Why (nano) size matters
Industry and government regulators maintain that the unique size and properties of nanoscale materials do not warrant a closer look at the potential health, safety and environmental impacts. The following extract from a paper produced by the ETC Group (Action Group on Erosion, Technology and Concentration) explains why size matters.
Born to be mild
CLIMBING up the evolutionary ladder, Homo sapiens were glad enough to take a deep breath when they clambered onto the seashore and then genetically out-distanced sabre-tooth tigers and mammoths. It was only when we were finally able to relax around the fire and we breathed in some of the soot that a minor shortcoming to our hard-won lungs manifested itself: our lungs are not well-equipped to deal with very small particles of matter, such as those found in smoke and, later, in industrial pollutants and car exhausts. When particulate matter is very, very small, it may be more than just our lungs that object. When molecules are small enough, it is possible for them to slip past the guardians in our respiratory systems, skip through our skin into unsuspecting cells, and (sometimes) cross through the blood-brain barrier. Human nature, it seems, grew up assuming that the nanoscale was ‘unnatural’.
Borne again
Noteworthy quantities of air-borne particles less than 100 nanometres (nm) in size came only with the industrial revolution in the form of air pollution, an unintended but largely unavoidable byproduct of high-temperature industrial processes. (A nanometre is one billionth of a metre.) In the last quarter of the last century, scientists began to explore the idea that not all nanoparticles (also called ultra fine particles or UFPs – particles less than 100 nm in size) belong to the class of polluting ‘effluent’. Nanoparticles can exhibit desirable properties that their bigger relations do not. For example, nanoparticles of titanium dioxide and zinc oxide used in sunscreens have the same chemical composition and formula (TiO2 and ZnO, respectively) as larger titanium dioxide and zinc oxide particles – the white glop that has been slathered on lifeguards’ noses for decades – but nanoparticles of TiO2 and ZnO are transparent. Also, materials that would normally be conductors of electricity can become insulators at the nanoscale, or vice versa.
While carbon black (i.e., soot produced from burning natural gas) has been manufactured in bulk quantities since the early 20th century (used as a reinforcing agent in car tyres), the intentional manufacture of chemically-precise nanoparticles to harness desirable characteristics got underway only in the mid-1970s. A Massachusetts company, Hyperion Catalysis, has been manufacturing carbon fibres since 1983 and another US company, Nanophase, has been selling nanoparticles of various metal oxides since the mid-1980s. In the past, effluent was generally seen as the unintended and undesirable byproduct of industry; in the case of ‘synthetic nanoparticles’, the effluent is the industry.
Affluent effluent
Already more than 140 companies worldwide are engaged in nanoparticle manufacture. By 2005, the global market for nanoparticles will come close to $1 billion. At least 44 elements in the Periodic Table are commercially available in nanoscale form (see below). A small Colorado startup called NanoProducts expects to have another 20 elements for sale in the near future. Earth’s remaining fifty or so elements are either radioactive, gaseous, or have a half-life so fleeting that FedEx would be delivering empty packages.
The explosion in ‘bulk nano’ means that nanoparticles are now in daily use in everything from popular sunscreens and sunglasses to L’Oréal cosmetics. Burn dressings treated with silver nanoparticles are used in over 100 of the 120 major burn centres in North America. Babolat incorporates carbon nanotubes into their tennis rackets to make them stronger without making them heavier. If the ball you’re hitting with your nanotube racket is the Wilson Double Core, it’s been treated with a nanoclay that locks in air. The fuel lines of many US and European cars, some Toyota auto bodies, and Renault’s plastic side panels all incorporate nanoscale materials. Kraft and the US Department of Agriculture (USDA) are researching the use of nanoparticles in food packaging and ultimately in food itself. Is there any reason to be concerned about the ‘appearance’ of invisible nanoparticles in so many consumer goods? Are some applications of nanomaterials safe and others not?
All aboard
No one denies that research in the area of nanoparticle toxicity is urgently needed. Vicki Colvin, Director of the Center for Biological and Environmental Nanotechnology at Rice University (Houston, TX, USA), has written, ‘In a field with more than 12,000 citations a year, we were stunned to discover no prior research in developing nanomaterials risk assessment models and no toxicology studies devoted to synthetic nanomaterials.’ John Bucher, of the National Institute of Environmental Health Sciences’ Environmental Toxicology Program in the USA, recently stated that ‘we don’t know the answers [to the questions related to nanomaterial toxicity]; we’ve just begun to ask the questions.’ Unfortunately, Colvin’s Center at Rice, one of six National Science Foundation multi-million-dollar research facilities dedicated to atomtechnology and the only one focused exclusively on the environment and the interface between biological and material atomtechnology, does not include toxicology as a research area.
