1. Health and environmental impacts of nanoparticles: too early for a risk assessment framework? Prof Jim Bridges Emeritus Professor of Toxicology and Environmental Health. Chair of the EU Scientific Committee for Emerging and Newly Identified Health Risks (SCENIHR)

2. NANOPARTICLES- THE OLD vs. NEW DEBATE OLD * Man has been exposed to nanoparticles since the first fire. Many industries produce NP/NF We don’t know enough about chemicals in general. NM is not a special case. NEW The engineered NM being produced are totally different to those from combustion etc. There will be a very widespread exposure of man /environment

3. NANOMATERIALS (NM) DEFINITIONS. Nanorod/nanofibre/nanotube (NF)- a discrete entity which has two dimensions of the order of 100nm or less and one long dimension Nanoparticle (NP)- a discrete entity with three dimensions of the order of 100nm or less. NB size distribution is an important consideration from both a scientific and regulatory perspective

4. TOPICS TO BE ADDRESSED Overview of current knowledge on the exposure and hazard aspects of NM A risk assessment framework for NM Priorities for further investigations

5. TOPIC 1 Overview of current knowledge on the exposure and hazard aspects of NM

6. PHYSICO-CHEMICAL CONSIDERATIONS Minimum data set needed?: size distribution, surface area, shape, persistence, reactivity, composition, stability. NM ◄---------► (NM)x I agglomerate ▼ solubilisation

7. INHALATION EXPOSURE The available methodology is inadequate to measure NP/NF routinely in various media. Consequently, data on uptake and fate in biological systems is rather limited. Most in vivo studies are via the inhalation route. Indication that as well as local effects, smaller particles can penetrate lung and enter the systemic circulation. Levels generally low? Different absorption at different locations?

8. EXPOSURE AND ABSORPTION Poor data on skin and gut absorption of NM. Data on uptake of micelles via lymph, IGA via Peyers patches and other large proteins etc indicates potential for absorption? Are particles coated as soon as they enter the body?

9. HAZARD. 1 * V. few NM have been studied. Some substances in a particular nanoform are more hazardous than in other physico- chemical forms. * In many publications the NM properties are not properly characterised. * A cut off point of 100nm is purely arbitrary from a hazard viewpoint

10. HAZARD 2 Some effects may be anticipated from non- NM eg C nanotubes and asbestos, ambient air particles and lung irritancy There is no conclusive evidence for NP/NF having unique hazardous properties although some possible mechanisms have been identified (eg effect on protein folding, electron release on activation)

11. SUMMARY OF THE CURRENT POSITION Lack of studies on end of use situations. * Particular methodological barriers to progress are: i) inadequate range and quality of reference materials ii) the lack of robust simple methods to determine the amounts of NM in various media iii) how to present NM to toxicity test systems without altering their key properties

12. SUMMARY OF THE CURRENT POSITION It is uncertain whether, from a risk assessment perspective, there is such a thing as a ‘typical’ or ‘representative’ NM.

13. TOPIC 2 A risk assessment framework effects on man and the environment for NM: the SCENIHR approach

14. THE NEED FOR A RISK ASSESSMENT FRAMEWORK To enable regulatory instruments to be put in place To identify NM’s that should be given priority for risk assessment (or should all NM be tested?) To identify knowledge gaps where research on health, safety and environmental aspects of NM’s is needed.

15. THE CLASSICAL HAZARD DRIVEN PARADIGM FOR RISK ASSESSMENT i) identification of the hazardous properties in suitable biological test systems and the dose response relationship ii) determination of the exposure to the substance of interest, to man / environmental species iii) characterisation of the fate in relevant biological systems (ADME) iv) Assessment of the risk under the specified exposure conditions.

16. Nature of NM may change during the life cycle Lack of sufficient knowledge of how NM behave in the body and in the environment Political/regulatory constraints on the use of in vivo testing How to define dose? PROBLEMS IN APPLYING RISK ASSESSMENT TO NANOMATERIALS

17. AN EXPOSURE DRIVEN FRAMEWORK : THE SCENIHR PROPOSAL.1. Stage1 A proper characterisation of the physico- chemical properties of the NM eg shape, size distribution, solubility, surface area and reactivity, stability. Priority should be on persistent entities with at least two dimensions in the nanoscale (NP/NF). Stage 2A Identification of realistic exposure scenarios for both man and other species. Further consideration needed in situations where significant exposure is identified.

18. FRAMEWORK RECOMMENDED BY SCENIHR 2. Stage 2B Consideration of toxicokinetic properties, particularly the potential for uptake by man and other species Stage 3 identification of hazardous properties using a tiered system of validated in vitro and in vivo methods (including consideration of mechanisms).

19. FRAMEWORK RECOMMENDED BY SCENIHR 3. Stage 4. - Characterisation of dose response relationships, - Conclusions on the human and environmental risks for each relevant exposure scenario - Identification of any uncertainties

20. CONCLUSIONS FROM A RISK ASSESSMENT PERSPECTIVE Priority needs to be given to those NM where significant exposure and uptake of man /environment may be anticipated to occur. There is no sound scientific basis for extrapolation of findings from one NM to another. Consequently, at the present, risk assessments must be on a case by case basis

21. COMPLEMENTARY APPROACHES FOR RISK ASSESSMENT Identifying NM for commercial development A two dimensional matrix (exposure vs effects) using expert judgement. Considering the resource implications Use of life cycle analysis

22. TOPIC 3. Priorities for further investigations

23. PRIORITIES a): RESEARCH AND DEVELOPMENT * Availability of a range of high quality, well characterised, reference NF/NP’s. Development of robust and reliable methods to measure or model the form of NF/NP’s in various media. Further characterisation of factors affecting uptake by various exposure routes Identification of the primary mechanisms involved in the interactions between NF/NP’s and biological systems

24. PRIORITIES b): ACCESS TO AND USE OF DATA * An evolving validated data base of RA’s on properly characterised nanomaterials Development of a classification system based principally on NM physico-chemical properties? A transparent and acceptable format for risk comparison and for risk benefit analysis

25. CONCLUSIONS The RA of NM cannot be based simply on the known properties of the same substance in another physical form, Extrapolation of findings between different NM is also problematic. Therefore each new NM needs to be considered separately (case by case). A flexible framework has been identified for prioritisation of RA’s. This needs to be reviewed regularly as new information becomes available. A major internationally co-ordinated effort to enhance the science base is needed that involves a range of stakeholders sharing information and views. What should we focus the debate on ?