Twenty years of in vitro nanotoxicology: how AI could make the difference.

More than two decades ago, the advent of Nanotechnology has marked the onset of a new and critical field in science and technology, highlighting the importance of multidisciplinary approaches to assess and model the potential human hazard of newly developed advanced materials in the nanoscale, the nanomaterials (NMs). Nanotechnology is, by definition, a multidisciplinary field, that integrates knowledge and techniques from physics, chemistry, biology, materials science, and engineering to manipulate matter at the nanoscale, defined as anything comprised between 1 and 100 nm. The emergence of nanotechnology has undoubtedly led to significant innovations in many fields, from medical diagnostics and targeted drug delivery systems to advanced materials and energy solutions. However, the unique properties of nanomaterials, such as the increased surface to volume ratio, which provides increased reactivity and hence the ability to penetrate biological barriers, have been also considered as potential risk factors for unforeseen toxicological effects, stimulating the scientific community to investigate to which extent this new field of applications could pose a risk to human health and the environment.

Trophic Transfer of Metal Oxide Nanoparticles in the Tomato-Helicoverpa armigera Food Chain: Effects on Phyllosphere Microbiota, Insect Oxidative Stress, and Gut Microbiome.

Understanding the trophic transfer and ecological cascade effects of nanofertilizers and nanopesticides in terrestrial food chains is crucial for assessing their nanotoxicity and environmental risks. Herein, the trophic transfer of La2O3 (nLa2O3) and CuO (nCuO) nanoparticles from tomato leaves to Helicoverpa armigera (Lepidoptera: Noctuidae) caterpillars and their subsequent effects on caterpillar growth and intestinal health were investigated. We found that 50 mg/L foliar nLa2O3 and nCuO were transferred from tomato leaves to H. armigera, with particulate trophic transfer factors of 1.47 and 0.99, respectively. While nCuO exposure reduced larval weight gain more (34.7%) than nLa2O3 (11.3%), owing to higher oxidative stress (e.g., MDA and H2O2) and more serious intestinal pathological damage (i.e., crumpled columnar cell and disintegrated goblet cell) by nCuO. Moreover, nCuO exposure led to a more compact antagonism between the phyllosphere and gut microbiomes compared to nLa2O3. Specifically, nCuO exposure resulted in a greater increase in pathogenic bacteria (e.g., Mycobacterium, Bacillus, and Ralstonia) and a more significant decrease in probiotics (e.g., Streptomyces and Arthrobacter) than nLa2O3, ultimately destroying larval intestinal immunity. Altogether, our findings systematically revealed the cascade effect of metal oxide nanomaterials on higher trophic consumers through alteration in the phyllosphere and insect gut microbiome interaction, thus providing insights into nanotoxicity and environmental risk assessment of nanomaterials applied in agroecosystems.

Surface Heterogeneity at the Polymer-Food Interface Influences Ag Migration from Plastic Packaging Incorporating Ag-Exchanged Zeolites.

Silver-enabled polymers, with their antimicrobial properties, could prolong the shelf life and maintain quality in packaged foods. However, there is limited understanding about how the Ag form in the polymer, food chemistry, and other factors affect the transfer (migration) of Ag from the polymer to the food under the intended conditions of use. In this study, we investigated the release of Ag from polymer composites (PCs) incorporating two different Ag-exchanged zeolites (Ag-Y), which have been explored as potential scaffolds for loading high concentrations of Ag within common polymers. We manufactured two Ag-Y films based on low-density polyethylene (LDPE): one incorporating ionic Ag (Ag+) and one incorporating nanoparticulate Ag (AgNPs), each with similar initial Ag concentrations. Then, we assessed the migration of Ag out of these PCs into food simulants under accelerated room temperature storage conditions. In all simulants investigated, the Ag+-Y/LDPE film exhibited a higher migration of Ag compared to the AgNP-Y/LDPE film, suggesting a lower fraction of readily releasable Ag in the latter material. Total Ag migration from AgNP-Y/LDPE over 10 days at 40 °C was 11.10 ± 2.05 ng cm-2 of packaging surface area in water, 7.63 ± 1.59 ng cm-2 in a 9 wt % aqueous sucrose solution, and 21.29 ± 1.98 ng cm-2 in a commercial sweetened carbonated beverage (Squirt). In contrast, Ag migration from Ag+-Y/LDPE was measured at 49.61 ± 3.46, 57.48 ± 9.65, and 91.54 ± 5.58 ng cm-2 in water, sucrose solution, and Squirt drink, respectively. Surface characterization techniques, including atomic force microscopy (AFM), scanning electron microscopy (SEM), and conductivity measurements, revealed the presence of exposed zeolite particles at the surface of the films, suggesting that direct interactions between Ag-exchanged zeolites and food components at the simulant-polymer interface play an important role in determining Ag migration from Ag-Y/LDPE PCs.

