Nanoparticle Cell Penetration - Aerosols: Measurement, Dosimetry, and Health Effects - page 221

inhaled nanoparticles of various types of materials (e.g., iridium) enter the blood at a rate of about
1% of the deposited dose (Kreyling et al., 2007). Similar values (1%-2% of the deposited dose enter-
ing the blood) have been reported for TiO 2 nanoparticles following instillation (Chen et al., 2006).
Lower concentrations (0.05%) of inhaled gold nanoparticles were reported to enter the blood follow-
ing instillation (Takenaka et al., 2006). Results from electron microscope morphometry (Mühlfeld
et al., 2007) have suggested that there is rapid transfer of 22 nm TiO 2 nanoparticles (count median
diameter) into the blood via the interstitium, within a very short space of time following deposition.
Although the mass fraction entering the blood may be small, the particle number that reaches these
other targets can be very great (Kreyling et al., 2007) and these organs are not necessarily equipped,
as the lungs are, to deal with large numbers of particles and so the effects may be more severe.
The endothelium is the key cell that particles must cross in order to gain access to the blood.
Many studies have made the assumption that particles deinitely cross the endothelium and have
reported effects on the endothelium and cellular elements of the blood. Carbon black nanoparticles
and PM 10 /PM 2.5 affect endothelial cells in ways that enhance coagulation (Gilmour et al., 2005)
and similarly pro-thrombotic effects in liver endothelium following treatment in vivo have been
reported (Khandoga et al., 2004). The endothelium, atherosclerotic lesions, and the clotting system
are key targets for nanoparticles in circulatory system. The potential cardiovascular impact of
engineered nanoparticles is a major concern given the data showing adverse cardiovascular as lead
effects of PM 10 /PM 2.5 (Schwartz and Morris, 1995) and recent work on diesel inhalation showing
effects on the endothelium that are very likely occurring via a mechanism involving oxidative
stress (Mills et al., 2005, 2009). There is experimental evidence that deposition of PM 10 /PM 2.5 in
the lungs accelerates and worsens atherosclerotic plaque development in animal models (Suwa
et al., 2002; Lippmann et al., 2005; Sun et al., 2005). The only data that indicate that engineered
nanoparticles might have similar effects are the inding that intratracheally administered CNT
causes oxidative stress and mitochondrial dysfunction in the aortae of mice (Li et al., 2007). This
does suggest that effects on the vascular wall might be a generic effect of nanoparticles. These
effects could be driven by the oxidative stress from the particle or the inlammation resulting from
the particles being deposited in the lungs. However, an alternative explanation is that the nanopar-
ticles enter the blood and cause a direct effect on the plaques by affecting the overlying endothe-
lium of entering the atherosclerotic lesion and affecting the stability of the plaque. Paradoxically,
given this concern, nanoparticulate iron has been used to image plaques where the particles have
been found to enter the macrophages in the plaque with, perhaps surprisingly, no adverse effects
reported (Trivedi et al., 2006).
9.5 TRANSLOCATION TO THE BRAIN
The present interest among the toxicology community in engineered nanoparticles translocat-
ing to non-pulmonary organs, in particular the CNS, was stimulated in part by a 2002 editorial
(Oberdörster and Utell, 2002) and the subsequent acknowledgment of the need for research in a
number of reviews (see, e.g., Borm and Kreyling, 2004; Hoet et al., 2004; Oberdörster et al., 2005;
Gwinn and Vallyathan, 2006; Peters et al., 2006).
The translocation of inhaled nanoparticles to the CNS has been postulated to occur via three
pathways: (1) across the BBB after their translocation into the blood circulation from deposits any-
where in the respiratory tract, (2) via the olfactory nerve from deposits on the olfactory mucosa and
uptake into the olfactory bulb, and (3) via paracellular or perineural pathways across the olfactory
mucosa and ethmoid bone into cerebrospinal luid (Oberdörster et al., 2004). Translocation to the
brain via the olfactory nerve has been a focus of recent research, given the estimated 80% probabil-
ity of inhaled NPs of ∼1 nm in size depositing in the nasopharyngeal region (ICRP, 1994).
Research on the translocation of nanoparticles to the CNS is widely cited to originate from stud-
ies in the 1940s using 30 nm polio virus particles (Bodian and Howe, 1941) and the 1970s using
50 nm colloidal gold particles (De Lorenzo, 1970) instilled intranasally. These early studies revealed