Rethinking Nanosafety Part II: Leveraging Progress to Pioneer New Approaches and Solutions

Part 2 of this Special Issue on rethinking nanosafety brings together another collection of papers from thought leaders in the field of nanosafety to inform, guide, and direct the current and future directions of nanosafety research for the betterment of human and environmental health, with a strong focus on regulatory aspects and risk governance as well as the role of alternative test methods including nanoinformatics, toxicogenomic approaches and advanced culture models. “Rethinking Nanosafety Part II” presents an additional 25 papers, contributed by authors from around the globe, addressing the role of the nanomaterials’ acquired corona, the opportunities presented by nanoinformatics and machine learning for rapid progress with reduced reliance on animal testing and faster, more reliable decision making, the generation of new insights from utilization of meta-analysis approaches integrating disparate data sets such that the sum exceeds the parts, and the role and approaches for risk governance of nanomaterials and nanotechnologies. With 5 Essays, 4 Concepts, 8 Reviews, 1 Communication and 7 Full Papers, readers are sure to find something of interest and inspiration for their future research in advancing our mechanistic understanding of the interactions of nanomaterials with living systems and the environment. The second part of the re-thinking nanosafety Special Issue starts with a reflection from Yuliang Zhao on the impact of nanosafety papers published over the last 15 years in this journal (Small) focusing on the key research trends identified and recommendations for some future research directions (10.1002/smll.202000980). Taking a more focused view, Youji Wang and colleagues have undertaken a meta-analysis of literature relating to the safety of Nano-TiO2 (10.1002/smll.202002019), which is extremely topical given the recent reclassification of the inhalable powder form of titanium dioxide as a category 2 suspected carcinogen under the EU's labelling and packaging (CLP) regulation.[1] Also related to European approaches to regulation of nanomaterials, and focusing on the ongoing issue faced by nanomaterials manufacturers of whether a product is nano or not, Hubert Rauscher and colleagues present two alternative approaches to answer this question - the JRC Flowchart which starts by identifying nanomaterials, and the NanoDefiner Framework which first identifies non-nanomaterials according to the European Commission's definition (10.1002/smll.202002228), which is based on the number fraction of particles <100 nm (2011/696/EU).[2] An excellent overview of the inherent difficulties in characterizing nanomaterials properties, the interaction of characterization with modelling and the framing of concerns regarding the reliability of research results in the context of research integrity is provided by Costas Charitidis and colleagues (10.1002/smll.202001590) who present a framework for responsible nanotechnology. Maria Dusinska and colleagues present their vision for governance of nanotechnologies and lay out the theoretical basis for the development, implementation, and operationalization of an effective, trustworthy and transparent risk governance framework and council for nanomaterials (10.1002/smll.202003303). A key aspect of all nanosafety research is compliance with ethical guidelines, both institutional, national, European and international; Ineke Malsch and co-authors present an approach to integrate guidelines for Ethical Impact Assessment (EIA) for nanomaterials and nanoenabled products into a modular decision support system for risk governance of nanomaterials (10.1002/smll.202002901). Given that uncertainty is well recognized as one of the major barriers to commercialization of nanoenabled products, a very timely Review of the knowns and unknowns in terms of the environmental safety of nanomaterials in commerce is presented by Rebecca Klaper (10.1002/smll.202000690) highlighting some of the remaining challenges and the new challenges introduced by multicomponent and complex nanomaterials. Dispersion and dosing of nanomaterials are critical aspects of all nanosafety studies, and indeed much research has been dedicated to these aspects. Daohui Lin and colleagues explore the impact of functionalization and oxidation of delaminated MXene Flakes in water, providing new insight into the environmental transformation and design of functional MXenes (10.1002/smll.202002433). Similarly, the transformations undergone by nanomaterials during and following dispersion in biological and environmental media determine their subsequent fate and behavior. Several papers in part 2 of this Special Issue explore further these transformations: Ruibin Li and colleagues provide a timely Review of the molecular mechanisms, characterization methods and utilities of nanoparticle biotransformation in nanosafety assessments (10.1002/smll.201907663) while Wolfgang Parak and colleagues present an 19F nuclear magnetic resonance (NMR) based methodology for measurement of the acquired protein corona in situ in biological media by measuring diffusion coefficients of the nanomaterials in the presence of proteins (10.1002/smll.202001160). The impact of nanomaterials transformations in the environment on their uptake, bioaccumulation and ultimate toxicity to environmental test species is reviewed by David Spurgeon and colleagues (10.1002/smll.202000618) while the role of environmental coronas in determining the biological effects of engineered nanomaterials and their mechanisms of toxicity is reviewed by Ming Xu and colleagues (10.1002/smll.202003691). The specific case study of the gut is highlighted in the Review of Kee Woei Ng and colleagues, who examine the implications of transformation of nanomaterials in the gut on the nanomaterials toxicity to the gut (10.1002/smll.202001246). A thought-provoking Essay from Peter Wick and colleagues suggests that understanding, reproducing, and modeling of nanomaterial biotransformation in biological environments is a central challenge, both in vitro and in silico, and that addressing these challenges will facilitate predictive nanotoxicology (10.1002/smll.201907650). The growing importance of modeling and in silico approaches is reflected in the timely Review by David Winkler, evaluating the role of artificial intelligence and machine learning in nanosafety, presenting the current state of the art, providing recommendations for future research foci and highlighting the need to allow these approaches to play a greater role in nanosafety in the future (10.1002/smll.202001883). Fred Klaessig reflects on the recent use of a computational model to support a recommended exposure