Toxicological Effects of Metal Nanomaterials - Safety of Nanomaterials along Their Lifecycle - page 200

assessment therefore requires in vivo studies. Most of the animal studies published
so far have focused on biodistribution of metal nanoparticles, whereas current data
regarding their toxicity in vivo are limited. In this section we will summarize reports
obtained from nonmammalian (zebrafish), rodent, and human exposure.
9.4.1 I n V IVo s tudies in n on -m ammalian a nimal m odels
Comparative toxicity studies of silver, gold, and platinum nanoparticles in zebraf-
ish models have found silver nanoparticles to exert the strongest adverse effects.
Exposure of zebrafish embryos to nanosilver (10-100 µg/mL, 5-35 nm in size)
resulted in a concentration-dependent mortality rate and hatching delay, whereas
platinum nanoparticles (10-100 µg/mL, 3-10 nm) only induced hatching delays
and gold nanoparticles (10-100 µg/mL, 5-35 nm) did not show any toxic behavior
(Asharani et al. 2011). Similarly, other groups reported that gold nanoparticles of
different sizes (11, 3, 5, 50, and 100 nm) did not show any adverse effects on embryo
development in zebrafish (Browning et al. 2009; Bar-Ilan et al. 2009), albeit all sizes
of silver nanoparticles (3, 5, 50, and 100 nm) tested generated a variety of embry-
onic morphological malformations and mortality (Bar-Ilan et al. 2009). These results
demonstrate the stronger hazard potential of nanosilver in comparison to other metal
nanoparticles, which is in good agreement with the toxicological findings obtained
by in vitro studies.
Exposure of zebrafish to copper nanoparticles (80 nm) revealed gill injury and
acute lethality with a 48 h LC 50 concentration of 1.5 mg/L (Griffitt et al. 2007).
Although the mechanisms of toxicity are still unclear, the authors demonstrated that
the effects were not solely due to dissolution, because copper nanoparticles pro-
duced different morphological effects and global gene expression patterns than sol-
uble copper (Griffitt et al. 2007). Similar findings were recently obtained for silver
nanoparticles and other aquatic model organisms—for example, Daphnia magna
(Georgantzopoulou et al. 2013). Georgantzopoulou et al. found silver nanoparticles
of different sizes (20, 23, 27, and 200 nm) to exert toxic effects on aquatic organ-
isms, with 23 nm silver particles being the most potent. These effects could not be
explained solely by soluble silver suggesting that the particulate material itself con-
tributes to toxicity (Georgantzopoulou et al. 2013). Such effects may, however, also
be indirect as they could be linked to a size- or surface-dependent biodistribution.
9.4.1.1 in Vivo Studies in Mammals
9.4.1.1.1 Oral Toxicity
For studies on oral toxicity, nanosilver particles of four different sizes (22, 42, 71,
and 323 nm) were used to feed mice at 1 mg/kg body weight/day for 14 days with no
significant toxic effects. However, when mice were fed for 28 days with the 42 nm
silver particles, an increase in inflammatory cytokines, signs of hepatotoxicity (i.e.,
increased alkaline phosphatase [ALP], aspartate aminotransferase [AST], alanine
aminotransferase [ALT]), and histopathological changes in the kidney were reported
with a NOAEL of 0.50 mg/kg body weight per day (Park et al. 2010). Likewise,
mice exposed to 60 nm silver particles (with 300 or 1,000 mg/kg body weight) in a
28-day repeat oral gavage study showed significantly enhanced values of ALP and