Chapter 8. Populations Susceptible to PM-related Health Effects 

Interindividual variation in human responses to air pollutants indicates that some populations 

are at increased risk for the detrimental effects of ambient exposure to an air pollutant (e.g., PM) 

(Kleeberger and Ohtsuka, 2005, 130489). The NAAQS are intended to provide an adequate margin 

of safety for both general populations and sensitive subgroups, or those individuals potentially at 

increased risk for health effects in response to ambient air pollution (see Section 1.1). To facilitate 

the identification of populations at the greatest risk for PM-related health effects, studies have 

evaluated factors that contribute to the susceptibility and/or vulnerability of an individual to PM. The 

definition for both of these terms has been found to vary across studies, but in most instances 

susceptibility refers to biological or intrinsic factors (e.g., lifestage, gender) while vulnerability 

refers to non-biological or extrinsic factors (e.g., socioeconomic status [SES]) (see Table 8-1). 

Additionally, in some cases, the terms “at-risk” and sensitive populations have been used to 

encompass these concepts more generally. However, in many cases a factor identified that increases 

an individual's risk for morbidity or mortality effects from exposure to an air pollutant (e.g., PM) can 

not be easily categorized as a susceptibility or vulnerability factor. For example, a population that is 

characterized as having low SES, traditionally defined as a vulnerability factor, may have less access 

to healthcare resulting in the manifestation of disease (i.e., a susceptibility factor), but they may also 

reside in a location that results in exposure to higher concentrations of an air pollutant, increasing 

their vulnerability. Therefore, the terms susceptibility and vulnerability are intertwined and at times 

can not be distinguished from one another. 

As a result of the inconsistencies in the definition of susceptibility and vulnerability presented 

in the literature as well as the inability to clearly delineate whether an identified factor increases an 

individual's susceptibility or vulnerability to an air pollutant, in this ISA, the term ‘susceptible 

population’ will be used as a blanket term and defined as the following: 

Populations that have a greater likelihood of experiencing health effects related to exposure to 

an air pollutant (e.g., PM) due to a variety of factors including, but not limited to: genetic or 

developmental factors, race, gender, lifestage, lifestyle (e.g., smoking status and nutrition) or 

preexisting disease; as well as, population-level factors that can increase an individual's 

exposure to an air pollutant (e.g., PM) such as socioeconomic status [SES], which 

encompasses reduced access to health care, low educational attainment, residential location, 

and other factors. 

 

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

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

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

December 2009 8-1 
Table 8-1. Definitions of susceptible and vulnerable in the PM literature. 

Definition Reference 

Susceptible: predisposed to develop a noninfectious disease 

Vulnerable: capable of being hurt: susceptible to injury or disease Merriam-Webster (2009, 192146) 

Susceptible: greater likelihood of an adverse outcome given a specific exposure, in comparison with the general 

population. Includes both host and environmental factors (e.g., genetics, diet, physiological state, age, gender, 

social, economic, and geographic attributes). 

Vulnerable: periods during an individual’s life when they are more susceptible to environmental exposures. 

American Lung Association (2001, 016626) 

Susceptible: innate (e.g., genetic or developmental) or acquired (e.g., age, disease or smoking or smoking) factors 

that make individuals more likely to experience effects with exposure to PM. 

Vulnerable: PM-related effects due to factors including socioeconomic status (e.g., reduced access to health care) or 

particularly elevated exposure levels. 

U.S. EPA. (2008, 157072) 

Susceptible: greater or lesser biological response to exposure. 

Vulnerable: more or less exposed. U.S. EPA (2009, 192149) 

Vulnerable: to be susceptible to harm or neglect, that is, acts of commission or omission on the part of others that 

can wound. Aday, LA. (2001, 192150) 

Susceptible:may be those who are significantly more liable than the general population to be affected by a stressor 

due to life stage (e.g., children, the elderly, or pregnant women), genetic polymorphisms (e.g., the small but 

significant percentage of the population who have genetic susceptibilities), prior immune reactions (e.g., individuals 

who have been “sensitized” to a particular chemical), disease state (e.g., asthmatics), or prior damage to cells or 

systems (e.g., individuals with damaged ear structures due to prior exposure to toluene, making them more sensitive 

to damage by high noise levels). 

Vulnerable: differential exposure and differential preparedness (e.g., immunization). 

U.S. EPA (2003, 192145) 

Susceptible: intrinsic (e.g., age, gender, pre-existing disease (e.g., asthma) and genetics) and extrinsic (previous 

exposure and nutritional status) factors. Kleeberger and Ohtsuka (2005, 130489) 

Susceptible:characteristics that contribute to increased risk of PM-related health effects (e.g., genetics, pre-existing 

disease, age, gender, race, socioeconomic status, healthcare availability, educational attainment, and housing 

characteristics). 

Pope and Dockery (2006, 156881) 

To examine whether air pollutants (e.g., PM) differentially affect certain populations, 

epidemiologic studies conduct stratified analyses to identify the presence or absence of effect 

modification. A thorough evaluation of potential effect modifiers may help identify populations that 

are more susceptible to an air pollutant (e.g., PM). Although the design of toxicological and 

controlled human exposure studies do not allow for an extensive examination of effect modifiers, the 

use of animal models of disease and the study of individuals with underlying disease or genetic 

polymorphisms do allow for comparisons between subgroups. Therefore, the results from these 

studies, combined with those results obtained through stratified analyses in epidemiologic studies, 

contribute to the overall weight of evidence for the increased susceptibility of specific populations to 

an air pollutant (e.g., PM). 

This chapter discusses the epidemiologic, controlled human exposure, and toxicological 

studies evaluated in Chapters 6 and 7 that provide information on potentially susceptible 

populations. The studies highlighted include only those studies that present stratified results (e.g., 

males vs. females or <65 vs. ≥ 65). This approach allowed for a comparison between populations 

exposed to similar PM concentrations and within the same study design. In addition, numerous 

studies that focus on only one potentially susceptible population can provide supporting evidence on 

whether a population is susceptible to PM exposure and are described in Chapters 6 and 7, but these 

studies are not discussed in detail in this chapter. Table 8-2 provides an overview of the factors 

examined in the current toxicological, controlled human exposure, and epidemiologic literature and 

the direction of the underlying evidence in determining whether a factor increases the susceptibility 

of a population to PM-related health effects. 

December 2009 8-2 
Table 8-2. Susceptibility factors evaluated. 

Factor Collective Evidence (+/-)2

Older Adults (≥ 65) + 

Children (<18)1 + 

Pregnancy and Developmental Effects +* 

Gender - 

Race/Ethnicity - 

Genetic factors 

- Genetic polymorphisms 

- Epigenetics 

+ 

Cardiovascular Diseases + 

Respiratory Illnesses + 

Respiratory Contributions to Cardiovascular Effects -* 

Diabetes +* 

Obesity +* 

Socioeconomic Status (SES) + 

Educational Attainment3 + 

Residential Location3 + 

Health Status (e.g., Nutrition)3 +* 

1 The age range that defines a child varies from study to study. In some cases it is <21 years old while in others it is <18 

years old (Firestone et al., 2007, 192071). For the purposes of this exercise children are defined as those individuals <18 

years old because the majority of epidemiologic studies consider individuals under the age of 18 children. 

2 This column identifies whether the "collective" evidence from studies evaluated found that a specific factor increased (+) 

or did not increase (-) a population's susceptiblity to PM exposure (i.e., PM exposure to all size fractions combined). In 

instances where only a few studies were evaluated for a speicifc factor it was not possible to clearly assign a (+) or (-) as a

result the direction of the preliminary evidence is identified along with (*) to represent that more information is warranted. 

