Page 355 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

322 SECTION | III Nanoparticles, Radiation and Carcinogens

VetBooks.ir the shape and degree of agglomeration (Brunner et al., people (e.g., asthmatics, chronic obstructive pulmonary
disease (COPD) patients) is a central mechanism by
2006). Soluble amorphous silicate, a negative control
which particles cause lung disease, primarily from organic
caused minimal response in either cell line, consistent
with its anticipated lack of toxicity (Brunner et al., 2006). dusts (Pickrell et al., 2009, 2010). Metal oxide nanoparti-
Crocidolite asbestos had a significant reduction in both cles may also have direct cytotoxic effects in lung cells
cell activity and cell number (DNA) in both cell lines. (Pickrell et al., 2010). After intratracheal instillation,
The mesothelioma cell line was more severely affected, ultrafine colloidal silica (UFCS) particles had greater
perhaps reflecting its metabolic activity. This toxicity was ability to induce tissue damage and inflammation
consistent with expectations from a positive control compared to fine colloidal silica (FCS) particles. Electron
(Brunner et al., 2006). Calcium phosphate had no signifi- microscopy demonstrated UFCS and FCS particles
cant cytotoxicity at 3 days; these data are consistent with on both bronchiolar and alveolar wall surfaces; type I
it having no toxicity like the negative control particle, epithelial cell necrosis and basement membrane damage
amorphous silica (Brunner et al., 2006). Insoluble metal was greater in UFCS than in FCS particles
oxides (TiO 2 , ZrO 2 and CeO 2 ) had modest toxicity at 3 (Kaemawatawong et al., 2005).
days of exposure that was most prominent in mesotheli- Inhalation of highly insoluble ultrafine particles (diame-
oma cells. By 6 days of exposure, these cells had returned ter 20 nm) of low intrinsic toxicity (TiO 2 )resulted in
to normal (Brunner et al., 2006). Morphologically, the pulmonary inflammatory responses. However, these effects
high dose of zirconium oxide caused the appearance of were not acute and occurred only after prolonged inhala-
decreased cell number and function, even after 6 days tion exposure of the aggregated ultrafine particles at high
3
incubation. These data are consistent with only a modest levels . 1 mg/m (Oberdo ¨rster et al., 1995). Ultrafine
health effect relative to the positive control (Brunner carbon particles are more toxic on an equal mass basis than
et al., 2006). Zinc and ferric oxide were slightly soluble fine carbon particles, but this is not true if they are exam-
and quite toxic to both cell lines after 3 days incubation ined on a total surface area basis (Oberdo ¨rster et al., 2010).
(Brunner et al., 2006). The authors advance no specific
explanation for zinc toxicity beyond chemical toxicity,
but experimental conditions suggest considerable local
Carbon Nanotubes
particle concentrations. For iron, the toxicity resulted
from free radical production from the Haber Weiss reac- Pharyngeal aspiration of single-walled carbon nanotubes
tion. Because this reaction occurred at 40-fold less than (SCWNT) elicited an acute pulmonary inflammation in
the chemical toxicity of iron, it is said to be specific for C57BL/6 mice that progressed to fibrosis and granulomas
the nanoparticle (Brunner et al., 2006). (Shvedova et al., 2005). SWCNT caused a dose-
In vitro analysis of particle size-related effects on alve- dependent release of protein, LDH, and gamma-glutamyl
olar macrophages, epithelial cells, and neutrophils, demon- transferase activities into bronchoalveolar lung washings
strates size- and oxidant-dependent responses. Increased (lavage). In addition, elevated 4-hydroxynonenal (oxida-
interleukin 6 (IL-6) in cultured lung cells suggested a tive biomarker), depleted glutathione in lungs, leukocyte
proinflammatory, oxidant response. Reduced cell numbers, accumulations, and cytokines were present in lavage
especially with Mn-containing nanoparticles, suggested fluids on days 1 7. This was followed by fibrogenic
cytotoxicity at high doses, probably from local concentra- transforming growth factor (TGF-β1) that peaked on day
tion of particles (Pickrell et al., 2010). These effects were 7. The progressive fibrosis found in mice exhibited two
observed after in vitro exposure to concentrated PM (2.5) distinct morphologies: SWCNT-induced granulomas, and
ambient particles collected in real time. Oxidative stress, diffuse interstitial fibrosis and alveolar wall thickening.
mediated by ROS, is an important mechanism of particle- Functional respiratory deficiencies and decreased bacterial
induced lung inflammation (Tao et al., 2003). clearance (Listeria monocytogenes) were found in mice
treated with SWCNT (Shvedova et al., 2005). In vitro
exposures of multiwalled carbon nanotubes to fibroblasts
INTRATRACHEAL
at high doses induces a similar inflammation (Ding et al.,
INSTILLATION PHARYNGEAL 2005). Equal doses of ultrafine carbon black particles
ASPIRATION or fine crystalline silica (SiO 2 ) did not cause either granu-
lomas or alveolar wall thickening. Instead, they caused
Ultrafine Particles
weaker pulmonary inflammation and damage (Shvedova
Exposure to ambient air pollution particles caused et al., 2005). Inhalation of multiwalled carbon nanotubes
increased cardiopulmonary morbidity and mortality, par- induced no lung changes, but marginal pulmonary and
ticularly with preexisting disease (Tao et al., 2003). systemic immunosuppression was observed (Mitchell
Exacerbation of pulmonary inflammation in susceptible et al., 2007).