Particle toxicology

Tai Lieu Chat Luong 0921—Prelims ——16/11/2006—20:34—VELU—15547—XML MODEL C – pp i–xvii 0921—Prelims ——16/11/2006—20:34—VELU—15547—XML MODEL C – pp i–xvii 0921—Prelims ——16/11/2006—20:34—VELU—15547—XML MODEL C – pp i–xvii 0921—Prelims ——16/11/2006—20:34—VELU—15547—XML MODEL C – pp i–xvii Foreword The association between lung diseases and the inhalation of dusts has been recognized throughout history, stretching back to Agricola and Paracelsus in the fifteenth and sixteenth centuries Needless to say the scientific endeavour associated with identifying the relationship between particle characteristics and pathological processes—the essence of modern particle toxicology— awaited the development of a contemporary understanding of both lung disease and the physicochemical nature and aerodynamic behaviour of particles These elements finally came together in the mid-twentieth century and modern approaches to understanding harmful inhaled particles can be first traced to quartz (crystalline silica) and its fibrogenic effects in the lungs Undeniably, in a truly applied toxicology approach to the notion that the surface reactivity of quartz was the harmful entity, a whole programme of toxicology-based therapy was undertaken, using aluminium to attempt to reduce the harmfulness of the quartz in already exposed subjects Meanwhile the epidemic of disease caused by asbestos, the other particle source of the twentieth century, was taking hold and by late- to mid-twentieth century, an understanding of the toxicology of asbestos began The full understanding of the asbestos hazard was, however, only realised in the 1980s and 1990s, following the rise in use of synthetic vitreous fibres in the years following the reduction in asbestos use In these years, ground-breaking studies demonstrated the importance of length and biopersistence, which explained differences between asbestos types and placed all respirable mineral fibres in a single toxicology paradigm that embraced both asbestos and the synthetic vitreous fibres In the 1990s, ambient particulate matter as a regulated air pollutant (PM10 1) became the focus of global concern This was initiated by epidemiological studies that were now able to process huge data sets on air quality and human morbidity and mortality Both cohort and time-series studies in many countries associated substantial premature mortality and excess morbidity in urban residents to their air pollution exposure, with particles as the most potent component of the air pollution cocktail Although the risks are low, particulate matter affects the whole population and the effects were still preset below the air quality standards It also became evident that certain groups, such as elderly and people with respiratory and cardiovascular diseases, were at increased risk Since then, particle toxicologists are faced with the fact that PM10 is a complex mixture by itself, whereas the risks identified in the epidemiologic studies are based on total mass concentrations A further reduction of the PM levels would be very expensive and a cost effective strategy was warranted There was an urgent need to identify the causal relationship between PM, (personal) exposure and associated health effects This recognition stimulated governments globally, and new funding flowed into particle toxicology research to identify the critical aspects that could be linked with the health effects observed in epidemiological studies It soon became clear that no single, omnipresent constituent could be identified that related to the variety of health effects It turned out to be a big challenge for many because of the variability in PM10 (size range, surface chemistry, agglomeration, shape, charge, chemical composition, et cetera), the focus on susceptibility factors (disease, age, and gender) and the lack of good in vitro and animal models to mimic these factors The increasing emphasis of PM toxicology on the cardiovascular system as a key target for adverse effects brought an entirely new dimension Particle toxicologists were forced to move out of their comfort zone in the respiratory tract and try to understand how inhaled particles could also affect the cardiovascular system or other target tissues such as the brain At the end of the twentieth century and the dawn of the twenty-first century, manufactured nanoparticles2 have come to Defined as mass of particles centered around an aerodynamic diameter of 10 mm Generally defined as particles with at least one dimension less than 100 nm 0921—Prelims ——16/11/2006—20:34—VELU—15547—XML MODEL C – pp i–xvii represent the new frontier for particle toxicologists based on nanotechnology’s potential to produce a wide range of new particles varying in size and chemistry Traditionally, particle dosimetry has always been linked with particle toxicology, due to the complex relationship between exposure and target dose Unexpected translocation of nanoparticles from the respiratory system to other organs and a recognition that manufactured nanoparticles could affect the skin and the gut—depending on the type of exposure—have extended the area of research Throughout the fifty