While it’s important for scientists in the field to acknowledge the lack of data, acknowledgement falls short when nanoparticles are already being sold to consumers. Public money devoted to the study of health and environmental impacts also falls short. In the USA, for example, only 2.9% of the $710 million budget for the National Nanotechnology Initiative is devoted to environmental implications, including applications.
Mountains and molehills?
While there is a mountain of data suggesting that nanoscale particles in pollutants such as car exhaust are toxic, some scientists insist that there could be significant differences between the ‘accidentally-manufactured’ particles in pollutants and intentionally-constructed nanoparticles. Conclusions about toxicity cannot and should not, they argue, be extrapolated from past studies of industrial pollutants.
So few toxicology studies have been conducted on synthetic nanoparticles, however, that the toxicity distinction between ‘intentional’ and ‘accidental’ nanoparticles remains largely theoretical. Some atomtechnologists point out that humans will not necessarily come into intimate contact with most synthetic nanoparticles – they will not become airborne in the way that car exhaust particles do – so the possibility of their toxicity is not relevant.
Research is underway, however, to use nanoparticles in drug delivery systems (some are being designed to cross the blood-brain barrier), for in vivo cell tracking, in food packaging, even in food products. Titanium dioxide (TiO2) nanoparticles are, for example, an ingredient in many transparent sunscreens and there are data suggesting that these could be harmful in certain forms. (See discussion below.)
There are two posited differences between unintended UFPs and ‘intentional’ nanoparticles: one, the surface chemistry of synthetic nanoparticles is uniform and can be controlled and, two, particle size can be controlled to be made homogeneous. In other words, if it turns out that the surface chemistry of a particular material is causing health problems (because, for example, the large surface area allows the particle to be so reactive that it becomes toxic), chemists can alter the surface chemistry to alleviate the problem. The (potential) ability to control surface chemistry to eliminate problems does no good, of course, until we know what the problems are.
With regards to homogeneous particle size, scientists have argued that if it turns out that a particular size-range is problematic, atomtechnologists will be able to calibrate their method of manufacture so they get the size that’s ‘just right’ to ensure health. It seems that around 70 nm is a problematic size for the lungs, 30 nm spells trouble for the central nervous system and 50 nm gives the green light to enter cells. Again, the (potential) ability to control particle size is only helpful if toxicology studies have been performed on synthetic nanoparticles demonstrating which sizes are problematic and which are not. It could be, in fact, that homogeneous particle size will make synthetic nanoparticles more dangerous than their non-uniform pollutant UFP cousins if they are all being made the ‘wrong’ size, a size that can potentially cause damage in cells or lungs or the central nervous system. A quick survey of TiO2 nanoparticles being sold in the US for use in cosmetics, for example, shows that their size is not exactly precision-tuned – the particles fall within a range between about 20 and 50 nanometres, encompassing the particle sizes that may allow entrance to the central nervous system and cells.
An even more fundamental problem is that, at this point, there is no standardised method for determining particle size. Dr Robert Shull of the National Institute of Standards and Technology (USA) has recently stated that there are somewhere between five and 10 methods used to measure particle size. The results can differ by a factor of two depending on the measuring method used. Dr Shull acknowledged this to be a ‘real serious problem’ and said that his agency will address it by assessing the various measurement techniques and coming up with a definitive method.
No one expects the scientific community to have all the answers at this early stage; every consumer would expect, however, that scientists and regulators get it right before nanoproducts are sold or released in the environment and before they potentially endanger the health of workers in labs and in manufacturing facilities. ETC Group finds two test cases particularly troubling.
Presumption of innocence I – the case of carbon nanotubes
Carbon nanotubes are straw-shaped molecules of pure carbon discovered by Sumio Iijima of Japan in 1991. They have been dubbed the ‘miracle molecule’ because they are 100 times stronger than steel and six times lighter. Nanotubes can be as small as 1 nm in diameter and as long as 100,000 nm. They can be single-walled, like straws, or they can be multi-walled, resembling posters in a mailing tube. Depending on how they are configured, they can act as semiconductors or as conductors.
