15 Susceptibility to Particle Effects Steven R. Kleeberger and Reuben Howden NationalInstituteofEnvironmental Health Sciences, NationalInstitutes of Health CONTENTS 15.1 Introduction 275 15.2 Susceptibility Factors 276 15.2.1 Genetic Background 276 15.2.2 Nongenetic Factors 279 15.3 Conclusions 282 References 282 15.1 INTRODUCTION Linkage between exposure to particulate matter (PM) ! 10 m minaerodynamic diameter (PM 10 ) and anumber of acuteand chronic health effects throughout the industrialized world hasbeen well established in epidemiological studies (e.g., [1–3]). Acute effects include mortality, hospitalization, increased respiratory symptoms, decreased lung function, increased plasma viscosity, changesin heartrate andheart rate variability(HRV),and pulmonary inflammation [4]. Chroniceffects associatedwith particulateexposures includeincreased mortality rates(e.g.,cancer), chronic cardiopulmonary disease,and decreased lung function [4]. Understanding themechanisms throughwhich particulateexposures causemorbidity andmortality continuestobeacritical public health concern. It is also clear that susceptibility to particle effects is not the same from one individual to the next, i.e., interindividualdifferencesinresponse to particulate exposures exist. The factors that determineinterindividual susceptibility are almost certainlycomplex, and may include intrinsic (host) and extrinsic (environmental) factors (Figure15.1). While considerable interest in genetic background as ahost factor for susceptibility to pollutants has been generated [5–8],other host factorsshouldalso be considered [9]. These may include gender,age, pharmacokinetic and phar- macodynamic response parameters (including particle deposition and clearance [10]), pre-existing disease, andnutrition.Furthermore, these factorsmay,and probablydo, interacttodetermine individual responsiveness. Numerous examples of gene Xgene, gene Xenvironment, and gene X gene Xenvironment interaction in the pathogenesis of lung disease have been described (e.g., [11]). Specific subpopulations may be particularly at risk to the toxic effects of particles. These sub- populations include the young and the elderly, patientswith pre-existing diseases such as pulmonary hypertension, chronic obstructivepulmonary disease (COPD),asthma,diabetes, and compromised immune systems[4,12,13].Environmental factorsthatmay impact an individual’s responseto particle exposure include coexposures and the physical environment (e.g., temperature, altitude). In this chapter,weidentify and briefly discuss factors that have been found to contribute to interindividual susceptibility to particulate exposures. We include reports using animal models, 275 © 2007 by Taylor & Francis Group, LLC humansubjects in clinical investigations, and epidemiological studies. Our overall objective is to provide the reader with aperspective on the relative importanceofthosefactorsthat may impact on individual particle susceptibility and to suggestwhere further investigation is needed to clarify susceptibility factors. 15.2 SUSCEPTIBILITY FACTORS 15.2.1 G ENETIC B ACKGROUND An extensive literature exists that describes interindividual differences in drug metabolism and susceptibility (e.g., [14–17]).Many of thesedifferences have been attributed to polymorphisms in genes that encode metabolism and phase two enzymes (e.g., N -acetyltransferase and G6PD). For example, geneticbackground has an importantroleindetermining susceptibility to infectious agents and pesticide exposures [18–20]. It is well known that many complex diseasesclusterin families, and clustering can be explained by genetic background,shared environment, or acom- binationofthe two. Twobroad research strategies have been utilizedtoidentifygenes [or quantitativetrait loci (QTLs)] that determinedisease susceptibility.The first is positional cloningorlinkage mapping,which exploits within-family associationsbetween marker alleles and putative trait-influencing alleles that arise within families [21].This approach is designed to identify association of achromosomal interval(s) within the entire genomethat may contain genes that arepolymorphic andmight accountfor thedifferentialresponse phenotypeunder study. Linkage mapping is applicable to human populations and animal models, and has had considerable success in Mendelian (single gene) diseases. The second approach (candidate gene or association study) chooses loci, which apriori are likelytodetermine the phenotype of interest. Linkage is assessed between