardiac arrest, or stroke.
Overall, the evidence is suggestive of, but
not sufficient to infer, a causal relationship.
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Table IS-7 (Continued): Summary of evidence from epidemiologic, controlled
human exposure, and animal toxicological studies on the
cardiovascular effects of short-term ozone exposure.
Conclusions from 2013 Ozone ISA
Conclusions from 2020 ISA
Heart failure, impaired
heart function
A limited number of animal toxicological
studies demonstrated ozone-induced
cardiovascular effects, including
decreased cardiac function.
Epidemiologic studies generally did not
observe associations between short-term
ozone exposure and cardiovascular
morbidity; studies of
cardiovascular-related hospital
admissions and ED visits did not find
consistent evidence of a relationship with
ozone exposure.
Multiple animal toxicological studies report
some indicators of impaired cardiac function
following short-term ozone exposure
(~200-300 ppb for 3-4 h). However, a recent
controlled human exposure study (100 and
200 ppb for 3 h) reported no changes in
measures of cardiac function. There is a
limited number of recent studies of hospital
admissions and ED visits that analyzed
associations with heart failure, and they
continue to report inconsistent associations
with short-term exposure to ozone.
Ischemic heart disease
Animal toxicological studies, although
few, demonstrated ozone-induced
cardiovascular effects, including
enhanced ischemia/reperfusion (l/R)
injury. Epidemiologic studies generally did
not observe associations between
short-term ozone exposure and
cardiovascular morbidity; studies of
cardiovascular-related hospital
admissions and ED visits did not find
consistent evidence of a relationship with
ozone exposure.
An animal toxicological study in SH rats
demonstrates ST segment depression
following an 800- but not 200-ppb exposure to
ozone for 4 h. However, no such changes are
observed in the single controlled human
exposure study (70 and 120 ppb for 3 h).
Recent epidemiologic studies consistently
report null or weak positive effect estimates in
analyses of Ml, including for STEMI and
NSTEMI.
Cardiac and endothelial
dysfunction
Animal toxicological studies, although
limited in number, demonstrated
ozone-induced cardiovascular effects,
including vascular disease and injury.
Recent animal toxicological studies
demonstrate generally consistent evidence for
impaired cardiac and endothelial function in
rodents following short-term ozone exposure of
400-1,000 ppb for 4 h. However, coherence
with controlled human exposure and
epidemiologic studies is lacking.
Cardiac
electrophysiology,
arrhythmia, cardiac
arrest
Animal toxicological studies, although
few, demonstrated ozone-induced
cardiovascular effects, including disrupted
nitric oxide-induced vascular reactivity.
Epidemiologic studies reported generally
positive associations for hospital
admissions or ED visits due to arrythmia
or dysrhythmia.
A small number of recent animal toxicological
studies demonstrate some evidence for
changes in indicators of conduction
abnormalities (800 but not 200 ppb for 3-4 h).
Multiple controlled human exposure studies
report little effect of short-term ozone exposure
on conduction abnormalities (70 and 120 ppb
for 2-3 h). Increases in out-of-hospital cardiac
arrests associated with 8-h max or 24-h avg
increases in ozone concentrations were
reported by a few case-crossover studies;
however, analyses of other endpoints
(e.g., dysrhythmia, arrhythmia, or atrial
fibrillation) generally report null results.
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Table IS-7 (Continued): Summary of evidence from epidemiologic, controlled
human exposure, and animal toxicological studies on the
cardiovascular effects of short-term ozone exposure.
Conclusions from 2013 Ozone ISA
Conclusions from 2020 ISA
Blood pressure
changes and
hypertension
A limited number of epidemiologic studies
reported inconsistent associations with
measures of blood pressure. Two studies
observed increases in DBP associated
with ozone concentration, but the
association was attenuated to null after
adjusting for PM2.5 concentrations.
Recent animal toxicological studies
demonstrate inconsistent effects of
ozone-induced effects on changes in blood
pressure (300 and 500 ppb for 3-8 h).
Multiple controlled human exposure studies
report no evidence of an ozone-induced effect
on blood pressure (120-700 ppb for 1-3 h),
while a single controlled human exposure
study reported a decrease in DBP. Few
epidemiologic panel studies evaluated blood
pressure, and the results were inconsistent.
Heart rate and heart
rate variability
Animal toxicological studies, although
few, demonstrated ozone-induced
cardiovascular effects, including
increased HRV. Controlled human
exposure studies provided some
coherence with the evidence from animal
toxicological studies, by demonstrating
increases and decreases in HRV
following relatively low (120 ppb during
rest) and high (300 ppb with exercise)
ozone exposures, respectively.
Evidence is inconsistent for changes in HR in
animals (~200-800 ppb for 3-8 h) and lacking
for changes in HR in healthy adults from
multiple controlled human exposure studies
(70-300 ppb for 1-4 h). With respect to HRV,
there is limited evidence for changes in animal
toxicological (200-800 ppb for 3-4 h) and
controlled human exposure (70-300 ppb for
1-4 h) studies. Similarly, recent epidemiologic
panel studies have reported inconsistent
associations between short-term exposure to
ozone and both HR and HRV.
Coagulation and
thrombosis
A controlled human exposure study
demonstrated changes in markers of
coagulation following short-term ozone
exposure. Specifically, there were
decreases in PAI-1 and plasminogen
levels and a trend toward an increase in
tPA. There was very limited animal
toxicological evidence that short-term
exposure to ozone could result in an
increase in factors related to coagulation.
Epidemiologic studies observed
inconsistent results for coagulation
biomarkers such as PAI-1, fibrinogen,
and vWF.
Recent animal toxicological studies provide
limited evidence for changes in factors that
may promote coagulation (250-1,000 ppb for
4 h). Similarly, there is limited additional
evidence from recent controlled human
exposure studies that short-term ozone
exposure can result in changes to markers of
coagulation that may promote thrombosis
(100-300 ppb for 1-2 h). Epidemiologic
studies continue to observe inconsistent
associations with changes in biomarkers of
coagulation.
Systemic inflammation
and oxidative stress
Controlled human exposure studies
demonstrated ozone-induced effects on
blood biomarkers of systemic
inflammation and oxidative stress.
There is inconsistent evidence from recent
animal toxicological studies for an increase in
markers associated with systemic inflammation
and oxidative stress (300-800 ppb for 2-24 h)
and some evidence for increases in markers of
systemic inflammation from CHE studies
(100-300 ppb for 0.5-4 h). Additionally, the
newly available epidemiologic panel study did
not observe an association between short-term
ozone concentrations and myeloperoxidase.
Stroke
A limited number of epidemiologic studies
observed inconsistent associations with
stroke.
Inconsistent results were observed in several
recent epidemiologic studies that analyzed
hospital admissions and ED visits for stroke
and stroke subtypes.
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Table IS-7 (Continued): Summary of evidence from epidemiologic, controlled
human exposure, and animal toxicological studies on the
cardiovascular effects of short-term ozone exposure.
Conclusions from 2013 Ozone ISA
Conclusions from 2020 ISA
Cardiovascular hospital
admissions and ED
visits
With few exceptions, studies of ozone
concentrations and cardiovascular
hospital admissions and ED visits for all
CVD diagnoses combined did not report
positive associations.
Recent studies that reported a risk ratio for
combined cardiovascular disease outcomes
show a similar inconsistent pattern to those
studies included in the 2013 Ozone ISA.
Cardiovascular Multicity epidemiologic studies observed
mortality positive associations for cardiovascular
mortality in all-year and summer/warm
season analyses. Lack of coherence with
epidemiologic studies of cardiovascular
morbidity remains an important
uncertainty.
A recent multicity study is consistent with the
evidence examining cardiovascular mortality
evaluated in the 2013 Ozone ISA.
Conclusions from the 2020 ISA include evidence from recent studies integrated with evidence included in previous Ozone ISAs
and AQCDs.
When considered as a whole, the evidence is "suggestive of, but not sufficient to infer, a
causal relationship" between short-term exposure to ozone and cardiovascular effects. This causality
determination represents a change from the conclusion in the 2013 Ozone ISA. This change is largely
because the number of controlled human exposure studies showing little evidence of ozone-induced
cardiovascular effects has grown substantially, while the epidemiologic evidence for ozone effects on
endpoints other than mortality continues to be limited. Consequently, the plausibility for a relationship
between short-term ozone exposure to cardiovascular health effects is weaker than it was in the previous
review, leading to the revised causality determination.
IS.4.3.5 Short-Term Exposure and Total Mortality
Recent multicity epidemiologic studies conducted in the U.S. and Canada continue to provide
evidence of consistent, positive associations between short-term ozone exposure and total mortality in
both all-year and summer/warm season analyses across different averaging times (i.e., max daily 1-hour
max, max daily 8-hour avg, 8-hour avg, and 24-hour avg; Table IS-8). Cause-specific mortality
(e.g., respiratory mortality, cardiovascular mortality) was assessed in a limited number of recent studies.
The evidence from these recent studies is consistent with the pattern of positive associations reported for
studies evaluated in the 2013 Ozone ISA. Lastly, most of the recent multicity studies examined
associations between short-term ozone exposure and mortality using ozone data collected before the year
2000, with only Di et al. (2017) including more recent ozone concentration data.
Recent studies continue to assess the influence of important potential confounders on the
ozone-mortality relationship, including copollutants, temporal/seasonal trends, and weather covariates.
Overall, these studies report that associations remain relatively unchanged across the different approaches
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used to control for each confounder. The assessment of potential copollutant confounding in recent
studies demonstrates that associations between short-term ozone concentrations and mortality remain
positive in copollutant models with PMio or NO2. Importantly, the issues surrounding the assessment of
potential copollutant confounding that complicate interpretation of the ozone-mortality relationship (as
detailed in the 2013 Ozone ISA) persist, specifically within studies that relied on PM data collected using
every 3rd- and 6th-day sampling schedules (U.S. EPA. 2013b).
Building upon the 2013 Ozone ISA, there remains strong evidence for respiratory effects due to
short-term ozone exposure (Appendix 3) that is consistent within and across disciplines and which
provides coherence and biological plausibility for the positive respiratory mortality associations reported
across epidemiologic studies. Although there remains epidemiologic evidence for ozone-induced
cardiovascular mortality along with animal toxicological evidence of cardiovascular effects, recent
controlled human exposure studies do not provide evidence that is consistent with the controlled human
exposure studies presented in the 2013 Ozone ISA showing cardiovascular effects. Additionally, there is
limited evidence from epidemiologic studies of relationships between short-term ozone exposure and
more severe cardiovascular effects, such as emergency department visits and hospital admissions. The
limited experimental evidence, in combination with the lack of coherence between experimental and
epidemiologic studies of cardiovascular morbidity, does not allow for an understanding of potential
biological pathways leading to cardiovascular mortality (Appendix 4) or other causes of mortality.
Overall, the recent multicity studies conducted in the U.S. and Canada provide additional support
for the consistent, positive associations with total mortality reported across multicity studies evaluated in
the 2006 Ozone AQCD (U.S. EPA. 2006a) and 2013 Ozone ISA (U.S. EPA. 2013b). These results are
supported by studies that further examine uncertainties in the ozone-mortality relationship, such as
potential confounding by copollutants and other variables, modification by temperature, and the C-R
relationship and whether a threshold exists. Although there continues to be strong evidence from studies
of respiratory morbidity to support respiratory mortality, there remains relatively limited biological
plausibility and coherence within and across disciplines to support the epidemiologic evidence for
cardiovascular mortality, the largest contributor to total mortality. Collectively, evidence is "suggestive
of, but not sufficient to infer, a causal relationship" between short-term ozone exposure and total
mortality.
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Table IS-8 Summary of evidence from epidemiologic studies on the association
of short-term ozone exposure with mortality.
Conclusions from 2013 Ozone ISA
Results and Conclusions from 2020 ISAa
Mortality
Consistent, positive associations were
reported across multicity and
multicontinent studies in combination with
strong evidence from studies of
respiratory morbidity. There was evidence
from a limited number of studies of
cardiovascular morbidity, providing
coherence and biological plausibility.
Evidence demonstrated that there was
a likely to be causal relationship
between short-term ozone exposure
and mortality.
Recent multicity studies continue to provide
evidence of consistent, positive associations,
which is supported by strong evidence from
studies of respiratory morbidity, providing
coherence and biological plausibility. Recent
studies of cardiovascular morbidity do not
provide coherence between experimental and
epidemiologic studies, and therefore, biological
plausibility for cardiovascular mortality is
limited. Evidence is suggestive of, but not
sufficient to infer, a causal relationship
between short-term ozone exposure and
mortality.
Epidemiologic evidence Multicity and multicontinent studies
provided evidence of consistent positive
associations for total (nonaccidental),
respiratory, and cardiovascular mortality.
Recent multicity studies continue to provide
evidence of consistent, positive associations
with total (nonaccidental), respiratory, and
cardiovascular mortality, but the cause-specific
mortality evidence is limited to one recent
multicity study.
Copollutant
confounding
Ozone-mortality associations remained
positive and relatively unchanged in
copollutant models with PM and PM2.5
components, but analyses of PM2.5
components are limited by the every-3rd
and 6th-day sampling schedule.
Recent multicity studies have conducted a
limited assessment of potential copollutant
confounding, but report that ozone-mortality
associations remain positive and relatively
unchanged in copollutant models with PM10
and NO2, the only pollutants assessed.
Biological plausibility
The strong and consistent evidence
within and across scientific disciplines for
respiratory morbidity provided coherence
and biological plausibility for respiratory
mortality. For cardiovascular mortality,
controlled human exposure and animal
toxicological studies provided initial
evidence supporting a biologically
plausible mechanism by which short-term
ozone exposure could lead to
cardiovascular mortality, but there was
inconsistency in results between
experimental and epidemiologic studies
of cardiovascular morbidity.
There continues to be strong and consistent
evidence within and across disciplines for
respiratory morbidity, which provides
coherence and biological plausibility for
respiratory mortality. Although there remains
evidence of cardiovascular mortality, recent
controlled human exposure studies do not
report evidence of cardiovascular effects in
response to short-term ozone exposure and
epidemiologic studies provide limited evidence
of associations with more sever cardiovascular
effects, such as emergency department visits
and hospital admissions. Collectively, there is
a lack of coherence between experimental and
epidemiologic studies providing limited
evidence of a biologically plausible pathway to
cardiovascular mortality or to other causes of
mortality.
Conclusions from the 2020 ISA include evidence from recent studies integrated with evidence included in previous Ozone ISAs
and AQCDs.
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IS.4.3.6 Other Health Endpoints
The evidence for the other health endpoints not discussed in previous sections, including
long-term ozone exposure and cardiovascular and metabolic effects and mortality, and short- and
long-term ozone exposure and reproductive effects, nervous system effects, and cancer, is limited or
inconsistent, resulting in causality determinations of either "suggestive of, but not sufficient to infer, a
causal relationship" or "inadequate to infer the presence or absence of a causal relationship." The
evidence for these health effects is summarized here, with more details of the evidence that formed the
basis for these conclusions in Appendix 4. Appendix 5. Appendix 6. and Appendix 7.
15.4.3.6.1 Long-Term Ozone Exposure and Cardiovascular Effects
Collectively, the body of evidence for long-term ozone exposure and cardiovascular effects is
"suggestive of, but not sufficient to infer, a causal relationship." Recent animal toxicological and
epidemiologic studies add to the body of evidence that formed the basis of the conclusions in the 2013
Ozone ISA for cardiovascular health effects. This body of evidence is limited, however, with some
experimental and observational evidence for subclinical cardiovascular health effects and little evidence
for associations with outcomes such as IHD or MI, HF, or stroke. The strongest evidence for the
association between long-term ozone exposure and cardiovascular health outcomes continues to come
from animal toxicological studies of impaired cardiac contractility and epidemiologic studies of blood
pressure changes and hypertension and cardiovascular mortality. Recent epidemiologic studies observed
positive associations with changes in blood pressure or hypertension, but animal toxicological studies do
not report effects of ozone on blood pressure changes. In conclusion, the results observed across both
recent and older experimental and observational studies conducted in various locations provide limited
evidence for an association between long-term ozone exposure and cardiovascular health effects.
