## 8 Conclusions and Future Directions  
The pervasive presence of plastic particles, particularly NPs, across all environmental matrices, including food, has sparked significant apprehension regarding human health. Their ubiquitous distribution and ability to permeate organisms and humans through various exposure pathways have heightened these concerns. Moreover, the unpredictable accumulation of NPs within organisms adds another layer of complexity. Compounding the issue is the challenge of accurately quantifying NPs in complex matrices, especially in biological samples rich in organic matter. Addressing this necessitates the development of improved collection and detection methods alongside the advancement of highly sensitive instrumentation for direct analysis of NPs in environmental matrices, human tissues, or biological models. While there have been advancements in extracting and quantifying NPs from certain biological samples [160], there remains substantial room for technological progress. For these advances, more precise detection of NP levels will follow, providing an improvement to human risk assessment. While we acknowledge the newly implemented regulations aimed at curtailing plastic production and waste, it is important to recognize that these measures do not offer a definitive solution to the widespread presence of plastic materials to which organisms are already exposed. At present, no barrier systems are available to definitively block or reduce plastic's entry into organisms. Regarding human health, and particularly neurotoxicity and neurodegenerative implications, great attention should be paid to this central issue, as demonstrated by the literature [161]. Experimental data from in silico, in vitro, and in vivo models (see Section 6)  
Figure 2: Neurorotoxicity and neurodegenerative effects of NPs at molecular level: Interaction of NPs with superoxide dismutase (SOD) and catalase affect the structure and function of these enzymes, leading to a high increase in reactive oxygen species (ROS); the NOTCH pathway, involved in regulating the proteolytic processes of amyloid precursors, is downregulated (red arrow) by NPs; _Nrf2_ gene activity is downregulated (red arrow), and the protein coded by this gene is a transcriptional factor that regulates antioxidant defense mechanisms and has key roles in neurodegenerative diseases; miR-21 and miR-155, related to neurodegeneration, are upregulated (green arrow); NPs’ interactions with protein folding can trigger the aggregation of amyloid proteins (\(\beta\)-amyloid). have evidenced the ability of NPs to accumulate in the brain by destroying the BBB's molecular structure and permeability. Very interestingly, PS particles of bigger dimensions (293 nm) have been found in brain tissues of experimental animals, suggesting the relevance of in-depth studies in this area of concern. Considering the various pathways through which particulate matter carrying NPs can access the brain, including the olfactory and trigeminal nerves, the vagal nerve, and the bloodstream, it is conceivable and expected that plastic particles can also breach the BBB directly through these routes. Similarly, the routes established for different environmental contaminants present in particulate matter can be extrapolated to NPs. Therefore, future research should prioritize understanding the precise mechanisms underlying the accumulation of plastic particles in the brain and their interactions with various metallo-enzymes involved in other pathogenic processes, as well as all potential epigenetic mechanisms. This research is pivotal for advancing our understanding of the neurotoxic and neurodegenerative effects of NPs themselves. Furthermore, the access of particulate matter to the brain, characterized by multiple organic and inorganic chemicals, and the environmental interaction of NPs with different pollutants and metals, pose another critical issue to be explored: the co-presence and co-transport of multiple chemicals with NPs and the subsequent interplay at the biological level.