European Cooperation
in Science and Technology
- COST ——————————
Secretariat
------
Brussels, 4 July 2012
COST 4155/12
MEMORANDUM OF UNDERSTANDING
Subject :
Memorandum of Understanding for the implementation of a European Concerted
Research Action designated as COST Action TD1204: Modelling Nanomaterial
Toxicity MODENA
Delegations will find attached the Memorandum of Understanding for COST Action as approved by
the COST Committee of Senior Officials (CSO) at its 185th meeting on 6 June 2012.
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MEMORANDUM OF UNDERSTANDING
For the implementation of a European Concerted Research Action designated as
COST Action TD1204
MODELLING NANOMATERIAL TOXICITY MODENA
The Parties to this Memorandum of Understanding, declaring their common intention to participate
in the concerted Action referred to above and described in the technical Annex to the Memorandum,
have reached the following understanding:
1.
The Action will be carried out in accordance with the provisions of document COST 4154/11
“Rules and Procedures for Implementing COST Actions”, or in any new document amending
or replacing it, the contents of which the Parties are fully aware of.
2.
The main objective of the Action is to produce Quantitative Nanostructure-Toxicity
Relationships (QNTR) models for nanomaterials, through the coordination of interdisciplinary collaborations of different stakeholder parties.
3.
The economic dimension of the activities carried out under the Action has been estimated, on
the basis of information available during the planning of the Action, at EUR 36 million in
2012 prices.
4.
The Memorandum of Understanding will take effect on being accepted by at least five Parties.
5.
The Memorandum of Understanding will remain in force for a period of 4 years, calculated
from the date of the first meeting of the Management Committee, unless the duration of the
Action is modified according to the provisions of Chapter V of the document referred to in
Point 1 above.
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TECHNICAL ANNEX
A. ABSTRACT AND KEYWORDS
Nanotechnology produces engineered nanomaterials (ENM) having new or enhanced physicochemical properties in comparison to their micron-sized counterparts. Some of these properties, like
the high surface area to volume ratio, make them potentially dangerous to humans as shown by
research in NANOTOXICOLOGY. To promote the development of a new generation of ENM that
are SAFE-by-DESIGN, an understanding of the relationship between the ENM STRUCTURE and
the biological ACTIVITY is needed. In this context, Quantitative Nanostructure-Toxicity
Relationships (QNTR) computational modelling technique is an effective alternative to
experimental testing since it enables the prediction of (eco)-toxicological effects based on ENM
structure only. The construction of QNTR model requires the integration of expertise of
nanomaterial scientists, (eco)-toxicologists, and modellers from academia, regulatory agencies and
industry. Therefore, a network for trans-disciplinary cooperation is needed. Thus, this COST Action
(MODENA – Modelling Nanomaterial Toxicity) will promote and realise through the coordination
of these inter-disciplinary collaborations of different parties with the ultimate aim of producing
QNTR models for ENM. The important benefits from MODENA include: (i) the development of a
new generation of SAFE-by-DESIGN ENM; (ii) the effective reduction of animal testing and (iii)
The creation of transparent, validated and rigorous QNTR tools for regulatory purposes in the field
of nanotoxicology according to OECD principles.
Keywords: Key Words: Nanotechnology, Nanoscience, Nanotoxicology, QSAR, QNTR, Database,
Human Health, Toxicology, Ecotoxicology, Nanomedicine
B. BACKGROUND
B.1 General background
Nanotechnology is recognised as one of the most important new technologies of the 21st century.
The global investment in nanotechnology from all public sources for 2008 exceeds $7 billion. The
market size for nanotechnology is expected to grow to over $3 trillion by 2015 with an estimate of
50,000 products containing engineered nanomaterials (ENM). Nanotechnology promises new
materials for industrial applications by having new or enhanced physico-chemical properties that
are different in comparison to their bulk or micron-sized counterparts. However, as in all industrial
applications, the potential exposure of humans and the environment to these materials is inevitable.
