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ISIS Press Release 04/12/03
Nanotox
*******
As nanotechnology is moving into producing tonnes of nanoparticles, Dr. Vyvyan
Howard (c.v.howard@...) explains why harmless materials become
dangerous when shrunk to the nanoscale.

A more technical fully referenced (http://www.i-sis.org.uk/full/NanotoxFull.php)
version of this article is posted on ISIS members’ website. Details here
(http://www.i-sis.org.uk/membership.php).
Introduction

The nano-technology industry has begun the bulk production of nanoparticles,
especially ultrafine particles for a range of commercial applications, from
titanium dioxide in sunscreens to carbon nanotubes for molecular electronics
(see "Nanotubes highly toxic" ( http://www.i-sis.org.uk/nanotubestoxic.php ) and
"Nanoshells cure or curse?" ( http://www.i-sis.org.uk/nanoshells.php ) this
series). Manufacturers are moving into production levels in excess of 100 tonnes
per annum.
Particles that can be breathed in are classified as: coarse (average diameter
less than 10micron); fine (average diameter less than 2.5 micron); and ultrafine
(average diameter less than one micron). One micron (m) is one millionth of a
metre and 1 000 nanometres (nm).
We have two defence mechanisms in the lung to deal with particles breathed in.
The first is a carpet of mucus that lines all but the most peripheral parts of
the lung. This carpet moves slowly upwards, carrying particles that have landed
on it, and is then swallowed. Particles that make it through this carpet of
mucus, which tend to be fine and ultrafine, get into the air sacs where gas
exchange between the air and the blood takes place. The surfaces of the air sacs
are patrolled by macrophages, scavenger cells that mop up particles. However,
macrophages appear to have difficulty recognising particles less than 70nm in
diameter, and in addition, they can be easily overwhelmed by too many particles.
It is illuminating to consider the types of particles we were exposed to
throughout the course of evolution. These consisted mainly of suspended sand and
soil particles and pollen grains; most of which are relatively coarse and are
trapped in the mucus before getting to the alveoli. There have always been
ultrafine particles (UFPs), mainly consisting of minute crystals of salt, which
become airborne through the action of the sea waves. These salt particles are
not toxic, however, because they are soluble in water. For particles less than
70 nm in diameter, there was nothing much in the air throughout our prehistory
of particular concern until we harnessed fire for use in our everyday life.
Research is revealing that when normally harmless bulk materials are made into
UFPs, they tend to become toxic. Generally, the smaller the particle, the more
reactive and toxic it becomes. This should come as no surprise, because that is
exactly how catalysts are prepared to enhance industrial chemical reactions. By
making particles of just a few hundred atoms, you create an enormous amount of
surface, which tends to become electrically charged and thus chemically
reactive. The upper size limit for the toxicity of UFPs is not fully known, but
is thought to lie between 65 and 200nm.
There is evidence that chronic exposure to particulate aerosols leads to
long-term health effects, primarily on the cardiovascular system. Most of these
studies have used coarse particles to assess the effects. More studies are now
using fine particles, though the question of whether it is more predictive of
harm than coarse particles is till being debated. There is also evidence that
short term effects from poor air quality is due to particle overloading. The
number of studies that have used UFPs is low, but there are indications that
UFPs are more hazardous than fine particles.
The main questions on the safety of nanoparticles are:
By what routes do UFPs get into the body and then where do they travel to?
What is the mechanism of toxic action and how does the reactive surface of UFPs
interact with the ‘wet biochemistry’ in the body?
What is the relative contribution of particle size versus particle composition
in the overall toxicity of UFPs?
Evidence of potential harm associated with UFPs comes from studies on toxicology
and absorption and fate of UFPs in whole animals and studies on mechanisms of
toxicity in cells and tissues.

