March 5, 2015

U.S. Environmental Protection Agency Headquarters, William Jefferson Clinton Building

1200 Pennsylvania Avenue, N.W., Washington, DC 20460

Dear Administrator McCarthy:

We are submitting the comments below in support of the proposed lowering of the Ozone standard, and to 

encourage you to set the new standard to the lower end of the proposed range. Specifically, we urge you to set the 

standard at 60-65 ppb, in order to protect vulnerable populations from the adverse health effects of ozone with an 

adequate margin of safety. As detailed below, the currently proposed standard of 65-70 ppb does not adequately 

account for excess risk encountered by pregnant women and populations who experience the cumulative effects of 

multiple physical and social stressors. In the attached document we discuss the evidence with regard to the 

increased risk encountered by these two vulnerable groups, the lack of explicit analysis in the risk assessment 

process, and the need for a larger margin of safety to adequately protect their health. In addition, we offer several 

recommendations for where language in the proposed rule should be altered to address this issue. Thank you for 

your work to protect the health of the public, and your attention to these comments in order to particularly protect 

vulnerable groups who are at increased risk for the adverse health effects of ozone.

Sincerely,

Chris Coombe, PhD, MPH, Assistant Research Scientist

University of Michigan School of Public Health

Kelly Ferguson, PhD, MPH, Research Fellow

University of Michigan School of Public Health

Patricia Koman, MPP, Senior Project Manager

University of Michigan School of Public Health

Natalie Sampson, PhD, MPH, Assistant Professor

College of Education, Health, & Human Services, University of Michigan-Dearborn

Amy Schulz, PhD, MPH, Professor

University of Michigan School of Public Health

Donele Wilkins, President/CEO

Green Door Initiative
2

March 6, 2015

Public Comment on the Federal Register, Vol. 79 No. 242

National Ambient Air Quality Standards for Ozone; Proposed Rule

Published December 17, 2014

Docket ID No. EPA-HQ-OAR-2008-0699

The legislative history of the Clean Air Act specifies the responsibility of the Environmental 

Protection Agency (EPA), through the National Ambient Air Quality Standards (NAAQS), to 

identify and to protect with an adequate margin of safety vulnerable populations who are at 

increased risk for adverse effects of air pollutants. The proposed revised ozone standard 

published in the EPA’s NAAQS for Ozone, signed by Administrator McCarthy on November 

25, 2014, would lower the standard from 75 ppb to a level in the range of 65-70ppb. These 

proposed standards are a step in the right direction, and we are supportive of lowering the 

level from 75 ppb to this range. However, based on evidence included in the Integrated 

Science Assessment (ISA) and highlighted in the Ozone Health Risk and Exposure 

Assessment (hereafter Ozone HREA) completed by the EPA1and echoing the 

recommendations made by the Clean Air Scientific Advisory Committee (CASAC),

2

the new 

standard should be lowered further to the range of 60-65 ppb to adequately protect 

previously unacknowledged vulnerable populations from the adverse health effects of ozone 

exposure with an adequate margin of safety.

The proposed standards do not adequately account for excess risk experienced by 

several important groups. These include pregnant women, populations experiencing 

cumulative effects of multiple physical and social stressors, and pregnant women in these 

populations. Due to the lack of explicit analysis of these groups in the risk assessment 

process, a larger margin of safety is needed to account for the underestimated number of 

individuals in the US who are at increased risk for health effects consequent to exposure. In 

the comments we present evidence that supports our recommendation for a larger margin 

of safety, including evidence of excess risk in these populations, and make 

recommendations for where language in the proposed rule should be altered.

Pregnant Women

Pregnant women were not examined in the Integrated Science Assessment (ISA) for 

Ozone and Related Photochemical Oxidants.3 Prenatal development is considered as a 

lifestage that is more susceptible to exposures, and reproductive and developmental 

consequences to the fetus are considered. However, the ISA summaries do not sufficiently 

address the elevated risk of ozone consequences experienced by the pregnant population, 

as they omit scientific evidence showing the increased vulnerability of this population 

completely. Pregnant women are an at-risk population because of: 1) a broader range of 

potential health consequences, and 2) increased dose of ozone for a given exposure level. 
3

Identification of exposures of concern to pregnant women and reduction of exposures is of 

great concern to the medical community, as illustrated by the 2013 Committee Opinion from 

the American College of Obstetricians and Gynecologists (ACOG) on Exposure to Toxic 

Environmental Agents.

