Download Nanotechnology and the occupational physician

Occupational Medicine 2006;56:312–316
doi:10.1093/occmed/kql053
IN-DEPTH REVIEW
...............................................................................................................................................................................................
Nanotechnology and the occupational physician
Anthony Seaton
...................................................................................................................................................................................
Abstract
Nanoparticles differ from the same material at larger scale in chemical and physical properties.
Evidence from studies of fibres leads to the conclusion that inhalation of nanotubes could be
dangerous and should be regulated. Air pollution research has suggested that particles may be more
toxic to cells at the nanoscale. At present the marketing of nanoparticles is advancing more rapidly
than research into their safety and toxicology, and one serious inhalation episode has been reported
in Germany from apparent use of a nanoproduct. This rapidly developing industry will make an
impact on the work of occupational physicians, first in universities and small concerns but later more
widely. The future safety of workers and consumers is dependent on research into hazard and risk,
an area in which the UK and most other countries are dragging their feet. However, a resource,
the Safety of Nanomaterials Interdisciplinary Research Consortium, has been established in the
UK to assist those active in this field.
...................................................................................................................................................................................
Key words
Nanoparticles; nanotubes; occupational exposure.
...................................................................................................................................................................................
Introduction
It is a commonplace that all new technologies arrive to
a fanfare, which is later followed by a reaction as adverse
consequences become apparent. More recently, this experience has led to a tendency for proponents of the new
to indulge in hyperbole about possible benefits to mankind or the environment while opponents predict dire
consequences from its application. The media tend to
prefer the dramatic, and publicize both extreme views,
leading to the public getting a distorted message depending on the source from which they derive their information. In the case of genetic modification, this led to very
restricted application in Europe of a technology that promised many benefits, the media having generally taken
the message of those opposed to it. It has to be understood
that nobody is disinterested in this process: the media
wish to sell their product, the enthusiasts wish to promote
their research or product and the opponents wish to publicize their cause and increase their sources of funding.
As the preceding papers make clear, nanotechnologies
present major economic and academic opportunities
wherever they may be developed, and the world’s largest
economies are already taking advantage of the possibilities they present. Benefits are likely to come from their
exploitation; are we able to predict and prevent adverse
consequences? With this in mind, the UK Government
Institute of Occupational Medicine, Edinburgh, UK.
Correspondence to: Anthony Seaton, Institute of Occupational Medicine,
Research Park North, Riccarton, Edinburgh EH14 4AP, UK.
E-mail: [email protected]
requested the Royal Society and Royal Academy of
Engineering [1] to set up a Working Group to consider
the opportunities and uncertainties and to advise on what
new regulation might be desirable. The Working Group
was broadly based, its members ranging from consumer
advocates and social scientists to engineers and nanoscientists. In this paper, I consider the main conclusions
of the Working Group in relation to hazards and how these
might impact on the role of occupational physicians.
Hazards and risks of nanomaterials
It is of course possible to predict that developments in
nanotechnologies, leading to faster communications,
greater miniaturization of devices, more effective explosives, more devastating armour-piercing shells and so on,
may be exploited to someone’s detriment, but these are
risks associated with many new technologies and not
confined to those in the nanofield. In considering specific nanotechnological risks, the Working Group concentrated on nanoparticles, in other words discrete pieces
of matter that had uniquely new properties because of
their scale. It is pertinent to recognize that matter will
not be produced at such small sizes unless it has exploitable properties that make it behave differently at that
scale. These properties are likely to affect not only its
chemistry and physics but also its behaviour in biological
systems. Here, it is possible to find some evidence by analogy with what is already known about exposure to more
mundane particles in the nanosize range. Two of these
are asbestos and combustion-generated nanoparticles.
The Author 2006. Published by Oxford University Press on behalf of the Society of Occupational Medicine.
All rights reserved. For Permissions, please email: [email protected]
A. SEATON: NANOTECHNOLOGY AND THE OCCUPATIONAL PHYSICIAN 313
What can be learned from the asbestos
experience?
While the risks from asbestos exposure are well known to
occupational physicians, the reasons that asbestos causes
these diseases are perhaps rather less so. The 2000 people who die each year currently in the UK from mesothelioma do so because of some specific properties of
asbestos that also made it the remarkably useful material that it once was. Its many applications relied on its
fine fibrous nature and its resistance to degradation—
its indestructibility. It is now known that its toxicity
depends on the diameter of individual fibres (it can be
inhaled to respiratory bronchiole level if 3 mm in diameter), the length of the fibres (they are not removable by
macrophages if 15 mm in length) and its resistance
to dissolution in the lung. Thus, fibres gain access, cannot be removed and ultimately cause an inflammatory
reaction that leads to fibrosis and carcinogenesis [2].