Question 1. Routes of access into, and travel around, the body
***********************************************
First, it should be noted that there appears to be a natural ‘passageway’ for
nanoparticles to get into and subsequently around the body. This is through the
openings in the natural membranes, which separate body compartments. These
openings are between 40 and 100 nm in size and are thought to be involved in the
transport of macromolecules such as proteins, and on occasion, viruses. They
also happen to be about the right size for transporting UFPs. Most of the
research on that has been performed by the pharmaceutical industry interested in
finding ways of improving drug delivery to target organs. This is particularly
so for the brain, protected by the ‘blood brain barrier’. It appears that
chemists are able to design UFPs that can hoodwink certain membranes into
allowing ‘piggybacking’ of novel chemicals across membranes that would not be
possible otherwise, and UFPs have already been made that can enhance drug
delivery to the brain.
Although this can offer clear advantages, the obverse of this particular coin
needs to be considered. When environmental UFPs (as from traffic pollution) gain
unintentional entry to the body, it appears that there is a mechanism that can
deliver them to vital organs. The body is then ‘wide open’ to any toxic effects
that they can exert. The probable reason why we have not built up any defences
is that such environmental UFPs were not part of the prehistoric environment in
which we evolved and therefore there was no need to develop defensive mechanisms
against them.
There is considerable evidence that inhaled UFPs can gain access to the blood
stream and are then distributed to other organs in the body. This has been shown
for synthetically produced UFPs such as bucky-balls – a form of carbon in which
60 carbon atoms are arranged like a football - which accumulate in the liver.
Another possible portal of entry into the body is via the skin. A number of
sunscreen preparations now available have incorporated nanoparticle titanium
dioxide. Recent studies have shown that particles of up to 1 m in diameter
(within the category of UFPs) can get deep enough into the skin to be taken up
into the lymphatic system, while particles larger than that were excluded. The
implication is that UFPs can and will be assimilated into the body through the
skin. The exact proportion of those deposited on the skin, which will be
absorbed, remains unknown. Using post mortem human skin, it has been shown that
dextran beads 0.5 to 1m can penetrate the rough outer layer (stratum corneum) of
the skin when flexed. The penetration occurred in over 50 % of the samples if
flexing was continued for 1 hour. In a small proportion of cases, the beads got
as far as the dermis (inner layer of the skin).

Question 2. The mechanism of toxic action
********************************
Studies on laboratory animals have looked at the ability of UFPS to produce
inflammation in lungs after exposure to UFP aerosols. The degree to which UFPs
appear to be able to produce inflammation is related to the smallness of the
particles, the ‘age’ of the aerosol and the level of previous exposure. It has
been proposed that the chronic inhalation of particles can set up a low grade
inflammatory process that can damage the lining of the blood vessels, leading to
arterial disease.
Studies on cells have confirmed the increased ability of UFPs to produce free
radicals that cause cellular damage. This damage can be manifested in different
ways, including genotoxicity and altered rates of cell death.

Question 3. Particle size versus particle composition
****************************************
Early indications were that certain metals might be more toxic as UFPs than
other materials. Since then, other studies have shown very similar toxicities
between different materials when presented as UFPs, for example latex and
titanium dioxide. More recently, attention is being concentrated on the effects
of ultrafine carbon black. What seems clear from all the papers is that exposure
of living systems to UFPs tends to increase oxidative stress, and therefore, the
effect of small size is considerably more important for UFP toxicity than the
actual composition of the material.

Conclusions
*********
There is evidence that UFPs can gain entry to the body by a number of routes,
including inhalation, ingestion and across the skin. There is considerable
evidence that UFPs are toxic and therefore potentially hazardous. The basis of
this toxicity is not fully established but a prime candidate for consideration
is the increased reactivity associated with very small size. The toxicity of
UFPs does not appear to be very closely dependent on the type of material from
which the particles are made, although there is still much research to be done
before this question is fully answered.
Dr. Vyvyan Howard is histo-toxicologist at University of Liverpool. A version of
this article first appeared as annex to "No Small Matter II: The Case for a
Global Moratorium" www.etcgroup.og


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