Application of Engineered Nanomaterials as Nanocatalysts in Catalytic Ozonation: A Review.

Given the growing scarcity of water and the continuous increase in emerging pollutants detected in water bodies, there is an imperative need to develop new, more effective, and sustainable treatments for wastewater. Advanced oxidation processes (AOPs) are considered a competitive technology for water treatment. Specifically, ozonation has received notable attention as a promising approach for degrading organic pollutants in wastewater. However, different groups of pollutants are hardly degradable via single ozonation. With continuous development, it has been shown that using engineered nanomaterials as nanocatalysts in catalytic ozonation can increase efficiency by turning this process into a low-selective AOP for pollutant degradation. Nanocatalysts promote ozone decomposition and form active free radicals responsible for increasing the degradation and mineralization of pollutants. This work reviews the performances of different nanomaterials as homogeneous and heterogeneous nanocatalysts in catalytic ozonation. This review focuses on applying metal- and carbon-based engineered nanomaterials as nanocatalysts in catalytic ozonation and on identifying the main future directions for using this type of AOP toward wastewater treatment.

Probabilistic material flow analysis of released nano titanium dioxide in Mexico.

Engineered Nanomaterials (ENMs) or products containing ENMs, known as nano-enabled products are commercialized globally by a large number of companies. Concern about the potential risks and negative impacts of releasing ENMs into the environment is under investigation. For this reason, methodologies to estimate the probable mass concentrations of ENMs released in different regions of the world have been developed. As a first attempt to estimate the probable mass flows of nanosized titanium dioxide (nano-TiO2) released in Mexico, we developed a Probabilistic Material Flow Analysis (PMFA) for 2015. The model describes probabilistic mass flows of released nano-TiO2 during the life cycle of sunscreens, coatings, ceramic, and other nano-enabled products, including the flows through the solid waste and wastewater management systems, as well as the transfer of nano-TiO2 to three environmental compartments (atmosphere, topsoil, and surface water). The PMFA incorporates the uncertainty related to the input data. We observed that the most significant nano-TiO2 flows occur to the surface water, landfill, and soil compartments, targeted as the main "hot-spots", where living organisms could be more exposed to this material. Further improvements in the model are needed due to some data gaps at some life cycle stages, for instance, solid waste management and reused wastewater manipulation for irrigation purposes. Finally, the model developed in this study can be adjusted to assess other ENM releases and can be beneficial for further investigation in fate modeling and environmental risk assessment.

A Network Toxicology Approach for Mechanistic Modelling of Nanomaterial Hazard and Adverse Outcomes.

Hazard assessment is the first step in evaluating the potential adverse effects of chemicals. Traditionally, toxicological assessment has focused on the exposure, overlooking the impact of the exposed system on the observed toxicity. However, systems toxicology emphasizes how system properties significantly contribute to the observed response. Hence, systems theory states that interactions store more information than individual elements, leading to the adoption of network based models to represent complex systems in many fields of life sciences. Here, they develop a network-based approach to characterize toxicological responses in the context of a biological system, inferring biological system specific networks. They directly link molecular alterations to the adverse outcome pathway (AOP) framework, establishing direct connections between omics data and toxicologically relevant phenotypic events. They apply this framework to a dataset including 31 engineered nanomaterials with different physicochemical properties in two different in vitro and one in vivo models and demonstrate how the biological system is the driving force of the observed response. This work highlights the potential of network-based methods to significantly improve their understanding of toxicological mechanisms from a systems biology perspective and provides relevant considerations and future data-driven approaches for the hazard assessment of nanomaterials and other advanced materials.

Environmental applications and risks of engineered nanomaterials in removing petroleum oil in soil.

