Table 5.

Summary of in vitro data on genotoxicity, gene expression of cellular transformation endpoints.

Endpoint	MWCNT study and tube length	SWCNT study and tube length
DNA oxidation products (FPG)	+ Visalli et al. (2015): 10–20 μm§§	+ Migliore et al. (2010): 0.5–100 μm
	+ Migliore et al. (2010): 5–9 μm	+ Vesterdal et al. (2014a): 1 μm
	+ Kermanizadeh et al. (2012), 0.7–3 and 0.7–4 μm	+ Jacobsen et al. (2008): 1 μm
	+ Darne et al. (2014) >0.8 μm	− Pelka et al. (2013): 0.05 μm
	− Cavallo et al. (2012): 0.5–200 μm
	− Ursini et al. (2014): 0.07–7.8 μm
	− Karlsson et al. (2008): 3–7 μm
	− Kermanizadeh et al. (2013): 0.7–3 and 0.7–4 μm
DNA breaks (SSB)	+ Cavallo et al. (2012): 0.5–200 μm	+ Lindberg et al. (2009)*: 0.5–100 μm
	+ Ghosh et al. (2011): 0.5–200 μm	+ Migliore et al. (2010): 0.5–100 μm
	+ Di Giorgio et al. (2011): 0.5–50 μm	+ Kim & Yu (2014): 20 μm
	+ Barillet et al. (2010): 0.1–20 μm†	+ Yang et al. (2009): 5 μm
	+ Visalli et al. (2015): 10–20 μm§§	+ Pacurari et al. (2008): 2–5 μm
	+ Migliore et al. (2010): 5–9 μm	+ Di Giorgio et al. (2011): 2–5 μm
	+ Ursini et al. (2014): 0.07–7.8 μm	+ Kisin et al. (2007): 1–3 μm
	+ Karlsson et al. (2008): 3–7 μm	+ Kisin et al. (2011): 1–3 μm
	+ Lindberg et al. (2013): 1–2 μm	+ Lindberg et al. (2013): 1–5 μm
	+ Aldieri et al. (2013): 1.1 μm (pristine)	+ Vesterdal et al. (2014a): 1 μm
	+ Darne et al. (2014) >0.8 μm	+ Pelka et al. (2013): 0.5 μm
	+ Kermanizadeh et al. (2012): 0.7–3 and 0.7–4 μm	+ Cicchetti et al. (2011): 0.8 μm
	+ Kermanizadeh et al. (2013): 0.7–3 and 0.7–4 μm	+ Alarifi et al. (2014): 0.3–0.5 μm
	+ Kim et al. (2016): 0.2 μm	− Bayat et al. (2015): 5 μm
	− Jackson et al. (2015): 5.7, 0.3–7, 0.7.4 μm‡	− Darne et al. (2014) >1 μm
	− Aldieri et al. (2013): 1.1 μm (purified)	− Jacobsen et al. (2008): 1 μm
	− Thurnherr et al. (2011): 2–5 μm
	− Darne et al. (2014) >1.5 μm or <1 μm
DNA breaks (DSB)	+ Cveticanin et al. (2010): 1–5 μm	+ Cveticanin et al. (2010): 1–5 μm§
	+ Guo et al. (2011): 1 μm	− Pacurari et al. (2008): 2–5 μm
	− Mrakovcic et al. (2015): 0.5–2 μm***	− Mrakovcic et al. (2015): 0.5–2 μm***
	− Ju et al. (2014): 1 μm
	− Barillet et al. 2010: 0.1–20, 1.5 μm
Chromosome damage	+ Di Giorgio et al. (2011): 0.5–50 μm	+ Di Giorgio et al. (2011): 2–5 μm
	+ Asakura et al. (2010): 5 μm	+ Catalán et al. (2012): 1–5 μm
	+ Catalán et al. (2012): 1–2 μm	+ Sargent et al. (2009): 1 μm
	+ Siegrist et al. (2014): 1 μm	+ Sargent et al. (2012): 1 μm
	− Kim et al. (2011): 0.15 or 10 μm	− Kim et al. (2015): 20 μm
	− Wirnitzer et al. (2009): 0.5–50 μm	− Naya et al. (2011): 1.2 μm
		− Ema et al. (2013a): not reported
Micronuclei	+ Wu et al. (2013): 10–30 μm	+ Migliore et al. (2010): 0.5–100 μm
	+ Di Giorgio et al. (2011): 0.5–50 μm	+ Kim & Yu (2014): 20 μm
	+ Visalli et al. (2015): 10–20 μm†††	+ Manshian et al. (2013): 5–30, 1–3, 0.4–0.8 μm
	+ Migliore et al. (2010): 5–9 μm	+ Di Giorgio et al. (2011): 2–5 μm
	+ Cveticanin et al. (2010): 1–5 μm	+ Cveticanin et al. (2010): 1–5 μm§
	+ Asakura et al. (2010): 5 μm	+ Kisin et al. (2011): 1–3 μm
	+ Kato et al. (2013): 1–4 μm	+ Cicchetti et al. (2011): 0.8 μm
	+ Tavares et al. (2014): 4.4 μm, 1.1 μm, 394 nm¶	+ Darne et al. (2014) >1 μm (+ in V79; − in SHE cells)
	+ Srivastava et al. (2011): 0.3–2 μm	− Lindberg et al. (2009): 0.5–100 μm*
	+ Darne et al. (2014) 1.5 μm or <1 μm	− Lindberg et al. (2013): 1–5 μm
	+ Darne et al. (2014) >0.8 μm	− Kisin et al. (2007): 1–3 μm
	+ Muller et al. (2008a): 0.7 μm (ground sample)	− Mrakovcic et al. (2015): 0.5–2 μm
	+ Muller et al. (2008b): 0.7 μm||	− Pelka et al. (2013): 0.5 μm
	+ Kim et al. (2016): 0.2 μm
	− Thurnherr et al. (2011): 2–5 μm
	− Lindberg et al. (2013): 1–5 μm
	− Szendi&Varga (2008): 1–2 μm
	− Mrakovcic et al. (2015): 0.5–2 μm
	− Ponti et al. (2013): 1.5 μm**
Mutations	− Asakura et al. (2010) hgprt, 5 μm	+ Manshian et al. (2013) hprt, 1–3 μm††
	− Taylor et al. (2014) Bacteria, 5–20 μm	+ Mrakovcic et al. (2015) hgprt, 0.5–2 μm¶¶
	− Kim et al. (2011) Bacteria, 10 or 0.15 μm‡‡	− Jacobsen et al. (2008) cII, 1 μm
	− Mrakovcic et al. (2015) hgprt, 0.5–2 μm¶¶	− Kim et al. (2016) Bacteria, 20 μm
	− Di Sotto et al. (2009) Bacteria, 5–7 μm	− Kisin et al. (2007) Bacteria, 1–3 μm
	− Wirnitzer et al. (2009) Bacteria, 0.2–1 μm	− Naya et al. (2011) Bacteria, 1.2 μm
		− Ema et al. (2013a) Bacteria, not reported
Gene expression (or protein)	+ Ravichandran et al. (2010) Trp53, p21 protein (up)	+ Sarkar et al. (2007) Atm (up)
	+ Srivastava et al. (2011) Trp53, Cdkn1a (up) Bcl2 (down)	+ Wang et al. (2011a) p53
	+ Kim et al. (2012) Cdkn2A (down) Bcl2 (up)	+ Pelka et al. (2013) p53
	+ Vankoningsloo et al. (2012) Bcl2 (down)	+ Wang et al. (2012) Bcl2 (down)
	+ Poulsen et al. (2013) Jun (up), Cdkn2c (down)
	+ Zhu et al. (2007) p53 (up)
	+ Zhang & Yan (2012) p21Cip1 (up), pRb (increased phosphorylation)
	− Zhang & Yan (2012) p53
In vitro cellular transformation		+Wang et al. (2011a) Morphologic transformation
		+ Lohchanoenkal et al. (2014) Morphologic transformation, HRAS protein expression

