Tag Archives: James C. Bonner

Lung injury, carbon nanotubes, and aluminum oxide

It’s pretty much undisputed that long, multi-walled carbon nanotubes (MWCNTs) are likely to present a serious health hazard given their resemblance to asbestos fibres. It’s a matter of some concern that has resulted in a US National Institute of Occupational Safety and Health (NIOSH) recommendation for workplace exposure to all carbon nanotubes that is stringent. (My April 26, 2013 posting features the recommendation.)

Some recent research from North Carolina State University (NCSU) suggests that there may be a way to make long, multi-walled carbon nanotubes safer. From an Oct. 3, 2014 news item on Nanowerk,

A new study from North Carolina State University and the National Institute of Environmental Health Sciences (NIEHS) finds that coating multiwalled carbon nanotubes (CNTs) with aluminum oxide reduces the risk of lung scarring, or pulmonary fibrosis, in mice.

“This could be an important finding in the larger field of work that aims to predict and prevent future diseases associated with engineered nanomaterials,” says James Bonner, a professor of environmental and molecular toxicology at NC State …

An Oct. 3, 2014 NCSU news release, which originated the news item, describes the research in a little more detail,

Multiwalled CNTs have a wide array of applications, ranging from sporting goods to electronic devices. And while these materials have not been associated with adverse health effects in humans, research has found that multi-walled CNTs can cause pulmonary fibrosis and lung inflammation in animal models.

“Because multiwalled CNTs are increasingly used in a wide variety of products, it seems likely that humans will be exposed to them at some point,” Bonner says. “That means it’s important for us to understand these materials and the potential risk they pose to human health. The more we know, the better we’ll be able to engineer safer materials.”

For this study, the researchers used atomic layer deposition to coat multiwalled CNTs with a thin film of aluminum oxide and exposed mice to a single dose of the CNTs, via inhalation.

The researchers found that CNTs coated with aluminum oxide were significantly less likely to cause pulmonary fibrosis in mice. However, the coating of aluminum oxide did not prevent lung inflammation.

“The aluminum oxide coating doesn’t eliminate health risks related to multi-walled CNTs,” Bonner says, “but it does lower them.”

Here’s a link to and a citation for the paper,

Atomic Layer Deposition Coating of Carbon Nanotubes with Aluminum Oxide Alters Pro-Fibrogenic Cytokine Expression by Human Mononuclear Phagocytes In Vitro and Reduces Lung Fibrosis in Mice In Vivo by Alexia J. Taylor, Christina D. McClure, Kelly A. Shipkowski, Elizabeth A. Thompson, Salik Hussain, Stavros Garantziotis, Gregory N. Parsons, and James C. Bonner. Published: September 12, 2014 DOI: 10.1371/journal.pone.0106870

This is an open access article.

The researchers offered this conclusion (part of the paper’s abstract),

These findings indicate that ALD [atomic layer deposition] thin film coating of MWCNTs with Al2O3 reduces fibrosis in mice and that in vitro phagocyte expression of IL-6, TNF-α, and OPN, but not IL-1β, predict MWCNT-induced fibrosis in the lungs of mice in vivo.

However, what I found most striking was this from the paper’s Discussion (section),

While the Al2O3 coating on MWCNTs appears to be the major factor that alters cytokine production in THP-1 and PBMCs in vitro, nanotube length is still likely an important determinant of the inflammatory and fibroproliferative effects of MWCNTs in the lung in vivo. In general, long asbestos fibers or rigid MWCNTs (i.e., >20 µm) remain in the lung and are much more persistent than shorter fibers or nanotubes [20]. Therefore, the nanotube fragments resulting from breakage of A-MWCNTs coated with 50 or 100 ALD cycles of Al2O3 would likely be cleared from the lungs more rapidly than uncoated long MWCNTs or those coated with only 10 ALD cycles of Al2O3. We observed that the fracturing of A-MWCNTs occurred only after sonication prior to administration to cells in vitro or mice in vivo. However, unsonicated A-MWCNTs could be more likely to fracture over time in tissues as compared to U-MWCNTs [uncoated]. We did not address the issue of A-MWCNT clearance before or after fracturing in the present study, but future work should focus the relative clearance rates from the lungs of mice exposed to A-MWCNTs in comparison to U-MWCNTs. Another potentially important consideration is whether or not ALD coating with Al2O3 alters the formation of a protein corona around MWCNTs. It is possible that differences in cytokine levels in the supernatants from cells treated with U- or A-MWCNTs could be due to differences in protein corona formation around functionalized MWCNTs that could modify the adsorptive capacity of the nanomaterial. Characterization of the protein corona and the adsorptive capacity for cytokines after ALD modification of MWCNTs should be another important focus for future work. [emphases mine]

In other words, researchers think coating long, MWCNTs with a certain type of aluminum might be safer due to its effect on various proteins and because coated MWCNTs are likely to fracture into smaller pieces and we know that short MWCNTs don’t seem to present a problem when inhaled.

