Nanomaterial - human health risk assessment -

1
Nanomaterial- human health risk assessment -

• Maria Wallén, toxicologist
• Reach Department
• Swedish Chemicals Agency (Kemikalieinspektionen)
• ____________________
• Biomaterials Research Center, Gothenburgs
  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

• Effects assessment
• Hazard identification
• Dose/response

• Exposure assessment
• Exposed populations
• Exposure patterns

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

• Phys/chem properties
• Large surface area per volume
• High reactivity

• Size and shape
• 1 - 100 nanometer

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

• 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)

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 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

13
LegislationREACH Regulation (EC) No
1907/2006Registation, Evaluation, Authorisation
and Restriction of Chemicals
REACH covers nanomaterials (EU Commission)
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

• 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

18
(No Transcript)
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 3/08Kemi Rapport 6/07 (sv)

• NanotechnologyHigh 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!