A new study about to be published in the European Respiratory Journal links workplace nanoparticle exposure to seven cases of serious and progressive lung disease in China – leading to two patient deaths – and presses a number of “hot” buttons when it comes to the safety of emerging nanotechnologies. To help place the study in context, I have posted separately the following pieces on 2020 Science, and also on the SAFENANO blog:

Nanoparticle exposure and occupational lung disease – six expert perspectives on a new clinical study
Observations from six leading experts on the study, and it’s significance

Is nanotechnology posed for the ride of its life?
A caution against overlooking the study’s true relevance in the rush to use it to justify pre-existing positions on nanotechnology

Further links to useful resources are included at the end of this blog.

Study Overview

In brief, the paper by Song et al. that appears in the European Respiratory Journal is a clinical study of 7 female Chinese workers who were diagnosed with unusual and progressive lung damage. Two of the women died as a result of the damage. All had been working for some months in a facility spraying a polyacrylic ester paste onto a polystyrene substrate that was subsequently heat-cured. The work was carried out in an enclosed space with little natural ventilation. Five months before the lung disease was identified, the local exhaust ventilation in the facility broke down – and from the account given was never mended.

All seven patients were suffering from shortness of breath, and pleural effusions (an excess of liquid in the cavity surrounding the lungs).  Lung tissue samples showed non-specific inflammation, pulmonary fibrosis, and foreign-body granulomas of the pleura – the membrane surrounding the lungs.  Five of the patients were found to have pericardial effusions – an excess of liquid around the heart.

On examination, investigators found ~30 nm diameter particles in fluid surrounding the lungs of the patients, and in the cytoplasm and nucleoplasm of cells lining the inside and outside of the patients’ lungs. They also found evidence of similar sized nanoparticles in the polyacrylic ester paste, and in the (defunct) workplace ventilation system. There were accounts of smoke being produced as the coated polystyrene was heat-cured.

Based on the presence of the nanoparticles in the workplace and the patients, the nature of the disease observed and previously published cell culture and animal exposure studies on the impacts of nanoparticles, the authors speculated that the lung disease – and the two deaths – were a direct result of the nanoparticle exposure. They conclude that

this may be the first study on the clinical toxicity in humans due to long-term exposure to nanoparticles, and so many questions need to be answered, more studies on the possible mechanisms, diagnosis, treatment and prevention of the ‘nano material-related disease’ are needed. These cases arouse concern that long-term exposure to some nanoparticles without protective measures may be related to serious damage to human lungs. It is impossible to remove nanoparticles that have penetrated the cell and lodged in the cytoplasm and caryoplasm of pulmonary epithelial cells, or that have aggregated around the red blood cell membrane.

In the press release accompanying the paper from the European Respiratory Journal, more explicit associations with the safety of nanotechnology are drawn:

While nanoparticles’ diminutive size means they have unprecedented physical properties (such as diffusion, resistance or flexibility of use) that are invaluable in industrial applications, it also raises the question of their toxicity for consumers and the workforce. Their tiny diameter means that they can penetrate the body’s natural barriers, particularly through contact with damaged skin or by inhalation or ingestion. Moreover, their toxicity has already been established in animals: mice were found to develop symptoms of inflammation and pulmonary fibrosis following application of carbon nanoparticles to the trachea. But until now no cases had been reported in humans. The revelations to be published in the ERJ by a Beijing team will thus break new ground and relaunch the debate on the dangers of nanotechnologies.

Given the buttons this paper and the associated press release hit – including nanoparticle safety, worker deaths and (in the press release) parallels with asbestos, this is a paper that could garner a lot of attention. I suspect that it will refocus attention on what is and isn’t known about the safe use of nanomaterials. Even though the logic is suspect from a purely scientific perspective, the two deaths and their association with nanoparticle exposure will most likely lead to some tough questions being asked by consumers and others on the safety of other nanomaterials. This may not be a bad thing, but at the same time it is important to understand the limitations of the study:

This is a clinical study and not a toxicology study: The investigators did not have the luxury of conducting controlled and well-designed experiments, but were placed in the position of detectives piecing together a series of events after the fact.  Inevitably, this leaves gaps in the information presented, but does not necessarily detract from the usefulness of the study.

The paper adds to the general knowledge base of how nanoparticle exposures might impact on human health. In this respect, it is an important addition to the literature.However, in isolation it tells us very little beyond this particular incident, and great care should be taken in extrapolating the findings to the handling of nanoparticles in general.  It is not possible to draw any general conclusions on the safe use of nanotechnologies from the study.

Interpretation of the study is hampered by a lack of exposure data. Nothing concrete is known about the nature or magnitude of the workplace exposures. It can be speculated (reasonably up to a point) that the workers were exposed to high airborne concentrations of a cocktail of materials that probably contained nanometer-scale particles in some form. What is not known is what the particles were made of of, whether they were inhaled as single particles or as large agglomerates or aggregates, or whether there was anything unusual about their surface–including the presence of adsorbed chemicals.  All of these pieces of information are important in making sense of the health effects seen.

There are no electron microscope images of the nanoparticles found in the workplace. The researchers note the presence of ~30 nm particles in the polyacrylate paste and the ventilation system.  But without images, this information isn’t much help in working out whether the presence of these particles was significant.

There is no chemical analysis of the particles found in the workplace or biological samples. This is a critical data gap – the information is needed to link the workplace material to the material found in the patients, and to establish whether these were polyacrylic particles, an inorganic additive to the paste, or something else.

There is no assessment of other plausible causes of the symptoms seen. The authors are quick to dismiss other possible causes (such as other fumes and vapors from the polyacrylic paste or the polystyrene substrate) and focus in on the nanoparticles.  But without further research, it is difficult to rule out the possibility of other factors playing a role here.

In discussing the relevance of the study, no distinction is made between different types of nanomaterials and their potential impacts. The authors cite the in vitro and in vivo behavior of a range of nanomaterials observed in previous studies and relate these findings to their own observations,.  But they fail to recognize that different nanoparticles behave in very different ways.  For instance, they refer to lung damage associated with inhaling carbon nanotubes in animals as being similar to some of the symptoms observed in their patients, without acknowledging that the particles they observe bear no resemblance to carbon nanotubes.   As a result, the authors propagate the idea that nanoparticles are a generic class of material – which research suggests they are not.

Despite these limitations, this is a strong clinical study, and if viewed appropriately, will most likely help avoid similar incidents in the future.

And as a final observation, it is worth noting that the illnesses and deaths observed would most likely not have occurred if long-accepted occupational practices had been followed.  The tragedy here is that, irrespective of the presence of nanoparticles, the illnesses and deaths could have been prevented if simple steps had been taken to reduce exposures.

Additional resources:

GoodNanoGuide
A community resource for working safely with engineered nanomaterials

SAFENANO
Further information on the Song study

ICON Blog
Further comments and reflections on the study from ICON

[8/20/09: link to paper updated]