Understanding the Broad Class of Carbon Nanotubes and Nanofibers (CNT/F) Used or Produced in U.S. Facilities

Engineered nanomaterials, such as carbon nanotubes and nanofibers (CNT/F), hold great promise for society by revolutionizing many industries with applications from medicine to manufactured composites. The properties that make them so promising may also have the potential to cause harm to people if inhaled. Understanding potential health effects, conducting field exposure studies, and developing good practices promotes safe handling and responsible development of products using these materials.

The US-EU Nano Environmental, Health, and Safety communities issued a challenge to characterize nanomaterials better and to design research studies informed by exposure assessment with the same materials used in industry at doses that represented actual use. A recently published series of NIOSH studies [1-9] have connected the initial toxicology findings of CNT/F with ongoing exposure assessment and human health effect studies to provide direct knowledge of the very materials currently being used in industry. The research not only addressed as-produced CNT/F, but also materials along the various manufacturing steps or life cycle, such as those modified after production by adding a coating to the surface and the products produced from those materials [4,5,9].

One project in the series [5-8] was a cross-sectional epidemiologic study to evaluate exposure and potential associated health effects in workers handling CNT/F. Workplace exposures were evaluated during multiple tasks at more than 20 facilities. From this research, it was clear that a wide variety of CNT/F, which included varying lengths and diameters, were being produced or utilized by manufacturers in the U.S. Simultaneous and comparative toxicity studies of such a broad class of CNT/F as that currently being produced or utilized in U.S facilities is lacking. This raised the research question: would the different-sized CNT/F materials have similar toxicity if inhaled? A recently published article in the journal Particle and Fibre Toxicology [10], “Physicochemical characterization and genotoxicity of the broad class of carbon nanotubes and nanofibers used or produced in U.S. facilities” addresses this issue. For successful commercialization, industrial hygiene, and a human health perspective, it is important for us to understand the relationship between different physicochemical characteristics of CNT/F and toxicological effects.

Study

In this current series of studies [10], with guidance from extensive facility exposure assessments, we selected six multi-walled carbon nanotubes (MWCNT) and two carbon nanofibers (CNF), collectively termed CNT/F, either manufactured or handled by U.S. companies, to evaluate four primary parameters of toxicity. Specific CNT/F types were selected to be broadly representative of those to which U.S. workers may be commonly exposed. A seventh MWCNT, Mitsui-7/MWCNT-7, was added as a benchmark material given its IARC classification as possibly carcinogenic to humans (Group 2B) and the large amount of historical toxicity data available for the four toxicity parameters.

The four parameters of toxicity included genotoxicity, inflammation, pathological changes, and the presence of CNT/F in areas of the body outside the lung, termed extrapulmonary translocation. For this section of the evaluation of CNT/F toxicities, all materials were extensively characterized, and genotoxicity in cultured cells was evaluated [10]. Manuscripts detailing the results of the studies on inflammation, pathological changes, and extrapulmonary translocation, are being drafted. Extensive physicochemical characterization, including prevalence and forms of bundled agglomerates (or assembled CNT/F structures) were also characterized because exposure assessment indicated that agglomerates, not singlets or individual fibers, are the most common form found in workers’ personal breathing zone samples. Genotoxicity was assessed by the ability of the CNT/F to induce inflammation, oxidative stress, micronuclei formation, and DNA double-strand breakage. Computational modeling was applied to physicochemical characteristics alone, and in conjunction with toxicological changes. Advances in computational analysis are being applied to the almost two decades of engineered nanomaterial research for grouping and permit the application of a novel addition to the multidisciplinary approach for understanding the physicochemical causes of toxicity. The modeling provides a means to group, or cluster, by material, as well as by response, to evaluate the relationship between physicochemical characteristics and various toxicity outcomes.

Findings

The major findings include:

• Not all CNT/F possess similar toxicity. This will be further illustrated in subsequent publications which evaluate inflammation, pathological changes, and translocation.
• Detailed physical dimension characteristics, not just the mean length and width, provide a more consistent grouping of CNT/F into toxicologically relevant categories.
• All CNT/F induced some degree of genotoxicity. Micronuclei formation, combined with cellular oxidative stress and evidence of DNA double-strand breaks, indicated CNT/F with increasing length and diameter caused slightly more toxicity.
• Interestingly, even a small percentage of CNT/F with increased length and diameter in a material can alter the toxicity of the material. It does not need to be the primary component of the material.