Source: Adapted, from Table 3 in Sections 4–6 of IARC monograph 111 (IARC, in press), which was originally developed by authors on this paper. This current table has been restructured and includes some different presentations of the data, such as indicating which material was tested for cancer in animals.

Abbreviations: Bcl2: B-cell cll/lymphoma 2; Bcl3: B-cell cll/lymphoma 3; Cdkn1a: cyclin-dependent kinase inhibitor 1a (P21, Cip1); Cdkn2a: cyclin-dependent kinase inhibitor 2a; Cdkn2c: cyclin-dependent kinase inhibitor 2c (P18, Inhibits CDK4); Egfr: epidermal growth factor receptor; Junb: Jun-B proto-oncogene; Myb: V-Myb avian myeloblastosis viral oncogene homolog; pRb: retinoblastoma protein; Trp53: tumor protein p53.

Notes: Levels of DNA damage, mutations, chromosome damage and cellular transformation are increased (+) or unaltered (−) in exposed cells compared to unexposed controls. Gene expressions include oncogenes, tumor suppressor genes, and genes involved in DNA repair and cell cycle regulation. (+) means a differential expression between control (untreated) and treated cells. Bold text refers to observation on materials that have been tested for carcinogenicity in animal models.

^*Contains a mixed material with more than 50% SWCNTs and 40% other nanotubes.

^†MWCNTs defined as “long” (0.1–20 μm) was genotoxic, whereas a “short” type (1–5 μm) was not genotoxic.

^‡Included 15 different materials, only MWCNT-7 and OECD materials MN400 and MN402 have been highlighted.

^§Same effect of pristine and amide-functionalized SWCNTs.

^¶Three materials did not generate micronuclei (369 nm, 726 nm, 3.4 μm).

^||Heating (2400 °C) of the ground sample abolished genotoxicity. Samples that were heated and subsequently ground increased the formation of MN.

^**Both pristine and functionalized forms.

^††Only material with 1–3 μm in length.

^‡‡Includes both “long” (approximately 10 μm) and “short” (150 nm) types of fibers.

^§§Also increased level of DNA strand breaks and FPG-sensitive sites after exposure COOH-functionalized MWCNTs.

^¶¶Also increased mutation frequency of COOH-functionalized SWCNTs. No effect of COOH-functionalized MWCNTs.

^***No effect of COOH-functionalized CNTs.

^†††Unaltered micronuclei frequency of COOH-functionalized MWCNTs.