# Safe Functional Modified CuO Nanoparticles?
## 2 Safe(r)-By-Design CuO Nanoparticles
### Doping  
In the Introduction it was noted that two studies [39; 40] claimed that safety-by-design was achieved by doping. Table 2 summarizes the characteristics of CuO nanoparticles contributing to hazard that these studies addressed and their findings regarding these characteristics as impacted by doping. As pointed out in the Introduction, [PERSON] et al. [39] studied the hatching inhibition of zebrafish embryos by Fe-doped CuO nanoparticles and found reduced inhibition of hatching, if compared with pristine CuO nanoparticles. [PERSON] et al. [39] also studied the effect of Fe-doped CuO nanoparticles on cytotoxicity in BEAS-2B and THP-1 (human) cell lines. In addition, [PERSON] et al. [59] studied exposure of (human) C6 glioma cell lines to Fe-doped and non-doped CuO nanoparticles. Both [PERSON] et al. [39] and [PERSON] et al. [59] found CuO nanoparticles were reduced by Fe-doping. As [PERSON] et al. [59] did show that the generation of reactive oxygen species (and its associated hazard) was to be unaffected by Fe-doping, whereas the release of Cu ions from CuO nanoparticles was slowed, reduced cytotoxicity was ascribed to the latter effect. [PERSON] et al. [60] tested the impact of CuO nanoparticles doped with 3.6% Fe against three microbial species (two bacteria and one yeast). A substantial antimicrobial activity was found. The experiments presented by [PERSON] et al. [39], [PERSON] et al. [60] and [PERSON] et al. [59] did not show that CuO nanoparticle hazard was eliminated by doping with Fe. Taking into account the uncertainties besetting extrapolation [49; 50; 51; 52; 58], these studies did not demonstrate that Fe-doped CuO nanoparticles can be safely used in the environment. \begin{table}
\begin{tabular}{c c c} \hline \hline \begin{tabular}{c} **Characteristics of Nanoparticle That Can** \\ **Contribute to Hazard** \\ \end{tabular} & \begin{tabular}{c} **Was This Addressed by [PERSON] et al. [39]? If** \\ **So, What Impact of Doping Was Found?** \\ \end{tabular} & \
\begin{tabular}{c} **Was This Addressed by [PERSON] et al. [40]? If** \\ **So, What Impact of Doping Was Found?** \\ \end{tabular} \\ \hline
\begin{tabular}{c} Release of metal ions \\ \end{tabular} & Yes, reduction of copper ion release was found. & No. \\ \hline Generation of reactive oxygens species (ROS) & No & Yes, a reduced generation of ROS was found \\ \hline \hline \end{tabular}
\end{table} 
Table 2: Characteristics of CuO nanoparticles that can contribute to hazard addressed by [PERSON] et al. [39] and [PERSON] et al. [40] and their findings regarding these characteristics as impacted by doping. The induced generation of ROS by Mn\({}_{3}\)O\({}_{4}\) nanoparticles as tested by [PERSON] et al. [40] was not eliminated by Zn doping. The aim of the doping experiments performed by [PERSON] et al. [40] has been to reduce the generation of ROS by keeping conduction band energy out of the biological redox potential range and having the edge of the Fermi energy (which dominates charge transfer) far away from the valence band energy edge. [PERSON] et al. [40] were successful as to the latter but not regarding the former. As the conduction band of CuO nanoparticles has been reported in the same range as biological redox potentials [61], it would seem that the doping strategy used by [PERSON] et al. [40] is also unlikely to eliminate the generation of ROS induced by doped CuO nanoparticles. [PERSON] et al. [40] did not address the impact of Zn-doping on the release of metal ions from Mn\({}_{3}\)O\({}_{4}\) nanoparticles, as they stated that these nanoparticles are insoluble. Insolubility, however, does not apply to CuO nanoparticles. In view of research presented by [PERSON] et al. [22], [PERSON] et al. [39] and [PERSON] et al. [59], the release of Cu ions from CuO nanoparticles in biologically relevant settings is well established. It might also be pointed out that [PERSON] et al. [62] and [PERSON] et al. [63] have presented evidence for the release of Mn ions from Mn\({}_{3}\)O\({}_{4}\) nanoparticles in organisms and cell lines.