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Nanomaterials:
Potential impact on human health
Paul J.A. Borm
Paris- OECD- june 7th 2005
Nanoparticles-already a bulk market
All
Various
Doubling from 493 € to 900
Mi in 2005
Metals
Biggest increase SiO2 expected
Al2O3
TiO2
SiO2
0
200
400
600
800
1000
Millions USD
Estimated global
Production rates for
Nanomaterials
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
Engineered NP
Porous Polymer
Shrinkage
200-10000 nm
Magnetite
Inductive
Heating
Drug Release
Drug in Matrix
For inductive drug release
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?
Intentionally produced NP
-already on the market
-Newly engineered
New products, applications
High added value
Negligible exposure (CNT, CB)
Low risk
Unintentionally produced NP
-Combustion
-Nucleation
No added value, extra cost
Considerable health risks
What are nanoparticles?
to a toxicologist
Nanoparticles
0.01
10
Particles in traditional dusty trades
0.1
1
100
1000
10mm
10,000nm
Smaller size means
different
interactions and
distribution
Cilia 0.25µm diameter
1.0µm
.
0.1µm
10µm 1 µm 0.1µm
.
N
Bronchial epithelium
Mit
Protein binding by NP may
have different consequences
Borm and Kreyling (2004)
J. Nanotech & NanoSci
Surface/Volume percentage
Nanosize has physical implications
100
High Surface/volume ratio:
• Suitable for catalysis,
• More soluble.
• More particles at similar mass.
• Not subject to gravity
10
1
0,1
0,01
0,001
0
200
400
600
800
1000
1200
Diameter (nm)
Nanosize has implications for surface
reactivity and chemistry
• Size does not allow stoichiometry,
• Cluster Irregularities.
• quantum effects
• Electron holes, reactive surface
TiO2
TiO2
Ti0.99O1.95
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.
However:
Most of the evidence for human effects is generated
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, TiO2, FexOy)
Little data on occupational exposure to manufactured
Nanoparticles. Available data suggest negligible
Inhalation exposure (= background).
A Bermuda Triangle
Combustion NP
Epidemiology
?
Toxicology
Bulk industrial NP ?
Engineered NP
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.
80
% lung tumours
70
60
Summary of inhalation (o)
and instillation studies (●)
With fine and ultrafine
particles
50
40
30
20
0.2-0.3 m2/rat
10
0
0.001
0.01
0.1
1
10
100
surface (m2/lung)
Ad 1:
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.
Borm et al (2004) Int J cancer
Ad2: qualitative differences:
Uptake of NP in the brain
Activation of inflammatory
Cascade in brain
Caldwell et al, 2005
Relation to Alzheimer?
Calderon-Garciduenas, et
al, 2004
?
Oberdorster et al, 2004
Carbon, Au, MnO
Relation to systemic
effects such as heart rate,
blood pressure changes
(Brook et al, 2002;
Lippman et al, 2005)
Hazard
x exposure
= Risk
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
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
State of the art: Little exchange between
companies or between companies and
Toxicological research institutes.
Producers and Users
of Nanomaterials
Research Institutes
Needed: networks to enable communication
and data exchange between nanoscience and
Toxicology.
NANOTECHNOLOGY
HYPE
Science
Fiction
Hazardous
area
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)