or so years that have seen the full flowering of the scientific discipline of particle toxicology, particle toxicologists have looked to mainstream molecular biology for their pathobiological paradigms, with the examples intra-cellular signalling pathways, inflammation biology, immunomodulation, and genotoxicity as prime examples They have also looked to chemistry and physics for an improved understanding of the particle characteristics that drive toxicity, including the assessment of free radical production and oxidative stress—a leading paradigm for how particles affect cells In addition they have worked in tandem with aerosol physicists and modellers to develop the dosimetric models that are so important, including the role of aerodynamic diameter in dictating the site of the deposition of particles Particle toxicologists have also worked with epidemiologists and most recently with cardiologists and neurologists, and the net result has been to produce a truly multidisciplinary science that uses computational modelling, in vitro techniques, and animal and human studies to address their hypotheses This volume represents the view of a number of world’s leading particle toxicologists in their chosen specialties, many of whom were involved in the events described above and in raising particle toxicology to the status that it has today Their chapters address the most important aspects of particle toxicology and confirm its status as a mature science As such, I believe that this volume is a database that provides not only a historical view, but most of all state-of-the-science concepts in a single volume It covers the broad spectrum of particle toxicology from particle characterization, respiratory tract dosimetry, cellular responses, inflammation, fibrogenesis, cardiovascular and neurological effects, and genotoxicity The chapters cover all kind of particle types, unlike previous books that have focused on single particle types, such as quartz or fibres and so forms an essential reference work Particle toxicology is different from any other toxicology Different in the sense that it has demonstrated that “dose,” as defined by Paracelsus, has more dimensions than mass per volume The book deals with the specific nature of particle toxicology in great detail, and I truthfully believe that this volume will provide the reader with a unique and practical insight into this fascinating branch of toxicology On behalf of the editors, Ken Donaldson and Paul Borm, I would like to thank the authors for their generous time in writing the chapters and the staff of Taylor & Francis for their excellent support in the production of the book Flemming R Cassee, Ph.D National Institute for Public Health and the Environment Bilthoven, The Netherlands 0921—Prelims ——16/11/2006—20:34—VELU—15547—XML MODEL C – pp i–xvii Preface The toxicology of particles is an absorbing area of research in which to work and when we conceived this book, we wanted to capture some of the fascination that we feel about our profession We are well-pleased with the result—everyone we invited to write a chapter agreed and almost everyone delivered a manuscript—a remarkable outcome in this time of conflicting deadlines It is difficult to keep up with the sheer quantity of data that accumulates on particle toxicology This has resulted in polarisation of meetings and specialists into particle types, thus there are meetings on PM or nanoparticles and there can be inadequate cross-talk This is unfortunate because of the benefits of understanding the toxicology of one particle type for understanding other particle types This volume deals with all particle types and offers state-of-the-science reviews that should benefit practitioners of the many disciplines who are involved in particle toxicology Particle toxicology is a “work in progress,” as witnessed by the rise of nanoparticle toxicology, and has become an important area of endeavour in toxicology, pollution science, respiratory medicine and increasingly, cardiovascular medicine This book is, therefore, timely and apposite to meeting this need for information We warmly thank the authors who have been involved in writing the various chapters of this book and the staff of Taylor & Francis for their invaluable and professional assistance in its realisation Ken Donaldson Paul Borm 0921—Prelims ——16/11/2006—20:34—VELU—15547—XML MODEL C – pp i–xvii 0921—Prelims ——16/11/2006—20:34—VELU—15547—XML MODEL C – pp i–xvii Editors Professor Dr Paul J.A Borm has been with the Centre of Expertise in Life Sciences (CEL) at Zuyd University in Heerlen, The Netherlands since 2003 Although his research work has concentrated mostly on lung diseases, his activities and coordination have always included a larger array of subjects related to (occupational) health care He is the author of more than 160 peer reviewed papers and more than 150 oral presentations on topics in occupational and environmental toxicology Professor Borm is a member of the German MAK-commission and the Dutch Evaluation committee on Occupational Substances (DECOS) He has been an invited member of expert groups such as IARC (1996), ILSI (1998), and