the phenotypeofinterest and markersflanking the candidate genes or the candi- date genesthemselves, andevaluates across-familyassociations. Theprincipleunderlying the associationofgeneticpolymorphisms not directly involved in disease pathogenesisisthatof linkage disequilibrium, whicharises from the coinheritance of alleles at loci that areinclose physicalproximityonanindividualchromosome[22].Emergent technologies,including gene and protein expression arrays, have been important developments in the ability to identify candidate susceptibility genes (Figure 15.2). Anumberoflaboratorieshaveusedpositionalcloning in animal models to determine whether genetic background is an important determinant of pulmonary responses to particulates. Ohtsuka et al. [23] studied the interstrain variance of lung responses to particle-associated sulfate (acid coated particles, (ACP)) in inbred strains of mice. The ACP modelwas chosenfor study Genetic Genetic background background Pre-existing Pre-existing disease disease Socioeconomic Socioeconomic status status Age Age Cardiopulmonary Cardiopulmonary responses responses Children Elderly Asthma COPD Diabetes Atherosclerosis Arrhythmia Inflammation Coagulation Antioxidant Innate immunity Education Nutrition Workplace Phenotypes Susceptibility factors FIGURE15.1 General susceptibility factors that mayinfluencecardiopulmonary responses to particle exposures. Particle Toxicology276 © 2007 by Taylor & Francis Group, LLC becausethe particles could be generated reproduciblyinthe laboratory andall micecould be exposedtothe ACP under similar conditions. Nine strains of inbred mice were exposed to ACP for4hinanose-onlychamber,and inflammation wasassessed after1,3,7,or14daysby bronchoalveolarlavage(BAL).Controlexposures were carbon black(CB)orsulfurdioxide alone. Innate immune response was assessed by measuring Fc-receptor mediated phagocytosis of BAL alveolar macrophages (i.e., quantitation of ingested sensitized sheep red blood cells). ACP exposure did not cause an appreciableinflammatory response in any of the strains at any time postexposure. However, significantinterstrain differences were found in Fc-receptor mediated phagocytosis by alveolar macrophages. Among the nine strains examined, C3H/HeJ(C3) mice were the most resistant and C57BL/6J (B6) were the most susceptible. Thesignificant interstrain variation in susceptibilityindicated astrong geneticcomponent contributed to ACP susceptibility. Agenome-wide search for linkage of the Fc-receptor mediated phagocytosis phenotype was performed in segregant populations derived from B6 and C3 mice using informative simplesequence length polymorphisms (SSLPs) distributed at approximately 10 centi-Morgan (cM)intervals throughout the genome. Intervalmapping by simple linear regression identified asusceptibility locus on chromosome 17 between approximately 16–22 cMs [24].An additionalQTL wasdetectedonchromosome11between D11Mit20 and D11Mit12 ,and no significant interaction between QTLs was detected. The presence of separatesusceptibility loci forthe phagocytosis phenotypewas consistent with thecosegregationanalysisfor this parameter [24]. Withinthe chromosome 17 QTL are anumber of candidate genes,including the proinflamma- tory cytokine Tnf (tumornecrosis factor-a ,TNF- a ), multiplehistocompatibilityloci, andheat shockproteins (HSP). Thechromosome11QTL alsocontainsanumberofcandidate genes, includingacluster of inducible cytokines and induciblenitric oxide synthase (iNOS). Interestingly, theseQTLsnearlyoverlapped similar QTLs identified forozone susceptibility. Thecommon linkagessuggest that similar geneticmechanismsmay contribute to pulmonary responses to ozone-induced inflammation andmacrophage phagocyticdysfunction induced by ACP, but further genetic analyses are required to confirm this hypothesis. Particle exposure Responses Pulmonary Cardiovascular Inflammation Heart rate Innate immunity Heart rate variability Antioxidant defense Arrhythmia Susceptibility factors Lungs Cardiovascular system Brain FIGURE 15.2 Schematic of the potential interactions between susceptibility factors (e.g., age, genetic back- ground, pre-existing disease, socioeconomic status)and therouteofparticleentry into thebody and physiological responses to the particles. Susceptibility to Particle Effects 277 © 2007 by Taylor & Francis Group, LLC Tolerance to air pollutant-induced pulmonary inflammatory and hyperpermeability effects has been demonstrated in animal models and human subjects(e.g., [25,26]).Wesselkamper et