# Chapter 8. Population s 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 am bient air pollution (see Section 1.1). To facilitate the identification of populations at the greatest ri sk for PM-related health effects, studies have evaluated factors that contribute to the susceptibilit y 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 fact ors (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 effect s from exposure to an air pollutant (e.g., PM) can not be easily categorized as a susceptibility or vulne rability factor. For example, a population that is characterized as having low SES, traditionally define d as a vulnerability factor, may have less access to healthcare resulting in the manifestation of dise ase (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 susceptibi lity 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 ai r 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 expe riencing health effects related to exposure to an air pollutant (e.g., PM) due to a variety of fa ctors including, but not limited to: genetic or developmental factors, race, gender, lifestage, li festyle (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)

.

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### Table 8-1. Definitions of susceptible an d 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 t he population who have genetic su sceptibilities), 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, socioeco nomic status, healthcare availabilit y, 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 eff ect 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 throu gh 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, c ontrolled human exposure, and toxicological studies evaluated in Chapters 6 and 7 that provide information on potentially susceptible populations. The studies highlighted include only t hose 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, controlle d human exposure, and epid emiologic literature and the direction of the underlying evidence in determining whether a factor increases the susceptibility of a population to PM-related health effects.

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### 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 Attainment 3 +

Residential Location 3 +

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 Suscep tible Populations

8.1.1. Lifestage

8.1. 1.1. Olde r Adults

Evidence for PM-related health effects in olde r adults spans epidemiologic, controlled human exposure, and toxicological studies. The 2004 PM AQCD found evidence for increased risk of cardiovascular effects in older adu lts 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 a ssociation 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 8-3In recent publications, the epidemiologic evidence for cardiovascular effects in older adults in response to short-term exposure to PM 10-2.5 and PM 2.5 is limited, but taken together with evidence from studies of PM 10 (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 PM 10-2.5 and PM 2.5 . 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 PM 2.5 . 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 PM 2.5 in Atlanta, Georgia, which is supported by the results from other studies that focused on short-term exposure to PM 10 (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 PM 2.5 , which is much longer than the lags examined by the other U.S.- and Canadian-based studies. Although studies have not consistently fo und 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 PM 2.5 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 PM 2.5 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 PM 2.5 and PM 10-2.5 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 develo pment 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 PM 2.5 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 si gnificant 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 PM 2.5 (Ostro et al., 2006, 087991 ) and PM 10 (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 fo r older adults compared to all ages in singlepollutant models, but a robust effect estimate in co-pollutant models with gaseous pollutants (i.e., PM 2.5 +CO and PM 2.5 +NO 2 ). These results differ from those in the all ages model (i.e., attenuation of the effect estimate in co-pollutant models with CO and NO 2 ), 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., PM 2.5 ) have found results

December 2009 8-4contradictory to those obtained in the short-te rm exposure studies. Villeneuve et al. (2002, 042576 ), Naess et al. (2007, 090736 ) and Zeger et al. (2008, 191951 ) report evidence of differing PM 2.5 relative risks by age, where risk declines with in creasing 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 PM 2.5 , PM 10-2.5 , and PM 10 , provide coherence and bi ological plausibility for the association between PM and cardiovascular morb idity in older adults. The clear pattern of positive associations only being observed in epidem iologic 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. popula tion 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. Chil dren

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 PM 10-2.5 and PM 2.5 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 PM 10-2.5 and PM 2.5 in Spokane, Washingon. In addition, Host et al. (2007, 155851 ) found an increase in respiratory-related hospital admissions with shortterm exposure to PM 10-2.5 among children ages 0-14 yr in 6 French cities. An examination of studies that also focused on PM 10 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 PM 2.5 in a “polluted chamber” found evidence for changes in lung function and pulmonary injury (e.g., incomplete alveolari zation). 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-so ot PM had a reduction in cell proliferation in the lung. Overall, the evidence from epidemiologic st udies that have examined the health effects associated with all size fractions of PM and toxicol ogical studies that have examined individual PM components provide additional support to the hypot hesis that children are more susceptible to respiratory effects from exposure to PM.



