Banning carbon nanotubes would be scientifically unjustified and damaging to innovation

To the Editor — In a recent correspondence, the Swedish non-profit organization ChemSec announced the addition of carbon nanotubes to the SIN (‘Substitute It Now’) list¹. Carbon nanotubes were added as an entire material class that “should be restricted or banned in the EU.” We believe that this recommendation confuses researchers and the public as it is based on evidence from a very narrow subset of data. Such a designation will likely hinder innovations that could lead to safe and effective applications of carbon nanotubes. Furthermore, this line of reasoning could damage other fields of science and technology, if applied similarly.

We have worked with carbon nanotubes since the 1990s, a time marked by excitement and confusion about the promises and concerns of nanomaterials^2,3. During this period, broad claims of toxicities were ascribed to carbon nanotubes, which were later found to apply only to a narrow subset of carbon nanotube preparations and/or exposure routes^4,5. Numerous subsequent publications that reported more nuanced results were given much less attention^6–8. Importantly, data showing a lack of toxicity are often not published, as they are usually considered ‘negative’ results⁹. Unfortunately, we are left with a one-sided story that damages research efforts. The recent report by the advocacy group ChemSec seems to have been confused by these issues.

The REACH (Registration, Evaluation, Authorisation and Restriction of Chemicals) legislation (and the recent amendments to the Toxic Substances Control Act (TSCA) in the USA) places the burden of proof on producers and importers of chemicals to demonstrate safety. The nanotechnology field subscribes to this principle and routinely conducts tests on the biocompatibility and potential biotoxicity of nanomaterials that are under development for medical and non-medical applications. REACH registration has been attained for limited quantities of three classes of carbon nanotube materials (932-414-1, 943-098-9 and 701-160-0). The inclusion of all carbon nanotubes in the SIN list discourages research and investment in these materials that are being applied, for instance, to treat kidney disease¹⁰, track viral outbreaks¹¹ and to investigate Parkinson’s disease¹². ChemSec should take special care to not inadvertently damage a research field by generalizing narrowly-applicable findings to a diverse family of materials, and to not misapply the solid precautionary principles on which REACH and TSCA are based.

Nanomaterial diversity leads to benefits and confusion

The problematic risk assessment of nanomaterials stems in part from the virtually infinite possible material variants and modifications¹³, leading to a variety of physical, chemical, mechanical and biological properties¹⁴. Under the umbrella of ‘carbon nanotubes’, which includes cylindrical carbon-based structures, physical dimensions vary by many orders of magnitude¹⁵. Carbon nanotube diameters may range from several ångströms to hundreds of nanometres, with lengths from nanometres to metres, in different forms such as powders, sponges, freestanding films, on substrates and dispersed in solutions. Moreover, they can be covalently or noncovalently functionalized with nearly every class of chemical species¹⁶, from rare earth metals to RNA. Nanotubes can be aggregated or organized into diverse microscopic or macroscopic structures with different strength and stiffness profiles. The resulting materials range from structures that resemble carbon fibres, to improve, for instance, the strength of building materials¹⁷ or to restore myocardial conduction in arrhythmic hearts¹⁸, to nanoscopic colloids that can interrogate the properties of living cells¹⁹, augment stem cell differentiation²⁰, or deliver RNA¹⁰. Carbon nanotubes have also been precisely synthesized into centimeter-long fibres²¹, while shorter, functionalized tubes can enter the lysosomes of cells for molecular imaging studies²². In applications such as nanobionics²³, gene delivery²⁴, image-guided surgery²⁵ and non-invasive disease monitoring²⁶, processed, functionalized carbon nanotubes have been successfully used without inducing toxicity in cells^27,28, small animals²⁹ or non-human primates³⁰.