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As these materials go through their life-cycle – from development, to manufacture, to consumer
usage, to final disposal – different human groups (workers, bystanders, consumers), animal species
(e.g. worm, fish or humans through secondary exposure) and environmental compartment (air, soil,
sediment, ground and surface water) will be exposed to them. Given the current pace of
development of ENM based applications and the current severely reduced time to market for new
ENM based products, risk assessors are challenged with the need to assess possible adverse effects
on strongly reduced timescales. A growing body of evidence has shown a range of toxic effects
from ENM, suggesting that even their low mass exposure will result in a risk to human health or the
environment. Furthermore, the toxicity of ENM can be attributed to some of their physico-chemical
properties such as surface area, charge or reactivity. Therefore there is a clear need for a better
understanding of the relationship between ENM properties and the adverse responses which they
evoke in living organisms. Clearly understanding this relationship will greatly help in designing
future ENM with the ‘safe by design’ approach. Identifying and quantifying the relationship
between ENM properties and the biological responses can be done by using Quantitative
Nanostructure-Toxicity Relationships (QNTR) models, which represent the extension to ENM of
the well-known Quantitative Structure-Toxicity Relationships (QSAR) models and can be used by
risk assessors and other stakeholders to effectively and quickly assess possible risk without the need
of extensive additional testing. With this COST Action, it will be possible harmonise all the
scientific advances that are necessary for the future use of reliable QNTR models in regulatory
contexts. Indeed, the European Union (EU) has set ambitious plans for the future of
Nanotechnology. Accordingly, the different member states and FP7 have made calls for proposals
to respond to these goals. This COST Action on the modelling of the toxicity of ENM by means of
QNTR will provide a robust mechanism for coordinating the research of leading-edge academic
groups within Europe in this area, focusing activities on key targeted areas rather than using the
normal fragmented approach. The involvement of industrial partners and of research groups will
also promote technology transfer between research organisations and industry and access to
essential data needed to advance QNTR. This Action has its strength in non-competitive research, in
flexible multinational cooperation and in solving cross-discipline challenges with the help of a
multidisciplinary approach. It will add synergy and added value to European research cooperation.
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B.2 Current state of knowledge
QTNR is ideal for a rapid assessment of toxicological hazards posed by ENM. The usefulness of
quantitative relationships that can model the impact of structural changes on toxicological endpoints
has been extensively proved in the pharmaceutical industry over several decades. Moreover, current
toxicological regulation, such as the Registration, Evaluation, Authorisation and Restriction of
Chemicals (REACH), strongly promotes the use of these predictive modelling. Available data are
so far insufficient or inadequate to meet this need. This is because research to determine impacts of
ENM on diverse biological systems, although essential for assessing their hazard, is timeconsuming and expensive, and has ethical implications when animals are used. In silico methods for
predicting biological effects of nanomaterials play an important, complementary role to that of
experimental researches. Due to the complexity of interactions of ENM with living organisms and
the increasing use of high-throughput content screening methods to generate large in vitro datasets,
risk analysis, statistical modelling and machine learning methods (e.g. neural networks) are
becoming methods of choice. They have been applied successfully to development of
pharmaceuticals and crop protection agents over the past several decades.
QSAR methods are increasingly being used by regulatory agencies for chemical risk assessment.
They have also been applied more recently to modelling the properties of materials, including
nanomaterials. Although QSAR techniques have only started to be used to predict biological effects
of nanomaterials they have shown encouraging initial results. However, nanomaterials present
significantly different obstacles to modelling compared to drugs and industrial chemicals because
their specific properties, such as size, shape, surface area, surface reactivity, so QNTR modelling
are therefore needed. Issues pertinent to the development of computational methods for modelling
nanomaterial properties and their biological effects will be central to this COST Action, together
with developments in research that are required if the regulation of nanomaterials is to be assisted
by computational tools within the next decade.
Application of QNTR involves several steps. Firstly, chemical or structural properties of ENM are
represented by mathematical objects called descriptors, many of which can be calculated or
measured.
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Examples of descriptors suitable for ENM include particle size, shape and surface area, ionisation
potentials of metals, heats of formation of metal oxide clusters, band gaps, zeta potentials, and
physicochemical properties (e.g. lipophilicity, hydrogen bond donor or acceptor strength) of
molecules covalently bound to ENM surfaces. Secondly, using additional mathematical techniques,
subsets of descriptors are chosen that are most likely to relate to the biological property (e.g. cell
apoptosis, metabolism, or signalling pathway modulation) being modelled. Statistical modelling or
machine learning methods, for example neural networks, generate mathematical models linking
descriptors to biological activity. Finally, the model’s robustness and ability to predict properties of
new materials is assessed by statistical cross-validation techniques, or by predicting properties of
materials in a test set not used to develop the model.
It is therefore clear that the QNTR models require considerable amount of data. Thus, identifying,
collecting and harmonising different datasets are important to the construction of QNTR models.
QNTR is ideal for rapidly exploring the effects of a large number of variables in complex scenarios
and has proven very useful in the pharmaceutical industry over several decades. Many important
pharmaceutical products now on the market were discovered and optimized in the past following
this QSAR approach (e.g. sulfamethoxazolo, cefalotin and analogs, and captopril). Examples of
statistical or machine learning methods used in the context of QNTR are neural networks, decision
trees, and support vector machines which are aimed to model the relationships between the
molecular structure and the biological properties. These are well validated and tested methods that
have been improved substantially over the past decade by incorporation of recent developments in
mathematics and statistics. QNTR can be used to form “categories” of similar structures whose
physicochemical and toxicological properties follow a regular and predictable pattern that can be
easily and confidently adopted as toxicological evidence for hazard assessment. The regulatory use
of chemical categories is promoted by international regulatory bodies because it provides a sound
basis for effective communication among all the stakeholders who will give different weight to
various decision criteria such as cost, efficacy and safety. The methods are robust and intrinsically
applicable to modelling a wide range of properties including material properties and biological
effects.
