Page 224 - Environmental Nanotechnology Applications and Impacts of Nanomaterials

Principles and Procedures to Assess Nanomaterial Toxicity 209

stress [17, 18]. More recently, PM exposure has also been linked to sys-
temic inflammatory effects in the cardiovascular system; this could be
due to either the ability of ambient PM to induce pulmonary inflam-
mation or the ability of the ultrafine particles (aerodynamic diameter
<100 nm) to gain access to the systemic circulation. Cellular studies have
generally supported the role of oxidative stress, pro-inflammatory
cytokines, and programmed cell death as relevant mechanisms of PM
injury [19, 20]. Ambient ultrafine particles have a higher pro-oxidative
potential than ambient particles of larger size [19].
In contrast to the heterogeneous characteristics of ambient PM, man-
ufactured NM are more homogeneous in shape, size, and form. In spite
of these differences, research into ambient PM has helped to establish
a number of principles that can be used to study NM toxicity. These
include recognition that small particle size, large surface area, chemi-
cal composition, and ability to catalyze ROS production are important
properties that determine PM-induced oxidant injury and inflammation
[6,7]. Additional NM properties may contribute to ROS generation and
oxidant injury and will be discussed throughout this chapter.
Oxidative stress refers to a state in which cellular GSH is depleted
while oxidized glutathione (GSSG) accumulates. Under normal cou-
pling conditions, ROS are generated at low frequency, mostly in mito-
chondria, and are easily neutralized by antioxidant defense mechanisms
such as the glutathione (GSH)/glutathione disulfide (GSSG) redox
couple. Ambient nanoparticles can elicit further ROS production in
mitochondria, in addition to ROS generation by catalytic conversion
pathways and NADPH oxidase activation [19, 21]. PM-induced ROS
production is dependent on the particles themselves, as well as the
redox cycling organic chemicals and transition metals that coat the par-
ticle surface [19, 21]. In addition to intrinsic redox cycling capabilities,
the metabolic transformation of these chemicals and their ability to
elicit intracellular calcium flux, disrupt electron flow in the mitochon-
drial inner membrane, perturb the permeability transition pore, and
deplete cellular GSH content could contribute to cellular ROS genera-
tion. While small amounts of ROS could be buffered by the antioxidant
defense pathways in the cell, excess amounts of ROS could lead to a drop
in the GSH/GSSG ratio. This elicits additional cellular responses.
Only a limited number of manufactured NM have so far been shown
to exert toxicity in tissue culture and animal experiments, and usually
at high doses. A recent study shows that the biological response of BV2
microglia to noncytotoxic concentrations of TiO induced a rapid
2
(<5 minutes) and sustained (120 minutes) release of reactive oxygen
species [22]. The kinetics of ROS production suggests that TiO stim-
2
ulates immediate oxidative burst activity in microglia and can also
interfere in mitochondrial energy production. Carbon nanostructures