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Particles:Particles:
Nanoparticles, FullerenesNanoparticles, Fullerenes
and Carbon Nano Tubesand Carbon Nano Tubes
Margarethe HofmannMargarethe Hofmann
MAT SEARCH, PullyMAT SEARCH, Pully
President SVMTPresident SVMT

Topics of the WorkshopTopics of the Workshop
 «��Environmental Aspects��» – latest research«��Environmental Aspects��» – latest research
activitiesactivities
 «��Material Safety Standards��» - required for«��Material Safety Standards��» - required for
safety of producers and consumerssafety of producers and consumers
 nearly or insoluble particlesnearly or insoluble particles

Properties of Nanoparticles (< 100 nm)
Zimmermann
K arg
Cyrys
Behrendt/Allessandrini
S chulz
Peters
Wolff
Schramm
Maier
AndraeWittmaa ck
Zimmermann
K arg
Cyrys
Behrendt/Allessandrini
S chulz
Peters
Wolff
Schramm
Maier
AndraeWittmaa ck
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
After: Wolfgang G. Kreyling, GSF – Forschungszentrum für Umwelt und Gesundheit, München

Current and Emerging Applications for Nanoparticles

Investors, Industrials, ScientistsInvestors, 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=7608http://www.smalltimes.com/document_display.cfm?document_id=7608

RegulationRegulation
 Currently, dosage of particles for regulation purposes is defined byCurrently, dosage of particles for regulation purposes is defined by
mass per unit volumemass per unit volume, however this does not take into account, however this does not take into account
particle size. Hence it is clear that agglomeration, particle size andparticle size. Hence it is clear that agglomeration, particle size and
surface reactivity will now have to be taken into account whensurface reactivity will now have to be taken into account when
deciding the regulation of nanoparticles.deciding the regulation of nanoparticles.
 The point was made however that there are many types ofThe point was made however that there are many types of
nanoparticles and that they should not be treated as ananoparticles and that they should not be treated as a general casegeneral case
when deciding regulation. To resolve this issue, further toxicologicalwhen deciding regulation. To resolve this issue, further toxicological
studies must be performed in order to effectively inform regulators.studies must be performed in order to effectively inform regulators.
 The point was also made that regulations mayThe point was also made that regulations may differ between localesdiffer between locales
e.g. in the USA sun creams are categorised as drugs for regulation,e.g. in the USA sun creams are categorised as drugs for regulation,
while in the UK they are regulated as cosmetics.while in the UK 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- or ultrafineInsoluble or nearly insoluble nano- or ultrafine
particlesparticles
 Research for developing standards together withResearch for developing standards together with
industryindustry
 Example 3R Foundation – reducing animalExample 3R Foundation – reducing animal
experimentsexperiments
SummarySummary

SummarySummary
 Define the hot spots of danger coming fromDefine the hot spots of danger coming from
nanoparticles – risk assessmentnanoparticles – risk assessment
 Road map – amount of particles on the market, exposure,Road map – amount of particles on the market, exposure,
uptakeuptake
 Road map for particles in research – nanotubes, CdSe etc.Road map for particles in research – nanotubes, CdSe etc.
 Develop models (in-vitro and in-vivo) for interactionDevelop models (in-vitro and in-vivo) for interaction
with the human bodywith the human body
 toxicity, biodistribution, allergiestoxicity, biodistribution, allergies

 Life Cycle assessment for chemicalsLife Cycle assessment for chemicals
adapted to nanoparticlesadapted to nanoparticles
 Define component by nanoparticle relevantDefine component by nanoparticle relevant
featuresfeatures
SummarySummary

SummarySummary
 Further detailed recommendationFurther detailed recommendation
 Need more information from responsibles inNeed more information from responsibles in
industry and related researchers, toxicologists, riskindustry and related researchers, toxicologists, risk
assessmentassessment
 Workshop SVMT-SATW-TOP NANO 21 onWorkshop SVMT-SATW-TOP NANO 21 on
«��Safety aspects of nanoparticles��»«��Safety aspects of nanoparticles��» November 2004November 2004

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

Nanoparticle Application 2003Nanoparticle Application 2003
 Established commercialEstablished 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 NanoparticleLaunch-Phase Nanoparticle
ApplicationsApplications
 Fabrics and Fabric Treatments
 Filtration Systems
 Dental Products
 Surface Disinfectants
 Diesel Fuel Additives
 Fuel and Explosive Additives
 Hazardous Chemical Neutralizers
 Developmental NanoparticleDevelopmental Nanoparticle
ApplicationsApplications
 Recharg. Lithium Ion Batteries
 Antioxidants
 Dental-Care Products
http://www.mindbranch.com

Nanotube Application 2003Nanotube Application 2003
 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 EnvironmentField of Concern in the Environment
 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 chain?Behaviour and influence of nanoparticles in the food chain?
 Filter-feeding organisms such as plankton regulate the intake andFilter-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 StandardsMaterial Safety Standards
 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 engineering)(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

Safety AspectsSafety Aspects
ProductionProduction
 New technologies, new particle formulationNew technologies, new particle formulation
 Production in clean rooms?
 Filter?
 Health aspects of employees?
 Classic production routesClassic production routes
 Learn from already existing safety standards?

EnvironmentEnvironment
 Functionalized particlesFunctionalized 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

Public HealthPublic Health
 Overall air pollution (e.g. cigarettes, diesel soot, tires, industrialOverall air pollution (e.g. cigarettes, diesel soot, tires, industrial
contamination)contamination)
 How far does nanotechnology boost danger?
 Need for more epidemiologic research?
 Daily life body exposure (cosmetics, paint, clothing, nutrition)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.)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?

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

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

Ten Toxic WarningsTen Toxic Warnings
1. 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 Warnings
6. 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

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