Ten years ago to the month, one of the first research reports detailing the challenges of ensuring the safe use of engineered nanomaterials was delivered to the UK Health and Safety Executive.  The report wasn’t for general release, and you’ll be hard pressed to find a copy of it in the public domain.  But as a co-author, I have a copy skulking around in my archives.  And given it’s ten year anniversary, I’ve been browsing through it, to find out how much has progressed—or not, as the case may be!

The report focused on ultrafine aerosols, and the Health and Safety Laboratory’s ability to respond to then-current, and future, research needs.  As such it was pretty wide ranging, and focused extensively on exposure to incidental nanoscale aerosols—such as welding fume and engine emissions—in the workplace.  But it did encompass the then-nascent field of nanotechnology and “nanophase material synthesis.”  And some of these early assessments of the field bear revisiting.

For anyone interested in what was being written about the potential health and safety issues raised by engineered nanomaterials ten years ago, I’ve extracted a few sections of the report below—for the full thing, you’ll have to go to the UK Health and Safety Executive.

My apologies that the post is so long—I’m only expecting a dedicated few to plough through it.  But at the least, you might want to skip to the end to see how the research recommendations of 1999 compare to those of today—you might be surprised!

A scoping study into ultrafine aerosol research and HSL’s ability to respond to current and future research needs.
IR/A/99/03

Kenny, Maynard et al. 1999

The introduction to the report starts:

Over the past few years a number of epidemiological studies have indicated a tentative link between ambient particulate concentrations, and morbidity and mortality rates (e.g. Dochery et al. 1993, Pope 1996, Schwartz et al. 1993, Schwartz et al. 1991).  In all studies, particles with an aerodynamic diameter less than 10 µm (the PM10 fraction) have been implicated as the key agents.  The lack of an apparent association between particles of specific composition and health effects has indicated the observed effects to be due to some physical aspect of the inhaled particles.  A further link between particle size and health has been indicated by Dochery et al. (1993) who showed a more positive correlation between ill health and particles smaller than 2.5 µm than was seen than with the PM10 fraction.  The possibility of correlations between particle size and number concentration and toxicity has been demonstrated by Oberdörster et al. (1995) by exposing rats to PTFE particles ~20 nm in diameter.  At concentrations of 106 particles cm-3 (corresponding to an equivalent mass concentration of approximately 60 µg m-3) rats exposed for 30 minutes died within 4 hours. At lower concentrations a steep dose response curve was observed between pulmonary inflammatory responses and particle number.  More recent research has begun to indicate a possible material-independent link between inhaled particle surface area and selected toxicological endpoints (e.g. Lison et al. 1997). The possibility of a relationship between fine inhaled particles and ill health is now readily accepted,  although research is still at a very early stage and most published data to date are open to a wide range of interpretations.  Tentative hypotheses concerning possible mechanisms leading to toxicity have been proposed (e.g. Schlesinger 1995, Seyton et al. 1995, Donaldson and McNee 1998), and the impact of inhaling ultrafine particles on both the respiratory and cardiovascular systems have been speculated on.  The US EPA have already acted, partially as a response to earlier epidemiological studies, and introduced the PM2.5 sampling standard for environmental particulates.  Whether the UK is to follow this lead is still under discussion.  However, despite these steps, research so far has raised more questions than answers.  There is debate over the interpretation of the epidemiological studies, and the appropriateness of chosen endpoints in toxicology tests.  Contradictory experimental results are beginning to be published regarding ultrafine particle impact on health (e.g. Pekkanen et al. 1997).  There also appear to be widely conflicting views on what constitutes an ultrafine particle, with implicit cut-off points ranging from 10 µm down to a few nm!

In amongst all the current confusion is the question of whether the alleged health implications of inhaling ultrafine aerosols are of relevance to the workplace.  Much has been made of the apparent health problems amongst vulnerable sectors of the general population following environmental exposures, and the argument is followed through to the conclusion that within a healthy workforce similar problems are unlikely to be seen (backed up by a lack of evidence of severe health problems that are clearly linked to ultrafine aerosols).  However, in part the current uncertainty over the toxicity of ultrafine particles is due to the very limited information available on the nature of so-called ultrafine particles.  Inhaled particles associated with health in epidemiology studies have been very poorly defined, and even the particles used in most well controlled in vitro and in vivo experiments have been poorly characterised.  Without basic information on particle size, morphology, composition and structure, it is clearly not feasible to make value judgements on the nature of inhaled particles, either in the general environment or in the workplace. In the light of the scarcity of information on particle characteristics, the Committee on the Medical Aspects of Air Pollutants has recommended the monitoring of such parameters at a number of environmental locations (COMEAP 1996).  Similar measurements will be essential within the workplace before further speculations on the importance of ultrafine aerosols are made.

