Particles: Nanoparticles, Fullerenes and Carbon Nano Tubes

1. Particles:Nanoparticles, Fullerenes and Carbon Nano Tubes Margarethe Hofmann MAT SEARCH, Pully President SVMT

2. Topics of the Workshop • « Environmental Aspects » – latest research activities • « Material Safety Standards » - required for safety of producers and consumers • nearly or insoluble particles

3. Properties of Nanoparticles (< 100 nm) • Chemical formation processes: • Polymerization (Emulsion) • Precipitation, Crystallization • Growth by coagulation, shrinkage • Aerosol formation processes: • Heterogeneous + homogeneous nucleation • Combustion, photochemical reactions; etc. • Growth by coagulation, shrinkage After: Wolfgang G. Kreyling, GSF – Forschungszentrum für Umwelt und Gesundheit, München

4. Current and Emerging Applications for Nanoparticles

5. Investors, Industrials, Scientists • U.S. venture capital firm Draper Fisher Jurvetson: „It would not invest in a nanotech business unless the products had already been proven safe“. • Germany-based Munich Re Group: „Up to now, losses involving dangerous products were on a relatively manageable scale, whereas, taken to extremes, nanotechnology products can even cause ecological damage which is difficult to contain” . • Patricia Pineau, a L’Oreal research adviser: “At each step of the product development – from the raw materials to the final formula – we evaluate the safety in vitro and then, only if the previous test is negative, in vivo on human volunteers” . • Ken Donaldson of the University of Edinburgh Medical School: „A new way of classifying nano-particles needs to be created, that takes more than size into account, but also the “full spectrum of toxicities“ that might arise from nanoparticles of different compositions“. http://www.smalltimes.com/document_display.cfm?document_id=7608

6. Nanotechnology: views of Scientists and Engineers Regulation Currently, dosage of particles for regulation purposes is defined by mass per unit volume, however this does not take into account particle size. Hence it is clear that agglomeration, particle size and surface reactivity will now have to be taken into account when deciding the regulation of nanoparticles. The point was made however that there are many types of nanoparticles and that they should not be treated as a general case when deciding regulation. To resolve this issue, further toxicological studies must be performed in order to effectively inform regulators. The point was also made that regulations may differ between locales e.g. in the USA sun creams are categorised as drugs for regulation, while in the UK they are regulated as cosmetics. Report of a workshop held as part of the Nanotechnology study (http://www.nanotec.org.uk/)

7. Summary • Insoluble or nearly insoluble nano- or ultrafine particles • Research for developing standards together with industry • Example 3R Foundation – reducing animal experiments

8. Summary • Define the hot spots of danger coming from nanoparticles – risk assessment • Road map – amount of particles on the market, exposure, uptake • Road map for particles in research – nanotubes, CdSe etc. • Develop models (in-vitro and in-vivo) for interaction with the human body • toxicity, biodistribution, allergies

9. Summary • Life Cycle assessment for chemicals adapted to nanoparticles • Define component by nanoparticle relevant features

10. Summary • Further detailed recommendation • Need more information from responsibles in industry and related researchers, toxicologists, risk assessment • Workshop SVMT-SATW-TOP NANO 21 on « Safety aspects of nanoparticles » November 2004

11. Particles • Ultrafine- or nanoparticles, colloids, aerosols are smaller than 100 nm. • In comparison with their source materials, such nanoparticles have different optical, electrical, mechanical, and chemical properties. • They are not only unique to this field of hi-tech; they are present in our everyday lives and at various conventional workplaces. After BIA-Report 7/2003

12. Nanoparticle Application 2003 • Established commercial nanoparticle applications • Tires, Other Rubber Products • Catalytic Converters • Photographic Supplies • Inks and Pigments • Coatings and Adhesives • Ultrafine Polishing Compounds • UV Absorbers for Sun Screens • Synthetic Bone • Ferrofluids • Optical Fiber Cladding • Launch-Phase Nanoparticle Applications • Fabrics and Fabric Treatments • Filtration Systems • Dental Products • Surface Disinfectants • Diesel Fuel Additives • Fuel and Explosive Additives • Hazardous Chemical Neutralizers • Developmental Nanoparticle Applications • Recharg. Lithium Ion Batteries • Antioxidants • Dental-Care Products http://www.mindbranch.com

