Silver nanoparticle (AgNP), neurotoxicity, and putative adverse outcome pathway (AOP): A review

Various silver nanoparticles (AgNPs) exist with different sizes, coatings, and shapes. AgNPs have unique physical and chemical properties, such as high surface-to-volume ratio and antimicrobial properties, which allow them to be used in a wide array of applications in consumer products and medical applications, including clothing, cosmetics, food packaging, medical devices, and wound dressings. They are also one of the most studied engineered nanomaterials (ENMs). Though the liver and lung have been identified as the primary targets of AgNP exposures, an increasing number of studies have reported accumulations of AgNPs in the brains of AgNP-exposed animals. These findings have raised concerns because the brain plays a critical function in our body and may have difficulty clearing AgNPs, unlike the liver and lung. Studies have been conducted to investigate potential neurotoxicity effects of AgNP exposures, but they use various types of AgNPs and routes of administration, which makes it difficult to compare across studies. Therefore, the goal of this review was to (1) assess factors that may affect AgNP-induced neurotoxicity, (2) identify potential mechanisms of neurotoxicity exerted by AgNPs, (3) review existing in vitro dose-response and in vivo exposure-response AgNP-induced neurotoxicity studies, and (4) provide an example application of benchmark doses (BMDs) in comparing across different studies. A combination of aggregate exposure pathway (AEP) and adverse outcome pathway (AOP) framework was utilized to link AgNP exposure sources and routes to molecular initiating events (MIEs) and then to adverse neurotoxicity outcomes at the cellular, organ, organism, and population levels. This review is the first to propose an AEP/AOP specific to AgNP-induced neurotoxicity, which may contribute toward identifying plausible key event relationships between MIEs and adverse neurotoxicity outcomes and improving the current risk assessment of AgNPs.