The recent tragic account of seven Chinese workers suffering—apparently—from nanoparticle-induced lung disease, is likely to raise serious concerns with anyone potentially exposed to similar particles.  Yet without the benefit of insight from scientists and others working on nanoparticles and their potential health impacts, it’s hard to get a handle on the study’s broader relevance.

When I first found out about the study, I asked six highly regarded experts familiar with the issues to share their thoughts on the work and its broader implications.  Their comments (below) reflect a range of perspectives and opinions, and hopefully provide a deeper insight into an important but far from conclusive piece of research…

[More information on this study and its relevance can be found here]

Professor Anthony Seaton MD

Professor Seaton is a distinguished clinical physician specializing in occupational health, and a highly regarded expert on the potential impacts of inhaling airborne nanoparticles. He is currently emeritus professor in the Department of Environmental and Occupational Medicine at the University of Aberdeen.

Although this paper has weaknesses, it contains a number of important messages. Essentially it is tragic story of a fatal industrial accident, from the rather sparse description in the text, consequent upon grossly inadequate health and safety measures in a workplace. A small number of unsophisticated young women and one man were exposed to a toxic mixture of dust and fumes in a small unventilated room and developed a progressive lung condition that has so far killed two of them and seriously disabled most. Similar episodes, almost always involving gases, have occurred in the past, but this one has unique features, notably the effect in causing effusion of fluid into the linings of the lung (the pleura) and heart (the pericardium), the finding of nanoparticles in the workplace and in the lungs and lung fluid of the workers, and the finding of a tissue reaction to particles in the lung lining. Most unfortunately, the authors were unable to obtain or report information on the chemical nature of the particles in the lungs or the workplace. While it remains an open question how far the illnesses reported were due to particles and how far to gases, it is my view that an important component must have been due to particles.

But… the messages:

1. It is not always known that a fume, by definition, comprises nanoparticles generated by heating. This process involved not only spraying of a powder but also heating of a plastic material and fume would undoubtedly have been produced (the authors describe “smoke”).
2. Heating of plastics will produce any number of organic chemicals in particulate and gaseous form, depending on temperature and the chemistry of the plastic. Many of these are very toxic to the lung.
3. In such circumstances, if the particles produced are insoluble, they are likely to be retained in the lung and other tissues. If also they have toxic surfaces, tissue reactions will occur, as apparently in this case.
4. Such dreadful episodes can be prevented (and generally are prevented) by well-established occupational hygiene measures. Those who decry the attitude of governments in the West to “Health and Safety” need to be aware that our attitude results from many similar experiences throughout our own industrial revolution and even occasionally nowadays.

So to me the message of this episode is that fumes and dusts are often toxic and if you ignore this, tragedies like this may occur. Appropriate workplace hygiene will prevent this in the nanotechnology industry as elsewhere. Please take note, and let’s not argue about whether this paper’s conclusions are right or wrong – that is not the message.

Professor Günter Oberdörster

Professor Oberdörster is considered by many to be the “father” of research into the toxicology of inhaled nanoparticles.  His group at the University of Rochester has led global research in this area for over two decades.

This is clearly a case of a very complex exposure to a lethal mixture of reactive gases and particles of different chemistry and sizes, including nano-sized particles. But, even more importantly, this is a case of a tragic accident with fatal outcome due to extremely poor industrial hygiene conditions.  To blame the resulting severe pathology and fatalities categorically on “nanoparticles” that were present in a paint paste is scientifically unjustified.  There are a number of potential mechanisms that may have been at play, including the formation of highly reactive gas phase polymer compounds generated by the heating of the spray painted styrene boards combined with immediate formation of condensation aerosols of ultrafine particles (fume) of different larger agglomeration and aggregation states (smoke was visible).  Such freshly heat-generated condensation aerosols can cause highly toxic acute effects. Well known examples include metal fume fever and polymer fume fever, which are generally of a short-lasting nature, but fatalities have been reported following polymer fume exposures.  Fume exposures can also result in an adaptive state and thereby protect the organism from untoward effects of subsequent exposures, which has been described already in the early part of the last century in human zinc metal fume exposed workers (could this explain the many months long exposure duration, until it was too late for the Chinese workers?). Even seemingly harmless actions such as heating ski wax onto ski surfaces has resulted in severe ARDS [Acute Respiratory Distress Syndrome]-like effects due to inhalation of the generated fumes, requiring hospitalization. Thus, fumes of freshly-generated thermodegradation products are clearly a well-recognized occupational hazard, as well as a potential hazard to consumers (e.g., exposure to fumes from heated PTFE in household cooking and other appliances).

