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

NanoSafetyCluster - Compendium 2012
Based on these issues, the key questions that were being
addressed within the NeuroNano project were directed towards
understanding the implications on each of these initial
observations, separately and in combination, on the potential for a
role for nanoparticles in neuro-degenerative diseases. Thus, the
overall objectives of the NeuroNano project are:
• To determine if engineered nanoparticles present a
significant neuro-toxicological risk to humans;
• to assess nanoparticle impacts on oxidative stress and
protein fibrillation;
• To correlate nanoparticle access to the brain with
induction of oxidative stress and/or protein fibrillation;
• To develop a simple screening and risk assessment matrix
for nanoparticles in neurodegenerative diseases.
Significant progress has being made in all areas of the project in
terms of clarifying all of the issues, and to date, no clear hazards
from the nanoscale have emerged.
2 Background
Neurodegenerative diseases currently affect over 1.6% of the
European population,(Alzheimer Europe 2006) with dramatically
rising incidence likely (in part) due to the increase of the average
age of the population. This is a major concern for all industrialized
societies. There is also some epidemiological evidence that
Parkinson’s disease is connected to environmental pollutants, and
it is often noted that historically, reports of Parkinson’s symptoms
only began to appear after widespread industrialization. There is
some general agreement that (for example) pesticides are
significant risk factors (McCormack 2002 ). There are also
persistent claims, based on epidemiology, that pollution may also
be a cofactor in Alzheimer’s disease, but here the evidence is
controversial. The risk that engineered nanoparticles could
introduce unforeseen hazards to human health is now also a
matter of deep and growing concern in many regulatory bodies,
governments and industry. Some comments about the topic have
appeared in the more general literature (Ball 2006; Phibbs-Rizzuto
2007).
The NeuroNano project builds on striking published findings, as
well as preliminary data from most of the project partners. Whilst
at the present time there is no evidence to suggest an association
between neurodegenerative disease and nanoparticles, given this
data is prudent to strengthen the confidence that no such link
exists. At present there is at most significant circumstantial
evidence that nanoscale particles could impact on such diseases.
The program will, mindful of the importance of the issues, exercise
extreme caution in interpreting the data, and a process of checking
in additional laboratories findings relating to a toxicity due to the
nanoscale will be implemented.
There is incontrovertible evidence that some engineered
nanoparticles (for example 6nm and 18nm gold nanoparticles),
entering intravenously or via the lungs can reach the brains of
small animals.(Kreyling 2007) Indeed, they lodge in almost all parts
of the brain, and there are no efficient clearance mechanisms to
remove them once there. Furthermore there are suggestions that
nanoscale particles arising from urban pollution reach the brains of
animals.(Elder 2007) The relevant particle fractions arise from
pollution but their structure and size are similar to engineered
carbon nanostructures. Secondly, any nanoparticles in contact
with tissue induce oxidative stress,(Brown 2001; Xia 2006; Brown
2007; Duffin 2007) as well as various inflammatory mechanisms
that could themselves lead to further oxidative stress (Block 2004;
Nel 2006). Finally, it has recently been discovered that
nanoparticles (many of significant industrial interest) can have
highly significant impacts on the rate of fibrillation of key proteins
associated with neurodegenerative diseases,(Linse 2007) and we
will report here significant new findings for the proteins associated
with Alzheimer’s (amyloid β) and Parkinson’s disease (α-synuclein).
Whilst the precise mechanisms leading to neurodegenerative
diseases are not fully clarified, it is broadly agreed that the key
effects involve the presence of early pre-fibrillar protein structures,
neuroinflammation and Reactive Oxygen Species (ROS)-related
processes. Thus, all of the links in the causal chain are now present
for a credible expectation that nanoparticles could have impacts
on the onset, progression or severity of neurodegenerative
diseases. The main ideas and interconnections between them are
laid out in Figure 1.
Figure 1. Overview of the interplay between various factors
regarding nanoparticle interactions with living systems that could
pose a risk for the development of neurodegenerative diseases.
This research program was deeply challenging, and entailed the
gathering of entirely new knowledge in a field
(neuronanotoxicology) that was itself emerging. It required the
marshalling of unique expertise, methodologies, techniques and
materials, many themselves completely new, and the whole never
before brought together in the required combination.
The overall science and technology objective of this program was
to determine if engineered nanoparticles could constitute a
significant neuro-toxicological risk to humans for
neurodegenerative diseases, such as Alzheimer’s and Parkinson’s
diseases. The project did not presume neurotoxic hazard, nor indeed
hope to discover such hazard. Thus, a major focus was on the
critical evaluation of the entire chain of reasoning leading to the
present concerns. This was achieved by the detailed determination
of cellular and molecular mechanisms involved along the whole
chain of effects induced by engineered nanoparticle-biological
interactions, all in a dose dependent manner. The emphasis on
mechanisms is important for it will advance the field of knowledge
of neuronanotoxicology, irrespective of whether any clear disease
endpoint emerges.
226 Compendium of Projects in the European NanoSafety Cluster