1. Risk Assessment - Scientific Challenges A Perspective from the NanoSafety Project Team
Jutta Jahnel

2. NanoSafety Project
NanoSafety – Risk Governance of Manufactured Nanoparticles
Commissioned by STOA, carried out by KIT-ITAS, Karlsruhe (project coordination) and ITA, Vienna as members of ETAG
STOA Project Supervisor: Prof. Vittorio Prodi, MEP
Duration: January 2010 – October 2011
The project deals with the governance of the potential environmental, health and safety risks of manufactured nanoparticles, the challenges for risk assessment and risk management and the regulation under uncertainty
Focus: Risk and concern assessments as well as risk management strategies as discussed or proposed for the EU or its member states
| Jutta Jahnel | ITAS |

3. Preconditions for risk assessment study
The presented results are based on an up-to-date literature review
Working definition: Manufactured Particulate Nanomaterials (MPN)
Focus: safety objective „human health“
Risk assessment is a prerequisite of science-based risk management and means the quantification of the probability of harmful effects caused by exposure to an agent
Situation:There is no generally accepted paradigm for risk assessment for nanomaterials or products containing them
Question: Could scientific data provide appropriate knowledge for policy makers to perform risk assessment?
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4. Risk Assessment Paradigm
According to OECD (2003): Environment Directorate. Description of selected key generic terms used in chemical/hazard assessment. OECD Series on Testing and Assessment Number 44. ENV/JM/MONO(2003).
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5. Toxicity Tests for Hazard Assessment
Nanotoxicology uses classical tools from toxicology:
Cell-free assays: properties like solubility, reactivity, agglomeration state, reactive oxygen species (ROS) generating potential
In vitro assays: biological tests with primary cells, cell-lines, organs
Challenge: potential evidence for human disease?
In vivo studies: effects on a whole living organism – laboratory animals - (acute/chronic toxicity, skin, respiratory and gastrointestinal tract)
Challenge: extrapolation of the data to humans, extrapolation from higher to lower doses, safety factors?
Human and epidemiological studies: occurrence and distributions of diseases in populations
Challenge: diseases caused by which kind of kown or unknown hazard endpoint?
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6. Toxicity Mechanisms for Hazard Assessment
Hazard endpoints:
Structure – toxicity relationship (free radical activity, chemical reactivity)
Increased production of reactive molecules like (ROS)
Inflammation (recruiting immune cells)
Genotoxicity (damage or changes of the DNA)
Cytotoxicity
Predicting ? Identification ?
Safety endpoints (impact on human health):
Respiratory, cardiovascular disease, allergic sensitisation
Fibrosis, cancer, bronchitis, immunopathology (asthma)
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7. Material based View: Exposure Scenarios
Material (chemical composition)
Manufacturing
Manufacturing
Application
Human
Uptake, distribution, accumulation
Disease
Suspended
Embedded
Surface bound
others
cosmetics
Size distribution
Morphology
Aggregation
others
Form 1
Mat. 1
food
Form 2
Consumer
Mat. 2
others
others
others
Worker
Public
Environment
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8. Limitations for Exposure Assessment
Lack of labelling and registration of nanoproducts
Missing lifecycle assessment of nanoproducts
Measurement and detection: MPN undergo changes during transmission into the environment, difficulty to differentiate engineered from non-engineered materials
Insufficient data available
| Jutta Jahnel | ITAS |

9. Entry into the Human Body (Uptake)
Lung: most important port of entry for airborne particles, uptake via inhalation, occupational exposure
Nasal cavity: uptake via inhalation, direct exposition of the olfactory nerve
Gastro-intestinal tract: MPN can cross epithelial, endothelial barries, only very few studies available, important entry for food applications
Skin: penetration of damaged skin can not be excluded, important entry for cosmetic applications
Parenteral via direct injection (medical context with own criteria for risk assessment)
| Jutta Jahnel | ITAS |

10. Translocation and Distribution (ADME profile)
Penetration through the air–blood tissue barrier in the lung
Penetration of the blood-brain barrier and blood-placenta barrier
Transport by the lymphatic system
Transport into secondary organs
Enrichment in liver, spleen, kidneys, reaching heart
Very little is known about the metabolization, excretion and elimination
There are different kind of hazards:
at sites of deposition,
due to translocation from pulmonary portal of entry into the blood, systemic consequences could in theory result in additional health effects like neurophysiological diseases
| Jutta Jahnel | ITAS |

11. Challenges for Risk Assessment
Definition of Manufactured Particulate Nanomaterials (MPNs) – a large variety of materials, different sizes and forms with a lack of common characteristics beside the nanoscale, no hazard classes
Detection (biological, technical matrices) and characterisation: intrinsic limitations
Dose and amount of MPN: missing concept
Dose = total amount of substance / time period
amount: mass? surface area? particle number? reactivity?
Methodology for Hazard Assessment: classical toxicology, lack of standardised methods, appropriate controls, suitability of high dose in vitro or in vivo studies
Exposure assessment: insufficient data for occupational, environmental and consumer scenarios, acute and chronic exposure
Case by case assessment (full dataset for every kind of MPN)
Reliable evidence for risk assessment only for a small selection of high abundant MPNs
| Jutta Jahnel | ITAS |

12. Conclusions for Selected MPN
Relevant
Properties
Toxicity Mechanisms
Relevent Exposure
Relevant Uptake
Carbon nanotubes
Form
Number of walls
Functionalisation
Metallic impurities
Production of ROS
Inflammation
Cytotoxicity
Occupational
Lung
(inhalation)
Fullerenes
Chemical structure
Surface modification
Water solubility
Genotoxicity
Cancerogenicity
Cosmetics
Skin
(dermal)
Nano-TiO2
Neurotoxicity
Spray applications
Nano-Ag
Release of Ag
Drugs
Wound-dressings
ENRHES (2010): Engineered Nanoparticles: Review of Health and Environmental Safety.
| Jutta Jahnel | ITAS |

13. Recent Toxicological Research Situation
Published interpretations of experimental results, especially those regarding potential impacts on human health and on the environment, are still insufficient, contradictory and controversial (concerns about quality, comparability and relevance)
Results of ‚no effects‘-experiments are usually not published
Questionable extrapolation of laboratory data (hazard endpoints) to an human health impact (safety endpoint)
Filling knowledge gaps by modelling, meta-analysis, well-linked and cross-talk between nanomedicine, nanoengineering and nanosafety (interdisciplinarity)
Systemic view in addition to separate analytic views for providing useful answers that can be translated into actions
Pragmatic preliminary risk assessment (levels of concern, risk classes) Criteria: physico-chemical properties, exposure, extent of knowledge
| Jutta Jahnel | ITAS |

14. Thank You for Your Attention
Project Team:
Ulrich Fiedeler
Julia Haslinger
Myrtill Simko
Torsten Fleischer
Jutta Jahnel
Stefanie Seitz
Jutta Schimmelpfeng
| Jutta Jahnel | ITAS |