Nanomaterials: Potential impact on human health

1. Nanomaterials: Potential impact on human health Paul J.A. Borm Paris- OECD- june 7th 2005

2. Nanoparticles-already a bulk market All Various Doubling from 493 € to 900 Mi in 2005 Biggest increase SiO2 expected Metals Al2O3 TiO2 SiO2 0 200 400 600 800 1000 Millions USD

3. Estimated global Production rates for Nanomaterials

4. Life Sciences and Nanomaterials • Imaging and microscopy, contrast fluids • Diagnostics and analysis (research) • Production of bio-active compounds (Lab-on-a-Chip) • Transport and dosing of drugs. • Intervention in biological processes (cell growth). • Nutrition (bioavailability, stability, optics). • Cosmetics (UV-filter). • Sensors ( MEMS)- nanorobots • Biomolecules for ICT (DNA computing). Nanoparticles and nanotubes are important parts in this toolbox

5. Engineered NP Porous Polymer Shrinkage Magnetite Inductive Heating 200-10000 nm Drug Release Drug in Matrix For inductive drug release

6. Intravenous delivery of engineered NP Needs to study a series of questions: • what happens to the particles • after release of drugs and coatings? • Is the surface active to • bind endogenous proteins? • Are NP being degraded, excreted • and/or cumulated?

7. Intentionally produced NP • already on the market • Newly engineered • Unintentionally produced NP • Combustion • Nucleation New products, applications High added value Negligible exposure (CNT, CB) Low risk No added value, extra cost Considerable health risks

8. What are nanoparticles? to a toxicologist

9. Particles in traditional dusty trades Nanoparticles 0.01 0.1 1 10mm 10 100 1000 10,000nm

10. Smaller size means different interactions and distribution Cilia 0.25µm diameter . 1.0µm 0.1µm 10µm 1 µm 0.1µm . . N Mit Bronchial epithelium

11. Protein binding by NP may have different consequences Borm and Kreyling (2004) J. Nanotech & NanoSci

12. Nanosize has physical implications • High Surface/volume ratio: • Suitable for catalysis, • More soluble. • More particles at similar mass. • Not subject to gravity Nanosize has implications for surface reactivity and chemistry • Size does not allow stoichiometry, • Cluster Irregularities. • quantum effects • Electron holes, reactive surface TiO2 TiO2 Ti0.99O1.95

13. Toxicological hazards of Nanoparticleswhat do we know? Have an active and large surface that can interact with many targets in the body Bad recognition by our immune system and even Enhance response to antigens Can cause acute inflammation with secondary effects such As cancer. Combustion nanoparticles cause worsening of heart disease, atherosclerosis and asthma. Are in the size of proteins and can interfere with normal cellular signaling pathways.

14. However: Most of the evidence for human effects is generated using unintentionally produced combustion Nanoparticles. Effects of manufactured Nanoparticles have mainly been studied with a small set of particles already on the market for decades (carbon black, TiO2, FexOy) Little data on occupational exposure to manufactured Nanoparticles. Available data suggest negligible Inhalation exposure (= background).

15. A Bermuda Triangle Combustion NP Epidemiology Toxicology ? Bulk industrial NP Engineered NP ?

16. Scenario’s to consider for testing and regulation of NP • Differences with fine particles merely quantitative (depends on effect) • Important qualitative differences in toxicity • Regulation driven by application. • Find means to extrapolate findings and build conceptual understanding • Invest in studies on environmental distribution, accumulation and effects.

17. Summary of inhalation (o) and instillation studies (●) With fine and ultrafine particles 0.2-0.3 m2/rat Ad 1: The carcinogenic response in the rat is driven by surface dose. This means that regulation of all particles could be done using A surface dose concept. Borm et al (2004) Int J cancer

18. Ad2: qualitative differences: Uptake of NP in the brain Activation of inflammatory Cascade in brain Caldwell et al, 2005 Relation to Alzheimer? Calderon-Garciduenas, et al, 2004 Relation to systemic effects such as heart rate, blood pressure changes (Brook et al, 2002; Lippman et al, 2005) ? Oberdorster et al, 2004 Carbon, Au, MnO

19. Hazard x exposure = Risk

20. What do we need to know about Nanomaterials? • Toxicity data in relevant models • Uptake and distribution • Measurement and Detection methods • Worker Protection and Industrial Hygiene • Environmental distribution and effects

21. How can we achieve this? • Bridging studies • Communication and exchange of data between area’s of application • Communication between disciplines • Develop and validate toxicicological testing protocols for nanoparticles

22. State of the art: Little exchange between companies or between companies and Toxicological research institutes. Producers and Users of Nanomaterials Research Institutes

23. Needed: networks to enable communication and data exchange between nanoscience and Toxicology.

24. NANOTECHNOLOGY Hazardous area HYPE Science Fiction

25. Current and recent initiatives on sustainable nanomaterials. • Meetings DG-SANCO (march 04) HSI (oct 04), Royal Society (july 04), ICON (dec 04) • EU research programs (e.g. NANOSAFE) • HESI-ILSI working groups (jan, feb 05) • ECETOC-White Paper (May 2005) and workshop (nov 05)