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Risk Assessment - Scientific Challenges A Perspective from the NanoSafety Project Team. Jutta Jahnel. NanoSafety Project. NanoSafety – Risk Governance of Manufactured Nanoparticles
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Risk Assessment - Scientific Challenges A Perspective from the NanoSafety Project Team JuttaJahnel
NanoSafety Project • NanoSafety – RiskGovernanceofManufacturedNanoparticles • Commissionedby STOA, carried out by KIT-ITAS, Karlsruhe (projectcoordination) and ITA, Vienna asmembers 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 | 21.11.2011
Preconditionsforriskassessmentstudy • The presentedresultsarebased on an up-to-date literaturereview • Working definition: Manufactured Particulate Nanomaterials (MPN) • Focus: safetyobjective „human health“ • Riskassessmentis a prerequisiteofscience-basedriskmanagementandmeansthequantificationoftheprobabilityofharmfuleffectscausedbyexposureto an agent • Situation:Thereisnogenerallyacceptedparadigmforriskassessmentfornanomaterialsorproductscontainingthem • Question: Couldscientificdataprovideappropriateknowledgeforpolicymakerstoperformriskassessment? | JuttaJahnel | ITAS | 21.11.2011
RiskAssessmentParadigm 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). | Jutta Jahnel | ITAS | 21.11.2011
Toxicity Tests for Hazard Assessment Nanotoxicologyusesclassicaltoolsfromtoxicology: • Cell-freeassays: propertieslikesolubility, reactivity, agglomerationstate, reactiveoxygenspecies (ROS) generating potential • In vitro assays: biologicaltestswithprimarycells, cell-lines, organs Challenge: potential evidencefor human disease? • In vivo studies: effects on a wholelivingorganism – laboratoryanimals - (acute/chronictoxicity, skin, respiratoryand gastrointestinal tract) Challenge: extrapolation of thedatatohumans, extrapolationfromhighertolowerdoses, safetyfactors? • Human andepidemiologicalstudies: occurrenceanddistributions of diseases in populations Challenge: diseasescausedbywhichkind of kownorunknownhazardendpoint? | Jutta Jahnel | ITAS | 21.11.2011
ToxicityMechanismsforHazardAssessment 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) | Jutta Jahnel | ITAS | 21.11.2011
Material based View: Exposure Scenarios Material (chemicalcomposition) 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 | Jutta Jahnel | ITAS | 21.11.2011
Limitations for Exposure Assessment • Lack oflabellingandregistrationofnanoproducts • Missinglifecycleassessment of nanoproducts • Measurement anddetection: MPN undergochangesduringtransmissionintotheenvironment, difficultytodifferentiateengineeredfrom non-engineeredmaterials • Insufficientdataavailable | Jutta Jahnel | ITAS | 21.11.2011
Entry intothe Human Body (Uptake) • Lung: mostimportantportofentryforairborneparticles, uptake via inhalation, occupationalexposure • Nasal cavity: uptake via inhalation, directexpositionoftheolfactory nerve • Gastro-intestinal tract: MPN cancrossepithelial, endothelialbarries, onlyveryfewstudiesavailable, importantentryforfoodapplications • Skin: penetrationofdamagedskincan not beexcluded, importantentryforcosmeticapplications • Parenteral via directinjection (medicalcontextwithowncriteriaforriskassessment) | Jutta Jahnel | ITAS | 21.11.2011
Translocationand Distribution (ADME profile) • Penetration throughtheair–bloodtissuebarrier in thelung • Penetration oftheblood-brainbarrierandblood-placentabarrier • Transport bythelymphaticsystem • Transport intosecondaryorgans • Enrichment in liver, spleen, kidneys, reachingheart • Verylittleisknownaboutthemetabolization, excretionandelimination Thereare different kind of hazards: • atsitesofdeposition, • due totranslocationfrompulmonaryportal of entryintotheblood, systemicconsequencescould in theoryresult in additional healtheffectslikeneurophysiologicaldiseases | Jutta Jahnel | ITAS | 21.11.2011
ChallengesforRiskAssessment | Jutta Jahnel | ITAS | 21.11.2011 • Definition of Manufactured Particulate Nanomaterials (MPNs) – a large variety of materials, different sizes and forms with a lack ofcommoncharacteristicsbesidethenanoscale, nohazardclasses • Detection (biological, technicalmatrices) andcharacterisation: intrinsiclimitations • Dose andamountof MPN: missingconcept Dose = total amountofsubstance / time period amount: mass? surfacearea? particlenumber? reactivity? • MethodologyforHazardAssessment: classicaltoxicology, 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 bycaseassessment (fulldatasetforeverykind of MPN) • Reliableevidenceforriskassessmentonlyfor a smallselectionofhigh abundant MPNs
Conclusionsfor Selected MPN ENRHES (2010): Engineered Nanoparticles: Review of Health and Environmental Safety. http://nmi.jrc.ec.europa.eu/documents/pdf/ENRHES%20pdf. | Jutta Jahnel | ITAS | 21.11.2011
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 | 21.11.2011
ThankYouforYour Attention Jutta.Jahnel@kit.edu Project Team: Torsten Fleischer Jutta Jahnel Stefanie Seitz Jutta Schimmelpfeng Ulrich Fiedeler Julia Haslinger Myrtill Simko | Jutta Jahnel | ITAS | 21.11.2011