Nanomaterials:Nanomaterials:Potential impact on human health Potential impact on human health

Paul J.A. Borm

Paris- OECD- june 7th 2005

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SiO2

TiO2

Al2O3

Metals

Various

All

Nanoparticles-already a bulk market

Doubling from 493 € to 900Mi in 2005

Biggest increase SiO2 expected

Millions USD

Estimated global Production rates forNanomaterials

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

Porous Polymer

Magnetite

Inductive

Heating

Engineered NP

Drug in Matrix

200-

1000

0 nm

Drug Release

Shrinkage

For inductive drug release

Intravenous delivery of engineered NPNeeds 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

Unintentionally produced NP-Combustion-Nucleation

New products, applicationsHigh added value

Negligible exposure (CNT, CB)Low risk

No added value, extra costConsiderable health risks

What are nanoparticles?

to a toxicologist

0.01 0.1 1 10m

NanoparticlesParticles in traditional dusty trades

10 100 1000 10,000nm

Smaller size means different interactions

and distribution

Smaller size means different interactions

and distribution

10µm 1 µm 0.1µm ..0µm

0.1µm

Cilia 0.25µm diameter

Bronchial epithelium

N

Mit

Protein binding by NP mayhave different consequences

Borm and Kreyling (2004)J. Nanotech & NanoSci

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0,01

0,1

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Diameter (nm)

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rfac

e/V

olu

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cen

tag

e

High Surface/volume ratio: • Suitable for catalysis, • More soluble. • More particles at similar mass. • Not subject to gravity

Nanosize has physical implications

Nanosize has implications for surface reactivity and chemistry

TiOTiO22 TiO TiO22 Ti Ti0.990.99OO1.951.95

• Size does not allow stoichiometry, • Cluster Irregularities.• quantum effects• Electron holes, reactive surface

Toxicological hazards of Nanoparticles

what do we know?Have an active and large surface that can interact withmany 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 unintentionallyunintentionally produced combustion Nanoparticles.

Effects of manufactured Nanoparticles have mainlybeen studied with a small set of particles alreadyon the market for decades (carbon black, TiO2, FexOy)

Little data on occupational exposure to manufactured Nanoparticles. Available data suggest negligibleInhalation exposure (= background).

Combustion NP

Engineered NPBulk industrial NP

Epidemiology

Toxicology?

?

A Bermuda Triangle

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 understanding5. Invest in studies on environmental

distribution, accumulation and effects.

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surface (m2/lung)

% l

un

g t

um

ou

rs

Summary of inhalation (o)and instillation studies (●)With fine and ultrafineparticles

0.2-0.3 m2/rat

Borm et al (2004) Int J cancer

The carcinogenic response in the rat is driven by surface dose.This means that regulation of all particles could be done usingA surface dose concept.

Ad 1:

Ad2: qualitative differences: Uptake of NP in the brain

Oberdorster et al, 2004Carbon, Au, MnO

Activation of inflammatoryCascade in brain Caldwell et al, 2005

Relation to Alzheimer?Calderon-Garciduenas, et al, 2004

Relation to systemic effects such as heart rate, blood pressure changes (Brook et al, 2002; Lippman et al, 2005)

?

Hazard = Riskx exposure

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

Producers and Users of Nanomaterials

Research Institutes

State of the art: Little exchange between companies or between companies and

Toxicological research institutes.

Needed: networks to enable communication

and data exchange between nanoscience and

Toxicology.

NANOTECHNOLOGY

HYPE

ScienceFiction

Hazardousarea

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)