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Preliminary work demonstrates that QNTR shows considerable promise for modelling ENM toxic
effects but scientific research on specific aspects of QNTR modelling (e.g. pristine ENM versus
ENM in biological environments) is still in their infancy and needs to be harmonised among
different disciplines. QNTR are also useful for predicting toxic effects of new ENM based on their
materials properties and for classifying ENM according to common properties or common
biological endpoints. Ultimately, the predictive power of QNTR will lead to considerable reduction
in the use of animal experimentation in the safety and hazard assessment of ENM.
B.3 Reasons for the Action
This Action will contribute to the promotion of European co-operation between scientists from
different COST countries. Some of the participants were actively involved in organising and
promoting the COST sponsored QNTR workshop in Maastricht (2011) where it emerges that the
complexity of the studied phenomena the participation of scientists, from different disciplines, is an
indispensable issue for an effective progress of QNTR. QNTR will bring together, with to the
crucial support of computer sciences (database, data mining) and mathematics, the considerable
knowledge in Metrology, exposure sciences, mammalian toxicology and eco-toxicology and
advanced material science.
This multi-disciplinary collaboration will put Europe at the forefront of ‘SAFE-by-DESIGN’
Nanotechnology, a topic with far reaching economic and environmental impact. Furthermore, the
development of QNTR as a tool for hazard assessment of ENM will also be useful for regulatory
agencies and industry while permitting to rationalise knowledge in advance material science and
(eco)-toxicology. The contribution of QNTR towards the reduction in animal experimentation for
regulatory purposes is especially important.
Finally, this co-operation is also an opportunity to involve and train young researchers by world
class scientists to create the critical mass for a sustainable future research in QNTR. This will also
strengthen capacity building and training programs to assist a harmonised scientific approach.
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B.4 Complementarity with other research programmes
Nanotechnology is central to the Economic Agenda of the European Union. The 7th Framework of
the EU has devoted a nanomaterials process (NMP) platform to promote research in
Nanotechnology which includes the research programmes on the safety of ENM. Of interest are the
recurrent Seventh Framework Programme (FP7) calls from the NMP platform on modelling the
toxicity of nanomaterials. This strategy is also being pursued in many European countries in their
national research and development programmes. QNTR modelling is also of interest to international
regulatory bodies and has been in included as a topic for inclusion in the Steering Group 7 (SG7)
discussion on alternative tests for ENM.
C. OBJECTIVES AND BENEFITS
C.1 Aim
The main objectives of the COST Action are: (i) to create and implement a road map for the
development of reliable QNTR models and associated tools; (ii) to bring together the expertise of
several scientific communities that currently lack interaction so that they will enable fast progress in
developing generic approaches to the use of QNTR techniques; (iii) to train of the new generation
of scientists by providing a pool of unique European and international acclaimed experts. The
fulfilment of these objectives will impact positively the future career of young scientists by
providing state-of-the-art network infrastructures. Furthermore, the Action believes that regular
workshops and schools will also contribute substantially to sharing the expertise of scientists
working on the development of QNTR with groups in industry and governmental regulatory agency
and will thus enable a rapid and operational knowledge transfer across the nanosafety and
nanomedicine stakeholders in order to create critical mass. In this respect it should explicitly be
noted that the field of QNTR and its applications is multidisciplinary by definition.
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C.2 Objectives
To reach the main objectives, the following secondary goals have been defined:
i)
To create a European network of experts, from Academia, National/European regulatory
agencies, European Technology platforms and clusters and Industry, working to promote the
exchange of expertise and information between these communities. The specific groups are
for:
ii)
1.
Synthesis and characterisation of ENM,
2.
Mammalian toxicology,
3.
In vitro toxicology
4.
Ecotoxicology,
5.
System biology,
6.
Informatics: Establishment of databases and modelling,
7.
Risk assessors
To train for the use of QNTR existing models designed and developed as part of research
programmes already funded at the national and European level (e.g. the FP7 NMP
programme).
iii)
To establish a strategy for further development of QNTR and promoting their use in
nanosafety and nanomedicine research and industry.
C.3 How networking within the Action will yield the objectives?
Objectives will be achieved through exactly planned operations like:
1.
Every participating country has their own national support project relevant to the development
of QNTR methods that can be used for the Action.
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2.
The main resources (manpower, equipment, infrastructure) and expertise needed to achieve
the goals of the Action are already available at the participating researchers (institutes,
universities and private sector collaborators) and put at the disposal of the Action, which
means effective, immediate start for the generation of results.
3.
Collaborators have quality-based working systems in required level certifying the outcomes
and concepts.
4.
There is systematic plan to achieve aims through multidisciplinary and scientific experts
network which have in their use the latest methods and tools.
5.
The experts know very well the prevailing scientific stage and its actual problems and what
needs to be developed.
6.
Among the participants there are researchers and risk assessors with experience in
computational models for regulatory purposes therefore ensuring that QNTR approaches will
be pertinent for hazard assessment according to the standards required by governmental
bodies and agencies operating within (eco)-toxicological regulations.