15.4.3.6.2 Long-Term Exposure and Metabolic Effects
In the 2013 Ozone ISA, evidence was insufficient to evaluate metabolic effects as a separate
health effect category. Therefore, no causality determinations for metabolic effects were made in that
document (U.S. EPA. 2013b). Since then, the epidemiologic and experimental literature investigating
long-term ozone exposure and outcomes related to metabolic effects has expanded substantially. Positive
associations between long-term exposure to ozone and diabetes-related mortality were observed in recent
evaluations of well-established cohorts in the U.S. and Canada. The mortality results are supported by
epidemiologic and experimental studies reporting effects on glucose homeostasis and serum lipids, as
well as other indicators of metabolic function (e.g., peripheral inflammation and neuroendocrine stress
response). Findings from an epidemiologic study of metabolic disease demonstrate increases in the
clinical diagnosis of metabolic syndrome. Additionally, in prospective cohort studies in the U.S. and
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Europe, increased incidence of type 2 diabetes is observed in association with long-term ozone exposure.
Despite an increased number of studies, many uncertainties remain regarding the metabolic effects related
to long-term ozone exposure. Most studies from the epidemiologic literature did not evaluate potential
copollutant confounding. There were a very limited number of studies available for review from the
animal toxicological literature; these studies had few overlapping endpoints, and furthermore, they were
primarily conducted by the same set of authors. Overall, considering the positive epidemiologic studies
and limited support from animal toxicological studies, the collective evidence is "suggestive of, but not
sufficient to infer, a causal relationship" between short-term exposure to ozone and metabolic
effects.
IS.4.3.6.3 Ozone Exposure and Reproductive Effects
Overall, the evidence is "suggestive of, but not sufficient to infer, a causal relationship"
between ozone exposure and (1) male and female reproduction and fertility and (2) pregnancy and
birth outcomes. Separate conclusions are made for these groups of reproductive effects because they are
likely to have different etiologies and critical exposure windows over different lifestages. The 2013
Ozone ISA concluded that the evidence was "suggestive of a causal relationship"1 between ozone
exposure and the inclusive category for all reproductive and developmental outcomes.
The strongest evidence in the 2013 Ozone ISA for effects on reproduction and fertility came from
epidemiologic and animal toxicological studies of sperm. Recent studies of sperm quality are consistent
with this evidence but remain limited. Uncertainties that contribute to the determination include a lack of
evaluation of copollutant confounding or multiple potential sensitive windows of exposure, and the
generally small sample size of studies in human subjects.
The strongest evidence in the 2013 Ozone ISA for effects on pregnancy and reproduction came
from epidemiologic studies of birth weight. Recent studies of birth weight are consistent with this
evidence but remain limited. There are several well-designed, well-conducted studies that indicate an
association between ozone and poorer birth outcomes, particularly for outcomes of continuous birth
weight and preterm birth. In particular, studies of preterm birth that examine exposures in the first and
second trimesters show fairly consistent positive associations (increased ozone exposures associated with
increased odds of preterm birth). In addition, some animal toxicological studies demonstrate decreased
birth weight and changes in uterine blood flow. Epidemiologic studies of continuous birth weight and
preterm birth did not generally adjust for potential copollutant confounding, although studies that did
appeared to show limited impacts. There is also inconsistency across exposure windows for associations
with continuous birth weight. Also, the magnitude of effect estimates varies.
1 Since 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.
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IS.4.3.6.4 Short-Term Ozone Exposure and Nervous System Effects
Overall, the evidence is "suggestive of, but not sufficient to infer, a causal relationship"
between short-term exposure to ozone and nervous system effects. The 2013 Ozone ISA concluded
that the evidence was "suggestive of a causal relationship"1 between short-term ozone exposure and
nervous system effects. The strongest evidence supporting this causality determination came from
experimental animal studies of CNS structure and function. Most of the recent experimental animal
studies demonstrate that short-term exposure to ozone induces oxidative stress and inflammation in the
central nervous system (Section 7.2.1.3). In some cases, these effects are associated with changes in brain
morphology and effects on neurotransmitters. In some instances, the effects of short-term ozone exposure
on the nervous system were exacerbated in aged animals. No epidemiologic studies of short-term ozone
exposure and nervous system effects were reviewed in the 2013 Ozone ISA, and the epidemiologic
evidence remains limited. Recent epidemiologic evidence consists only of a study reporting an association
between short-term ozone exposure and depressive symptoms, and several studies of hospital admissions
or ED visits for symptoms related to a range of nervous system diseases or mental disorders
(e.g., multiple sclerosis, Alzheimer's disease, Parkinson's disease, depression, psychiatric disorders).
These findings for depressive symptoms are coherent with experimental animal studies showing
depression-like behaviors in rodents. Biological plausibility of these effects is supported by multiple
toxicological studies in laboratory animals showing inflammation and morphological changes in the brain
following short-term ozone exposure (Section 7.2.1.2).
IS.4.3.6.5 Long-Term Ozone Exposure and Nervous System Effects
Overall, the evidence is "suggestive of, but not sufficient to infer, a causal relationship"
between long-term ozone exposure and nervous system effects. This conclusion is consistent with that
of the 2013 Ozone ISA. The strongest evidence supporting the causality determination for long-term
ozone exposure and nervous system effects from the 2013 Ozone ISA came from animal toxicological
studies demonstrating effects on CNS structure and function, with several studies indicating the potential
for neurodegenerative effects similar to Alzheimer's or Parkinson's diseases in a rat model. The body of
evidence has grown since the 2013 Ozone ISA. Recent epidemiologic studies have examined nervous
system effects, including cognitive effects, depression, neurodegenerative disease, and autism. Although
the epidemiologic evidence remains limited, the strongest evidence is for effects on cognition in adults.
Recent experimental animal studies continue to provide coherence for these effects. Several recent animal
toxicological studies report increased markers of oxidative stress and inflammation, including lipid
peroxidation, microglial activation, and cell death following long-term exposure to ozone. There was
some evidence to support that aged and young populations may have increased sensitivity to ozone
exposure. Uncertainties that contribute to the causality determination include the limited number of
epidemiologic studies, the lack of consistency across the available studies of Alzheimer's and Parkinson's
disease, and the limited evaluation of copollutant confounding in these studies. In addition, the evidence
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supporting the biological plausibility of the associations with autism or ASD in epidemiologic studies is
limited.
15.4.3.6.6 Long-Term Ozone Exposure and Cancer
The evidence describing the relationship between exposure to ozone and cancer remains
"inadequate to infer the presence or absence of a causal relationship." In the 2013 Ozone ISA, very
few studies were available to assess the relationship between long-term ozone exposure and cancer. The
few available epidemiologic and animal toxicological studies indicated that ozone exposure may
contribute to DNA damage. However, given the overall lack of studies, the 2013 Ozone ISA concluded
that the evidence was inadequate to determine whether a causal relationship existed between long-term
ozone exposure and cancer. More recent studies provide some additional animal toxicological evidence of
DNA damage. In addition, several, but not all, recent cohort and case-control studies have observed
positive associations between long-term ozone exposure and lung cancer incidence or mortality. Several
of the studies evaluating lung cancer mortality were conducted in populations that had already been
diagnosed with cancer in a different organ system. Associations between ozone exposure and other types
of cancer were generally null. Given the limited evidence base, the lack of an evaluation of copollutant
confounding in epidemiologic studies reporting associations, and the evaluation of study populations that
had already been diagnosed with cancer in several of the epidemiologic studies, the evidence is not
sufficient to draw a conclusion regarding causality.
15.4.3.6.7 Long-Term Ozone Exposure and Mortality
Collectively, this body of evidence is "suggestive of, but not sufficient to infer, a causal
relationship" between long-term ozone exposure and total mortality. Recent epidemiologic studies
add to the limited body of evidence that formed the basis of the conclusions of in 2013 Ozone ISA for
total mortality. This body of evidence is generally inconsistent, with some U.S. and Canadian cohorts
reporting modest positive associations between long-term ozone exposure and total mortality, while other
recent studies conducted in the U.S, Europe, and Asia reporting null or negative associations. The
strongest evidence for the association between long-term ozone exposure and total (nonaccidental)
mortality continues to come from analyses of patients with pre-existing disease from the Medicare cohort
and from recent evidence demonstrating positive associations with cardiovascular mortality. The evidence
from the assessment of ozone-related respiratory disease, with more limited evidence from cardiovascular
and metabolic morbidity, provides some biological plausibility for mortality due to long-term ozone
exposures. In conclusion, the inconsistent associations observed across both recent and older cohort and
cross-sectional studies conducted in various locations provide limited evidence for an association between
long-term ozone exposure and mortality.
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IS.4.4 At-Risk Populations
Interindividual variation in exposure to or human responses to ambient air pollution exposure can
result in some groups or lifestages being at increased risk for health effects. The NAAQS are intended to
protect public health with an adequate margin of safety. In so doing, protection is provided for both the
population as a whole and those potentially at increased risk for health effects in response to exposure to a
criteria air pollutant [e.g., ozone; see Preamble to the ISAs (U.S. EPA. 2015)1. There is interindividual
variation in both physiological responses, and exposure to ambient air pollution. The scientific literature
has used a variety of terms to identify factors and subsequently populations or lifestages that may be at
increased risk of an air pollutant-related health effect, including susceptible, vulnerable, sensitive, at risk,
and response-modifying factor rVinikoor-Imler et al. (2014); see Preamble to the ISAs (U.S. EPA. 2015)1.
Acknowledging the inconsistency in definitions for these terms across the scientific literature and the lack
of a consensus on terminology in the scientific community, "at-risk" is the all-encompassing term used in
ISAs for groups with specific factors that increase the risk of an air pollutant (e.g., ozone)-related health
effect in a population, as initially detailed in the 2013 Ozone ISA (U.S. EPA. 2013b). Therefore, this ISA
takes an inclusive and all-encompassing approach and focuses on identifying those populations or
lifestages potentially "at risk" of an ozone-related health effect.
As discussed in the Preamble to the ISAs (U.S. EPA. 2015). the risk of health effects from
exposure to ozone may be modified as a result of intrinsic (e.g., pre-existing disease, genetic factors) or
extrinsic factors (e.g., sociodemographic or behavioral factors), differences in internal dose (e.g., due to
variability in ventilation rates or exercise behaviors), or differences in exposure to air pollutant
concentrations (e.g., more time spent in areas with higher ambient concentrations). Some factors may lead
to a reduction in risk and are recognized as such during the evaluation. However, in order to inform
decisions on the NAAQS, this ISA focuses on identifying those populations or lifestages at greater risk.
While a combination of factors (e.g., residential location and socioeconomic status [SES]) may increase
the risk of ozone-related health effects in portions of the population, information on the interaction among
factors remains limited. Thus, this ISA characterizes the individual factors that potentially result in
increased risk for ozone-related health effects [see Preamble to the ISAs (U.S. EPA. 2015)1.
IS.4.4.1 Approach to Evaluating and Characterizing the Evidence for At-Risk Factors
The ISA takes a pragmatic approach to identifying and evaluating factors that may increase the
risk of a population or specific lifestage to an ambient air ozone-related health effect; this approach is
described in detail in the Preamble to the ISAs (U.S. EPA. 2015) and illustrated in Table IS-9. While
Appendix 3-Appendix 7 include a discussion of some populations and lifestages in order to explicitly
characterize the causal nature between ozone exposure and health effects based on the body of evidence
(e.g., children, individuals with asthma), this section focuses on summarizing evidence that can inform
the identification of such populations and lifestages. Those populations and lifestages explicitly
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considered in this ISA include those with pre-existing asthma, children, older adults, and outdoor
workers, for which there was adequate evidence of increased risk in the 2013 Ozone ISA.
The evidence evaluated in this section includes relevant studies discussed in
Appendix 3-Appendix 7 of this ISA and builds on the evidence presented in the 2013 Ozone ISA (U.S.
EPA. 2013b). Based on the approach developed in previous ISAs (U.S. EPA. 2016. 2013a. b), recent
evidence is integrated across scientific disciplines and health effects, and where available, with
information on exposure and dosimetry. In evaluating factors and population groups, greater emphasis is
placed on the evidence for those health outcomes for which a "causal" or "likely to be causal"
relationship is concluded in Appendix 3-Appendix 7 of this ISA.
Table IS-9 Characterization of evidence for factors potentially increasing the
risk for ozone-related health effects.
Classification Health Effects
Adequate There is substantial, consistent evidence within a discipline to conclude that a factor results in a
evidence population or lifestage being at increased risk of air pollutant-related health effect(s) relative to
some reference population or lifestage. Where applicable, this evidence includes coherence
across disciplines. Evidence includes multiple high-quality studies.
The collective evidence suggests that a factor results in a population or lifestage being at
increased risk of air pollutant-related health effect(s) relative to some reference population or
lifestage, but the evidence is limited due to some inconsistency within a discipline or, where
applicable, a lack of coherence across disciplines.
The collective evidence is inadequate to determine whether a factor results in a population or
lifestage being at increased risk of air pollutant-related health effect(s) relative to some reference
population or lifestage. The available studies are of insufficient quantity, quality, consistency,
and/or statistical power to permit a conclusion to be drawn.
Evidence of no There is substantial, consistent evidence within a discipline to conclude that a factor does not
effect result in a population or lifestage being at increased risk of air pollutant-related health effect(s)
relative to some reference population or lifestage. Where applicable, the evidence includes
coherence across disciplines. Evidence includes multiple high-quality studies.
As discussed in the Preamble to the ISAs (U.S. EPA. 2015). consideration of at-risk populations
includes evidence from epidemiologic, controlled human exposure, and animal toxicological studies, in
addition to relevant exposure-related information. Regarding epidemiologic studies, the evaluation
focuses on those studies that include stratified analyses to compare populations or lifestages exposed to
similar air pollutant concentrations within the same study design along with consideration of the
strengths and limitations of each study. Other epidemiologic studies that do not stratify results but instead
examine a specific population or lifestage can provide supporting evidence for the pattern of associations
observed in studies that formally examine effect measure modification. Similar to the characterization of
Suggestive
evidence
Inadequate
evidence
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evidence in Appendix 3-Appendix 7. the greatest emphasis is placed on patterns or trends in results
across studies. Experimental studies in human subjects or animal models that focus on factors, such as
genetic background or health status, are evaluated because they provide coherence and biological
plausibility of effects observed in epidemiologic studies. Also evaluated are studies examining whether
factors may result in differential exposure to ozone and subsequent increased risk of ozone-related health
effects. Conclusions are made with respect to whether a specific factor increases the risk of an
ozone-related health effect based on the characterization of evidence using the framework detailed in
Table III of the Preamble (U.S. EPA. 2015). and presented in Table IS-9.
IS.4.4.2 Summary of At-Risk Populations
The 2013 Ozone ISA (U.S. EPA. 2013b) concluded that there was adequate evidence to classify
individuals with pre-existing asthma, children and older adults, individuals with reduced intake of certain
nutrients (i.e., vitamins C and E), and outdoor workers as populations at increased risk to the health
effects of ozone. These conclusions were based on the consistency in findings across studies, as well as
on coherence of results from different scientific disciplines. Recent studies provide additional evidence
that individuals with pre-existing asthma and children are at increased risk of the effects of ozone. There
is relatively little recent evidence to add to the evidence presented in the 2013 Ozone ISA for older adults,
individuals with reduced intake of certain nutrients, and outdoor workers.
Recent, large multicity epidemiologic studies conducted in the U.S. expand upon evidence from
the 2013 Ozone ISA to provide further support the relationship between ozone and ED visits and hospital
admissions for asthma among individuals with pre-existing asthma (Table IS-10; Section IS.4.4.3.1).
Generally, studies comparing age groups also reported higher magnitude associations for
respiratory hospital admissions and ED visits for children (Section IS.4.4.4.1) than for adults. In addition,
recent evidence from studies of nonhuman primates and rodents demonstrate ozone-induced respiratory
effects and support the biological plausibility of associations observed in epidemiologic studies between
long-term exposure to ozone and the development of asthma in children. Specifically, these experimental
studies indicate that early-life ozone exposure can cause structural and functional changes that could
potentially contribute to airway obstruction and increased airway responsiveness. Also, children have
both higher exposure (due to increased time spent outdoors) and dose (due to their greater ventilation
rate). Childrens' respiratory systems are also still undergoing lung growth.
