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Nanomaterial- human health risk assessment -
Maria Wallén, toxicologist
Reach Department
Swedish Chemicals Agency (Kemikalieinspektionen)
____________________Biomaterials Research Center, Gothenburg´s university
Nov 13, 2008
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• 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
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Human health risk assessment of chemicals
Risk characterisationExposure level / Effect level
Information on Exposure Phys/chem prop Toxicokinetics Effects
Effects assessment•Hazard identification•Dose/response
Exposure assessment•Exposed populations•Exposure patterns
Exposure humans NOAEL animals
Extrapolate experimental animal data to human situation
Risk management
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Human health risk assessment of nanomaterials
Do we need to study nanomaterials differently compared to bulk chemicals?
To be investigated!
?
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Definition
?To be agreed!
Phys/chem properties•Large surface area per volume•High reactivity
•Intentionally formed•Unintentionally formed•Natural occurrance
Quantum effectsUnique optical, electricaland magnetic properties
Size and shape•1 - 100 nanometer
C60-fullerene
SWCNT
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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?
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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
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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
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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?
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• OECD; Environment DirectorateWorking 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)
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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
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Fullerenes (C60) JP, US --- CN
SWCNTs JP, US ---
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
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LegislationREACH Regulation (EC) No 1907/2006
Registation, Evaluation, Authorisation and Restriction of Chemicals
?
How do REACH apply to nanomaterials?
To be considered!
”REACH covers nanomaterials”(EU Commission)
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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)
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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…..
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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)
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• 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
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Nanomaterials in products (examples)
• Electronics• Househould products• Clothes and textiles• Sport items• Automobiles• Toys• Hygiene articles• Cosmetic products• Food and food additives• Pharmaceuticals
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Toxicity of nanomaterials
Are nanomaterials toxic to human health?
?
Knowledge is limited
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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
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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)
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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
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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
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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
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Very limited knowledge
• Effects on the skin• Effects on the reproductive system and foetuses• Mutagenicity• Cancer• Effects on the immune system
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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.
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KemI Report 3/08Kemi Rapport 6/07 (sv)
NanotechnologyHigh risks with small particlesA compilation of available knowledge concerning risks for health and environment from nanotechnology, and proposals on measures for how to fill the identified knowledge gaps
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Thank you for your attention!
