Risk Assessment - Scientific Challenges A Perspective from the NanoSafety Project Team

KIT – University of the State of Baden-Wuerttemberg and National Research Center of the Helmholtz Association

INSTITUTE FOR TECHNOLOGY ASSESSMENT AND SYSTEMS ANALYSIS (ITAS)

www.kit.edu

Risk Assessment - Scientific Challenges A Perspective from the NanoSafety Project Team

Jutta Jahnel

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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 | 21.11.2011

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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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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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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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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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Material based View: Exposure Scenarios


Material (chemical composition)

Application Human

Consumer

Worker

Public

Uptake, distribution, accumulation

Disease

cosmetics

food

others

Mat. 1

Mat. 2

others

Manufacturing

Environment

Size distribution

Morphology

Aggregation

others

Suspended

Embedded

Surface bound

others

Form 1

Form 2

others

Manufacturing

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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


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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)


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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


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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

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Conclusions for Selected MPN

RelevantProperties

Toxicity Mechanisms

Relevent Exposure

Relevant Uptake

Carbon nanotubes FormNumber of wallsFunctionalisationMetallic impurities

Production of ROSInflammationCytotoxicity

Occupational Lung (inhalation)

Fullerenes Chemical structureSurface modificationWater solubility

Production of ROSGenotoxicityCancerogenicity

Cosmetics Skin(dermal)

Nano-TiO2 Production of ROSInflammationGenotoxicityNeurotoxicity

Spray applicationsOccupational

Lung (inhalation)

Nano-Ag Production of ROSInflammationGenotoxicityCytotoxicityRelease of Ag

DrugsWound-dressingsOccupational

Lung (inhalation)


ENRHES (2010): Engineered Nanoparticles: Review of Health and Environmental Safety. http://nmi.jrc.ec.europa.eu/documents/pdf/ENRHES%20pdf.

http://nmi.jrc.ec.europa.eu/documents/pdf/ENRHES%20pdf

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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

Recent Toxicological Research Situation


14 | Jutta Jahnel | ITAS | 21.11.2011

Thank You for Your Attention

[email protected]

Project Team:

Ulrich FiedelerJulia HaslingerMyrtill Simko

Torsten FleischerJutta JahnelStefanie SeitzJutta Schimmelpfeng

mailto:[email protected]

Documents

Risk Assessment - Scientific Challenges A Perspective from the NanoSafety Project Team