22 TheToxicology of Inhaled Particles: Summing Up an Emerging Conceptual Framework KenDonaldson MRC/University of Edinburgh Centre for Inflammation Research, University of Edinburgh Lang Tran Institute of Occupational Medicine Paul J. A. Borm Centre of ExpertiseinLife Sciences, Hogeschool Zuyd CONTENTS 22.1 Overview 413 22.2 Defining the Particle Toxicology Endeavor 414 22.3 Classical Toxicology 415 22.4 Exposure 415 22.4.1 Exposure at Portal of Entry 415 22.4.2 Toxicokinetics and Translocation from the Portal of Entry 415 22.4.3 Brain 416 22.4.4 Blood 416 22.5 Dose and the Concept of Biologically Effective Dose (BED) 416 22.5.1 AGeneralized Paradigm of Particle Toxicity Based on BED 418 22.5.2 Oxidative Stress as an Early Biological Effect Marker of BED for Different Pathogenic Particles 418 22.6 Response 420 22.6.1 The Occupational Setting 420 22.6.2 The Environmental Setting 420 22.7 Conclusions 421 References 421 22.1 OVERVIEW The chapters in this book set out the state-of-the-science for particle toxicology as it pertains in the early twenty-first century. It points out the maturity of this area of applied science, and toxicology is, aboveall,anapplied science. Toxicology’s primary aim is to provide hazarddata forrisk 413 © 2007 by Taylor & Francis Group, LLC assessment towards safe waysofworkingand living with the chemicalsweencounter on adaily basis, which all have inherent toxicity for biological systems. In particle toxicology, we seek to provide the data that will allow us to manage the risk associated with living in atmospheres that are often complex mixtures of particles of varying toxicity. However, mechanistic particle toxicology crosses over into mainstream molecular medicine and can provide important clues to the basis of othertypesofdisease. Our studies of the cardiovascular system,oxidative stress and molecular signalinginrelationtoparticlesoffer an understandingthatisgenerallyapplicable. Thisis eminently clear from the pages of this book where high quality and innovative research approaches are demonstrated in addressing the issues relating to particle effects. This chapter aims to draw together the various threads in the fabric of particle toxicology and present anew unifying concept, albeit simplified and incomplete, for this discipline. It is clear that the rise in nanotechnological applications and products has and will have ahuge impact on particle toxicology. Nanoparticle researchhas become the key area for study by particle toxicologists. It represents aconsiderablechallenge with new portalsofentry, such as the skin and the gut and new target organssuch as the blood and brain. Additionally, pharmacological uses of nanoparticles have caused arealignment and whole new areas of researchare opening up that build on the kind of expertise owned by particle toxicologists. 22.2 DEFINING THE PARTICLE TOXICOLOGY ENDEAVOR Particle toxicologists study particles in two main ways: 1. Studies aimed at refiningthe dose-metric; or put simply, “ What is it about particles that makes them harmfulornot?” 2. Mechanistic studies; or put simply,“How do harmful particlescause harm?” Studies aimed at refining the dose metric Knowledge is incompleteand we are not fully aware of the nature of the harmfuldose (the quantity of the particle’s physicochemistry that drives adverse effects; see below) for manyparticle types. If we fully understood what made any particle type harmful, we could focus in on that parameter for measurement and so improverisk management. Historically,there have been frequent mismatches betweenthe currentdose-metrics andour existing knowledgeofthe toxicologyofsometypesofparticles. For example, asbestosand otherfibers are measured as mass of all airborne fibers visible by light microscopy longerthan 5 m m(with diameter ! 3 m mand aspect ratio O 3:1). However, toxicological research has shown that fibers that arebothbiopersistentand longer than about 20 m mare thepathogenicones (Donaldson 2004). Despite this, the “old” fiber standardremains, and it takes no account of the issues of length or solubility. In the case of PM 10 ,the mass of particles around10 m mare measured but much of this massisharmless, e.g. salt. However, smaller particles(PM 2.5 )ortransition metals (Donaldson et al. 2004a)oroxidant generation (Schaumann et al. 2004)might be better predictors for health effects. Mechanistic studies These studies aim to understand the cellular and molecular basisofthe toxic effects of particles and the sum of their interactions with biological systems. Such studies contribute to risk assessment by providing amore complete frameworkfor our understandingof how particles behave in the body, the effects they have on cells and how beinginthe body changes them. In combination with toxicokinetics, which describehow fast and to which extent particlesget distributed to different organs or tissues, such studies allow the entire “life history” of particles in the body to be traced. These mechanistic studies offer the possibility of therapeutic intervention in the process of disease.Anexample is the currentexploration of soluble TNF-receptors in the treatmentofIPF,asaresult of initialworkonTNF- a in fibroticdisorders caused by quartz- containing dust (Piguetetal. 