There are an estimated 16 major producers of carbon nanotubes worldwide. The global market for carbon nanotubes was estimated at $12 million in 2002, but is expected to grow to $430 million by 2004. Two Japanese companies have been launched to make nanotubes in bulk quantities: Frontier Carbon Corporation (a joint venture of Mitsubishi Corp. and Mitsubishi Chemical Corp.) plans to produce 40 tons of nanotubes this year and Carbon Nanotech Research Institute aims for an annual production of 120 tons. In the USA, Carbon Nanotechnologies, Inc. has plans for a new plant that will produce between 150 and 300 tons per year of single-walled nanotubes. Electronics giant NEC plans to start selling nanotube fuel cells for laptops and mobile phones within a year and nanotube flat screen displays shortly thereafter.
Because nanotubes have a high aspect ratio (i.e., they are needle-like in shape), there was some speculation initially that they could behave like asbestos fibres if they became airborne and were inhaled. Until this year, there existed only one published study addressing the issue of carbon nanotube toxicity: researchers at the University of Warsaw concluded, after a four-week trial in which nanotubes had been injected into the tracheas of guinea pigs, that working with nanotubes was ‘unlikely to be associated with any health risk’.
A second nanotube toxicity study at the Johnson Space Center (NASA) got underway last year. Hardly had the NASA researchers begun when the Financial Times pre-emptively (and mistakenly) assured its readers that the soon-to-be-released NASA study would give nanotubes its second clean bill of health. Then, in February, rumours circulated that all was not well. The research team posted an abstract of their study on the American Chemical Society’s website. A fuller report was presented at the Society’s national meeting in New Orleans on 24 March. Rather than declaring carbon nanotubes safe, the researchers warned that the carbon tubes they tested (three different kinds) were more toxic than quartz dust – the material that causes silicosis among miners and railroad workers. One of the researchers recently told New Scientist, ‘The message is clear. People should take precautions. Nanotubes can be highly toxic.’
To make matters more complicated, a third study on nanotube toxicity, this one by DuPont Haskell Laboratory for Health & Environmental Sciences, was also presented at the American Chemical Society’s meeting in New Orleans, immediately following the presentation of the NASA study. This study concluded that nanotubes are less toxic than quartz dust and that their harmful effects appear to lessen after two months.
Like Goldilocks with her three bowls of porridge, we now have ‘way too toxic’, ‘a little bit toxic’, and ‘just right’ to pick from: three studies running the gamut of possible conclusions. None of the studies looked at health effects after 90 days. All three studies used a similar protocol – nanotubes were injected into the rodents (instillation) rather than allowing them to breathe nanotubes (inhalation), a method that both presenters in New Orleans acknowledged to be inferior. Inhalation studies are technologically difficult to perform in any case, but in the case of carbon nanotubes, where prices can reach $750/gram, even dedicated research scientists will wince at letting mice breathe in nanotubes at their leisure. It’s like feeding pearls to swine! A further sobering reality is to consider the limited scope of the three studies: all three considered the toxicity of only single-walled nanotubes of carbon, which means that the possible toxicity of buckyballs, multi-walled carbon nanotubes, nanohorns and nanotubes made from other elements is still an open question. All three studies considered the effects on only one organ, the lungs. The possibility of translocation to the detriment of other organs was not considered, though translocation in the body is a real concern.
Presumption of innocence II – the case of nanoparticles of titanium dioxide and zinc oxide
Possibly the most ubiquitous use of nanoparticles to date is in cosmetics. Larger particles of titanium dioxide (TiO2) and zinc oxide (ZnO) have been used in sunscreens for decades since they both effectively scatter light including harmful UV rays. They act as physical ‘blockers’ or ‘reflectors’ giving sunscreens an opaque, white appearance. However, if the crystals are reduced to the nanoscale, both titanium dioxide and zinc oxide lose their characteristic white colour and become transparent, allowing visible light to pass but still blocking UV rays. Taking advantage of this nanoscale property change, companies including BASF and L’Oréal have created transparent sunscreens and UV-resistant cosmetics incorporating these metal oxide nanoparticles.
Unfortunately, transparency isn’t the only change associated with these nano-sized metal oxides. While both zinc oxide and titanium dioxide are generally considered inert in their larger form, nanoparticles of both substances can be highly photo-reactive in the presence of UV light, which is partially absorbed into the particle. As a result, nano-titanium dioxide, for example, can exert a ‘strong oxidising power that attacks organic molecules’ and can produce free radicals (i.e., unstable fragments of molecules that are highly reactive). Many applications of nano-titanium dioxide seek to harness this photo-reactive property, including solar cell research, water cleanup techniques, and even self-cleaning windows that repel dirt in the presence of natural UV light. At Argonne National Laboratory in the USA, scientists have developed a method of using photo-reactive TiO2nanocrystals to break DNA strands as a more precise genetic engineering technique. Others have proposed that in some forms, nanoscale TiO2 could be used to fight cancer or even anthrax.
