The Toxicology of Nanoparticles Rodger Duffin ELEGI Laboratory, QMRI Edinburgh University Edinburgh Scotland
Nanoparticle toxicology: the knowledge gap between accidental versus engineered nanoparticles Nanoparticles Source Exposure Toxicology Accidental from combustion Road vehicles, Fossil fuel Cooking e.g. diesel Low exposure Everyone +++++ Manufactured (1) Bulk nanoparticles in industry e.g. carbon black, TiO2 High exposure Workers ++++ Manufactured (2) Medical nanoparticles High blood exposure - pre-existing disease ++ Manufactured (3) Engineered nanoparticles in the Nanotechnology industry e.g. buckyballs, nanotubes High exposure Workers then Low exposure everyone +/-
Systems that are targets for toxicity of airborne NPs brain Particles Nanoparticles Circulation (endothelium) Lung Inflammation Liver/ spleen Thrombogenesis Atheromatous plaques Autonomic nervous system? Cardiovascular deaths, hospitalisations COPD, asthma, lung cancer Based on assumption that the effects of PM are driven by NP and on experimental data with a few model NP
Where do nanoparticles go when they are breathed in?
Particles in the centri-acinar region of the lung after 3 months breathing titanium dioxide
Nanoparticles may redistribute from the respiratory tract to the brain and blood..
Translocation of inhaled ultrafine particles to the brain 1.5 μg C 13 /gram organ 1.0 Lung 0.5 Olfactory 0.0-1 0 1 2 3 4 5 6 7 Days after Exposure Cerebrum Cerebellum G. Oberdörster, Z.Sharp, V. Atudorei, A. Elder, R. Gelein, W. Kreyling, C. Cox Translocation of inhaled ultrafine particles to the brain Inhalation Toxicology in Press
What effects do nanoparticles have in the lungs
Nanoparticles cause more inflammation in BAL than the same mass of fine respirable particles composed of the same material; instillation of 125mg g into rats - lavaged 18-24 hours later Fine nanoparticle PMN (millions ±SEM) 4 3 2 1 Carbon Black 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Titanium dioxide Polystyrene latex
A range of fine and nanoparticle-sized low toxicity, low solubility particles cause inflammation in relation to surface area dose, not mass dose Mean PMN in lavage (millions) Dose expressed as mass instilled 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 0 200 400 600 800 1000 1200 Mass instilled (μg) 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 Dose expressed as surface area instilled 0.0 200.0 400.0 600.0 800.0 1000.0 Surface area instilled (cm2) Duffin R, Clouter A, Brown DM, C. L. Tran, MacNee W, Stone V, and Donaldson K. 2002. The importance of surface area and specific reactivity in the acute pulmonary inflammatory response to particles. Ann Occup.Hyg 46 Suppl 1:242-245.
Oxidative activity of fine (Fine CB) and nanoparticle carbon black (NPCB) after 1000 seconds using Dichlorofluorescein Nanoparticle 600 500 NPCB 400 100nm 100nm Fine Fluorescence 300 intensity 200 100 Fine CB 0 0 10 20 30 40 50 60 70-100 Particle dose (μg/ml) Wilson, M. R., J. H. Lightbody, K. Donaldson, J. Sales, and V. Stone. 2002. Interactions between ultrafine particles and transition metals in vivo and in vitro. Toxicol.Appl.Pharmacol. 184:172-179.
Hypothetical mechanisms of inflammation and oxidative stress caused by different nanoparticles Fuel combustion Different nanoparticles cause oxidative stress because of different properties Organics Diesel Surfaces Carbon black Diesel Free radicals Metals Diesel Welding fume Oxidative stress Inflammation? Engineered nanoparticles
Inhaled nanoparticles and the cardiovascular system
PM 10 increase and acute effects % Increase 4 3 2 Mortality Hospitalisation and related Symptoms 1 The nanoparticles in PM10 are probably responsible Total Resp Cardiovascular All resp. COPD Pneumonia Asthma Cardiovascular Upper resp Lower resp Asthma Cough Percentage acute change in any health end-point for a 10μg/m 3 increase in PM 10 From Pope 2000 (summarised from over 100 studies)
Linking pulmonary inflammation to systemic cardiovascular effects Particles/PM 10 Inflammation Airways inflammation Asthma, COPD exacerbation Direct effect of bloodborne particles Atherogenic plaque formation is an inflammatory process Coronary artery disease worsening Deaths, hospitalisation
Engineered nanoparticles Designed for diverse uses within the nanotechnology industry- variable compositions and surfaces polymer zirconium gold cobalt
Engineered nanoparticles? Toxicology? A few studies suggest that they can cause cell death, inflammation and oxidative stress/ No general rules yet to let us think that learning about one type of NP tells us about another type DEFRA/ EU/global programmes/rice University. NNP SnIRC see SnIRC.org
Nanotubes Multi-walled carbon nanotubes 50μm x <100nm Asbestos
Bronchogenic carcinoma Asbestos -related- lung diseases Pleural mesothelioma Asbestosis Honeycomb lung Pleural plaque
Nanotubes What makes asbestos pathogenic? Thin, long and insoluble in the lungs Nanotubes Long up to mm! Thin - SW<5nm MW < 200nm Insoluble treated with acid to clean them
Nanoparticle toxicology: the knowledge gap between accidental versus engineered nanoparticles Nanoparticles Source Exposure Toxicology Accidental from combustion Road vehicles, Fossil fuel Cooking e.g. diesel Low exposure Everyone +++++ Manufactured (1) Bulk nanoparticles in industry e.g. carbon black, TiO2 High exposure Workers ++++ Manufactured (2) Medical nanoparticles High blood exposure - pre-existing disease ++ Manufactured (3) Engineered nanoparticles in the Nanotechnology industry e.g. buckyballs, nanotubes High exposure Workers then Low exposure everyone +/-