The majority of evidence for older adults being at increased risk of health effects related to ozone
exposure comes from studies of short-term ozone exposure and mortality evaluated in the 2013 Ozone
ISA (Section IS.4.4.4.2).
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Table IS-10 Summary of evidence for populations at increased risk to the health
effects of ozone.
Conclusions from 2013 Ozone ISA Conclusions from 2020 ISA
Adequate evidence
Pre-existing
asthma
Collective evidence from controlled human
exposure studies is supported by animal
toxicological studies. Some, but not all,
epidemiologic studies report greater risk of
health effects among individuals with
asthma.
Evidence from controlled human exposure and
animal toxicological studies provide biological
plausibility for the associations observed in
epidemiologic studies of short-term ozone
exposure and asthma exacerbation. Results from
experimental studies in humans demonstrate that
ozone exposures lead to increased respiratory
symptoms, lung function decrements, increased
airway responsiveness, and increased lung
inflammation in individuals with asthma.
Children
Controlled human exposure and animal
toxicological studies provide evidence of
increased risk from ozone exposure for
younger ages, which is coherent with
findings from epidemiologic studies that
report larger associations for respiratory ED
visits and hospital admissions for children
than adults.
Recent, large multicity epidemiologic studies
conducted in the U.S. expand upon previous
evidence and support an association between
ozone and ED visits and hospital admissions for
asthma, which are strongest in children between
the ages of 5 and 18; animal toxicological studies
in infant monkeys and neonatal rats show that
early-life ozone exposure can cause structural
and functional changes that could potentially
contribute to airway obstruction and increased
airway responsiveness.
Older adults Epidemiologic studies report consistent
positive associations between short-term
ozone exposure and mortality in older
adults.
Controlled human exposure studies demonstrate
changes in FEVi and FVC among older adults at
a relatively light activity level and brief duration of
ozone exposure, though these responses are not
greater than in other age groups; evidence from
studies of metabolic effects is inconsistent.
Outdoor workers Strong evidence from 2006 Ozone AQCD, No recent information has been evaluated that
which demonstrated increased exposure, would inform or change prior conclusions,
dose, and ultimately risk of ozone-related
health effects in this population supports that
there is adequate evidence to indicate that
increased exposure to ozone through
outdoor work increases the risk of
ozone-related health effects.
Genetic factors Multiple genetic variants have been No recent information has been evaluated that
observed in epidemiologic and controlled would inform or change prior conclusions,
human exposure studies to affect the risk of
ozone-related respiratory outcomes and
support is provided by animal toxicological
studies of genetic factors.
Individuals with reduced intake of vitamins E No recent information has been evaluated that
and C are at risk for ozone-related would inform or change prior conclusions,
respiratory effects based on substantial,
consistent evidence both within and among
disciplines.
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Table IS-10 (Continued): Summary of evidence for populations at increased risk
to the health effects of ozone.
Conclusions from 2013 Ozone ISA
Conclusions from 2020 ISA
Suggestive evidence
Sex
Pre-existing
obesity
Evidence for increased risk for ozone-related No recent information has been evaluated that
health effects present for females in some would inform or change prior conclusions.
studies and males in other studies; some
indication that females are increased risk of
ozone-related respiratory hospital
admissions and ED visits.
Multiple epidemiologic, controlled human
exposure, and animal toxicological studies
report increased ozone-related respiratory
health effects among obese individuals.
Recent animal toxicological studies expand upon
previous evidence and continue to indicate that,
compared to lean mice, obese mice exhibit
enhanced airway responsiveness and pulmonary
inflammation in response to acute ozone
exposures.
Most studies report that individuals with low
SES and those living in neighborhoods with
low SES are more at risk for ozone-related
respiratory hospital admissions and ED
visits; inconsistent results for mortality and
reproductive outcomes.
No recent information has been evaluated that
would inform or change prior conclusions.
Inadequate evidence
Race/ethnicity A small number of studies provide
inadequate evidence that there may be
race-related increase in risk of ozone-related
health effects for some outcomes.
No recent information has been evaluated that
would inform or change prior conclusions.
Pre-existing
COPD
Epidemiologic studies indicate that persons
with COPD may have increased risk of
ozone-related cardiovascular effects, but
little information is available on whether
COPD leads to an increased risk of
ozone-induced respiratory effects.
Small number of recent studies provided
inadequate evidence to determine whether COPD
results in an increased risk of ozone-related
health effects.
Pre-existing CVD
Most short-term exposure studies did not
report increased ozone-related
cardiovascular morbidity for individuals with
pre-existing CVD. Limited number of studies
examined whether CVD modifies the
association between ozone and respiratory
effects. Some evidence that CVD increases
risk of ozone-related total mortality.
Some studies provide evidence that
cardiovascular disease exacerbates the
respiratory effects of ozone exposure; a limited
number of recent epidemiologic cohort studies
observed increased risk estimates for incident
diabetes among those with pre-existing
hypertension or among subjects that had some
pre-existing condition (Ml, COPD, hypertension,
or hyperlipidemia) compared to those without
pre-existing disease.
Pre-existing
diabetes
There are a limited number of epidemiologic
studies and lack of controlled human
exposure studies or toxicological studies to
determine whether pre-existing diabetes
modifies ozone effects on health.
A small number of studies provide inadequate
evidence that individuals with pre-existing
metabolic disease may be at greater risk of
mortality associated with long-term ozone
exposure.
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Table IS-10 (Continued): Summary of evidence for populations at increased risk
to the health effects of ozone.
Conclusions from 2013 Ozone ISA
Conclusions from 2020 ISA
Smoking
There are a limited number of studies and
insufficient coherence for differences in
ozone-related health effects by smoking
status.
No recent information has been evaluated that
would inform or change prior conclusions.
COPD = chronic obstructive pulmonary disease; CVD = cardiovascular disease; ED = emergency department; FE\A| = forced
expiratory volume in 1 second; FVC = forded vital capacity; Ml = myocardial infarction; SES = socioeconomic status.
IS.4.4.3 Pre-existing Disease
Individuals with some pre-existing diseases may be at greater risk of an air pollution-related
health effect because they may be in a compromised biological state that can vary depending on the
disease and severity. The 2013 Ozone ISA (U.S. EPA. 2013b) concluded that there was adequate
evidence that those with pre-existing respiratory disease, specifically asthma, were at greater risk for the
health effects associated with exposure to ozone, but that evidence was inadequate to determine whether
those with COPD, cardiovascular disease, or diabetes were at increased risk of ozone-related health
effects. Of the recent epidemiologic studies evaluating effect measure modification by pre-existing
disease or condition, most focused on asthma, COPD, or cardiovascular disease. Table IS-11 presents the
prevalence of these diseases according to the Centers for Disease Control and Prevention's (CDC's)
National Center for Health Statistics (Blackwcll et al.. 2014). including the proportion of adults with a
current diagnosis categorized by age and geographic region. The large proportions of the U.S. population
affected by many chronic diseases, including various respiratory and cardiovascular diseases, indicates
the potential public health impact, and thus, the importance of identifying populations that may be at
increased risk for ozone-related health effects.
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Table IS-11 Prevalence of respiratory diseases, cardiovascular diseases,
diabetes, and obesity among adults by age and region in the U.S. in
2012.
Adults
(18+)
Age (%)a
Region (%)b
Chronic
Disease/Condition
N (in
thousands)
18-44
45-64
65-74
75+
North-
east
Midwest
South
West
All (N, in
thousands)
234,921
111,034
82,038
23,760
18,089
42,760
53,378
85,578
53,205
Selected respiratory diseases
Asthma0
18,719
8.1
8.4
7.8
6.0
9.2
8.1
7.3
7.8
COPD—chronic
bronchitis
8,658
2.5
4.7
4.9
5.2
3.2
4.4
3.9
2.4
COPD—
emphysema
4,108
0.3
2.3
4.7
4.7
1.3
2.0
1.9
1.0
Selected cardiovascular diseases/conditions
All heart disease
26,561
3.8
12.1
24.4
36.9
10.0
11.6
11.6
9.3
Coronary heart
disease
15,281
0.9
7.1
16.2
25.8
5.3
6.5
7.0
5.1
Hypertension
59,830
8.3
33.7
52.3
59.2
21.4
24.1
26.6
21.5
Stroke
6,370
0.6
2.8
6.3
10.7
1.8
2.5
3.0
2.5
Metabolic disorders/conditions
Diabetes
21,391
2.4
12.7
21.1
19.8
7.6
8.4
10.0
7.3
Obesity (BMI
>30 kg/m2)
64,117
26
33.7
29.7
18
25.1
29.9
29.9
25.2
Overweight (BMI
25-30 kg/m2)
78,455
31.4
36.8
40.7
38.6
34.3
34.1
34.2
35.3
BMI = body mass index; COPD = chronic obstructive pulmonary disease.
Percentage of individual adults within each age group with disease, based on N (at the top of each age column).
Percentage of individual adults (18+) within each geographic region with disease, based on N (at the top of each region column).
°Asthma prevalence is reported for "still has asthma."
Source: Blackwell et al. (2014): National Center for Health Statistics: Data from Tables 1 -4, 7, 8, 28, and 29 of the Centers for
Disease Control and Prevention report.
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IS.4.4.3.1 Pre-existing Asthma
Asthma is the leading chronic illness affecting children. Approximately 8% of adults and 9% of
children (age <18 years) in the U.S. currently have asthma (Blackwcll et al.. 2014; Bloom et al.. 2013).
Regarding consideration of those with asthma potentially being at increased risk for an ozone-related
health effect, it is important to note that individuals with asthma, and children in general, tend to have a
higher degree of oronasal breathing, which can result in greater penetration of ozone into the lower
respiratory tract.
The 2013 Ozone ISA concluded that there is adequate evidence that individuals with asthma are
at increased risk of health effects related to ozone exposure; this conclusion is based on a number of
controlled human exposure, epidemiologic, and animal toxicological studies. Consistent with this
evidence, recent, large multicity epidemiologic studies conducted in the U.S. expand upon evidence from
the 2013 Ozone ISA to provide further support for an association between ozone and ED visits and
hospital admissions for asthma. Hospital admission and ED visit studies that presented age-stratified
results reported the strongest associations in children between the ages of 5 and 18 years. Additionally,
associations were observed across a range of ambient ozone concentrations and were consistent in models
where exposure was assigned using either measured or modeled ozone concentrations. While there is a
lack of recent epidemiologic studies conducted in the U.S. or Canada that have examined respiratory
symptoms and medication use, lung function, and subclinical effects in people with asthma, a large body
of evidence from the 2013 Ozone ISA (U.S. EPA. 2013b) reported ozone associations with these less
severe indicators of asthma exacerbation that provide support for the ozone-related increases in asthma
hospital admissions and ED visits observed in recent studies.
Evidence from controlled human exposure and animal toxicological studies provide biological
plausibility for the associations observed in epidemiologic studies of short-term ozone exposure and
asthma exacerbation. Results from experimental studies in humans demonstrate that ozone exposures lead
to increased respiratory symptoms, decrements in lung function, increased airway responsiveness, and
increased lung inflammation in individuals with asthma. However, observed responses across the range of
endpoints did not generally differ due to the presence of asthma. Animal toxicological studies similarly
found that ozone exposures altered lung function measures, increased airway responsiveness, and
increased pulmonary inflammation and bronchoconstriction in allergic animals. In contrast to controlled
human exposure studies, there was some evidence from studies of rodents that the observed respiratory
effects were enhanced in allergic animals compared to naive animals.
Overall, recent evidence expands upon evidence available in the 2013 Ozone ISA and is adequate
to conclude that individuals with pre-existing asthma are at greater risk of ozone-related health effects
based on the substantial and consistent evidence within epidemiologic studies and the coherence with
toxicological studies.
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IS.4.4.3.2 Pre-existing Chronic Obstructive Pulmonary Disease
Chronic obstructive pulmonary disease (COPD) comprises chronic bronchitis and emphysema
and affects approximately 8.6 million adults in the U.S. (Table IS-11). In the U.S., over 4% of adults
report having chronic bronchitis and almost 2% report having emphysema (Pleis et al.. 2009). Chronic
lower respiratory disease, including COPD, was ranked as the third leading cause of death in the U.S. in
2011 (Hovert and Xu. 2012). Given that people with COPD have compromised respiratory function and
underlying respiratory tract inflammation, it is plausible that they could be at increased risk for an array of
ozone-related health effects.
Epidemiologic studies evaluated in the 2013 Ozone ISA indicate that individuals with COPD may
have increased risk of ozone-related cardiovascular effects, but little information was available on
whether COPD leads to an increased risk of ozone-induced respiratory effects. A limited number of recent
epidemiologic studies provide inconsistent evidence that individuals with pre-existing COPD could be at
greater risk for respiratory health effects associations with ozone exposure. Overall, a limited number of
recent studies add to the scarce evidence available in the 2013 Ozone ISA and, collectively, is inadequate
to conclude whether or not individuals with pre-existing COPD are at greater risk of ozone-related health
effects.
IS.4.4.3.3 Pre-existing Obesity
Obesity, defined as a BMI of 30 kg/m2 or greater, is an issue of increasing importance in the U.S.,
with self-reported obesity at 39.8% of the general population in 2016, up from 26.7% in 2009 (Hales et
al.. 2017). BMI may affect ozone-related health effects through multiple avenues, including systematic
inflammation, increased pre-existing disease, and poor diet. Increased risk of air pollution-related health
effects has been observed among obese individuals compared with nonobese individuals (U.S. EPA.
2009). The 2013 Ozone ISA concluded that there was suggestive evidence for increased ozone-related
respiratory health effects among obese individuals. This conclusion was based on evidence from
controlled human exposure studies and epidemiologic studies reporting greater lung function decrements
in obese compared with nonobese individuals, as well as enhanced pulmonary inflammation in genetically
and dietarily obese mice (U.S. EPA. 2013b).
Recent animal toxicological studies expand the body of evidence evaluated in the 2013 Ozone
ISA and continue to indicate that, compared with lean mice, obese mice exhibit enhanced airway
responsiveness and pulmonary inflammation in response to acute ozone exposures. In contrast, a recent
controlled human exposure study reported evidence of ozone-related increases in pulmonary
inflammation in both obese and normal-weight adult women during exercise, but inflammatory responses
did not differ between the groups. Overall, recent studies contribute some additional support to the
evidence available in the 2013 Ozone ISA and there is suggestive evidence indicating that individuals
with pre-existing obesity are at potentially increased risk of ozone-related health effects based on the
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limited evidence within epidemiologic studies and some coherence from controlled human exposure and
animal toxicological studies.
15.4.4.3.4 Pre-existing Metabolic Syndrome
Metabolic syndrome is a clinical diagnosis used to describe a collection of risk factors that
include high blood pressure, dyslipidemia (elevated triglycerides and low levels of high-density
lipoprotein [HDL] cholesterol), obesity (particularly central obesity), and increased fasting blood glucose
(Albcrti et al.. 2009). The presence of these risk factors may predispose an individual to an increased risk
of type 2 diabetes and cardiovascular disease. In the 2013 Ozone ISA, a limited number of epidemiologic
studies provided inadequate evidence to indicate whether individuals with metabolic syndrome (generally
indicated by a diabetes diagnosis) were at an increased risk of ozone-related health effects compared with
those without diabetes.
In recent studies of a diabetes-prone mouse model, subacute ozone exposure increased airway
inflammation and proinflammatory genes in lung tissue (Section 3.1.6.2). In contrast, an epidemiologic
panel study observed a negative association between increased ozone exposure and pulmonary
inflammation in adults with type 2 diabetes mellitus. This inverse association may be explained by
negative correlations with copollutants that demonstrated strong positive associations with pulmonary
inflammation in the same population. Overall, a limited number of recent studies add to the small body of
evidence available in the 2013 Ozone ISA and, collectively, the evidence is inadequate to conclude that
individuals with pre-existing metabolic disease are at greater risk of ozone-related health effects.
