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NANOTECHNOLOGY AND HEALTH: CHALLENGES FOR RESEARCH IN SUPPORT OF EUROPEAN UNION POLICIES

Hermann Stamm

Institute for Health and Consumer ProtectionJoint Research Centre, Ispra

http://www.jrc.ec.europa.eu

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• Scratch resistant painting• New drug delivery systems• Intelligent clothing• Fabrics to resist stains• Thermochromic glass• Light bicycle frames• Fuel cells• Electronic devices

‘Nano’ Everywhere - Benefits and Promises

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What is the issue?Why is support needed?

What are the needs?

The role of the Joint Research Centre

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What is ‘nano’

1 nm = 0,000000001 m =

10-9 m

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NANOSCALE

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What is NANOTECHNOLOGY

• Typical size scale: ca. 1 nm – about 100 nm• Create and exploit size-dependent properties and new

functions of matter at the nanoscale• Manufacture new devices by manipulating material at the

nanoscale

Under discussion!!

Not accidental!!

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Benefits Risks

• Improved Health• Smarter Electronics• Advanced agriculture• Cleaner sources of energy• Environmental remediation • Enhanced security• ……….

• Nanoparticles may translocate to organs and cause toxic effects

• Environmental impact of nanoparticles unknown

• ……….• Threats to privacy – covert

surveillance• Exacerbation of social inequality• ……….

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Manufactured Nanoparticles – what is the difference?

• Quantum effects lead to special mechanical, electronic, optical and magnetic properties

• Chemical reactivity very different compared to bulk material

• Large specific surface• New chemical forms:

fullerenes, nanotubes

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Manufactured Nanoparticles – what is the difference?

• Quantum effects lead to special mechanical, electronic, optical and magnetic properties

• Chemical reactivity very different compared to bulk material

• Large specific surface• New chemical forms:

fullerenes, nanotubes

Specific Surface

0

0,2

0,4

0,6

0,8

0 10 20 30 40 50 60

Size [nm]R

atio

of S

urfa

ce M

olec

ules

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NT Consumer Products on the Market

Source: Woodrow Wilson Databank http://www.nanotechproject.org/

DNA Skin Optimizer

Donny the Dog Plush Toy

Samsung®Washing Machine

TiO2 Automotive Sunscreen

Lexon Nano-Silver Sock

Antibacterial Kitchenware Nano Care Technology, Ltd.

Babolat® NS™Tour Tennis Racket

Ultima® Photo PaperEastman Kodak® Company

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212 230

321 356

475

580

0

100

200

300

400

500

600

Num

ber o

f Pro

duct

s

Mar 8, 2006 Apr 22, 2006 Sep 29, 2006 Nov 26, 2006 May 16, 2007 Oct 2, 2007

Total Products Listed

NT Consumer Products on the Market

Source: Woodrow Wilson Databank http://www.nanotechproject.org/

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NT Consumer Products on the Market

356

67 46 6644 33 21 17

0

50

100

150

200

250

300

350

400

Num

ber o

f Pro

duct

s

Health andFitness

Home andGarden

Electronics& Comp.

Food andBeverage

CrossCutting

Automotive Appliances Goods forChildren

Product Categories

Source: Woodrow Wilson Databank http://www.nanotechproject.org/

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Toxicity of manufactured nanomaterials?

• Studies with ultrafine particles from combustion processesexhibit different biokinetics and effects

• Epidemiological studies demonstrate the relation between air pollution and cardiovascular diseases

• Experiences with fibre toxicology (asbestos, silicates…)

RISK: Toxicity of Nanomaterials

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CHALLENGES FOR POLICY

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Nanotechnology – Challenges for Policy

• High expectations on contribution to economic growth, jobs, social welfare and sustainable development

• Nanotechnology pervades many different traditional scientific disciplines and technological fields

• Implications of the use of nanotechnology are very diverse and depend on application areas

• Uncertainties about health and environmental impacts• Different societal perceptions and ethical concerns• Little trust in industrial risk managers and public regulators

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How does legislation deal with risks?HAZARD (IDENT. & CHAR) EXPOSURE ASSESSMENT

RISK ASSESSMENT

RISK MANAGEMENT

Scientific Uncertainty

Public Perception

Precautionary Principle Principle of

proportionality

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EU Regulation relevant for EHS aspects of NT

• General Safety of Consumer Products

• Plant Protection Products• Biocides• New Approach Legislation• Cosmetic Products• Aerosol Dispensers• Medicinal Products• Cars• Food Legislation

1. Chemicals Legislation (REACH)

2. Worker Protection3. Environmental Legislation

– Integrated Pollution Prevention and Control

– Major-accidents, Seveso II Directive– Water– Waste

Product LegislationHorizontal Legislation

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EU Regulation relevant for EHS aspects of NT

• General Safety of Consumer Products

• Plant Protection Products• Biocides• New Approach Legislation• Cosmetic Products• Aerosol Dispensers• Medicinal Products• Cars• Food Legislation

1. Chemicals Legislation (REACH)

2. Worker Protection3. Environmental Legislation

– Integrated Pollution Prevention and Control

– Major-accidents, Seveso II Directive– Water– Waste

Product LegislationHorizontal Legislation

Health safety and environmental protection aspects associated with nanotechnologies are in principle covered.

Need for modification?

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RESEARCH FOR POLICY SUPPORT

The JRC as a research based policy support organization

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1. How to characterize nanoparticles?2. What determines their toxicity?3. Exposure?