4

1. Pregnant women are at risk for a broader range of adverse health effects

consequent to ozone exposure that are not applicable to the rest of the population. 

These include: a) preeclampsia, a hypertensive disorder of pregnancy; and b) birth 

outcomes, which can be detrimental to maternal physical and mental health.

a. Preeclampsia is a hypertensive disorder that is specific to pregnancy which 

puts the mother at an increased risk of mortality during pregnancy and also for 

an increased risk of cardiovascular disease later in her life.5 Additionally, 

preeclampsia is a risk factor for adverse birth outcomes such as fetal growth 

restriction and preterm birth. New studies have been published since the Ozone 

ISA was completed demonstrating strong evidence for an association between 

exposure to ozone during pregnancy and the development of preeclampsia.

6, 7

Despite the inability to demonstrate clear causality in most epidemiologic 

research, a number of the studies in this realm have provided evidence for such 

a relationship by measuring exposure prior to delivery.8, 9 Notably, a systematic 

review and meta-analysis of these studies showed that a 10 ppb increase in 

ambient ozone levels in the first or second trimester is associated with an 

approximately 10 percent increase in risk of developing a hypertensive 

disorder of pregnancy.

6 Of additional importance mean/median ambient air 

concentrations of ozone from the studies included in that meta-analysis were 

much lower than the current standard (22-40 ppb).6There is mechanistic 

evidence from in vitro and animal studies to support a causal association 

between ozone exposure and hypertension or preeclampsia in pregnancy. 

Briefly, ozone has been shown to induce maternal and placental oxidative 

stress,

10 which can lead to apoptosis of the syncytiotrophoblast and narrowing of 

the spiral arterioles that are crucial for sufficient placental blood flow.11-14 This 

impaired placentation is the suspected cause of hypertensive disorders of 

pregnancy.11, 15 While not published in time to be considered in the Ozone ISA, 

the compelling nature of this new evidence for a causal relationship between 

ozone exposure and preeclampsia should be considered now, as part of this 

standard review. In particular, this can be addressed by moving toward the 

lower standard of 60-65 ppb, which provides a larger margin of error to better 

protect pregnant women from adverse health effects of ozone exposures.

b. Birth outcomes, including but not limited to fetal mortality, premature birth, low 

birth weight, and birth defects have been associated with ozone exposure, with 

suggestive evidence of a causal relationship. These findings have been 
4

adequately summarized in the ISA of ozone,

3

although this document excludes 

additional convincing evidence published since 2011.8, 16 Nevertheless, the 

impact of these outcomes on the mothers themselves has not been sufficiently 

emphasized. Not only are reproductive effects only applicable to women 

undergoing pregnancy, but in addition to negative health repercussions for the 

fetus, these effects can have adverse physical (e.g., C-section) and mental17-20

health consequences for the mother.

2. Pregnant women have an increased dose of ozone and other air pollutants

following exposure as compared to non-pregnant women of the same age. This is a 

result of increased metabolic rate (i.e., amount of oxygen consumed) during 

pregnancy, which has been well-established.21-23 Since the primary route of 

exposure for air pollutants is through inhalation, it follows that dose would be higher 

in pregnant women although, to our knowledge, this has not been directly 

demonstrated in epidemiologic, animal, or modeling studies.

Additionally, pregnant women represent a large proportion of the US population. For 2013,

the National Vital Statistics Reports from the US Department of Health and Human services 

estimated 3,957,577 births.24 This underestimates the number of pregnancies, but 

otherwise translates to pregnant women accounting for 1.25% of the population that year.