al. [27] evaluated the interstrainvariation in the ability of inbred mice to “become tolerant” to the toxic effects of repeated exposure to zinc oxide (ZnO). These investigators found significant interstrain variation in the inflammatory cell and hyperpermeability responses to single and multiple ZnO exposures. Agenome-scan for susceptibility QTLs for the development of pulmonary tolerance to ZnOinaDBA/2J andBalb/cByJ intercross cohort from mice identifiedasignificant QTLon chromosome 1, and suggestive QTLs on chromosomes 4and 5[28].Toll-like receptor 5(Tlr5) was identified as acandidate susceptibility gene in the chromosome 1QTL, and functional analysis confirmed arole for Tlr5 in particle tolerance [28].This represents the first attempt to identify the genesresponsiblefor thedevelopmentoftolerance, andconfirmationofcandidate genesin additional models and humansubjects may have important implications for understanding suscep- tibility and resistancetorepeated exposures to pulmonary toxicants. Wesselkamper et al. [29] developed another modelofparticle susceptibility and acute lung injury using nickel sulfate aerosol.Continuousexposure of mice to 150 mcg/m 3 of nickel sulfate causesdeath in astrain-dependentmanner; A/J mice were significantly more susceptibletothe aerosol than B6 mice [29].AQTL analysiswith backcross mice from A/Jand B6 progenitors identified asignificant QTL on chromosome 6, and suggestive QTLs on chromosomes1and 12. This study suggestedthat susceptibility to irritant-induced lung injury and subsequent survival was thus dependent on relatively few loci [30].Anumber of interesting candidate genes were identified in theseQTLs, including transforming growth factor alpha ( Tgfa), and proof-of-concept testing in this model has begun. This group has alsoused gene expression arrays to identify candidate genes for particle-induced lung injury [31,32]. This approach led to the identification of transforming growth factor beta ( Tgfb)and macrophage-stimulating 1receptor (Mst1r) as candidate suscep- tibility genes,and functionalanalyses have confirmed an important rolefor both in the injury that follows exposure to nickel sulfate aerosol. We have also comparedthe lung injury responses to residualoil fly ash (ROFA) exposure in inbred mousestrains [33].Significantinterstrain (genetic)variation wasobservedinROFA- induced lung inflammation andhyperpermeability, andC3mice were most resistanttothe ROFA-induced injury responses, whileB6mice were among themostsusceptible. Interestingly, ROFA-induced lung injury was significantly greater in C3H/HeOuJ mice compared to C3. C3H/HeOuJand C3 mice differ only at aloss of function mutation in toll-like receptor4 ( Tlr4)that confers resistance to endotoxinand ozone in the C3 strain. ROFA also significantly enhanced transcript and protein levels of lung TLR4 in C3H/HeOuJ,but not in C3 mice. Further- more, ROFA activated downstream TLR4 signaling molecules (i.e., MyD88, TRAF6, IRAK-1, NF- k B, MAPK, AP-1) to agreater extent in C3H/HeOuJ mice than in C3 mice before the development of pulmonary injury.These results supportanimportantcontributionofgenetic background to particle-mediated lung injury and suggestthat Tlr4 is acandidatesusceptibility gene. Gilmour et al. [34] also found that pulmonary responses to combustion source PM in hypertensive rats are mediated through TLR4 signaling. Interestingly, Hollingsworth et al. [35] found that the pulmonary inflammatory responses to ROFA were not different in B6 mice with targeted deletion of Tlr4 compared to wild type mice, and may suggestthat the interaction between Tlr4 and genetic back- ground (strain) is an important consideration in pulmonary response to ROFA. It is interesting to note that similar QTLs have been identified for multiple independent models of susceptibility to pollutant-induced inflammation, injury, and immune dysfunction. For example, nearly identical QTLs on chromosomes 17 and 11 have been found to explain asignificant portion of the genetic variance in susceptibility to ACP, ozone-induced inflammation, and ozone-induced lung injury and death. Further, theseQTLs were also found to have an important roleinbleomycin- and radiation-induced lung injury in the mouse[36,37]. The common linkage suggests that similar mechanisms control susceptibility to the various environmental agents [38]. Particle Toxicology278 © 2007 by Taylor & Francis Group, LLC Evidence for an important role of genetic background in susceptibility to particle effects in human populations has