Page 222 - Environmental Nanotechnology Applications and Impacts of Nanomaterials

Principles and Procedures to Assess Nanomaterial Toxicity 207

TABLE 6.1 NM Effects as the Basis for Pathophysiology and Toxicity
Experimental NM Effects Possible Pathophysiological Outcomes

ROS generation* Protein, DNA & membrane injury,* oxidative stress †
†
Oxidative stress* Phase II enzyme induction, inflammation ,
mitochondrial perturbation*
Mitochondrial perturbation* Inner membrane damage,* PTP opening,* energy
failure,* apoptosis,* apo-necrosis, cytotoxicity
†
Inflammation* Tissue infiltration with inflammatory cells ,
†
†
†
fibrosis , granulomas , atherogenesis , acute
phase protein expression (e.g., C-reactive protein)
Uptake by reticulo-endothelial Asymptomatic sequestration and storage in liver,*
†
system* spleen, lymph nodes , possible organ enlargement
and dysfunction
Protein denaturation, Loss of enzyme activity,* auto-antigenicity
degradation*
Nuclear uptake* DNA damage, nucleoprotein clumping,* autoantigens
Uptake in neuronal tissue* Brain and peripheral nervous system injury
†
†
†
Perturbation of phagocytic Chronic inflammation , fibrosis , granulomas ,
function,* “particle overload,” interference in clearance of infectious agents †
mediator release*
Endothelial dysfunction, effects Atherogenesis,* thrombosis,* stroke, myocardial
on blood clotting* infarction
Generation of neo-antigens, Autoimmunity, adjuvant effects
breakdown in immune
tolerance
Altered cell cycle regulation Proliferation, cell cycle arrest, senescence
DNA damage Mutagenesis, metaplasia, carcinogenesis
Adapted from [11].
*Limited experimental evidence
†
Limited clinical evidence
inflammation, apoptosis, necrosis, fibrosis, hypertrophy, metaplasia,
and carcinogenesis (Table 6.1). Although oxidative stress feeds into most
of these outcomes, it is important to mention that it is by no means the
only injury mechanism that will cause such pathological outcomes.
Other forms of injury include the disruption of biological membranes,
protein denaturation, DNA damage, immune reactivity, and the for-
mation of foreign body granulomas. In fact, one of the first biological
interactions that take place when a nanoparticle penetrates or enters
a tissue is contact with the surface membrane of the target cell. This
interaction can lead to membrane damage based on particle properties
such as hydrophobicity, cationic charge, or detergent activity that allow
the particle contact, penetration, or disruption of membrane integrity.
The cell may respond by leakage of intracellular content, intracellular
2+
Ca release, and the induction of apoptosis. To mention but one exam-
ple, some cationic dendrimers are capable of disrupting cell membranes
by being able to pull off lipid molecules, leading to the formation of