Introduction to the themed collection on nanoceria research

There are great expectations for the beneficial applications of nanotechnology, however our understanding of their adverse effects is quite limited. Researchers who have been focusing on creating novel nanomaterials, developing or identifying applications, or describing adverse effects often have not been collaborating or communicating sufficiently to advance nanomaterials in a coordinated, planned effort. This is particularly true for nanoceria, which has demonstrated utility in diverse applications (as an abrasive catalyst in chemical mechanical planarization/polishing, as a catalyst in fuel cell power generation and catalytic converters, and in fuel borne additives). As such it is expected to have future application in fuel cells and batteries, and has shown benefit in treating numerous medical conditions that have inflammatory and oxidative injury components. Researchers investigating nanoceria had been disseminating their findings through publication and presentation at research conferences, with little overlap. Recognizing that there was little communication but controversy among researchers investigating nanoceria's beneficial and adverse effects, Robert Yokel proposed a workshop to bring together researchers to discuss its yang and yin. In discussion with other researchers about the central unknowns, the key question was identified: why are some studies negative while others are positive for adverse effects of nanoceria? This raised questions whether differences in nanoceria synthesis, structure, size, or dose account for these apparent differences.

Based on the enthusiasm and willingness of nanoceria researchers for a forum to address the key question, a workshop was organized to discuss what we know, identify data gaps, and suggest what needs to be determined (research recommendations) about the biological, human health, environmental, and societal improvement aspects of nanoceria. Given the divergent opinions and experiences among the researchers engaged in studying nanoceria, there was agreement that a common venue to discuss this topic was desirable. The willingness of the Sustainable Nanotechnology Organization to sponsor this workshop, the acceptance of this venue by the researchers investigating nanoceria including financial stakeholders, and the ability to attract workshop participants among those attending the Second Annual Sustainable Nanotechnology Organization Conference made this workshop possible. The workshop was held November 2, 2013 in Santa Barbara, California, the day before the Second SNO Conference, and was attended by 27 people, from the United States, Canada, England, and Saudi Arabia.

To organize the workshop a Steering committee comprising Philip Demokritou, Harvard, Environmental Health; Joseph S. Erlichman, St. Lawrence University, Biology; William T. Self, University of Central Florida, Burnett School of Biomedical Sciences; Jason M. Unrine, University of Kentucky, Plant and Soil Sciences; and Robert A. Yokel, University of Kentucky, Pharmaceutical Sciences, identified the key topics related to the uncertainties of nanoceria. Seven topics were identified, to be addressed by panels of active nanoceria researchers. The workshop structure followed the aim of Dahlem workshops (https://mitpress.mit.edu/sites/default/files/titles/content/9780262033480_pre_0001.pdf). The goal was to establish an interdisciplinary communication process aimed at expanding the boundaries of current knowledge, to give researchers the opportunity to address problems that are of high-priority interest in an effort to identify gaps in knowledge, to pose questions aimed at directing future inquiry, and to suggest innovative ways of approaching controversial issues, through an international, interdisciplinary exchange of scientific information and ideas. Each topic was discussed by a panel of at least two researchers from different institutions who had published their findings related to the topic, not all of whom had previously collaborated. The goal was to provide diversity of perspective and perhaps opinion, and to create, if possible, some consensus among the panel members of the panel's topic. Each panel prepared a position paper prior to the workshop that addressed their topic, under the direction and coordination of a panel leader. The panel leader presented their panel's position paper during the workshop, which was then discussed. Following the workshop the panel leaders coordinated revision of their pre-workshop position papers to reflect the discussion during the workshop, updated the papers, and submitted them for peer review as the reviews published in this journal.