These physical properties, together with another that
depends on the chemical reactivity of the fibre’s surface,
dictate its hazard, and the risk from inhalation then
depends on individual dose. All fibres would be expected to conform to this rule, the differences between
them depending on subtle differences in their physicochemical constitution. Thus chrysotile asbestos is
generally less likely to cause mesothelioma than the amphiboles as it is more soluble in lung, while the naturally
occurring erionite, that caused mesothelioma in villagers
in Turkey, is more dangerous because of increased surface reactivity.
Carbon and other nanotubes are even finer than asbestos fibres and may be produced at lengths that would
make it difficult for them to be removed if inhaled. They
are also extremely strong and likely to persist in tissue
once introduced. It is predictable that, if inhaled in sufficient quantity, they could cause mesothelioma. As
pointed out by Paracelsus, dose is critical. Individuals
dying from asbestos diseases usually have millions of fibres per gram of dried lung tissue, the consequence of
exposures of several fibres per millilitre (or more realistically, hundreds of fibres per breath or millions of fibres
inhaled per day) over several months or years of exposure.
It follows from this that tight regulation of a new nanotube industry will be required to prevent exposure not
only of production workers but also of those who may
be exposed ultimately in the use and disposal of products containing the tubes. At present, the nascent industry is small and the tubes adhere together tightly
in clumps; it is predictable that this will not always be
the case.
The lessons from air pollution research
When combustion occurs, nuclear particles of carbon are
formed that aggregate together into somewhat larger but
still nanometre diameter masses. Interest in the toxicity of
such particles arose from the convergence of two streams
of research: one, by Oberdörster and his colleagues in
Rochester, NY, USA, had been investigating the deposition and clearance of nanometre-sized particles in the
lungs of rats [3], while the other, by US epidemiologists,
had shown relationships between air pollution and deaths
at remarkably low concentrations [4]. In an attempt to
explain these latter observations, particularly relating to
death from cardiac disease, it was suggested that such
very small (primarily carbon) particles could exert toxic
effects because of their ability to cause inflammation and
secondary effects on blood coagulation when present in
very large numbers, even though the total mass inhaled
was very small [5]. Subsequent epidemiological work has
given limited support to this complex hypothesis, in
showing some evidence of changes in inflammatory
markers and coagulation factors in relation to air pollution exposure, but as yet little evidence that such effects
are due particularly to the nanometre-sized particles. On
the other hand, there is now considerably more experimental evidence that nanoparticles are markedly more
toxic than the same material at a larger scale [6]. Some
of this enhanced toxicity may be explicable in terms of
surface contamination—air pollution particles, for example, are usually contaminated by metallic ions and
organic molecules—but size alone seems also to be
important. Below about 40 nm diameter, particles behave differently not only physically but also possibly in
the way they interact with cell membranes [7]; indeed,
there is evidence that inhaled nanoparticles may even
access the brain, perhaps by neural conduction along
olfactory or trigeminal nerves [8].
With respect to lung toxicity, there is sufficient evidence to conclude that for all inhaled particles, a primary
determinant of toxicity is total inhaled surface area and
that this is increased or decreased by additional properties of the surface, particularly its ability to release free
radicals in reaction with tissue [9,10]. The most obvious
pathological explanation of such toxicity is inflammation,
but it is possible also that, without causing inflammation,
lower nanoparticle number concentrations might have
direct effects on lung endothelial cells, leading to secondary vascular changes that increase risks of heart attack
in both the long and short term [11].
At present these conclusions are based on a combination of experimental work, epidemiology and speculation,
and the occupational physician will be aware of some
anomalous findings. For example, welders and many
other skilled tradespeople are commonly exposed to
fumes comprising high number concentrations of nanoparticles, yet they do not seem to have a high death rate
from cardiac disease. Some of the highest exposures to
particles (and nitrogen dioxide) occur in the kitchen, but
few adverse effects have to date been associated with
these exposures. There is clearly much still to understand
314 OCCUPATIONAL MEDICINE
about nanoparticle exposure. Nevertheless, a warning
has been sounded—small particles behave differently
and in general are more toxic than the same material
in larger size. They thus require special attention from
regulators.
Where might problems be foreseen with
nanoparticles?
In the associated commercial exhibition at a scientific
meeting on nanotechnology in Japan in 2006, several
hundred companies were showing products. It was apparent that most of these, including many nanoparticles,
were available to the market. One researcher reported
informally that a sample he had been sent had caught fire
spontaneously in the mail. Although feeling somewhat
uneasy, I originally wrote: ‘‘. . . as far as we know, nobody
has yet been harmed by deliberately manufactured nanomaterials.’’ On that very day in April 2006, however, the
German Federal Institute for Risk Assessment recalled
an aerosol, Magic Nano, marketed for bathroom cleaning and hygiene purposes, the use of which had caused
respiratory problems in more than 90 customers, of
whom several had been hospitalized with severe pulmonary oedema [12]. It remains unclear as to what this
product contained, but it appears that the intention was
to create a nanolayer of silica on surfaces. It does not
take much imagination to speculate what effect such a
nanolayer might have on the alveoli.
