ToxSci Advance Access originally published online on September 25, 2007
Toxicological Sciences 2008 101(1):179-180; doi:10.1093/toxsci/kfm249
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To the Editor
Université catholique de Louvain, Industrial Toxicology and Occupational Medicine, 1200 Brussels, Belgium
Received August 20, 2007; accepted August 20, 2007
In their recent publication in Toxicological Sciences Mitchell et al. (2007) report on the lung and systemic responses to carbon nanotubes (CNT) in mice. After 14 days of inhalation exposure to a maximum of 5 mg CNT/m3, no significant lung toxicity was reported but immunological changes were noted in the spleen. These results contrast with the marked inflammatory and fibrotic lung responses reported by other investigators who used single wall CNT intratracheal (i.t.) injection in mice (Lam et al., 2004
) or rats (Warheit et al., 2004), pharyngeal aspiration of single wall CNT in mice (Shvedova et al., 2005) or i.t. injection of multiwall CNT (MWCNT) in rats (Muller et al., 2005).
Mitchell et al. confronted in particular their results with our finding of severe inflammatory and fibrotic lung changes after i.t. administration (Muller et al., 2005) and argued that the results of these early experiments are probably of little relevance to assess the hazard of MWCNT because they could not be reproduced upon inhalation exposure. Although this conclusion may be correct for several other reasons, we believe that it cannot be drawn from the data presented by the authors. Several major differences indeed exist between both studies.
First, and most importantly, the inhalation study by Mitchell et al. (2007) was not conducted with MWCNT. The detailed and careful physicochemical characterization of the material included in the publication indeed indicates that herringbone carbon nanofibers, not MWCNT, were used (transmission electron microscopy [TEM] image on Fig. 2B in the publication). This herringbone carbonaceous material is not a nanotube but a nanofiber (Melechko et al., 2005). Although MWCNT consists of multiple graphene sheets rolled into concentric cylinders such that the lattices of carbon atoms remain continuous around the circumference and parallel to the axis of the nanotube, the herringbone structure comprises graphite layers arranged at a variable angle to the axis of the filament, forming a stacked and discontinuous arrangement of cones.
Carbon nanofibers are intrinsically less perfect than MWCNT as they have graphitic edge terminations exposed on their surface. They have many properties in common with carbon nanotubes and share some potential applications (e.g., gas storage, filtration). They do, however, not share all of the properties of CNT, mainly those based on their structure (e.g., mechanical strength of carbon nanofibers is several orders of magnitude lower than that of CNT) (Melechko et al., 2005).
Thus, the MWCNT picture shown in Fig. 1 of the publication by Mitchell et al. (2007) is misleading because it represents a material that was not tested in this study. For the same reason, the title of the publication is also misleading.
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The doses of material tested in both studies were also significantly different. The mass dose of MWCNT that we instilled varied between 2 and 20 mg/kg b.w., whereas the maximal calculated deposited dose of nanofibers was 2.7 mg/kg b.w. When examining the histological sections obtained at the end of the exposure period (Fig. 7), the actual deposited dose may probably even be lower. This could be easily checked by measuring the particle content in lung tissue by using one of the metallic contaminants as a tracer. Moreover, the specific surface area (s.s.a.) of the nanofibers was 100 m2/g, whereas our MWCNT had an s.s.a. of about 300 m2/g. Because the prevailing view is that surface reactivity and hence surface area are important determinants of the toxicity for low solubility particles (Lison et al., 1997
; Donaldson et al., 2006; Monteiller et al., 2007), the maximal doses tested varied by a factor of at least 20 between both studies.
The materials were not tested in the same species. While nanofibers were tested in mice, MWCNT were tested in rats which usually appear more sensitive to inhaled particles than mice (Elder et al., 2005).
The observation period also differed between both studies: 60 versus 14 days for MWCNT and nanofibers, respectively. As acknowledged by Mitchell et al. (2007), it cannot be excluded that effects of nanofibers could appear at later time points.
The biopersistence of tested materials in the lung is another important determinant of toxicity. We found that a substantial fraction of instilled MWCNT was still present after 60 days in the rat lung. Although the biopersistence of herringbone nanofibers was not assessed in mice, the apparently very low burden of material on the lung sections shown in Fig. 7 may also suggest that this material was rapidly cleared from the lung.
We conclude that:
- (1) A detailed physicochemical characterization of the tested material, including a TEM analysis, is essential to adequately characterize the hazard of inhaled particles (Oberdörster et al., 2005). This appears even more critical for nanomaterials in view of the large array of diverse materials that are currently produced and put on the market, sometimes with subtle and possibly confusing variations.
- (2) Although experimental results obtained with i.t. administration of CNT may, in turn, prove to be of little relevance to assess the health risk of these materials, this issue cannot be resolved yet on the basis of existing data.
- (2) Although experimental results obtained with i.t. administration of CNT may, in turn, prove to be of little relevance to assess the health risk of these materials, this issue cannot be resolved yet on the basis of existing data.
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