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Persistent Pulmonary Fibrosis, Migration to the Pleura, and Other Preliminary New Findings after Subchronic Exposure to Multi-Walled Carbon Nanotubes

Posted on by Vincent Castranova, PhD, Ann Hubbs, PhD, Dale Porter, PhD, and Robert Mercer, PhD

Multi-walled carbon nanotubes, known as MWCNTs for short, are a type of engineered nanomaterial that shows promise for various applications. These include the potential for creating stronger, more durable building materials; improving cancer therapies; creating more efficient means of energy generation, storage, and transmission; and speeding computer processes. However, as with other types of engineered nanomaterials, the potential occupational health implications of MWNCTs are not well understood at this emergent stage of the technology. A broad group of health and safety practitioners and business observers have agreed that research is vital for determining if MWCNTs pose a health risk for workers engaged in their production and industrial use, and for informing the responsible development of this technology. There is general agreement that this issue must be approached in a proactive manner with good research in order for society to benefit from the many promises this new class of materials has to offer.

One critical avenue of research explores the toxicological aspects of MWCNTs. Some of the critical questions that need to be addressed are these:

  • Once these materials enter the body, how do they interact with the body’s biological systems?
  • What effects may occur in the genes, cells, or tissues as a result?
  • Do those effects pose a health risk, either in themselves, or as early warnings of subsequent effects?

The National Institute for Occupational Safety and Health (NIOSH) has worked closely with its partners to stimulate, design, conduct, and report pioneering research in this area. Today, at the 2009 Annual Meeting of the Society of Toxicology, a team of NIOSH researchers reported new, preliminary scientific findings that add significantly to the data that scientists and policymakers need in ongoing risk assessment. The preliminary findings were presented at the conference to keep NIOSH’s colleagues and partners up to date on this research, and to engage their interaction in the setting of the scientific forum. An abstract of these preliminary findings can be found in The Toxicologist 108:A2193, 2009. Because we know there will be wide interest in these preliminary data as a result of the conference presentation, we wanted to comment on the research here, and to note that the preliminary data have not yet been formally peer-reviewed. More complete data will be included in articles that we are preparing for future publication in the peer-reviewed scientific literature.

The NIOSH investigators reported on a scientifically ambitious study of laboratory mice exposed to multi-walled carbon nanotubes by pharyngeal aspiration causing the lab animal to inhale a small drop of liquid with suspended material that closely resembles inhalation of the same material suspended in the air. The research showed inflammation in the lungs of the mice, and fibrosis in their lungs, which persisted following exposure. Such effects are similar to the interstitial pulmonary fibrosis reported previously by NIOSH researchers using single-walled carbon nanotubes.

Most significantly in terms of generating new knowledge, the study demonstrated the ability of MWCNTs to migrate from the lungs to the pleura (the tissue that surrounds the lungs). The preliminary findings are the first to demonstrate that carbon nanotubes aspirated by laboratory mice can actually migrate from the alveoli in the lungs (the tiny structures in the lung that are critical for gas exchange), through the lungs, to the pleura. The preliminary findings offer significant new evidence of MWCNTs appearing to behave like durable fibers in that they translocate to the pleura.

The preliminary findings are not definitive in answering two questions:

  1. If inhaled by workers, would MWCNTs or the broader class of carbon nanotubes migrate from the workers’ lungs to the pleura?
  2. If MWCNTs migrated to the pleura after being inhaled into the lungs, would they cause mesothelioma like another well-studied fiber, asbestos?

However, the preliminary findings provide the first scientific evidence ever that such migration is possible, given similarities between the body systems of the mouse and those of humans. These preliminary findings, when combined with previous studies by other investigators, which reported inflammation and mesothelioma of the abdominal lining after intraperitoneal instillation (injection into the lining of the abdominal cavity) of MWCNTs in mice, provide additional justification for further research.

There are limitations to the study that need to be explored, addressed, and answered by further research before the findings can be used with confidence for human risk assessment. These limitations involve the magnitude of the dose, the means of exposure (pharyngeal aspiration), and the generalizability from the strain of mice used, the C57BL/6J type. These findings point to the need for further studies with different doses, by inhalation, and a different species, such as the rat.

In the interim, as we prepare them for peer-reviewed publication and look ahead to subsequent research needs, these new preliminary findings reinforce the need to adopt a system of prudent risk management practices, including a continued rigorous approach to controlling occupational exposures among workers during the production and use of MWCNTs. As new research continues to address a number of health and safety questions, there will continue to be a degree of uncertainty that requires a prudent and proactive strategy. This strategy of prudence is outlined in NIOSH’s document Approaches to Safe Nanotechnology along with interim recommendations for controlling such exposures pending further research to fill gaps in present knowledge. Additional resources pertaining to NIOSH findings and recommendations on the occupational health and safety implications of nanotechnology can be found on NIOSH’s nanotechnology topic page. NIOSH is gratified that its strategic research program has formed the basis for both national and international recommendations and policies.