In reading this, it is important to remember that the state of the science is ten years on from when this was written—there are now a wealth of publications on the potentially health-relevant behavior of nanometer-scale particles.  Yet the framework of questions set out largely remains as relevant now as it did then.

Perhaps more interestingly, in 1999 the discussion was focused on understanding and managing the health impacts of inhaled particles, NOT whether those particles could be classified as arising from nanotechnology or not.  As a result, the document tends to be more grounded in the science of how fine particles potentially impact on health, rather than how the poorly defined field of “nanotechnology” might lead to health effects.

The report goes on to consider the generation of ultrafine aerosols in the workplace:

In general, very little is known about any aspect of ultrafine aerosols in the workplace.  There are a number of processes such as welding and soldering where intuitively one would expect large numbers of sub-µm particles.  However even in these areas, detailed measurements of particle size do not appear to have been made.  There is a general feeling that in situations where large concentrations of particles are generated, agglomeration will remove ultrafine particles from the aerosol before it is inhaled, thus removing the need to consider ultrafines. However this has not been verified, and evidence exists for significant mass concentrations of ultrafines existing close to generation sources.  Interestingly, researchers are currently speculating that agglomerates with ultrafine primary particles may have the equivalent impact on the lungs as the individual primary particles.  More is known about the products of internal combustion engines, although mainly from the view point of monitoring and reducing environmental emissions.  However very little information on the nature of individual particles in the workplace exists.

Ultrafine aerosols tend to be formed either through nucleation (in particular homogeneous nucleation), gas to particle reactions or through the evaporation of liquid droplets.  The majority of workplace ultrafine particles are likely to arise from the nucleation route, either as combustion products, or within saturated vapours arising from other sources (e.g. welding, smelting, laser ablation).  Evaporation of sub-micron and even micron sized droplets of relatively high purity solvents will result in very small particles.  Where the initial particles are highly charged, there is the possibility of any resulting fine particles exceeding the Rayleigh charge limit and fragmenting into even finer particles.  This is a recognised method of generating ultrafine particles through electrospraying.  To what extent this generation route is present in the workplace is unknown, although it is used for the specific generation of ultrafine particles during nanofabrication.  Gas to particle generation of ultrafine aerosols accounts for the majority of non-combustion particles in the environment, although again the significance of this route within the workplace is unclear.

Following current interest in nanophase technology, and the use of ultrafine particles as precursors in nanophase materials, it is likely that the next few years will see an increase in the industrial generation and use of ultrafine particles.  At present the planned generation of particles tends to be isolated to the production of ultrafine metal oxides such as TiO2, ZnO and fumed silica.  Ultrafine carbon black is also currently generated on a commercial scale. Although the full extent to which ultrafine aerosols are generated as an unwanted by-product within industry is still largely unknown, there are clear cases where the generation rate is high, such as in welding and from internal combustion engines.  Even so, data on the nature of generated aerosols in these areas are sparse.

There follows an assessment of different sources of nanoscale particles in the workplace, from welding to plastic fumes from laser cutting, and a range of other sources.  This is all interesting information, but here I want to focus on the section on ultrafine aerosol precursors in nanophase technology:

Over the last ten years, interest in the unique properties associated with materials having structures on a nanometer scale has been increasing at something approaching an exponential rate.  By restricting ordered atomic arrangements to increasingly small volumes, materials begin to be dominated by the atoms and molecules at the surfaces of these ‘domains’, often leading to properties that are startlingly different from the bulk material.  As the domains become smaller, and hence more dominated by surface atoms and surface energies, so the properties become increasingly unique from either the bulk material or the constituent atoms. So for instance, a relatively inert metal or metal oxide may become a highly effective catalyst when manufactured as ultrafine particles; opaque materials may become transparent when composed of nanoparticles, or vice versa; conductors may become insulators, and insulators conductors; nanophase materials may have many times the strength of the bulk material.  All of these effects and many more have been observed with various materials.  Such material properties that are unique to nanostructured materials that have excited both the scientific and industrial communities in recent years.