Unfortunately, every broad claim of concern resulting from a study using one variant of carbon nanotubes reverberates throughout the entire research field. For example, studies using long, insoluble nanotube aggregates with large diameters, administered via instillation (that is, depositing a bolus in the animal), reported lung toxicity in mice^31,32. As a result, measures have been in place since the early 2000s to prevent human exposure to airborne nanotubes. However, it was later reported that proper functionalization can abrogate lung toxicity⁷. Moreover, soluble, short nanotubes showed no toxicities in primates, as measured by blood chemistry, haematology and pathology³⁰. Unfortunately, these results did not reach the prominence of the earlier publications and were apparently not considered in the ChemSec report⁶.

Conclusion from the World Health Organization

Scrutiny from regulatory intergovernmental agencies has resulted in the recognition of nanomaterial diversity. In 2014, the International Agency for Research on Cancer (IARC) published a monograph evaluating the carcinogenic risks of carbon nanotubes³³. The monograph concluded that ‘single-walled carbon nanotubes are not classifiable as to their carcinogenicity to humans (Group 3)”³⁴. A review published in the same year concluded that the majority of studies did not characterize the properties of the nanomaterials, which considerably reduced their significance⁹. Additionally, many of these earlier studies were performed with nanotubes that were long, improperly stabilized by excipients leading to aggregation, administered to animals in the microgram scale and/or contained metal catalysts. Both ChemSec and IARC monographs cite the ‘suspected carcinogen’ status of “Carbon Nanotube Single-walled (>55%) below 2 nm (diam.) and 5–15 micrometer length (EC no. 608-533-6)”. However, ChemSec decided that data from a preparation with up to 45% impurities and with lengths above 5 micrometres could accurately reflect the carcinogenicity of all single-walled carbon nanotubes. The disagreement in the conclusions of the IARC and ChemSec stems from the decision of the IARC Working Group which stated: “CNT cannot be considered as a single well-defined substance but as families of different materials, the number of which is growing dramatically.” In 2019, the Working Group recommended re-evaluation of multiwalled carbon nanotubes as a high priority due to the availability of new bioassays and mechanistic evidence³⁵. Based on the body of recent evidence, single-walled carbon nanotubes were not recommended for re-evaluation³⁵.

A way forward

Human and environmental safety are a top priority; however, engineering of novel technologies progresses only through research and development. As our understanding of a material increases, so does our ability to safeguard against its harms by engineering it into safe formulations, such as silica³⁶ and iron oxide³⁴ — materials that can either pose inhalation hazards or be injected into humans for imaging³⁷/therapeutic³⁸ applications. Nanotechnology researchers are well aware that the unique properties of nanomaterials, which hold the potential for technological advancements, can also lead to unique biological interactions³⁹. To enable precise mapping of nanomaterial identity and biological interactions, a comprehensive set of standards governing material characterization, biological characterization and details of experimental protocols was proposed in 2018 and reported in Nature Nanotechnology⁴⁰. Additionally, the multiple routes of potential exposure result in a different set of risk parameters and safety concerns. Although the nanomaterial community is becoming aware of the importance of using standardized and accepted characterization methods (for example, Organisation for Economic Co-operation and Development (OECD) guidelines), we are still at the early stages of defining distinct nanomaterial preparations related to specific toxicities. A standardized safety and material-handling procedure should be established for dispersed engineered nanomaterials; for example, those exposed to easily aerosolizable materials should wear appropriate respiratory protection. As applications are realized, the entire life cycle of safety should be assessed, including production, manufacturing, shipping, use and end-of-life. These will be very different for carbon nanotubes used, for example, in drugs and medical devices (where each step of the supply and use chain is tightly controlled) versus consumer products such as batteries and sensors. The criteria used by ChemSec for toxicity are well-reasoned. However, guidelines must only be applied to the specific sub-classes of nanomaterials for which evidence is available. Such a precise approach to regulating individual nanomaterial preparations certainly requires more effort; however, conclusions of safety or toxicity have to be based on experimental data in the right context. We call on ChemSec to modify the record of carbon nanotubes in the SIN list, to remove the broad claims of toxicity for an entire material class, and to delineate the specific materials for which data actually exist.