15.4.4.3.5 Pre-existing Cardiovascular Disease
Cardiovascular disease has become increasingly prevalent in the U.S., with about 12% of adults
aged 45-64 years reporting a diagnosis of heart disease (Table IS-11). This number doubles to 24%
among adults aged 65-74 years and is even higher for adults aged 75 years and older. A high prevalence
of other cardiovascular-related conditions has also been observed, such as hypertension which is prevalent
among more than 50% of older adults. In the 2013 Ozone ISA, most epidemiologic studies evaluating
short-term ozone exposure did not report increased risk of cardiovascular morbidity for individuals with
pre-existing cardiovascular disease. There was some evidence from a limited number of epidemiologic
studies that those with pre-existing cardiovascular disease were at greater risk of ozone-related mortality
compared with those without pre-existing cardiovascular disease. Overall, the 2013 Ozone ISA concluded
that the evidence was inadequate to classify pre-existing cardiovascular disease as a potential at-risk
factor for ozone-related health effects.
Several recent studies evaluated respiratory effects of acute ozone exposure (0.2-1 ppm,
3-6 hours) in rodents with cardiovascular disease. Some of the studies provide evidence that
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cardiovascular disease exacerbates the respiratory effects of ozone exposure. Injury, inflammation, and
oxidative stress measured in the respiratory system, lung function changes, and increased airway
responsiveness were documented in animals with cardiovascular disease in response to ozone exposure.
Acute ozone exposure in animal models of hypertension resulted in enhanced injury and inflammation
measured in the respiratory system, and airway responsiveness compared with healthy animals. A limited
number of recent epidemiologic cohort studies evaluated the potential for pre-existing cardiovascular
disease to modify associations between long-term ozone exposure and metabolic effects. These studies
observed increased risk estimates for incident diabetes among those with pre-existing hypertension or
among subjects that had some pre-existing condition (MI, COPD, hypertension, or hyperlipidemia)
compared with those without pre-existing disease. Overall, a limited number of recent studies add to the
evidence available in the 2013 Ozone ISA and, collectively, are inadequate to conclude whether
individuals with pre-existing metabolic disease are at greater risk of ozone-related health effects.
IS.4.4.4 Lifestage
Lifestage refers to a distinguishable time frame in an individual's life characterized by unique and
relatively stable behavioral and/or physiological characteristics that are associated with development and
growth (U.S. EPA. 2014). Differential health effects of ozone across lifestages could be due to several
factors. With regard to children, the human respiratory system is not fully developed until 18-20 years of
age; therefore, it is biologically plausible for children to have increased intrinsic risk for respiratory
effects if exposures are sufficient to contribute to potential perturbations in normal lung development.
Moreover, children in general may experience higher exposure to ozone than adults based on more time
spent outdoors while exercising during afternoon hours when ozone concentrations may be highest. The
ventilation rates also vary between children and adults, particularly during moderate/heavy activity.
Children have higher ventilation rates relative to their lung volume, which tends to increase the dose
normalized to lung surface area. Older adults, typically considered those 65 years of age or greater, have
weakened immune function, impaired healing, decrements in pulmonary and cardiovascular function, and
greater prevalence of chronic disease ITable IS-11; Blackwell et al. (2014)1. which may contribute to, or
worsen, health effects related to ozone exposure. Also, exposure or internal dose of ozone may differ
across lifestages due to varying ventilation rates, increased oronasal breathing at rest, and time-activity
patterns.
For decades, children, especially those with asthma, and older adults have been identified as
populations at increased risk of health effects related to ozone exposure (U.S. EPA. 2013b. 2006a.
1996a). Long-standing evidence from controlled human exposure studies demonstrated that children have
greater spirometric responses to ozone compared with middle-aged or older adults (U.S. EPA. 1996a). In
addition, epidemiologic studies reported larger associations for respiratory hospital admissions and ED
visits for children than for adults, and animal toxicological studies demonstrated ozone-induced health
effects in immature animals, including infant monkeys (U.S. EPA. 2013b). Compared with other age
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groups, there was evidence for an increased risk of mortality associated with ozone exposure among older
adults (U.S. EPA. 2013b. 2006a). The 2013 Ozone ISA concluded that there was adequate evidence that
children and older adults are at increased risk of ozone-related health effects.
15.4.4.4.1 Children
Recent, large multicity epidemiologic studies conducted in the U.S. expand on evidence from the
2013 Ozone ISA and provide further support for an association between short-term ozone exposure and
ED visits and hospital admissions for asthma. Hospital admission and ED visit studies that presented
age-stratified results reported the strongest associations in children between the ages of 5 and 18 years.
The evidence relating new-onset asthma to long-term ozone exposure is supported by toxicological
studies in infant monkeys, which indicate that postnatal ozone exposures can lead to the development of
asthma. This nonhuman primate evidence of ozone-induced respiratory effects supported the biological
plausibility of associations between long-term exposure to ozone and the development of asthma in
children observed in epidemiologic studies. Specifically, these experimental studies indicate that
early-life ozone exposure can cause structural and functional changes that could potentially contribute to
airway obstruction and increased airway responsiveness.
Overall, recent evidence expands upon evidence available in the 2013 Ozone ISA and is adequate
to conclude that children are at greater risk of ozone-related health effects based on the substantial and
consistent evidence within epidemiologic studies and the coherence with animal toxicological studies.
15.4.4.4.2 Older Adults
Collectively, the majority of evidence for older adults being at increased risk of health effects
related to ozone exposure comes from studies of short-term ozone exposure and mortality. Many of these
were evaluated in the 2013 Ozone ISA. As reported in the 1996 and 2006 Ozone AQCDs (U.S. EPA.
2006a. 1996a). decrements in lung function and increases in respiratory symptoms in response to ozone
exposure decreased with increasing age. However, whether inflammatory responses persisted with
increasing age remained unstudied at the time of the 2013 Ozone ISA (U.S. EPA. 2013b). Two recent
controlled human exposure studies demonstrate inflammatory responses in older adults, but it is not
possible to quantify inflammatory response as a function of age because of differences in experimental
protocols (i.e., duration of exposure to ozone, ozone concentration, activity level, and post-exposure time
of sputum collection). A recent controlled human exposure study also demonstrates changes in FEVi and
FVC among adults aged 55-70 years at a relatively light activity level and brief duration of exposure, but
a statistically significant interaction with age was not observed. This is generally consistent with studies
evaluated in previous assessments that showed ozone-associated lung function decrements declining with
age, but still being present in adults 50-60 years of age. This recent study was conducted at a lower ozone
delivery rate, which is more representative of that likely to occur in the ambient environment and shows
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small lung function decrements occurring in groups of older adults ranging up to 70 years of age. These
recent studies demonstrate that inflammatory responses and lung function changes following ozone
exposure can occur in older adults, but do not indicate greater responses in older adults than other age
groups.
Overall, recent studies add little to the evidence available in the 2013 Ozone ISA. This evidence
is adequate to conclude that older adults are at greater risk of ozone-related health effects.
IS.5 Evaluation of Welfare Effects of Ozone
The scientific evidence for welfare effects of ozone is largely for effects on vegetation and
ecosystems and effects on climate. Appendix 8 presents the most policy-relevant information related to
this review of the NAAQS for ecological effects of ozone. Appendix 9 presents the most policy-relevant
information related to this review of the NAAQS for effects on climate. The framework for causal
determinations [see Preamble (U.S. EPA. 2015)1 has been applied to the body of scientific evidence to
examine effects attributed to ozone exposure. Conclusions from the 2013 Ozone ISA and key findings
that inform the current causality determinations for welfare effects of ozone are summarized in
Table IS-12.
Table IS-12 Summary of evidence for welfare effects of ozone.
Endpoint
Conclusions from 2013 Ozone ISA
Conclusions from 2020 ISA3
Visible foliar injury
Section 8.2
Causal relationship
Visible foliar injury from ozone exposure was
well characterized and documented over
several decades of research prior to the 2013
Ozone ISA on sensitive tree, shrub,
herbaceous, and crop species in the U.S. Some
sensitive species that show visible injury
identified in field surveys are verified in
controlled exposure settings. Ozone
concentrations are high enough to induce
visible symptoms in sensitive vegetation.
Causal relationship
Studies published since the 2013 Ozone ISA
strengthen previous conclusions that there is
strong evidence that ozone causes foliar
injury in a variety of plant species. The use of
bioindicators to detect phytotoxic levels of
ozone is a longstanding and effective
methodology and is supported by more
information on sensitive species.
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Table IS-12 (Continued): Summary of evidence for welfare effects of ozone.
Endpoint
Conclusions from 2013 Ozone ISA
Conclusions from 2020 ISA3
Reduced
vegetation growth
Section 8.3
Causal relationship
Studies added to the evidence from the 2006
AQCD and earlier assessments and indicated
that ozone reduced growth of vegetation.
Studies from the Aspen FACE experiment
showed reduction in total biomass in aspen,
paper birch, and sugar maple, findings which
were overall consistent with OTC studies in
previous NAAQS reviews. Meta-analysis
showed ambient ozone concentrations (approx.
40 ppb avg across all hours of exposure)
decreased annual total biomass growth of forest
species by an avg of 7% with potentially greater
exposures with elevated ozone. Studies also
demonstrated that ozone alters biomass
allocation, generally reducing C allocated to
roots.
Causal relationship
New evidence from controlled exposure
experiments and illustration of potential
impacts using models built with empirical data
strengthen previous conclusions that ozone
reduces plant growth and biomass. Additional
studies find that ozone significantly changes
patterns of carbon allocation below and
aboveground.
Reduced plant No separate causality determination;
reproduction included with plant growth
Section 8.4 Evidence from studies that ozone alters
reproduction in herbaceous and woody plant
species adds to evidence from the 2006 AQCD
(primarily in herbaceous and crop species) for
ozone effects on metrics of plant reproduction.
Causal relationship
A new meta-analysis published since the
2013 Ozone ISA provides strong and
consistent evidence for negative effects of
ozone on plant reproduction. For all exposure
categories evaluated, including the lowest
exposure category of <40 ppb, between one
and eight metrics of reproduction significantly
decreased. In addition, more evidence is
available that plant reproductive tissues are
directly affected by ozone exposure.
Increased tree Causality not assessed
mortality Evidence built on observations from the 2006
Section 8.4.3 Ozone AQCD of decline of conifer forests over
time observed in several regions affected by
elevated ozone along with other factors (Valley
of Mexico, southern France, Carpathian
Mountains). At the Aspen FACE site, there was
reduced growth and increased mortality of a
sensitive aspen clone.
Likely to be causal relationship
In a new large-scale multivariate analysis
evaluating tree mortality over a 15-year
period ozone significantly increased tree
mortality in 7 out of 10 plant functional types
in the eastern and central U.S. An Aspen
FACE study shows that sensitive aspen
genotypes have increased mortality
compared to tolerant genotypes.
Reduced yield and
quality of
agricultural crops
Section 8.5
Causal relationship
Detrimental effects of ozone on crop production
were recognized since the 1960s. There are
well-documented yield losses in a variety of
agricultural crops with increasing ozone
concentration. Ozone also decreased crop
quality. Modeling studies at large geographic
scales showed ozone generally reduced crop
yield, but effects vary across regions and
species.
Causal relationship
Greenhouse, OTC, FACE, and modeling
studies published since the 2013 Ozone ISA
strengthen previous conclusions that ozone
reduces yield in major U.S. crops including
wheat, soybean, and other non-soy legumes.
Advances in characterization of ozone effects
on U.S. crop yield include further geographic
and temporal refinement of ozone sensitivity.
For soybean, there are updated
exposure-response curves.
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Table IS-12 (Continued): Summary of evidence for welfare effects of ozone.
Endpoint
Conclusions from 2013 Ozone ISA
Conclusions from 2020 ISA3
Altered herbivore
growth and
reproduction
Section 8.6
Causality not assessed
A meta-analysis of 16 studies found that
elevated ozone decreased development time
and increased pupal mass in insect herbivores.
Other field and laboratory studies reported
species-level and community-level responses in
insects yet the directionality of response to
ozone was mixed. This is congruent with
findings from the 2006 AQCD and 1996 AQCD,
where statistically significant effects on
herbivorous insects were observed, but did not
provide any consistent pattern of response
across growth, reproduction, and mortality
endpoints.
Likely to be causal relationship
There is a large body of evidence showing
altered growth and reproduction in insect
herbivores. More research has since been
published on a range of species and at
varying levels of ozone exposure although
there is no clear trend in the directionality of
response for most metrics. The most
commonly measured responses are
fecundity, development time, and growth.
Alteration of
plant-insect
signaling
Section 8.7
Causality not assessed
A few experimental and modeling studies
reported altered chemical signaling in
insect-plant interactions due to ozone exposure.
The effect of ozone on chemical signaling is an
emerging area of study that may result in further
elucidation of effects with more empirical data.
Likely to be causal relationship
Laboratory, greenhouse, OTC, and Finnish
FACE experiments expand the evidence for
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. Affected plant-insect interactions
include plant defense against herbivory and
insect attraction to plants. New evidence
includes consistent effects in multiple insect
species.
Reduced
productivity in
terrestrial
ecosystems
Section 8.8.1
Causal relationship
Studies from long-term FACE experiments
provided evidence of the association of ozone
exposure and reduced productivity at the
ecosystem scale. Results across different
ecosystem models were consistent with the
FACE experimental evidence. Models
consistently found that ozone exposure
negatively impacted indicators of ecosystem
productivity. Studies at the leaf and plant scales
show that ozone decreased photosynthesis and
plant growth, providing coherence and
plausibility for reported decreases in ecosystem
productivity. Magnitude of response varied
among plant communities.
Causal relationship
Modeling studies and controlled exposure
experiments (including Aspen FACE),
published since the 2013 Ozone ISA
strengthen previous conclusions. Much of the
research is confirmatory, with some work
providing new mechanistic insight into the
effects of ozone on productivity and creating
a more nuanced understanding of how these
effects vary among species, communities,
and environmental conditions.
Reduced carbon
sequestration in
terrestrial
ecosystems
Section 8.8
Likely to be causal relationship
Studies add to the strong and consistent
evidence in the 2006 AQCD that ozone
decreases plant photosynthesis. Most
assessments of the effects of ozone on
terrestrial C are from model simulations.
Likely to be causal relationship
Several new model simulations strengthen
previous conclusions from the 2013 Ozone
ISA by providing further support for regional
and global scale decreases in terrestrial C
sequestration from ozone pollution; however,
these relationships are spatially and
temporally dependent. One empirical study
from the Aspen FACE experiment adds to the
evidence base for reduced ecosystem C
content.
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Table IS-12 (Continued): Summary of evidence for welfare effects of ozone.
Endpoint
Conclusions from 2013 Ozone ISA
Conclusions from 2020 ISA3
Alteration of
belowg round
biogeochemical
cycles
Section 8.9
Causal relationship
It has been documented since the 2006 Ozone
AQCD that while belowground roots and soil
organisms are not exposed directly to ozone,
belowground processes could be affected by
ozone through alterations in the quality and
quantity of carbon supply to the soils from
photosynthates and litterfall. The 2013 Ozone
ISA presented evidence that ozone was found
to alter multiple belowground endpoints
including root growth, soil food web structure,
soil decomposer activities, soil respiration, soil
carbon turnover, soil water cycling, and soil
nutrient cycling.
Causal relationship
New evidence confirms conclusions from the
2013 Ozone ISA on effects on soil
decomposition, soil carbon, and soil nitrogen.
The direction and magnitude of these
changes often depends on the species, site,
and time of exposure.
Alteration of
terrestrial
community
composition
Section 8.10
Likely to be causal relationship
The body of evidence is for effects on
community composition shifts in terrestrial plant
communities. For broadleaf forests, the
ozone-tolerant aspen clone was the dominant
clone at the Aspen FACE site. In grasslands,
evidence generally showed shifts from
grass-legume mix to grass species. A shift in
community composition of bacteria and fungi
was observed in both natural and agricultural
systems, although no general pattern could be
discerned.
Causal relationship
Recent evidence builds upon the conclusions
of the 2013 Ozone ISA by strengthening the
understanding of effects of ozone on forest
and grassland communities and confirming
that effects upon soil microbial communities
are diverse. New observational and
experimental studies of ozone effects on tree
species extend to regional forest composition
in the eastern U.S. In grasslands, new studies
are consistent with previous research that
ozone shifts grassland community
composition.