25

The Federal Register26 (Part I, Section A) states “The requirement that primary standards 

provide an adequate margin of safety was intended to address uncertainties associated with 

inconclusive scientific and technical information available at the time of standard setting” 

and that factors considered in developing an adequate margin of safety include “such 

factors as the nature and severity of health effects, the size of sensitive population(s) at risk, 

and the kind and degree of the uncertainties that must be addressed.” A number of 

important sensitive populations, such as children, were included in this process. However, 

adult pregnant women represent a large sensitive at-risk population that was not considered 

adequately in the ISA or in the Ozone HREA and, thus, the standard of 0.065 to 0.070 ppm 

for ozone proposed in the Federal Register (Section I, part 2) was developed with an 

inadequate margin of safety. Consequently the lower range of 0.060 to 0.065 ppm should 

be set as the primary standard and the following language should be edited in the federal 

register to recognize the additional uncertainty in risk estimates that this sensitive 

population adds:

1) Part II, Section B (pg. 75246), Health Effects Information, identifies “new 

epidemiologic studies published since the last review on effects associated with 

both short- and long-term exposures.” Five adverse health effects are listed that 

have new (published since the 2008 review) supportive evidence. We suggest 

that a 6th effect be listed as follows:
5

(6) Recent data from peer-reviewed studies provide evidence that pregnant 

women are an at-risk population. Exposure to ozone during pregnancy is 

associated with hypertensive disorders of pregnancy, such as preeclampsia,6, 7

that can have short- and long-term consequences to the mother including 

cardiovascular disease and death.5 Birth outcomes associated with ozone 

exposure also have adverse physical and mental consequences to the mother.17-

20 In addition to these health consequences, pregnant women may experience 

higher doses of ozone for a given exposure level due to elevated respiratory 

rates during pregnancy.21-23

2) Part II, Section B, Part 2, Section c (pg. 75261), Cardiovascular Effects, 

examines ways in which the studies of cardiovascular effects of ozone exposure 

have recently expanded. Following the synopsis from the ozone ISA we suggest 

the following short paragraph on cardiovascular effects in pregnant women be 

added:

Since the publication of the ISA, we have also examined cardiovascular effects of 

ozone exposure among pregnant women which differ from those of the general

population. Specifically, there is adequate epidemiologic evidence that ozone 

exposure during pregnancy is associated with increased risk of developing 

preeclampsia, a hypertensive disorder of pregnancy that can lead to maternal 

mortality and increased risk of cardiovascular morbidities later in life.6, 7

Furthermore, previously examined toxicological evidence demonstrating the 

potential for ozone to induce an inflammatory and oxidative state in tissue 

provide a mechanistic pathway to support these associations, as preeclampsia 

results from poor implantation consequent to these environments.

11, 15

Populations with Multiple Risk Factors

The rationale in the proposed standard and the Health Risk and Exposure 

Assessment for Ozone (HREA) did not adequately account for the combined effects 

of exposures to multiple chemical and non-chemical (social) risk factors. 

Specifically, the Ozone HREA did not account for more adverse effects due to already 

compromised health, criteria laid out in the PM2.5 decision. In the most recent NAAQS

review process for PM2.5, the EPA designated four ways to establish a margin of safety for 

at-risk populations.26, 27 Vulnerability or risk was defined as meeting any one of the following 

criteria: 1) Higher levels of ambient exposure; 2) Higher dose at a given level of ambient 

exposure; 3) More adverse effects at a given level of ambient exposure; and 4) More 

adverse effects due to already compromised health. While these criteria were included for 

the PM2.5 margin of safety determination, the EPA only included criteria 1-3 above for the 

development of the revised Ozone standard. Although contained in the American Thoracic 

Society statement28 and previous NAAQS reviews, the fourth criteria was omitted from the
6

CASAC correspondence with Administrator Jackson in the February 2013 to CASAC.29 The 

rationale for eliminating the fourth criteria of population consequence is not discussed. We 

argue that this approach is inadequate. The absence of a clear methodology to account for 

the cumulative effects due to already compromised health from multiple social and chemical 

exposures contributes to an underestimate of the margin of safety and a departure from 

previous considerations.