also emerged. Forexample, Schwartz et al. [39] found changesinthe high frequency(HF)component of HRV associated with exposure to PM2.5 only in individualswithout theglutathione-S-transferaseM1(GSTM1)allele.Noparticle effects on HRV were foundin individuals with normal GSTM1 .These investigators also found that use of statins reversed the particle effects on HRV in the GSTM1 null subjects. This gene Xdrug Xenvironment interaction on HRV demonstrates the complex nature of susceptibility to particle effects in human populations. Adonis et al. [40] found an association between abiomarker (1-OH-P) of exposure to PAHs in diesel exhaustand the presence of the CYP1A1*2A genotype, and may be useful in identifying individuals at higher risk among thoseexposedtodiesel exhaust. Interestingly, the GSTM1 null genotypewas notassociatedwiththe exposurebiomarker, though an interaction between CYP1A1 *2A and GSTM1 maybeinformative.These studies supportthe notion that oxidative stress may be an important component of particle toxicity, and that individuals with compromised antioxidant defenses may be at enhanced risk to the injurious effects of particles. 15.2.2 N ONGENETIC F ACTORS Factors other than genetic background that are involved in cardiopulmonarysusceptibility to particle exposure are also of considerable importanceinunderstandingthe etiology of this public health concern (Figure 15.2). It is criticaltounderstand which subsections of the general population are susceptible to particulate exposure in order to reducethe health risks. While it is beyond the scope of this chapter to discuss all nongenetic componentsassociated with susceptibility, we will focus on three important subgroups: age; pre-existing disease; socioeconomic status (Table 15.1). Age.Elderly individuals and developing infantsare at particularrisk from exposure to particu- late air pollution. Anumber of epidemiological and laboratory studies have addressed thisconcern, TABLE 15.1 RepresentativeInvestigations of the Effects of Age, Pre-Existing Disease, and SocioeconomicStatus on Responsivity to Particle Effects Subgroup Study type Conclusion Reference Age Epidemiology Elderly individuals with high airway hyperresponsivenessand IgE were susceptible to air pollution including PM 10 Boezen et al. [47] Mouse The regulation of heart rate was altered when senescent AKR/J mice were exposed to carbon black Tankersley [53] Epidemiology The risk of respiratorymortality in postneonatal infants increased in relation to PM 10 increases Ha et al. [45] Pre-existing disease Epidemiology Individuals with congestive heart failure, arrhythmia or atherosclerosis are at risk Brook et al. [55] Epidemiology COPD and asthma increase susceptibility via elevated oxidative stress Li et al. [61] Human subjects Higher fine particle deposition was found in subjects with obstructive lung disease Kim and Kang [64] Socioeconomic Epidemiology Higher particle associated mortality rates were found in low socioeconomic regions Jerret et al. [67] Epidemiology Low education levels and employment in manufacturing present additional particle related health risks Levy et al. [68] Field study Antioxidantsupplementation attenuated lung function responses to particle exposure Romieu et al. [70] Susceptibility to Particle Effects 279 © 2007 by Taylor & Francis Group, LLC but the health effects associated with infant exposure to particulate matter has not been studied in sufficient detail.Pre- and perinatal infants can be affected by particulate air pollution, including increasesinfetal mortality[41]and lowbirth weight [42,43].These effectsofparticulate air pollution are of greatconcern since, for example, the relationship betweenlow birth weight and infant mortality is well known. Evidence for infant health risk associated with particle exposure was also provided by Woodruff et al. [44].Inthisstudy,increased levels of PM 10 were linkedto respiratory illness and sudden infant deathsyndrome in 1–11 month old children. Another epide- miologicalstudies reported that postneonatal infantsare highlysusceptible to increasesin respiratory mortality in relationtoparticulate exposure [45].Inthisstudy,dailymortality records from 1995 to 1999 in Seoul were used to establish subsections in the Korean population that were susceptible to air pollution. Subsections of the population were divided into3age groups: 1month–1 year;2–64 years; and individuals 65 years and over. Theauthors reported that post- neonates had the highest relative risk (1.142) of total or