I’m looking at an electron microscope image of a carbon nanotube – as I cannot show it here, you’ll have to imagine it.  It shows a long, straight, multi-walled carbon nanotube, around 100 nanometers wide and 10 micrometers long.  There is nothing particularly unusual about this.  What is unusual is that the image also shows a section of the lining of a mouse’s lung.  And the nanotube is sticking right through the lining, like a needle through a swatch of felt.

The image was shown at the annual Society of Toxicology meeting in Baltimore last week, and comes from a new study by researchers at the National Institute for Occupational Safety and Health (NIOSH) on the impact of inhaled multi-walled carbon nanotubes on mice.

It’s highly significant because it takes scientists a step closer to understanding whether carbon nanotubes that look like harmful asbestos fibers, could cause asbestos-like disease…

Questions were raised about carbon nanotubes and their superficial similarity to asbestos fibers as far back as 1992.  Yet it wasn’t until last year that research was published suggesting carbon nanotubes that look like harmful asbestos fibers could possibly also cause asbestos-like diseases—specifically the disease of the lungs’ lining mesothelioma.

The Poland study, published in the journal Nature Nanotechnology, indicated that development of the disease mesothelioma was theoretically possible following inhalation exposure.  But it didn’t establish whether exposure could occur to asbestos-like carbon nanotubes in practice or, if they were inhaled, whether the nanotubes could move to and penetrate the sensitive outer layer of the lungs.

Both steps would have to occur for there to be a chance of mesothelioma developing.

The current study from NIOSH seems to close the loop on one of those steps.  Some caution is needed here as the research has yet to be peer reviewed (see Richard Denison’s comments for instance).  Yet the findings are so significant that NIOSH thought it important to keep people abreast of developments before the work is finally reviewed and published.

In the study, a suspension of carbon nanotubes was introduced into the mice lungs using the pharyngeal aspiration technique, and the movement of the nanotubes through the lungs subsequently tracked.  The researchers found that some of the nanotubes migrated from the alveoli in the lungs (the tiny sacs where oxygen passes form the air to the blood) to the pleura—the delicate membrane surrounding the lungs.  As seen in the image described above, there was direct evidence that some of these needle-like fibers physically penetrated through the lung lining, into the region where mesothelioma can develop.

The researchers are at pains to point out that these data are preliminary, and are not conclusive.  The results could have been influenced by the way the nanotubes were delivered to the lungs, the amount of material applied, or the types of animals used.  Nevertheless, they demonstrate that, in principle, some forms of carbon nanotubes have the potential to migrate to the outer layer of the lungs.  And this, combined with the data from Poland et al., raises the stakes considerably regarding potential health impacts.

The data from this study will be peer-reviewed and published shortly, allowing a more critical evaluation.  But given the significance of the preliminary findings, it seems  there is an urgent need for a more extensive strategic research program to establish how harmful different types of carbon nanotubes are, and how they can be handled safely.

Without this, it’s hard to see how manufacturers will be able to make informed choices on good practices that don’t either endanger workers and users, or place an overwhelming burden on production processes.

In the meantime, the best advice seems to be: Take great care to avoid airborne exposures when working with carbon nanotubes that bear a physical resemblance to asbestos.

Given the recent surge in 2020science readers (thanks to Lon S. Cohen at Mashable), I thought it about time I did a short retrospective—a taster for the type of stuff you can expect to read here.  So here are five pieces from the past year that cover everything from nanotechnology to synthetic biology, and ethics to the trials of being on the scientific meeting circuit—all from the perspective of emerging technologies.

Enjoy!

Asbestos-like nanomaterials – should we be concerned? It seems that when the possible downsides of nanotechnology are broached, it doesn’t take long for the “A” word to surface.  But what is the truth—if any—behind comparisons between nanomaterials and asbestos?  From January 2009.

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Nanotechnology—In bed with Madonna? How do you squeeze Madonna, John Kerry, nanotechnology and Elle magazine into the same blog?  With difficulty is the correct answer I think, but somehow they all managed to appear together in this piece from April 2008.

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Synthetic biology, ethics and the hacker culture. What the heck is synthetic biology, is “biopunk” a real word, and are the 21st century equivalents of computer hackers going to reconfigure life as we know it?  I can’t promise any easy answers, but hopefully this post from June 2008 helps set the scene.

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Geoengineering: Does it need a dose of geoethics? We’ve all heard of bioethics, but if the earth can be treated like one massive complex organism, do we need the planetary equivalent of bioethics—“geoethics” perhaps?  From January 2009.

