GUEST EDITORIAL Perspective on Current Alternatives in Nanotoxicology Research Todd A. Stueckle, PhD, and Jenny R. Roberts, PhD T he evolution of nanotechnology proceeds at an unprecedented rate due to major investments in research and development from public and private sectors. Incorpora- tion of engineered nanomaterials (ENMs) into novel or re- placement technologies has impacted a diverse number of industrial, commercial, consumer, and health-care services and products. Use of ENMs in many industries has, however, raised concerns with all routes of exposure (dermal, oral, in- halation, and parenteral) in occupational, consumer, and en- vironmental settings. Given the sheer number, diversity, and wide use of ENMs, toxicology studies are unable to keep pace. Risk-assessment frameworks specific to nanomaterials that incorporate alternative testing have been proposed. However, most of the past and current models depend heav- ily on mammalian animal model testing. 1,2 These time- and resource-intensive studies, although informative, are clearly unable to assess the avalanche of ENM-enabled technologies and the wide range of exposures that may result. This fact, coupled with general societal pressure to reduce animal use, has resulted in calls for tiered and integrative testing strategies using high-throughput in silico, in vitro, and other alternative models to screen and assess ENMs along their chemical life cycle. 3–6 Major goals of the OECD, 7 ENPRA, 8 Nano GO, 9 and NNI NEHI 10 working groups for nanotoxicology testing are the development and use of predictive models. Research has shown that the inherent small size, large surface area, and other unique physical and chemical properties of ENMs result in adsorption, distribution, metabolism, and excretion (ADME) and biological responses not observed in their larger counterpart materials. Toxicity responses following exposure can occur earlier (or on longer time frames), at lower doses, and in other organs far removed from the original site of ex- posure that are not observed with their larger counterparts. Interactions with biomolecules and organism environment can drastically change an ENM’s physical (size, shape) and chemical (solubility) properties, resulting in differences in par- ticle fate, ADME, and potential biological response, including novel effects on immune, cardiovascular, development (e.g., stem cell), reproductive, and neurological systems. 11–16 These difficulties represent a major challenge for 21st- century toxicology and safe-by-design material development. Critical considerations for toxicological assessments include robust material characterization, transformations along an ENM’s life cycle, understanding of potential particle transfor- mations in different biological mediums (e.g., biocorona, sol- ubilization, etc.), modeling and use of appropriate deposited dose and dose metrics, 17 appropriate in vitro model for both exposure and response that aligns with in vivo adverse out- come, and increased development and use of standardized as- says for read-across purposes. 6–8 Current advances in machine learning, in silico, in vitro, and tissue model techniques have placed predictive modeling of the in vivo response with an integrative alternative tiered toxicity testing strategy a potential attainable long-term goal for nanotechnology risk assessment. 13,18 Acellular assays, in vitro assays, and advances in ‘‘omics’’ coupled with com- putational modeling may provide a suite of biomarkers for high-throughput screening assays predictive of in vivo toxic- ity. 19 Further model and method development in complex cell and tissue culture systems, including air–liquid interface culture, 20 cellular co- and tri-cultures, biocorona and ADME systemic toxicology, organ-on-a-chip, and other alternative animal models, 21 has placed in vitro screening techniques at the forefront of nanotoxicology testing for responsible nanotechnology development. This special issue highlights three research papers that tackle several of these issues utiliz- ing alternative approaches. Nanomaterials encounter a milieu of proteins and lipids upon in vivo exposure, resulting in a unique surface biocor- ona that can change the surface properties of the material and influence its fate and biological reactivity. 22 Numerous studies have investigated this phenomenon, with the major- ity of the work focused on protein binding and using con- trolled or healthy model systems. Little information exists, however, on how biocorona formation differs in unhealthy, altered, or potentially compromised biological systems, such as preexisting disease states or genetic differences. A study by Kobos et al. investigates this possibility by incubating two different types of gold nanoparticles (AuNPs) in human serum followed by (1) an integrated proteomic/lipido- mic analysis of the biocorona and (2) screening of human macrophage response upon exposure. Serum from obese in- dividuals resulted in low lipid content in AuNP biocorona and a differential macrophage response compared to serum from healthy individuals. Improved screening techniques on human sera collected from different human subpopula- tions with specific comorbidities could help improve under- standing of innate immune response and improve prediction of clinical outcomes. Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, West Virginia. APPLIED IN VITRO TOXICOLOGY Volume 5, Number 3, 2019 ª Mary Ann Liebert, Inc. DOI: 10.1089/aivt.2019.29020.jrr 111 Downloaded by 54.163.42.124 from www.liebertpub.com at 05/23/20. For personal use only.