respiratory mortality upon exposure to PM 10 when comparedtoelderly individuals (1.023)and the intermediate age group (1.008). This suggests that infants are at greater riskthan the elderly, and that particle related illness at ayoung agecouldlead to importantdevelopmental consequences that mayaffect these individuals in later life. Theaged as asecondsubgroup of the general population are more susceptibletoparticles than younger adults. The elderlysharemanyofthe sameresponses to particle exposure as children and they include thosealready discussedabove in additiontoairway hyperresponsiveness (AHA)and allergic reaction mediated by immunoglobulin E(IgE).Furthermore, women may be at greater risk because they have higher AHA than men [46].Concomitant AHA and high levels of IgE have been reportedtoresult in highersusceptibility to PM 10 exposure than either AHA or high levels of IgE alone [47]. However,the mechanismsinvolved in theseresponses to particle air pollution are currently not clear. Recently, anumber of epidemiological and observational experimental studies have investi- gated apossibleassociationbetween particulateair pollutionexposureand changesinthe regulation of the heart as arisk phenotype. An association between changes in HRV and increased cardiovascular (CV) risk hasbeenestablished forsometime[48].For example, myocardial infarction patients with lowHRV aremorelikelytosuffercomplications than patients with normal HRV.Therefore, reduced HRV during or following exposure to particles could provide insight into the potential mechanisms involved in susceptibility. Epidemiological studies have shownchangesinHRV that were associated with changesinambient particulate matter. Such changesinHRV are believed to indicate agreaterriskoflife threatening arrhythmia or the occurrence of fatal CV events in thosewith pre-existingCVorcardiopulmonary disease. Reduced HRV in the elderly has been reported during or followingperiods of higher ambient PM [49,50]. It has been suggested that health status may be an important factor in determining the degreeofPMinduced HRV changes[51].Itisimportant to note that methodsdesigned for HRV measurement require controlled laboratory conditions for ECG recording. Since epidemiologists are forced to use ambulatoryECG data for HRV, results from these studies can be difficult to interpret.Controlled studies usingmicehaveshown reductionsinheartrate(HR)and HRV following exposure to ultrafineparticles [52].These responses occurred within an hour of the bolus exposure but were transient and values returnedtobaseline rapidly. Moreover, in these young and healthy mice, baseline HR and HRV did not predict the response to PM exposure. In aged mice, carbon black (CB)induced changes in the autonomic nervous system that differed according to the degree of aging[53].Inolder, but healthy mice, CB exposure resulted in changes in thesympatheticnervous system. Conversely, in terminallysenescent mice changesinthe parasympathetic nervous system were observed following CB exposure and these changeswere related to HR regulation. Pre-existing disease.Pre-existing disease increases susceptibility to environmental pollution such as particles. While manydisease states are likelytobeinvolved, there is some evidence Particle Toxicology280 © 2007 by Taylor & Francis Group, LLC available to suggestthat CV and respiratory illnesses and diabetesare important. In the previous sectionresponses to PM exposure were discussed, and thesebiologic systemsmay becomeover- whelmed if underlying disease exists. Moreover,early development of disease can be accelerated by frequent exposure to particles. For example, Sun et al. [54] demonstrated that long-term exposure to PM 2.5 altered vascular tone, induced vascular inflammation, and potentiated athero- sclerosis in ApoE-/- mice. PM hasbeen associatedwithincreased hospital admissions andCVmortality duetoCV disease.Those with congestive heart failure, arrhythmia and atherosclerosis appeartobemostat risk [55].Park et al. [56] reportedthat afamily historyofischaemic heartdisease (IHD), hyperten- sion, anddiabetes are allassociated with susceptibilitytoPM. Increasesinblood coagulation factorsare also known to occur with PM exposure, and could have fatal consequences in individuals with IHD, hypertension,and atherosclerosis. One studyused amarker of potential myocardial ischaemia and found an increasedriskofS-T segmentdepression duringanexercise testthat associated with ultra fine particlesand PM 2.5 [57].Furthermore, additional risk