Occupational physicians will be familiar with the process of assessing risk in relation to determining the intrinsic hazard of materials and the potential exposure of
human beings to them. Thus, one might consider the
case of nanotubes. In terms of intrinsic hazard, there is
a good case for regarding them as likely to be quite toxic
but experimental studies to date have been difficult to
interpret since the tubes aggregate together and it is
difficult to dose rats with them in the way asbestos has
been tested. However, the results to date are not reassuring [13]. The problems of their separation give
some hope that exposure to individual fibres may not
be very great but there are real problems in measuring
them in air [14]. For the moment, it would be no bad
thing if they were to be treated by those making and
using them as though they were asbestos.
In terms of potential exposure, it is important to consider the life history of products containing nanotubes.
They will undoubtedly be used to strengthen and give
new properties to materials. What will happen to these
materials? Will they be machined? How will they be disposed of ? At an early stage in development of the technologies, these matters need to be considered in the
light of our tragic experience with asbestos. At present,
those potentially exposed are mainly in university laboratories and small pilot plants and many of the relevant
processes are enclosed. However, it is easy to persuade
a laboratory worker to give you a bottle of nanotubes,
which look just like soot. I recall a time when it was
equally easy to get a sample of crocidolite asbestos.
A similar approach may be used in considering any
new nanoparticle. How toxic is it? How will it be
produced? What will it be used for? How might it be
misused? How will it be degraded or disposed of ? Who
may be exposed, and to how much, in these different
stages of its life history? If, for example, it is to be added
as a catalyst to fuel for the worthy purpose of increasing
efficiency and reducing CO2 emissions, does it increase
or decrease the toxicity of the exhaust emissions? If it
is to be added to a cosmetic such as a lipstick or a sunscreen, does it reduce or increase the adverse effects of
ultraviolet radiation on the skin? If it is a metallic particle to be used in medical imaging, does the toxicological
testing include consideration of the possibility that it
might have adverse effects on the endothelium and heart?
At present the most likely scenarios of risk from
nanoparticles are as follows:
• Accidental inhalation episodes from commercial
products
• Inhalation episodes among production workers/fitters
in pilot plants
• Insidious inhalation of nanotubes by production
workers
• Skin damage from careless use of new particles in
cosmetics
• Explosion/fire in pilot operations
• Unexpected reactions to nanomedicines or imaging
agents injected intravenously.
The role of the occupational physician
The training of occupational physicians traditionally
includes consideration of diseases regarded as of largely
historic interest. But at one time the use of lead and mercury, the hewing of stone and the mining of precious
metals and coal were at the very forefront of the technologies of industrialization. We continue to learn hard lessons from unrecognized hazards associated, for example,
with PVC production, use of solders in electronics and
the introduction of cheap latex for unnecessary use of
rubber gloves in the National Health Service. With
the introduction of nanotechnologies we have had the
opportunity, perhaps uniquely, to make a guess at
what problems may lie ahead and take steps to reduce
any risks. But where do we start?
There are many uncertainties with respect to the toxicity of new nanoparticles and those producing them have
an obligation to take seriously the possibility that they
may be more dangerous than more mundane materials. Many such people are in universities, where there
has traditionally been a rather lax attitude to health and
safety. Occupational physicians and safety officers now
A. SEATON: NANOTECHNOLOGY AND THE OCCUPATIONAL PHYSICIAN 315
responsible for such institutions should investigate what
is going on and what precautions are being taken to
protect researchers and workers in spin-off companies.
In general, nanoparticles in air behave like gases and
people can be protected against them by traditional
methods. This includes consideration of what happens
during process breakdown or cleaning operations. Their
measurement is an issue however. The normal background of particles in an indoor environment may be
several thousand nanoparticles per millilitre—how may
emissions of manufactured nanoparticles from a process
be quantified against this? And what is the best way of
measuring them? The small companies involved in manufacture are in particular need of help and such companies rarely have the resources to employ specialist
advisors. Here there is a role for government, probably
through the Department of Trade & Industry, to ensure
that appropriate help is available. If the product is
intended for the market-place, expert advice is needed
on its toxic potential. How far an occupational physician is responsible for ensuring the safety of a product
outside the workplace is questionable, but managers
may look to us for general advice on toxicity and anyone
aware of such a product made by their employer has an
ethical obligation to point out possible unrecognized
hazards. It is well to know where to go for advice on
these matters.