13. Nanotube Application 2003 • Commercial Nanotube Applications • Automotive Components • Electronics Production/Clean-Room Equipment • Scanning Microscope Tips • Sports Equipment • Launch-Phase Nanotube Applications • Field Emission Devices • X-Ray Devices • Flat-Panel Displays • Other Field Emission Applications • Developmental Nanotube Applications • Semiconductors • Drug-Delivery Systems • Fuel Cells http://www.mindbranch.com

14. Field of Concern in the Environment • Behaviour and influence of nanoparticles in the biota? • Nanoparticles may influence the biosphere • Structural transition by liquids like water (biogenic nanoparticles) • Chemical/physical transition by recycling (combustion) • Behaviour and influence of nanoparticles in the food chain? • Filter-feeding organisms such as plankton regulate the intake and distribution of these nanoparticles? • Further uptake by fishes, birds, large animals • Biodistribution of nanoparticles in the body? • Lung, liver, blood, etc. • Manipulation of of cells and/or genes by nanoparticles? • Transfection • Formation/initiation of tumour cells • Misfunction of proteins after adsorption

15. Way of assimilation and incorporation • Lung • Smoking, diesel soot, tires, rubber products • Smoke and exhaust of welding, soldering, foundaries, injection molding, grinding and polishing • Nanoparticles based ceramics, quantum dots • Nanoparticles based medical products (aerosols) • Skin • Cosmetics, pharmaceutics, paintings • Intravenious, intraarticular, systemic • Drugs, diagnostic agents, food

16. Way of assimilation and incorporation • Modes of action and mechnisms • Lymphatic system • Blood system • Nervous systems • Cells - cell interaction • Uptake in the cells and the nucleus

17. Material Safety Standards • No standards exist for nanoparticles • FDA list “Generally Recognized As Safe” (GRAS) – applicable to nanosized particles? • MAK not applicable for nanoparticles? • In-vivo-solubility of nanoparticles – no method • Nanopathology ?

18. Strategy for sustainable risk assessment NP Organ of intake Genomic screening (gene array) Proteomic verification (RT-PCR) Cells, proteins, fluids, tissues Secondarytarget organ Deleterious effects (inflammation, cytotoxicity, muta- + cancerogenesis) Risk assessment Regulation Classical tests not sufficiently specific and not adequate for a comprehensive risk assessment of multiple interactions of NP with biological systems After W. G. Kreyling, GSF - Forschungszentrum für Umwelt und Gesundheit, Institut für Inhalationsbiologie, Neuherberg

19. Material Standards • Physical standards for surface roughness, subsurface properties, form (flatness, sphericity, asphericity) glass, ceramics and metals are urgently needed. • Besides those standards, made of anorganic materials, equivalent standards are very desired for nanotechnology in all kind of processes (manufacture, monitoring, measurement) of organic materials including living cells in special cases. Position paper on „The need for measurement and testing in nanotechnology“ Compiled by the High Level Expert Group on Measurement and Testing, Under the European Framework Programme for Research and Development 2002 - HLEG_nanotech_full_final_11/3/02

20. Analytic Aspects • Analytics (measurement and test engineering) – air, surface, liquid, body • Particle concentration • Particles size and form, particle agglomerates • Particle surface • charge, • coating after synthesis, within the environment • Dissolution and recombination

21. Safety Aspects Production • New technologies, new particle formulation • Production in clean rooms? • Filter? • Health aspects of employees? • Classic production routes • Learn from already existing safety standards?

22. Safety Aspects Environment • Functionalized particles • Influence on biota: internalization of particles • Influence on the biosphere • Nanoparticles in a matrix • Recycling, waste/material combustion • Pollution, smoke, dust • Reduced size and size distribution, higher internalization

23. Safety Aspects Public Health • Overall air pollution (e.g. cigarettes, diesel soot, tires, industrial contamination) • How far does nanotechnology boost danger? • Need for more epidemiologic research? • Daily life body exposure (cosmetics, paint, clothing, nutrition) • Information of customers? • Future requirements for industry? • Challenges and requirements for research (medical, basic, engineering) • Future tailored particles (e.g. in life sciences, transport, etc.) • Challenges and requirements for research (medical, basic, enginering) • Support and requirements for industry? • Information of customers?

