ISIS Report 04/12/03
As nanotechnology is moving into producing tonnes of nanoparticles,
Dr. Vyvyan Howard explains why
harmless materials become dangerous when shrunk to the nanoscale.
A more technical fully referenced version of this article is posted on
ISIS members website. Details here.
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" and "Nanoshells cure or
curse?" 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
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
The main questions on the safety of nanoparticles are:
- By what routes do UFPs get into the body and then where do they
- 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.
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