There is scientific consensus that the effects of exposures to environmental contaminants 

differ based on vulnerabilities such as underlying health status and the presence of copollutants.30 Furthermore, there is increasing recognition that social conditions can amplify 

the adverse effects of environmental agents on health,

30, 31 contributing to excess risk and 

racial, ethnic and socioeconomic disparities in health. The methodologies used in the 

current Ozone HREA do not adequately account for vulnerabilities that accrue through the 

combined effects of multiple social and physical environmental exposures. This point is also 

explained by the CASAC in the Federal Register (Part II, Section C, Part 2b), which notes,

“Although the EPA indicates less confidence in the likelihood of adverse health effects as 

O3 exposures decline, it also notes that controlled human exposure studies that provided 

the basis for health benchmark concentrations have not evaluated at-risk populations.”26

To evaluate the potential implications of these uncertainties, in the HREA a limited number 

of sensitivity analyses were conducted. For example, in models estimating exposures of 

concern among children who did not spend any time in school (to mimic children spending 

large amounts of time outdoors in the summer; Section 5.4.3.1), the number experiencing 

exposures of concern increased by approximately 30%.1These models suggest that 

populations experiencing multiple vulnerabilities (e.g., heightened exposure due to 

increased outdoor activity, increased dose due to heightened respiration, and asthma

combined) may experience more frequent exposures of concern than indicated by models 

that do not account for multiple vulnerabilities. As a result of these uncertainties, a larger 

margin of safety is needed to adequately protect public health in vulnerable populations, 

and we support a rule that establishes an ozone standard between 60-65 ppb.

Several reports have highlighted the importance of understanding the aggregation of risks 

from multiple environmental stressors. These include the National Research Council's 

(NRC) 1994 report Science and Judgment in Risk Assessment,

32 the 1997 report by the 

Presidential/ Congressional Commission on Risk Assessment and Risk Management 

entitled Risk Assessment and Risk Management in Regulatory Decision-Making,

33 and most 

recently the National Research Council’s 2009 report on Science and Decisions.

30

Individuals who experience multiple social, physical and chemical environmental stressors 

are at increased risk of disease. The Ozone HREA suggests that communities with ozone 

monitors differ little in terms of demographic characteristics from the national population.

1

However, this analysis does not address population level variations in susceptibilities to 

adverse effects of ozone exposure.
7

The proposed ozone regulatory standards note guidance from the American Thoracic 

Society (ATS) regarding definitions of adverse effects at the population level. Specifically, 

guidance from ATS states that “Exposure to air pollution that increases the risk of an 

adverse effect to the entire population is adverse, even though it may not increase the risk 

of any individual to an unacceptable level. For example, a population of asthmatics could 

have a distribution of lung function such that no individual has a level associated with 

clinically important impairment. Exposure to air pollution could shift the distribution to levels 

that still do not bring any individuals to a level that is associated with clinically relevant 

effects. However this would be considered to be adverse because individuals within the 

population would have diminished reserve function, and therefore would be at increased 

risk for further environmental insult” (Part II, Section B, Part 3).26, 34

For example, a recent multicity time series study cited in the Federal Register followed four 

cohorts of Medicare enrollees with chronic conditions that might predispose them to ozone 

related effects from 1985-2006.35 This study reported an association between long term 

(warm season) exposure to ozone and elevated risk of mortality in the cohort that had 

previously experienced an emergency hospital admission due to chronic obstructive 

pulmonary disease. To the extent that such susceptibilities are differentially distributed 

within and between communities, there may be differential health effects at any given level 

of ozone exposure,36-42 and communities may experience the combined effects of multiple 

vulnerabilities associated with adverse effects. Thus, lowering the ozone standards would 

prevent heightened effects on health, and ultimately, to health disparities in these 

communities.

The purpose of selecting primary standards that provide an adequate margin of safety is to 

both prevent pollution levels that have been demonstrated as harmful, and to prevent lower 

pollution levels that may pose an unacceptable risk of harm, even if the risk is not precisely 

identified. The EPA’s current methods for identifying populations at risk do not adequately 

account for multiple amplifying risk factors, including physical, social, and chemical 

exposures, and their combined impact on health effects associated with exposure to ozone.

Consequently, the standards set with these methods are inadequate to protect health in 

communities with these multiple risk factors. Thus, the primary standard should be set in the 

lower range of the standard recommended by CASAC (60-65ppb).