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Enough meetings already! Ever get jealous of the scientific jet-set, swanning between “prestigious” speaking engagements in exotic places?  Don’t bother—the reality is far from glamorous, as this post from May last year tries to capture.  Fortunately, there are occasional compensations, albeit in unlikely forms!

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I’m afraid the “A” word just won’t go away.  It seems that every time people start thinking about the possible health effects of long, thin, fibrous nanomaterials, the question pops up “is this the next asbestos?”  You’d have thought that the issue would have been resolved by now—after all, nanomaterials like carbon nanotubes have been around for some time.  But as the years go by the question persists, and the answer remains elusive.  I’d like to say that this isn’t for want of trying, but sadly there hasn’t been that much interest in funding the right research so far.

This blog was prompted by the recent publication of a report assessing the state of knowledge on fiber-like nanoparticles and their potential health impacts.  The report, commissioned by the Department for Environment, Food and Rural Affairs (DEFRA) in the UK and prepared/published by the Institute for Occupational Medicine (IOM), addresses whether “High Aspect Ratio Nanoparticles” (aka “HARN”) should raise the same health concerns as asbestos fibres.  Here we go again you might say—and indeed the report covers a lot of old ground.  Yet repetitive as the messages might be, the reality is that this is an issue which remains far from being resolved, and could cost some sectors of the nanotechnology industry dearly if clear information and safe working guidelines aren’t forthcoming soon.

To be honest, the report is not an easy read—it was prepared as a report to a government department, and reads as a report to government department.  In other words, it’s not that accessible to anyone outside the immediate target audience.  Nevertheless, it does contain critical information on how this specific class of engineered nanomaterials should be approached if it is to be used safely and successfully.

I’ll get to the report’s key points in a moment.  But first it is worth sketching out an incomplete but interesting nevertheless timeline for carbon nanotube safety questions—picking on carbon nanotubes as, in certain forms, they are the archetypal HARN…

Carbon nanotubes were observed by a number of researchers between the 1950’s and 1980’s, although the relevance of the observations went largely unnoticed (I hate to say it, but Wikipedia covers this pretty well).  It wasn’t until Sumio Ijima published the paper “Helical microtubules of graphitic carbon” in the journal Nature in 1991 that things began to get interesting.

The following year there was a letter published in the same journal raising a cautious note.  The letter was written in response to an article by Paul Calvert on the potential utility of emerging nanofibers—including carbon nanotubes.  In it, Gerald Coles—an occupational hygienist—writes:

“Sir—Attractive though they are, the technical properties of ultra-thin man-made fibres pointed out by Paul Calvert (Nature 357 365; 1992) should not hide the potential—at least for those fibres resistant to biological degradation in vivo—for related occupational risks to workers.

Fortunately, most reinforcing fibres hitherto produced in quantity have, as Calvert pointed out, been of diameter 10 µm or more; the practical risk from occupational or other exposure to their airborne dusts remains doubtful.  But work on fibres other than asbestos has shown the morphology and biological persistence of fibrous materials to be of greater significance in relation both to pnemoconiosis and, more seriously, to mesothelioma, than their chemical constitution.

A need for stringent precautions in preventing occupational exposure to the dusts of these thinner materials might well result in cost increases in manufacture that would outweigh the “dramatic reduction in production costs” hypothesized by Calvert.”

Nothing much happened then until 1998, when Science reporter Bob Service filed a news piece under the headline “Nanotubes: The Next Asbestos?” Service writes

“The dangers of asbestos first came to light in the early 1960s, when studies linked exposure to these silicate fibers with mesothelioma–a rare cancer of the lining of the chest or abdomen that’s commonly fatal. Asbestos fibers were found to be so small that they could be inhaled into the deep lung, where they could stick around for decades. Once there, metals in the silicate fibers could act as catalysts to create reactive oxygen compounds that go on to damage DNA and other vital cellular components.

Whether nanotubes could reproduce this behavior is unknown: Their toxicity has yet to be tested. But already views on their safety differ sharply. “[Nanotubes] may be wonderful materials,” says Art Langer, an asbestos expert at the City University of New York’s Brooklyn College. “But they reproduce properties [in asbestos] that we consider to be biologically relevant. There is a caution light that goes on.” Most notably, says Langer, nanotubes are the right size to be inhaled, their chemical stability means that they are unlikely to be broken down quickly by cells and so could persist in the body, and their needlelike shape could damage tissue.”

Did these concerns lead to action?  Nope.  A few studies began to emerge a few years later observing unusual effects in the lungs associated with single walled carbon nanotubes (see for instance Lam’s review)—but in the main these weren’t materials that physically resembled asbestos.