1990). Particle Toxicology414 © 2007 by Taylor & Francis Group, LLC 22.3 CLASSICAL TOXICOLOGY The classical toxicology paradigm of exposure–dose–response can be used for particles as for any other toxin. Exposure, dose and response togetherwith ADME/toxicokinetics allow us to describe the detailed historyofatoxin in the body. Completetoxicokinetics analysis is not available for any pathogenicparticle. Most pathogenicparticles have not been considered to be metabolized and excreted in anyconventionalway.However, nanoparticles, becauseoftheir smallness, may undergo such changes(Oberdo ¨ rster et al. 2005b). Thefuller our understandingofthese processes, the better we will be able to interpret toxicology studies and understand the nature of the toxiceffect of any particle. Of exposure, dose and response, we are especially focused on “dose” as akey to understanding molecular and cellular toxicity as well as contributing to understandingthe best metric. For nanoparticles, the dose-metric is not yet elucidated and is likelytovary with different particle typessincethey can be composed of arange of materials and can be different sizes and shapes. The concept of a“biologically effective dose” (BED) is an important one for particles since all particle exposures are mixed. We can hypothesize that there is one or more actual component of this total dose that actually drives the adverse effect, and this is the BED. 22.4 EXPOSURE 22.4.1 E XPOSURE AT P ORTAL OF E NTRY In the past, particle toxicology was concerned almost exclusively the lungs.With the advent of nanoparticle toxicology there has been asea change in howinhalation particle toxicology is viewed (Donaldson et al. 2004b). Following inhalation of nanoparticles, the blood and brain are seen as secondary targets for particle effects (Oberdo ¨ rster et al. 2005a, 2005b). The aerodynamic diameter is the key particle parameter that predicts whether any particle gains access to the lungs and it alsodetermines the site of particle deposition in the lungs (Gehr et al. 2000). Aerodynamic diameter is important for deposition of biggerparticleswith impaction and sedimentation beingthe main processes, whilst thesebecome less important as size diminishes and diffusion comes to dominate the deposition process. For fibers,interception is an important depo- sition process whereby the extremities of the fiber make contact with airspacewalls while the center of gravity of thefiberisfollowing theairstreamatabifurcations (Morganand Seaton1995). Depositionofcompact particles occurs as particles fall outinaccordwith their weight,i.e., sedimentation. Theyalsodeposit by impactionasparticles fail to negotiate bifurcations and collide with the bronchial wall;deposition at bifurcations is increased also by the normal turbulence that results from the disruption to the even flowofair at thesepoints. Finally, the smallest particles reach the distal lungs to the point where the net flow of air is zero,where they move by molecular (Brownian) motionand they deposit efficiently by diffusion. For thesereasons, deposition in the lung is highly focalasaresult of the dose being applied to certain anatomical areas/hot-spots, such as the bifurcations of airways and the centriacinar region. At thesehot-spots, deposition can be 100- fold higher than in adjacent areas (Balashazy et al. 2003). 22.4.2 T OXICOKINETICS AND T RANSLOCATION FROM THE P ORTAL OF E NTRY Up until recently, the translocation of particles from their site of entry to other target organswas not considered amajor issue. However, because of data showing nanoparticle translocation from the lungs (Hoetetal. 2004; Nemmar et al. 2004), there is increasing concern in this regard. To date, animal studies show sometranslocation of radioactive nanoparticles from the lungs to the blood following instillation exposure (Nemmar et al. 2001)and to the brain following inhalation exposure (Oberdo ¨ rster et al. 2004)(Figure22.1). There is no evidence for this type of translocation following inhalation of any nanoparticle type in man at the time of writing. Aflow diagram of the hypothetical TheToxicology of Inhaled Particles 415 © 2007 by Taylor & Francis Group, LLC fate and effects of nanoparticles is shown in Figure 22.2,based on limited animal studies with afew selected nanoparticle types. 