7.
The participants have extensive experience in managing and developing scientific programs at
European and International level.
C.4 Potential impact of the Action
As explained above, this COST Action has the potential to exert a positive impact in many ways
1.
Economically by promoting the development of new ‘safe by design’ ENM
2.
Regulatory by allowing risk assessors to rapidly take informed decisions on the possible risks
of newly developed ENM
3.
Scientifically (by overcoming all the scientific barriers and experimental fragmentation
leading towards the adaptation of the QSAR paradigm to ENM)
4.
Ethically (by refining, reducing and replacing the use of experimental animals).
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Some additional benefits linked to this Action are as follows:
1.
Predictions from QNTR can be used for the classification and labelling of ENM in the
framework of toxicological regulations such as the European regulation REACH and
international regulatory body activities.
2.
The participating groups, the larger scientific communities and many national and EU funded
programmes will benefit from advances in this field and the synergistic effects generated by
sharing of expertise and of teaching young scientists.
C.5 Target groups/end users
Results of the Action will not only be a significant benefit for scientists researching on the different
disciplines involved in the Action (e.g. materials science, (eco)-toxicology) but on European policy
makers who in view of the results will be able to launch new initiatives to develop safer ENM and
nanotechnology, and the public in general, who are really concerned about the potential health
problems and environmental effects of ENM. For this reason special efforts will be dedicated to the
assessment and communication of all the inherent uncertainties that could prove to be crucial during
decision-making on the basis of QNTR.
In this respect, the COST Action MODENA, which coordinates the scientific innovations within
Europe in this important area, has the potential for economic, environmental and societal benefits.
From this point of view, results of the Action have the potential for industrial and societal benefits;
not only in the sustainable, intelligent and inclusive Nanotechnology sector but positive effects will
also be observed in many other areas such as ethics and regulatory policy making.
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D. SCIENTIFIC PROGRAMME
D.1 Scientific focus
This Action will focus on the development and implementation of QNTR models. The three main
issues for QNTR are:
1.
Defining the biologically relevant entity
Unlike chemicals, the surface properties of nanomaterials can change in an environment-specific
manner. When they are taken up by humans a nano-bio interface (corona), consisting mainly of
proteins in the systemic circulation and of phospholipids in the lung, is generated. In the natural
environment, ENM may be coated with ions, proteins, or other molecules like humic substances,
depending on whether they are in a stream, soil or other compartment. Protein or phospholipid
binding to ENM in biological fluid is not a static process, being characterised by continuous
association and dissociation events that reach equilibrium, whereupon continued exchange does not
affect the corona composition. The composition of the protein corona may be considered a
fingerprint of a specific nanomaterial in a given compartment. However, if the nanoparticle moves
from one compartment to another (e.g. from the lung to blood), the corona will be modified and
changing the ENM properties over time. Another dynamic process occurring in biological systems
is the exchange between the agglomerated and the dispersed forms of ENM, which may change as
the environment changes and this is currently poorly understood. In addition, potential dissolution
of ENM in certain environments may be modified by the composition and surface coverage of the
corona. Modelling and prediction of the biological effects of nanomaterials requires a better
understanding of these dynamic processes through experiments. High throughput experimental
methods can give this information through rapid measurements of binding affinities of many
potential corona components and nanoparticle types, potentially many thousands of experiments.
This will allow the generation of QNTR models linking nanoparticle and adsorbent properties to the
resultant nanoparticle corona composition that can be used to predict corona formation more
broadly. The data can also parameterise and validate competitive binding models that predict corona
properties in different environments.
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ENM may enter the human body by various routes, such as the mouth, nose, skin or eyes. Methods
using radioactive tracers and magnetic resonance imaging can track movement of ENM around the
body. Other techniques such as electron and confocal microscopy can image ENM in cells. New
experimental techniques like scanning near-field ultrasonic holography and Focused Ion Beam
(FIB) allow much-improved imaging of the interaction of ENM with cells, increasing knowledge of
uptake and fate, as well as, effect on cell function. These methods require further development to
allow in vivo tracking of ENM at the typical concentrations in the body during likely occupational
exposure, to determine their kinetics of transport, and fate.
Once the nanoparticle characterisation, corona composition, and translocation data described above
become available in sufficient quality and for a wide range of environments and nanoparticle types,
we will gain the ability to understand and predict the bioactive species for ENM in many
environments. To this end, QSAR approaches can play a valuable role. They can model and predict
the in situ forms of ENM, and the time- and environment-dependent changes in the nanoparticle
composition from the high throughput experimental data.
2.
Selection of the right assays
Clearly, generation of large volumes of in vivo data is not possible from ethical or cost perspectives.