In the tragic industrial accident in the Chinese factory reported here, the paint paste was described as a mix of many organic components that contained additionally nanoparticles of polyacrylate (~30nm) as did the collected dust, but neither detailed characterization nor pictures are provided. Are they identical to the nanoparticles found in fluids and tissues of the patients? Unfortunately, there is a complete lack of the characterization of the nanoparticles found in the effusion fluids and lung tissue, and no attempt was made to compare these to those contained in the paint and dust. Conceivably, when inhaled they could act as carriers of reactive gas phase constituents, or otherwise they could just signal a breakdown of epithelial barriers in the lung, which increased their biodistribution to interstitial, pleural and other sites where they were found, if indeed they were the same. Thus, the question:  “Did polyacrylate nanoparticles cause, or contribute to the cause of, the observed severe pathology, or are they just ‘passive bystanders’ in this complex mixed exposure scenario?” cannot be answered.  We simply do not know, but what is obvious is that proper industrial hygiene would have prevented such a horrific accident.  Given this clear message it is not obvious why the authors identify a need for “more studies on … prevention of the ‘nanomaterial related disease’ “. No, we do not need more studies on how to prevent future accidents like this one, just proper well-established common sense industrial hygiene measures will do that. And yes, we need to identify hazardous nanomaterials and the characteristics that make them hazardous; key is, however, to use readily available preventive measures to monitor and avoid exposure until we know better and are able to set scientifically founded safe exposure limits.

This case should not be used to bedevil nanotechnology, and a conclusion that nanoparticles generically are to blame is very unfortunate.  Because of this, the paper is likely to make a big splash in the media. It is important that terrible incidents like this be published, despite the lack of rigorous scientific analysis that should have been included. Such accidents serve as warnings and grim reminders of the need for workers’ protection, whether exposure to nanomaterials is involved or not. Indeed, earlier incidents of severe cases of organising pneumonia including fibrosis resulting in six fatalities in textile paint spraying operations occurred in the early 1990’s in Spain (long before the awareness of media and scientists for “nano”). It should have been a strong message for the necessity of precautionary protective measures in paint spraying industrial applications.

Professor Ken Donaldson

A toxicologist specializing in workplace lung diseases, Professor Donaldson is one of the world’s leading authorities on the health impacts of inhaling airborne nanoparticles.  His group at the University of Edinburgh has conducted extensive research into the potential health impacts of inhaling nanomaterials.

This is a puzzling case. There is no conventional particle exposure that does this kind of damage to the lungs. Not even long-term exposure to high levels of the most toxic dusts known. Even when asbestos affects the pleura it takes tens of years of exposure. In the past there was a report of a highly toxic, hot Teflon particle exposure from overheated frying pans where the particles had highly toxic free radicals on their surface that disappeared rapidly with time; that is a possibility here. The damaging exposure was clearly a toxic cocktail of particles and chemicals and so is a highly unusual case that sheds little light on the hazards from the vast majority of nanoparticles used in workplaces, which do not have a reactive surface. It may yet turn out that the particles are a by-product of the chemical reaction and not the main cause of the injury.  If a very toxic chemical exposure involves the formation of nanoparticles as part of its chemistry, which is quite possible, they may not necessarily be the main toxin; they could be just an epiphenomenon. I notice that the cell that was stuffed with particles seemed to be alive and well.

Chemical exposures in the past might have produced nanoparticles but since no-one looked for them they may never have been implicated. In the current climate of concern over nanoparticles the reverse is true and there may be a rush to judgement implicating the nanoparticles in the adverse effects. I think the paper should never have been published without characterising the exposure and the toxicological reactivity of the nanoparticles before blaming the effects on them. If the effects were due to highly toxic short-lived free radicals on the particle surfaces then it informs a tiny sub-division of nanoparticles that really represent a chemical exposure and certainly no member of the public would ever get a substantial exposure to this material. A well-regulated workplace with proper controls would have prevented this accident. Therefore the paper by Song et al. demonstrates a failure of occupational hygiene and worker protection in the chemical industry, that happened to have involve nanoparticles, rather than a helpful insight into nanoparticle toxicology.

Professor Vicki Stone

Editor of the journal Nanotoxicology and a professor of toxicology at Napier University in Edinburgh, Professor Stone is a foremost expert on the mechanisms by which nanoparticles potentially interact with the body and cause harm.