Oil-contaminated soil posed serious threats to the ecosystems and human health. The unique and tunable properties of engineered nanomaterials (ENMs) enable new technologies for removing and repairing oil-contaminated soil. However, few studies systematically examined the linkage between the change of physicochemical properties and the removal efficiency and environmental functions (e.g., potential risk) of ENMs, which is vital for understanding the ENMs environmental sustainability and utilization as a safety product. Thus, this review briefly summarized the environmental applications of ENMs to removing petroleum oil from complex soil systems: Theoretical and practical fundamentals (e.g., excellent physicochemical properties, environmental stability, controlled release, and recycling technologies), and various ENMs (e.g., iron-based, carbon-based, and metal oxides nanomaterials) remediation case studies. Afterward, this review highlights the removing mechanism (e.g., adsorption, photocatalysis, oxidation/reduction, biodegradation) and the impact factor (e.g., nanomaterials species, natural organic matter, and soil matrix) of ENMs during the remediation process in soil ecosystems. Both positive and negative effects of ENMs on terrestrial organisms have been identified, which are mainly derived from their diverse physicochemical properties. In linking nanotechnology applications for repairing oil-contaminated soil back to the physical and chemical properties of ENMs, this critical review aims to raise the research attention on using ENMs as a fundamental guide or even tool to advance soil treatment technologies.

A scoping review to evaluate occupational controls and their effectiveness when handling engineered nanomaterials in workplaces.

Research has shown that controlling worker exposure to engineered nanomaterials (ENMs) helps to reduce the exposure risk to employees in workplaces. This study aimed to identify the available evidence on the effectiveness of various control methods used in the workplace to reduce worker exposure to ENMs. The search was conducted in databases-Medline, OVID, Scopus, Science Direct, Web of Science, and Cochrane and the gray literature published from January 2010 to December 2022. The search keywords included ENM controls and their efficiency in workplace environments. Of the 152 studies retrieved, 22 were included in the review. The control measures in the review included (1) substitution controls; (2) engineering measures (i.e., isolation, direct source extraction, and wetting technologies); (3) personal protective equipment; and (4) administrative and work practices. The study results indicate that the above-mentioned control measures were effective in reducing ENM exposures. This information can be used to help employers choose the most effective controls for their workplaces.

From papers to RDF-based integration of physicochemical data and adverse outcome pathways for nanomaterials.

Adverse Outcome Pathways (AOPs) have been proposed to facilitate mechanistic understanding of interactions of chemicals/materials with biological systems. Each AOP starts with a molecular initiating event (MIE) and possibly ends with adverse outcome(s) (AOs) via a series of key events (KEs). So far, the interaction of engineered nanomaterials (ENMs) with biomolecules, biomembranes, cells, and biological structures, in general, is not yet fully elucidated. There is also a huge lack of information on which AOPs are ENMs-relevant or -specific, despite numerous published data on toxicological endpoints they trigger, such as oxidative stress and inflammation. We propose to integrate related data and knowledge recently collected. Our approach combines the annotation of nanomaterials and their MIEs with ontology annotation to demonstrate how we can then query AOPs and biological pathway information for these materials. We conclude that a FAIR (Findable, Accessible, Interoperable, Reusable) representation of the ENM-MIE knowledge simplifies integration with other knowledge. SCIENTIFIC CONTRIBUTION: This study introduces a new database linking nanomaterial stressors to the first known MIE or KE. Second, it presents a reproducible workflow to analyze and summarize this knowledge. Third, this work extends the use of semantic web technologies to the field of nanoinformatics and nanosafety.

The addition of mammalian cell culture medium impacts nanoparticle toxicity in zebrafish.

Engineered nanomaterials (ENMs) are ubiquitous in contemporary applications, yet their environmental and human health impacts remain inadequately understood. This study addresses the challenge of identifying potential risks associated with ENM exposure by highlighting the significant variability in existing research methodologies. Without a systematic collection of toxicological data that encompasses standardized materials, relevant platforms, and assays, the task of identifying potential risks linked to ENM exposure becomes an intricate challenge. In vitro assessments often use media rich in ionic species, such as RPMI and fetal bovine serum (FBS). Zebrafish embryos, known to develop normally in low-ionic environments, were exposed to Cerium Oxide, Zinc Oxide, and Graphene Oxides in different media at varying concentrations. Here, we discovered that zebrafish embryos tolerated a mix of 80 % RPMI, 2 % FBS, and 1 % antibiotic cocktail. The results revealed that adverse effects observed in zebrafish with certain nanomaterials in Ultra-Pure (UP) water were mitigated in cell culture medium, emphasizing the importance of revisiting previously considered non-toxic materials in vitro. The zebrafish results underscore the importance of utilizing a multidimensional in vivo platform to gauge the biological activity of nanomaterials accurately.

