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The toxicology of NMP (What adverse effects might we expect from exposure to NMP)

The toxicology of NMP (What adverse effects might we expect from exposure to NMP). Professor Ken Donaldson ELEGI Colt Laboratory Centre for Inflammation Research, Edinburgh University, Medical School, Edinburgh , Scotland. What diseases do particle cause or worsen?.

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The toxicology of NMP (What adverse effects might we expect from exposure to NMP)

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  1. The toxicology of NMP (What adverse effects might we expect from exposure to NMP) Professor Ken Donaldson ELEGI Colt Laboratory Centre for Inflammation Research, Edinburgh University, Medical School, Edinburgh , Scotland

  2. What diseases do particle cause or worsen? Airways – white bronchial tubes Parenchyma – pink alveoli Pleura – outside surface lung surface and chest wall surface Cardiovascular system – blood vessels and heart

  3. If NMP have effects based on the occupational paradigm? Exposure – High (mg/m3 analogous to workplace) –peaks during shifts , zero at other times Typical particles - Silica, asbestos, welding fume, nuisance dusts Exposed population - Predominantly healthy males <65 years old – no susceptibles due to healthy worker effect Typical responses - Pneumoconiosis, COPD, cancer, asthma

  4. If NMP had effects based on the environmental (PM10) paradigm? Exposure - Low (tens of ug/m3 as per urban environment) constant with peaks Exposure to - urban PM10 containing combustion-derived nanoparticles Exposed population - Everyone but acute effects are only seen in susceptible and aged, ill populations with pre-existing oxidative stress and inflammation = susceptibility Typical responses – In susceptible populations - Exacerbations of COPD/asthma, exacerbations of cardiovascular disease, cancer In normals – very little except likely contribution to chronic disease

  5. Factors contributing to toxic response to particles in the lungs Generally low for NMP but exceptions e.g. quartz, metals Intrinsic toxicity of the material i.e. hazard For NMP could be chronic or brief Variable but low for NMP?? Length of exposure Exposure concentration Contribute to dose

  6. That fraction of the total dose that actually delivers toxicity General scheme for what happens when harmful particles deposit in the lungs

  7. Quartz Area of reactive (unblocked or unpassivated) surface Respirable mass Asbestos Biopersistent fibres longer than ~ 20mm Fibres longer then 5mm, >3mm diameter and Aspect Ratio>3 PM10 Organics/metals/surfaces Mass by PM10 convention Welding fume (NP) Soluble transition metals Respirable mass Diesel soot Organics/metals/surfaces Contained in PM10 Carbon black (NP) Surface area Nuisance dust standard of respirable mass We are not good at measuring the BED in our metrics Particle Biologically effective dose Current metric

  8. Oxidative adducts of DNA Stimulation of fibroblast growth and ECM secretion Airways inflammation Airways inflammation/ adjuvant effect Asthma COPD, Cancer Pneumoconiosis, The central hypothetical role of inflammation in the occupational paradigm Occupational particles Inflammation

  9. Superimposed on Airways inflammation of Asthma, COPD Atheromatous plaque formation is an inflammatory process Endothelial dysfunction Increased inflammatory activity in plaques Exacerbation Hospitalisation Death (COPD) Plaque rupture Pro-thrombotic state thrombosis Myocardial infarction Mortality The central hypothetical role of inflammation in the environmental paradigm PM10 Inflammation

  10. The ubiquitous role of oxidative stress in particle effects

  11. Toxicology testing approaches • Approach depends on aim - screening, mechanisms, regulatory • NMP studies will be screening and mechanisms • Characterising the physico-chemistry – surface area, size etc, metals – aiming towards a structure:activity paradigm? • In vitro cell-free – e,g detecting free radical –generation, complement activation etc • In vitro cells – huge number of endpoints but should be pathophysiologically-relevant i.e. tells us about something we already understand as having a role in disease e.g. ability to cause a pro-inflammatory effect • In vivo- particle are instilled into or inhaled by rodents - lungs are then examined for effects (huge number of potential endpoints)

  12. However, when plotted alongside particles of known toxicity, the ash was less than coalmine dust and quartz (see vertical axes). Rats inhaled ash along with a control dust TiO2 that is low in toxicity – at the same mass burden the ash was more inflammogenic as shown by more PMN in the lavage Example of an inhalation study with a NMP – Montserrat ash The importance of using controls to contextualise the response

  13. Summing up- toxicology of NMP • Particle toxicology is a mature science- we know what to do …but… • Does NMP as a grouping make sense? • Coalmine dust, quartz and asbestos are NMP but they are looked on as occupational diseases • Do we have a disease from environmental exposures to NMP? • How many people are at risk – in UK?, in Europe? In the world? • What is the documented burden of ill-health due to environmental exposures to NMP? • Only if there is a recognition that environmental exposures to NMP constitute a substantial health risk will funding be diverted from other known substantial heath risks • …….Discuss

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