3 These factors are surrogates of socioeconomic status and are discussed within this subsection of the chapter.

8.1. Potentially Susceptible Populations 

8.1.1. Lifestage 

8.1.1.1. Older Adults 

Evidence for PM-related health effects in older adults spans epidemiologic, controlled human 

exposure, and toxicological studies. The 2004 PM AQCD found evidence for increased risk of 

cardiovascular effects in older adults exposed to PM (U.S. EPA, 2004, 056905). Older adults 

represent a potentially susceptible population due to the higher prevalence of pre-existing 

cardiovascular and respiratory diseases found in this age range compared to younger age groups. The 

increased susceptibility in this population can primarily be attributed to the gradual decline in 

physiological processes as part of the aging process (U.S. EPA, 2006, 192082). Therefore, some 

overlap exists between potentially susceptible older adults and the population that encompases 

individuals with pre-existing diseases (Kan et al., 2008, 156621). Epidemiologic studies that conduct 

age stratified analyses primarily focus on the association between short-term exposure to PM and 

cardiovascular morbidity, but additional studies have examined the association between PM and 

respiratory morbidity and mortality. 

December 2009 8-3 
 In recent publications, the epidemiologic evidence for cardiovascular effects in older adults in 

response to short-term exposure to PM10-2.5 and PM2.5 is limited, but taken together with evidence 

from studies of PM10 (e.g., Larrieu et al., 2007, 093031; Le Tertre et al., 2002, 023746), supports the 

increased risk of cardiovascular morbidity in older adults. Host et al. (2007, 155851) found an 

increase in cardiovascular disease (CVD) hospital admissions in individuals >65 yr compared to all 

ages for short-term exposure to both PM10-2.5 and PM2.5. Barnett et al. (2006, 089770) analyzed data 

from several cities across Australia and New Zealand and found that the excess risk of 

hospitalizations for cardiac diseases, congestive heart failure (CHF), ischemic heart disease (IHD), 

myocardial infarction (MI), and all CVD was greater among patients aged ≥ 65 yr as compared to 

those individuals <65 years in response to short-term exposure to PM2.5. U.S.- and Canadian-based 

studies that examined the association between short-term exposure to PM and cardiovascular 

morbidity primarily found no evidence for increased risk among older adults. Metzger et al. (2004, 

044222) found no evidence of effect modification by age for cardiovascular outcomes and short-term 

exposure to PM2.5 in Atlanta, Georgia, which is supported by the results from other studies that 

focused on short-term exposure to PM10 (Fung et al., 2005, 074322; Zanobetti and Schwartz, 2005, 

088069). However, Pope et al. (2008, 191969) observed an increased risk of HF hospital admissions 

in older adults (i.e., ≥ 65 yr) in Utah, but the study used a 14-day lagged cumulative moving average 

of PM2.5, which is much longer than the lags examined by the other U.S.- and Canadian-based 

studies. Although studies have not consistently found an association between short-term exposure to 

PM and respiratory-related health effects in older adults, some studies have reported an increase in 

respiratory hospital admissions in individuals 65 years of age and older (e.g., Fung et al., 2005, 

093262). 

Additional evidence for an increase in cardiovascular and respiratory effects among older 

adults has been observed in controlled human exposure and dosimetry studies. Devlin et al. (2003, 

087348) found that older subjects exposed to PM2.5 concentrated ambient particles(CAPs) 

experienced significant decreases in heart rate variability (HRV) (both in time and frequency) 

immediately following exposure, when compared to healthy young subjects. In addition, Gong et al 

(2004, 055628) reported that older subjects demonstrated significant decreases in HRV when 

exposed to PM2.5 CAPs, but this study did not compare the response in older subjects to those 

elicited by young, healthy individuals. However, the study did find that healthy older adults were 

more susceptible to decreases in HRV compared to those with an underlying health condition (i.e., 

chronic obstructive pulmonary disease [COPD]) in response to PM exposure (Gong et al., 2004, 

055628). Dosimetry studies have shown a depression of PM2.5 and PM10-2.5 clearance in all regions of 

the respiratory tract with increasing age beyond young adulthood in humans and laboratory animals. 

These results suggest that older adults are also susceptible to PM-related respiratory health effects 

(Section 4.3.4.1). 

Animal toxicological studies have attempted to characterize the relationship between age and 

PM-related health effects through the development of models that mimic the physiological 

conditions associated with older individuals. For example, Nadziejko et al. (2004, 055632) observed 

arrhythmias in older, but not younger, rats exposed to PM2.5 CAPs. In addition, another study 

(Tankersley et al., 2004, 094378) that used a mouse model of terminal senescence demonstrated 

altered baseline autonomic tone in response to carbon black exposure, which may subsequently 

affect the quality and severity of cardiovascular responses (Tankersley et al., 2007, 097910). 

Reductions in cardiac fractional shortening and significant pulmonary vascular congestion upon 

exposure to carbon black were also reported in older mice (Tankersley et al., 2008, 157043). Overall, 

these studies provide biological plausibility for the increase in cardiovascular effects in older adults 

observed in the controlled human exposure and epidemiologic studies. 

Recent epidemiologic studies have also found that individuals >65 years of age are more 

susceptible to all-cause (nonaccidental) mortality upon short-term exposure to both PM2.5 (Ostro et 

al., 2006, 087991) and PM10 (Samoli et al., 2008, 188455; Zeka et al., 2006, 088749), which is 

consistent with the findings of the 2004 PM AQCD. Of note are the results from Ostro et al. (2006, 

087991) that reported a slight increase in mortality for older adults compared to all ages in singlepollutant models, but a robust effect estimate in co-pollutant models with gaseous pollutants 

(i.e., PM2.5+CO and PM2.5+NO2). These results differ from those in the all ages model (i.e., 

attenuation of the effect estimate in co-pollutant models with CO and NO2), which suggests that 

older adults are more susceptible to PM exposures, even though the age-stratified effect estimates in 

single-pollutant models did not significantly differ. Epidemiologic studies that examined the 

association between mortality and long-term exposure to PM (i.e., PM2.5) have found results 

December 2009 8-4 
contradictory to those obtained in the short-term exposure studies. Villeneuve et al. (2002, 042576), 

Naess et al. (2007, 090736) and Zeger et al. (2008, 191951) report evidence of differing PM2.5 

relative risks by age, where risk declines with increasing age starting at age 60 until there is no 

evidence of an association among persons ≥ 85 yr. 

The evidence from epidemiologic, controlled human exposure, and toxicological studies that 

focused on exposures to PM2.5, PM10-2.5, and PM10, provide coherence and biological plausibility for 

the association between PM and cardiovascular morbidity in older adults. The clear pattern of 

positive associations only being observed in epidemiologic studies conducted in non-U.S. locations 

brings into question the influence of PM composition on health effects. However, the difference in 

effects observed between U.S. and Canadian, and international studies could also be due to possible 

differences in the identification of CVD-related morbidity and mortality between the studies 

evaluated. Although most studies examined the effect of PM on CVD outcomes in older adults, the 

additional evidence from epidemiologic studies that focus on respiratory morbidity and mortality in 

response to short-term exposure to PM also indicate that older adults represent a susceptible 

population. As the demographics of the U.S. population shift over the next 20 years with a larger 

percentage of the population (i.e., 13% of the population in 2011 and a projected 20% in 2030) 

encompassing individuals ≥ 65 yr (U.S. Census, 2000, 157064), an increase in the number of 

PM-related health effects (e.g., cardiovascular and respiratory morbidity, and mortality) in 

individuals ≥ 65 years of age could occur. 

8.1.1.2. Children 

Children have generally been considered more susceptible to PM exposure due to multiple 

factors including more time spent outdoors, greater activity levels, exposures resulting in higher 

doses per body weight and lung surface area, and the potential for irreversible effects on the 

developing lung (U.S. EPA, 2004, 056905). The 2004 PM AQCD found that studies which stratify 

results by age typically report associations between PM and respiratory-related health effects in 

children, specifically asthma (U.S. EPA, 2004, 056905). Of the recent epidemiologic studies 

evaluated, only a few have examined the association between PM10-2.5 and PM2.5 and respiratory 

effects in children. Mar et al. (2004, 057309) found increased respiratory effects (e.g., wheeze, 

cough, lower respiratory symptoms) in children 7-12 years of age compared to individuals 20-51 

years of age in response to exposure to both PM10-2.5 and PM2.5 in Spokane, Washingon. In addition, 

Host et al. (2007, 155851) found an increase in respiratory-related hospital admissions with shortterm exposure to PM10-2.5 among children ages 0-14 yr in 6 French cities. An examination of studies 

that also focused on PM10 provide additional support for PM-induced respiratory effects in children 

(Mar et al., 2004, 057309; Peel et al., 2005, 056305). A recent toxicological study provides 

biological plausibility for the increase in PM-related respiratory effects in children observed in the 

epidemiologic studies. Mauad et al. (2008, 156743) using both prenatal and postnatal mice exposed 

to ambient PM2.5 in a “polluted chamber” found evidence for changes in lung function and 

pulmonary injury (e.g., incomplete alveolarization). Additionally, Pinkerton et al. (2004, 087465; 

2008, 190471) found evidence suggesting that the developing lung is more susceptible to PM by 

demonstrating that neonatal rats exposed to iron-soot PM had a reduction in cell proliferation in the 

lung. Overall, the evidence from epidemiologic studies that have examined the health effects 

associated with all size fractions of PM and toxicological studies that have examined individual PM 

components provide additional support to the hypothesis that children are more susceptible to 

respiratory effects from exposure to PM. 