Dr. Castranova is chief of the Pathology and Physiology Research Branch (PPRB) in the Health Effects Laboratory Division (HELD). Dr. Hubbs is a veterinary pathologist, Dr. Porter is a pulmonary toxicologist, and Dr. Mercer is a bio-engineer in PPRB/HELD. The authors all have expertise in pulmonary toxicology.

Posted on by Vincent Castranova, PhD, Ann Hubbs, PhD, Dale Porter, PhD, and Robert Mercer, PhDTags

25 comments on “Persistent Pulmonary Fibrosis, Migration to the Pleura, and Other Preliminary New Findings after Subchronic Exposure to Multi-Walled Carbon Nanotubes”

Comments listed below are posted by individuals not associated with CDC, unless otherwise stated. These comments do not represent the official views of CDC, and CDC does not guarantee that any information posted by individuals on this site is correct, and disclaims any liability for any loss or damage resulting from reliance on any such information. Read more about our comment policy ».

    As a University of Miami graduate student taking an Environmental Health course, I have become increasingly aware of the possible health risks associated with the use of carbon nanotubules in various applications.

    Despite ongoing research to assess the associated health risks, I understand that many manufacturers in the United States are already employing this emerging technology to improve their products which, as a result, may pose an exposure threat to their workers. However, I am also concerned with the exposure threat to consumers. Among the applications you mentioned, I have read that carbon nanotubules are used in producing textiles, ceramics, plastics, rubber, and even cosmetics. As a consumer, is there any way of knowing which “every day” products currently on the market have been manufactured using nanotechnology?

    NIOSH is the federal agency responsible for conducting research and providing guidance to protect workers from risks they face on the job. NIOSH is carrying out a program of research on nanotechnology applications to be able to make science-based recommendations to protect workers who manufacture or use nanomaterials in their job. Your question specifically relates to risk associated with nanotechnology in consumer products, which is not an area that the NIOSH nanotechnology research program investigates. You may be able to find information related to nanotechnology and consumer products from the National Institutes of Health, the U.S. Food and Drug Administration, the U.S. Environmental Protection Agency, or the U.S. Consumer Product Safety Commission.

    This is an important article because it highlights the attention we must pay to potential new risks we are creating as we advance with new technology. Given the current emphasis on prevention in medicine, have there been any efforts directed at educating those people who are working with these hazardous materials? Have there been any human cases of mesothelioma or lung edema or any other illness associated with MWCNTs?

    Thank you for your comment. As results of new research become available in this emerging field NIOSH works to inform workers, employers, policy makers, worker representatives, and others of the findings. The document, Approaches to Safe Nanotechnology reviews what is currently known about nanoparticle toxicity and control. Additionally, when the NIOSH Nano Field Team visits a worksite and observes hot spots of nanoparticle aerosol generation, they meet with plant representatives and recommend control measures. After implementation of such controls, air sampling is repeated to determine effectiveness.

    In response to your question about disease in humans, to date, there have been no case reports of disease in workers producing or using nanoparticles.

    I am also a graduate student at the University of Miami, in an Environmental Health class. I have read attentively your article as well as the NIOSH document “Approaches to Safe Nanotechnology”. According to the latter, “the techniques used to measure fiber concentrations in the workplace (e.g., phase contrast microscopy) would not be able to detect individual carbon nanotubes (diameter <100 nm), nor bundles of carbon nanotubes with diameters less than 250 nm [Donaldson et al. 2006]". Other measuring techniques, such as electronic microscopy, are more effective in measuring smaller nanotubes and are currently being used. However, I assume that they are much more expensive. I am wondering whether there are studies in progress to show differences in health effects of MWCNTs based upon their size and whether all MWCNTs are detectable with our current measuring techniques?

    When we generate an aerosol of carbon nanotubes in the laboratory, we evaluate the size of airborne structures by transmission electron microscopic evaluation of filter samples collected at various stages by a MOUDI cascade impactor. This technique can detect all MWCNT.

    We are evaluating the impact of carbon nanotube size in bioactivity. We have studied single-walled carbon nanotubes and multi-walled carbon nanotubes. We plan to study long vs. short and thick vs. thin multi-walled carbon nanotubes as well. It is likely the size, surface modification, and agglomeration state impact bioactivity.