The publication by Song et al. claims to have identified evidence that nanoparticles can cause adverse health effects, specifically on the lungs of women employed in a poorly ventilated working environment.  Unfortunately the publication contains a number of flaws, which make this conclusion hard to believe or confirm.  Firstly, the cocktail of chemicals and particles to which the women were exposed was very complex, containing many substances which are potentially toxic.  This cocktail was poorly understood as the authors were unable to sample and analyse the actual cocktail mixture directly to determine the real composition.  This is often a problem with studies of this type, but usually authors would acknowledge the limitations that this lack of information imposes when trying to draw conclusions.  These authors do not seem to have fully appreciated these limitations causing them to jump to conclusions.

The authors also showed some interesting pictures of particles within the lungs of these women.  However, they did not provide any evidence to show that these particles were derived from the working environment – this could have been achieved through microscopes that can analyse the particle chemical composition.  Humans constantly inhale particles from a wide variety of sources, including traffic, domestic and industrial pollution.  It is therefore important to confirm that these particles were gained specifically from the working environment before the fumes associated with their employment can be blamed for the health effects observed.

Therefore, at this time, this paper does not effectively illustrate adverse clinical effects of nanoparticles in a worker population, but it does raise the issue that we need to be careful and vigilant in future.

Dr. Rob Aitken

Director of Strategic Consulting at the Institute of Occupational Medicine in Edinburgh and director of the SAFENANO initiative, Dr. Aitken has a wealth of experience addressing workplace safety and health.  He is a leading international expert in developing safe practices for working with engineered nanomaterials—including nanoparticles.

This tragic event is a shocking example of what can go wrong if a proper care is not taken with basic industrial hygiene. There can be little doubt that these serious health effects have been caused as a result of a workplace exposure. The workplace, where a complex mixture of chemicals was being sprayed, and heating activities producing smoke being carried out, in an closed room with no effective ventilation and entirely inappropriate personal protective equipment seems inexcusable.

However, the key question which remains unanswered at this time is “exposure to what?” The exposure assessment in the study is poorly described. It seems from the information provided that these unfortunate workers were handling a paste composed of a complex mixture including butanoic acid, butyl ester, N-butyl ether, acetic acid, toluene, di-tert-butyl peroxide,1- butanol, acetic acid ethenyl ester, isopropyl alcohol and ethylene dioxide and finally some type of nanoparticle,  30 nm in diameter. Although the authors describe the nanoparticles found as being polyacrylate, the characterisation within the study provides no clear information about either the nanoparticles’ composition or their quantity within the paint paste. The nanoparticles seem to have been found in the dust in the air but again no indication of the airborne concentration, or the proportion of the mass attributable to them.  Likewise, the same nanoparticles seem to have been found in the biological samples, but again there is no indication or estimation of in what quantity.

On the evidence presented is not possible to say with any certainty that the nanoparticles in question caused the effects, and I suspect that on this basis alone the paper will be quickly dismissed by scientific communities.  However neither is it possible to say that they are not responsible, and the alarm that such a paper is capable of raising amongst a broader audience is not to be taken lightly.

There are some parallels with earlier scares, most notably the infamous “magic nano” incident. Where the Chinese incident seems to be different is that there really are nanoparticles here, albeit of apparently unknown composition. However, just like the earlier event, it is not enough to point the finger of blame at other possible culprits, the seriousness of this event demands further investigation, no matter how difficult that is.

Was this event caused by exposure to some type of nanoparticles? I don’t know, but it would certainly be ill advised to be too quick to dismiss the possibility.

Dr. Kristen Kulinowski

Dr. Kulinowski is Director of the International Council On Nanotechnology (ICON) at Rice University, and a global leader in developing safe and responsible nanotechnologies.  Under her direction, ICON has established the foremost on-line database of nanotechnology health and environmental impact research papers, and the GoodNanoGuide—an initiative to enable people share and develop the best possible practices for working safely with engineered nanomaterials.

I was impressed by the exhaustive clinical detail presented by the physicians to support their case that exposures in the workplace resulted in harm to these women. What I would have liked to see is more analysis of the particles themselves and how they were produced. What are the particles made of? Is there any corresponding toxicity literature investigating the same particle types in animal models? Were the particles part of the paste or created by the spraying or drying process? Not clear.

It’s also not clear if the answers to those questions really inform the lessons we might draw from this incident. Whether these were incidental or manufactured nanoparticles is somewhat beside the point. The real tragedy here is that these workers could have been protected if a conventional chemical hygiene plan had been implemented that included a working ventilation system and personal protective equipment. Preventing inhalation of 30-nm nanoparticles can be as simple as the proper use of an inexpensive mask sold by your neighborhood home improvement store. But even this basic protective measure was not employed in this workplace.

We can do better than this. A lot better. The tools are out there; it’s up to us to use them.

(Kristen has posted further comments on the new study on the ICON blog)