8.1.2. Pregnancy and Developmental Effects 

While the majority of the literature focuses on epidemiologic studies that examine the 

potential health effects (e.g., low birth weight, growth restriction) attributed to in utero exposure to 

PM (see Section 7.4), it is unclear if the health effects observed are due to soluble fractions of PM 

that cross the placenta or physiological alterations in the pregnant woman. In the case of exposure to 

PM, adverse health effects in the offspring could be mediated by potentially greater susceptibility in 

the pregnant woman. For example, an inflammatory response leads to differential activation of 

multiple genes involved in immune response and regulation, cell metabolism, and proliferation all of 

which can lead to health effects in the developing fetus (Fedulov et al., 2008, 097482). Toxicological 

December 2009 8-5 
studies have recently examined whether exposure to air pollutants during pregnancy leads to 

increased allergic susceptibility in the offspring. Fedulov et al. (2008, 097482) used an animal model 

to examine the effect of diesel exhaust particles (DEPs) along with an immunologically “inert” 

particle (TiO2) on pregnant mice. The authors found that pregnant mice exhibited a local and 

systemic inflammatory response when exposed to either DEP or TiO2, which was not observed in 

control, non-pregnant mice. In addition, the offspring of exposed pregnant mice developed AHR and 

allergic inflammation. This study suggests that exposure to PM2.5, and even relatively inert particles, 

during pregnancy can potentially lead to increased allergic susceptibility in offspring and 

subsequently the development of asthma. 

8.1.3. Gender 

The 2004 PM AQCD did not find consistent evidence for a difference in health effects by 

gender. However, there appeared to be gender differences in the localization of particles when 

deposited in the respiratory tract and the deposition rate due to differences in body size, conductive 

airway size, and ventilatory parameters (U.S. EPA, 2004, 056905). For example, females have 

proportionally smaller airways and slightly greater airway reactivity than males (Yunginger et al., 

1992, 192074). 

 Few recent epidemiologic studies have conducted gender-stratified analyses when examining 

the association between either short- or long-term exposure to PM10-2.5 or PM2.5. Similar to the 

studies evaluated in the 2004 PM AQCD, the current literature has not found a consistent pattern of 

associations by gender for any health outcome. Pope et al. (2006, 091246) observed a slightly larger, 

non-significant, association between short-term exposure to PM2.5 and daily hospital admission for 

acute IHD events in males. An examination of gender-specific effects by both Ostro et al. (2006, 

087991) and Franklin et al. (2007, 091257) found conflicting associations by gender for multiple 

cause-specific mortality outcomes. The inconsistency in associations between males and females is 

further highlighted in studies that examined the health effects associated with long-term exposure to 

PM10-2.5 and PM2.5. Chen et al. (2005, 087942) found larger effects in females for congestive heart 

disease (CHD) mortality upon long-term exposure to PM10-2.5 in three California cities. Naess et al. 

(2007, 090736), also observed slightly larger effect estimates in females for CVD and lung cancer 

mortality upon long-term exposure to PM2.5, but for COPD mortality the greatest association was 

found in males. 

 The majority of the epidemiologic studies that examined the association between exposure to 

PM and gender focused on exposure to PM10. Although most of these studies do not attribute the 

association to specific size fractions (i.e., PM10-2.5 or PM2.5) or provide insight as to whether one size 

fraction may be driving the observed effect, the studies of PM10 provide further support that gender 

does not appear to differentially affect PM-related health outcomes. Neither Zanobetti and Schwartz 

(2005, 088069) nor Wellenius et al. (2006, 088748) found gender to be a significant effect modifier 

of the risk estimates associated with short-term exposure to PM10 and cardiovascular hospital 

admissions. These results are consistent with those found in other studies that examined the 

association between short-term exposure to PM10 and both cardiovascular and respiratory hospital 

admissions (Luginaah et al., 2005, 057327; Middleton et al., 2008, 156760). Additional studies that 

examined the effects of short-term and long-term exposure to PM10 on respiratory morbidity and 

mortality (Boezen et al., 2005, 087396; Chen et al., 2005, 087942; Zanobetti and Schwartz, 2005, 

088069; Zeka et al., 2006, 088749) found results that are consistent with those reported in studies of 

PM10-2.5 and PM2.5 (i.e., gender is not likely to be an effect modifier). 

Although human clinical studies are not typically powered to detect differences in response 

between males and females, one study did report significantly greater decreases in blood monocytes, 

basophils, and eosinophils in females compared to males following controlled exposures to UF EC 

(Frampton et al., 2006, 088665). Overall, the evidence from primarily epidemiologic studies that 

examined the association between short- and long-term exposure to PM10-2.5 and PM2.5, along with 

the supporting evidence from PM10 studies, further confirms that although differences in dosimetry 

exist between males and females, neither gender consistently exhibits a higher disposition for PMrelated health effects. 

December 2009 8-6 
8.1.4. Race/Ethnicity 

The 2004 PM AQCD (U.S. EPA, 2004, 056905) did not evaluate the potential susceptibility of 

individuals of different races and ethnicities to PM exposure. The results from epidemiologic studies 

evaluated in this review that examined the potential effect modification of the PM-morbidity and -

mortality relationships by race and ethnicity varied depending on the study location. In an analysis of 

the PM2.5-mortality relationship, Ostro et al. (2006, 087991) stratified the association by race and 

ethnicity, and observed a positive and marginally significant effect for whites and Hispanics, but not 

for blacks, in response to short-term exposure to PM2.5 in 9 California counties. An additional 

analysis performed by Ostro et al. (2008, 097971) in 6 California counties using PM2.5 and various 

PM2.5 components, also found a significant association between mortality, specifically cardiovascular 

mortality, and Hispanic ethnicity (Ostro et al., 2008, 097971). It should be noted that neither study, 

Ostro et al. (2006, 087991) nor Ostro et al. (2008, 097971), controlled for potential confounders 

(e.g., SES factors and location of residence) of the association observed between PM2.5 exposure and 

Hispanic ethnicity. As a result, Ostro et al (2008, 097971) speculated that the increased PM2.5- mortality risks observed for Hispanics could be due to a variety of factors including, higher rates of: 

non-high school graduates, obesity, no leisure-time activity, and alcohol consumption within the 

Hispanic population in California. Additional evidence for the potential susceptibility of individuals 

by race and ethnicity were derived from studies on the health effects associated with short-term 

exposure to PM10. Wellenius et al. (2006, 088748) observed that race (i.e., white vs. other) did not 

significantly modify the association between short-term exposure to PM10 and CHF hospital 

admissions. Additionally, Zeka et al. (2006, 088749) did not observe any difference in mortality 

effect estimates when stratifying by race (i.e., black and white) upon short-term exposure to PM10. 

To date, dosimetry studies have not extensively examined differences in particle deposition between 

races or ethnicities to confirm the epidemiologic findings. Although not extensively analyzed, 

toxicological studies have examined PM responses in different mouse and rat strains, and reported 

greater CV effects (Kodavanti et al., 2003, 051325; Tankersley et al., 2007, 097910) and 

compromised host defense (Ohtsuka et al., 2000, 004409) for some strains. These studies provide 

some support, in terms of biological plausibility, for differences in PM-induced health effects by race 

or ethnicity. However, it is unclear how the difference in the response to PM in different mouse or rat 

strains extrapolates to PM-induced differences between races or ethnicities. Overall, the results from 

the studies that examined the potential effect modification of PM associations by race and ethnicity 

provide some evidence for increased risk of mortality in Hispanics upon short-term exposure to 

PM2.5. However, the evidence for this association is derived from two studies conducted in 

California, and it is unclear if the studies adequately controlled for potential confounders. Additional 

studies conducted in other locations that stratify results by ethnicity have not yet been conducted to 

substantiate these results. 

