Evaluating the mechanistic evidence and key data gaps in assessing the potential carcinogenicity of carbon nanotubes and nanofibers in humans

Abstract

In an evaluation of carbon nanotubes (CNTs) for the IARC Monograph 111, the Mechanisms Subgroup was tasked with assessing the strength of evidence on the potential carcinogenicity of CNTs in humans. The mechanistic evidence was considered to be not strong enough to alter the evaluations based on the animal data. In this paper, we provide an extended, in-depth examination of the in vivo and in vitro experimental studies according to current hypotheses on the carcinogenicity of inhaled particles and fibers. We cite additional studies of CNTs that were not available at the time of the IARC meeting in October 2014, and extend our evaluation to include carbon nanofibers (CNFs). Finally, we identify key data gaps and suggest research needs to reduce uncertainty. The focus of this review is on the cancer risk to workers exposed to airborne CNT or CNF during the production and use of these materials. The findings of this review, in general, affirm those of the original evaluation on the inadequate or limited evidence of carcinogenicity for most types of CNTs and CNFs at this time, and possible carcinogenicity of one type of CNT (MWCNT-7). The key evidence gaps to be filled by research include: investigation of possible associations between in vitro and early-stage in vivo events that may be predictive of lung cancer or mesothelioma, and systematic analysis of dose-response relationships across materials, including evaluation of the influence of physico-chemical properties and experimental factors on the observation of nonmalignant and malignant endpoints.

Keywords: Cancer mechanisms; carbon nanofibers; carbon nanotubes; cell proliferation; fibrosis; genotoxicity; inflammation; lung cancer; mesothelioma; particle retention; pulmonary; translocation.

Figure 1

Evidence considered in IARC two-tier cancer evaluation process (IARC 2006). Source: IARC Monograph Program; IARC (2006); Cogliano (2011). [Copyright permission from IARC. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Volume 111. Some Nanomaterials and Some Fibres. IARC, Lyon (in press)].

Figure 2

Role of mechanistic evidence in IARC cancer hazard classifications: possible modulation of default classification group based on human and animal evidence (IARC 2006). ESLC: Evidence suggesting lack of carcinogenicity. Source: IARC Monograph Program; IARC (2006); Cogliano et al. (2008). [Copyright permission from John Wiley and Sons Inc. for Environmental and Molecular Mutagenesis].

Figure 3

Key events in cancer pathways: Indirect genotoxicity of particles or fibers via persistent inflammation. Source: Adapted from a figure developed by Y Morimoto and N Kobayashi for IARC Monograph 111. [Copyright permission from IARC. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Volume 111. Some Nanomaterials and Some Fibres. IARC, Lyon (in press)].

Figure 4

Mechanisms of genomic instability generated by fibres: Cancer arises from genomic instability (GIN), and the genotoxic effects of CNTs are consistent with an ability to generate GIN. Inhaled CNTs induce a local inflammation associated with the production of cytokines, growth factors (GFs), and reactive oxygen species (ROS) (see chapters on inflammation and Figure 4), which can induce genomic insult and stimulate cell growth. Otherwise, fibres can be internalised by many cell types, resulting in a physical insult due to fibre load. In these “targeted and/or fibre-loaded” cells, the lesions in DNA produce defects in DNA structure. DNA breakage is generated by replication stress, and mitosis stress generates both DNA breaks and chromosome defects. Various repair mechanisms and cell cycle checkpoints are then activated to control genome integrity. Unrepaired or error-prone repair processes can entail mutations, chromosomal rearrangements and variations in chromosome number or morphology, which are the causes of genomic instability (GIN). Selection and amplification of genomically unstable cells can progress to lung cancer and mesothelioma. Source: Adapted from a figure developed by M-C Jaurand for IARC Monograph 111 (IARC, in press). [Copyright permission from IARC. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Volume 111. Some Nanomaterials and Some Fibres. IARC, Lyon (in press)].

Figure 5

Schematic of the tracheobronchial and alveolar airway path to the pleura for the human lung. G1 and G2 signify the last two conducting airway generations prior to reaching the designated terminal bronchiole opening into respiratory bronchioles and alveolar ducts. Source: Figure prepared by M-C Jaurand for this article. [Tracheobronchial and alveolar pathway is reprinted from Comparative Biology of the Normal Lung, 2nd ed., Plopper CG and Hyde DM, Epithelial cells of the bronchiole, pp. 83–92, 2015, with permission from Elsevier; while thoracic and pleural region is adapted from Sureka et al. (2013), with use permitted by the Indian Journal of Radiology].