Most nanophase materials are fabricated either from the liquid state, or the aerosol state, although some routes combine the two.  The liquid route perhaps gives more control over the process in some cases.  However there is a general feeling at the present that using aerosols is an inexpensive and versatile route to constructing these materials.  Although there are many different production methods being explored, the general approach is to generate, capture and process an aerosol of particles with the dimensions of the final nanostructure.  Typically this requires the generation of particles from 1 to 2 nm in diameter up to around 20 – 30 nm in diameter, depending on the required properties of the final material.  Generation rates in research laboratories tend to be low (of the order of mg/hour), although where industrial production of nanoparticles has commenced, production rates of the order of tonnes per hour are seen.

At present, nanophase materials are an emerging technology, with the emphasis most definitely still on the research lab.  However, there is considerable commercial commitment to the field, and it is certain that as scale-up problems are overcome, the mass production of both nanoparticles and nanophase materials will increase rapidly world-wide.  When this occurs, the unique health problems associated with a unique product that can neither be treated as a bulk material or on a molecular level will have to be fully addressed.  In the meantime, there is a clear need to keep up to date with both developments in the technology, and any health concerns that may be associated with it.

Over the past ten years, commercial-scale production of nanoscale materials has moved on significantly, although perhaps not as much as some would have predicted.  Yet the issues surrounding their safety still reflect (by on large) the issues raised here.

The report summarizes the state of nanotechnology research in 1999—which I’ll skip over—and goes on to consider where the rather quaintly termed nanophase technology was heading:

The indication from the scientific press is that there are as many potential applications for nanophase technology as there are groups working in the field.  However a relatively small number of areas can be identified where commercial production of materials is most likely to be seen in the next 5 – 10 years.  To understand the commercial pressure behind the progress of nanophase technology and its likely integration into industry, you only have to consider the potential market for successful applications.  In the electronics industry in particular, the revenue arising from nanotechnology is likely to be well in excess of hundreds of billions of dollars.  In other areas, such as coatings and catalysts, similar markets exist for successful applications.  The market for ‘intelligent’ drug delivery systems, if successful, is likely to be immense.  Reflecting this, the pharmaceutical industry is currently investing in excess of $14B per annum into advanced delivery systems.

Electronic applications

The reduction in particle size has a profound effect on electronic structure as nanometre dimensions are reached, leading to a number of unique electronic properties seen in individual and groups of nanoparticles.  As an illustration, Si, which is semiconducting in the bulk solid, may be used to form nanometre sized pseudo-crystals with one of two types of atomic structure dominating its faces.  Particles with one structure are fully conducting. Those with the other are good insulators. What does this mean/what are the general implications?

Perhaps the most widely recognised electronic property of nanoparticles is their ability to act as quantum dots.  In arrays of such particles, the overall electronic characteristics are dominated by quantum effects within the particles, leading to novel applications.  For instance, quantum dot devices can be used to create high efficiency LED’s and electroluminescent plastics.  High frequency solid state lasers based on quantum dot technology are expected to form the basis of a major breakthrough in telecommunications, leading to significantly higher communication bandwidths.  High speed and high capacity computer memory will also be possible using quantum dot technology.  Success in fabricating viable quantum dot devices will bring about a major technological step within the electronics industry, leading to a $B production industry, although progress at present is limited by the need to fabricate very precise arrays of well characterised particles.  Current approaches include the use of colloids, nanolithography and aerosols.

Porous nanostructured semiconductors such as silicon have recently been shown to have electroluminescent properties.  If this can be fabricated into integrated circuits, the basis for the next generation of high speed optoelectronic computers will be laid.  Nanoparticles are also being found to lead to improved properties in resistors and capacitors.  Ultrafine conducting particles embedded in an insulating matrix have been shown to give a great range of resistances as well as showing very high temperature stability.  Similarly, the use of nanoparticles in capacitors has been shown to give a high dielectric permitivity and a low dissipation factor, making them ideal for high speed computer memory.

A particularly interesting phenomenon seen in nanophase materials is that of electrochromism; the modification of optical properties by the application of an electric field. Windows or mirrors coated with thin layers of these materials show variable light transmittance or reflection based on the magnitude of an applied electric field.  It has also been found that nanophase materials may be used to form thin transparent films with high conductivity.

A number of other important areas relating to electronics are increasingly relying on the use of nanostructured materials.  Solid state gas sensors show improved sensitivity when using films of sintered nanometre particles; high temperature superconductors have a higher performance when formed of nanostructured materials; thermocouples benefit from nanostructure and the magnetic properties of some nanostructured materials is already exploited to the full in magnetic storage media.