8.1.5. Gene-Environment Interaction 

A consensus now exists that gene-environment interactions merit serious consideration when 

examining the relationship between ambient exposures to air pollutants and the development of 

health effects (Gilliland et al., 1999, 155792; Kauffmann et al., 2004, 090968). These potential 

interactions were not evaluated in the 2004 PM AQCD. Inter-individual variation in human 

responses to air pollutants suggests that some populations are at increased risk of detrimental effects 

due to pollutant exposure, and it has become clear that the genetic makeup of an individual can 

increase their susceptibility (Kleeberger and Ohtsuka, 2005, 130489). Gene-environment interactions 

can result in health effects due to: genetic polymorphisms, which result in the lack of a protein or a 

change that makes a functionally important protein dysfunctional; or genetic damage in response to 

an exposure which potentially leads to a health response (e.g., formation of benzo [a] pyrene DNA 

adducts in response to PM exposure). In this review, the majority of studies examine 

gene-environment interactions due to genetic polymorphisms. In order to establish useful links 

between polymorphisms in candidate genes and adverse health effects, several criteria must be 

satisfied: the product of the candidate gene must be significantly involved in the pathogenesis of the 

adverse effect of interest; and polymorphisms in the gene must produce a functional change in either 

the protein product or in the level of expression of the protein (U.S. EPA, 2008, 157075). Further, the 

issue of confounding by other environmental exposures must be carefully considered. 

December 2009 8-7 
It has been hypothesized that the cardiovascular and respiratory health effects that occur in 

response to short-term PM exposure are mediated by oxidative stress (see Section 5.1.1). Research 

has examined this hypothesis by primarily focusing on the glutathione-S transferase (GST) genes 

because they have common, functionally important polymorphic alleles that significantly affect 

antioxidant defense function in the lung, and approximately half of the white population has a 

polymorphic null allele, resulting a large potential study population (Schwartz et al., 2005, 086296). 

Exposure to free radicals and oxidants in air pollution leads to a cascade of events, which can result 

in a reduction in glutathione (GSH), and an increase in the transcription of GSTs. Individuals with 

genotypes that result in reduced or absent enzymatic activity are likely to have reduced antioxidant 

defenses and potentially increased susceptibility to inhaled oxidants and free radicals. 

Numerous studies have examined the role of genetic polymorphisms on PM-related 

cardiovascular health effects using the Normative Aging Study cohort. Schwartz et al. (2005, 

086296) and Chahine et al. (2007, 156327) found that individuals with null GSTM1 alleles had a 

larger decrease in HRV upon short-term exposure to PM2.5 compared to individuals with at least one 

allele. Polymorphisms in the HO-1 promoter resulted in lowered HRV upon short-term exposure to 

PM2.5 in individuals with the long repeat polymorphism compared to those individuals with the short 

repeat polymorphism (Chahine et al., 2007, 156327). In addition, Schneider et al. (2008, 191985) 

found that diabetic individuals with null GSTM1 alleles had larger decrements in FMD (i.e., flowmediated dialation of the brachial artery), suggesting alterations in endothelial function. A controlled 

human exposure study (Gilliland et al., 2004, 156471) also examined whether genetic 

polymorphisms increase the susceptibility of individuals to respiratory morbidity in response to PM 

exposure. Gilliland et al. (2004, 156471) examined the effect of allergens and DEPs on individuals 

with either null genotypes for GSTM1 and GSTT1 or GSTP1 codon 105 variants. The authors found 

that individuals with the GSTM1 null or the GSTP1 I105 wildtype genotypes were more susceptible 

to allergic inflammation upon exposure to allergen and DEPs. Additional genes within the GST 

pathway have also been examined (e.g., NQO1), but the sample sizes are relatively small, which 

prohibits the analysis of the potential effect modification of PM-related health effects by these genes 

(e.g., Schneider et al., 2008, 191985). 

The interaction between GST genes and PM exposure has recently been extended to studies 

that examined the effect of PM exposure on birth outcomes. A recent study (Suh et al., 2008, 

192077) that examined the effect of high PM10 exposures during the third trimester of pregnancy on 

the risk of preterm delivery, found that women with the GSTM1 null genotype were at an increased 

risk of preterm birth. When examining the interaction between high PM10 concentrations during the 

third trimester of pregnancy and the presence of the GSTM1 null genotype on the risk of preterm 

delivery, there was evidence for a synergistic gene-environment interaction in pregnant women. This 

effect could occur due to oxidative stress induced by metals contained in PM10, and subsequently 

could be modified by polymorphisms of the GSTM1 gene. This oxidative stress causes oxidative 

DNA damage in fetal tissues, which may lead to preterm delivery via a reduction in placental blood 

flow. 

An examination of other genes outside the GST pathway have also been conducted to 

determine if specific polymorphisms increase the susceptibility of individuals to PM. Baccarelli et al. 

(2008, 157984) in the Normative Aging Study observed that individuals with polymorphisms in 

MTHFR (C677T methylenetetrahydrofolate reductase), an alteration associated with reduced 

enzyme activity, and cSHMT (cytoplasmic serine hydroxymethyltransferase) (i.e., [CT/TT] MTHFR 

and [CC] cSHMT genotypes), alterations associated with higher homocysteine levels, have a 

reduction in SDNN, upon exposure to PM2.5. Peters et al. (2009, 191992) examined single nucleotide 

polymorphisms (SNPs) in the fibrinogen gene in myocardial infarction survivors to assess whether 

exposure to PM10 altered steady state levels of fibrinogen, which has been implicated in promoting 

atherothrombosis. The authors found that individuals with single nucleotide polymorphisms (SNPs) 

in the fibrinogen gene have higher baseline fibrinogen levels which when combined with the 

inflammatory effects (i.e., increased fibrinogen levels) associated with exposure to PM could 

increase their risk of PM-related cardiovascular health effects. These results taken together suggest 

that individuals with null alleles or specific polymorphisms in genes that mediate the antioxidant 

response to oxidative stress, regulate enzyme activity, or regulate levels of procoagulants are more 

susceptible to PM. However, in some cases genetic polymorphisms may actually reduce an 

individual’s susceptibility to PM-related health effects. For example, Park et al. (2006, 091245) 

found that individuals with two hemochromatosis (HFE) polymorphisms (C282Y and H63D), which 

result in an increase in iron uptake, had smaller reductions in HRV upon exposure to PM2.5. This 

December 2009 8-8 
effect could possibly be due to the reduction in free iron that enters oxidation-reduction (redox) 

reactions and the subsequent reduction in reactive oxygen species (ROS). 

More recently, studies have begun to focus on epigenetic effects associated with PM exposure 

(i.e., the effect of PM on DNA methylation) due to the fact that DNA methylation can result in gene 

alterations. The limited number of epidemiologic studies that examined epigenetic effects have 

found some evidence that long-term exposure to PM2.5 and PM10 can influence DNA methylation 

(Baccarelli et al., 2009, 188183; Tarantini et al., 2009, 192010). Additionally, a toxicological study 

found some evidence of hypermethylation of spermatogonial stem cells in response to the PM 

component of ambient urban air (Yauk et al., 2008, 157164). Although epigenetic effects have been 

observed in response to PM exposure in some studies additional research is needed to more 

accurately characterize these associations. 

Overall, the evidence suggests that specific genetic polymorphisms can potentially increase 

the susceptibility of an individual to PM exposure, but protective polymorphisms also exist, which 

may diminish the health effects attributed to PM exposure in some individuals. In addition, the 

studies that examine genetic polymorphisms or epigenetics can potentially provide additional 

information that can aid in identifying the specific pathways and mechanisms by which PM initiates 

health effects. 