ECVAM (1997), and he has been the organizer of many international meetings and workshops on occupational risk factors He is an editorial board member for Human Experimental Toxicology and Inhalation Toxicology and a co-editor of Particle and Fibre Toxicology The combination of his know-how in pharmacology, toxicology, and management of interdisciplinary research projects and teams are among his skills In his current function at Zuyd University, he is trying to interface fundamental and applied sciences with developments and needs in the public and private sector, such as health care, functional foods, and nanotechnologies Dr Borm is involved in a number of large-scale projects including education in nanotechnology, technology accelerator using nanotechnology, and cell therapy Apart from his position at Zuyd, Borm holds management contracts with start-ups (Magnamedics GmbH) and grown-ups in Life Sciences Drug delivery and/or toxicological testing of drug delivery tools are core businesses in these activities Ken Donaldson is professor of respiratory toxicology in the Medical School at the University of Edinburgh, where he is co-director of the Edinburgh Lung and the Environment Group Initiative Colt Laboratory—a collaborative research institute involving the Edinburgh University Medical School, Napier University, and the Institute of Occupational Medicine, carrying out research into disease caused by inhaled agents, predominantly particles He has carried out 27 years of research into the inhalation toxicology of all medically important particle types—asbestos, man-made vitreous fibres, crystalline silica, nuisance dusts, ultrafine/nanoparticles, particulate air pollution (PM10), and organic dust, as well as ozone and nitrogen dioxide He is a co-author of over 250 peer-reviewed scientific articles, book chapters, and reviews on lung disease caused by particles and fibres Dr Donaldson is a member of three government committees—COMEAP (Committee on the Medical Effects of Air Pollution), which advises the government on the science of air pollution; EPAQS (Expert Panel on Air Quality Standards), which provides independent advice to the government on air quality issues (ad hoc member); and the Advisory Committee on Hazardous Substances, which provides expert advice to the government on the science behind hazardous chemicals He has advised WHO, EU, US EPA, UK, HSE, and other international bodies on the toxicology of particles He is a registrant of the BTS/IOB Register of Toxicologists, a Eurotox-registered toxicologist, a Fellow of the Royal College of Pathologists, a Fellow of the Society of Occupational Medicine, and he has a DSc for research in toxicology of particle-related lung disease He is the founding editor in chief, along with Paul Borm, of the journal Particle and Fibre Toxicology 0921—Prelims ——16/11/2006—20:34—VELU—15547—XML MODEL C – pp i–xvii Index particle-mediated extracellular oxidative stress, 89–110 periphery, particle clearance, 61–62 structure, 353–353 weights, pulmonary toxicity testing and, 321 Lymph nodes, particle clearance and, 62–63 Lymphatic level, rodent lungs and, 359 M Macrophages, 148 epithelial cells interaction between, 189–191 modeling of, 191 particle proinflammatory effects on, 183–191 phagocytic cells, 148 signaling mechanisms, particles and, 187–189 Magnetic nanocarriers, 399–401 nanoparticles, 388–390 particles, luminescent species, 388–390 Magnetoliposomes, 395–396 Manganese (Mg), 101 MAPK See mitogen-activated protein kinase Mechanisms, particle deposition, 54–55 Medicine, nanoparticles and, 387–405 benefits of, 388–401 future of, 405 hazards and risks, 401 imaging and diagnostic tools, 388–389 magnetic particles, 388–390 Membranes animal studies, 146 cell culture studies, 146–152 cellular, 142 nanoparticles adverse health effects of, 142–143 visualization of, 144–145 particle interaction, 139–154 particle-cell interactions, mechanisms of, 152–154 stability, 153–154 tissue, 140 visualization, laser scanning microscopy, 144 transmission electron microscopy, 144 Metal chelation proteins, 97 exposure particulate-matter, 161–163 pulmonary diseases associated with, 162–163 human brain pathology and, 343–345 induced signaling, pathophysiological effects of, 164–165 particle-associated, 161–175 particles, oxidant injury mechanism, 164 reactive nitrogen species, 163–164 oxygen species, 163–164 Mexico City, air pollution and, 334–337 clinical studies of children, 341–342 Microscopy 429 laser scanning, 144 new techniques and tools, 144 transmission electron, 144 Mineralogy, pathogenic particles, 13–34 Minerals, health issues, 15 Mircorbicidal activity, 310–311 Mitochrondria, 120 Mitogen-activated protein kinases, (MAPK), 200–202 cascade, 307 Modeling particle deposition, 54–55 Models, pulmonary toxicity testing and, 317–329 Molecular basis, Alzheimer’s Disease, 332–333 Mouse airways, ultrafine particles and, retention in, 63–64 Mucins, 96 N NADPH oxidase, 120 Nanodevices, 392–393 Nanomaterials, 392 Nanoparticles dosimetry and, 382 drug delivery tools, 393–401 fluorescent, 390–391 hazards and risks current data carbon nanotubes, 403–404 dendrimers, 404 fullerenes, 404 