Particles:Particles:Nanoparticles, Nanoparticles, Fullerenes and Fullerenes and

Carbon Nano Tubes Carbon Nano Tubes Margarethe HofmannMargarethe HofmannMAT SEARCH, PullyMAT SEARCH, Pully

President SVMTPresident SVMT

Topics of the WorkshopTopics of the Workshop

« Environmental Aspects » – latest « Environmental Aspects » – latest research activitiesresearch activities

« Material Safety Standards » - « Material Safety Standards » - required for safety of producers and required for safety of producers and consumersconsumers

nearly or insoluble particlesnearly or insoluble particles

Properties of Nanoparticles (< 100 nm)Properties of Nanoparticles (< 100 nm)

Z i m m e r m a n n

K a r g

C y r y s

B e h r e n d t /A l l e s s a n d r i n i

S c h u l z

P e t e r s

W o l ff

S c h r a m m

M a i e r

A n d r a eW i t t m a a c k

Z i m m e r m a n n

K a r g

C y r y s

B e h r e n d t /A l l e s s a n d r i n i

S c h u l z

P e t e r s

W o l ff

S c h r a m m

M a i e r

A n d r a eW i t t m a a c k

Aerosol formation processes:

• Heterogeneous + homogeneous nucleationHeterogeneous + homogeneous nucleation

• Combustion, photochemical reactions; etc.Combustion, photochemical reactions; etc.

• Growth by coagulation, shrinkageGrowth by coagulation, shrinkage

Aerosol formation processes:

• Heterogeneous + homogeneous nucleationHeterogeneous + homogeneous nucleation

• Combustion, photochemical reactions; etc.Combustion, photochemical reactions; etc.

• Growth by coagulation, shrinkageGrowth by coagulation, shrinkage

Chemical formation processes:

• Polymerization (Emulsion)

• Precipitation, Crystallization

• Growth by coagulation, shrinkage

Chemical formation processes:

• Polymerization (Emulsion)

• Precipitation, Crystallization

• Growth by coagulation, shrinkage

After: Wolfgang G. Kreyling, GSF – Forschungszentrum für Umwelt und Gesundheit, München

Current and Emerging Applications for Nanoparticles

Investors, Industrials, Investors, Industrials, ScientistsScientists

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

Regulation Regulation

Currently, dosage of particles for regulation purposes Currently, dosage of particles for regulation purposes is defined by is defined by mass per unit volumemass per unit volume, however this , however this does not take into account particle size. Hence it is does not take into account particle size. Hence it is clear that agglomeration, particle size and surface clear that agglomeration, particle size and surface reactivity will now have to be taken into account reactivity will now have to be taken into account when deciding the regulation of nanoparticles. when deciding the regulation of nanoparticles.

The point was made however that there are many The point was made however that there are many types of nanoparticles and that they should not be types of nanoparticles and that they should not be treated as a treated as a general casegeneral case when deciding regulation. when deciding regulation. To resolve this issue, further toxicological studies To resolve this issue, further toxicological studies must be performed in order to effectively inform must be performed in order to effectively inform regulators. regulators.

The point was also made that regulations may The point was also made that regulations may differ differ between localesbetween locales e.g. in the USA sun creams are e.g. in the USA sun creams are categorised as drugs for regulation, while in the UK categorised as drugs for regulation, while in the UK they are regulated as cosmetics. they are regulated as cosmetics.

Nanotechnology: views of Scientists

and Engineers

Report of a workshop held as part of the Nanotechnology study (http://www.nanotec.org.uk/)

Insoluble or nearly insoluble nano- Insoluble or nearly insoluble nano- or ultrafine particlesor ultrafine particles

Research for developing standards Research for developing standards together with industrytogether with industry Example 3R Foundation – reducing Example 3R Foundation – reducing

animal experimentsanimal experiments

SummarySummary

SummarySummary

Define the hot spots of danger coming Define the hot spots of danger coming from nanoparticles – risk assessmentfrom nanoparticles – risk assessment Road map – amount of particles on the market, Road map – amount of particles on the market,

exposure, uptakeexposure, uptake Road map for particles in research – Road map for particles in research –

nanotubes, CdSe etc.nanotubes, CdSe etc.

Develop models (in-vitro and in-vivo) for Develop models (in-vitro and in-vivo) for interaction with the human bodyinteraction with the human body toxicity, biodistribution, allergiestoxicity, biodistribution, allergies

Life Cycle assessment for Life Cycle assessment for chemicals adapted to chemicals adapted to nanoparticlesnanoparticles Define component by nanoparticle Define component by nanoparticle

relevant featuresrelevant features

SummarySummary

SummarySummary

Further detailed recommendationFurther detailed recommendation Need more information from Need more information from

responsibles in industry and related responsibles in industry and related researchers, toxicologists, risk researchers, toxicologists, risk assessmentassessment

Workshop SVMT-SATW-TOP NANO Workshop SVMT-SATW-TOP NANO 21 on « Safety aspects of 21 on « Safety aspects of nanoparticles » nanoparticles » November 2004November 2004

ParticlesParticles

Ultrafine- or nanoparticles, colloids, Ultrafine- or nanoparticles, colloids, aerosolsaerosols are smaller than 100 nm. are smaller than 100 nm.

In comparison with their source In comparison with their source materials, such nanoparticles have materials, such nanoparticles have different optical, electrical, mechanical, different optical, electrical, mechanical, and chemical properties. and chemical properties.