In 1997, scientists from Oxford (UK) and Montreal (Canada) isolated titanium dioxide nanoparticles from over-the-counter sunscreens and observed their behaviour when introduced to human cells. They found that these nanoparticles oxidised to produce hydroxyl radicals, which inflicted substantial damage to the cell’s DNA. The concern was that rather than averting skin cancer, the use of these nanoparticles instead threatened to exacerbate it. Although the upper layers of skin are dead, nano-sized particles may be able to get into deeper layers of the skin, particularly if the skin is flexed during movement, as well as into hair follicles and wounds.
In research that considers the impact of TiO2 on the lungs, it has already been established that ultrafine TiO2 exhibits toxic characteristics. A comprehensive review of titanium dioxide smoke toxicity by the US Army consistently found significant toxic effects associated with inhalation of ultrafine titanium dioxide smoke that did not occur for larger particles. They recommended that safe exposure limits for TiO2 nanoparticles be set at least eight times lower than exposure limits for normal titanium dioxide particles.
Government regulators and industry players seem to respond to demonstrated risks in different ways. On the one hand, some nanoparticle producers have altered their particles to reduce or eliminate free radical production, either by coating the particles in organic or inorganic ingredients such as silica or by adding antioxidants and vitamins to mop up free radicals. By contrast, governments have tended to disregard the size-dependent risks associated with nanoparticles. After an off-record meeting with the cosmetics industry, the EU Scientific Committee for Cosmetic Products and Non-Food Products Intended for Consumers issued an opinion that titanium dioxide particles are a safe component in sunscreen ‘whether or not subjected to various treatments (coating, doping, etc.), irrespective of particle size.’ The US Food and Drug Administration (FDA) was also deliberate in its decision not to distinguish between nanoparticles and their larger relations. In a final monograph on sunscreen ingredients, they ruled: ‘The agency is aware that sunscreen manufacturers are using micronised titanium dioxide to create high SPF products that are transparent and aesthetically pleasing on the skin. The agency does not consider micronised titanium dioxide to be a new ingredient but considers it a specific grade of the titanium dioxide originally reviewed by the Panel.’ Pointing out that ‘fines’ have been part of commercially used titanium dioxide powders for decades, they decided that nanoparticles were simply ‘a refinement of particle size distribution’.
By taking this approach, both the US government and the European Union may have inadvertently established a principle of ‘substantial equivalence’ (see box), based on dubious assumptions. While the modifications made by some nanoparticle TiO2 producers to modify their particles may well have rendered them safe for use in sunscreens, there is no independent body to assess this, no requirement for toxicity studies nor any regulations to prevent manufacturers from using unmodified nanoparticles.
Furthermore, there are many other commercial uses of photo-reactive titanium dioxide nanoparticles ranging from self-cleaning windows to flat screen display technology that are coming to market unregulated. Could these nanoparticles become ambient in the environment over a product’s lifetime or during production or disposal? Do they pose a risk to the health of workers who manufacture them?
Breaking the brain barrier
Confronted with this scientific muddle, ETC Group contacted Dr Vyvyan Howard of the Developmental Toxico-Pathology unit of the University of Liverpool’s Department of Human Anatomy and Cell Biology. In 1999, Dr Howard, as president of the Royal Microscopy Society, co-edited the first collection of papers to examine the toxicity of nanoparticulates. The papers are authored by leading scientists in the fields of air pollution and particle toxicology. We asked Dr Howard to undertake a literature search relating to the effects of nano-sized particles on human health and the routes by which nanoparticles can enter the body.
Dr Howard’s most important conclusion is that more research is urgently needed and that there are many indications that ultrafine particles could enter the human body and pose a human health hazard. Among his conclusions:
‘Research is now showing that when normally harmless bulk materials are made into ultrafine particles they tend to become toxic. Generally, the smaller the particles, the more reactive and toxic their effect. This should come as no surprise, because that is exactly the way in which catalysts are made, 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.’
Beyond concern that nanoparticles could enter the body through the lungs or through the digestive tract, Dr Howard also notes the risk that ultrafine particles could enter through the skin. ‘Recent studies have shown that particles of up to 1 m in diameter (i.e. within the category of “fine” particles) can get deep enough into the skin to be taken up into the lymphatic system, while particles larger than that did not. The implication is that ultrafine particles can and will be assimilated into the body through the skin.’