The next major milestone was in 2006, when a bunch of us published the commentary “Safe Handling of Nanotechnology” in Nature.  Here we stated

“Fibre-shaped nanomaterials possibly represent a unique inhalation hazard, and their pulmonary toxicity should be evaluated as a matter of urgency. Inhalation of a sufficient dose of asbestos fibres can lead to the malignant disease mesothelioma, the causation of which is related to the length, width and chemistry of the fibres, as well as their ability to persist in the lungs.

Although it is not clear whether fibre-shaped nanoscale particles formed from carbon and other materials will behave like asbestos or not, some materials are sufficiently similar to cause concern: any failure to pick up asbestos-like behaviour as early as possible would be potentially devastating to the health of exposed people and to the future of the nanotechnology industry. We propose that the potential health impact of high-aspect-ratio, biopersistent engineered nanotubes, nanowires and nanofibres is systematically investigated within the next 5 years.”

Since then, there have been a couple of studies exploring the potential of fiber-like carbon nanotubes to cause mesothelioma—most notably the Poland et al. study that appeared in Nature Nanotechnology in 2008.  The study indicated (in a nutshell) that carbon nanotubes that look like harmful asbestos fibers, seem to behave like harmful asbestos fibers.

Looking through this rather roughly sketched out timeline, it is clear that questions over similarities between carbon nanotubes and asbestos have been circulating for some years, yet little has been done to discover the extent of this similarity, and actions that need to be taken as a consequence.

So back to the DEFRA report.  In amongst a whole heap of scientific information, there are some key messages that come through:

The Fiber Paradigm. Over the years, experts have developed a profile for fibers that are more likely to be harmful if inhaled.  According to this profile, for something to show asbestos-like toxicity, it needs to satisfy three criteria:

• Diameter: Fibres must be thin enough reach past the upper  airways and into the sensitive region of the lungs where oxygen diffuses into the bloodstream.  (Penetration into the lungs is not affected that much by fiber length.)
• Length: Fibers must be long enough to initiate harm through mechanisms such as frustrated phagocytosis—where the lung’s natural defenses break down because scavenger cells (macrophages) cannot physically engulf the fibers.
• Biopersistence: Fibers must stick around for a long time in the lungs (tens of years) without dissolving or breaking up.

There are other factors that may be important in determining toxicity, but these are the big three.

High Aspect Ratio Nanoparticles and the Fiber Paradigm. The review concluded that there are some HARN that satisfy the profile of the fiber paradigm—certain forms of carbon nanotubes in particular—and that these should be approached with caution.  Quoting from the document:

“This review has identified many similarities between HARN and asbestos with regard to their physico-chemical properties and toxicological effects and has concluded that there is sufficient evidence to suggest that HARN which have the same characteristics (diameter, length and biopersitence) as pathogenic fibres are likely to have similar pathology.”

Identifying potentially harmful asbestos-like substances. The review’s authors put together a handy flow-chart for identifying nanomaterials which might be more likely to cause harm in a similar way to asbestos.  It’s just a suggestion, but I thought it was a useful one:

Research priorities: Finally, the report’s authors highlight areas requiring further research if progress is to be made:

• Hazard Identification: The characterisation of the physico-chemical properties
  of HARN especially the length of the fibres and their biopersistence
• Dose-Response Assessment: Acute and chronics adverse effects of HARN;
  Cellular and molecular mechanisms of HARN toxicity investigated with in vitro
  and in vivo models
• Exposure Assessment: Identification and quantification of the routes (e.g.
  inhalation, dermal); the pattern and the  intensity of exposure
• The Risk Assessment of HARN: Combining exposure and Hazard to
  calculate the health risks from exposure to HARN.

To me, this seems a no-brainer.  Carbon nanotubes in particular are such an important material that we cannot afford not to commercialize them.  But at the same time, it would be morally reprehensible to plow ahead without heeding the warning signs that this material—in some forms at least—needs to be handled with care.  It still amazes me that 17 years after health and safety questions were first raised, we are still framing the questions rather than finding the answers.

Hopefully though this will change and the DEFRA report will be the precursor to some solid research.  It’s certainly needed.

Mix carbon nanotubes and asbestos together (metaphorically) and you get an explosive mix—at least if news coverage of the latest publication coming out of Professor Ken Donaldson’s team is anything to go by.  The research—published on-line today in Nature Nanotechnology—is the first to explicitly test the hypothesis that long carbon nanotubes behave like long asbestos fibres in the body.