8.1.6. Pre-Existing Disease 

In 2004, the National Research Council (NRC) published a report that emphasized the need to 

evaluate the effect of air pollution on susceptible populations, including those with respiratory 

illnesses and cardiovascular diseases (NRC, 2004, 156814). The 2004 PM AQCD included 

epidemiologic evidence suggesting that individuals with pre-existing heart and lung diseases, as well 

as diabetes may be more susceptible to PM exposure. In addition, toxicological studies that used 

animal models of cardiopulmonary diseases and heightened allergic sensitivity found evidence of 

enhanced susceptibility. More recent epidemiologic and human clinical studies have directly 

examined the effect of PM on individuals with pre-existing diseases and toxicological studies have 

employed disease models to identify whether exposure to PM disproportionately effects certain 

populations. 

8.1.6.1. Cardiovascular Diseases 

The potential effect of underlying cardiovascular diseases on PM-related health responses has 

been examined using epidemiologic studies that stratify effect estimates by underlying conditions or 

secondary diagnoses, and toxicological studies that use animal models to mimic the physiological 

conditions associated with various cardiovascular diseases (e.g., MI, ischemia, and atherosclerosis). 

A limited number of controlled human exposure studies have also examined the potential 

relationship between CVD and exposure to PM in individuals with underlying cardiovascular 

conditions, but these studies have provided somewhat inconsistent evidence for these associations. 

The majority of the epidemiologic literature that examined the association between short-term 

exposure to PM and cardiovascular outcomes focuses on cardiovascular-related hospital admissions 

and emergency department (ED) visits. Hypertension is the pre-existing condition that has been 

considered to the greatest extent when examining the association between short-term exposure to PM 

and cardiovascular-related HAs and ED visits. Pope et al. (2006, 091246) found no evidence of 

effect modification of the IHD ED visit association with PM2.5 in individuals with secondary 

hypertension in Utah. This is consistent with the results of both Wellenius et al. (2006, 088748) in 7 

U.S. cities and Lee et al. (2008, 192076) in Taipei, which found that hypertension did not modify the 

association between PM10 and cardiovascular-related health outcomes. These results differ from 

those presented by Peel et al. (2007, 090442), in Atlanta, which observed that exposure to PM10

resulted in an increase in ED visits for arrhythmias and CHF in individuals with underlying 

hypertension. An additional study conducted by Park et al. (2005, 057331) in Boston found that 

underlying hypertension increased associations between HRV, specifically a reduction in the HF 

parameter, and short-term exposure to PM2.5. Park et al. (2005, 057331), in the analysis mentioned above, examined other underlying 

cardiovascular conditions and found associations between PM2.5 and HRV in individuals with 

pre-existing IHD. In a toxicological study, Wellenius et al. (2003, 055691) examined the effects of 

December 2009 8-9 
PM2.5 CAPs exposure on induced myocardial ischemia in dogs, which mimics the effects associated 

with IHD. The authors found that exposure to PM2.5 prior to the induced ischemia increased 

ST-segment elevation, indicating greater ischemia than air-exposed animals (Wellenius et al., 2003, 

055691). A follow-up study implicated impaired myocardial blood flow in the response (Bartoli et 

al., 2009, 179904). 

 Additional studies examined the effects of PM on cardiac function in individuals with 

dysrhythmia. Peel et al. (2007, 090442) observed some evidence for an increase in ED visits for IHD 

for individuals with secondary dysrhythmia and PM10 exposure. However, when examining CHF 

hospital admissions in 7 U.S. cities, Wellenius et al. (2006, 088748) found no evidence for effect 

modification of PM10 exposure in individuals with secondary dysrhythmia. 

 Limited evidence is available from epidemiologic studies that examined other pre-existing 

cardiovascular conditions, such as CHF and MI. Pope et al. (2006, 091246) observed an increase in 

hospital admissions for acute IHD in individuals with underlying CHF upon short-term exposure to 

PM2.5. However, Peel et al. (2007, 090442) did not find that underlying CHF contributed to an 

increase in the association between IHD ED visits and short-term exposure to PM10. Zanobetti and 

Schwartz (2005, 088069) also examined the potential effect modification of the association between 

PM10 and cardiovascular-related health effects in individuals with CHF, but used MI hospital 

admissions as the outcome of interest. Underlying CHF was not found to increase MI hospital 

admissions for exposure to PM10 in the cohort of more than 300,000 hospital admissions. 

Wellenius et al. (2006, 088748) examined the effect of previous diagnoses of acute MI on the 

association between CHF hospital admissions and short-term exposure to PM10 in 7 U.S. cities. In 

this study, Wellenius et al. (2006, 088748) found no evidence of effect modification of the 

relationship between PM10 and CHF hospital admissions by previous acute MI. Toxicological studies 

have provided additional evidence for the cardiovascular health effects associated with exposure to 

PM in individuals with underlying MI. Anselme et al. (2007, 097084) and Wellenius et al. (2006, 

156152) examined the arrhythmic effects of PM on rats that experienced an MI using two different 

models. Wellenius et al. (2006, 156152) used a post-myocardium sensitivity model (acute MI) and 

observed that exposure to PM2.5 CAPs decreased ventricular premature beats and spontaneous 

supraventricular ectopic beats. In contrast, the MI model of chronic heart failure (i.e., rats that 

experienced an MI 3 mo prior to exposure), demonstrated a prominent increase in the incidence of 

premature ventricular contraction when exposed to DE (Anselme et al., 2007, 097084). The 

discrepancy in effects observed between studies could be due to differences in the MI model or the 

PM exposure (i.e., CAPs vs. DE). 

Additional toxicological studies examined the association between PM and pre-existing 

cardiovascular diseases using a murine model of atherosclerosis (ApoE-/- mouse). For example, 

Campen et al. (2005, 083977; 2006, 096879) examined the heart rate and ECG effects of acute 

exposure to PM on ApoE-/- mice. With DE, dramatic bradycardia and T-wave depression were 

observed that were attributable to the gases (Campen et al., 2005, 083977), while whole gasoline 

emissions induced T-wave alterations that required particles (Campen et al., 2006, 096879). 

However, these studies along with others that used this mouse model (see Section 6.2 and 7.2) did 

not compare the effects observed with the ApoE-/- mouse to other non-diseased mouse models, so it is 

unclear if the responses would differ if other strains were used in the same experimental protocol. 

 Controlled human exposure studies that examined the effect of pre-existing diseases on 

cardiovascular outcomes with exposure to PM are less consistent and difficult to interpret in the 

context of the results from the epidemiologic and toxicological studies. Mills et al. (2007, 091206; 

2008, 156766) investigated the effects of dilute DE, or fine and ultrafine CAPs, respectively, on 

subjects with coronary artery disease and prior MI. Exposure to dilute DE was found to promote 

exercise-induced ST-segment changes indicating myocardial ischemia, as well as inhibit endogenous 

fibrinolytic capacity (Mills et al., 2007, 091206). The physiological responses observed in Mills et 

al. (2007, 091206) provides a measure of coherency with the cardiovascular effects observed in 

epidemiologic studies, including increases in hospital admissions and ED visits for IHD and stroke 

associated with exposure to PM. An examination of fine and ultrafine CAPs that were low in 

combustion derived particles, were not found to exhibit any significant effects on vascular function 

(Mills et al., 2008, 156766). Routledge et al. (2006, 088674) reported no change in HRV in a group 

of adults with coronary artery disease following exposure to ultrafine carbon particles, which may be 

explained in part by the use of medication (beta blockers) among the majority of the subjects. 

Although the epidemiologic studies did not examine potential effect modification of pre-existing 

cardiovascular conditions on effects associated with long-term exposure to PM, a few 

December 2009 8-10 
toxicological studies exposed animals with underlying cardiovascular conditions to PM for 

months. In studies that focused on the cardiovascular effects following subchronic exposure to 

PM in ApoE-/- mice, relatively consistent physiological effects were observed across studies. 