## 8.1.2. Pregnancy and Devel opmental Effects

While the majority of the literature focuses on epidemiologic studies that examine the potential health effects (e.g., low birth weight, grow th 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 inflammato ry response leads to differential activation of multiple genes involved in immune response and regula tion, cell metabolism, and proliferation all of which can lead to health effects in th e developing fetus (Fedulov et al., 2008, 097482 ). Toxicological

December 2009 8-5studies 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 partic les (DEPs) along with an immunologically “inert” particle (TiO 2 ) on pregnant mice. The authors found that pregnant mice exhibited a local and systemic inflammatory response when exposed to either DEP or TiO 2 , which was not observed in control, non-pregnant mice. In addition, the off spring of exposed pregnant mice developed AHR and allergic inflammation. This study suggests that exposure to PM 2.5 , 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 eviden ce 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 depositi on 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 conduct ed gender-stratified analyses when examining the association between either shor t- or long-term exposure to PM 10-2.5 or PM 2.5 . 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 PM 2.5 and daily hospital admission for acute IHD events in males. An examination of ge nder-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
PM 10-2.5 and PM 2.5 . Chen et al. (2005, 087942 ) found larger effects in fe males for congestive heart disease (CHD) mortality upon long-term exposure to PM 10-2.5 in three California cities. Naess et al. (2007, 090736 ), also observed slightly larger effect es timates in females for CVD and lung cancer mortality upon long-term exposure to PM 2.5 , 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 PM 10 . Although most of these studies do not attribute the association to specific size fractions (i.e., PM 10-2.5 or PM 2.5 ) or provide insight as to whether one size fraction may be driving the observed effect, the studies of PM 10 provide further support that gender does not appear to differentially affect PM-related h ealth 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 PM 10 and cardiovascular hospital admissions. These results are consistent with those found in other studies that examined the association between short-term exposure to PM 10 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 PM 10 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
PM 10-2.5 and PM 2.5 (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 si gnificantly 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 PM 10-2.5 and PM 2.5 , along with the supporting evidence from PM 10 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 poten tial effect modification of the PM-morbidity and - mortality relationships by race and ethnicity varied depending on the study location. In an analysis of the PM 2.5 -mortality relationship, Ostro et al. (2006, 087991 ) stratified the association by race and ethnicity, and observed a positive and marginally si gnificant effect for whites and Hispanics, but not for blacks, in response to short-term exposure to PM 2.5 in 9 California counties. An additional analysis performed by Ostro et al. (2008, 097971 ) in 6 California counties using PM 2.5 and various
PM 2.5 components, also found a significant association be tween 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 PM 2.5 exposure and Hispanic ethnicity. As a result, Ostro et al (2008, 097971 ) speculated that the increased PM 2.5 - 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 eviden ce for the potential susceptibility of individuals by race and ethnicity were derived from studies on the health effects associated with short-term exposure to PM 10 . Wellenius et al. (2006, 088748 ) observed that race (i.e., white vs. other) did not significantly modify the association between short-term exposure to PM 10 and CHF hospital admissions. Additionally, Zeka et al. (2006, 088749 ) did not observe any difference in mortality effect estimates when strati fying by race (i.e., black and white) upon short-term exposure to PM 10

. To date, dosimetry studies have not extensively ex amined 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 betw een 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
PM 2.5 . However, the evidence for this association is derived from two studies conducted in California, and it is unclear if the studies ade quately controlled for potential confounders. Additional studies conducted in other locations that stratify re sults 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 (K leeberger 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 protei n 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 polym orphisms. In order to establish useful links between polymorphisms in candidate genes and adve rse 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 th e gene must produce a functional change in either the protein product or in the level of e xpression of the protein (U.S. EPA, 2008, 157075 ). Further, the issue of confounding by other environmental exposures must be carefully considered.

December 2009 8-7It 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 focusi ng 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 ap proximately half of the white population has a polymorphic null allele, resulting a large poten tial 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 increas e 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 Normativ e 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 PM 2.5 compared to individuals with at least one allele. Polymorphisms in the HO-1 promoter re sulted in lowered HRV upon short-term exposure to
PM 2.5 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 allerg en 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 expos ure 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 PM 10 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 PM 10 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-e nvironment interaction in pregnant women. This effect could occur due to oxidative stress induced by metals contained in PM 10 , 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 sus ceptibility 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 associate d with higher homocysteine levels, have a reduction in SDNN, upon exposure to PM 2.5 . Peters et al. (2009, 191992 ) examined single nucleotide polymorphisms (SNPs) in the fibrinogen gene in myocardial infarction survivors to assess whether exposure to PM 10 altered steady state levels of fibrinogen, which has been implicated in promoting atherothrombosis. The authors found that individua ls 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 PM 2.5 . This

December 2009 8-8effect 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 PM 2.5 and PM 10 can influence DNA methylation (Baccarelli et al., 2009, 188183 ; Tarantini et al., 2009, 192010 ). Additionally, a toxicological study found some evidence of hypermethylation of sper matogonial 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 studi es 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 speci fic pathways and mechanisms by which PM initiates health effects.



