Evaluating the Mechanistic Evidence and Key Data Gaps in Assessing the Potential Carcinogenicity of Carbon Nanotubes and Nanofibers in Humans

HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Crit Rev Manuscript Author Toxicol. Author Manuscript Author manuscript; available in PMC 2018 January 01. Published in final edited form as: Crit Rev Toxicol. 2017 January ; 47(1): 1–58. doi:10.1080/10408444.2016.1206061. Evaluating the mechanistic evidence and key data gaps in assessing the potential carcinogenicity of carbon nanotubes and nanofibers in humans Eileen D. Kuempela,†, Marie-Claude Jaurandb,c,d,e, Peter Møllerf, Yasuo Morimotog, Norihiro Kobayashih, Kent E. Pinkertoni, Linda M. Sargentj,‡, Roel C. H. Vermeulenk, Bice Fubinil,†, and Agnes B. Kanem,§,€ aNational Institute for Occupational Safety and Health, Cincinnati, OH, USA bInstitut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche, UMR 1162, Paris, France cLabex Immuno-Oncology, Sorbonne Paris Cité, University of Paris Descartes, Paris, France dUniversity Institute of Hematology, Sorbonne Paris Cité, University of Paris Diderot, Paris, France eUniversity of Paris 13, Sorbonne Paris Cité, Saint-Denis, France fDepartment of Public Health, University of Copenhagen, Copenhagen, Denmark gDepartment of Occupational Pneumology, University of Occupational and Environmental Health, Kitakyushu City, Japan hNational Institute of Health Sciences, Tokyo, Japan iCenter for Health and the Environment, University of California, Davis, California, USA jNational Institute for Occupational Safety and Health, Morgantown, West Virginia, USA kInstitute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands lDepartment of Chemistry and “G.Scansetti” Interdepartmental Center, Università degli Studi di Torino, Torino, Italy mDepartment of Pathology and Laboratory Medicine, Brown University, Providence, RI, USA 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 CONTACT E. D. Kuempel, [email protected], National Institute for Occupational Safety and Health, Cincinnati, OH, USA. †Co-Chair of Subgroup on Mechanisms and Other Related Data (Mechanisms Subgroup) for IARC Monograph 111. ‡Member of Subgroup on Studies of Cancer in Experimental Animals and also the Mechanisms Subgroup. §Chair of Working Group for IARC Monograph 111. €All coauthors were members of the International Agency for Research on Cancer (IARC) Monograph 111 Subgroup on Mechanistic and Other Relevant Data (a.k.a. Mechanisms Subgroup), and all members of the Mechanisms Subgroup participated in this paper. Declaration of interest The affiliation of the authors is as shown on the cover sheet. The authors were all originally selected by IARC to participate in the review of the carcinogenic hazard of carbon nanotubes held in October 2014, a review they participated in as independent scientists. As noted in the article, that review will be published by IARC as Monograph 111 [now published, May 19, 2017; available from: http://monographs.iarc.fr/]. This paper was prepared by the authors as an independent endeavor. This review, the interpretations, the conclusions drawn, and the recommendations made are exclusively those of the authors and are not necessarily those of their employers or IARC. None of the authors have appeared in either legal or regulatory proceedings related to the contents of the paper. The findings and conclusions in this article are those of the authors and do not necessarily represent the views of the National Institute for Occupational Safety and Health. Supplemental material Supplemental material for this article is available online here. Kuempel et al. Page 2 of the in vivo and in vitro experimental studies according to current hypotheses on the Author ManuscriptAuthor Manuscript Author Manuscript Author Manuscript Author 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 Introduction Scope and objectives In October 2014, the International Agency for Research on Cancer (IARC) convened a monograph meeting of international experts on the carcinogenicity of three fiber or fiber-like materials, including fluoro-edenite, silicon carbide whiskers, and carbon nanotubes (CNTs) (Grosse et al. 2014). The monograph expert group included subgroups in epidemiology, animal studies, and mechanisms. Of the three substances evaluated, CNTs were the most diverse and heterogeneous group of materials, had the most extensive scientific literature, and yet also had the most uncertainty regarding the available evidence for specific types of CNTs. The Mechanisms Subgroup was tasked with examining the extensive mechanistic data and identifying key data gaps. CNT heterogeneity and data gaps for most types of CNTs resulted in a high degree of uncertainty with regard to assessing the potential carcinogenicity of the various types of CNTs to which people (especially workers) could potentially be exposed. The purpose and scope of this critical review paper are to further examine the available evidence, including the additional studies on CNTs that were published after the IARC Monograph 111 meeting and the published studies on carbon nanofibers (CNF) (CNF was not evaluated in the IARC Monograph 111). In addition, some key areas of evidence such as the mechanisms of cell proliferation were examined in greater depth. A diversity of expert judgments was expressed within the subgroup, as summarized in the IARC 111 monograph (in press) and in this paper with regard to interpreting the strength of the mechanistic evidence on the potential carcinogenicity of CNTs. Agreement was generally achieved on the key areas of evidence needed to evaluate the potential carcinogenicity of CNTs and Crit Rev Toxicol. Author manuscript; available in PMC 2018 January 01. Kuempel et al. Page 3 CNFs, which are based on current hypotheses on the carcinogenicity of inhaled particles and Author ManuscriptAuthor Manuscript Author Manuscript Author Manuscript Author fibers, as well as missing information concerning that evidence. This follow-on paper also examines whether the additional data evaluated since the monograph meeting provide any new insights on the physico-chemical and other factors that may be associated with the potential cancer risk of occupational exposure to airborne CNTs and/or CNFs. This review includes those studies that provide information on the doses and responses to CNTs or CNFs in rodent lungs, pleura, or peritoneum, as well as in vitro studies in human or rodent cells at relevant experimental conditions. Consideration is given to the dose–response relationships in the animal studies compared to the estimated equivalent pulmonary or pleural doses of CNTs or CNFs in humans with potential occupational airborne exposures. The objective of this follow-on review (as in the original review for the IARC Monograph 111 meeting on CNTs) is to critically evaluate the available evidence on the key steps in the development of cancer in the lungs or mesothelium associated with exposure to CNTs or CNFs. Studies were examined for the availability of relevant data across the various types of CNTs and CNFs and for consistency or differences in the results on cancer or precursor events. Data gaps in the key biological events are identified, as well as the research needs to strengthen the evidence for making decisions about the potential carcinogenicity of specific CNTs or CNFs or categories of materials. Worker exposures and lung responses Workers in facilities that produce or use CNTs and/or CNFs have the potential for inhalation exposure when these particles become airborne and enter the workers’ breathing zone. Workplace airborne exposure concentration measurements have been reported in several studies of single-walled or multi-walled CNTs (SWCNT, MWCNT, respectively) (Maynard et al. 2004; Han et al. 2008; Bello et al. 2008, 2009, 2010; Tsai et al. 2009; Johnson et al. 2010; Lee et al. 2010; Cena & Peters 2011; Dahm et al. 2011, 2012) and CNFs (Methner et al. 2007, 2012; Evans et al. 2010; Birch et al. 2011; Dahm et al. 2015). For a complete review of the CNT occupational

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