Alteration of
ecosystem water
cycling
Section 8.11
Likely to be causal relationship
Ozone can affect water use in plants and
ecosystems through several mechanisms
including damage to stomatal functioning and
loss of leaf area. Several field and modeling
studies showed an association of ozone
exposure and the alteration of water use and
cycling in vegetation and ecosystems. Direction
of response varied among studies.
Likely to be causal relationship
New evidence is consistent with the findings
in the 2013 Ozone ISA. New evidence
identifies a relationship between ozone and
wood anatomy associated with water
transport. Additional studies add to the
evidence base for decreased root growth and
density. New empirical and modeling studies
continue to show reduced sensitivity of
stomatal closing in response to ozone. There
are a few studies that scale-up these changes
to effects on ecosystem scales including a
study linking ozone effects on tree growth and
water use to ecosystem stream flow in six
watersheds in eastern U.S. forests and from
Aspen FACE.
Radiative forcing
(RF)
Section 9.2
Causal relationship
The 2013 Ozone ISA reported an RF of
0.35 W/m2 from tropospheric ozone from
preindustrial times to the present (1750 to 2005)
based on multimodel studies as reported in the
AR4 IPCC assessment.
Causal relationship
New evidence is consistent with the findings
in the 2013 Ozone ISA. The most recent
IPCC assessment, AR5, reports tropospheric
ozone RF as 0.40 (0.20 to 0.60) W/m2, which
is within range of previous assessments
(i.e., AR4). There have also been a few
individual modeling studies of tropospheric
ozone RF since AR5 which reinforce the AR5
estimates and the causal relationship
between tropospheric ozone and RF.
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Table IS-12 (Continued): Summary of evidence for welfare effects of ozone.
Endpoint Conclusions from 2013 Ozone ISA Conclusions from 2020 ISA3
Likely to be Causal Relationship
Consistent with previous estimates, the effect
of tropospheric ozone on global surface
temperature continues to be estimated at
roughly 0.1-0.3°C since preindustrial times,
with larger effects regionally. In addition to
temperature, ozone changes have impacts on
other climate metrics such as precipitation
and atmospheric circulation patterns. Current
limitations in climate modeling tools, variation
across models, and the need for more
comprehensive observational data on these
effects represent sources of uncertainty in
quantifying the precise magnitude of climate
responses to ozone changes, particularly at
regional scales.
AQCD = Air Quality Criteria Document; AR4 = IPCC Fourth Assessment Report; AR5 = IPCC Fifth Assessment Report;
FACE = free-air carbon dioxide enrichment; IPCC = Intergovernmental Panel on Climate Change; NAAQS = National Ambient Air
Quality Criteria; OTC = open-top chamber; RF = radiative forcing.
Conclusions from the 2020 ISA include evidence from recent studies integrated with evidence included in previous Ozone ISAs
and AQCDs.
Temperature,
precipitation and
related climate
variables
Section 9.3
Likely to be Causal Relationship
The increase of tropospheric ozone abundance
has contributed an estimated 0.1-0.3°C
warming to the global climate since 1750 based
on studies included in the AR4 IPCC
assessment.
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IS.5.1 Ecological Effects
The evidence for ozone effects on vegetation and ecosystems is best understood in the context of
some general concepts within ecology. Ecosystems1 are inherently complex and inter-connected.
Ecosystem structure may be described by a variety of measurements used to assess ozone response at
different levels of biological organization [i.e., suborganismal, organism, population,2 community;3 Suter
et al. (2005)1. For example, ozone effects on sensitive species at the whole-plant scale of biological
organization (i.e., reduced growth and biomass, reduced plant reproduction, decreased yield) cascade up
to effects on population and community structure and ecosystem function (Figure IS-3). "Function" refers
to the suite of processes and interactions among the ecosystem components that involve energy or matter.
Examples include water dynamics and the flux of trace gases from processes such as photosynthesis,
decomposition, or carbon cycling. Ecosystem changes are often considered undesirable if important
structural or functional components of the ecosystems are altered following pollutant exposure (U.S.
EPA. 2013a. 1998). Methods to assess effects of ozone on ecological structure and function range from
indoor controlled environment laboratory and greenhouse studies to field observational studies where
biological changes are measured in uncontrolled situations with high natural variability (U.S. EPA. 2015).
Free-air carbon dioxide/ozone enrichment (FACE) systems are a more natural way of estimating ozone
effects on aboveground and belowground processes. Research conducted at the SoyFACE facility in
Illinois (to study responses in soybean fields) and the Aspen FACE (in operation from 1998 to 2011)
system in Wisconsin (to study responses in broadleaf forest) have contributed a substantial body of robust
evidence that supports the characterization of ozone effects at multiple scales. Experimental
methodologies and approaches are summarized in Section 8.1.2.
1 A functional unit consisting of living organisms (biota), their nonliving environment and the interactions
within and between them (IPC'C. 2014).
2 An ecological population consists of interbreeding groups of individuals of the same species that occupy a defined
geographic space. Metrics to assess response in ecological populations include changes over time in abundance or
density (number of individuals in a defined area), age or sex structure, and production or sustainable rates of harvest
(Barnthouse et al.. 20081.
3 Interacting populations of different species occupying a common spatial area form a community (Barnthouse et al..
2008). Community level attributes affected by pollutants include species richness, species abundance, composition,
evenness, dominance of one species over another, or size (area) of the community (U.S. EPA. 2013a).
IS-67
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03 exposure
..........
*r ¦
* 03 uptake & physiology
Antioxidant metabolism upregulated
Decreased photosynthesis
Decreased stomatal conductance
or sluggish stomatal response
Effects on leaves
•Visible foliar injury
•Altered leaf production
•Altered leaf chemical composition
Plant growth
•Decreased biomass accumulation
•Altered root growth
•Altered carbon allocation
•Altered reproduction
1 -Altered crop quality
1
Belowground processes
•Altered litter production and decomposition
•Altered soil carbon and nutrient cycling
•Altered soil fauna and microbial communities
g
CD
—1
CD
0
GJ
CO
CD
3
CO
<
1 >
Affected ecosystem services
•Decreased productivity
•Decreased C sequestration
• Decreased crop yield
•Altered water cycling
•Altered community composition
•Altered pollination
•Altered forest products
Source: Adapted from U.S. EPA (2013b).
Figure IS-3 Illustrative diagram of ozone effects cascading up through scales
of biological organization from the cellular level to plants and
ecosystems.
Ozone effects 011 ecosystems are also inter-connected to human health and well-being. The term
"ecosystem services" refers to a concept that ecosystems provide benefits to people, directly or indirectly
(Costanza et al.. 2017). and these benefits are socially and economically valuable goods and services
deserving of protection, restoration, and enhancement (Bovd and Banzhaf. 2007). The concept of
ecosystem services recognizes that human well-being and survival are not independent of the rest of
nature and that humans are an integral and inter-dependent part of the biosphere. Preservation of
ecosystem structure and function contributes to the sustainability of ecosystem services that benefit
human welfare and society. Ecosystem services affected by ozone include productivity, carbon
sequestration, crop yield, water cycling, pollination, and production of forest commodities (Figure IS-3).
Tropospheric ozone affects terrestrial ecosystems across the entire continuum of biological
organization from the cellular and subcellular level to the individual organism up to ecosystem level
IS-68
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processes and services (Figure IS-3). For ozone, the majority of evidence for ecological effects is for
vegetation. Damage to terrestrial ecosystems caused by ozone is largely a function of damage to plants,
which starts with uptake of ozone into the leaf via stomata (gas exchange openings on leaves).
Subsequent reactions with plant tissues produce 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) including reduction in
aboveground and belowground growth, altered reproduction, and decreased yield. Plant-fauna linkages
affected by ozone include herbivores that feed on ozone-damaged plants and interactions mediated by
volatile plant signaling compounds (Section IS.5.1.3). Ozone can result in broad changes in ecosystems
such as productivity and carbon sequestration (Section IS.5.1.4). belowground processes
(Section IS.5.1.5). terrestrial community composition (Section IS.5.1.6). and water cycling
(Section IS.5.1.7). Effects of ozone exposure on aboveground and belowground ecosystem components,
across trophic levels, and on carbon allocation at multiple scales of biological organization are described
for forests (Section IS.5.1.8.1) and grasslands (Section IS.5.1.8.2).
IS.5.1.1 Visible Foliar Injury
In the 2013 Ozone ISA the evidence was sufficient to conclude a causal relationship between
ozone exposure and visible foliar injury on sensitive vegetation across the U.S. Visible foliar injury
(Figure IS-4) resulting from exposure to ozone has been well characterized and documented in over six
decades of research on many tree, shrub, herbaceous, and crop species using both long-term field studies
and laboratory approaches (U.S. EPA. 2013b. 2006a. 1996b. 1986. 1978; NAPCA. 1970; Richards et al..
1958). Recent experimental evidence continues to show a consistent association between visible injury
and ozone exposure (Section 8.2). In a recent global-scale synthesis documenting foliar injury from ozone
exposure in the field, across gradients, or in controlled ozone experiments, at least 179 of the identified
plant species have populations in the U.S. (Table 8-4). The use of sensitive species as biological
indicators to detect phytotoxic levels of ozone is a longstanding and effective methodology. More
recently, ozone-sensitive species planted in ozone gardens serve as a source of data on plant responses
and as an educational outreach tool. Although visible injury is a bioindicator of the presence of phytotoxic
concentrations of ozone in ambient air, it is not always a reliable predictor of other negative effects on
vegetation (e.g., growth, reproduction), and foliar injury can vary considerably between and within
taxonomic groups (U.S. EPA. 2013b). Since the 2013 Ozone ISA, new sensitive species showing visible
foliar injury continue to be identified and the role of modifying factors such as soil moisture and time of
day in visible foliar injury symptoms are further characterized (Section 8.2 and Section 8.12). New
information is consistent with the conclusions of the 2013 Ozone ISA that the body of evidence is
sufficient to infer a "causal relationship" between ozone exposure and visible foliar injury.
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Note: Tulip poplar (Liriodendrori tulipifera) on the left arid black cherry (Prunus serotiria) on the right.
Source: USDA Plants Database. Forest Service Forest Inventory and Analysis Program,
Figure IS-4 Representative ozone foliar injury in two common tree species in
the U.S.
IS.5.1.2 Whole-Plant Effects
The phytotoxicity of tropospheric ozone has been documented for over 50 years in a variety of
plant species (U.S. EPA. 2013b. 2006a. 1996b. 1986. 1978). Qzone-mduced oxidative damage at the
biochemical and leaf-level (Figure IS-3) lead to changes in photosynthesis and carbon allocation which
scale up to reduced growth and impaired reproduction in individual plants. Plant growth is assessed by
quantification of biomass, and analysis of patterns in carbon allocation to aboveground and belowground
plant parts. Direct exposure of reproductive tissues to ozone or indirect effects due to injury of vegetative
tissues results in fewer total available resources to invest in flowers or seeds. In plants cultivated for
agricultural production, damage due to ozone is assessed as reduced crop yield and quality. The evidence
supports causal relationships between ozone and plant growth, plant reproduction, and crop yield, and a
likely to be causal relationship between ozone and tree mortality. Such relationships indicate detrimental
effects of ozone at the individual-organism scale of biological organization.
In the 2013 Ozone ISA the evidence was sufficient to conclude a causal relationship between
ozone exposure and reduced growth of native woody and herbaceous vegetation. As reported in previous
assessments, ozone has long been known to cause decreases in growth which is documented in many
species including herbaceous plants, grasses, shrubs, and trees (U.S. EPA. 2013b. 2006a. 1996b. 1986.
1978). In an analysis conducted in the 2013 Ozone ISA, effects on growth from the Aspen FACE site
closely agreed with exposure-response functions based on data from earlier OTC experiments (U.S. EPA.
2013b). New controlled exposure experiments consistently demonstrate reduced plant growth, and models
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built with empirical data illustrate potential larger-scale impacts (Section 8.3). In support of findings in
the 2013 Ozone ISA and prior AQCDs, a recent international synthesis of studies published over the past
five decades documents reductions in biomass due to ozone exposure. At least 69 plant species of those
documented in the study have populations in the U.S. (Table 8-7). In addition to reduced growth,
numerous studies from different ecosystems find ozone significantly changes patterns of carbon allocation
below- and aboveground. New evidence from Aspen FACE for effects on growth and biomass of
vegetation includes shifts in wood anatomy (e.g., vessel size and density) and altered distribution of roots
across the soil profile following long-term exposure to elevated ozone. Biomass allocation within an
individual plant is relevant to whole plant growth and function. New studies provide context for scaling
up long-known detrimental effects of ozone on photosynthesis and growth on numerous plant species to
changes at the community and ecosystem level (Section 8.3.3). New information is consistent with the
conclusions of the 2013 Ozone ISA that the evidence is sufficient to infer a "causal relationship"
between ozone exposure and reduced vegetation growth.
Ozone effects on metrics of plant reproduction (e.g., flower number, fruit number, fruit weight,
seed number, rate of seed germination) in multiple experimental settings (e.g., in vitro, whole plants in the
laboratory, whole plants and/or reproductive structures in the green house, and whole plant communities
in the field) reported in the 2006 Ozone AQCD, the 2013 Ozone ISA, and this ISA clearly show ozone
reduces plant reproduction [Section 8.4; U.S. EPA (2013b. 2006a)]. A qualitative review in the 2006
Ozone AQCD showed that plant reproductive organs may be particularly sensitive to ozone injury (Black
et al.. 2000). The biological mechanisms underlying ozone's effect on plant reproduction are twofold.
They include both direct negative effects on reproductive tissues and indirect negative effects that result
from decreased photosynthesis and other whole-plant physiological changes. Since the 2013 Ozone ISA,
a quantitative meta-analysis of >100 independent studies of crop and noncrop species (published from
1968 to 2010) showed statistically significant and sometimes large decreases in reproduction (Leisner and
Ainsworth. 2012). Two metrics of plant reproduction, fruit number and fruit weight, show greater
reductions under increased ozone when combined across species for ozone concentrations that span 40 to
>100 ppb; other metrics do not show such reductions or do so across a narrower range of ozone
concentrations. In addition, there is more recent evidence that plant reproductive tissues are directly
affected by ozone exposure. There are a few new studies on the effects of ozone on phenology
(i.e., timing of germination and flowering), and similar to previously reviewed studies, they have less
consistent results than the studies on plant reproduction. In the 2013 Ozone ISA, plant reproduction was
considered with plant growth. Increased research and synthesis on ozone effects on plant reproduction
(Table 8-9) warrants a separate causality category and evidence is now sufficient to infer a "causal
relationship" between ozone exposure and reduced plant reproduction.
Multiple studies from different research groups show the co-occurrence of ozone exposure and
increased mortality of trees (Section 8.4.3 and Table 8-10). Evidence for plants other than trees is
currently lacking. Studies linking ozone and tree mortality are consistent with known and well-established
individual plant-level mechanisms that explain ozone phytotoxicity, including variation in sensitivity and
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tolerance based on age class, genotype, and species. Increased mortality is also consistent with effects at
higher levels of biological organization, including changes in vegetation cover and altered community
composition (Section 8.10). Since the 2013 Ozone ISA, a large-scale empirical analysis was conducted of
factors contributing to annual mortality of trees using over three decades of Forest Inventory and Analysis
data. This U.S. Forest Service data showed a significant positive correlation between 8-hour max ozone
concentration and tree mortality. Ozone significantly increased tree mortality in 7 out of 10 plant
functional types in the eastern and central U.S. (Dictzc and Moorcroft. 2011). Experimentally, elevated
ozone exposure has been shown to increase mortality in sensitive aspen genotypes (Moran and Kubiske.
2013). This evidence is considered with studies from the 2006 AQCD and 2013 Ozone ISA where decline
of conifer forests under ozone exposure was continually observed in several regions [Valley of Mexico,
southern France, Carpathian Mountains; U.S. EPA (2013b. 2006a)]. Previous evidence and new evidence
evaluated here is sufficient to infer a "likely to be causal relationship" between ozone exposure and
tree mortality.