Coatings

Using nanophase materials to coat a wide range of substrates is being explored, and has been exploited in a wide range of applications.  Hard nanophase coatings are important in the construction industry.  The use of coatings with specific optical properties is of interest within the glass and photographic film industries.  Dry coating technology is also benefiting from nanophase materials.  It has been shown that the transport properties of large particles may be radically altered by the addition of a thin coating of fine particles of a suitable material.  For instance, coating starch grains with fumed silica results in a highly flowable powder.  In many cases, this coating need only be of the order of nanometres thick, and the use of nanoparticles in dry coating processes is already under investigation.

Chemical-mechanical polishing using nanoparticle slurries.

Surface polishing is a critical step in the processing of silicon wafers prior to semiconductor chip fabrication.  Surface blemishes are a major source of both wafer and chip rejection in the electronics industry.  By using polishing slurries consisting of nanoparticles, planarisation of wafer surfaces with fewer blemishes is possible.

Drug delivery systems.

A key goal in current drug delivery system research is the development of ‘intelligent’ systems that will deliver doses to specific sites within the body.  One approach being actively considered is the use of coated nanoparticles.  These would be capable of penetrating capillaries and being transported directly to the target site.  The coating would include the drug to be delivered, components to prevent an immune response from the body and components to achieve site-specific or condition-specific delivery.

Nanoparticle catalysts

The modified surface chemistry of nanoparticles is well recognised for its catalytic properties in many materials.  This, together with the associated surface area to mass ratio for such particles, has led to intense interest in nanostructured catalysis within many fields.

After laying out the state of the science regarding the potential risks of inhaling nanoscale particles (which has advanced considerably over the past ten years), the report summarises (on the health impacts):

There has been little work in this field to date, so it is difficult to draw meaningful general conclusions from the published data. One of the reasons for this lack of data appears to be the difficulty in generating particles of standard and known size for use in in vitro studies. Particles used in both in vitro and in vivo studies have also tended to be relatively poorly characterised. Different effects both in vitro and in vivo have been observed with different sources of ultrafine particles, so the responses measured may be a function of the particle constituents rather than the particles per se. The differences observed have been attributed to the ability of particles with a particular composition to have different levels of free radical activity at their surface. Whilst there has been some work investigating synergy between acid aerosols and ultrafine particles (see below), there has been no work investigating the synergy between ultrafine particles and other potential airborne contaminants, e.g. allergens, VOC’s and bacteria. Some of the animal models used to demonstrate toxicological endpoints require exposure regimes which are far in excess of any possible exposure in humans (e.g.  6 hours a day, 5 days a week for 3 months). Therefore, the extrapolation of such health effect data to humans should be treated with some caution.
…
Interest in possible health effects following inhalation of ultrafine particles is high at present, and research is beginning to follow this interest.  Inhalation toxicology has taken over from epidemiology over the past few years, and dominates the field at present.  Dose response relationships in rodents are being seen that indicate particle number or surface area to be more appropriate metrics than mass.  The possibility of ultrafine particles acting as vectors to transport  acids and metals to the alveolar region of the lung is also being explored.  However it is recognised that many of the current approaches being taken are lacking in various aspects, particularly regarding the significance of chosen endpoints and the characterisation of particle exposure, and a number of groups are now beginning to address these issues.  This is an area that is particularly ripe for good research proposals to sympathetic funding bodies. The need to fully characterise the particles used in exposure and inhalation tests, as well as those that people are exposed to in the workplace and environment, is well understood, although the right combination of technical skills to achieve this seems to be lacking in many establishments.  In particular there would appear to be significant scope for transferring analytical electron microscopy skills used in materials science and nanostructure analysis to the analysis of ultrafine aerosol particles.  There is also a recognised need for in-vitro test systems that allow cell cultures to be exposed to the aerosol, rather than a particulate suspension.  A small number of research groups are currently developing test systems allowing direct aerosol deposition.  Funding for fine particle research (PM2.5 sampling, and mass-based aerosol sampling) still dominates, but all aspects of ultrafine particle research are on the increase, and it is likely that the next few years will see significant funding opportunities and research in this area.  Driven by concerns over environmental exposure, together with the need to address exposure limits for nuisance dusts, there is increasing interest in examining the impact of ultrafine particle exposure in the workplace.