However, regulators need to estimate the potential hazard of a given nanomaterial in the workplace,
home, or environment. Consequently, it is essential to understand the major mechanisms of toxicity
for nanomaterials and define relevant in vitro testing procedures (assays) that can measure the toxic
effects of the nanomaterials and that correlate well with the effects of nanomaterials in vivo. The
selection of biological properties measured will almost certainly be end-use dependent, depending
on whether human or environmental effects are the subjects of concern. As with nanoparticle
characterisation, and corona composition measurement, high throughput and high content screening
(measuring several biological responses in cells simultaneously) in vitro toxicity assays developed
for the pharmaceutical industry can be adapted for ENM. This will greatly increase the amount of
nanotoxicity data that can be generated for use in modelling and to improve our knowledge of
mechanisms of toxicity of ENM.
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3.
Modelling the complex nanomaterial-biology interactions
In QNTR methods, the bioactive form of ENM for a given environment is converted into suitable
descriptors such as size, ionisation potential of metals, or number and types of functional groups in
surface modified ENM. In vivo or relevant in vitro, data together with physicochemical descriptors
that can effectively describe crucial structural properties that modulate (eco)-toxicological
endpoints are then used to train these models. For instance the mathematical representations of an
ENM (i.e. descriptors) can be applied to a neural network input layer and with a suitable number of
hidden layers the network generates a predicted value for the biological response at the output layer.
This is compared with experimentally measured biological responses for each nanoparticle in the
data set and the error used to modify the weights in the neural network to improve the predictions.
Once validated (i.e. with international regulatory body principles for QSAR validation), the model
can be used to predict properties of new nanomaterials, or to elucidate biological mechanisms and
processes.
The large volumes of data that the high throughput experimental methods referred to above will
allow the development of QNTR models for properties such as corona composition for specific
environments, in vitro. Such models will firstly allow in vitro responses of new nanomaterials to be
predicted and then allows experimental work to be focused more effectively by identifying
additional properties of particular concern. QNTR modelling of large data sets therefore requires
cycles of iteration to be established between experimentalists and modellers that will allow
predictions to be tested and subsequently, models refined. The refined models will be better
predictors of biological responses to new nanomaterials. Ultimately, in vivo effects of ENM are the
most important for regulatory purposes, although they are the most expensive and difficult to obtain
by experiment. The combination of results from in vitro assays (or predictions from QNTR models
of in vitro assays) and nanomaterials descriptors such as size, shape, composition, zeta potential,
elemental and molecular properties and corona composition constitute nanoparticle ‘fingerprints’
that can be used to derive QNTR models of in vivo activity.
Needless to say, there is a clear need for the construction of database to store and retrieve data for
modelling purposes. These databases can be considerably large and complex due to the types of
data stored. Data mining techniques will be needed to identify trends and patterns in these complex
datasets.
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Two of the major challenges to applying QNTR methods to modelling biological properties of
ENM are:
1.
insufficient experimental data on corona composition and in vitro and in vivo effects
(discussed above)
2.
the need for better ‘nanoparticle-specific’ descriptors. Nanomaterials differ substantially in
structure from small organic molecules for which the existing descriptors were developed.
Although existing descriptors work well for modelling some nanomaterials, it is clear that
further research is required to generate nanomaterials-specific mathematical descriptors.
D.2 Scientific work plan methods and means
The Action’s scientific program is divided into three Working Groups (WG) focusing on major
disciplines related to the development and use of QNTR. The Management Committee (MC), in
coordination with WG leaders and the Short-Term Scientific Mission (STSM) Coordinator will
create a Steering Committee for an efficient administrative and scientific management. Indeed, the
development of QNTR models requires the synergy among three areas of expertise: physical
Chemistry (WG1), (eco)-Toxicology (WG2) and Modelling (WG3). With to the harmonisation of
all the ongoing research in these fields, MODENA will provide an optimal network and “knowhow” for a successful interaction among them. The implementation and monitoring of the strategic
vision exposed in this COST Action will be overseen by the Steering Committee which will be
created in coordination with WG leaders and the STSM manager.
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WG1 Synthesis and Characterisation of ENM
This WG is responsible for the MODENA activities on synthesis and metrology of ENM. The
specific objectives of WG1 are to study the synthesis of ENM with controlled composition, size,
area and nano-texture and to develop of strategies to immobilise ENM in matrices, on substrates
with minimum effect on the desired properties and surface reactivity and identify the relevant
datasets for QNTR modelling. This rigorous approach will permit the development of QNTR
models on the basis of carefully characterised and selected ENM. The knowledge derived from
QNTR would help in designing new ENM that would minimise their potential hazard (i.e. the
SAFE-by-DESIGN concept). This information is the basis to assess structural, physicochemical and
toxicological features that will be related to property and toxicity.