In the 2013 Ozone ISA, the evidence was sufficient to conclude a causal relationship between
ozone exposure and reduced yield and quality of agricultural crops. The detrimental effect of ozone on
crop production has been recognized since the 1960s, and a large body of research has subsequently
characterized decreases in yield and quality of a variety of agricultural and forage crops (U.S. EPA.
2013b. 2006a. 1996b. 1986. 1978). The 1986 Ozone AQCD and 1996 Ozone AQCD reported new OTC
experiments on growth and yield, including U.S. EPA's National Crop Loss Assessment Network
(NCLAN), that served at the basis for exposure-response functions for agricultural crop species (U.S.
EPA. 1996b. 1986). As in noncrop plants, the concentrations at which damage is observed vary from
species to species and sometimes between genotypes of the same species.
There is a considerable amount of new research on major U.S. crops, especially soybean, wheat,
and other non-soy legumes at concentrations of ozone occurring in the environment (Section 8.5). For
soybean, further refinement of exposure-response curves and analysis of yield data identified a critical
level of 32 ppb (7-hour seasonal mean) at which a 5% loss can occur (Osborne et al.. 2016). At
SoyFACE, a linear decrease in yield at the rate of 37 to 39 kg per hectare per ppb ozone exposure over
40 ppb (AOT40) was observed across two growing seasons (Betzelberger et al.. 2012). Meta-analyses
published since the 2013 Ozone ISA provide further supporting evidence that current levels of ambient
ozone decrease wheat growth and yield and affect reproductive and developmental plant traits important
to agricultural and horticultural production (Section 8.5). Recent advances in characterizing ozone's
effects on U.S. crop yield include further geographic and temporal refinement of ozone sensitivity and
national-scale estimates of crop losses attributable to ozone. Previous research highlighted in the 2013
Ozone ISA and previous AQCDs show ozone effects on crop yield and crop quality (U.S. EPA. 2013b.
2006a. 1996a. 1986. 1978). New information is consistent with the conclusions of the 2013 Ozone ISA
that the body of evidence is sufficient to infer a "causal relationship" between ozone exposure and
reduced yield and quality of agricultural crops.
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IS.5.1.3 Effects on Plant-Fauna Interactions
In addition to detrimental effects on plants, elevated ozone can alter ecological interactions
between plants and other species, including (1) herbivores consuming ozone-exposed vegetation,
(2) pollinators and seed dispersers, and (3) predators and parasitoids of insect herbivores. Many of these
interactions are mediated through volatile plant signaling compounds (VPSCs), which plants use to signal
to other community members (Section 8.7). Elevated tropospheric ozone has been shown to alter the
production, emission, dispersion, and lifespan of VPSCs thereby reducing the effectiveness of these
signals. VPSCs play an important role in attracting pollinators, and their alteration can affect the crucial
ecosystem service of pollination of wild plants and crops. Ozone exposure also modifies chemistry and
nutrient content of leaves (U.S. EPA. 2013b). which may affect the physiology and behavior of
herbivores (Section 8.6).
Previous ozone assessments have evaluated studies examining ozone-insect-plant interactions and
found information on a wide range of insect species studied in the orders Coleoptera (weevils, beetles),
Hemiptera (aphids), and Lepidoptera [moths, butterflies; U.S. EPA (2013b. 2006a. 1996b}]. The majority
of studies focused on growth and reproduction while fewer studies considered herbivore survival and
population- and community-level responses to ozone. Although statistically significant effects were
frequently observed, they did not provide any consistent pattern of response across growth, reproduction,
and mortality endpoints. Research has since been published on additional species and at varying levels of
ozone exposure, although there is no clear trend in the directionality of response for most effects
(Section 8.6). The most commonly measured responses are fecundity, development time, growth, and
feeding preferences (Table 8-14). The strongest evidence of ozone effects is from herbivorous insects
with limited evidence from vertebrate feeding studies. Changes in nutrient content and leaf chemistry
following ozone exposure likely account for observed effects in herbivores. The body of evidence is
sufficient to infer a "likely to be causal relationship" between ozone exposure and alteration of
herbivore growth and reproduction.
In the 2013 Ozone ISA, a few experimental and modeling studies reported altered insect-plant
interactions that are mediated through chemical signaling (U.S. EPA. 2013b). New empirical research
from laboratory, greenhouse, OTC, and FACE experiments expand the evidence for 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 and Table 8-17). New evidence
includes consistent effects in multiple insect species, although this research has examined only a small
fraction of the total number of chemical-signaling responses potentially affected by ozone. Elevated
ozone (>50 ppb) degrades some plant VPSCs, changing the floral scent composition and reducing floral
scent dispersion. Preference studies in a few insect species show reduced pollinator attraction, decreased
plant host detection, and altered plant host preference in the presence of elevated, yet environmentally
relevant ozone concentrations. Exposure to elevated ozone had variable effects on VPSCs emissions and
on the stability of individual volatile compounds with potentially important ecological implications for
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plant-insect signaling involved in defense against herbivory. To attract predators and parasitoids that
target phytophagous insects, plants emit more VPSCs. Parasitoid-host attraction was either reduced,
enhanced, or unaffected by elevated ozone. The body of evidence is sufficient to infer a "likely to be
causal relationship" between ozone exposure and alteration of plant-insect signaling.
IS.5.1.4 Reduced Productivity and Carbon Sequestration
The evidence in the 2013 Ozone ISA was sufficient to conclude a causal relationship between
ozone exposure and reduced plant productivity (U.S. EPA. 2013b). Studies at the leaf and plant scale
show that ozone decreases plant growth, providing biological plausibility for decreases in ecosystem
productivity. Evidence of decreased ecosystem productivity from ozone exposure comes from many
different experiments with different study designs in a variety of ecosystems: OTC experiments;
long-term, ecosystem-manipulation, chamberless exposure experiments (Aspen FACE, SoyFACE,
FinnishFACE); empirical models using eddy covariance measures; forest productivity models
parameterized with empirical physiological and tree life history data; and various well-studied ecosystem
models and scenario analysis (Section 8.8.1). New information is consistent with the conclusions of the
2013 Ozone ISA that the body of evidence is sufficient to infer a "causal relationship" between ozone
exposure and reduced productivity in terrestrial ecosystems.
The evidence in the 2013 Ozone ISA was sufficient to conclude a likely causal relationship
between ozone exposure and decreased terrestrial carbon sequestration (U.S. EPA. 2013b).
Ozone-mediated changes in plant carbon budgets result in less carbon available for allocation to various
pools: reproductive organs, leaves, stems, storage, and roots as well as maintenance, defense, and repair.
Changes in allocation (Section 8.8.3) can scale up to population- and ecosystem-level effects, including
changes in soil biogeochemical cycling (Section 8.9). increased tree mortality (Section 8.4.3). shifts in
community composition (Section 8.10). changes to species interactions (Section 8.6). declines in
ecosystem productivity and carbon sequestration (Section 8.8). and alteration of ecosystem water cycling
(Section 8.11). The relationship between ozone exposure and terrestrial C sequestration is difficult to
measure at the landscape scale. Most of the evidence regarding this relationship is from model
simulations, although this endpoint was also examined in a long-term manipulative chamberless
ecosystem experiment (Aspen FACE). For example, experiments at Aspen FACE found ozone exposure
caused a 10% decrease in cumulative (Net Primary Production) and an associated 9% decrease in
ecosystem C storage, although the effects of ozone gradually disappeared towards the end of the 10-year
exposure (Talhelm et al.. 2014; Zak etal.. 2011) possibly due to loss of ozone-sensitive individuals and
lower ozone exposures in the last 3 years. Additional studies at this research site suggests that the effects
of ozone on plant productivity will be paralleled by large and meaningful decrease in soil C, but the
experimental observations reviewed did not find a direct link between ozone, NPP, and soil C pools. It is
likely that stand age and development and disturbance regimes are complicating factors in the partitioning
of ecosystem-level effects of ozone exposure on carbon sequestration. Even with these limitations, the
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results from the Aspen FACE experiment and the model simulations provide further evidence that is
consistent with the conclusions of the 2013 Ozone ISA that the body of evidence is sufficient to infer a
"likely to be causal relationship" between ozone exposure and reduced carbon sequestration in
ecosystems.
15.5.1.5 Belowground Processes/Biogeochemical Cycles
In the 2013 Ozone ISA, the evidence was sufficient to conclude that there is a causal relationship
between ozone exposure and the alteration of belowground biogeochemical cycles (U.S. EPA. 2013b). It
has been documented since the 2006 Ozone AQCD (U.S. EPA. 2006a) that while belowground roots and
soil organisms are not exposed directly to ozone, below-ground processes can be affected by ozone
through alterations in the quality and quantity of carbon supply to the soils from photosynthates and
litterfall (Andersen. 2003). The 2013 Ozone ISA presented evidence that ozone was found to alter
multiple belowground endpoints including root growth, soil food web structure, soil decomposer
activities, soil respiration, soil carbon turnover, soil water cycling, and soil nutrient cycling. The new
evidence since the 2013 Ozone ISA (U.S. EPA. 2013b) included in this assessment confirms ozone effects
on soil decomposition (Section 8.9.1). soil carbon (Section 8.9.2). and soil nitrogen (Section 8.9.3).
although the direction and magnitude of these changes often depends on the species, site, and length of
exposure. As in the 2013 Ozone ISA, the evidence is sufficient to conclude that there is a "causal
relationship" between ozone exposure and the alteration of belowground biogeochemical cycles.
15.5.1.6 Terrestrial Community Composition
In the 2013 Ozone ISA, the evidence was sufficient to conclude that there is a likely causal
relationship between ozone exposure and the alteration of community composition of some ecosystems,
including conifer forests, broadleaf forests, and grasslands, and altered fungal and bacterial communities
in the soil in both natural and agricultural systems (U.S. EPA. 2013b). Ozone effects on individual plants
can alter the larger plant community as well as the belowground community of microbes and
invertebrates, which depend on plants as carbon sources. Ozone may alter community composition by
having uneven effects on co-occurring species, decreasing the abundance of sensitive species and giving
tolerant species a competitive advantage. Key new studies (Wang et al.. 2016; Gustafson et al.. 2013)
model ozone effects on regional forest composition in the eastern U.S. Additionally, a global-scale
synthesis of decades of research on an array of ozone effects on plants confirms that some plant families
(e.g., Myrtaceae, Salicaceae, and Onagraceae) are more susceptible to ozone damage than others
(Bergmann et al.. 2017). This lends biological plausibility to a mechanism by which elevated ozone alters
terrestrial community composition by inhibiting or removing ozone-sensitive plant species or genotypes,
which alters competitive interaction to favor the growth or abundance of ozone-tolerant species or
genotypes. In grasslands, previous evidence included multiple studies from multiple research groups to
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show that elevated ozone shifts the balance among grasses, forbs, and legumes (Section 8.10.1.2). There
are new studies with findings consistent with earlier research (Section 8.10). including new studies from
European grasslands that found exposure-response relationships between ozone and community
composition. The 2013 Ozone ISA presented multiple lines of evidence that elevated ozone alters
terrestrial community composition, and recent evidence strengthens our understanding of the effects of
ozone upon plant communities, while confirming that the effects of ozone on soil microbial communities
are diverse (Table 8-20). The evidence is sufficient to conclude that there is a "causal relationship"
between ozone exposure and the alteration of community composition of some ecosystems.
15.5.1.7 Ecosystem Water Cycling
In the 2013 Ozone ISA, the evidence was sufficient to conclude a likely causal relationship
between ozone exposure and the alteration of ecosystem water cycling (U.S. EPA. 2013b). Ozone can
affect water use in plants and ecosystems through several mechanisms, including damage to stomatal
functioning and loss of leaf area, which may affect plant and stand evapotranspiration and lead, in turn, to
possible effects on hydrological cycling. Although the 2013 Ozone ISA found no clear universal
consensus on leaf-level stomatal conductance response to ozone exposure, many studies reported
incomplete stomatal closure and loss of stomatal control in several plant species, which result in increased
plant water loss [Section 9.4.5; U.S. EPA (2013b)l. Additionally, ozone has been found to alter plant
water use through decreasing leaf area index, accelerating leaf senescence, and by causing changes in
branch architecture, which can significantly affect stand-level water cycling. There is mounting
biologically relevant, statistically significant, and coherent evidence from multiple studies of various
types about the mechanisms of ozone effects on plant water use and ecosystem water cycling (reduced
leaf area, reduced leaf longevity, changes in root and branch biomass and architecture, changes in vessel
anatomy, stomatal dysfunction, reduced sap flow; rSection 8.111). Additionally, there are a few strong
studies that scale up these changes to effects on ecosystem scales and show significant effects. The most
compelling evidence is from six watersheds in eastern forests and from Aspen FACE (Kostiainen et al..
2014; Sun et al.. 2012). This new information adds to the evidence base in the 2013 Ozone ISA and
supports the conclusion that the body of evidence is sufficient to infer a "likely to be causal
relationship" between ozone exposure and the alteration of ecosystem water cycling.
15.5.1.8 Integration of Ozone Effects in Ecosystems
IS.5.1.8.1 orests
The effects of ozone exposure on U.S. forests have been an active area of research for over
50 years; evaluation of the role of ozone in forest health declines in the mixed conifer forest of the San
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Bernardino Mountains began in the early 1960s (Miller and McBride. 1999). Since that time, studies have
confirmed variation in sensitivity to ozone exposure in trees and plants based on age class, genotype, and
species (U.S. EPA. 2013b. 2006a. 1996b). There has been strong and consistent evidence from multiple
studies that ozone-induced oxidative damage leads to declines in photosynthesis and carbon gain, which
scale up to reduced growth in individual plants rSection 8.3; U.S. EPA (2013b. 2006a. 1996bVI. For
example, studies from the Aspen FACE experiment have shown that ozone caused reduction in total
biomass in quaking aspen (Populus tremuloides), paper birch (Betulapapyrifera), and sugar maple [Acer
saccharum; U.S. EPA (2013b)l. These findings were overall consistent with open-top chamber studies
that established ozone exposure-response relationships on growth in a number of native U.S. tree species
detailed in previous NAAQS reviews (U.S. EPA. 2013b); these species include aspen, black cherry
(Prunus serotinci), tulip poplar (Liriodendron tulipifera), white pine (Pinus strobus), and ponderosa pine
(Pinusponderosa). In addition to overall reductions in growth, there is evidence that ozone changes plant
growth patterns by significantly reducing root growth in some tree species. New information reviewed in
the current document support earlier conclusions that ozone reduces photosynthesis, growth, and carbon
allocation in a number of plant species found in forest ecosystems.
In addition to declines in root carbon allocation, results from Aspen FACE and other
experimental studies reviewed in the 2013 Ozone ISA consistently found that ozone exposure reduced
litter production and altered leaf chemistry in trees (U.S. EPA. 2013b). These direct effects of ozone on
plants may lead to changes in soil properties and processes in forests, but these changes are dependent on
species and genotype of community members, and potentially on other factors like the stage of stand
development.
Ozone effects on tree water use can also scale up to significant and measurable effects on
ecosystem water cycling in forests. Ozone-mediated impairment of stomatal function in plants has been
documented for decades (Keller and Hasler. 1984). although impairment seems to be species specific.
Studies continue to show reduced sensitivity of stomatal closing in response to various factors (light,
vapor pressure deficit, temperature, soil moisture) when exposed to ozone ("sluggish stomata") in a
number of species. A recent meta-analysis of ozone effects on stomatal response in 68 species (including
trees, crops, and grassland) found that trees were the most adversely affected, with 73% showing an
altered stomatal response. In this synthesis, 4 tree species exhibited sluggish stomata and 13 showed
stomatal opening in response to ozone (Mills et al.. 2016; Mills et al.. 2013). Ozone exposure has also
been linked to decreased water use efficiency and changes in sap flow (Mclaughlin et al.. 2007a;
Mclaughlin et al.. 2007b) and to reduced late-season stream flow in eastern forest ecosystems (Sun etal..
2012).
Differences between species in ozone sensitivity leads to significant changes in forest community
composition, as ozone sensitive trees decline and are replaced by less sensitive ones (Section 8.10.1.1).