Critical Review: Uptake and Translocation of Organic Nanodelivery Vehicles in Plants.

Nanodelivery vehicles (NDVs) are engineered nanomaterials (ENMs) that, within the agricultural sector, have been investigated for their ability to improve uptake and translocation of agrochemicals, control release, or target specific tissues or subcellular compartments. Both inorganic and organic NDVs have been studied for agrochemical delivery in the literature, but research on the latter has been slower to develop than the literature on the former. Since the two classes of nanomaterials exhibit significant differences in surface chemistry, physical deformability, and even colloidal stability, trends that apply to inorganic NDVs may not hold for organic NDVs, and vice versa. We here review the current literature on the uptake, translocation, biotransformation, and cellular and subcellular internalization of organic NDVs in plants following foliar or root administration. A background on nanomaterials and plant physiology is provided as a leveling ground for researchers in the field. Trends in uptake and translocation are examined as a function of NDV properties and compared to those reported for inorganic nanomaterials. Methods for assessing fate and transport of organic NDVs in plants (a major bottleneck in the field) are discussed. We end by identifying knowledge gaps in the literature that must be understood in order to rationally design organic NDVs for precision agrochemical nanodelivery.

Co-exposure of butyl benzyl phthalate and TiO2 nanomaterials (anatase) in Metaphire guillelmi: Gut health implications by transcriptomics.

During the COVID-19 pandemic, an abundance of plastic face masks has been consumed and disposed of in the environment. In addition, substantial amounts of plastic mulch film have been used in intensive agriculture with low recovery. Butyl benzyl phthalate (BBP) and TiO2 nanomaterials (nTiO2) are widely applied in plastic products, leading to the inevitable release of BBP and nTiO2 into the soil system. However, the impact of co-exposure of BBP and nTiO2 at low concentrations on earthworms remains understudied. In the present study, transcriptomics was applied to reveal the effects of individual BBP and nTiO2 exposures at a concentration of 1 mg kg-1, along with the combined exposure of BBP and nTiO2 (1 mg kg-1 BBP + 1 mg kg-1 nTiO2 (anatase)) on Metaphire guillelmi. The result showed that BBP and nTiO2 exposures have the potential to induce neurodegeneration through glutamate accumulation, tau protein, and oxidative stress in the endoplasmic reticulum and mitochondria, as well as metabolism dysfunction. The present study contributes to our understanding of the toxic mechanisms of emerging contaminants at environmentally relevant levels and prompts consideration of the management of BBP and nTiO2 within the soil ecosystems.

Unveiling combined ecotoxicity: Interactions and impacts of engineered nanoparticles and PPCPs.

Emerging contaminants such as engineered nanoparticles (ENPs), pharmaceuticals and personal care products (PPCPs) are of great concern because of their wide distribution and incomplete removal in conventional wastewater and soil treatment processes. The production and usage of ENPs and PPCPs inevitably result in their coexistence in different environmental media, thus posing various risks to organisms in aquatic and terrestrial ecosystems. However, the existing literature on the physicochemical interactions between ENPs and PPCPs and their effects on organisms is rather limited. Therefore, this paper summarized the ecotoxicity of combined ENPs and PPCPs by discussing: (1) the interactions between ENPs and PPCPs, including processes such as aggregation, adsorption, transformation, and desorption, considering the influence of environmental factors like pH, ionic strength, dissolved organic matter, and temperature; (2) the effects of these interactions on bioaccumulation, bioavailability and biotoxicity in organisms at different trophic levels; (3) the impacted of ENPs and PPCPs on cellular-level biological process. This review elucidated the potential ecological hazards associated with the interaction of ENPs and PPCPs, and serves as a foundation for future investigations into the ecotoxicity and mode of action of ENPs, PPCPs, and their co-occurring metabolites.