    I am also with the group of students in the Environmental Health class at the University of Miami. I was wondering whether any research was being done to study and develop personal protective equipment for professional exposure to nanoparticles. The European Strategy for Nanosafety published a document in 2008 in which fibrous filtration seems to be very effective for respiratory exposure to nanoparticles. Protective clothes however seem to be unequally efficient depending on the fabric and the microtexture.

    Are there any on-going studies on protective equipment? Are there new regulations regarding use of protective equipment for professional exposure?

    NIOSH has an active research program looking at the effectiveness of PPE against nanomaterials. The recently published Approaches to Safe Nanotechnology report provides an overview of what is currently known. Ongoing NIOSH research projects related to the effectiveness of protective clothing and respiratory protection are also discussed in another NIOSH report Progress Toward Safe Nanotechnology in the Workplace. In the United States, the Occupational Safety and Health Administration (OSHA) develops and enforces workplace protection standards. The OSHA website contains a list of current standards (including PPE) that may be applicable in situations where employees are exposed to nanomaterials.

    In the 2008 paper by Poland et al. on the potential for long thin multi-walled carbon nanotubes to show asbestos-like pathogenicity (see [http://2020science.org/2008/05/21/8521-carbon-nanotubes-the-new-asbestos-not-if-we-act-fast/]), we noted that a potential link with the disease mesothelioma could not be established without more information on nanotube behavior in two areas. These were the ability of long thin nanotubes to become airborne and inhaled in sufficient quantities to cause harm, and the ability of inhaled nanotubes to migrate to and penetrate the outer lining of the lungs.

    This new research suggests that, if inhaled, long thin multi-walled carbon nanotubes do have the potential to migrate through the lungs and penetrate the pleura. While the research still needs to be peer reviewed, it appears to take us very much closer to establishing that certain multi-walled carbon nanotubes could present a significant health hazard, and suggests that the material is handled and used with caution.

    In the meantime, there is a pressing need for this research to be reviewed and published as soon as possible, and for a strategic plan of research to establish the boundaries within which this innovative material can be used safely.

    NIOSH is working with researchers at Oregon State University (OSU) to make the Nanoparticle Information Library available online as part of the OSU Nanomaterial-Biological Interactions Knowledgebase (NBI). Once the transfer is complete, we will link to the NIL from the NIOSH website.

    *Update, 11/23/09: The Nanoparticle Information Library is now available and can be accessed at http://www.cdc.gov/niosh/topics/nanotech/NIL.html

    Is there a specific type of respirator mask which can filter CNTs and prevent their inhalation into the body? How can one select an appropriate respirator mask if they plan to work with CNTs?

    NIOSH-approved air-purifying respirators with different filter designations (e.g., N95, N99, N100) will provide varying levels of expected filtration performance against nanoparticles. Based upon the scientific literature (see below), NIOSH-approved air-purifying respirators do capture nanoparticles larger than ~3 nm in size and should capture similarly sized carbon nanotubes as well. Any decision to use respiratory protection should be based on assessment of the hazard of the material and the risk posed by potential exposure of the worker. A careful hazard analysis of the tasks that involve the production, manipulation of use of the carbon nanotubes should be conducted. Guidance on how to conduct a qualitative assessment is contained in the appendix to Approaches to Safe Nanotechnology. With carbon nanotubes, the toxicology information is still developing, but recent research reports indicate the need for a prudent and protective approach.

    Should you choose to use respiratory protection, all of the provisions of a full respiratory protection program should be followed, including medical clearance, proper fit testing, training, and maintenance. For respirator selection, please refer to the NIOSH respirator selection logic. Approaches to Safe Nanotechnology provides an overview of filtration, respiratory protection, and respirator selection.

    Recent Publications
    1. Comparison of nanoparticle filtration performance of NIOSH-approved and CE-marked particulate filtering facepiece respirators. Rengasamy-S; Eimer-BC; Shaffer-RE. Ann Occup Hyg 2009 Mar; 53(2):117-128
    2. Filtration performance of NIOSH-approved N95 and P100 filtering facepiece respirators against 4 to 30 nanometer-size nanoparticles. Rengasamy-S; King-WP; Eimer-BC; Shaffer-RE. J Occup Environ Hyg 2008 Sep; 5(9):556-564

    I find this article a bit dated. The key question which remains unanswered is why the mesothelium should be so sensitive to carbon nanotubes only! Why papers as this one always use the magic word “carbon nanotubes”? I feel that it is necessary to question the full fibrous nanoparticle spectrum, not just carbon. As one example, zinc oxide is far more dangerous compared to carbon and nobody is discussing risks of this material?

    The NIOSH Nanotechnology Research Center has projects investigating the bioactivity of titanium nanospheres vs nanowires, silicon nanowires, ultrafine carbon black, nano cerium oxide, single and multiwalled carbon nanotubes, silver nanoparticles, and iron oxide nanoparticles. We also anticipate a study on coated vs uncoated zinc oxide, i.e., soluble vs less soluble.