implants, 404–405 quantum dots, 403 toxicological effects, 402–403 blood, 402 brain, 402–403 cardiovascular system, 402 medicine, 387–405 benefits of, 388–401 future of, 405 hazards and risks and, 401 membranes, adverse health effects of, 142–143 visualization of, 143–145 nanodevices, 392–393 nanomaterials, 392 quantum dots, 391–392 Nanotechnology, 7–8 Nanotubes, 403–404 Neurodegeneration, 343–345 Neurological effects, animal studies and, 311 Nickel, 101–102 signaling effects and, 168–169 Nitrogen species, reactive, 163–164 Nitrosative stress, 119–132 Non silicates, 21–23 Non-cellular particle mediated ROS generation, 120–124 Nonphagoctic cells, 148 Nonredox active metals, 102–104 aluminium (Al), 102–103 lead (Pb), 103 zinc (Zn), 102 0921—INDEX —16/11/2006—15:52—RATHNAS—15570—XML MODEL C – pp 425–434 430 Nuclear factor-kB AP-1, particle-induced activation, 129–130 particles, 128–130 induced activation, 129 RNS regulation of, 128–130 ROS regulation of, 128–130 signaling pathways and, 202–204 O Organic compounds bioavailability of, 213–215 inflammation, 216–220 effects of, 218–219 oxidative stress, 214–216 fraction, 213 Organics, particle-associated, 211–220 Orthosilicates, 14, 16 Oxidants DNA damage and, 292 generation, 290–291 injury, metal particles and, 164 Oxidative stress, 89–110 air-lung interface antioxidant defenses, 92–97 particle-induced oxidation reactions, 109–110 ambient PM, RTLF antioxidants, 109 diesel exhaust particle exposure, 107–108 early marker, biologically effective dose and, 418–420 hypothesis of, particulate matter health effects, 90–91 induction of, 98–104 nonredox active metals, 102–104 redox active metals, 98 measurement, 306 organic compounds and, 215–216 particle associated quinone toxicity, 103 induced animal studies, evidence from, 106–107 toxicity, 105–106 particulate matter caused injury, 172–175 toxicity, determinants of, 104–105 signaling in, 161–175 Oxygen species, reactive, 163–164 Ozone, particulate air pollutants and, 81–84 P PAHs See Polycyclic aromatic hydrocarbons Particle antioxidant defenses, 131–132 associated metals, signaling in, 161–175 organics compounds, 215–216 fraction, 213 particulate matter and, 211–221 polyaromatic hydrocarbons (PAH), 211 proinflammatory signaling and, 211–220 Particle Toxicology quinone toxicity, 103 cell membrane interactions adhesive interactions, 153–154 dynamics of, 153–154 endocytosis uptake, 152 mechanisms of, 152–154 membrane stability, 153–154 passive uptake, 152–153 pores transport, 152 thermodynamics, 153 thermodynamics fluid-liquid interface, 153 vapor-liquid interface, 153 characterization, 304 clearance airways, 60–61 ICRP model of, 59–64 lung disease patients, 63 periphery, 61–62 lymph nodes, 62–63 rodent lungs and, 354–364 ultrafine particles, 63 composition, 50 density, 50–51 deposition, 53–57 children, 56 mechanisms of, 54–55 modeling of, 54–55 patients, 55–56 transformation during inhalation, 53–54 dosimetry, 47–69 clearance, 57–64 man and animal, 53 particle parameters, 49–53 regional particle deposition, 53–57 retention, 57–64 secondary target organs, 64–69 secondary target organs, interest in, 64–69 total particle deposition, 53–57 effect on cardiovascular system, 259–260 immune system, 245–252 effects, susceptibility factors, 276–281 age, 279 genetic background, 276–279 other than genetic, 279–282 pre-existing disease, 279 socioeconomic status, 279 susceptibility to, 275–282 epithelium, biochemical reaction to, 58–59 genotoxic effects, 285–294 apoptosis, 293–294 cell cycle arrest, 293–294 DNA damage repair, 292–294 investigations, 286–288 studies In Vitro, 287 In Vivo, 288 heterogeneity, 50 homogeneity, 50 0921—INDEX —16/11/2006—15:52—RATHNAS—15570—XML MODEL C – pp 425–434 Index immune system allergic responses, 249–250 pathogens, 246–248 toll like receptors, 248–249 induced activation, Nuclear factor-kB and, 129 apoptosis, 130 inflammation epithelial cells, 185–187 modeling of, macrophages, epithelial cells, 191 oxidation reactions, air-lung interface and, 109–110 oxidative stress, evidence from animal studies, 106–107 toxicity, 105–106 inflammation and disease, 183–185 interaction, membranes and, 139–154 macrophages epithelial cells, 189–191 signaling mechanisms, effects of, 187–189 mediated cellular RNS generation, 127–128 ROS generation, 124–126 extracellular oxidative stress, 89–110 nuclear factor-kB, 128–130 parameters, 49–53 composition, 50 density, 50–51 exposure-dose-response paradigm, 51–53 heterogeneity, 50 homogeneity, 50 properties, 51 shape, 50 size, 49–50 toxicological aspects, 51 particulate exposure to 131–132 proinflammatory effects of, 183–191 properties, 51 retention, rodent lungs and, 354–364 risk assessment, genotoxicity, 291–292 shape, 50 particle toxicity and, 301–302 size, 49–50 particle toxicity and, 300–301 technology, ultrafine particulate matter (PM), 7–8 testing, genotoxic effects and, 286 toxicity biologically effective dose and, 418 factors affecting, 300–303 biopersistence, 303 free radicals, 303 shape, 301–302 size, 300–301 transition metals, 302 toxicological testing, approaches to, 299–312 toxicology, 1–34 asbestos, ambient particles, 5–7 classical, 415 coal mine