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

2. 02004006008001000 SiO 2 TiO 2 Al 2 O 3 Metals Various All Nanoparticles-already a bulk market Doubling from 493 € to 900 Mi in 2005 Biggest increase SiO 2 expected 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. Porous Polymer Magnetite Inductive Heating Engineered NP Drug in Matrix 200-10000 nm Drug Release Shrinkage 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. 0.01 0.1 1 10  m Nanoparticles Particles in traditional dusty trades 10 100 100010,000nm

10. Smaller size means different interactions and distribution  10µm 1 µm 0.1µm. .0µm 0.1µm Cilia 0.25µm diameter Bronchial epithelium N Mit

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

12. High Surface/volume ratio: Suitable for catalysis, More soluble. More particles at similar mass. Not subject to gravity Nanosize has physical implications Nanosize has implications for surface reactivity and chemistry TiO 2 TiO 2 Ti 0.99 O 1.95 Size does not allow stoichiometry, Cluster Irregularities. quantum effects Electron holes, reactive surface

13. Toxicological hazards of Nanoparticles what 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 unintentionally 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, TiO 2, Fe x O y ) Little data on occupational exposure to manufactured Nanoparticles. Available data suggest negligible Inhalation exposure (= background).

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

16. Scenario’s to consider for testing and regulation of NP 1.Differences with fine particles merely quantitative (depends on effect) 2.Important qualitative differences in toxicity 3.Regulation driven by application. 4.Find means to extrapolate findings and build conceptual understanding 5.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 m 2 /rat Borm et al (2004) Int J cancer 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. Ad 1:

18. Ad2: qualitative differences: Uptake of NP in the brain Oberdorster et al, 2004 Carbon, Au, MnO 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) ?

19. Hazard = Risk x exposure

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

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

24. NANOTECHNOLOGY HYPE Science Fiction Hazardous area

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)