Toxicological Effects of Metal Nanomaterials - Safety of Nanomaterials along Their Lifecycle - page 201

cholesterol in the blood, suggesting liver damage (Kim et al. 2008). This may indi-
cate the impact of exposure time on the toxicological outcome.
A study by Zhang et al. investigated the toxic effects of gold nanoparticles of
13.5 nm diameter in mice following oral administration (Zhang et al. 2010). Mice
were fed over 14 to 28 days with different nanoparticle concentrations ranging from
137.5 to 2,200 µg/kg body weight, and animal survival rates, animal mass, and
effects on hematology and morphology were investigated. At low concentrations,
the gold nanoparticles did not display toxic behavior, whereas at higher concentra-
tions (1,100 µg/kg) a significant decrease in body weight, thymus and spleen index,
and red blood cells was observed. The authors also compared other administration
routes (intraperitoneal and tail vein injection) and found orally and intraperitoneally
administered gold nanoparticles to yield the highest toxicity (Zhang et al. 2010).
Chen et al. reported an effect of size on acute toxicity of copper particles in mice
(Chen et al. 2006). Oral exposure of mice to 23.5 nm copper nanoparticles led to
injuries in the kidney, liver, and spleen with LD 50 values of 413 mg/kg body weight
(i.e., moderately toxic), whereas microsized copper particles (17 µm) were virtually
nontoxic with LD 50 values of >5,000 mg/kg body weight (Chen et al. 2006).
9.4.1.1.2 Pulmonary Toxicity
The in vivo studies addressing the inhalation route of exposure generally investigate
pulmonary toxicity after instillation of nanoparticles into the animal lungs or after
animal exposure via inhalation. Silver nanoparticles have been shown to induce pul-
monary inflammation in different inhalation studies. Sung et al., for instance, con-
ducted a 90-day inhalation exposure of rats to 20 nm silver nanoparticles (6 h/day) and
found inflammatory responses and alterations in the lung function at low, medium,
and high particle doses (48.94, 133.19, or 514.78 µg/m 3 ; Sun, Liu, and Wang 2008;
Sung et al. 2009). They determined a NOAEC of 100 µg/m 3 . Similar signs of toxicity
and a similar NOEAC (117 µg/m 3 ) were recently obtained in a 12-week inhalation
study conducted in rats with 14-15 nm silver nanoparticles (Song et al. 2013). In
contrast, in a subacute murine inhalation model, a 10-day exposure (4 h/day) to small
silver nanoparticles (5 ± 2 nm primary size) at a dose of 3.3 mg/m 3 demonstrated
only minimal pulmonary toxicity (Stebounova et al. 2011), and no significant toxic
effects were reported in rats exposed to nanosilver (15 nm) at concentrations rang-
ing from 0.48 to 61.24 µg/m 3 for 14 days (6 h/day) (Ji et al. 2007). As a whole these
results indicate that—depending on the duration of exposure—the accumulated lung
burden, the biodistribution of silver nanoparticles, and, most likely, the subsequent
release of ions from the secondary sites have an influence on the response to inhaled
nanosilver.
For other metal nanoparticles, information on pulmonary toxicity is very lim-
ited. Intratracheal instillation of platinum nanoparticles in mice has been reported to
induce different inflammatory markers (Park et al. 2010). Intratracheal instillation of
a single dose (1 mg/kg body weight) of nanosized platinum (21 nm) led to a signifi-
cant increase in inflammatory cytokines (IL-1, TNFα, IL-4, IL-5, IL-6, and TGF-β)
in the BAL fluid for up to 28 days after instillation. Moreover, histopathological
investigations revealed infiltration of macrophages and neutrophils in the lungs.
Based on these findings, the authors suggest that platinum nanoparticles may induce