dust, ambient particles, 5–7 defining, 414 dose, 416–420 431 dosimetry model, contribution to, 379–382 exposure, 415–416 blood, 416 brain, 416 entry portal, 415 historical development, 1–2 quartz, role of, 4–4 research, asbestos, 2–4 research, coal, 2–4 transformation in epithelial lung lining fluid, 57–58 translocated, 266–268 types, pulmonary toxicity testing and, 320 ultrafine, 63–69 Particulate air pollutants ozone and, 81–84 small airway remodeling, 75–85 antioxidant defenses and, 131–132 Particulate matter (PM), associated metals, human brain pathology and, 343–345 organics, 212–220 environmental, 260–268 health effects, oxidative stress and, 90–91 injury caused by, oxidative stress, 172–175 mechanism of action, immune system and, 250–252 metal exposure and, 161–163 oxidative stress, 90–91, 172–175 small airway remodeling and, 78–81 toxicity, determinants of, 104–105 toxicology studies, heart rate regulation, 265–266 ultrafine, 7–8 Particulates activation by, cell-signaling pathways and, 200–202 cell-signaling pathways, 197–204 signaling pathways, 200–202 Pathogenesis Alzheimer’s Disease, 332–333 COX2, 334 Pathogenic particles airborne rock dusts, 23–26 chain silicates, 16 mineralogy of, 13–34 minerals, health issues, 15 non silicates, 21–23 orthosilicates, 14, 16 ringsilicates, 14, 16 rock quarrying, 23–26 rural, 26–34 sheet silicates, 17–19 structure, 13–34 technogenic, 26–34 tectosilicates, 19–21 urban, 26–34 Pathogens, immune system and, 246–248 Patients particle deposition, 55–56 Phagocytic cells, 148 Plaque stability, environmental particulate matter and, 262–263 Platelets, 308 effects of translocated particles, 267 0921—INDEX —16/11/2006—15:52—RATHNAS—15570—XML MODEL C – pp 425–434 432 PM See particulate matter Polyaromatic hydrocarbons (PAH), 211 diesel exhaust particles (DEP), 211 Polycyclic aromatic hydrocarbons (PAHs) induced oxidative stress, 103–104 Polymer carriers, 398–399 Pores transport, 152 Pre-existing disease, particle effects susceptibility factors and, 279 Primary genotoxicity, particle risk assessment and, 291–292 Proinflammatory signaling, particle-associated organics, 211–221 Properties, particle, 51 Pulmonary disease, metal exposures and, 162–163 histopathological evaluations, 325 inflammation, 262, 323 toxicity, testing models, 317–329 biossay bridging studies, 318 methods, 319–321 animals, 320 bronchoalveolar lavage, 321 general experimental design, 319 lung cell proliferation, 320–321 lung histopathology studies, 321 particle types, 320 statistical methods, 321 results, 321–325 bronchoalveolar lavage (BAL) fluid, 323–325 lung cell proliferation, 321–323 lung weights, 321 testing models, TiO2 particulate formulation, 317–329 Q Quantum dots, 391–392 nanoparticle hazards and risks, 403 Quarrying, pathogenic particles and, 23–26 Quartz, particle toxicology and, role of, 4–4 Quinone toxicity, 103 R Rat airways, ultrafine particles and, retention in, 63–64 Reactive nitrogen species, 163–164 Reactive oxygen species (ROS) cellular, sources of, 120 generation, 104 cellular, 127 non-cellular particle mediated, 120–124 asbestos, 122–123 coal dust, 122 other particles, 123–124 silica, 120–122 metals and, 163–164 other particles residual oil fly ash (ROFA), 123 welding, 123–124 Particle Toxicology wood smoke, 124 particle-mediated cellular, 124–126 asbestos, 125–126 coal dust, 125 other particles, 126 silica, 124–125 regulation, nuclear factor-kB and, 128–130 Red blood cells, 148 nonphagoctic cells, 148 Redox active metals chromium (Cr), 102 copper (Cu), 100–101 iron (Fe), 98 manganese (Mg), 101 nickel, 101–102 oxidative stress induction of, 98 vanadium, 101 Regional particle deposition, 53–57 Residual oil fly ash (ROFA), ROS generation and, 123 Respiratory tract, toll like receptions and, 248–249 Response, animal studies and, 310 Retention particles and, 57–64 ultrafine particles mouse airways, 63–64 in rat airways, 63–64 Ringsilicates, 14, 16 Risk assessment, human lung dosimetry model and, 375–379 RNS regulation, nuclear factor-kB and, 128–130 Rock dusts 23–26 Rock quarrying, pathogenic particles and, 23–26 Rodent lungs, particle retention and clearance alveolar surface, 356–358 interstitium, 358–359 lymphatic level, 359 mathematical description, 356–359 model, 354–364 compartments, 355–356 formulation, 356–359 parameters, 362–363 structure, 354–355 ROFA See residual oil fly ash ROS cellular, sources of, 120 ROS See reactive oxygen species RTLF antioxidants, 109 Rural pathogenic particles, 26–34 S Secondary genotoxicity, particle risk assessment and, 291–292 secondary target organs particle dosimetry and, 64–69 ultrafine particles and translocation into, 65–66 Shape, particle, 50 particle toxicity and, 301–302 Sheet silicates, 17–19 Signaling effects copper, 165–166 0921—INDEX —16/11/2006—15:52—RATHNAS—15570—XML MODEL C – pp 425–434 Index iron, 166–168 nickel, 168–169 vanadium, 169–170 zinc, 170–172 pathways activator protein-1, 200–202 Fos/Jun family members, 200–202 mitogen-activated protein kinases (MAPK), 200–202 nuclear factor-kB, 202–204 other types, 204 metal-induced, pathophysiological effects of, 164–165 oxidative stress and, 161–175 particle-associated metals and, 