WG2 Toxicity of ENM
This WG is responsible for the MODENA activities on toxicity and eco-toxicity of ENM by
identifying the relevant datasets. The specific objectives of WG2 are to study and assess the toxicity
and eco-toxicity prepared of the ENM prepared inWG1. WG1 and WG2 will interface to assess
relationships between toxicity parameters and structural, chemical and reactive features which will
deliver preliminary models for WG3. The choice of the (eco)-toxicological studies will be taking
regulatory requirements into account at an early stage in order to deliver models of practical interest
for all the stakeholders. Moreover, a direct interaction among (eco)-toxicologists and modellers will
enable the characterisation of toxicological dataset that are optimised for QNTR modelling. Indeed,
thus far, (eco)-toxicological studies have been conducted without taking into consideration criteria
that can permit the elaboration of effective QNTR modelling. In the context of this WG, (eco)toxicologists will have the unique opportunity to strengthen the interface between human and
environmental hazard assessment of ENM.
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WG3 QNTR modelling and Database
This WG is responsible for MODENA activities on identifying and quantifying the relationship
between ENM properties and the biological responses using the pertinent physiochemical
descriptors. It will also collect and organise the datasets identified in WG1 and WG2 by means of
databases. Special attention will be paid to the description of chemical interactions between surfaces
and biological molecules, in order to develop an insight into the rationale behind QNTR. This
analysis will enable the definition of specific physicochemical descriptors that are able to capture
specific properties of ENM as opposed to bulk materials. MODENA will also establish a close
collaboration between modellers and (eco)-toxicologists so that mechanistic considerations on
toxicological mode of actions will be taken into account when interpreting the logic underlying the
developed QNTR models. This approach will enhance the epistemological interpretation of the final
outputs of MODENA while enabling the definition of mechanistic chemical categories that are
currently used in the framework of toxicological regulations to fill data gaps. This WG will also
work closely with end users and risk assessors in industry and regulatory agencies.
In all WG, the following tasks are recurrent:
1.
Review state-of-the-art development in its target topic (WG1, WG2 and WG3);
2.
Contribute to Workshops and Training Schools and identify relevant European and
international scientists for invitation to these events;
3.
Identify and obtain relevant datasets, assess and identify the relevant uncertainties that could
impact on the predicted endpoints;
4.
Contribute to the MODENA website;
5.
Contribute to the scientific management of MODENA through progress reports;
6.
Contribute to the strategy for the development of QNTR.
7.
Contribute to the identification, recognition and dissemination of the established QNTR
models as animal replacement (based on the 3R’s – Reduction, Refinement and Replacement)
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E. ORGANISATION
E.1 Coordination and organisation
The Action organisations will follow the general COST rules described in the "Rules and
Procedures for Implementing COST Actions". The following positions will be created and named at
the first MC meeting during the Kick-off Workshop. These positions will be preferably assigned to
ESR (Early Stage Researchers) who will get directly exposed to science management and
coordination, giving them more visibility. Gender and age balance will be sought in every
organisation aspect of the Action, while keeping emphasis on excellence.
1.
The MANAGEMENT COMMITTEE (MC) Chair and Vice-Chair will coordinate the Action.
2.
The Action will have three scientific WORKING GROUPS (WGs). Each will have its WG
leader.
3.
A SHORT-TERM SCIENTIFIC MISSION (STSM) COORDINATOR will be established.
4.
A DISSEMINATION COORDINATOR will be established, who will take care of publicising
the scientific results of the Action, through its website and in coordination with other
initiatives, like elaboration of special issues in a journal or a dedicated booklet. An official
website will be developed to foster communication (intranet site) and dissemination (regular
web), as commented in section H.
5.
For a dynamic management, a STEERING COMMITTEE comprising members of the MC,
Chair, Vice-Chair, WG leaders and STSM Coordinator and Dissemination Coordinator will
be established. It will coordinate events such as conferences/workshops, dissemination
activities, Training Schools, Special issues. Regular meetings of the Steering Committee will
be held on telephone-conference or Internet basis for an efficient inexpensive management of
the Action. These decisions and their reasoning will be sent to the MC for approval, via
“written procedure” using Internet facilities. In any case, major issues will be handled directly
by the Management Committee at its annual meeting.
A KICK-OFF meeting will be held at the beginning of the Action in order to crystallise Action
details, publicise the Action and call for new members to join the defined WGs. A first MC meeting
will then be held to elect the MC Chair, Vice-Chair, WG leaders, STSM and Dissemination
Coordinators.
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E.2 Working Groups
The Action will coordinate a multidisciplinary collaboration and networking among complementary
groups. Continuous coordination and interaction of the research among WGs will be fostered by
Training Schools and STSM involving all WGs.
WGs will have annual meeting, celebrated during the Annual Workshop/MC meeting, to optimise
travel budget, so that most budget effort may concentrate on STSM’s and Training Schools, as the
key instruments to implement coordination of research activities among laboratories. Additional
WG meetings will happen by taking advantage of other events, like a conference at which WG
members may convene, and essentially via telephone conference and Internet means.
This Action stands on three WGs, as described in section D.2, focusing on major disciplines related
to different aspects of QNTR: WG1 on Synthesis and Characterisation of ENM; WG2 on Toxicity
of ENM and WG3 on QNTR modelling and Database.