Computational Nanotoxicology Models for Environmental Risk Assessment of Engineered Nanomaterials.

Although engineered nanomaterials (ENMs) have tremendous potential to generate technological benefits in numerous sectors, uncertainty on the risks of ENMs for human health and the environment may impede the advancement of novel materials. Traditionally, the risks of ENMs can be evaluated by experimental methods such as environmental field monitoring and animal-based toxicity testing. However, it is time-consuming, expensive, and impractical to evaluate the risk of the increasingly large number of ENMs with the experimental methods. On the contrary, with the advancement of artificial intelligence and machine learning, in silico methods have recently received more attention in the risk assessment of ENMs. This review discusses the key progress of computational nanotoxicology models for assessing the risks of ENMs, including material flow analysis models, multimedia environmental models, physiologically based toxicokinetics models, quantitative nanostructure-activity relationships, and meta-analysis. Several challenges are identified and a perspective is provided regarding how the challenges can be addressed.

Chitosan-Se Engineered Nanomaterial Mitigates Salt Stress in Plants by Scavenging Reactive Oxygen Species.

Soil salinity seriously hinders the sustainable development of green agriculture. The emergence of engineered nanomaterials has revolutionized agricultural research, providing a new means to overcome the limitations associated with current abiotic stress management and achieve highly productive agriculture. Herein, we synthesized a brand-new engineered nanomaterial (Cs-Se NMs) through the Schiff base reaction of oxidized chitosan with selenocystamine hydrochloride to alleviate salt stress in plants. After the addition of 300 mg/L Cs-Se NMs, the activity of superoxide dismutase, catalase, and peroxidase in rice shoots increased to 3.19, 1.79, and 1.85 times those observed in the NaCl group, respectively. Meanwhile, the MDA levels decreased by 63.9%. Notably, Cs-Se NMs also raised the transcription of genes correlated with the oxidative stress response and MAPK signaling in the transcriptomic analysis. In addition, Cs-Se NMs augmented the abundance and variety of rhizobacteria and remodeled the microbial community structure. These results provide insights into applying engineered nanomaterials in sustainable agriculture.

Toxicity mechanism of engineered nanomaterials: Focus on mitochondria.

With the rapid development of nanotechnology, engineered nanomaterials (ENMs) are widely used in various fields. This has exacerbated the environmental pollution and human exposure of ENMs. The study of toxicity of ENMs and its mechanism has become a hot research topic in recent years. Mitochondrial damage plays an important role in the toxicity of ENMs. This paper reviews the structural damage, dysfunction, and molecular level perturbations caused by different ENMs to mitochondria, including ZnO NPs, Ag NPs, TiO2 NPs, iron oxide NPs, cadmium-based quantum dots, CuO NPs, silica NPs, carbon-based nanomaterials. Among them, mitochondrial quality control plays an important role in mitochondrial damage. We further summarize the cellular level outcomes caused by mitochondrial damage, mainly including, apoptosis, ferroptosis, pyroptosis and inflammation response. In addition, we concluded that reducing mitochondrial damage at source as well as accelerating recovery from mitochondrial damage through ENMs modification and pharmacological intervention are two feasible strategies. This review further provides new insights into the mitochondrial toxicity mechanisms of ENMs and provides a new foothold for predicting human health and environmental risks of ENMs.

A Comprehensive Ecotoxicity Study of Molybdenum Disulfide Nanosheets versus Bulk form in Soil Organisms.

The increasing use of molybdenum disulfide (MoS2) nanoparticles (NPs) raises concerns regarding their accumulation in soil ecosystems, with limited studies on their impact on soil organisms. Study aim: To unravel the effects of MoS2 nanosheets (two-dimensional (2D) MoS2 NPs) and bulk MoS2 (156, 313, 625, 1250, 2500 mg/kg) on Enchytraeus crypticus and Folsomia candida. The organisms' survival and avoidance behavior remained unaffected by both forms, while reproduction and DNA integrity were impacted. For E. crypticus, the individual endpoint reproduction was more sensitive, increasing at lower concentrations of bulk MoS2 and decreasing at higher ones and at 625 mg/kg of 2D MoS2 NPs. For F. candida, the molecular endpoint DNA integrity was more impacted: 2500 mg/kg of bulk MoS2 induced DNA damage after 2 days, with all concentrations inducing damage by day 7. 2D MoS2 NPs induced DNA damage at 156 and 2500 mg/kg after 2 days, and at 1250 and 2500 mg/kg after 7 days. Despite affecting the same endpoints, bulk MoS2 induced more effects than 2D MoS2 NPs. Indeed, 2D MoS2 NPs only inhibited E. crypticus reproduction at 625 mg/kg and induced fewer (F. candida) or no effects (E. crypticus) on DNA integrity. This study highlights the different responses of terrestrial organisms to 2D MoS2 NPs versus bulk MoS2, reinforcing the importance of risk assessment when considering both forms.