161–175 Silica non-cellular particle mediated ROS generation and, 120–122 particle-mediated cellular RNS generation and, 127–128 ROS generation and, 124–125 Silicates chain, 16 sheet, 17–19 Size, particle, 49–50 toxicity and, 300–301 Small airway remodeling, 75–85 airway wall remodeling, 78–81 consequences, 84–85 consequences, clinical COPD, 84–85 epidemiology, 75–76 high-PM exposure, 76–78 particulate air pollutants, 75–85 PM studies, 78–81 Small molecular weight antioxidants, 93 Socioeconomic status, particle effects susceptibility factors and, 279 Statistical methods, pulmonary toxicity testing and, 321 Structure, pathogenic particles, 13–34 Systemic inflammation, 262 T Technogenic pathogenic particles, 26–34 Tectosilicates, 19–21 TGF-b asbestos and, 230–232 cell biology of, disease process, 232–236 controlled by TNF-a, 236–238 development of IPF, 231 molecular biology of, disease process, 232–236 Thermodynamics fluid-liquid interface, particle-cell membrane interactions and, 153 particle-cell membrane interactions and, 153 vapor-liquid interface, particle-cell membrane interactions and, 153 Thrombogenesis, environmental particulate matter and, 263–265 TiO2 particulate formulation, pulmonary toxicity testing models and, 317–329 Tissue membranes, 140–142 433 TNF-a asbestos and, 230–232 cell biology of, disease process, 232–236 development of IPF, 230 molecular biology of, disease process, 232–236 TGF-b controlled by, 236–238 Toll like receptions, respiratory tract, 248–249 receptors, immune system and, 248–249 Total particle deposition, 53–57 Toxicity In Vitro assessment, 304–309 blood, effects on, 308–309 brain, effects on, 308–309 cell proliferation, 305 signaling cascades, 306–308 stimulation, 305 cytokine measurement, 306 cytotoxicity, 305 oxidative stress measurement, 306 tests, types, 309 particle-induced, 105–106 Toxicokinetics, entry portal and, 415–416 Toxicological aspects, particles and, 51 effects, nanoparticles hazards and risks, 402–403 blood, 402 brain, 402–403 cardiovascular system, 402 paradigm, 310 testing animal studies, 309 approaches to, 299–312 In Vitro assessment, 304–309 lengths of, 310 particle characterization, 304 toxicity, 300–303 Toxicology classical, 415 inhaled particles and, 413–421 particle, 1–34 studies, environmental particulate matter and, 261 atherosclerosis, 262–263 endogenous fibrinolysis, 263–265 endothelial function, 263–265 heart rate regulation, 265–266 plaque stability, 262–263 thrombogenesis, 263–265 vascular inflammation, 262–263 Transcription factor activation, 307–308 Transferrin, 97 Transition metals, particle toxicity and, 302 Translocated particles, effects of, 266–258 blood, 266–269 endothelial cells, 267 endothelium, 266–269 platelets, 267 Translocation entry portal and, 415–416 0921—INDEX —16/11/2006—15:52—RATHNAS—15570—XML MODEL C – pp 425–434 434 ultrafine particles and, 65–66 circulation system, 65–66 secondary target organs, 65–66 Transmission electron microscopy, 144 analytical, 144 conventional, 144 Triple cell culture studies, 150–152 U Ultrafine particles, accumulation animal data, 66–68 human data, 66 chronic exposure of, long-term accumulation, 68–69 clearance of, 63 mouse airways, retention in, 63–64 rat airways, retention in, 63–64 translocation of, 65–66 circulation system, 65–66 secondary target organs, 65–66 Particle Toxicology Ultrafine particulate matter (PM), nanotechnology, 7–8 Urate, 94 Urban pathogenic particles, 26–34 V Validation, exposure-dose-response models and, 366–367 Vanadium, 101 signaling effects and, 169–170 Vapor-liquid interfaces, particle-cell membrane interactions and, 153 Vascular inflammation, environmental particulate matter and, 262–263 W Welding particulates, ROS generation and, 123–124 Wood smoke, ROS generation and, 124 Zinc (Zn), 102 signaling effects and, 170–172 0921—INDEX —16/11/2006—15:52—RATHNAS—15570—XML MODEL C – pp 425–434 Mucus 0921—Color Insert—13/11/2006—12:22—CRCQCER—XML MODEL C – pp 1–8 Sufactant proteins P P P P A PL PL L P A L P P P L PP A P LA P P P P PP P P P Oxiadtion Nitration Thiolation Altered extrzcellur redox Oxidised products LOPs Altered protein function / inactivation Organics Carbon care Blood Mucus Unmodified P P A PL PL L P A A P L PP L PA P P P Modified P Organics Carbon care Transition metals P P P P P P P P P P Epi FIGURE 5.4 Particle-RTLF interactions Inhaled particles depositing in the airways may become trapped by the layer of mucus and transported from the airways by the mucocillary elevator Those particles that are retained in the airways can either leach soluble components into the RTLF that oxidize antioxidants, lipid, and protein components of the RTLF, or absorb the oxidized or native RTLF components onto their surface These interactions therefore alter both the redox state of the RTLF, which will impact upon the underlying cells, as well as modifying the particle surface that ultimately reaches the underlying epithelium, or that is intercepted by alveolar macrophages within the extracellular compartment Antioxidants Lipids Metal binding proteins Anti-proteases anti-oxidant enzymes Blood RTLF Transition metals Alveolar macrophage FIGURE 7.4 Laser scanning microscopy micrographs of fluorescent polystyrene spheres (1, 0.2, 0.078 and 0.02 mm) taken up by macrophages in the absence or presence of cytochalasin D (cytD) F-Actin is shown in red, particles are green The xy and xz projections allow the clear differentiation between intracellular (arrows) and extracellular (arrowheads) particles Yellow open arrowheads mark the position of projections Scale bar is mm (Pictures with 1, 0.2, and 0.078 mm particles are reproduced from Geiser, M., Rothen-Rutishauser, B., Kapp, N., Schuărch, S., Kreyling, W., Schulz, H., Semmler, M., Im Hof, V., Heyder, J., and Gehr, P., Environ Health Perspect., 2005, (accepted, doi:10.1289/ehp.8006) With permission.) 