3 fundamental questions

Integrated Testing Strategy• Physico-chemical characterization• In silico studies• In vitro test systems• In vivo studies

Risks of Manufactured Nanomaterials

JRC

• Hazard identification• Hazard characterization• Exposure assessment

RISKASSESSMENT

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Understanding the biological response• Size and Shape

– Size distribution– Shape

• State of Dispersion– Agglomeration/Aggregation

• Physical and Chemical Properties

– Crystalline phase and crystallite size

– Water solubility– Electro-optical properties

• Surface Area and Porosity• Surface Chemistry

– Surface composition– Catalytic properties– Surface charge– Reactivity– Adsorption/desorption of molecules

EFFECT

• Translocation from portal of entry to target organs

• Protein binding properties

• Cellular uptake• Accumulation and

retention

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Dose–Effect Relationship In vitro Tests

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IC50 = 20nM

-9 -8 -7 -6

0

1

2

3

4

5

Concentration Test chemical (log M)

Res

pons

e(a

.u.)

Non-toxic

CytotoxicIC50

Dose–Effect Relationship In vitro Tests

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Dose metrics• Mass?• Surface area?• Number of particles?

Dose–Effect Relationship In vitro Tests

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In vitro Test Method Development2 µm

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324 nm324 nm

In vitro Test Method Development2 µm

Balb/3T3 clone A31-1-1, immortalised mouse fibroblasts

Results cytotoxicity

Co-nano

In vitro toxicological profile

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2h

0

50

100

150

1 10 100 1000

Concentrazione (µM)C

FE (%

)

CoCl2

Conano

72h

0

50

100

150

1 10 100 1000

Concentrazione (µM)

CFE

(%)

CoCl2

Conano

control 10µM

30µM 50µM

70µM 100µM

In vitro Test Method Development2 µm

Balb/3T3 clone A31-1-1, immortalised mouse fibroblasts

Results cytotoxicity

Co-nano

In vitro toxicological profile

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Cobalt aggregates in immortalised mouse fibroblast (Balb/3T3 cell) by Scanning Electron Microscope (SEM-EDX).Cells were exposed for 24h to 10µM Co-nano, dehydrated and treated using Critical Point Dryer technique. Cobalt aggregates in immortalised mouse fibroblast (Balb/3T3 cell) by Scanning Electron Microscope (SEM-EDX).Cells were exposed for 24h to 10µM Co-nano, dehydrated and treated using Critical Point Dryer technique.

In vitro Test Method Development2 µm

Balb/3T3 clone A31-1-1, immortalised mouse fibroblasts

Results cytotoxicity

Co-nano

In vitro toxicological profile

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In vitro Test Method Development

DNA damage chromosomal aberration

carcinogenicity Balb/3T3 clone A31-1-1, immortalised mouse fibroblasts

Genotoxicityand carcinogenic potential

Co-nano

In vitro toxicological profile

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Bio/non-bio Interfaces

Essential in protein-surface interactions:

– Interaction forces between material surfaces and proteins control protein conformation and orientation

– Protein-surface interactions control protein exchange at surface and final equilibrium in biological medium

After Lynch and Dawson, Nanotoday 2008, (3) 1-2ß

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350 nm 670 nm350 nm 670 nm

R RRH H H H H H H HH H H H

R RRH H H H H H H HH H H H

R R R R R R R R R R RR R R R R R R R R R R R RR R

MHD or HDT

Nano MHD/HDT

350 nm 670 nm350 nm 670 nm

R RRH H H H H H H HH H H H

R RRH H H H H H H HH H H H

R R R R R R R R R R RR R R R R R R R R R R R RR R

MHD or HDT

Nano MHD/HDT

Bio – Non-Bio Surface Interaction

• xxxx

300

200

100

(a.u.)

300

200

100

(a.u.)

300

200

100

(a.u.)

300

200

100

(a.u.)

Fluorescence map

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• Automation is necessary for assay standardization and production of high quality data

• High-throughput protocols for screening

• Use the test platform for the rigorous and systematic assessment of novel in vitro tests.

• Important role for test method validation

In vitro Testing Technologiesand Assay Automation

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Process Automation of in vitro tests

IDBS – ActivityBase™ Suite• Experimental design• Results and properties database• Data mining and SA analysis

D

B - Ay = A+1+ (C/x)

IC50

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• Surface Science − Bio/non-bio interfaces– Central to the understanding of the biological response of

nanostructured materials• Nanotoxicology

– physico-chemical characteristics of nanoparticles – development of reference materials– In vitro test methods, biosensor development– In silico studies, database development

• Molecular and cell imaging for advanced in vitro testing• Assay Automation • Risk assessment and information management tools

JRC Nanobiotechnology Research

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Science for Policy Support

Science Nano - Science and Technology

Test methods

Phys.-chem. characterization

Human Health: Hazard Identificationand characterization

Environment: Hazard Identificationand characterization

Results Representative Material Set

Human HealthRisk Characterization

Environment:Risk Characterization

DeliverablesMaterial Properties

Toxicity Data

Standards

Test Methods

Reference Materials

Risk Assessment Methodology

Users European Commission, Standardization Bodies, EU Agencies, International Organisations, Industry, Citizens, …

Knowledge

Gap

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JRC Nanotechnology Policy Support

European Commission Directorates General

• Enterprise and Industry• Environment• SANCO• Employment, Social

Affairs and Equal Opportunities

• Competitive Activities FP6/7

• Testing and guidelines (OECD, …)

• Standardization issues (ISO, CEN)

• EFSA Working Group on Nanotechnology

• Collaboration on nanotechnology related issues with ECHA

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CHALLENGES FOR RESEARCH IN SUPPORT OF EUROPEAN UNION POLICIES

Is the regulatory framework appropriate?Close the knowledge gap – produce data

Develop integrated risk assessment methodologiesPerform underpinning research for health, safety and the

environment

The JRC as a research based policy support organization

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Joint Research Centre (JRC)

Robust science for policy making

Web: www.jrc.ec.europa.eu

Contact: jrc-info@ec.europa.eu

Thank you for your attention