has been associated with ahigh concentration of plasma fibrinogen [58],giving the impression that susceptibility to particlesmay be partly dependant upon the number of these riskfactorsthat are present together. Cardiovascularinjury or risk, in association with particle exposure, has also been linked to diabetes. Zanobetti and Schwartz[59] reportedthat the percentage increaseinPM 10 -related CV hospitaladmission in diabetics was twice as high as thoseofnondiabetics. Theauthors suggested that this observation might be associated with upregulation of inflammatory activity in diabetics, which may confer heightened susceptibility to PM. Patients with diabetes also present several risk factors associated independentlywith CV disease and exposuretoPM. If compensatory mechanismshaveabaselinereduction in capacity because of pre-existingdisease,subsequent exposure to PM may overwhelm these systemscausingsevereillness or sudden death [60]. Pre-existing COPD andasthmaare knowntoincrease susceptibilitytoparticleexposure perhapsdue to asignificant,additional oxidativestress [61].InCOPDpatients, all cause associationswithparticle exposure were 10 times greaterwhencomparedtoall subjects in a recentstudy [62].Potential mechanismsfor this high level of susceptibility in thesepatients includedecreasedantioxidant defenses [63]and higherfine particle deposition in the lungs of patients with obstructive airways disease [64].Induction or exacerbation of asthmatic symptoms by exposure to particles has also been well established. In arecent study, fractionalexhaled nitric oxide (FE NO )was used as anoninvasive method of estimating airway inflammation [65].FE NO was measured overa12-dayperiod whilelocal particle levels were monitored.FE NO levels were associated with changes in PM 10 and PM 2.5 in the elderly asthmatic patients. These data were in agreement with an earlier studybythis group that showed similar results in asthmatic children [66]. Socioeconomicstatus.Subsectionsofacitywide population in an intraurban area with low socioeconomic status have been associated with highermortality rates in relation to ambient air pollution [67].Low educationlevelsand employmentinmanufacturingpresentadditional particle-related health risks [68].Proposed explanations for this effect of socioeconomic status andeducation attainmentinclude higherworkplace particleexposures forthose workingin manufacturing materialdeprivation and poor materialconditions [69].Also, lower socioeconomic status has been associated with less exposure measurement error sincethereindividuals are less mobile[69].Since these groups must tolerate adisproportionatelevelofsusceptibility to air pollution related health risks, they would account for alarge percentage of emissions control benefits [68].Low socioeconomic status may also affect the ability of people to achieve adequate nutrition. Poor nutritionstatus hasbeen suggested as another particle susceptibility factor [69]. Inadequate nutritioncouldcompromiseantioxidant defenses thus increasing particlesuscep- tibility—a recentstudy showed reduced particulateeffectsonlung functionafter dietary supplementation with antioxidants [70].The importanceofthisfactor becomes apparent when considering the fact that poor nutritional status is possibleacross all socioeconomic classes. Susceptibility to Particle Effects 281 © 2007 by Taylor & Francis Group, LLC 15.3 CONCLUSIONS It is clear from the above discussion that genetics background is acriticalcomponent to inter- individual susceptibility to particle exposure. Further investigation is of greatimportance if our understandingofthe genetic contribution to particle associated health risks is to be improved. 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The ACP modelwas chosenfor study Genetic Genetic background background Pre-existing Pre-existing disease disease Socioeconomic Socioeconomic status status Age Age Cardiopulmonary Cardiopulmonary responses responses Children Elderly Asthma COPD Diabetes Atherosclerosis Arrhythmia Inflammation Coagulation Antioxidant Innate. immunity Education Nutrition Workplace Phenotypes Susceptibility factors FIGURE15.1 General susceptibility factors that mayinfluencecardiopulmonary responses to particle exposures. Particle Toxicology2 76 © 2007 by Taylor & Francis Group, LLC becausethe particles. 15 Susceptibility to Particle Effects Steven R. Kleeberger and Reuben Howden NationalInstituteofEnvironmental Health Sciences, NationalInstitutes of Health CONTENTS 15. 1 Introduction 275 15. 2