25. Properties of Nanoparticles to be determined • Chemistry • Surface chemistry, surface charge • Combination of elements (transition metals) • Dissolution and recombination • Adsorption, desorption, catalytic activity …. • Physics • (Quantum) size and form effect • Volume - Surface properties • Transport ….. • Biology • Uptake: histospecific, cellular, subcellular (nucleus) • Blood compatibility, rheological effects …..

26. Material Safety Standards Exposure • During manufacturing + processing at the workplace • Single nanoparticle product (aerosol, colloid) • Concentration (air, skin) • Exposure periods assessable • General population + population during use + application • Multiple products at low concentrations (exhaust, cosmetics, medical products) • Undefined exposure periods and concentration

27. RISK = HAZARD + EXPOSURE (ASSESSMENT) • Too often, the ‘exposure’ part of this equation is omitted and hazard is equated with risk. This is an important oversight because there can be little risk to even hazardous materials provided there is no exposure. Thus, the exposure component of the risk equation is vital. • Example: recent toxicity studies have demonstrated that high-dose, intratracheally-instilled, single walled carbon nanotubes in the lungs of rats may produce unusual foreign-body tissue reactions. • Physiological relevance: occupational exposure assessment studies have indicated that aerosol exposure levels of carbon nanotubes in the workplace were, in this case, negligible. After David B. Warheit in Materialstoday February 2004

28. Translocation of Nanoparticles After W. G. Kreyling, GSF - Forschungszentrum für Umwelt und Gesundheit, Institut für Inhalationsbiologie, Neuherberg

29. Translocation of Nanoparticles After David B. Warheit in Materialstoday February 2004

30. Ten Toxic Warnings • 1997 - Titanium dioxide/zinc oxide nanoparticles from sunscreen are found to cause free radicals in skin cells, damaging DNA. (Oxford University and Montreal University) Dunford, Salinaro et al. • March 2002 – „… engineered nanoparticles accumulate in the organs of lab animals and are taken up by cells…“ Dr. Mark Wiesner • March 2003 - „.. studies on effects of nanotubes on the lungs of rats produced more toxic response than quartz dust.“ „Scientists from DuPont Haskell laboratory present varying but still worrying findings on nanotube toxicity. Nanotubes can be highly toxic." - Dr. Robert Hunter (NASA researcher) • March 2003 - Dr. Howard: the smaller the particle, the higher its likely toxicity and that nanoparticles have various routes into the body and across membranes such as the blood brain barrier. ETC Group • July 2003 - Nature reports on work by CBEN scientist Mason Tomson that shows buckyballs can travel unhindered through the soil. "Unpublished studies by the team show that the nanoparticles could easily be absorbed by earthworms, possibly allowing them to move up the food-chain and reach humans" - Dr. Vicki Colvin, the Center's director. http://online.sfsu.edu/~rone/Nanotech/nanobraindamage.htm

31. Ten Toxic Warnings • January 2004 - Dr. Günter Oberdörster: nanoparticles are able to move easily from the nasal passageway to the brain. • January 2004 - Nanosafety researchers from University of Leuven, Belgium in Nature: nanoparticleswill require new toxicity tests: "We consider that producers of nanomaterials have a duty to provide relevant toxicity test results for any new material, according to prevailing international guidelines on risk assessment. Peter H. M. Hoet, Abderrrahim Nemmar and Benoit Nemery, University of Belgium(14) • January 2004 - Nanotox 2004: Dr. Vyvyan Howard presents initial findings that gold nanoparticles can move across the placenta from mother to fetus. • February 2004 - Scientists at University of California, San Diego discover that cadmium selenide nanoparticles (quantum dots) can break down in the human body potentially causing cadmium poisoning. "This is probably something the [research] community doesn't want to hear." - Mike Sailor, UC San Diego.(16) • March 2004 - Dr. Eva Oberdörster: buckyballs (fullerenes) cause brain damage in juvenile fish along with changes in gene function. "Given the rapid onset of brain damage, it is important to further test and assess the risks and benefits of this new technology before use becomes even more widespread." - Dr. Eva Oberdörster. http://online.sfsu.edu/~rone/Nanotech/nanobraindamage.htm

32. Material Safety Standards Exposure to nanoparticles • Smoking, diesel soot, tires, rubber products • Smoke and exhaust of welding, soldering, foundaries, injection molding, grinding and polishing • Nanoparticles based ceramics, quantum dots • Nanoparticles based medical products (aerosols) • Cosmetics, pharmaceutics, paintings • Drugs, diagnostic agents, food