Given the extensive use of unregulated titanium dioxide nanoparticles in popular over-the-counter skin care products as well as wide use of nanoparticles in cosmetics and wound dressings, this conclusion is of immediate concern to government agencies and consumers. ‘In vitro studies on living cells have confirmed the increased ability of UFPs to produce free radicals which then cause cellular damage,’ Dr Howard adds.
One of the most surprising conclusions of Dr Howard’s survey is that, ‘It does seem, in the light of current knowledge, that the size effect is considerably more important to UFP toxicity than the actual composition of the material.’ In other words, whether the nanoparticles are carbon or titanium or even latex may not be as important as their size.
Dr Howard ends his survey with the following comment, ‘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 related to 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.’
Mandatory moratorium
Based on our initial research on the safety of nanoparticles (see ETC Communiqué‚ ‘No Small Matter’, May/June 2002), ETC Group called for a mandatory moratorium on the use of synthetic nanoparticles in the lab and in any new commercial products. The move was almost universally condemned by the industry. Some argued that it would be impossible to prove the safety of nanoparticles if laboratories couldn’t undertake tests. Others worried that a moratorium would simply drive research underground where it would become more dangerous.
On the contrary, ETC Group has stressed that, although a moratorium is the only responsible avenue open at this time, it need not be long-lasting. Researchers should come together immediately to propose the ‘best practices’ possible for laboratory workers within the internationally-recognised concept of the Precautionary Principle. Assuming that agreement can be reached quickly within the scientific community, these ‘best practices’ should be adopted by the governments of countries where research is underway. The ‘best practices’ should include clear monitoring mechanisms and reporting procedures that will allow governments – in conjunction with scientists – to amend lab protocols as new information becomes available.
Simultaneously, the international community must begin work on a legally-binding mechanism to govern atomtechnology, based on the Precautionary Principle, one that will look beyond laboratory research to consider the wider health, socio-economic and environmental implications of nanoscale technologies. This protocol should be embedded in one or more of the relevant United Nations agencies such as the UN Environment Programme (UNEP), International Labour Organisation (ILO), World Health Organisation (WHO), or Food and Agriculture Organisation (FAO). Ultimately, ETC Group believes that the international regulations for atomtechnology should be incorporated under a new International Convention for the Evaluation of New Technologies (ICENT).
The bottom-up line
The atomtech community has had a quarter-century to come to grips with the obvious health and environmental questions that inevitably arise when dealing with such a powerful set of new technologies. Governments have failed to act responsibly. Lab workers and consumers should not be exposed to nanoparticles in the absence of credible scientific evaluation under government regulation. (Some institutions, for example, have no safety rules for nanoparticle production; others insist their workers wear surgical masks and at least one insists that their workers treat nanoparticles on the same level as they would the HIV/AIDS virus.)
The failure of governments to act now may unnecessarily endanger the future of a powerful and potentially beneficial technology. For the protection of both society and science, the responsible option is to call for an immediate moratorium on the laboratory use of synthetic nanoparticles. In the absence of toxicology studies, ETC Group believes that governments must also urgently consider extending the moratorium to products that place consumers in direct contact with synthetic nanoparticles through their skin, lungs or digestive systems.
Governments seem to agree that atomtechnologies will bring about the next industrial revolution. As though it was a mantra, they are telling themselves they won’t make the same mistakes they made with the introduction of biotechnology. Would that they were right! In ignoring the uniqueness of quantum characteristics, governments have allowed atomtech to move much faster than biotech. They have accepted mass manufacture of un-tested nanoparticles and have allowed commercialisation of consumer products containing nanoparticles without taking seriously the possible health and environmental effects. Given that atomtech is still in its infancy, this is an extraordinarily risky way to run a revolution.
Is the call for a moratorium a thinly-veiled ploy to squelch nanotech? Hardly. It is crucial that governments think in the long term while insuring that the foundations of this ‘bottom-up’ technology are solid. In the absence of toxicology studies, transparent regulations and widespread public discussion on socio-economic, health and environmental impacts of atomtech, governments must act responsibly by adopting a moratorium on laboratory use of synthetic nanoparticles.
The above is extracted from an Occasional Paper (Vol. 7, No. 1, April 2003) by the ETC Group. The ETC Group – the Action Group on Erosion, Technology and Concentration – formerly the Rural Advancement Foundation International (RAFI), is a Canada-based international civil society organisation dedicated to the advancement of cultural and ecological diversity and human rights. The full text of this paper, including endnotes, is available on the ETC Group’s website, www.etcgroup.org.