Araujo et al. (2008, 156222) exposed mice to ultrafine CAPs and observed enhanced size of 

early atherosclerotic lesions. Similarly, Chen and Nadziejko (2005, 087219) and Sun et al. (2005, 

087952; 2008, 157033) exposed mice to PM2.5 CAPs with the same results. An additional 

long-term exposure study observed a decreasing trend in heart rate, physical activity, and 

temperature along with biphasic responses in HRV (SDNN and rMSSD) upon exposure to CAPs 

(Chen and Hwang, 2005, 087218). 

While the majority of the literature examines the potential modification of the association 

between PM and non-fatal cardiovascular health effects, a few new studies have also examined 

effect modification in mortality associations. Zeka et al. (2006, 088749) found an increase in risk 

estimates for associations between PM10 and mortality in individuals with underlying stroke, while 

Bateson et al. (2004, 086244) found evidence for effect modification of the PM-mortality association 

in individuals with CHF. 

Collectively, the evidence from epidemiologic and toxicological, and to a lesser extent, 

controlled human exposure studies indicates that individuals with underlying cardiovascular diseases 

are susceptible to PM exposure. Although the evidence for some outcomes was inconsistent across 

epidemiologic and toxicological studies, this could be due to a variety of issues including the PM 

size fraction used in the study along with the study location. Even with these caveats, a large 

proportion of the U.S. population has been diagnosed with cardiovascular diseases (i.e., 

approximately 51.6 million people with hypertension, 24.1 million with heart disease, and 14.1 

million with coronary heart disease [see Table 8-3]), and therefore represents a large population that 

is potentially more susceptible to PM exposure than the general population. 

Table 8-3. Percent of the U.S. population with respiratory diseases, cardiovascular diseases, and 

diabetes. 

Age Regional 

Adults (18+)* 18-44 45-64 65-74 75+ NE MW S W 

Chronic Condition/ 

Disease Number (x 106

) % % % % % % % % % 

RESPIRATORY DISEASES 

Asthma* 24.2 11.0 11.5 10.5 11.7 9.3 11.7 11.5 10.5 10.8 

Asthma (<18 yrs) 6.8* 9.3* --- --- --- --- --- --- --- --- 

COPD 

Chronic bronchitis 9.5 4.3 2.9 5.5 5.6 6.7 3.8 4.4 4.9 3.5 

Emphysema 4.1 1.8 0.3 2.4 5.0 6.4 1.4 2.3 1.9 1.6 

CARDIOVASCULAR DISEASES 

All heart disease 24.1 10.9 3.6 12.3 26.1 36.3 10.8 12.7 10.9 9.2 

Coronary heart disease 14.1 6.4 0.9 7.2 18.4 25.5 6.4 7.6 6.6 4.7 

Hypertension 51.6 23.4 77 32.4 52.7 53.5 22.2 23.7 25.3 20.6 

Stroke 5.6 2.6 0.5 2.4 7.6 11.2 2.1 2.8 2.9 2.2 

Diabetes 17.1 7.8 2.6 10.4 18.2 17.9 7.2 8.1 8.0 7.4 

* All data for adults except asthma prevalence data for children under 18 years of age, from CDC (2008, 156324; 2008, 156325). For adults prevalence data based off adults 

responding to “ever told had asthma.” 

Source: Data from Pleis and Lethbridge-Çejku (2007, 156875); CDC (2008, 156324; 2008, 156325).

December 2009 8-11 
8.1.6.2. Respiratory Illnesses 

Investigators have examined the effect of pre-existing respiratory illnesses on multiple health 

outcomes (e.g., mortality, asthma symptoms, CHF) in response to exposure to ambient levels of PM. 

Animal models have been developed and/or human clinical studies conducted to examine the 

possible PM effects on pre-existing respiratory conditions in a controlled setting. 

 Epidemiologic studies have examined the effect of short-term exposure to PM on the 

respiratory health of asthmatic individuals measuring a variety of respiratory outcomes. Asthmatic 

individuals were found to have an increase in medication use (Rabinovitch et al., 2006, 088031), 

respiratory symptoms (i.e., asthma symptoms, cough, shortness of breath, and chest tightness) (Gent 

et al., 2003, 052885), and asthma symptoms (Delfino et al., 2002, 093740; 2003, 050460) with shortterm exposure to PM2.5; and morning symptoms (Mortimer et al., 2002, 030281) and asthma attacks 

(Desqueyroux et al., 2002, 026052) with short-term exposure to PM10. Toxicological studies that have used ovalbumin-induced allergic airway disease models 

provide evidence which supports the findings of the epidemiologic literature. Morishita et al. (2004, 

087979) used this model to assess the health effects of PM2.5 components. In response to short-term 

exposure to CAPs from Detroit, an area with pediatric asthma rates three times the national average, 

rats with allergic airway disease were found to preferentially retain PM derived from identified local 

combustion sources in association with eosinophil influx and BALF protein content after an acute 

exposure (Morishita et al., 2004, 087979). These findings suggest that individuals with allergic 

airways conditions are more susceptible to allergic airways responses upon exposure to PM2.5, which 

may be partially attributed to increased pulmonary deposition and localization of particles in the 

respiratory tract (Morishita et al., 2004, 087979). An additional study (Heidenfelder et al., 2009, 

190026) examined whether genes are differentially expressed upon exposure to PM. They found that 

exposure to CAPs increased the expression of genes associated with inflammation and airway 

remodeling in rats with allergic airway disease. Although the evidence is much more limited, not all 

of the toxicological studies evaluated that examined the effect of underlying respiratory conditions 

on PM-related respiratory morbidity focused on allergic airways disease. Using an animal model of 

emphysema (i.e., papain-treated mice), Lopes et al. (2009, 190430) found that papain-treated mice 

exposed to urban ambient PM demonstrated a statistically significant increase in mean linear 

intercept, a measure of airspace enlargement, compared to saline-treated controls exposed to filtered 

air. These results provide preliminary evidence, which suggests that non-allergic respiratory 

morbidities may also increase the susceptibility of an individual to PM-related respiratory effects. 

The results from the epidemiologic and toxicological studies that focused on underlying 

allergic airways disease is supported by a series of controlled human exposure studies which have 

shown that exposure to DEPs increases the allergic inflammatory response in atopic individuals 

(Bastain et al., 2003, 098690; Diaz-Sanchez et al., 1997, 051247; Nordenhall et al., 2001, 025185). 

However, not all controlled human exposure studies have found evidence for differences between the 

respiratory effects exhibited by healthy and asthmatic individuals. Studies by Gong et al. (2003, 

042106; 2004, 055628; Gong et al., 2008, 156483) reported that healthy and asthmatic subjects 

exposed to coarse, fine and ultrafine CAPs, exhibited similar respiratory responses. However, it 

should be noted that these studies excluded moderate and severe asthmatics that would be expected 

to show increased susceptibility to PM exposure. 

 In addition to examining the association between exposure to PM and respiratory effects in 

asthmatics, some studies examined whether individuals with COPD represent a potentially 

susceptible population. Desqueyroux et al. (2002, 026052) did not observe an increase in the 

exacerbation1 of COPD in response to short-term exposure to PM2.5. However, studies that examined 

the effect of PM on lung function in individuals with COPD (Lagorio et al., 2006, 089800; Trenga et 

al., 2006, 155209) observed declines in FEV1, and FEV1 and FVC, respectively in response to PM10

and/or PM2.5. Silkoff et al. (2005, 087471) observed associations between PM10 and a reduction in 

FEV1 and PM2.5 and a reduction in PEF, in those with COPD, but only during one winter of the 

analysis. Only one controlled human exposure study examined the effects of PM on COPD subjects 

and found no significant difference in respiratory effects between healthy and individuals with 

COPD upon exposure to PM2.5 CAPs (Gong et al., 2004, 055628). On the other hand the results from 

dosimetry studies have shown that COPD patients have increased dose rates and impaired 

 

1

 Desqueyroux et al. (2002, 026052) defined a COPD exacerbation as (a) decrease in “vesicular” breath sound, (b) bronchial obstruction, 

(c) tachycardia or arrhythmia, or (d) cyanosis. 

December 2009 8-12 
mucociliary clearance relative to age matched healthy subjects, suggesting that individuals with 

COPD are potentially at a greater risk of PM-related health effects (Sections 4.2.4.5 and 4.3.4.3). 