E.3 Liaison and interaction with other research programmes
The Action will establish collaboration with Industry organisations. The Action will also be of
interest to other COST Actions, such as:
1.
TD1002 | European network on applications of Atomic Force Microscopy to NanoMedicine
and Life Sciences (AFM4NanoMed&Bio).
2.
MP0903 | Nanoalloys as advanced materials: from structure to properties and applications
(NANOALLOY)
3.
TD1007 | Bimodal PET-MRI molecular imaging technologies and applications for in vivo
monitoring of disease and biological processes
4.
FA0904 | Eco-sustainable food packaging based on polymer nanomaterials
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5.
CM1102 | Multivalent Glycosystems for Nanoscience - MultiGlycoNano
6.
TD1105 | European Network on New Sensing Technologies for Air-Pollution Control and
Environmental Sustainability – EuNetAir
7.
MP0701 | Composites with Novel Functional and Structural Properties by Nanoscale
Materials (Nano Composite Materials-NCM)
8.
CM1104 | Reducible oxide chemistry, structure and functions
9.
FA0904 | Eco-sustainable food packaging based on polymer nanomaterials
Communications with these Actions will be established as soon as this Action becomes operative.
Suitable relations include the invitation of members of these Actions for ‘Inter-Action’ lectures or
the formation of joint workshops. This Action will also be pro-actively in contact with the NMP F7
projects on Nanosafety, specially the projects on the ‘Modelling of the Toxicity of Nanomaterials’.
Finally, this Action will be in direct communication with the WG on Database and Modelling of the
NANOSAFETY cluster. This Action will also seek to contribute to the European Technology
Platforms and Clusters: ETP-Nanomedicine, EPOSS, Nanofuture, Pharmaceutical etc. where QNTR
methods will be needed.
E.4 Gender balance and involvement of early-stage researchers
This COST Action will respect an appropriate gender balance in all its activities and the
Management Committee will place this as a standard item on all its MC agendas. The Action will
also be committed to considerably involve early-stage researchers. This item will also be placed as a
standard item on all MC agendas.The positions described for Coordination and Organisation (E.1)
will be preferably assigned to ESR who will get directly exposed to science management and
coordination, giving them more visibility. Gender and age balance will be sought in every
organisation aspect of the Action, with emphasis on excellence.
An important mission for this Action is to rise a new generation of scientists whose training is at the
interfaces between medicine, biology, biochemistry, chemistry and physics so that they can efficient
understand, describe and handle the relationships between ENM features and their toxicology. For
that reason, this Action aims at exposing ESR to this multidisciplinary topic.
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A key element is a multidisciplinary training, not available elsewhere. For such a reason, the Action
will organise two Training Schools so that experienced well-known researchers from biology,
medicine, chemistry will train ESR with different backgrounds on the concept, methods and
technologies available. This will expose ESR to peers, senior researchers and methodologies that
will result in synergetic interbreeding of complementary knowledge addressing the same problem:
nanotoxicity. This Action will educate a new generation of researchers exposed.
During the Training School, the ESR will have chance to be exposed not only to the concept but
also to hands-on cases. Debate will be a key element in the Training Schools; ESR will present their
needs and their wealth of knowledge.
This TRAINING SCHOOL will be funded by the Action to COST members, but it will be open to
non-COST members. This will increase the visibility of the Action and help cross-fertilisation. To
increase the visibility of these Training Schools, they will be organised by COST in coordination
with other agencies, groups or universities particularly relevant in aspects of nanotoxicology.
In general, the organisation and coordination of activities like Training Schools, Workshops, WG
meeting, and positions defined for the Action management will essentially be assigned to ESR
members looking for a gender balance.
F. TIMETABLE
The Action will run on a 4-year basis. Some key aspects scheduled to occur in these years are
summarised below.
YEAR #1: The Management Committee (MC) of the Action will be formed at the beginning of the
year at a Kick-off meeting. This will increase the visibility of the action since it will be in the frame
of a workshop to trigger the visibility of the Action and call for new members to join the different
WGs already defined. This will consolidate the WGs. Research details will be better defined during
this period. After the first 6 months a first progress assessment will internally be made to nail down
research direction details. A Training School will be organised during the first year to expose WG
members to complementary disciplines and facilitate communication and multidisciplinary
collaboration.
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YEAR #2: Mid-term report (prepared during the annual MC/workshop meeting) will occur this year
and the progress of different research lines will be assessed. This time will be used to decide if
some activities are to be terminated and others to be promoted. This will be a key year for research
progress in different WGs and to foster collaboration among WGs based on the multidisciplinary
training delivered by the first Training School.
YEAR #3: The MC will meet once; the Working Groups meeting and workshop shall coincide with
the MC meeting. Based on the first year Training School, a second one will be scheduled for the 3rd
year, attending key formation demands. As in the previous, hands-on activities will be a key part for
solid training of ESR members. Sessions will be used to discuss how to implement developments
into research, protocols and regulations. The Annual workshop of this year will have particular
visibility, probably celebrating it next to a major international event relevant to some aspect of
toxicity. Action members and non-members will contribute to this conference, and we will organise
a special issue with selected papers to disseminate the state of the art and to show the contribution
of our Action to it.