In brief, the study (which I was a co-author on) used an established method to test whether a fibrous material has the potential to lead to the disease mesothelioma—a cancer of the outer lining of the lungs that can take decades to develop following exposure.  In the method, samples of material are injected into the abdominal space of mice, where inflammation and the formation of granulomas in the lining tissue (the mesothelium) are studied over a seven-day period.  Previous research has established that the combined presence of fibres, inflammation and granulomas is a very strong indicator that mesothelioma will occur in the long-term.  While the method uses lining of the abdominal space, it is highly predictive of what happens in the same tissue surrounding the lungs, if it is exposed to durable fibres.

Five materials were tested in this study: short amosite asbestos fibres, long amosite asbestos fibres, short and/or tangled multi walled carbon nanotubes (two samples), long straight multi walled carbon nanotubes (two samples), and carbon black (compact graphite-based particles.  The results: fibres longer than 15 micrometers to 20 micrometers (whether asbestos or carbon nanotubes) led to a positive response; short/compact particles did not.

This is the first study to demonstrate that carbon nanotubes that physically resemble harmful asbestos fibres, can also behave like harmful asbestos fibres.

What the study does not address is whether exposure to long straight carbon nanotubes will occur or, if it does, whether these fine fibres will reach the mesothelium surrounding the lungs, and go on to cause mesothelioma.

But the results are sufficiently compelling to suggest urgent action is needed if we are to prevent a long lasting legacy of harm from some forms of carbon nanotubes, and ensure the emergence of safe and trusted carbon nanotube applications.

First and foremost, targeted research is needed to validate this study, assess the magnitude and nature of likely carbon nanotube exposures—from material production to product disposal—and evaluate whether inhaled nanotubes can work their way to the outer lining of the lungs.  The current U.S. federal strategy for nanotechnology-related environmental, health and safety research (PDF, 2.2 MB) does not specifically address the health impacts of carbon nanotubes (despite a recommendation from the UK Royal Society and Royal Academy of Engineering in 2004 to carry out exactly this type of research).  Perhaps it’s time to rethink what is important here.

But action is also needed now to ensure carbon nanotube exposures to workers and users are kept as low as possible.  This means developing appropriate exposure measurement methods, applying effective control and containment protocols, and agreeing on benchmark exposure levels to use in the absence of more formal exposure limits.  The recent BSI Guide to safe handling and disposal of manufactured nanomaterials (PD 6699-2:2007, see also“Safe nanotechnology in the workplace: A practical guide”) recommends a benchmark exposure level of 0.01 fibres/ml for carbon nanotubes in the absence of any other information—this would seem to be good advice for long carbon nanotubes, until more is known about their exposure potential and hazardous nature. Long multi-walled carbon nanotubes can currently be purchased from outlets like CheapTubes Incorporated for as little as 40 cents a gram (as long as you by them in kilogramme quantities), yet the health and safety advice still assumes these are as harmless as graphite—this has to change.

And thirdly, action is needed to ensure transparency—making sure regulators, industries and consumers know which types of carbon nanotubes are being used, where they are being used, and what precautions should be taken to ensure safe use.

Carbon nanotubes have great potential as a unique material that can be used in many unique and beneficial ways—from reducing our environmental impact to curing diseases.  But mis-steps now could easily undermine trust in this nascent industry, and prevent the material’s potential from being realized.

The comparison with asbestos is firmly grounded in the physical resemblance between certain forms of the two materials, and this alone should stimulate clear action to ensure safe use.  But the health impacts of asbestos exposure still resonate through society—deaths from asbestos-related disease are not expected to peak for another ten years—and the mere suggestion of similarities between nanotubes and asbestos fibres could cause investors and users to shy away from this new technology unless there are clear assurances that health and safety concerns are being fully addressed.

Widespread pickup in the media of the current study suggests that people care about carbon nanotubes, and whether they are safe.  The good news is that we still have time to ensure they are used safely—but only if we act now and act fast.

Additional Resources

Carbon nanotubes introduced into the abdominal cavity of mice show asbestos-like pathogenicity in a pilot study.  Poland et al. (2008). doi:10.1038/nnano.2008.111

Carbon nanotubes display asbestos-like behaviour – a SAFENANO commentary by Ken Donaldson

Project on Emerging Nanotechnologies

Nanotechnology consumer products inventory

International Council On Nanotechnology backgrounder on multi walled carbon nanotunes and mesothelioma

NIOSH Science Blog

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This post first appeared on the SAFENANO blog in May 2008