22.4.3 B RAIN Limited studies indicate that nanoparticles can gain access to the brain via the nose and the nerves that run from the olfactory epithelium into the olfactory lobes of the brain (Oberdo ¨ rster et al. 2004). Nothing is known of the dosimetry in relation to exposure, nor whether this is generic propertyof nanoparticles. However, giventhe ubiquitousness of combustion-derived nanoparticles in our environment, if this is ageneral property of NP, then it is likely that we all have aburden of nanoparticles in our brain. Indirectevidence that this is indeed true and that there mightbeadverse effects on the brain comes from studies in Mexico City describing unusualbrain pathology in the young (Calderon-Garciduenas et al. 2004). It is not knownifnanoparticles can generally cross the blood/brain barrier, but medicalnanoparticles have been designed to efficiently translocate to the brain from the blood (Kreuter et al. 2002). 22.4.4 B LOOD Limited data indicates that nanoparticles can pass from the lungs to the blood (Kreyling et al. 2002a; Kreyling et al. 2002b; Nemmar et al. 2004). In the blood, particlescan have arange of effects on blood componentsand associated cells, such as endothelial cells, monocytes and platelets (Hoet, Nemmar, and Nemery2004). Exposuretocombustion-derived nanoparticles andPMhaveshown effectsatthe level of theendothelium to impair vasomotion in a humanmodel (Mills et al. 2005), which is knowntobearisk factor for myocardial infarction. Concomitant pro-thromboticeffects thatwould favorthrombuspropagation in the eventof atherothrombosis were also reported (Millsetal. 2005). Few studies have reported the effect of engineered nanoparticles on the cardiovascular system (Radomski et al. 2005), but several studies have identified that exposure to PM or CAPS enhances severity of atherogenesis in Watanaberabbitsand ApoE mice (Suwa et al. 2002;Chen and Nadziejko 2005;Sun et al. 2005). Since particle based systems are being explored for molecular imaging in atherosclerotic disease,more research in this area is needed. 22.5 DOSE AND THE CONCEPT OF BIOLOGICALLYEFFECTIVE DOSE (BED) The internal dose is the quantity of atoxin that gains access to the body. For inhalation exposure, because of particle clearance, of course, the fraction of the deposited dose that remains in a long-lived compartment like the interstitium or in long-lived macrophage accumulations can take Redistribution Potential effects Brain Blood Nanoparticles Respiratory tract Degeneration Atherothrombosis Inflammation, etc. FIGURE 22.1 Outline of the potential toxicokinetic pathways for inhaled nanoparticles to translocate and have effects in the body following inhalation exposure. Particle Toxicology416 © 2007 by Taylor & Francis Group, LLC part in toxic reactions, and it is less than the “total dose” that is breathed in and that deposits. This is then acted on by the milieu in the interstitium or in cells to cause dissolution of non- biopersistent particles or components. This may release harmful soluble components as well as harmless soluble components, which are cleared or metabolized. The BED is auseful concept, being that fraction of the total dose that is sufficiently biopersistent and also sufficiently active to cause an adverse effect such as oxidative stress, adduct formation, etc.Thiscan be understood in that all realistic particle exposures are particles that are multi-component and poly-dispersed and within this totaldose, we canidentify sub-fractionsthatare likely to be more harmfulor effective than others. For example, PM 10 is measured by the mass metric, yet avariable and often substantialquantity of the massofPM 10 is sea salt, which is likelytobecompletely invisible to the lung following exposure at ambientlevels,i.e., aharmless dose. Conversely,the transitionmetals can be seen to be driving the oxidative stress and inflammatory effects of PM in human (Schaumann et al. 2004)and animal models (Jimenezetal. 2000; Campen et al. 2001; Campenetal. 2002; Molinelli et al. 2002), yet this component would contribute very little to mass. Thus the transition metals can be seen as the BED,and their ability to cause oxidative stress is an early biological effect. Other examples of BED are the amount of “free” or “clean” quartz surfacesthat are available to interact with cells that drive quartz’sinflammatory effects (Donaldson and Borm 1998)and the proportion of biopersistent, long ( O 20 m m) fibers,which drive the pathogenicity of afiber sample (Donaldson and Tran 2004c). The concept of the BED is showninFigure 22.2. Deposited particles Cleared by mucociliary clearance Particles interstitialised/ sequestered in long- lived macrophages Biopersistent particles Ineffective dose Biological effective dose Adverse effect Dimension factor Soluble toxins Non-biopersistent particles Metabolism to urine/bile* *may be relevant for nanoparticles FIGURE 22.2 The relationship between deposited particles, biopersistence and the BED. TheToxicology of Inhaled Particles 417 © 2007 by Taylor & Francis Group, LLC 22.5.1 AGENERALIZED P ARADIGM OF P ARTICLE T OXICITY B ASED ON BED These factorscan be assembled into asmall number of sources of BED that allow us to present a generalized paradigm for the total BED in the lungs