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 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 www.kemi.se

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

? Definition To be agreed! Size and shape Phys/chem properties 1 - 100 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 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

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) 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) 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 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

Definition of nanomaterials Registration Chemical Safety Assessment 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

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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 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