YEAR #4: The MC will hold a concluding meeting at the end of the year, during which the Final
Report will be finalised. During this year, a Strategic Initiative Workshop shall be organised with
the goal to bring leading industry and academia fellows along with policy makers (in Europe, US,
Asia, and Oceania) together, and to create a forum to foster implementation of progress and
connection in the growing knowledge on Nanotoxicology, ENM synthesis/characterisation and
protocols. The workshop will have a final deliverable, in the form of a booklet with key
recommendations on Nanotoxicology, progress made in general analysed from the perspective of
the Action. It will bring an outlook on quantitative knowledge of nanotoxicology, challenges and
recommendations.
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Table 1 summarises the MODENA activities and Timeline.
YEAR
MONTH ACTIVITY
1st
MODENA kick-off workshop and first MC meeting. Appointment of Chair,
1
vice-chair, STSM coordinator, Dissemination coordinator, WG leaders and
Steering Committee. Call for WG membership applications
3
Deadline for WG membership applications
4
Definition of WGs, and start-up of activities
9
First TRAINING SCHOOL
12
Activity Report first year
2nd
18
Second MC meeting and MODENA workshop with WG meetings. Assessment
on Action progress and research lines and actions to be taken.
24
Mid-term report
31
Second TRAINING SCHOOL
33
Third MC meeting and MODENA workshop with WG meetings
42
STRATEGIC INITIATIVE WORKSHOP
46
Booklet based on conclusion from the Strategic Initiative Workshop
48
Final MC meeting and MODENA workshop with WG meetings
3rd
4th
G. ECONOMIC DIMENSION
The following COST countries have actively participated in the preparation of the Action or
otherwise indicated their interest: DE, ES, FI, FR, IE, IT, NL, SE, UK. On the basis of national
estimates, the economic dimension of the activities to be carried out under the Action has been
estimated at 36 Million € for the total duration of the Action. This estimate is valid under the
assumption that all the countries mentioned above but no other countries will participate in the
Action. Any departure from this will change the total cost accordingly.
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H. DISSEMINATION PLAN
H.1 Who?
The results will be disseminated to three target groups the scientific community (academy and
industry), to the policy makers and to the general public.
1.
Researchers in medicine, chemistry, biochemistry, biology, and medicine from Academia or
Industry. In particular, researchers close to nanotoxicity, nanomaterial synthesis,
nanomedicine, modelling and characterisation.
2.
Policy makers and agencies in charge of toxicity and public health in Europe, Asia, Oceania,
America and International.
3.
Public in general.
H.2 What?
The Action web-site will aim at all target audiences, it will be updated by the Action ́s
Dissemination Coordinator. Its contents will cover:
-
Fundamental on nanotoxicology, fundamentals on nanomaterials, fundamentals on
characterisation of nanomaterials and their industrial applications
-
State of the art and recent developments.
-
Case studies of general interest.
-
Link to scientific papers published by the Action
-
Link to any dissemination activity
It will serve as core material for final booklet based on the Action.
Target 1. Scientific and Industrial community will be reached via standard means used in the
scientific communication:
-
Articles in journals, reviews and books.
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-
Presentations at scientific conferences, international conferences and the Action’s annual
Workshop, which will be publicised and open to non-COST members.
-
Reports on the Action website.
-
Training Schools, open to non-COST members.
Target 2. Policy makers and agencies, will have access to the Action website and will receive
information from the Action, flyers will be prepared for their information. These will include place
the progress in its social and economic frame. A final Exploratory Workshop will be organised at
the end of the Action to trigger visibility of the progress and promote implementation of knowledge
developed in the Action.
Target 3. General Public. The Website is a key element. In addition, the Action will make:
-
Articles in science magazines and newspapers.
-
V and web-based science shows/sites
-
Radio or TV interviews.
-
Take advantage of science dissemination activities organised by local governments and
science museums.
H.3 How?
1.
Each Action member will acknowledge COST funding in peer-reviewed papers, conference,
website, and general dissemination initiatives. Each Action member will also highlight COST
funding at conference presentations and,if possible, say some words about it.
2.
COST logo will be at conference presentations and website of each WG laboratory member,
with active links to COST general site and this Action website.
3.
Action´s Annual Workshop and Training Schools will have maximum visibility in academia
and industry, through website, event announcement and alerts at dedicated websites about
forthcoming events. Workshops and Training Schools allow direct feedback and interaction.
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4.
Each Action Member at an interview or program in the media will mention COST support.
5.
All Action members will contact the members’ university/research centre dissemination agent
to use their means and will pro-actively contact press, radio, TV, web media when groundbreaking and general interest developments are achieved.
6.
All these initiatives will be reflected on the Action website.
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