A few of the epidemiologic studies examined the effect of underlying respiratory illnesses on 

the association between short- and long-term exposure to PM and mortality. Using different 

pre-existing respiratory illnesses, Zeka et al. (2006, 088749) and De Leon et al. (2003, 055688) 

found that short-term exposure to PM10 increased the risk of nonaccidental mortality for pneumonia 

and circulatory mortality for all respiratory illnesses, respectively. Additionally, Zanobetti et al. 

(2008, 156177) observed an association between long-term exposure to PM10 and mortality in 

individuals that had previously been hospitalized for COPD. Although these studies do not examine 

additional size fractions of PM, together they highlight the potential effect of underlying respiratory 

illnesses on the PM-mortality relationship. 

Overall, the epidemiologic, controlled human exposure, and toxicological studies evaluated 

provide biological plausibility for the increased health effects observed in epidemiologic studies 

among asthmatic individuals in response to PM exposure. Although, the evidence from studies that 

examined associations between PM and health effects in individuals with COPD is inconsistent, 

taken together individuals with COPD and asthma represent a large percent of the U.S. population 

(~45 million people), which may be more susceptible to PM-related health effects (Table 8-3). 

8.1.6.3. Respiratory Contributions to Cardiovascular Effects 

Although the majority of health effects observed in individuals with pre-existing respiratory 

illnesses were associated with respiratory illness exacerbations, studies also examined whether 

underlying respiratory illnesses can lead to cardiovascular effects in response to PM exposure. 

Controlled human exposure and toxicological studies have also observed some cardiovascular effects 

in individuals with pre-existing respiratory illnesses. Gong et al. (2003, 042106) observed acute 

responses in the cardiovascular system and systemic circulation among asthmatic individuals after 

exposure to PM2.5 CAPs. However, respiratory disease has not consistently been observed to affect 

cardiovascular response in controlled human exposure studies. In a toxicological study, Batalha et al. 

(2002, 088109), using a chronic bronchitis animal model, found that the pulmonary artery 

lumen-to-wall ratio was decreased in rats exposed to PM2.5 CAPs, although the induced bronchitis 

didn’t seem to affect the response. The majority of epidemiologic studies that examined whether 

underlying respiratory illnesses contributed to the manifestation of PM-related cardiovascular 

hospital admission or ED visits, did not report increases in effects for a variety of cardiovascular 

outcomes (e.g., IHD, arrhythmias, CHF, MI) for individuals with underlying respiratory infection 

(Wellenius et al., 2006, 088748), pneumonia (Zanobetti and Schwartz, 2005, 088069), or COPD 

(Peel et al., 2007, 090442; Wellenius et al., 2005, 087483). However, Yeatts et al. (2007, 091266), in 

a panel study, found evidence for cardiovascular effects, specifically reductions in HRV parameters, 

in asthmatic adults upon short-term exposure to PM10-2.5. It must be noted that most of the 

aforementioned epidemiologic studies focused on exposure to PM10, and, therefore, it is unclear how 

these results compare to those found in the controlled human exposure and toxicological studies that 

focused on exposure to PM2.5 (e.g., CAPs). Thus, it is unclear if individuals with underlying 

respiratory illnesses represent a population that is potentially susceptible to PM-related 

cardiovascular effects. 

8.1.6.4. Diabetes and Obesity 

It has been hypothesized that the systemic inflammatory cascade leads to an increase in 

cardiovascular risk (Dubowsky et al., 2006, 088750). As a result, individuals with conditions linked 

to chronic inflammation (i.e., diabetes and obesity), have been examined to determine whether 

diabetes or obesity facilitate the manifestation of PM-mediated health effects, and, therefore, 

represent a potentially susceptible population. 

Epidemiologic studies have examined whether diabetes modifies the association between 

cardiovascular health effects and PM exposure, but these studies have primarily focused on shortterm exposure to PM10. Time-series studies have provided evidence through an examination of 

hospital admission and ED visits and mortality, which suggests an increase in health effects in 

diabetic individuals in response to PM exposure. Multicity studies have found upwards of 75% 

greater risk of hospitalization for cardiac diseases in individuals with diabetes upon exposure to 

PM10 (Zanobetti and Schwartz, 2002, 034821). Studies conducted in Atlanta, Georgia have also 

December 2009 8-13 
found increased risk for cardiovascular-related ED visits in diabetics, specifically for IHD, 

arrhythmias, and CHF (Peel et al., 2007, 090442). Additional studies found some evidence that 

individuals with diabetes are at increased risk of mortality upon exposure to PM10 (Zeka et al., 2006, 

088749) and PM2.5 (Goldberg et al., 2006, 088641). However, some studies (both multicity and 

single-city) have not observed a modification of the risk of cardiovascular ED visits and hospital 

admissions in response to exposure to PM10 in diabetics (Pope et al., 2006, 091246; Wellenius et al., 

2006, 088748; Zanobetti and Schwartz, 2005, 088069). 

Panel and cohort studies have been conducted to determine the physiological changes that 

occur in individuals with diabetes in response to PM exposure. These studies examined both changes 

in inflammatory markers along with specific physiological alterations in the cardiovascular system. 

Schneider et al. (2008, 191985) in a panel study of 22 individuals with type 2 diabetes mellitus in 

Chapel Hill, NC found evidence that ambient exposure to PM2.5 enhanced the reduction in various 

markers of endothelial function. Liu et al. (2007, 156705) observed an increase in end-diastolic FMD 

and end-systolic FMD, and decreases in end-diastolic basal diameter and end-systolic basal diameter 

in diabetics upon exposure to PM10. The authors also observed positive associations with FMD and 

blood pressure in diabetic individuals. A controlled human exposure study conducted by Carlsten et 

al. (2008, 156323) found that DE did not elicit any prothrombotic effects in subjects with metabolic 

syndrome, which consists of physiological alterations similar to those observed in both diabetic and 

obese individuals. An examination of biomarkers found mixed results, with Liao et al. (2005, 

088677) observing an increase in vWF; Liu et al. (2007, 156705) observing an increase in TBARS, 

but not CRP or TNF-α; and Dubowsky et al. (2006, 088750) observing an increase in CRP and 

WBCs. Overall, it is unclear how differences in each of the aforementioned biomarkers contribute to 

the potential overall cardiovascular effect observed in diabetic individuals; however, an increase in 

inflammation, oxidative stress, and acute phase response may contribute to cardiovascular effects. A 

recent toxicological study (Sun et al., 2009, 190487), also demonstrated the potential for PM-related 

health effects in diabetics. Sun et al. (2009, 190487) found that PM2.5 CAPs exposure for 4 mo can 

exaggerate insulin resistance, visceral adiposity, and inflammation in a diet-induced obesity mouse 

model. 

 Overall, epidemiologic studies have reported evidence for increased effects in diabetics in 

response to PM exposure, with preliminary evidence for pathophysiologic alterations from 

toxicological studies. This potentially susceptible population is large, with an estimated 17.1 million 

diabetic individuals in the U.S. (Table 8-3). However, the limited evidence from toxicological and 

controlled human exposure studies along with the lack of studies that examined additional PM size 

fractions warrants additional research to confirm the associations observed and to identify the 

biological pathway(s) that may result in a greater response to PM in diabetics. 

In addition to diabetes, obesity has been examined as a health condition with the potential to 

lead to an increase in PM-related health effects. Only a few recent studies have examined the 

potential effect modification of PM risk estimates by obesity. Schwartz et al. (2005, 086296) 

reported a change in HRV in obese (i.e., BMI ≥ 30 kg/m2

) compared to non-obese subjects, while 

Dubowsky et al. (2006, 088750) observed an increase in inflammatory markers (i.e., CRP, IL-6, and 

WBC) in response to short-term exposure to PM2.5 among obese individuals. Additionally, Schneider 

et al. (2008, 191985) found some evidence for a larger reduction in FMD in individuals with a BMI 

>30 kg/m3

 in response to PM2.5 exposure. These effects could be due, in part, to a higher PM dose 

rate in obese individuals, which has been demonstrated in children by Bennett and Zeman (2004, 

155686). These investigators also reported that tidal volume and resting minute ventilation increased 

with body mass index. Although a limited amount of research has been conducted to examine PMrelated health effects in obese individuals there is an increasing trend of individuals within the U.S. 

that have been defined as overweight (BMI ≥ 25.0) or obese (BMI ≥ 25.0), with the prevalence of 

overweight individuals increasing from 20-74% from 1960 to 2004, and the prevalence of obese 

individuals increasing from 13.3-32.1% (NCHS, 2006, 198921). 