0921—Color Insert—13/11/2006—12:25—CRCQCER—XML MODEL C – pp 1–8 FIGURE 7.6 Laser scanning microscopy and transmission electron microscopy images of triple co-cultures with epithelial cells, macrophages, and DCs grown on a filter insert (a, a , a 00 ) Epithelial cells are shown in yellow, macrophages (AM) in turquoise, and dendritic cells (DC) in pink Macrophages reside on the surface of the epithelial cells, whereas dendritic cells were localized at the bottom side of the insert (a) Represents xy and xz projections; yellow arrowheads mark the position of projections (a and a 00 ) are 3D reconstructions from the data set, (a ) from the upper side, (a 00 ) from the lower side (b, c, d) mm particles uptake in triple cell co-cultures Triple cell co-cultures were incubated for 24 h, fixed and stained afterwards for F-Actin (red) and CD14 (b, turquoise) or CD86 (c, turquoise) Particles (green) were found in CD14 positive (b, arrows), in epithelial cells (b, arrowhead), and in CD86 positive dendritic cells (c, arrows) Images represent xy and xz projections; yellow arrowheads mark the position of projections Transmission electron microscopy images of triple co-cultures exposed 24 h to mm particles (d) Particles (d, arrows) were found within epithelial cells (Ep), macrophages (AM), and dendritic cells (DC) (a, a , a 00 ) Scale bar is 10 mm; (b, c) scale bar is mm; (d) scale bar is mm (Images b, c and d are reproduced from Rothen-Rutishauser, B M., Kiama, S G., and Gehr, P., Am J Respir Cell Mol Biol., 32, 281–289, 2005 With permission.) 0921—Color Insert—13/11/2006—12:26—CRCQCER—XML MODEL C – pp 1–8 FIGURE 7.7 Laser scanning microscopy micrographs of fluorescent polystyrene spheres (1, 0.2, 0.078 and 0.02 mm) taken up by red blood cells Autofluorescence of the cells is shown in red, particles are green The xy and xz projections allow the clear differentiation between internalized (arrows) and extracellular (arrowheads) particles Yellow open arrowheads mark the position of the projections Scale bar is mm (Pictures with 1, 0.2, and 0.078 mm particles are reproduced from Geiser, M., Rothen-Rutishauser, B., Kapp, N., Schuărch, S., Kreyling, W., Schulz, H., Semmler, M., Im Hof, V., Heyder, J., and Gehr, P., Environ Health Perspect., 2005, (accepted, doi:10.1289/ehp.8006) With permission.) 0921—Color Insert—13/11/2006—12:28—CRCQCER—XML MODEL C – pp 1–8 FIGURE 12.2 Histopathology (a) Lung of a mouse (Bl6/129) 48 h after exposure to chrysotile asbestos The lesion (box) located at the alveolar duct (AD) bifurcation near the ends of the terminal bronchioles (TB) is hypercellular and hypertrophic, with increased extracellular matrix, macrophages (M) and interstitial cells (IN) (b) Higher magnification of lesion (X40) (c) TNF-aRKO mice fail to develop fibroproliferative lesions in response to asbestos This knockout animal exhibits a normal duct bifurcation (arrow) 48 h after asbestos exposure Photographs reproduced with permission FIGURE 12.3 TGF-b1 expression in lungs of mice 48 h after exposure to chrysotile asbestos (a) Immunohistochemistry using an antibody to TGF-b1 latent associated peptide demonstrates expression of TGF-b1 protein in epithelial cells and macrophages (b) Higher magnification from 3A Developing lesion exhibits robust staining of epithelium, macrophages and interstitial cells (X40) Photograph (a & b) courtesy of Dr Derek Pociask, Tulane University Health Science Center (c) TGF-b1 in situ hybridization (ISH) of a typical bronchiolar alveolar duct region Numerous epithelial cells and macrophages express TGF-b1 mRNA (d) Developing lesion with epithelium (arrow) and macrophages (arrow heads) positive for TGF-b1 ISH (X40) 0921—Color Insert—13/11/2006—12:28—CRCQCER—XML MODEL C – pp 1–8 COX2 / 18s rRNA (x 102 molec / fmol) (a) (d) * 4 Low High * Low High COX2 IR (% pos.) (b) COX2 IR (% pos.) COX2 / 18s rRNA (x 102 molec / fmol) FIGURE 19.3 Reactive gliosis and astrocytic proliferation in the frontal cortex white matter of healthy Mexico City dogs Glial cells and proliferating astrocytes were localized in paraffin sections of frontal cortex of Mexico City dogs by immunohistochemistry using fluorescein-labeled anti-glial fibrillary acidic protein (GFAP, green) and phycoerythrin-labeled anti-bromodeoxyuridine (BrdU, red), respectively, and examined by confocal microscopy: (a) 3-year-old male, (b) 5-year-old female, and (c) 14-year-old female Gliosis worsens with age Images represent maximum intensity projections, showing