Species-specific responses to ozone in terms of plant growth reductions and biomass allocation are a
possible mechanism for these community shifts. In a model simulation of long-term effects of ozone on a
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typical forest in the southeastern U.S. involving different tree species with varying ozone sensitivity,
Wang et al. (2016) found that ozone significantly altered forest community composition and decreased
plant biodiversity. Models using Aspen FACE data confirm that ozone effects on tree biomass and
productivity scale to affect community composition at the genotype and species level (Moran and
Kubiske. 2013). In simulations using Aspen FACE data of northern forests at the landscape level over
centuries, elevated ozone altered species abundance and the speed of replacement and succession
(Gustafson et al.. 2013). Multiple studies from different research groups show the co-occurrence of ozone
exposure and increased mortality of trees (Section 8.4.3). In a Bayesian empirical model built with field
measurement data from the U.S. Forest Service's Forest Inventory and Analysis program, ozone
significantly increased tree mortality in 7 out of 10 plant functional types in the eastern and central U.S.
(Dictzc and Moorcroft. 2011).
IS.5.1.8.2 Grasslands
In grassland ecosystems, herbaceous plants and grasses in particular are the dominant vegetation
rather than shrubs or trees. There is a wide range of sensitivity to ozone in grassland plant communities.
For example, studies going back to the 1996 Ozone AQCD show varying ozone sensitivity within the
genus Trifolium (clover) and general shifts in community biomass that favors grass species (U.S. EPA.
1996a). Evidence reviewed in the 2013 Ozone ISA from a large-scale ozone fumigation experiment in
grasslands demonstrated ozone decreases gross primary productivity in these systems (Yolk etal.. 2011).
Experiments reviewed in the 2013 Ozone ISA and previous AQCDs and the current Ozone ISA generally
show ozone associated with biomass loss, and a decrease in nutritive quality of forage species. Further,
ozone responses differed across species of grassland plants (Yolk et al.. 2006). Ozone effects on seed
production, germination, and flower number and date of peak flowering have been demonstrated in
representative grassland species (Section 8.4).
In grasslands, ozone effects on biodiversity or species composition may result from competitive
interactions among plants in mixed-species communities. Studies from mesocosm, OTC, and FACE
experiments generally show a shift in the biomass from grass-legume mixtures over time, in favor of
grass species. There are also new studies from European grasslands that found exposure-response
relationships for community composition (Section IS.5.1.9) that included some species that also grow in
the U.S. In the 2013 Ozone ISA, a review of ozone sensitive plant communities [identified as sensitive if
they had six or more species that exhibited significant ozone-caused changes in biomass in peer-reviewed
controlled experiments; Mills et al. (2007)1 found that the largest number of these sensitive communities
were associated with grassland ecosystems (U.S. EPA. 2013b). Among grassland ecosystems, alpine
grassland, subalpine grassland, woodland fringe, and dry grassland were identified as the most
ozone-sensitive communities. Ozone effects on grassland ecosystems extend belowground to the
associated soil microbial communities (Section 8.10.2). which show changes in proportions of bacteria or
fungi in response to elevated ozone and to fauna that feed on grassland vegetation.
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IS.5.1.9 Exposure-Response Relationships
For over 40 years, controlled ozone exposure experiments have yielded a wealth of information
on exposure-response relationships. Ozone exposure response has been demonstrated in many tree and
herbaceous species, including crops (U.S. EPA. 2013b. 2006a. 1996b. 1986. 1978). As described in
Section IS.3.2. various indices have been used to quantify ozone exposure in plants, including
threshold-weighted (e.g., SUM06) and continuous sigmoid-weighted (e.g., W126) functions. Weighting
of cumulative indices takes into account the greater effects of ozone on vegetation with elevated ozone
concentrations. As ozone concentrations increase, plant defense mechanisms are overwhelmed and the
capacity of the plant to detoxify reactive oxygen species is compromised (U.S. EPA. 2013b). For decades,
it has also been well characterized that plant sensitivity varies by time of day and development stage.
Growth responses vary depending on the growth stage of the plant. Furthermore, the time of highest
ozone concentrations may not occur at the time of maximum plant uptake. Weighted hourly
concentrations during the daylight hours and during the growing season are the most important variables
in a cumulative exposure index (U.S. EPA. 2013b). For vegetation, quantifying exposure with indices that
accumulate the ozone hourly concentrations and preferentially weight the higher concentrations improves
the explanatory power of exposure for effects on growth and yield, compared with using indices based on
mean and peak exposure values.
None of the information on the effects of ozone on vegetation published since the 2013 Ozone
ISA has modified conclusions on quantitative exposure-response relationships. Since the 2013 Ozone
ISA, there have been a few new experimental studies that add more exposure-response relationship
information to the large historical database available on U.S. plants (Section 8.13.2). In a new
experimental study, Betzelberger et al. (2012) studied seven cultivars of soybean at the SoyFACE
experiment in Illinois. They found that the cultivars showed similar responses in a range of ozone
exposures expressed as AOT40 (Section IS. 3.2). These results support conclusions of previous studies
(Betzelberger et al.. 2010) and the 2013 Ozone ISA that sensitivity of current soybean genotypes is not
different from early genotypes; therefore, soybean response functions developed in the NCLAN program
remain valid. A study by Neufeld et al. (2018) provided information on foliar injury response on two
varieties of cutleaf coneflower (Rudbeckia laciniata). For example, one variety had statistically detectable
foliar injury when the 24-hour W126 index reached 23 ppm hour (12-hour AOT40 = 12 ppm hour).
Although recent U.S. exposure-response studies in experimental systems are limited, U.S. and
international syntheses have highlighted response function information (e.g., biomass growth, foliar
injury, yield) for grassland and other plant species that occur in the U.S. (see Section 8.13.2). For
example, in a synthesis of previously published studies, linear relationships of biomass growth in
response to ozone were found using AOT40 for 87 grassland species that occur in Europe (van Goethem
et al.. 2013). Seventeen of these species are native to the U.S. and 65 additional species have been
introduced to the U.S. and may have significant ecological, horticultural, or agricultural value (USDA.
2015). This study has the most significant amount of new exposure response information for plants in the
U.S.
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IS.5.2
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
the radiative forcing metric. 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).
Through this effect on the Earth's radiation balance, tropospheric ozone plays a major role in the climate
system, and increases in its ozone abundance contribute to climate change (Mvhrc et al.. 2013).
For ozone effects on climate (Appendix 9). there are inter-connections to human health and
ecosystems. As discussed in the 2013 Ozone ISA, the Earth's atmosphere-ocean system responds to
changes in radiative forcing with a climate response, including a change in near-surface air temperature
with associated impacts on precipitation and atmospheric circulation patterns. This climate response
causes downstream climate-related health and ecosystem effects, such as the combined health effects of
both climate (e.g., heat waves) and ozone air quality or redistribution of diseases or ecosystem
characteristics. Feedbacks from both the direct climate response and such downstream effects can, in turn,
affect the abundance of tropospheric ozone and ozone precursors through multiple mechanisms
(Figure IS-5). Variations in climate can potentially alter the conditions that lead to the formation,
transport, and persistence of ozone in the troposphere (Appendix 1). as well as increase the vulnerability
of plants and ecosystems. The degree to which climate and weather alter the effects of ozone is context
and species specific because damage to terrestrial ecosystems caused by ozone is largely a function of
plant uptake. Factors that modify the effects of ozone in ecosystems, including carbon dioxide, weather,
and climate are discussed in Section 8.12.
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Source: U.S. EPA (2013b).
Figure IS-5 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.
Characterization of ozone impacts on radiative forcing (Section 9.2) builds on the findings in the
2013 Ozone ISA and draws heavily on the IPCC Assessment Reports. In the 2013 Ozone ISA, the
evidence was sufficient to conclude a causal relationship between tropospheric ozone and radiative
forcing (U.S. EPA. 2013b). The 2013 Ozone ISA reported a radiative forcing (RF) of 0.35 W/m2 from the
change in global tropospheric ozone abundance from preindustrial times to the present (1750 to 2005)
based on multimodel studies (Forster et al.. 2007). The most recent IPCC assessment, AR5, reports global
tropospheric ozone RF as 0.40 (0.20 to 0.60) W/m2 (Mvhre et al.. 2013). which is within range of
previous assessments (i.e., AR4). There have also been a few individual studies of tropospheric ozone RF
(Section 9.2) since AR5, including the study of tropospheric ozone RF based on the Coupled Model
Intercomparison Project Phase 6 (CMIP6) data set, and the Atmospheric Chemistry and Climate Model
Intercomparison Project (ACCMIP) multimodel study of tropospheric chemistry, all of which reinforce
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the AR5 estimates and continues to support a "causal relationship" between tropospheric ozone and
RF.
In the 2013 Ozone ISA, the evidence was sufficient to conclude a likely to be causal relationship,
via radiative forcing, between tropospheric ozone and climate change (now referred to as "temperature,
precipitation, and related climate variables"; the revised title for this causality statement provides a more
accurate reflection of the available evidence) (U.S. EPA. 2013b). New studies reviewed in Section 9.3 are
consistent with previous estimates and the effect of global, total tropospheric ozone increases on global
mean surface temperature continues to be estimated at roughly 0.1-0.3°C since preindustrial times (Xic et
al.. 2016; Mvhre et al.. 2013). with larger effects regionally. In addition to temperature, ozone changes
affect other climate metrics such as precipitation and atmospheric circulation patterns (Macintosh et al..
2016; Allen et al.. 2012; Shindell et al.. 2012). All of this evidence reinforces a "likely to be causal
relationship" between temperature, precipitation, and related climate variables.
IS.6 Key Aspects of Health and Welfare Effects Evidence
There is extensive scientific evidence that demonstrates health and welfare effects from exposure
to ozone. In assessing the older and more recent evidence, the U.S. EPA characterizes the key strengths
and remaining limitations of this evidence. In the process of assessing the evidence across studies and
scientific disciplines and ultimately forming causality determinations, the U.S. EPA takes into
consideration multiple aspects that build upon the Hill criteria (Hill. 1965) and include, but are not limited
to, consistency in findings, coherence of findings, and evidence of biological plausibility [see U.S. EPA
(2015)1. As documented by the extensive evaluation of evidence throughout the subsequent Appendices
to this ISA, the U.S. EPA carefully considers uncertainties in the evidence, and the extent to which recent
studies have addressed or reduced uncertainties from previous assessments, as well as the strengths of the
evidence. Uncertainties considered in the epidemiologic evidence, for example, include potential
confounding by copollutants or covarying factors and exposure error. The U.S. EPA evaluates many other
important considerations (not uncertainties) such as coherence of evidence from animal and human
studies, heterogeneity of risk estimates, and the shape of the concentration-response relationships. All
aspects are considered along with the degree to which chance, confounding, and other biases affect
interpretation of the scientific evidence in the process of drawing scientific conclusions and making
causality determinations. Uncertainties do not necessarily change the fundamental conclusions of the
literature base. In fact, some conclusions may be robust to such uncertainties. Where there is clear
evidence linking ozone with health and welfare effects with or despite minimal remaining uncertainties,
the U.S. EPA makes a determination of a causal or likely to be causal relationship.
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IS.6.1 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 ozone exposure (Figure IS-6). 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 systematically considered and assessed, including
the inherent strengths, limitations, and uncertainties in the overall body of evidence, resulting in the
causality determinations detailed in Table IS-1. Through identification of the strengths and limitations in
the evidence, this ISA may help in the prioritization of research efforts to support future ozone NAAQS
reviews.
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, as well as 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. Depth is
further demonstrated through the variety of the study designs used across the scientific disciplines and
exposure duration periods.
In this ISA, systematic review methodologies are applied to identify and characterize this
expansive evidence base (see Appendix 10 for details). The evidence is integrated from (1) a variety of
study designs within the same scientific discipline, (2) different scientific disciplines, and (3) a span of
different health endpoints within a health effect category. Finally, a formal framework is applied
systematically to draw conclusions about the causal nature of the relationship between ozone exposure
and health effects (U.S. EPA. 2015).
A first step in integrating evidence for a health effect category is to consider the biological
plausibility of health responses observed in association with ozone exposure. The process for
characterizing biological plausibility is described in Section IS.4.2. Recent studies in humans and animals
expand on findings from prior assessments (U.S. EPA. 2013b. 2006a. 1996a) to further understand
plausible pathways that may underlie the observed respiratory health effects related to short-term
exposure to ozone (Figure 3-1). Consistent evidence for several respiratory endpoints within a large
number of animal toxicological, controlled human exposure, and epidemiologic studies, as well as
coherent evidence across these studies contribute to a large degree of certainty in assessing the
relationship between short-term ozone exposure and this health effect category. Furthermore, uncertainty
is addressed by epidemiologic studies that examine potential copollutant confounding, examine different
model specifications, and account for potential confounders.
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Causality Determinations for Health Effects of Ozone
2020 Ozone ISA
Short-term
exposure
Kespiraiory
Long-term
exposure
Metabolic
Short-term
exposure
+
Long-term
exposure
+
Cardiovascular
Short-term
exposure
i
Long-term
exposure
0)
E
o
o
Nervous System
Short-term
exposure
O
.c
*¦*
CO
Long-term
exposure
~o
=5
"O
Male/Female
Reproduction
and Fertility
Long-term
*
o
Q.
<1)
Pregnancy and
Birth Outcomes
exposure
*
Cancer
Long-term
exposure
Mortality
Short-term
exposure
i
Long-term
exposure
Causal J Likely causal Q Suggestive Q Inadequate
+ new causality determination; 1 causality determination changed from likely
causal to suggestive; * change in scope of health outcome category from 2013
Ozone ISA
Figure IS-6 Causality determinations for health effects of short- and
long-term exposure to ozone.
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Both older and more recent studies provide evidence for biologically plausible pathways that may
underlie respiratory effects related to long-term ozone exposure, and metabolic effects related to
short-term exposure. Epidemiologic studies of long-term ozone exposure and respiratory effects are
supported by numerous animal toxicological studies examining related endpoints. This coherence reduces
some of the uncertainty related to the independence of the ozone effect, though there are some remaining
uncertainties for these health effects. For example, there are still relatively few studies evaluating the
effect of ozone exposure on metabolic effects in human populations (i.e., controlled human exposure or
epidemiologic studies).
With regard to short-term ozone exposure and cardiovascular health effects, there is some
evidence for biologically plausible pathways for the worsening of IHD or HF, the development of heart
attack or stroke, and cardiovascular-related ED visits and hospital admissions (Figure 4-1). However, the
evidence comes mainly from animal toxicological studies, is generally not supported by controlled human
exposure studies, and is limited for epidemiologic studies. While there is some epidemiologic evidence
that short-term ozone concentrations are associated with total mortality, the evidence of plausible steps
that could lead to death (e.g., IHD, HF) are lacking in epidemiologic studies that examined these types of
endpoints (e.g., hospital admissions for IHD or HF). Furthermore, controlled human exposure studies in
healthy adults generally do not show that short-term ozone exposure leads to the types of intermediate
health effects (e.g., impaired vascular function, changes in ECG measures) that could lead to IHD or
stroke. Most of the studies supporting the biological plausibility of epidemiologic studies of mortality are
from animal studies that are not generally supported by studies in humans.
Older and recent studies examining short- or long-term ozone exposure and several other health
effects (i.e., nervous system effects, reproductive effects, cancer) are few or report inconsistent evidence
of an association with the health effect of interest. For these health effects, there is often limited
coherence across studies from different scientific disciplines, and limited evidence for biologically
plausible pathways by which effects could occur. Other sources of uncertainty, such as limited assessment
of potential copollutant confounding, are inherent in these evidence bases.
There is strong and consistent animal toxicological evidence linking short- and long-term ozone
exposure with respiratory, cardiovascular, and metabolic health effects. However, several uncertainties
should be considered when evaluating and synthesizing evidence from these studies. Experimental 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 reasonable study length. 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. For example, animal toxicological studies generally
expose rodents to 250 to >1,000 ppb, while controlled human exposure studies generally expose humans
to 60 to 300 ppb. Additionally, a number of animal toxicological studies were performed in rodent disease
models, while controlled human exposure studies generally are conducted in healthy individuals. This
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difference could explain some of the inconsistencies across studies between these scientific disciplines.
