The Current Understanding of Autophagy in Nanomaterial Toxicity and Its Implementation in Safety Assessment-Related Alternative Testing Strategies

Abstract

Nanotechnology has rapidly promoted the development of a new generation of industrial and commercial products; however, it has also raised some concerns about human health and safety. To evaluate the toxicity of the great diversity of nanomaterials (NMs) in the traditional manner, a tremendous number of safety assessments and a very large number of animals would be required. For this reason, it is necessary to consider the use of alternative testing strategies or methods that reduce, refine, or replace (3Rs) the use of animals for assessing the toxicity of NMs. Autophagy is considered an early indicator of NM interactions with cells and has been recently recognized as an important form of cell death in nanoparticle-induced toxicity. Impairment of autophagy is related to the accelerated pathogenesis of diseases. By using mechanism-based high-throughput screening in vitro, we can predict the NMs that may lead to the generation of disease outcomes in vivo. Thus, a tiered testing strategy is suggested that includes a set of standardized assays in relevant human cell lines followed by critical validation studies carried out in animals or whole organism models such as C. elegans (Caenorhabditis elegans), zebrafish (Danio rerio), and Drosophila (Drosophila melanogaster)for improved screening of NM safety. A thorough understanding of the mechanisms by which NMs perturb biological systems, including autophagy induction, is critical for a more comprehensive elucidation of nanotoxicity. A more profound understanding of toxicity mechanisms will also facilitate the development of prevention and intervention policies against adverse outcomes induced by NMs. The development of a tiered testing strategy for NM hazard assessment not only promotes a more widespread adoption of non-rodent or 3R principles but also makes nanotoxicology testing more ethical, relevant, and cost- and time-efficient.

The Era of Nanomaterials: A Safe Solution or a Risk for Marine Environmental Pollution?

“…AgNPs ecotoxicity has been largely documented both in terrestrial and aquatic environments and on various taxa from bacteria to fish including mammalian cell lines [ 38 , 108 , 109 , 110 , 111 , 112 ]. The release of Ag + from dissolved NPs in exposure media has been recognized as a driver to explain the observed toxicity; however, a nanoparticle-based effect has been also reported [ 50 , 51 , 52 , 54 , 58 , 113 , 114 ]. Therefore, an ecosafety assessment of AgNPs for environmental applications is mandatory and can be achieved using bioassays as suitable tools to support their use in situ .…”

Glycan Nanobiosensors

“…Moreover, NPs can be accumulated in various organs for longer periods than traditional pharmaceutical agents generating oxidative stress, inflammation, cell death and agglomerates within vessels [ 31 ]. There is a need for the development of new assays consisting of several approaches [ 31 ] including assessment of toxicity of NPs by aquatic organisms [ 32 ], which will take into consideration factors such as size, shape, surface area, surface charge, porosity or hydrophobicity which influence the functions and toxicity of nanomaterials [ 33 , 34 ]. It has been established that NPs are able to activate an immune response and induce phagocytic cells that will eliminate them from the bloodstream or may induce immunostimulation which may promote inflammatory disorders or even immunosuppression which increases the host’s susceptibility to infections and cancer.…”

Surmounting the endothelial barrier for delivery of drugs and imaging tracers

“…To overcome this hurdle, the correct protocols should be developed to assess NP safety. This includes implementing the tiered testing strategy, which uses autophagy as a marker for NPinduced toxicity in a high-throughput in vitro screening assay, followed by validation in animals or whole organism models [83]. In addition, Afantitis and colleagues developed tools for in silico nanosafety assessments that predicts the toxicity of nanomedicine, emphasizing the benefits of adopting the 'safe-by-design' approach [84].…”