for any specific particle type.The paradigm may be similarordifferentfor pathogenicity of particlesinother sites, such as blood or brain. For insoluble particles, it is only the surface layerthat makes contact with the biological system and so can be considered to mediate the harm.For this reason, the surface area has come to the fore as a dose-metric that effectivelydescribes the potential toxicity of particles, rather than total mass or particle number. Theparticle’s surface is likely to vary in intrinsic reactivity/toxicity, depending on the materialand (nanoscale) the patternofwhich the particle is made. Therefore, intrinsic reactivity is amultiplierofsurface area to obtain the total reactive surface produced by any mass of particles. In addition, we know from the asbestos and SVF experience that, for fibers, length can be important and so we can add “shape” as afactor. In addition, studies of PM 10 ,welding fume, etc. tell us that many particles are complexand contain soluble components that can have considerable toxic potential. Additionally, the length of time that the particle is likelytopersist and not be cleared determines the length of time that the BED is applied to the system;thus abiopersistence factor is required.Taking these factorstogether, we have aparadigm that couldpredict the toxicity of aparticle in the lungs. Thethree main attributes for the biologically effective dose of aparticle to acell are: 1. Surface attribute Z surfacearea ! specificsurfacereactivity (i.e., reactivity perunit SA)! surface availability 2. Dimension attributeZ lengthC diameter (mainly length if greater than acriticallength) 3. Composition attribute Z Volume! specific volumetric reactivity (i.e., the toxic material per unit volume)! availability ( Z release rate i.e., amount per unit time) For acute effects the BED is related to the Potency, which can be best described as the sum of (1)C (2)C (3). For chronic effects the biopersistence playsadominantrole and the BED is best described by the product of biopersistence and potency: Biologically effective dose Z Bio-persistence ! Potency This equation reflects the issue of translocation but deals specifically with the toxic outcome of the interaction between aparticle and acell. We do not think we are yet in aposition where we can even approach thedevelopment of aparadigm fortranslocation that is based on structure. Table 22.2 showsattributes contributing to Bio for several particle types: 22.5.2 O XIDATIVE S TRESS AS AN E ARLY B IOLOGICAL E FFECT M ARKER OF BED FOR D IFFERENT P ATHOGENIC P ARTICLES Inspection of Table 22.1 raises questionsastohow so manydifferent chemical and physical entities (length, soluble toxins of different types, different surfaces) could all constitute somecommon form of “harmful dose” to the machinery of the cell. However, this may be understood in the findingsthat the ability to deliver oxidative stress is acommon property of harmfulparticles. This oxidative stress can emanate from the particle itself and it can alsobeaconsequence of the cellular and/or the inflammatory response induced by the particle (Donaldson et al. 2003; Knaapen et al. 2004). There is ahighly plausible link between oxidative stress and inflammation (Barrett et al. 1999; Tao et al. 2003; Donaldson et al. 2005b), with many oxidative stress-responsive pathways signaling for pro-inflammatory gene transcription (Piette et al. 1997;Rahmanand MacNee 2000). There is alsoaclear link between oxidativestress andadducts such as 8-hydroxy-deoxyguanosine, the hydroxyl radical-induced adductofguanine, which is involvedincarcinogenesis(Lloyd et al. 1998; Tsurudomeetal. 1999; Maengetal. 2003).Manypathogenicparticle typeshavebeen Particle Toxicology418 © 2007 by Taylor & Francis Group, LLC shown to activate NF-k B(Schinsand Donaldson 2000)and cause inflammation (Donaldson and Tran 2002). The role of the surface is emphasized by studies showing that the ability of quartz to deliver oxidative stress is dramatically lowered by surface coating (Knaapen et al. 2002). Combustion-derived NP have their effects by oxidative stress and inflammation (Donaldson et al. 2005a), and several engineered NP types have been described as having oxidative stressing TABLE 22.1 Table Showsthe BED foraNumber of ParticleTypes That Are Well Studied and the Mismatch with TheirExposure Metric Particle BiologicallyEffective Dose Current Metric Quartz Area of reactive (unblocked or unpassivated) surface Respirable mass Asbestos Biopersistent fibers longer than w 20 m mFibers longer then 5 m m, O 3 m mdiameterand aspect ratioO 3 PM 10 Organics/metals/surfaces Mass by PM 10 convention Welding fume (NP) Soluble transition metals Respirable mass Diesel soot (NP) Organics/metals/surfaces Contained in PM 10 Carbon black (NP) Surface area Nuisance dust standard of respirable mass TABLE 22.2 RelativeImportance of Properties Contributing to the BEDofDifferent Particle Ty pes Surface Attribute Dimension Attribute CompositionAttribute Particle type Surface Area Surface Reactivity Length a Soluble Toxins b Biopersistence c Quartz CCCCCC No No CCCC Amphiboleasbestos CCC CC CCCC CCCC Welding fume CCC No No CCCCC C ROFA CC C No CCCC C PM10 CC C No CCC C NP carbon black CCCC C No No CCCC a Longer than 20 m m. b E.g., metals, organics. c More plusses equals more SA, reactivity, soluble toxins or biopersistence. TABLE 22.3 OxidativeStress Mechanism forDifferent Particle Types Source of oxidative stress Exemplar Particle Mechanism of Generation Oxidative Stress Reference Surface reactivity Quartz Chemical groups on fracture surfaces (Vallyathanetal. 