Of course, there’s the research from Duke University (my Oct. 3, 2014 post) which suggests CNTs could present a different set of problems over time as they accumulate in the environment.

Nanomaterials, toxicology, and alternatives to animal testing

It seems that alternatives to animal testing may offer some additional capabilities for nanotoxicology studies according to an Aug. 21, 2013 news item on Nanowerk,

A group of international experts from government, industry and academia have concluded that alternative testing strategies (ATSs) that don’t rely on animals will be needed to cope with the wave of new nanomaterials emerging from the boom in nanoscience and nanotechnology. …

… Tests on laboratory mice, rats and other animals have been the standard way of checking new materials for health and environmental effects. Since those tests are costly, labor-intensive and time-consuming, workshop participants considered whether ATSs could have a larger role in checking the safety of ENMs [engineered nanomaterials].

They concluded that rapid cellular screening, computer modeling and other ATSs could serve as quick, cost-effective and reliable approaches for gathering certain types of information about the health and environmental effects of ENMs. “After lively discussions, a short list of generally shared viewpoints on this topic was generated, including a general view that ATS approaches for ENMs can significantly benefit chemical safety analysis,” they say.

The experts have had their consensus statement from the workshop published and before offering a citation for and a link to the statement, here’s the Abstract,

There has been a conceptual shift in toxicological studies from describing what happens to explaining how the adverse outcome occurs, thereby enabling a deeper and improved understanding of how biomolecular and mechanistic profiling can inform hazard identification and improve risk assessment. Compared to traditional toxicology methods, which have a heavy reliance on animals, new approaches to generate toxicological data are becoming available for the safety assessment of chemicals, including high-throughput and high-content screening (HTS, HCS). With the emergence of nanotechnology, the exponential increase in the total number of engineered nanomaterials (ENMs) in research, development, and commercialization requires a robust scientific approach to screen ENM safety in humans and the environment rapidly and efficiently. Spurred by the developments in chemical testing, a promising new toxicological paradigm for ENMs is to use alternative test strategies (ATS), which reduce reliance on animal testing through the use of in vitro and in silico methods such as HTS, HCS, and computational modeling. Furthermore, this allows for the comparative analysis of large numbers of ENMs simultaneously and for hazard assessment at various stages of the product development process and overall life cycle. [emphasis mine] Using carbon nanotubes as a case study, a workshop bringing together national and international leaders from government, industry, and academia was convened at the University of California, Los Angeles, to discuss the utility of ATS for decision-making analyses of ENMs. …

It seems that ATS has opened the door to more comprehensive testing (as per life cycles) than has previously been possible.

For the curious, here’s the citation for and the link to the published paper,

A Multi-Stakeholder Perspective on the Use of Alternative Test Strategies for Nanomaterial Safety Assessment by Andre E. Nel, Elina Nasser, Hilary Godwin, David Avery, Tina Bahadori, Lynn Bergeson #, Elizabeth Beryt, James C. Bonner, Darrell Boverhof, Janet Carter, Vince Castranova, J. R. DeShazo, Saber M. Hussain ●, Agnes B. Kane, Frederick Klaessig, Eileen Kuempel, Mark Lafranconi, Robert Landsiedel, Timothy Malloy, Mary Beth Miller, Jeffery Morris, Kenneth Moss, Gunter Oberdorster, Kent Pinkerton, Richard C. Pleus, Jo Anne Shatkin, Russell Thomas, Thabet Tolaymat, Amy Wang, and Jeffrey Wong. ACS Nano, Article ASAP DOI: 10.1021/nn4037927 Publication Date (Web): August 7, 2013

Copyright © 2013 American Chemical Society

This article is behind a paywall.

US multicenter (Nano GO Consortium) study of engineered nanomaterial toxicology

Nano Go Consortium is the name they gave a multicenter toxicology study of engineered nanomaterials which has pioneered a new approach  in the US to toxicology research. From the May 6, 2013 news item on Azonano,

For the first time, researchers from institutions around the country have conducted an identical series of toxicology tests evaluating lung-related health impacts associated with widely used engineered nanomaterials (ENMs).

The study [on rodents] provides comparable health risk data from multiple labs, which should help regulators develop policies to protect workers and consumers who come into contact with ENMs.

The May 6, 2013 North Carolina State University news release, which originated the news item, describes the results from one of two studies that were recently published by the Nano GO Consortium in Environmental Health Perspectives,

The researchers found that carbon nanotubes, which are used in everything from bicycle frames to high performance electronics, produced inflammation and inflammatory lesions in the lower portions of the lung. However, the researchers found that the nanotubes could be made less hazardous if treated to remove excess metal catalysts used in the manufacturing process or modified by adding carboxyl groups to the outer shell of the tubes to make them more easily dispersed in biological fluids.

