1. Nanomaterial - human health risk assessment -
Maria Wallén, toxicologist
Reach Department
Swedish Chemicals Agency (Kemikalieinspektionen)
____________________
Biomaterials Research Center, Gothenburg´s university
Nov 13, 2008

2. Risk assessment in general Risk assessment and nanomaterials
Definition of nanomaterial
Issues to be considered in testing
Legislation (REACH regulation)
Nanomaterials in products
Nanomaterials and human exposure
Nanomaterials and human toxicity

3. Human health risk assessment of chemicals
Information on
Exposure Phys/chem prop Toxicokinetics Effects
Exposure assessment
Exposed populations
Exposure patterns
Effects assessment
Hazard identification
Dose/response
Exposure humans
NOAEL animals
Extrapolate experimental animal data to human situation
Risk characterisation
Exposure level / Effect level
Risk management

4. Human health risk assessment of nanomaterials
Do we need to study nanomaterials
differently compared to bulk chemicals? ?
To be investigated!

5. ? Definition To be agreed! Size and shape Phys/chem properties
nanometer
Phys/chem properties
Large surface area per volume
High reactivity
Unique optical, electrical
and magnetic properties
Quantum effects
Definition
Intentionally formed
Unintentionally formed
Natural occurrance
C60-fullerene ?
To be agreed!
SWCNT

6. Issues to be considered in the risk assessment of nanomaterials (1)
Exposure
What are the relevant exposure metrics?
Which data can be reliably collected?
Analytical methodologies
Effects of adsorption and aggregation
Measurement strategies
How should uncertainty of data be handled?

7. Issues to be considered in the risk assessment of nanomaterials (2)
Physical-chemical properties
Aggregation (nanomaterial – nanomaterial interaction)
Water solubility (nanomaterial held in a colloidal suspension)
Shape
Particle size distribution
Specific surface area
Surface chemistry

8. Issues to be considered in the risk assessment of nanomaterials (3)
Toxicokinetics – ADME (Absorption, Distribution, Metabolism, Elimination)
The small particle size
The shape and surface composition
Aggregation may produce particles too large for absorption
Interaction with molecules (proteins, lipids, salts, etc) in the biological environment leading e.g. to extensive tissue retention

9. Issues to be considered in the risk assessment of nanomaterials (4)
Effect endpoints
Endpoints for testing
Testing methods
Sample preparation and dosimetry
How to prepare the dosing material
How to administer dosing material for tox. test
Estimating dose
Deposition of small materials?

10. Exposure measurement and assessment
OECD; Environment Directorate Working Party on Manufactured Nanomaterials (WPMN)
Exposure measurement and assessment
Investigate the possible use of current OECD test guidelines
The role of alternative (non in vivo) test methods
Risk assessment
Safety testing of a representative set of manufactured nanomaterials (Sponsorship programme)

11. Sponsorship Arrangement (OECD)
To agree on a list of representative manufactured nanomaterials
To develop a programme to test nanomaterials for human health and environmental safety

12. Fullerenes (C60) JP, US --- CN SWCNTs CA, FR, DE, EC, CN, BIAC MWCNTs
KR, BIAC
Silver nanopart.
KR, US
AU, CA, DE
AU, FR, EC, CN
Iron nanopart.
BIAC
CA, US
Carbon black
DE, US
Titanium dioxide DE
CA, KR, ES, US, BIAC
FR, CN
Aluminium oxide
Cerium oxide
US, UK/BIAC(NIA) NL
AU, DE, EC
Zinc oxide
UK/BIAC(NIA)
AU, US, BIAC(CEFIC)
AU, CA
Silicon dioxide EC
KR, BIAC(CEFIC)
FR, EC
Polystyrene KR
Dendrimers ES US
Nanoclays

13. Legislation REACH Regulation (EC) No 1907/2006 Registation, Evaluation, Authorisation and Restriction of Chemicals
”REACH covers nanomaterials”
(EU Commission) ?
How do REACH apply to nanomaterials?
To be considered!