To address the key question, the Steering committee identified 7 major topics, proposed questions within each topic, and identified scientists actively engaged in nanoceria research who could constitute panels to address each topic. Panel 1 was asked to address the current and proposed uses of nanoceria and the basis (properties) for their use. Kenneth Reed led this panel that described the solid state structural and catalytic chemistry of ceria and nanoceria that provide the foundation for the many, and often reported as contradictory, effects of nanoceria (DOI: 10.1039/C4EN00079J). Panel 2 was asked: based on the chemistry of nanoceria, is it possible for the same element to behave both as a pro-oxidant and anti-oxidant depending on variables such as the method of synthesis, physico-chemical properties, environmental conditions, or other properties? Is it possible to yield both positive and negative outcomes simply based on chemistry in the absence of biological interactions? Eric Grulke's group delved into nanoceria's properties and the effects of its environment on those properties that influence its effects (DOI: 10.1039/C4EN00105B). The third panel was asked the following questions. What are the salient physico-chemical properties contributing to the potential positive and negative aspects of nanoceria in a biological system? Are we really studying the same particles with slight variations in size and physico-chemical properties or do they behave as independent entities? Is this the result of differences in chemistry or downstream effects that emerge once these materials interact with biological moieties? Sudipta Seal led the group that focused on the environmental factors that influence nanoceria's redox properties, how it interacts with biological systems, and the resultant effects (DOI: 10.1039/C4EN00052H). The 4th major topic was the biological identity of nanoceria and its influence on the biological response in in vitro and in vivo systems. This included the extent that in vitro studies recapitulate the in vivo condition and whether the biological response is a product of the synthetic identity of the nanoceria or its biological identity (i.e. particle + adsorbed proteins)? Carl Walkey focused on nanoceria's biological identity and how that influences its biological response, particularly the protein corona. Given the dearth of specific information on protein coating of nanoceria in biological systems, this topic was incorporated into the next panel's report. Panel 5 was asked to address the yang: the therapeutic development of nanoceria. This included how exposure level and route and experimental preparation/model influence the different reported effects of nanoceria, the considerations to develop nanoceria as a therapeutic agent, the biological targets, and how to deliver nanoceria to its desired location and dose while ensuring safety. William Self's group focused on the reported beneficial applications of nanoceria to address these questions. His group's report will be forthcoming. In contrast to the yang, panel 6 was charged with addressing the yin: the toxicological risks of nanoceria, its fate, and how the exposure level, exposure route and experimental preparation/model influence the reported effects of nanoceria. They were also encouraged to suggest how safer by design concepts might be applied to nanoceria. This panel reviewed nanoceria's pharmacokinetics and reported short and long term adverse effects following exposure by different routes and exposures as well as results of in vitro studies that provide insight into mechanisms underlying the adverse effects. Results of a safer by design study were reviewed (DOI: 10.1039/C4EN00039K). Panel 7 was asked to address what is known about the life cycle of nanoceria, its environmental fate and transport, exposure pathways, and adverse effects on ecological receptors. To provide this environmental perspective Jason Unrine's panel reviewed the production and use, release, fate and transformations, exposure levels and pathways, and effects on ecological entities (DOI: 10.1039/C4EN00149D).

The workshop was made possible by the financial support from the Sustainable Nanotechnology Organization; NSF grant CBET-1343638 to UCSB; and the Tracy Farmer Institute for Sustainability and the Environment, Department of Pharmaceutical Sciences, Office of the Vice President for Research, and Associate Dean for Research of the College of Pharmacy, University of Kentucky.

It was proposed that Environmental Science: Nano, official publisher for the Sustainable Nanotechnology Organization, put out an invitation to researchers to submit unpublished research findings with nanoceria for inclusion in this themed collection. The peer-reviewed submissions that were accepted and appear in the collection add to the value of this themed collection of Environmental Science: Nano as a source of the current status of this multifaceted family of nanomaterials. The cover image for this themed collection was created by Matt H. Hazzard, bio-medical illustrator; Matthew J. Beck; and Robert A. Yokel to illustrate some of the key points discussed in the workshop and addressed in the reports published in this focused collection: nanoceria sources, its auto-catalytic valence cycling, and its chemical structure influencing its valence state and reactivity, all of which impinge on the human, to produce potential beneficial and adverse effects.

---