## 8.1.6. Pre-Existing Disease

In 2004, the National Research Council (NRC) publ ished 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 exposu re. In addition, toxicological studies that used animal models of cardiopulmonary diseases and he ightened allergic sensitivity found evidence of enhanced susceptibility. More recent epidemiologi c 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. Card iovascular Diseases

The potential effect of underlying cardiovascular diseases on PM-related health responses has been examined using epidemiologic studies that st ratify effect estimates by underlying conditions or secondary diagnoses, and toxicological studies that use animal models to mimic the physiological conditions associated with various cardiovascular dis eases (e.g., MI, ischemia, and atherosclerosis). A limited number of controlled human exposur e 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 th at examined the associa tion 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 examini ng 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 PM 2.5 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 PM 10 and cardiovascular-related health outcomes. These results differ from those presented by Peel et al. (2007, 090442 ), in Atlanta, which observed that exposure to PM 10 resulted in an increase in ED visits for arr hythmias 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 betw een HRV, specifically a reduction in the HF parameter, and short-term exposure to PM 2.5

. Park et al. (2005, 057331 ), in the analysis mentioned above, examined other underlying cardiovascular conditions and found associations between PM 2.5 and HRV in individuals with pre-existing IHD. In a toxicological study, Wellenius et al. (2003, 055691 ) examined the effects of

December 2009 8-9PM 2.5 CAPs exposure on induced myocardial ischemia in dogs, which mimics the effects associated with IHD. The authors found that exposure to PM 2.5 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 PM 10 exposure. However, when examining CHF hospital admissions in 7 U.S. cities, Wellenius et al. (2006, 088748 ) found no evidence for effect modification of PM 10 exposure in individuals with secondary dysrhythmia. Limited evidence is available from epidemiol ogic 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
PM 2.5. 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 PM 10 . Zanobetti and Schwartz (2005, 088069 ) also examined the potential effect modification of the association between
PM 10 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 PM 10 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 admi ssions and short-term exposure to PM 10 in 7 U.S. cities. In this study, Wellenius et al. (2006, 088748 ) found no evidence of effect modification of the relationship between PM 10 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 PM 2.5 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 examin ed 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 an d 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 myo cardial ischemia, as well as inhibit endogenous fibrinolytic capacity (Mills et al., 2007, 091206 ). The physiological response s observed in Mills et al. (2007, 091206 ) provides a measure of coherency with the cardiovascular effects observed in epidemiologic studies, including increases in hospita l 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 ex hibit 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 modifi cation of pre-existing cardiovascular conditions on effects associat ed with long-term exposure to PM, a few

December 2009 8-10

### toxicological studies exposed animals with unde rlying cardiovascular conditions to PM for months. In studies that focused on the cardiova scular 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 PM 2.5 

### 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 PM 10 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 di agnosed with cardiovasc ular diseases (i.e., approximately 51.6 million people with hypertensi on, 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 respirator y 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 10 6 ) % % % % % % % % %

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. Resp iratory 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 PM 2.5 ; and morning symptoms (Mortimer et al., 2002, 030281 ) and asthma attacks (Desqueyroux et al., 2002, 026052 ) with short-term exposure to PM 10

. Toxicological studies that have used ovalbumi n-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 PM 2.5 components. In response to short-term exposure to CAPs from Detroit, an area with pediatri c asthma rates three times the national average, rats with allergic airway disease were found to pr eferentially 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 a llergic airways responses upon exposure to PM 2.5 , 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 e xpressed 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 stat istically significant increase in mean linear intercept, a measure of airspace enlargement, comp ared to saline-treated controls exposed to filtered air. These results provide preliminary eviden ce, 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 allerg ic 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 ha ve found evidence for differences between the respiratory effects exhibited by healthy and asth matic 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 exacerbation 1 of COPD in response to short-term exposure to PM 2.5 . 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 FEV 1 , and FEV 1 and FVC, respectively in response to PM 10 and/or PM 2.5 . Silkoff et al. (2005, 087471 ) observed associations between PM 10 and a reduction in
FEV 1 and PM 2.5 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 PM 2.5 CAPs (Gong et al., 2004, 055628 ). On the other hand the results from dosimetry studies have shown that COPD patie nts have increased dose rates and impaired

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

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

December 2009 8-12mucociliary clearance relative to age matched healthy subjects, suggesting that individuals with COPD are potentially at a greater risk of PM-relate d health effects (Sections 4.2.4.5 and 4.3.4.3). A few of the epidemiologic studies examined th e effect of underlying respiratory illnesses on the association between short- and long-term e xposure 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 PM 10 increased the risk of nonaccidental mortality for pneumonia and circulatory mortality for all respiratory illn esses, respectively. Addi tionally, Zanobetti et al. (2008, 156177 ) observed an association between long-term exposure to PM 10 and mortality in individuals that had previously been hospitalized for COPD. Although these studies do not examine additional size fractions of PM, together they highli ght 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 susc eptible to PM-related health effects ( Table 8-3 ).