Conclusions

Depending on the parameter, the toxicity of CNT/F is likely to vary by the component material or group of materials with similar physicochemical characteristics. Importantly, understanding the potential for toxicity of a CNT/F in relationship to potential worker or consumer exposure, especially as the materials progress from production to product, is critical for understanding the potential impact on human health. To enable that understanding, integrating exposure and toxicity assessments provides direct feedback and representative study design. These results will help inform guidance for the responsible handling and commercialization of CNT/F.

Aaron Erdely, PhD, is a research biologist in the NIOSH Health Effects Laboratory Division 

Kelly Fraser is a graduate student at West Virginia University and working in the NIOSH Health Effects Laboratory Division

Vamsi K. Kodali, PhD, is an associate service fellow in the NIOSH Health Effects Laboratory Division

Charles L. Geraci, Jr., PhD, CIH, FAIHA, is Associate Director for Emerging Technologies in the NIOSH Office of the Director

Matthew M. Dahm, PhD, MPH, is a research industrial hygienist in the NIOSH Division of Field Studies and Engineering

Mary K. Schubauer-Berigan, PhD, was a research epidemiologist in the NIOSH Division of Field Studies and Engineering and is currently the group head for the Monographs Programme at the International Agency for Research on Cancer

References

1. Dahm MM, Evans DE, Schubauer-Berigan MK, Birch ME, Fernback JE. Occupational exposure assessment in carbon nanotube and nanofiber primary and secondary manufacturers. Ann Occup Hyg. 2012;56 5:542-56; doi: 10.1093/annhyg/mer110.
2. Erdely A, Dahm M, Chen BT, Zeidler-Erdely PC, Fernback JE, Birch ME, et al. Carbon nanotube dosimetry: from workplace exposure assessment to inhalation toxicology. Particle and Fibre Toxicology. 2013;10 1:53; doi: 10.1186/1743-8977-10-53.
3. Dahm MM, Schubauer-Berigan MK, Evans DE, Birch ME, Fernback JE, Deddens JA. Carbon Nanotube and Nanofiber Exposure Assessments: An Analysis of 14 Site Visits. Ann Occup Hyg. 2015;59 6:705-23; doi: 10.1093/annhyg/mev020.
4. Bishop L, Cena L, Orandle M, Yanamala N, Dahm MM, Birch ME, et al. In vivo toxicity assessment of occupational components of the carbon nanotube life cycle to provide context to potential health effects. ACS Nano. 2017;11 9:8849-63; doi: 10.1021/acsnano.7b03038.
5. Dahm MM, Schubauer-Berigan MK, Evans DE, Birch ME, Bertke S, Beard JD, et al. Exposure assessments for a cross-sectional epidemiologic study of US carbon nanotube and nanofiber workers. Int J Hyg Environ Health. 2018;221 3:429-40; doi: 10.1016/j.ijheh.2018.01.006
6. Beard JD, Erdely A, Dahm MM, de Perio MA, Birch ME, Evans DE, et al. Carbon nanotube and nanofiber exposure and sputum and blood biomarkers of early effect among U.S. workers. Environ Int. 2018;116:214-28; doi: 10.1016/j.envint.2018.04.004.
7. Schubauer-Berigan MK, Dahm MM, Erdely A, Beard JD, Eileen Birch M, Evans DE, et al. Association of pulmonary, cardiovascular, and hematologic metrics with carbon nanotube and nanofiber exposure among U.S. workers: a cross-sectional study. Part Fibre Toxicol. 2018;15 1:22; doi: 10.1186/s12989-018-0258-0.
8. Schubauer-Berigan MK, Dahm MM, Toennis CA, Sammons DL, Eye T, Kodali V, et al. Association of occupational exposures with ex vivo functional immune response in workers handling carbon nanotubes and nanofibers. Nanotoxicology. 2020;14 3:404-19; doi: 10.1080/17435390.2020.1717007.
9. Kang J, Erdely A, Afshari A, Casuccio G, Bunker K, Lersch T, Dahm MM, Farcas D, Cena L. Generation and characterization of aerosols released from sanding composite nanomaterials in industrial scenarios. NanoImpact, 2017;5:41-50.
10. Fraser K, Kodali V, Yanamala N, Birch ME, Cena L, Casuccio G, Bunker K, Lersch TL, Evans DE, Stefaniak A, Hammer MA, Kashon ML, Boots T, Eye T, Hubczak J, Friend SA, Dahm M, Schubauer-Berigan MK, Siegrist K, Lowry D, Bauer AK, Sargent LM, Erdely A. Physicochemical characterization and genotoxicity of the broad class of carbon nanotubes and nanofibers used or produced in U.S. facilities. Part Fibre Toxicol. 2020 Dec 7;17(1):62. doi: 10.1186/s12989-020-00392-w.