The researchers also found that titanium dioxide nanoparticles also caused inflammation in the lower regions of the lung. Belt-shaped titanium nanoparticles caused more cellular damage in the lungs, and more pronounced lesions, than spherical nanoparticles.

Here’s a link to and a citation for this study on rodents,

Interlaboratory Evaluation of Rodent Pulmonary Responses to Engineered Nanomaterials: The NIEHS NanoGo Consortium by James C. Bonner, Rona M. Silva, Alexia J. Taylor, Jared M. Brown, Susana C. Hilderbrand, Vincent Castranova, Dale Porter, Alison Elder, Günter Oberdörster, Jack R. Harkema, Lori A. Bramble, Terrance J. Kavanagh, Dianne Botta, Andre Nel, and Kent E. Pinkerton. Environ Health Perspect (): .doi:10.1289/ehp.1205693  Published: May 06, 2013

And the information for the other study which this consortium has published,

Interlaboratory Evaluation of in Vitro Cytotoxicity and Inflammatory Responses to Engineered Nanomaterials: The NIEHS NanoGo Consortium by Tian Xia, Raymond F. Hamilton Jr, James C. Bonner, Edward D. Crandall, Alison Elder, Farnoosh Fazlollahi, Teri A. Girtsman, Kwang Kim, Somenath Mitra, Susana A. Ntim, Galya Orr, Mani Tagmount8, Alexia J. Taylor, Donatello Telesca, Ana Tolic, Christopher D. Vulpe, Andrea J. Walker, Xiang Wang, Frank A. Witzmann, Nianqiang Wu, Yumei Xie, Jeffery I. Zink, Andre Nel, and Andrij Holian. Environ Health Perspect (): .doi:10.1289/ehp.1306561 Published: May 06, 2013

Environmental Health Perspectives is an open access journal and the two studies are being offered as ‘early’ publication efforts and will be updated with the full studies at a later date.

Most interesting for me is the editorial offered by four of the researchers involved in the Nano GO Consortium, from the editorial,

Determining the health effects of ENMs presents some unique challenges. The thousands of ENMs in use today are made from an enormous range of substances, vary considerably in size, and take a diversity of shapes, including spheres, cubes, cones, tubes, and other forms. They are also produced in different laboratories across the world using a variety of methods. In the scientific literature, findings on the properties and toxicity of these materials are mixed and often difficult to compare across studies. To improve the reliability and reproducibility of data in this area, there is a need for uniform research protocols and methods, handling guidelines, procurement systems, and models.

Although there is still much to learn about the toxicity of ENMs, we are fortunate to start with a clean slate: There are as yet no documented incidences of human disease due to ENM exposure (Xia et al. 2009). Because ENMs are manmade rather than natural substances, we have an opportunity to design, manufacture, and use these materials in ways that allow us to reap the maximum benefits—and minimal risk—to humans.

With $13 million from the American Recovery and Reinvestment Act (2009), the National Institute of Environmental Health Sciences (NIEHS) awarded 13 2-year grants to advance research on the health impacts of ENMs (NIEHS 2013). [emphasis mine] Ten grants were awarded through the National Institutes of Health (NIH) Grand Opportunities program and three were funded through the NIH Challenge Grants program. One goal of this investment was to develop reliable, reproducible methods to assess exposure and biological response to nanomaterials.

Within the framework of the consortium, grantees designed and conducted a series of “round-robin” experiments in which similar or identical methods were used to perform in vitro and in vivo tests on the toxicity of selected nanomaterials concurrently at 13 different laboratories.

Conducting experiments in a round-robin format within a consortium structure is an unfamiliar approach for most researchers. Although some researchers acknowledged that working collaboratively with such a large and diverse group at times stretched the limits of their comfort zones, the consortium ultimately proved to be “greater than the sum of its parts,” resulting in reliable, standardized protocols that would have been difficult for researchers to achieve by working independently. Indeed, many participants reflected that participating in the consortium not only benefitted their shared goals but also enhanced their individual research efforts. The round-robin approach and the overall consortium structure may be valuable models for other emerging areas of science.

Here’s a link to and a citation for the Consortium’s editorial, which is available in full,

Nano GO Consortium—A Team Science Approach to Assess Engineered Nanomaterials: Reliable Assays and Methods by Thaddeus T. Schug, Srikanth S. Nadadur, and Anne F. Johnson. Environ Health Perspect 121(2013). http://dx.doi.org/10.1289/ehp.1306866 [online 06 May 2013]

I like the idea of researchers working together across institutional and geographical boundaries as that can be a very powerful approach. I hope that won’t devolve into a form of institutionalized oppression where individual researchers are forced out or ignored. In general, it’s the outlier research that often proves to be truly groundbreaking, which often generates extraordinary and informal (and sometimes formal) resistance. For an example of groundbreaking work that was rejected by other researchers who banded together informally, there’s Dan Shechtman, 2011 Nobel Laureate in Chemistry, famously faced hostility from his colleagues for years over his discovery of quasicrystals.