Timing, hosts and locations of (grouped) events of NanoImpactNet

vitro findings with in vivo models; (iv) for Exposure and Risk
Assessment: To use data from this project and other sources
(including US data) to: (1) model exposure and the exposuredose-response
relationships by means of mathematical
modelling such as PBPK and QSAR-like methods, and extend
these deterministic models into probabilistic models (2) to
conduct the risk assessment with uncertainty analysis; (v) for
Risk Management: To develop and implement a strategy for
dissemination to maximize the anticipated high impact of our
findings.
Physico-chemical characteristics
(size, shape, surface area, charge, reactivity etc...)
Concentration,
duration
Sources
(workplace, ambient)
Exposure
Deposition
Dosemetrics
(specific surface area, length, etc...)
Distribution in
target organs (lung, liver etc...),
excretion, clearance
Dose Response
Fig 1. The Exposure-Dose-Response paradigm
The main deliverables of ENPRA are:
Oxidative stress
Inflammation
Genotoxicity
Fibrosis
Developmental toxicity
A novel risk assessment approach – with uncertainty analysis -
specific to ENP;
In vitro and in silico models of exposure-dose-response
relationships for 5 target organs and 5 endpoints to be used for
the hazard assessment of ENP and considered for highthroughput
screening tests;
In vivo models for the hazard assessment of ENP to
complement the REACH and OECD guidelines.
The rationale of the ENPRA project is to generate essential data
on ENP characteristics and toxicity to be used with data from
other sources for a risk assessment of ENP.
Using the traditional Risk Assessment approach as starting
point, our approach consists of:
Hazard Identification: We will implement (i) a comprehensive
set of measurements of the physico-chemical characteristics of
ENP, both in bulk samples and in body tissues; (ii) common
protocols for ENP characterization and preliminary validation of
measurement techniques; (iii) relationship between particle
characteristics and hazards.
Dose-Response Assessment: We will implement a development
of in vitro testing systems using models representing the most
important target systems affected by ENP.
These in vitro tests need to be verified with in vivo models,
(carefully designed to minimize the numbers of animals used
and/or their inconvenience).
The verified tests will be validated by a round robin process
between the ENPRA partners.
NanoSafetyCluster - Compendium 2012
The selected in vitro tests could then be integrated as part of a
low-cost, high-throughput screening test system, as a cost
effective way of testing a large number of ENP expected to
enter the EU market in the near future.
The in vitro data will be used to develop a QSAR model linking
ENP characteristics with the adverse effects.
The in vivo models will also be considered as additions to OECD
guidelines for regulatory toxicology tests of ENP.
The design of our in vitro and in vivo studies takes into account
the need to promote the principles of 3R.
Exposure Assessment: We will review existing exposure models
in the public domain; Collect exposure information from existing
EU and National Project and from our US partner; Construct a
model of ENP exposure in occupational settings; Extend the
traditional risk assessment approach by quantifying the
uncertainty in ENP exposure.
Risk Assessment: We will extend the current risk assessment
approach to ENP by building mathematical models of exposuredose-response,
including uncertainty analysis, to be used in
estimating the DNEL and make comparison to the values
obtained in Exposure Assessment.
Risk Management: We will implement a communication strategy
to bring the ENPRA results to stakeholders including
government agencies and Nanotechnology industry.
The approach proposed by ENPRA is in line with the grand
challenges described in our article in Nature4. The rationale of
ENPRA is summarised graphically in Figure 2.
The ENPRA Consortium To implement the ENPRA plan, we have
assembled a consortium of 21 partners (15 Europeans and 6
Americans) with an excellent academic record measured in
hundreds of publications on Nanotoxicology (and three relevant
articles in Nature and Nature Nanotechnology). Our partners
also include prominent members of government bodies,
participating in the regulatory process, on both sides of the
Atlantics (e.g. JRC and US EPA, NIOSH). Most importantly,
different groups within the ENPRA consortium have experience
in working together in FP projects as well as other national
projects and will be able to share their extensive experience on
working with ENP in achieving the objectives laid out in ENPRA.
Hazard Identification
Panel of ENP
with measured
list of
physico-chemical
properties
Dose-Response Assessment
in vivo
dose-response
Risk Assessment
Assess Risk
by comparing
exposure level with DNEL
Compendium of Projects in the European NanoSafety Cluster 17
in vivo
models
in vitro
models
in vitro
dose-response
Establish
QSAR model
Exposure Assessment
Probabilistic Model of
Derived
Exposure
No Effect Level
(Intensity, frequency)
(DNEL)
Combining
Exposure and Hazard
for Uncertainty Analysis
Probabilistic
PBPK/PD
model
in vitro/in vivo
comparison
Development of
toolbox of
alternative tests
Extrapolation
Fig 2. The rationale of the ENPRA approach
Estimation
Human
Dose-Response
Risk Management
Dissemination and Impact
Inform
regulatory
processes,
stakeholders
promote
refine
reduction
replacement (3R)
of animal expts