    This website is a great tool and all the information contained is extremely relevant. As a University of Miami graduate student taking an Environmental Health course, I have become interested in health risks associated with the use of carbon nanotubules in industry and by the general consumer. I have read the article and the documents attached and I became aware of health risk associated with the usage of nanoparticles and the ongoing efforts to try to measure exposure and to decrease these risks.

    However, I assume that this is mostly for big companies that handle nanoparticles as part of their production efforts. My questions:

    A) how can the information contained in the website reach more people ( I did only become aware of it through the course I am taking), especially the general public since it is being use more and more frequently in many products.

    B) are employees and employers that handle nanoparticles required to learn about the risks involved in handling this particles; especially employees, because it is difficult to know that something is wrong if one does not know what to look for especially if it requires a chronic exposure.

    C) are there any specific laws that regulate this process?

    D) in the cases of independent contractors, is there a way to protect those people from exposure since they fall outside of the regulatory system of a big company e.g. If they manufactured a product does their responsibility end when they sell it? Should these people not be required to be educated as well?

    E) in an ideal world shouldn’t the product’s effect on health be tested first before it gets release to the market? That happens with every new drug. I understand that the applications for nanotechnology are immense but should there not have been more knowledge about it before it got released, especially since some of the already known effects are irreversible.

    F) in the cases where a chronic exposure is assumed to be required to produce an effect are there any plans for a large prospective study evaluating people exposed that finally develop the signs and symptoms?

    Thank you for the response

    Thank you for your comment. In answer to your questions:

    A) This blog is only one aspect of the NIOSH strategy to disseminate information on occupational exposure to nanomaterials. We also maintain a nanotechnology topic page on the NIOSH website and distribute new information via print and other traditional media outlets. NIOSH research focuses on occupational exposures. Information for the general public may be obtained from the National Institutes of Health, the U.S. Food and Drug Administration, the U.S. Environmental Protection Agency, or the U.S. Consumer Product Safety Commission.

    B) NIOSH has produced and is continually updating a document on the NIOSH website entitled Approaches to Safe Nanotechnology. This document targets employees and employers and is highly cited.

    C) In the United States, the Occupational Safety and Health Administration (OSHA) develops and enforces workplace protection standards. The OSHA website contains a list of current standards that may be applicable in situations where employees are exposed to nanomaterials.

    D) See B) above.

    E) Many nanomaterials have not been considered new materials by regulatory agencies such as EPA and the regulations for fine-sized particles of the same chemical composition have applied. This is slowly changing in the case of MWCNT where EPA is now requiring toxicity data for production.

    F) We do not have any plans yet because cohorts of exposed workers have not yet been identified. However, this is considered by many to be a high priority area.

    Hi,
    I have read your blog and it’s excellent information share here. But I have one question please share your opinion here…

    How to determine the purity of the Nanotube?

    Purity of carbon nanotubes is determined by X-ray photoelectron spectroscopy and transmission electron microscopy. Metal contamination is determined by coupled plasma-optical emission spectroscopy.

    Hi!
    I am wondering if a material reinforced with carbon nano particles subjected to grinding and cutting and perhaps scratching on the surface with a sharp tool, can induce any health hazards for the worker, for instance as carbon nano tubes as dust?

    What kind of respiratory mask would you recommend for this purpose? Is ventilation required? How severe will the risk remain if the area is not ventilated.

    Thank you for a great forum.

    There is not a large body of evidence in this area. However, there is some evidence that drilling, cutting, or sanding of composites containing carbon nanofibers can generate airborne nanomaterials. It would be prudent to have ventilatory controls and/or use N95 or better respiratory protection.

    Thank you for this article. It is very informative. I am so glad that I get to read this to understand it. thank you. I would like to be informed of any new articles and publications that you have.

    What kind of respiratory mask would you recommend for this purpose? Is ventilation required? How severe will the risk remain if the area is not ventilated

    Thank you for your comment.

    1.What kind of respiratory mask would you recommend for this purpose?
    Containment and ventilator control is preferred over dependence on personal protective equipment. Please see the response to comment 7 above regarding respiratory protection.
    2.Is ventilation required?
    Local exhaust ventilation has been shown to be effective in controlling engineered nanomaterial emissions. (Methner MM. J. Occup. Environ. Hyg. 5:D63-D69, 2009.)
    3.How severe will the risk remain if the area is not ventilated?
    Risk would depend on the biological hazard potential of the particle in question and the airborne exposure level.

    Thank you for another great article. Where else could anyone get that kind of information in such a perfect way of writing? I have a presentation next week, and I am on the look for such information.

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