limit for nanoparticulate silver, examining physiologically based toxicokinetics modeling in terms of data availability, model verification and validation, and regulatory acceptance (e.g., by the European Food Safety Authority) of the resulting models (10.1002/smll.201907667). Haralambos Sarimveis and colleagues present deep learning models applied to microscopic images of Daphnia magna that can automatically detect possible malformations, such as effects on the length of the tail, and the overall size, and uncommon lipid concentrations and lipid deposit shapes, due to direct or parental exposure to nanomaterials, classifying the extent of toxicity present (10.1002/smll.202001080) that can be used for predicting multigenerational effects. Important advances toward increasingly realistic exposure conditions include the development of nanoenabled sensors for detection of cell phenotypic changes induced by ultralow exposure to nanomaterials, where conventional methods show normal cellular activity as reported by Vincent Rotello and colleagues (10.1002/smll.202002084). An alternatives perspective for deducing the risks posed by nanomaterials to human health is presented by Shareen Doak and colleagues (10.1002/smll.202002002) who suggest that research needs to focus urgently on understanding the usefulness, applicability, cost–time efficiency, and predictability of these advanced models to facilitate their uptake into regulatory assessment. Hang Xiao and colleagues investigated the effects of foodborne TiO2 nanoparticles in mice, finding that stronger adverse effects were present in obese mice compared to non-obese mice, in terms of induction of gut microbiota dysbiosis, colonic inflammation as evidenced by increased abundance of pro-inflammatory immune cells and cytokines in the colonic mucosa, and proteome alterations (10.1002/smll.202001858) providing important information related to the aforementioned reclassification of TiO2 materials as potentially carcinogenic by inhalation. Application of two emerging methodologies (toxicogenomics expression profiles and precision cut lung slices) were used to identify a set of biomarkers for subsequent assessment of induction of lung inflammation and fibrosis by nanomaterials and establishment of an adverse outcome pathway in the paper presented by Sabina Halappanavar and colleagues (10.1002/smll.202000272). An important step toward demonstrating the mechanistic similarities between healthy/asthmatic models of 3D air–liquid interface cultures of donor-derived human bronchial epithelia cells, and mouse lung tissue, following exposure to copper oxide nanomaterials is presented by Harri Alenius and colleagues, who showed using transcriptomics analysis that, despite differences in taxonomy and cellular complexity between the systems, a core subset of matching genes cluster mouse and human samples strictly based on nanomaterial dose/exposure severity (10.1002/smll.202000527) supporting the use of non-animal methods for hazard assessment. In contrast, despite all the progress in development of alternative test systems, the complexity of the human body leads Mark Miller and Craig Poland to advocate the need for further controlled exposures of nanomaterials in human volunteers in order to establish no-effect limits, biological mechanisms, and provide vital data for the risk assessment of nanomaterials (10.1002/smll.202001516) in their Essay “Nanotoxicology: The Need for a Human Touch?” Finally, given the close interplay between nanosafety and applications of nanomaterials in medicine, two articles evaluate progress toward translation of nanomedicines from lab to clinic: Huan Meng and colleagues evaluate the role of safety considerations of nanomedicines as being a key step toward their translation into clinical use (10.1002/smll.202000673), while Ennio Tasciotti and colleagues present a set of biological parameters that can be used to assess cell stress related to nanoparticle exposure and the subsequent recovery of cell processes as a function of endosomal escape of the nanoparticles, which is a critical step for their effective use as nanomedicines (10.1002/smll.201907693). We would like to again take this opportunity to thank all the authors and contributors to Part 2 of this Special Issue, which truly captures the breath of nanosafety research and its pioneering and innovation-focused approach to understanding both the impact of nanomaterials on living systems and the impact of living systems on the nanomaterials, the dynamic and evolving interplay between the two, and their combined impact for risk assessment and risk governance. We are confident that the advances, insights and recommendations included herein will captivate and inspire the imagination of nanomaterials and nanosafety researchers across the globe. We also express our sincere thanks to the editorial team of Small, especially Dr. Ulf Scheffler and Dr. Amanda Mickley-Gass for their untiring support. This 2-part Special Issue would not have been possible without their extended support. Chunying Chen is a principal investigator at the Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety in the National Center for Nanoscience and Technology of China. She was one of the earliest researchers worldwide studying nanosafety, and has made key contributions toward a systematic understanding of the toxicology and safety of nanomaterials, and her pioneering contributions to understanding of the nano–bio interface and the fate of nanomaterials in biota have provided fundamental insights for rational design of precision nanomedicine. David T. Leong is an associate professor of chemical and biomolecular engineering at the National University of Singapore. His research aims to discover novel nano-biology and to use this knowledge to develop nanoparticle specific rules that drive certain cellular effects and enable design of better (safer) nanomaterials. He also investigates the nanotoxicology of common and uncommon nanomaterials using a variety of cell lines to represent the various major tissues/organs of the body from the mouth to the gut, from the lungs to the kidneys and blood vessels, in both 2D and 3D culture systems. Iseult Lynch is Chair of Environmental Nanosciences at the School of Geography, Earth and Environmental Sciences, University of Birmingham. She has been at the forefront of nanosafety research for close to 15 years, having pioneered the concept of the nanomaterials protein (biomolecule) corona and more recently, the environmental or eco-corona. Her research aims to understanding the interface between engineered nanomaterials and the environment (abiotic and biotic components) and how this determines the nanomaterials’ ultimate fate and behavior in organisms and the environment.