Immunotoxicity of engineered nanomaterials and their role in asthma.

The toxicity of engineered nanomaterials (ENMs) in vivo and in vitro has formed the basis of most studies. However, the toxicity of ENMs, particularly on the immune system, i.e. immunotoxicity, and their role in manipulating it, are less known. This review addresses the initiation or exacerbation as well as the attenuation of allergic asthma by a variety of ENMs and how they may be used in drug delivery to enhance the treatment of asthma. This review also highlights a few research gaps in the study of the immunotoxicity of ENMs, for example, the potential drawbacks of assays used in immunotoxicity assays; the potential role of hormesis during dosing of ENMs; and the variables that result in discrepancies among different studies, such as the physicochemical properties of ENMs, differences in asthmatic animal models, and different routes of administration.

A systematic review of the risk management frameworks for potentially toxic chemical elements.

In the last 50 years, various frameworks have been used to control and manage potentially toxic chemical risks; however, these chemicals continue to negatively impact environmental and human health. This work was intended to provide a systematic review of the literature on essential aspects of current risk management frameworks for potentially toxic chemicals. The frameworks were reviewed using Organisation for Economic Co-operation and Development (OECD) principles that focus on elements, successes, shortcomings, similarities, and dissimilarities premised on the experiences of many countries. Keywords such as heavy metals, health risk, industrial chemicals, potentially toxic elements, chemical pollutants, and risk management framework were utilised to search the literature from databases and other sources. Ten risk framework documents selected from an initial yield of 1349 using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow processes met the inclusion criteria. The key elements of risk frameworks that were identified included the risk assessment paradigm, iteration, tiered approach, weight of evidence, uncertainty analysis, and multi-criteria decision analysis among others. Notable gaps in risk frameworks that required improvements to effectively manage health risks posed by potentially toxic chemicals were identified. While existing risk frameworks have made significant contributions to human health and environmental protection, new and comprehensive frameworks are needed to address the novel and dynamic risks posed by toxic industrial chemicals. Also, there is a need to promote the use of risk management frameworks in developing countries through technology transfer and the provision of financial assistance to improve environmental and public health protection from toxic chemicals.

Nanotechnologies for environmental remediation and their ecotoxicological impacts.

Environmental nanoremediation is an emerging technology that aims to rapidly and efficiently remove contaminants from the polluted sites using engineered nanomaterials (ENMs). Inorganic nanoparticles which are generally metallic, silica-based, carbon-based, or polymeric in nature serve to remediate through chemical reactions, filtration, or adsorption. Their greater surface area per unit mass and high reactivity enable them to treat groundwater, wastewater, oilfields, and toxic industrial contaminants. Despite the growing interest in nanotechnological solutions for bioremediation, the environmental and human hazard associated with their use is raising concerns globally. Nanoremediation techniques when compared to conventional remediation solutions show increased effectivity in terms of cost and time; however, the main challenge is the ability of ENMs to remove contaminants from different environmental mediums by safeguarding the ecosystem. ENMs improving the accretion of the pollutant and increasing their bioavailability should be rectified along with the vigilant management of their transfer to the upper levels of the food chain which subsequently causes biomagnification. The ecosystem-centered approach will help monitor the ecotoxicological impacts of nanoremediation considering the safety, sustainability, and proper disposal of ENMs. The environment and human health risk assessment of each novel engineered nanomaterial along with the regulation of life cycle assessment (LCA) tools of ENMs for nanoremediation can help investigate the possible environmental hazard. This review focuses on the currently available nanotechnological methods used for environmental remediation and their potential toxicological impacts on the ecosystem.