The report covers a lot of ground on exposure measurement and control, which I won’t duplicate here (although a lot of the information remains highly pertinent).  Instead, I’ll jump right to the end of the report, where a number of research recommendations are made.  Remembering that these are focused specifically on inhalation exposure in the workplace, they sound surprisingly contemporary, being written 10 years ago:

Full quantification of ultrafine aerosol exposure in the workplace:

• Measurement of number, size, surface area, composition, morphology, structure
• Investigation of the surface properties of workplace particles.
• Investigation of surface enrichment, role of modified surface activity below 10 nm, relevance of internal structure.
• Development of instrumentation and analytical techniques for surface area
• measurement and individual particle characterisation (Analytical Electron Microscopy)

Targeted epidemiology and toxicology studies.

• Epidemiological evidence for ultrafine particle toxicity in the workplace
• Toxicity of well defined particles, and of particles characteristic of those found in the workplace.
• Investigation of mechanisms resulting in toxic responses, in relation to the known physical and chemical attributes of workplace particles.

Instrumentation

• Identification of deficiencies in instrumentation and monitoring requirements, and development of new technologies and methods.

Control

• Reassessment of  the applicability of conventional control systems (including RPE) to reduce exposure to ultrafine particles, and the development of new approaches to exposure control.

Exposure Limits

• Assessment of current exposure limits in the light of available data on ultrafine particle toxicity, and the development of more appropriate approaches to exposure limits.

Ten years on, it is surprising how relevant this document still is.  The major issues facing the safe use of nanomaterials were reasonably clear ten years back.  And many of the research needs raised then remain today.  Progress certainly has been made since then, and an understanding of the types of nanomaterials of greater concern has increased—the 1999 report doesn’t mention carbon nanotubes for instance.  But on the flip side, this is a report that was clearly unencumbered by the politics of nanotechnology that seem to have diffused through things today

Perhaps most surprisingly though, is that governments and others are still talking about the same issues – often as if they have discovered them for the first time – without doing that much about them.  It would be churlish to ask where we might have been now if some of those 1999 recommendations were listened to.  But at least I can ask where we might be in 2019, if only we can break out of this endless cycle of re-inventing the nanotech risk report!

Endnote

Because this was an internal report, I have been careful to extract only parts of it that are of general interest and are not in any sense proprietary.  That said, there is a lot of information in the full report that would be helpful to anyone grappling with addressing and managing potential occupational risks arising from nanoscale particle exposure in the workplace.  It would be great if the UK Health and Safety Executive could release it for public use!

References

COMEAP (1996).  Non-biological particles and health.   HMSO Publications.

Dochery, D. W., Pope, C. A., Xu, X., Spengler, J. D., Ware, J. H., Fay, M. E., Ferris, B. G. and Speizer, F. E. (1993).  An association between air pollution and mortality in six U.S. cities.  N. Engl. J. Med, 329, 24, 1753-1759.

Donaldson, K. and McNee, W. (1998).  The mechanics of lung injury caused by PM10.  In: Air Pollution and Pealth.  Eds:  Hester and Harrison.  Royal Society of Chemistry.  ISBN 0-85404-245-8.  pp21-32.

Lison, D., Lardot, C., Huaux, F., Zanetti, G. and Fubini, B. (1997).  Influence of particle surface area on the toxicity of insoluble manganese dioxide dusts. Arch. Toxicol. 71, 725-729

Oberdörster, G., Gelein, R. M., Ferin, J. and Weiss, B. (1995).  Association of particulate air pollution and acute mortality:  involvement of ultrafine particles?  Inhal. Toxicol., 7, 111-124.

Pekkanen J, Timonen KL, Ruuskanen J, Reponen A, Mirme A (1997) Effects of ultrafine and fine particles in urban air on peak expiratory flow among children with asthmatic symptoms. Environ Res 74: 24-33

Pope, C. A. (1996).  Adverse health effects of air pollutants in a nonsmoking population.  Toxicology, 111, 149-155.

Schlesinger, R. B. (1995).  Toxicological evidence for health effects from inhaled particulate pollution:  does it support the human experience?  Inhal. Toxicol., 7, 99-109.

Schwartz, J., Spix, C., Wichmann, H. E. and Malin, E. (1991).  Air pollution and acute respiratory illnessin five German communities.  Environ. Res., 56, 1-4.

Schwartz, J., Slater, D., Larson, T. V., Pierson, W. E. and Koenig, J. Q. (1993).  Particulate air pollution and hospital emergency room visits for asthma in Seattle.  Am. Rev. Respir. Dis., 147, 826-831.

Seyton, A., MacNee, W., Donaldson, K. and Godden, D. (1995).  Particulate air pollution and acute health effects.  The Lancet, 345, 176-178.