They are not only unique to this field of They are not only unique to this field of hi-tech; they are present in our everyday hi-tech; they are present in our everyday lives and at various conventional lives and at various conventional workplaces. workplaces.

After BIA-Report 7/2003

Nanoparticle Application Nanoparticle Application 20032003

Established commercial Established commercial nanoparticle applicationsnanoparticle 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 Launch-Phase Nanoparticle ApplicationsNanoparticle Applications Fabrics and Fabric Treatments Filtration Systems Dental Products Surface Disinfectants Diesel Fuel Additives Fuel and Explosive Additives Hazardous Chemical

Neutralizers Developmental Developmental

Nanoparticle Applications Nanoparticle Applications Recharg. Lithium Ion Batteries Antioxidants Dental-Care Products

http://www.mindbranch.com

Nanotube Application Nanotube Application 20032003

Commercial Nanotube ApplicationsCommercial Nanotube Applications Automotive Components Electronics Production/Clean-Room Equipment Scanning Microscope Tips Sports Equipment

Launch-Phase Nanotube ApplicationsLaunch-Phase Nanotube Applications Field Emission Devices X-Ray Devices Flat-Panel Displays Other Field Emission Applications

Developmental Nanotube ApplicationsDevelopmental Nanotube Applications Semiconductors Drug-Delivery Systems Fuel Cells

http://www.mindbranch.com

Field of Concern in the Field of Concern in the EnvironmentEnvironment

Behaviour and influence of nanoparticles in the biota?Behaviour and influence of nanoparticles in the biota? Nanoparticles may influence the biosphereNanoparticles may influence the biosphere Structural transition by liquids like water (biogenic nanoparticles)Structural transition by liquids like water (biogenic nanoparticles) Chemical/physical transition by recycling (combustion)Chemical/physical transition by recycling (combustion)

Behaviour and influence of nanoparticles in the food Behaviour and influence of nanoparticles in the food chain? chain? Filter-feeding organisms such as plankton regulate the intake and Filter-feeding organisms such as plankton regulate the intake and

distribution of these nanoparticles? distribution of these nanoparticles? Further uptake by fishes, birds, large animalsFurther uptake by fishes, birds, large animals

Biodistribution of nanoparticles in the body?Biodistribution of nanoparticles in the body? Lung, liver, blood, etc. Lung, liver, blood, etc.

Manipulation of of cells and/or genes by nanoparticles?Manipulation of of cells and/or genes by nanoparticles? TransfectionTransfection Formation/initiation of tumour cellsFormation/initiation of tumour cells Misfunction of proteins after adsorptionMisfunction of proteins after adsorption

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

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

Way of assimilation and incorporation

Material Safety Material Safety StandardsStandards

No standards exist for nanoparticlesNo 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 ?

Strategy for sustainable risk assessment

Classical tests not sufficiently specific and not adequate for a comprehensive risk assessment of multiple interactions of NP with biological systems

Deleterious effects (inflammation,

cytotoxicity, muta- + cancerogenesis)

Genomic screening

(gene array)

Proteomic verification

(RT-PCR)Secondary

target organ Risk

assessment

Regulation

Organ of intake

Cells, proteins, fluids, tissues

NP

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

Material StandardsMaterial 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

Analytic AspectsAnalytic Aspects AnalyticsAnalytics (measurement and test (measurement and test

engineering) 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

Safety AspectsSafety Aspects

Production Production New technologies, new particle New technologies, new particle

formulationformulation Production in clean rooms? Filter? Health aspects of employees?

Classic production routesClassic production routes Learn from already existing safety

standards?

Safety AspectsSafety Aspects

EnvironmentEnvironment Functionalized particles Functionalized particles

Influence on biota: internalization of particles

Influence on the biosphere

Nanoparticles in a matrixNanoparticles in a matrix Recycling, waste/material combustion

Pollution, smoke, dustPollution, smoke, dust Reduced size and size distribution,

higher internalization

Safety AspectsSafety AspectsPublic HealthPublic Health Overall air pollution (e.g. cigarettes, diesel soot, tires, Overall air pollution (e.g. cigarettes, diesel soot, tires,

industrial contamination)industrial contamination) How far does nanotechnology boost danger? Need for more epidemiologic research?

Daily life body exposure (cosmetics, paint, clothing, Daily life body exposure (cosmetics, paint, clothing, nutrition)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, Future tailored particles (e.g. in life sciences, transport, etc.)etc.)

Challenges and requirements for research (medical, basic, enginering)

Support and requirements for industry? Information of customers?

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 …..

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

Material Safety Standards

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

Translocation of Translocation of NanoparticlesNanoparticles

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

After David B. Warheit in Materialstoday February 2004

Translocation of Translocation of NanoparticlesNanoparticles

Ten Toxic WarningsTen Toxic Warnings1. 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.

2. March 2002 – „… engineered nanoparticles accumulate in the organs of lab animals and are taken up by cells…“ Dr. Mark Wiesner

3. 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)

4. 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

5. 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

Ten Toxic WarningsTen Toxic Warnings6. January 2004 - Dr. Günter Oberdörster: nanoparticles are able

to move easily from the nasal passageway to the brain.

7. January 2004 - Nanosafety researchers from University of Leuven, Belgium in Nature: nanoparticles will 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)

8. January 2004 - Nanotox 2004: Dr. Vyvyan Howard presents initial findings that gold nanoparticles can move across the placenta from mother to fetus.

9. 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)

10. 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

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

Material Safety Standards