1994) Soluble metals ROFA, welding fume Fenton chemistry (Shi 2003 3196/id) Organics DEP, PM 10 Redox cycling of quinones etc. (Squadrito et al. 2001) Shape Amphibole asbestos Transition metals (Lund and Aust 1991) TheToxicology of Inhaled Particles 419 © 2007 by Taylor & Francis Group, LLC effects(Hussain et al.2005; Mannaetal. 2005;Sayes et al. 2005). Attributescontributing to oxidative stressing potential of different particle typesisshowninTable 22.3. 22.6 RESPONSE Particle-related lung diseases of various types can be seen in both occupational and environmental settings, and both the pattern and intensityofthe exposure can differ quite distinctly betweenthese two (Table 22.4). 22.6.1 T HE O CCUPATIONAL S ETTING Traditional particle-associated lung diseases are those seen in occupational settings and the clas- sical particles are quartz, asbestos,coalmine dust, etc. High airbornemassexposures, characteristic of historic workplaces, leadstothe responses of pneumoconiosis andCOPD(Table22.4).In addition, there are cancers andasthmaarising in workplaces due to particleexposures. The worker population can generally be seen as ahealthy,predominantly male population that can in general tolerate such exposures well,atleast at the commencement of their exposure, because of the “healthy worker” status. The “healthy” status within the workforce is conserved by the simple process that thosewho are adversely affected by exposure to the dusty atmosphere leave to take up alternative employment leaving only ahealthy workforce. 22.6.2 T HE E NVIRONMENTAL S ETTING There is awell-documentedlink between exposure to environmental particles(PM 10 )and morta- lity/morbidity in airways and cardiovascular disease and cancer(Pope and Dockery 1999;Pope et al. 2003). These low mass exposures commonly affect susceptible populations of patients with existing lung disease (asthma and COPD) or cardiovascular disease to producequite adifferent exposure pattern and response (Table 22.4). Aged populations and those with airways disease and cardiovascular disease have pre-existing oxidativestress as part of the inflammatory components of their conditions, and this couldbeafactor in making them susceptibletoparticle effects driven by oxidative stress. Common features of the two paradigms are encapsulatedinFigure22.3,where the common roles of oxidative stress and inflammation are emphasized. With NP, translocation and effects distal to the site of deposition come intoplay and render the whole equationmore complex. However, the TABLE 22.4 Characteristics of Inhalation Exposure to Particles Typical Particle Ty pes Exposed Population ExposureTypical Responses Occupational Silica, asbestos, welding fume, manufactured nanoparticles, organic particles (grain, cotton) Predominantly healthy males ! 65 years old High Pneumoconiosis, COPD, cancer, asthma Environmental PM 10 containing combustion- derived nanoparticles Everyone including susceptible and O 65 years old, ill populations with pre-existing inflammation and oxidative stress Low Exacerbations of COPD/asthma, cardiovascular disease, diabetes, cancer Particle Toxicology420 © 2007 by Taylor & Francis Group, LLC basic principle of particle toxicology will be seen to apply and the responses should be interpretable in the light of the foregoing discussion. 22.7 CONCLUSIONS The shape of this chapter emergedwhile we were puttingtogether and reviewingall the chapters of the book.Webelieve that it represents the first effort to try and develop asingle conceptual frameworkfor theadverse effects of pathogenicparticles, anditisundoubtedly simplified. 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Hogeschool Zuyd CONTENTS 22. 1 Overview 413 22. 2 Defining the Particle Toxicology Endeavor 414 22. 3 Classical Toxicology 415 22. 4 Exposure 415 22. 4.1 Exposure at Portal of Entry 415 22. 4.2 Toxicokinetics. Different Pathogenic Particles 418 22. 6 Response 420 22. 6.1 The Occupational Setting 420 22. 6.2 The Environmental Setting 420 22. 7 Conclusions 421 References 421 22. 1 OVERVIEW The chapters in this. book set out the state-of-the-science for particle toxicology as it pertains in the early twenty-first century. It points out the maturity of this area of applied science, and toxicology is, aboveall,anapplied