For those physicians involved in advising regulators,
there are particular difficulties. It is usual to regulate particulate aerosols by reference to exposure limits, but this
is not usually practicable since devices for quantifying
nanoparticles in air are not yet readily available and in
any case it is not clear what metric would provide the
most relevant index of toxic hazard.
Where do we go from here?
At the time of the Working Group report, it was reasonable to be optimistic that possible risks had been foreseen
and that the recommendations made to prevent serious
problems would ensure as far as practicable that adverse
consequences would be avoided. However, one crucial
recommendation was that there was a need for research
into metrication, toxicology, workplace exposures to
nanoproducts and life cycles of nanoproducts. Another
was that the relevant regulators should consider the
particular issues arising from nanoproducts in their specialist areas. Unfortunately, the latter depends to some
extent on the results of the former, and the UK response has been slower than one would have wished. In
particular, no new money for research has been identified. As the German episode illustrates, the market is
racing ahead of governmental responses.
It will be clear, from this and the preceding papers,
that nanoparticles differ from the same material at a larger
scale, in chemical, physical and biological properties.
They are therefore new chemicals, and need to be regulated as such. At present and in the near future, most will
be produced in small quantities, outwith the REACH
regulations. But they clearly need specific regulations.
We need to understand the toxicology of nanoparticles
aimed at the market, the ways to protect workers and
customers from adverse effects, how best to measure
them in air and other media, how they should be labelled
in products and whether disposal is likely to produce any
problems for the environment or people. Regulators, industry and academic researchers involved in nanotechnology need a multidisciplinary resource to which they
can go for help in these matters, as recommended by
the Working Group. At present in the UK, this only exists
as an informal, unfunded collaboration, the Safety of
Nanomaterials Interdisciplinary Research Consortium,
which is however available for help with research and
advice (www.snirc.org).
Conflicts of interest
None declared.
References
1. Royal Society and Royal Academy of Engineering. Nanoscience and Nanotechnologies: Opportunities and Uncertainties.
London: The Royal Society, 2004.
2. Mossman BT, Bignon J, Corn M, Seaton A, Gee JBL.
Asbestos: scientific developments and implications for public policy. Science 1990;247:294–301.
3. Oberdörster G, Ferin J, Lehnert BE. Correlation between
particle size, in vivo particle persistence and lung injury.
Environ Health Perspect 1994;102(Suppl. 5):173–179.
4. Schwartz J, Morris R. Air pollution and hospital admissions for cardiovascular disease in Detroit, Michigan. Am
J Epidemiol 1995;142:23–35.
5. Seaton A, MacNee W, Donaldson K, Godden D. Particulate air pollution and acute health effects. Lancet 1995;
345:176–178.
6. Donaldson K, Stone V, Seaton A, MacNee W. Ambient
particles and the cardiovascular system: potential mechanisms.
Environ Health Perspect 2001;109(Suppl. 4):523–527.
7. Geiser M, Rothen-Rutishauser B, Kapp N et al. Ultrafine
particles cross cellular membranes by non-phagocytic
mechanisms in lungs and in cultured cells. Environ Health
Perspect 2005;113:1555–1560.
8. Oberdorster G, Sharp Z, Atudorei V et al. Translocation
of inhaled ultrafine particles to the brain. Inhal Toxicol
2004;16:537–545.
9. Brown DM, Wilson MR, MacNee W, Stone V, Donaldson
K. Size-dependent pro-inflammatory effects of ultrafine
polystyrene particles: a role for surface area and oxidative
stress in the enhanced activity of ultrafines. Toxicol Appl
Pharmacol 2001;175:191–199.
316 OCCUPATIONAL MEDICINE
10. Dick CAJ, Brown D, Donaldson K, Stone V. The role of
free radicals in the toxic and inflammatory effects of four
different ultrafine particle types. Inhal Toxicol 2003;15:
39–52.
11. Gilmore PS, Morrison ER, Vickers MA et al. The procoagulant effects of environmental particles (PM10).
Occup Environ Med 2005;62:164–171.
12. Weiss R. Nanotech product recalled in Germany.
Washington Post, 14 April 2006.
13. Lam CW, James JT, McCluskey R, Hunter RL. Pulmonary
toxicity of single-wall carbon nanotubes in mice 7 and
90 days after intratracheal instillation. Toxicol Sci 2004;
77:126–134.
14. Maynard AD, Baron PA, Foley M, Shvedova AA,
Kisin ER, Castranova V. Exposure to carbon nanotube
material: aerosol release during the handling of unrefined
single wall carbon nanotube material. J Toxicol Environ
Health 2004;67:87–107.