8.1.7. Socioeconomic Status 

SES is a composite measure that usually consists of economic status, measured by income; 

social status measured by education; and work status measured by occupation (Dutton and Levine, 

1989, 192052). Based on data from the U.S. Census Bureau in 2006, from among commonly-used 

indicators of SES, about 12% of individuals and 11% of families are below the poverty line 

(U.S. Census, 2009, 192147). Although the measure of SES is composed of a multitude of 

December 2009 8-14 
surrogates, each of these linked factors can influence an individual’s susceptibility to PM-related 

health effects. Additionally, low SES individuals have been found to have a higher prevalence of 

pre-existing diseases; inadequate medical treatment; and limited access to fresh foods leading to a 

reduced intake of antioxidant polyunsaturated fatty acids and vitamins, which can increase this 

population's susceptibility to PM (Kan et al., 2008, 156621). 

Surrogates of SES, such as educational attainment, have been shown in some studies to 

modify health outcomes of PM exposure for a population. Within the U.S. approximately 16% of the 

population does not have a high school degree and only 27% have a bachelor’s degree or higher 

level of education (U.S. Census, 2009, 192148). Educational attainment generally coincides with an 

individual’s income level, which is correlated to other surrogates of SES, such as residential 

environment (Jerrett et al., 2004, 087379). Franklin et al. (2008, 097426) noted an increased risk in 

mortality associated with short-term exposure to PM2.5 and its components for individuals with low 

SES while additional analyses stratified by education level have also observed consistent trends of 

increased mortality for PM2.5 and PM2.5 species for individuals with low educational attainment 

(Ostro et al., 2006, 087991; Ostro et al., 2008, 097971; Zeka et al., 2006, 088749). This is further 

supported by a reanalysis of the ACS cohort (Krewski et al., 2009, 191193), which found moderate 

evidence for increased lung cancer mortality in individuals with a high school education or less 

compared to individuals with more than a high school education in response to long-term exposure 

to PM2.5. However, when examining education level and IHD mortality due to long-term exposure to 

PM2.5 Krewski et al. (2009, 191193) observed an inverse relationship. 

Epidemiologic studies have also examined additional surrogates of SES, such as residential 

location and nutritional status to identify their influence on the susceptibility of a population. Jerrett 

et al. (2004, 087379) examined the modification of acute mortality effects due to particulate air 

pollution exposure by residential location in Hamilton, Canada using educational attainment as a 

surrogate for SES. The authors found that the area of the city with the highest SES characteristics 

displayed no evidence of effect modification while the area with the lowest SES characteristics had 

the largest health effects. Likewise, Wilson et al. (2007, 157149) examined the effect of SES on the 

association between mortality and short-term exposure to PM in Phoenix, but used educational 

attainment and income to represent SES. When stratifying Phoenix into central, middle, and outer 

rings of varying urban density central Phoenix, the area with the lowest SES, was found to exhibit 

the greatest association with PM2.5. However, the association with urban density differed when 

examining PM10-2.5, with the greatest effect being observed for the middle ring. Yanosky et al. (2008, 

192081) examined whether long-term exposure to traffic-related pollutants, using NO2 as a 

surrogate, varied by SES at the block group level. The authors found higher levels of NO2 associated 

with lower SES areas, which suggests that lower SES individuals are disproportionately exposed to 

traffic-related pollutants, which includes PM. 

Nutritional deficiencies have been associated with increased susceptibility to a variety of 

infectious diseases and chronic health effects. Low SES may decrease access to fresh foods, and thus 

be related to nutritional deficiencies that could increase susceptibility to PM-related health effects. 

Baccarelli et al. (2008, 157984) examined the association between exposure to PM2.5 and HRV in 

individuals with polymorphisms in MTHFR and cSHMT genes, which are associated with reduced 

enzyme activity and increased risk of CVD. The authors found that when individuals with these 

genetic polymorphisms increased their intake (above median levels) of B6, B12, or methionine no 

PM2.5 effect on HRV was observed. 

8.1.8. Summary 

Upon evaluating the association between short- and long-term exposure to PM and various 

health outcomes, studies also attempted to identify populations that are more susceptible to PM. 

These studies did so by: conducting stratified analyses; examining individuals with an underlying 

health condition; or developing animal models that mimic the physiological conditions associated 

with an adverse health effect. These studies identified a multitude of factors that could potentially 

contribute to whether an individual is susceptible to PM (Table 8-2). Although studies have primarily 

used exposures to PM10 or PM2.5, the available evidence suggests that the identified factors may also 

enhance susceptibility to PM10-2.5. The majority of observations made during the evaluation of the literature reviewed in this ISA 

are consistent with those reported in the 2004 PM AQCD. An evaluation of age-related health effects 

suggests that older adults have heightened responses for cardiovascular morbidity with PM exposure. 

December 2009 8-15 
In addition, epidemiologic and toxicological studies provide evidence, which indicates that children 

are at an increased risk of PM-related respiratory effects. It should be noted that the health effects 

observed in children could be initiated by exposures to PM that occurred during key windows of 

development, such as in utero. Studies that focus on exposures during development have reported 

inconsistent findings (see Section 7.4.), but a recent toxicological study suggests that inflammatory 

responses in pregnant women due to exposure to PM could result in health effects in the developing 

fetus. 

Epidemiologic studies have also examined whether additional factors, such as gender, race, or 

ethnicity modify the association between PM and morbidity and mortality outcomes. Consistent with 

the findings of the 2004 PM AQCD, gender and race do not seem to modify the association between 

PM and morbidity and mortality outcomes. However, some evidence, albeit from two studies 

conducted in California, suggest that Hispanic ethnicity may modify the association between PM and 

mortality. 

Recent epidemiologic and toxicological studies provided evidence that individuals with null 

alleles or polymorphisms in genes that mediate the antioxidant response to oxidative stress (i.e., 

GSTM1), regulate enzyme activity (i.e., MTHFR and cSHMT), or regulate levels of procoagulants 

(i.e., fibrinogen) are more susceptible to PM exposure. However, some studies have shown that 

polymorphisms in genes (e.g., HFE) can have a protective effect upon PM exposure. Additionally, 

preliminary evidence suggests that PM exposure can impart epigenetic effects (i.e., DNA 

methylation), however, this requires further investigation. 

Collectively, the evidence from epidemiologic and toxicological, and to a lesser extent, 

controlled human exposure studies indicate increased susceptibility of individuals with underlying 

cardiovascular diseases and respiratory illnesses, specifically asthma, to PM exposure. Additional 

controlled human exposure and toxicological studies provide some evidence for increased PMrelated cardiovascular effects in individuals with underlying respiratory health conditions. However, 

the results are not consistent with epidemiologic studies, resulting in the need for further 

investigation. 

Recently studies have begun to examine the influence of preexisting chronic inflammatory 

conditions, such as diabetes and obesity, on PM-related health effects. These studies have found 

some evidence for increased associations for cardiovascular outcomes along with physiological 

alterations in markers of inflammation, oxidative stress, and acute phase response. However more 

research is needed to thoroughly examine the effect of PM exposure on obese individuals and to 

identify the biological pathway(s) that could lead to increased susceptibility of diabetic and obese 

individuals to PM. 

There is also evidence that SES, measured using surrogates such as educational attainment or 

residential location, modifies the association between PM and morbidity and mortality outcomes. In 

addition, nutritional status, another surrogate of SES, has been shown to have protective effects 

against PM exposure in individuals that have a higher intake in some vitamins and nutrients. 

Overall, the epidemiologic, controlled human exposure, and toxicological studies evaluated in 

this review provide evidence for increased susceptibility for various populations. Although the level 

of evidence varies depending on the factor being evaluated collectively, it can be concluded that 

some populations are more susceptible to PM than the general population. 

December 2009 8-16 
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