the maximum intensity of all layers along the viewing direction The inserts represent 3D reconstructions from the same data sets (Pictures were taken by Dr Barbara Rothen-Rutishauser Ph.D Institute of Anatomy, University of Bern, Bern, Switzerland.) (e) 0.3 * 0.2 0.1 0.0 Low High (c) Low High (f) FIGURE 19.4 COX2 expression in frontal cortex (a–c) and hippocampus (d–f) COX2 mRNA abundance was measured by RT-PCR and normalized for 18s rRNA levels COX2 protein was localized in sections of paraffin-embedded tissues by IHC and its abundance was measured by quantitative image analysis COX2 mRNA was significantly elevated in the high exposure group in both frontal cortex (a, p Z 0.009), and hippocampus (d, p Z 0.04) COX2 immunoreactivity (IR) was significantly elevated in the high exposure group in frontal cortex (b, p Z 0.01), but not in hippocampus (e) Means G SEMs are shown in A, B, D, and F (c) Representative COX IHC in frontal cortex from a subject in the high exposure group showing strong staining of endothelial cells in the capillaries (*), and pyramidal neurons (arrow), while other neurons were negative (arrowheads) Scale Z 20 mm (f) Representative COX IHC in dentate gyrus from a subject in the high exposure group showing COX2 positive neurons (arrowheads) and capillaries (short arrow) Scale Z 15 mm (Caldero´n-Garciduen˜as, L et al., Brain inflammation and Alzheimer’s-like pathology in individuals exposed to severe air pollution, Toxicol Pathol., 32, 650–658, 2004 With permission.) 0921—Color Insert—13/11/2006—12:29—CRCQCER—XML MODEL C – pp 1–8 * p * p (a) (b) Aβ42 IR (% pos.) 15 10 * 10 * * Low High Low High Frontal cortex Hippocampus (c) (d) (e) FIGURE 19.5 Ab42 accumulation in frontal cortex and hippocampus Ab42 was localized in sections of paraffin-embedded tissues by IHC (a) Anti-Ab42 stained pyramidal neurons (p), astrocytes (arrows) and astrocytic processes (arrowheads) around blood vessels (*) (b) In addition to accumulation in pyramidal neurons, (p) Ab42 was deposited in smooth muscle cells (arrows) in cortical arterioles (*) A dead neuron surrounded by glial cells is indicated (arrowhead) (c and d) Quantitative image analysis of Ab42 IHC showed a significant increase in Ab42 immunoreactivity (Ab42 IR) in both frontal cortex (c, * p Z 0.04) and hippocampus (d, * p Z 0.001) in the high exposure group MeansGSEMs are shown (e) Ab42 IHC of frontal cortex from a 38-year-old subject from Mexico City showing diffuse plaque-like staining with surrounding reactive astrocytes (arrows) Scale Z 20 mm (Caldero´n-Garciduen˜as, L et al., Brain inflammation and Alzheimer’slike pathology in individuals exposed to severe air pollution, Toxicol Pathol., 32, 650–658, 2004 With permission.) FIGURE 19.8 Reactive pathology and breakdown of the BBB in frontal cortex of an 11-year-old Mexico City male Paraffin embedded frontal cortex was stained with hematoxylin and eosin (a) and anti-GFAP (b and c) (a) There are numerous perivascular macrophages with hemosiderin-like granules and free RBC surrounding a blood vessel A neuron is seen in the lower left corner (b) Same 11-year-old child showing reactive gliosis in subcortical frontal white matter (GFAP) (c) A 17-year-old Mexico City male with reactive astrocytes around cortical frontal blood vessels The vessel is surrounded by macrophages loaded with hemosiderin-like pigment (GFAP) Leaking blood vessels are indirect evidence of a breakdown of the BBB 0921—Color Insert—13/11/2006—12:30—CRCQCER—XML MODEL C – pp 1–8 Blood vessel Neovascular endothelum Red blood cell Drug Irradation activates nanoparticles Tumour cell Normal cell Cytotoxic payload released into targeted cancer cell, leading to cell death 0,3-50 μm FIGURE 21.3 Multi-component targeting strategies using nanoparticles in treating cancer Nanoparticles extravasate into the tumor stroma through the fenestrations of the angiogenic vasculature, demonstrating targeting by enhanced permeation and retention The particles carry multiple antibodies, which further target them to epitopes on cancer cells, and direct antitumour action Nanoparticles are activated and release their cytotoxic action when irradiated by external energy Not shown: nanoparticles might preferentially adhere to cancer neovasculature and cause it to collapse, providing anti-angiogenic therapy The red blood cells are not shown to scale; the volume occupied by a red blood cell would suffice to host 1–10 million nanoparticles of 10 nm diameter (Reproduced from Ferrari, M., Nat Rev., 5, 161–171, 2005 With permission.) Inductive "Drug release" 37° C Drug >40° C FIGURE 21.5 Graph illustrating a contactless controllable drug carrying system based on thermosensitive magnetic nano- and micro particles The insert shows the application of the system with Rhodamine B encapsulated beads that is released after heating up to 458C By encapsulating ferro (i)magnetic colloids into the polymer matrix and exposing these magnetic beads to an external high frequency magnetic field (induction coil, magnetic amplitude 10–50 kA/m, 0.3–0.5 MHz), the subsequent shrink process can be remotely induced 0921—Color Insert—13/11/2006—12:32—CRCQCER—XML MODEL C – pp 1–8