Pregnant Women Experiencing Multiple Risk Factors

The EPA should recognize that pregnant women living in communities that 

experience multiple chemical and non-chemical exposures (i.e., psychosocial 

stressors) are particularly vulnerable, and their risks should be recognized in the 

final ozone rule, as well as in assessment documents (e.g., economic benefits, HREA 

and ISA) for future NAAQS reviews. This is consistent with the ACOG Committee Opinion 

on Exposure to Toxic Environmental agents, which state: “Many environmental factors 
8

harmful to reproductive health disproportionately affect vulnerable and underserved 

populations, which leaves some populations, including underserved women, more 

vulnerable to adverse reproductive and developmental health effects than other 

populations.”4 Pregnancy can be a time of increased vulnerability to air pollution exposure 

due to physiological changes that are occurring and increased dose as well as broader 

range of potential adverse health effects, as described above. As has been underscored in 

a recent report from the National Research Council, the effects of low-dose exposures to 

environmental contaminants “may be quite different based on vulnerabilities” such as 

underlying health status and the presence of “additional” or “background” environmental 

exposure.30

As one example, there is growing evidence that ozone contributes to metabolic disorders in 

animal models,

43 and that metabolic disorders exacerbate other adverse health effects of 

exposure to ozone.

44, 45 Furthermore, low income women of any race/ethnicity and women 

of color across socioeconomic status experience excess risk of metabolic disorders46 and 

those metabolic disorders are associated with adverse birth outcomes.

47 Recognizing that 

pregnant women who live in low income and/or medically underserved communities are 

both more likely to experience adverse health effects due to underlying health issues or 

additional exposures to other environmental toxins,48, 49 it is particularly important to provide 

an additional margin of error to protect pregnant women residing in such communities. 

Conclusions

The failure to explicitly account for the vulnerability of pregnant women as well as 

populations exposed to multiple chemical and non-chemical stressors, such as those in low 

income communities and communities of color, underestimates the adverse health effects 

of ozone. For this reason the proposed ozone standard should be set at the 60-65 ppb 

range to incorporate a larger margin of safety. By the HREA’s own calculations (Table 

ES7)37 setting the Ozone Standard toward the lower end of the proposed range (60-65 

ppb), rather than the higher end of 65-70 ppb would, by 2025, prevent an additional (over 

the 65-70 ppb):

 1300-3700 short-term exposure related deaths, 

 64,000 to 840,000 asthma attacks in children

 770,000 to 900,000 missed school days

 1300-3700 premature deaths

 2900 to 3700 asthma-related emergency room visits, and 

 115,000 to 160,000 missed workdays.

These numbers underestimate the actual positive impact of the lower standard because the 

ISA and HREA do not include pregnant women and communities exposed to multiple 

chemical and non-chemical exposures as vulnerable populations. Under the Clean Air Act, 

EPA has a duty to protect at-risk populations with an adequate margin of safety. To do so, 
9

EPA must fully assess the risk to pregnant women, populations experiencing the cumulative 

effects of multiple social and chemical exposures, and, particularly, pregnant women within 

those populations. In conclusion, we ask that you:

 Select a standard in the 60-65 ppb range in order to provide an adequate margin of 

safety for these at-risk populations.

 Strengthen the discussion in the Federal Register with regards to pregnant women, 

as described specifically above, and to populations with multiple risk factors.

 In future HREAs, more adequately account for the vulnerabilities of pregnant women 

and populations exposed to multiple chemical and social exposures, using for 

example, the population level criteria for risk suggested by the American Thoracic 

Society described above.

We are happy to meet with you to discuss or clarify any aspect of our comments.

Respectively submitted,

Chris Coombe, PhD, MPH, Assistant Research Scientist

University of Michigan School of Public Health

Kelly Ferguson, PhD, MPH, Research Fellow

University of Michigan School of Public Health

Patricia Koman, MPP, Senior Project Manager

University of Michigan School of Public Health

Natalie Sampson, PhD, MPH, Assistant Professor

College of Education, Health, & Human Services, University of Michigan-Dearborn

Amy Schulz, PhD, MPH, Professor

University of Michigan School of Public Health

Donele Wilkins, President/CEO

Green Door Initiative
10

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