CEFIC Stakeholder Dialogue : “Enabling responsible innovations of nanotechnologies”

1. CEFIC Stakeholder Dialogue: “Enabling responsible innovations of nanotechnologies” Accelerated Innovation in Nanomanufacturing…….Research Strategies for addressing Ethical, Environmental, Health, safety and responsibilities Professor Terry Wilkins Yorkshire Forward Professor of Nanomanufacturing Innovation CEO, Nanomanufacturing Institute, University of Leeds, UK Brussels, 24 June 2008

2. Topics • Why E, H & S considerations are important • Strategies for addressing E, H &S • Latest position on Carbon Nanotubes • Ethics debate and public engagement • Concluding remarks

3. Brain Skin gut blood liver endothelium spleen heart atherogenic plaques Nanoparticles & Health N a n o p a r t i c l e s Nose Lung Professor K Donaldson, U Edinburgh

4. Research funding in Europe • Substantial interdisciplinary research is needed • Member States have responded to the challenge Eg: • UK 46 Projects (6 Env) • CH 24 Projects (2 Env) • DK 12 Projects (1 Env) • EC has developed a visionary strategic approach: • (Helped by Expert Advisory Group and Programme Committee) • Largest source of funds for collaborative research • Sought to develop and stimulate international collaborations

5. EU Investment in Nano E, H & S Research € Millions

6. A Strategy for Nanotoxicity for Research? Interdisciplinary science research skills are needed for toxicology studies of new nanomaterials: • Materials Characterisation(size, shape & chemical properties) • Data mining & QSAR • Cell Membrane penetration • DNA damage(free radical & oxidative damage) • Intra-cell interactions (Inc Mutagenicity) • Whole organ effects • Whole organism effects • Clinical studies • Environmental impact • E, H & S Monitoring tools (Sensors & High-throughput systems) Leeds research strategy

7. Leeds QSAR Nanotoxicity Research CapabilityIntegrated Data Mining Tool Box Descriptor calculation • Data Mining Toolbox • Regression • PCA and ICA • ART2 networks • Kohonen networks • K-nearest neighbours • Fuzzy c-means • Decision trees and rules • Feedforward neural networks (FFNN) • Summary statistics • Visualisation • Mixture QSAR models • Data Pre-processing • Scaling • Missing values • Outlier identification • Feature extraction • Discovery Validation • Statistical significance • Results for training and test sets • Data import • Excel • ASCII Files • Database • XML • Results Presentation • Graphs • Tables • ASCII files Professor Xue Wang, IPSE, Leeds

8. Lipid Bilayer Sensors Nanoparticle passing through lipid bilayer changes electrical properties – detected at electrodes Dr Andrew Nelson, SOMS, Leeds

9. Examples of Comet Assay Results • Strategy • Assess DNA damage in: • Lung epithelial cells • Skin epithelial cells • Gut CaCo2 cells Minimal Mild • Study • Size • Shape • Structure • (Bio)chemistry Moderate Severe Professor Alastair Hay, LIGHT, Leeds

10. supF Mutation Assay (Secondary screen for germ cell mutation risk) Human cells supF . + pSP189 Damaged DNA is replicated in human cells and mutants are screened for in E.coli mutant Professor Alastair Hay, LIGHT, Leeds

11. New approaches for occupational exposure monitoring Leeds was the first trial site for UK government Health and Safety Executive’s new equipment for monitoring nanoparticles in the atmosphere …..biggest contribution to nanoparticles in our laboratories’ atmosphere was from traffic exhausts from road outside!!!!!

12. The Challenge of Standardisation Can pragmatic approaches of the past help us? Rosalyn Yalow’s invention of radioimunnoassay stimulated an explosion of new clinical assays for diseases based on impure, degraded and poorly characterised proteins…… • ….Yet we made useful diagnoses and later through good normative research we iterated to: • Pure and fully characterised reference materials • Proper standards • International consensus on clinical ranges • Improved our diagnoses and patient management

13. Recent Nature Nanotechnology Letter Professor K Donaldson, U Edinburgh

14. A key parameter in the paradigm The Asbestos Pathogenicity Paradigm • Asbestos is harmful because the fibres it releases into the air are:- • thin, • long, • do not dissolve in the lungs Professor K Donaldson, U Edinburgh

15. Short straight Long straight Long tangled Short tangled Incomplete or frustrated phagocytosis Complete phagocytosis Long amosite CNTlong2 GOOD = cleared from lung BAD = pro-inflammatory Long Tangled Short Tangled Short NT Morphology Long Straight Mechanism for the Harmfulness of Long Straight Fibres

16. Conclusions of Poland et al’s Study • Quantitative Structure activity relationships (QSAR) control particle toxicity • The onus is on toxicologists to determine them and put them to use in models to predict toxicity without recourse to animal experimentation • The fibre QSAR is mature and predicts that any fibre longer than about 15microns, that is thin (less than 3-5 microns) and biopersistent (does not dissolve so the dose builds up) will be pathogenic • All fibres so far studied have conformed to this paradigm – asbestos, glass fibres, ceramic fibres, para-aramid fibres, MWCNTs etc • Our study confirmed the length-dependent pathogenicity of MWCNT , using a direct mesothelial exposure model. • Further research is needed to determine if inhaled long MWCNT can reach the pleural mesothelium , and what the levels of long MWCNT in workplaces are. Professor K Donaldson, U Edinburgh

17. “I value democratic procedures, but only when they give the right result” The Navigator Problem Or ? George Bush Ethics & Nanotechnology? Plato Research by Rob Naylor IDEA Applied Ethics Centre, Leeds

18. The best: • Vision • Strategy • Technologies • People & just do it! The Navigator Problem Henry The Navigator Ethics, E, H & S for NanotechnologySolving Plato’s problem? Plato

19. Conclusions • Europe has a distinguished track record, led by industry, in innovation of Safety, Health and Environment standards & procedures (E.g. HAZOP, COSHH etc)……. …….But the world moves on. There has been a healthy debate on the societal issues since 2000 and both EU industry and the regulators (REACH) are preparing: • We now need to get on with the science and deliver new knowledge • The science is complex and needs interdisciplinary research • Planned FP7 EU/US Joint Calls key for success • China (CAS) and India are keen to join in • Global collaboration makes sense • Work with industry to inform regulation (REACH & EPA) • Involve citizens every step of the way Learn from the best practice of the past to earn our ‘License to Operate’ in the future

20. INTERIM ADVICE on Wastes containing unbound Carbon Nanotubes - 19 May 2008 The hazard classification of CNTs should be similar to asbestos Unbound CNT waste should be rendered safe by exposure to 850 deg C for at least 2 seconds US NNI Reauthorisation Bill Prioritize nanoscale characterization and metrology research as the basis for understanding and addressing any risks or dangers associated with nanoparticles and nanomaterials. FDA does not have separate category yet for nano materials (Inc. CNTs) but is keeping the situation under review Stop Press