Nanomaterial
- human health risk assessment Maria Wallén, toxicologist
Reach Department
Swedish Chemicals Agency (Kemikalieinspektionen)
____________________
Biomaterials Research Center, Gothenburg´s university
Nov 13, 2008
www.kemi.se
• 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
www.kemi.se
Human health risk assessment of chemicals
Exposure
Information on
Phys/chem prop Toxicokinetics
Effects
Exposure assessment
Effects assessment
•Exposed populations
•Exposure patterns
•Hazard identification
•Dose/response
Exposure humans
NOAEL animals
Extrapolate experimental
animal data to human situation
Risk characterisation
Exposure level / Effect level
www.kemi.se
Risk management
Human health risk assessment of
nanomaterials
Do we need to study nanomaterials
differently compared to bulk chemicals?
?
To be investigated!
www.kemi.se
Size and shape
•1 - 100 nanometer
Unique optical, electrical
and magnetic properties
Phys/chem properties
•Large surface area per volume
•High reactivity
Quantum effects
Definition
•Intentionally formed
•Unintentionally formed
•Natural occurrance
?
C60-fullerene
To be agreed!
SWCNT
www.kemi.se
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?
www.kemi.se
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
www.kemi.se
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
www.kemi.se
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?
www.kemi.se
• 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)
www.kemi.se
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
www.kemi.se
Fullerenes (C60)
SWCNTs
JP, US
JP, US
---
CN
---
CA, FR, DE, EC,
CN, BIAC
MWCNTs
JP, US
KR, BIAC
CA, FR, DE, EC,
CN, BIAC
Silver nanopart.
KR, US
AU, CA, DE
AU, FR, EC, CN
Iron nanopart.
CN
BIAC
CA, US
Carbon black
---
---
DE, US
Titanium dioxide DE
CA, KR, ES, US, BIAC
FR, CN
Aluminium oxide ---
---
DE, US
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
---
US
US
www.kemi.se
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!
www.kemi.se
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)
www.kemi.se
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…..
www.kemi.se
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)
www.kemi.se
• Reach Competent Authorities subgroup on
Nanomaterials (Reach CASG Nano) 2008-2012
– Definition of nanomaterials
– Registration
– Chemical Safety Assessment
– Classification and labelling
– Testing methods inclusive alternative methods
– Safety data sheet (SDS)
– Authorisation and Restrictions
– Guidance
www.kemi.se
www.kemi.se
Nanomaterials in products (examples)
•
•
•
•
•
•
•
•
•
•
Electronics
Househould products
Clothes and textiles
Sport items
Automobiles
Toys
Hygiene articles
Cosmetic products
Food and food additives
Pharmaceuticals
www.kemi.se
Toxicity of nanomaterials
Are nanomaterials toxic to
human health?
?
Knowledge is limited
www.kemi.se
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
www.kemi.se
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)
www.kemi.se
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
www.kemi.se
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
www.kemi.se
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
www.kemi.se
Very limited knowledge
•
•
•
•
•
Effects on the skin
Effects on the reproductive system and foetuses
Mutagenicity
Cancer
Effects on the immune system
www.kemi.se
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.
www.kemi.se
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
www.kemi.se
Thank you for your attention!
www.kemi.se