Controlled human exposure studies do not typically include unhealthy or diseased individuals for ethical
reasons; therefore, this represents an important uncertainty to consider in interpreting the results of these
studies. Additional animal toxicological studies conducted at lower concentrations could help to reduce
this uncertainty. Finally, in addition to 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 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 may contribute to the lack of coherence between results of experimental animal and human
studies. Dosimetric studies of animals and humans might inform understanding of the potential role of
such differences.
Controlled human exposure studies provide the strongest evidence for the effects of short-term
ozone exposure on respiratory effects. There are, however, several limitations of controlled human
exposure studies. These include the study of generally healthy individuals and the measurement of
relatively minor health effects (or indices of health effects) for ethical reasons (unhealthy or very sick
people are studied rarely). Therefore, individuals that may be at greater risk are not included in controlled
human exposure studies. However, controlled human exposure studies offer several strengths for studying
human health effects from ozone exposure. The experimental nature of controlled human exposure studies
allows them to virtually eliminate the chance, bias, and other potential confounding factors inherent in
observational epidemiologic studies. In addition, controlled human exposure studies are not susceptible to
some of the uncertainties commonly attributed to animal toxicological studies, such as the need to
extrapolate between animal models and humans, and the use of relatively high ozone concentrations
compared with concentrations typically encountered in ambient air.
Though 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 populations that cannot typically be included in controlled human exposure studies, such as
children, pregnant women, and individuals with pre-existing disease. In addition, 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. Many epidemiologic
studies have been conducted in diverse geographic locations, encompassing different population
demographics, and using a variety of exposure assignment techniques. They continue to report consistent,
positive associations between short-term ozone exposure and health effects. When combined with
coherent evidence from experimental 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.
The most common source of uncertainty in epidemiologic studies of ozone is exposure
measurement error. The majority of recent epidemiologic studies of long-term ozone exposure use
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concentrations from fixed-site monitors as exposure surrogates. Some recent epidemiologic studies
incorporate new ozone exposure assignment methods that integrate several sources of available data
(i.e., satellite observations, CTM predictions, and ambient monitors) into a spatiotemporal model. These
hybrid methods are well validated by ozone monitors in areas with moderate to high population density,
and they better allow for the inclusion of populations from less urban areas, where monitor density is
lower. Relatively low spatial variability of ozone (compared with UFP, CO, NO2, or SO2) in most
locations increases confidence in application of these methods for predicting ozone exposure.
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.
Additionally, the populations included in epidemiologic studies have long-term, variable, and
uncharacterized exposures to ozone and other ambient pollutants. Epidemiologic studies evaluate the
relationship between health effects and specific ozone concentrations during a defined study period. The
generally consistent and coherent associations observed in these epidemiologic studies contribute to the
causality determinations and the conclusions regarding the causal nature of the effect of ozone exposure
on health effects, However, they do not provide information about which averaging times or exposure
metrics may be eliciting the health effects under study.
Each of 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 between short-term ozone concentrations and health effects. For long-term exposure
studies, exposure measurement error can bias effect estimates in either direction, although it is more
common that effect estimates are underestimated. Underestimation of health effect associations in short-
and long-term ozone exposure studies implies that true health effect associations are even larger than
what is reported in epidemiologic studies. The magnitude of bias in the effect estimate is likely small for
ozone, because ozone concentrations do not vary over space as much as other criteria pollutants, such as
NOx or SO2 (Section 2.6).
Copollutant analyses were limited in epidemiologic studies evaluated in the 2013 Ozone ISA but
indicated that associations between ozone concentrations and health effects were not confounded by
copollutants or aeroallergens (U.S. EPA. 2013b). Copollutant analyses are more prevalent in recent
studies and continue to suggest that observed associations are independent of coexposures to correlated
pollutants or aeroallergens. Despite expanded copollutant analyses in recent studies, determining the
independent effects of ozone in epidemiologic studies is complicated by the high copollutant correlations
observed in some studies, and the possibility for effect estimates to be overestimated for the pollutant
measured with less error in copollutant models (Section 2.5). That said, some studies report modest
copollutant correlations, which suggests that strong confounding due to copollutants is unlikely. In
addition, evidence from copollutant models is available for a small subset of all the pollutants that
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co-occur with ozone in the air. Nonetheless, the consistency of associations observed across studies with
different copollutant correlations, the generally robust associations observed in copollutant models, and
evidence from other scientific disciplines generally provide compelling evidence for an independent
effect of ozone exposure on human health and reduce the uncertainties associated with potential
copollutant confounding.
The 2013 Ozone ISA noted that multicity epidemiologic studies, particularly examining
short-term ozone exposure and mortality, reported evidence of heterogeneity in the magnitude and
precision of risk estimates across cities. There are few recent multicity studies of short-term ozone
exposure and health effects that could allow an evaluation of such heterogeneity; thus, the uncertainty
identified in the 2013 Ozone ISA remains.
Examination of the concentration-response (C-R) relationship has primarily been conducted in
studies of short-term ozone exposure and respiratory health effects or mortality, with some more recent
studies characterizing this relationship for long-term ozone exposure and mortality. Across recent studies
that used a variety of statistical methods to examine potential deviations from linearity, evidence
continues to support a linear C-R relationship, but with less certainty in the shape of the curve at lower
concentrations (i.e., below 30-40 ppb). In addition, some studies evaluate the potential for a
population-level threshold, below which health effects would unlikely be observed. Generally, these
studies conclude that if a population-level threshold exists, it would occur at lower concentrations
(i.e., below 30-40 ppb) where there is less certainty in the ozone-health effect relationship due to few
observations at these lower concentrations. Similar to the uncertainty mentioned previously, the
populations included in epidemiologic studies have long-term, variable, and uncharacterized exposures to
ozone and other ambient pollutants. Epidemiologic studies evaluate the C-R relationship between health
effects and specific ozone concentrations during a defined study period. The generally consistent C-R
relationships observed in these epidemiologic studies do not indicate which averaging times or exposure
metrics may be eliciting the health effects under study.
IS.6.2 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 IS-2
and effects on climate in Table IS-3.
IS.6.2.1 Ecological Effects
A large body of scientific evidence spanning more than 60 years clearly demonstrates there are
effects on vegetation and ecosystems attributed to ozone exposure resulting from anthropogenic activities
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(U.S. EPA. 2013b. 2006a. 1996b. 1986. 1978: NAPCA. 1970: Richards et al.. 1958). There is high
certainty in ozone effects on impairment to leaf physiology as mechanisms for cascading effects at higher
levels of biological organization (e.g., plant growth, ecosystem productivity; Section 8.1.3: Figure IS-7).
The overwhelming strength of many of the studies is that they consist of controlled ozone exposure to
plants, plots of forests, and crop fields to eliminate any confounding factors (Section 8.12). For example,
for ozone effects on plants, there are robust exposure response functions (i.e., from carefully controlled
experimental conditions, involving multiple concentrations and based on multiple studies) for about a
dozen important tree species and ten major commodity crop species.
The use of visible foliar injury to identify phytotoxic levels of ozone is an established and widely
used methodology. However, foliar injury is not always a reliable indicator of other negative effects on
vegetation (e.g., growth, reproduction), and there is a lack of quantitative exposure-response information
that accounts for the important role of soil moisture in foliar injury. As documented in the 2013 Ozone
ISA (Table IS-12) and retained in the current Ozone ISA (Figure IS-7). there are causal relationships
between ozone exposure and visible foliar injury at the individual-organism level, and causal relationships
between ozone exposure and reduced plant growth and crop yield from the individual to population
levels. Since the 2013 Ozone ISA (U.S. EPA. 2013b). a meta-analysis of existing literature on plant
reproductive metrics and new research support a causal relationship between ozone exposure and reduced
plant reproduction. In the previous ISA, plant reproduction was considered within the broader category of
growth but the current body of evidence for this endpoint warrants a separate causality category.
While the effect of ozone on vegetation is well established in general, there are some knowledge
gaps regarding precisely which species are sensitive and what exposures elicit adverse responses for many
species. Currently there are over 40,000 plants and lichens occurring in the U.S. as documented by the
USDA PLANTS database (USDA. 2015). It not feasible to know what the effects are on all U.S. species
and what the ecological consequences of the differential sensitivities are of these species. However, there
have been many important trees, crops, and other plants studied to indicate the potential array of
ecological effects in the U.S. The exposure-response relationships for a subset of individual plants are
discussed in Section 8.13. Within and between these species there is a range of sensitivities, and it is
difficult to identify the representativeness of these relationships within the wider population of plants that
occur in the U.S. There are also uncertainties about how plant responses change with age and size. The
technique of meta-analysis is one approach that can be used to consolidate and extract a summary of
significant responses from a selection of previously published studies. These meta-analyses can show
patterns of cause and effect relationships between ecological endpoints and ozone exposure; they are
robust enough to overcome individual variation and are useful for looking at trends in plant response
across, for example, geographic locations, environmental conditions, plant functional groups, and
ecosystems.
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Causality Determinations for Ecological Effects of Ozone
Scale of Ecological Response
Ecosystem
Belowground
Biogeochemical Cycles
Water Cycling
Carbon Sequestration
Productivity
Community
Biodiversity
Terrestrial Community Composition!
Species Interactions
Plant-Insect Signaling +
Population
Individual
Survival
Trees+
Growth
Plants
Herbivores +
Reproduction
Plants+
Herbivores +
Yield
Agricultural Crops
Individual
Visible Foliar Injury
Causal |^| Likely Causal |
+ new causality determination;!causality determination changed from likely to be
causal to causal
Figure IS-7 Causality determinations for ecological effects of ozone across
biological scales of organization and taxonomic groups.
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The majority of evidence for ecological effects of ozone is for vegetation. Fewer studies examine
plant-ozone-insect interactions. There are multiple, statistically significant findings showing ozone effects
on fecundity and growth in insect herbivores. However, no consistent directionality of response is
observed across the literature, and uncertainties remain in regard to different plant consumption methods
across species and the exposure conditions associated with particular severities of effects. There is also
variation in study designs and endpoints used to assess ozone responses. Most responses observed in
insects appear to be indirect (i.e., mediated through ozone effects on vegetation, although direct effects of
ozone exposure on insects could also play a role). New research in chemical ecology has provided clear
evidence of ozone modification of VPSCs and behavioral responses of insects to these modified chemical
signatures; however, most of these studies have been carried out in laboratory conditions rather than in
natural environments. Characterization of airborne pollutant effects on chemical signaling in ecosystems
is an emerging area of research with information available on a relatively small number of insect species
and plant-insect associations and knowledge gaps in the mechanisms and consequences of modulation of
VPSCs by ozone.
There are some uncertainties in characterizing how ozone damage to leaves and individual plant
species scale up to ecological communities and ecosystem processes. Although estimating ozone effects
to the ecosystem level remains a challenge, there is a large body of knowledge of how ecosystems work
gained through ecological observations and models that simulate processes at multiple scales. The models
attempt to capture interactive effects of multiple stressors in ecosystems in the field. Studies of ozone
effects beyond the plant scale use a combination of empirical studies and statistical modeling, or large
controlled exposure ecosystem experiments, or field observations along ozone gradients. Interactive
effects in natural ecosystems with multiple stressors (e.g., drought, disease) are difficult to study, but can
be addressed through different statistical methods. For example, multivariate models and mechanistic
models have been used for studying ozone with other environmental factors [e.g., Dietze and Moorcroft
(2011)1 and for scaling up ozone effects on tree growth and water use to ecosystem stream flow [e.g., Sun
et al. (2012)1. Another approach is to use meta-analysis techniques to examine trends across large
geographic areas or at higher biological levels of organization (e.g., plant functional groups, forest types).
More research on ecosystem-level responses will strengthen understanding of how effects at lower levels
of biological organization influence higher level responses.
In general, the most promising approaches to estimating or characterizing ozone effects at the
ecosystem level include evaluation of ecological response using a suite of parameters and
exposure-response functions, both empirical and modeled. The quantitative uncertainty of empirically
observed variables in ecology is determined by the use of statistics. In general, ecological endpoints
affected by ozone were reported in the ISA if they were statistically significant. In addition, models of
chemical and ecological processes provide representations of biological interactions through
mathematical expressions. The models used can be complex, including many interacting variables. Each
of the input variables in a model has some uncertainty. Models can also be evaluated on the basis of the
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mechanistic understanding of how ecological systems work and how ozone effects may propagate
through ecological systems.
IS.6.2.2 Effects on Climate
Ozone is an important greenhouse gas and increases in its abundance have affected the Earth's
climate. Over the last century, global average surface air temperature has increased by approximately
1.0°C, and emissions of greenhouse gases are the dominant cause (Wucbblcs et al.. 2017; IPC'C. 2013).
There are many other aspects of the global climate system that are changing in addition to this warming,
including melting glaciers, reductions in snow cover and sea ice, sea level rise, ocean acidification, and
increases in the frequency or intensity of many types of extreme weather events (Wucbblcs et al.. 2017).
The magnitude of future climate change, globally and regionally, and in terms of both temperature
increases and these other types of associated impacts, will depend primarily on the amount of greenhouse
gases emitted globally (Wucbblcs et al.. 2017; IPC'C. 2013). The most recent IPCC report, AR5, which is
a comprehensive assessment of the peer-reviewed literature, reported global tropospheric ozone RF as
0.40 (0.20 to 0.60) W/m2 (Mvhrc et al.. 2013). In the 2013 Ozone ISA, there was a causal relationship
between tropospheric ozone and RF and a likely to be causal relationship between tropospheric ozone and
climate change (U.S. EPA. 2013b). None of the new studies support a change to either causality
determination (Figure IS-S).
While the warming effect of tropospheric ozone in the climate system is well established in
general, various uncertainties render the precise magnitude of the overall effect of tropospheric ozone on
climate more uncertain than that of the we 11-mixed greenhouse gases (Mvhrc etal.. 2013). These include
several uncertainties associated with estimating the magnitude of RF attributed to tropospheric ozone
increases, such as uncertainties in estimating preindustrial ozone concentrations. In addition, 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 RF is particularly
sensitive to changes in ozone concentrations) are not captured well by models. Substantial variation also
exists across models. Such modeling uncertainties make it especially difficult to provide precise
quantitative estimates of the climate effects of regional-scale ozone changes.
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Causality Determinations for Tropospheric Ozone and
Climate Change
Radiative Forcing
Temperature, precipitation and
related climate variables
Causal B-l Likely Causal
Figure IS-8 Causality determinations for tropospheric ozone and climate
change.
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IS.7 References for Integrative Synthesis
Adams. WC. (2002). Comparison of chamber and face-mask 6.6-hour exposures to ozone on
pulmonary function and symptoms responses. Inhal Toxicol 14: 745-764.
http://dx.doi.org/10.1080/0895837029008461Q
Adams. WC. (2003). Comparison of chamber and face mask 6.6-hour exposure to 0.08 ppm ozone via
square-wave and triangular profiles on pulmonary responses. Inhal Toxicol 15: 265-281.
http://dx.doi.org/10.1080/0895837039Q168283
Adams. WC. (2006). Comparison of chamber 6.6-h exposures to 0.04-0.08 ppm ozone via square-
wave and triangular profiles on pulmonary responses. Inhal Toxicol 18: 127-136.
http://dx.doi.org/10.1080/089583705003061Q7
Alberti. KG; Eckel. RH: Grundy. SM; Zimmet. PZ; Cleeman. JI; Donato. KA: Fruchart. JC; James.
WP; Loria. CM; Smith. SC. (2009). Harmonizing the metabolic syndrome: A joint interim
statement of the International Diabetes Federation Task Force on Epidemiology and Prevention;
National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation;
International Atherosclerosis Society; and International Association for the Study of Obesity.
Circulation 120: 1640-1645. http://dx.doi.org/10.1161 /CIRCULATIONAHA. 109.192644
Allen. RJ; Sherwood. SC; Norris. JR; Zender. CS. (2012). Recent Northern Hemisphere tropical
expansion primarily driven by black carbon and tropospheric ozone. Nature 485: 350-354.
http://dx.doi .org/10.103 8/nature 11097
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