Biomedical Engineering Reference
In-Depth Information
•
Gross necroscopy: Gross necroscopy can reveal valuable information about the specific
toxicity of NMs. Severe intestinal bleeding was observed after the intravenous adminis-
tration of G7 amine-terminated PAMAM dendrimers in CD-1 mice (Greish et al. 2012).
The histology of the lung and liver was performed to evaluate the toxicity of SWCNTs
(Oberdorster et al. 2005).
1.7.3.1 Absorption, Distribution, Metabolism, Excretion, and Pharmacokinetic Studies
Absorption, distribution, metabolism, excretion, and pharmacokinetic (ADME/PK) studies are vital
tools to evaluate the occupational health impact and potential hazards of NMs to human beings.
The pharmacokinetic and biodistribution behaviors of NMs is essential to understand, as it reflects
the in-depth concentration of NMs in each organ, which can be used as the basis of phase I clinical
studies in humans. Radiolabeling studies with gamma emitters, such as
125
I, is a popular method of
in vivo
NP quantification. A biodistribution profile of PAMAM dendrimers with differential surface
charges and sizes was evaluated via
125
I labeling in CD-1 mice (Greish et al. 2012).
99
Tc was used
in the scintigraphy imaging of nanoscale
N
-(hydroxypropyl) methacrylamide copolymers in mice
(Line et al. 2005). The limitation of this method is the stability of the nanoconstruct-radiolabel
conjugates, which needs to be evaluated before beginning the imaging study. The application of
ICP-MS can eliminate the aforementioned limitations and provide acute quantifications of NMs in
parts per million levels. The biodistribution profile of gold nanorods and spheres in tumor-bearing
mice was evaluated and analyzed by ICP-MS (Arnida et al. 2011).
1.7.3.2 Genotoxicity and Carcinogenic Studies
The mutagenic, teratogenic, and carcinogenic potential of NMs are being evaluated in these stud-
ies. Widely accepted
in vivo
genotoxicity tests are the metaphase chromosomal analysis and the
bone marrow micronucleus test. In 1975, Schmid developed the mouse bone marrow micronu-
cleus test as an alternative to cytogenic studies on mammalian bone marrow cells (Hayashi et al.
1983). The damage to the chromosome or mitotic apparatus (resulting in micronucleus forma-
tion), as a consequence of NMs exposure in animal bone marrow cells, is being detected by the
micronucleus test. Micronuclei (MNi) are formed because of acentric fragments of chromosomes
or due to chromosomal breakages or mitotic spindle apparatus damages (Sarto et al. 1987). FCM
has been used to differentiate bone marrow cells from abnormal, peripheral RBCs (Sarto et al.
1987). Teratogenic studies are not regularly required as part of toxicity studies. Such studies follow
the International Conference on Harmonization (ICH) of Technical Requirements for Registration
of Pharmaceuticals for Human Use guidelines (Baber 1994). ICH guidelines involve segments of
test procedure standardizations for fertility and reproductive performance, embryo-fetal develop-
ment, perinatal, and postnatal analyses on maternal and newborn cases.
In vivo
carcinogenic studies
involve long-term observation for the development of tumors following the administration of either
single- or repeated-dose NMs. It requires a large number of animals and usually extends up to 30
months.
Apart from the aforementioned studies, chronic and subchronic studies are essential to assess the
toxic effects of NMs, which are nonbiodegradable and consist of metal oxides, such as gold, carbon,
and silica particles. In such cases, acute and subacute observations are not sufficient to evaluate the
safety of NPs due to their long residence times in the body.
The major challenges, or the most discouraging aspects, of
in vivo
tests are its length, expense,
and ethical issues. Even though
in vivo
tests may counter most of the limitations faced by
in vitro
studies, there are still many challenges that impede their use for the assessment of nanotoxicity.
First, there is difficulty in determining the actual dosages of NMs in the environment to which ani-
mal and humans are exposed, owing to their small size and quantity. Sometimes, if the concentra-
tion of the known dose is high, it may lead to agglomeration. Vehicles are used for dose delivery in
order to avoid agglomeration. It is another challenge to ensure that the vehicle used for delivery does