## 8.1. 6.3. Resp iratory Contributions to Cardiovascular Effects

Although the majority of health effects observed in individuals with pre-existing respiratory illnesses were associated with respiratory illne ss exacerbations, studies also examined whether underlying respiratory illnesses can lead to cardi ovascular effects in response to PM exposure. Controlled human exposure and toxicological studies have also observed some cardiovascular effects in individuals with pre-existing resp iratory illnesses. Gong et al. (2003, 042106 ) observed acute responses in the cardiovascular system and systemic circulation among asthmatic individuals after exposure to PM 2.5 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 PM 2.5 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 th e 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 PM 10-2.5 . It must be noted that most of the aforementioned epidemiologic studies focused on exposure to PM 10 , 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 PM 2.5 (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. Diab etes 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 betweencardiovascular health effects and PM exposure, but these studies have primarily focused on shortterm exposure to PM 10 . 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 exposur e. Multicity studies have found upwards of 75% greater risk of hospitalization for cardiac diseases in individuals with diabetes upon exposure to
PM 10 (Zanobetti and Schwartz, 2002, 034821 ). Studies conducted in Atlanta, Georgia have also

December 2009 8-13found 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 increa sed risk of mortality upon exposure to PM 10 (Zeka et al., 2006, 088749 ) and PM 2.5 (Goldberg et al., 2006, 088641 ). However, some studi es (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 PM 10 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 physiol ogical 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 eviden ce that ambient exposure to PM 2.5 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-diastoli c basal diameter and end-systolic basal diameter in diabetics upon exposure to PM 10 . 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 e ach 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 PM 2.5 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 popul ation 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 examin ed 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 es timates by obesity. Schwartz et al. (2005, 086296 ) reported a change in HRV in obese (i.e., BMI ≥ 30 kg/m 2 ) 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 PM 2.5 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/m 3 in response to PM 2.5 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% fro m 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 occupa tion (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 8-14surrogates, 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 attain ment, have been shown in some studies to modify health outcomes of PM exposure for a popula tion. 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 PM 2.5 and its components for individuals with low SES while additional analyses stratified by educati on level have also observed consistent trends of increased mortality for PM 2.5 and PM 2.5 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 PM 2.5 . However, when examining education level a nd IHD mortality due to long-term exposure to
PM 2.5 Krewski et al. (2009, 191193 ) observed an inverse relationship. Epidemiologic studies have also examined add itional surrogates of SES, such as residential location and nutritional status to identify their influe nce 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 Hamilt on, 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 expo sure 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 PM 2.5 . However, the association with urban density differed when examining PM 10-2.5 , 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 NO 2 as a surrogate, varied by SES at the block group level. The authors found higher levels of NO 2 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 in crease susceptibility to PM-related health effects. Baccarelli et al. (2008, 157984 ) examined the association between exposure to PM 2.5 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 B 6 , B 12 , or methionine no
PM 2.5 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 PM 10 or PM 2.5 , the available evidence suggests that the identified factors may also enhance susceptibility to PM 10-2.5

. The majority of observations made during the eval uation of the literature reviewed in this ISA are consistent with those reported in the 2004 PM AQC D. An evaluation of age-related health effects suggests that older adults have heightened responses for cardiovascular morbidity with PM exposure.

December 2009 8-15In addition, epidemiologic and toxicological studies provide evidence, which indicates that children are at an increased risk of PM-related respiratory ef fects. 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 fo cus 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 c ould result in health effects in the developing fetus. Epidemiologic studies have also examined whethe r 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. Howe ver, some evidence, albeit from two studies conducted in California, suggest that Hispanic ethni city 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 increa sed 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 epidemiol ogic 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 usi ng surrogates such as educational attainment or residential location, modifies the association betw een PM and morbidity and mortality outcomes. In addition, nutritional status, another surrogate of SE S, 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 e xposure, 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

# Chapter 8 References

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