14. Issues to be considered in the REACH regulation and nanomaterials (examples)
Obligation to register substances (Article 6, 7)
Requirements for Safety Data Sheets (SDS) (Article 31)

15. Obligation to register
Any manufacturer or importer of a substance in quantities of one tonne or more per year shall submit a registration to the Agency.
Any producer or importer of articles shall submit a registration to the Agency, if
the substance is present in articles in quantities over one tonne per producer or importer per year…..

16. Safety Data Sheets (SDS)
The supplier of a substance shall provide the recipient of the substance with a safety data sheet if
the substance meets the criteria for classification as dangerous (CMR); or
the substance meets the criteria as persistent, bioaccumulative and toxic (PBT) …., or
… an equivalent level of concern… (eg endocrine disrupters)

17. Definition of nanomaterials Registration Chemical Safety Assessment
Reach Competent Authorities subgroup on Nanomaterials (Reach CASG Nano)
Definition of nanomaterials
Registration
Chemical Safety Assessment
Classification and labelling
Testing methods inclusive alternative methods
Safety data sheet (SDS)
Authorisation and Restrictions
Guidance

19. Nanomaterials in products (examples)
Electronics
Househould products
Clothes and textiles
Sport items
Automobiles
Toys
Hygiene articles
Cosmetic products
Food and food additives
Pharmaceuticals

20. Toxicity of nanomaterials
Are nanomaterials toxic to human health? ?
Knowledge is limited

21. Exposure to humans - workers, consumers, man via the environment -
Uptake via
The lungs, the oral route, the skin, the olfactory nerve to the brain
Passage via
Blood-brain barrier
Cell membranes into mitochondria and cell nucleus
Localised to
e.g. liver, spleen, lymph nodes, bone marrow, brain

22. Effects on the lungs (1) Size
high amount in the lungs of nanosized particles (TiO2 and Al2O3) compared to larger particles of the same substances  greater pulmonary inflammatory response (rats, mice)
Shape
high amount in the lungs of nanotubes (15-20 µm; SWCNT) compared to nanoparticles (quantum dots )  greater inflammatory response (often discussed in relation to asbestosis) (rats)

23. Effects on the lungs (2) Surface area
Nanoparticles with greater surface area were more cytotoxic than larger particles of equivalent mass (SiO2) (in vitro)  might explain pulmonary fibrosis

24. Effects on the cardiovascular system
Air pollution (nanosized particles)
cause oxidative stress (rats; inhalation)  may lead to inflammation and myocardial cell injuries
SWCNT respiratory exposure
Induces oxidative stress and injuries in the vessel cells (mice; instilled in the lungs)  might lead to cardio-vascular diseases such as artherosclerosis
Nanoparticles
can modify blood clotting factors (mice; ip)  may lead to thrombosis

25. Effects on the nervous system
Positively charged nanoparticles (emulsifying wax) have toxic effect at the blood-brain barrier (rats; in situ brain perfusion)  disturbances of the BBB may lead to modified toxicity for nanosized material and chemicals in general

26. Very limited knowledge
Effects on the skin
Effects on the reproductive system and foetuses
Mutagenicity
Cancer
Effects on the immune system

27. Finally,
We need advise how to deal with nanomaterials in the legislation
There are large uncertainties and limited knowledge on human health risks of nanomaterials
There is a need to understand how to assess exposure to nanomaterials
There is a need to establish adequate testing methods to evaluate the toxicity of nanomaterials
There are problems to communicate possible risks caused by nanomaterials.

28. KemI Report 3/08 Kemi Rapport 6/07 (sv)
Nanotechnology High risks with small particles
A compilation of available knowledge concerning risks for health and environment from nanotechnology, and proposals on measures for how to fill the identified knowledge gaps
Thank you for your attention!