Metadata Stewardship in Nanosafety Research: Community-Driven Organisation of Metadata Schemas to Support FAIR Nanoscience Data.

The emergence of nanoinformatics as a key component of nanotechnology and nanosafety assessment for the prediction of engineered nanomaterials (NMs) properties, interactions, and hazards, and for grouping and read-across to reduce reliance on animal testing, has put the spotlight firmly on the need for access to high-quality, curated datasets. To date, the focus has been around what constitutes data quality and completeness, on the development of minimum reporting standards, and on the FAIR (findable, accessible, interoperable, and reusable) data principles. However, moving from the theoretical realm to practical implementation requires human intervention, which will be facilitated by the definition of clear roles and responsibilities across the complete data lifecycle and a deeper appreciation of what metadata is, and how to capture and index it. Here, we demonstrate, using specific worked case studies, how to organise the nano-community efforts to define metadata schemas, by organising the data management cycle as a joint effort of all players (data creators, analysts, curators, managers, and customers) supervised by the newly defined role of data shepherd. We propose that once researchers understand their tasks and responsibilities, they will naturally apply the available tools. Two case studies are presented (modelling of particle agglomeration for dose metrics, and consensus for NM dissolution), along with a survey of the currently implemented metadata schema in existing nanosafety databases. We conclude by offering recommendations on the steps forward and the needed workflows for metadata capture to ensure FAIR nanosafety data.

PBPK Modeling of Slightly Soluble Silver Nanomaterials and Regulatory Acceptance.

International efforts to promote predictive toxicology incorporate some form of modeling based on the regularities, insights, and hypotheses gained from analyzing laboratory studies compiled in databases. While there has been a broad commentary on definitions, metadata, and test methodologies, all necessary to establishing data repositories, there has been less on translating the resulting insights into computational models. The recent use of a computational model to support a recommended exposure limit for nanoparticulate silver is an opportunity to examine physiologically based toxicokinetics in terms of data availability, model verification and validation, and regulatory acceptance. The resulting suggestions align with findings from the EU-US Roadmap Nanoinformatics 2030 and the 2018 acceptance of a computational model by the European Food Safety Authority.

Nanomaterial categorization for assessing risk potential to facilitate regulatory decision-making.

For nanotechnology to meet its potential as a game-changing and sustainable technology, it is important to ensure that the engineered nanomaterials and nanoenabled products that gain entry to the marketplace are safe and effective. Tools and methods are needed for regulatory purposes to allow rapid material categorization according to human health and environmental risk potential, so that materials of high concern can be targeted for additional scrutiny, while material categories that pose the least risk can receive expedited review. Using carbon nanotubes as an example, we discuss how data from alternative testing strategies can be used to facilitate engineered nanomaterial categorization according to risk potential and how such an approach could facilitate regulatory decision-making in the future.

Evaluation of exposure concentrations used in assessing manufactured nanomaterial environmental hazards: are they relevant?

Manufactured nanomaterials (MNMs) are increasingly produced and used in consumer goods, yet our knowledge regarding their environmental risks is limited. Environmental risks are assessed by characterizing exposure levels and biological receptor effects. As MNMs have rarely been quantified in environmental samples, our understanding of exposure level is limited. Absent direct measurements, environmental MNM concentrations are estimated from exposure modeling. Hazard, the potential for effects on biological receptors, is measured in the laboratory using a range of administered MNM concentrations. Yet concerns have been raised regarding the "relevancy" of hazard assessments, particularly when the administered MNM concentrations exceed those predicted to occur in the environment. What MNM concentrations are administered in hazard assessments and which are "environmentally relevant"? This review regards MNM concentrations in hazard assessments, from over 600 peer-reviewed articles published between 2008 and 2013. Some administered MNM concentrations overlap with, but many diverge from, predicted environmental concentrations. Other uncertainties influence the environmental relevance of current hazard assessments and exposure models, including test conditions, bioavailable concentrations, mode of action, MNM production volumes, and model validation. Therefore, it may be premature for MNM risk research to sanction information on the basis of concentration "environmental relevance".

A multi-stakeholder perspective on the use of alternative test strategies for nanomaterial safety assessment.

There has been a conceptual shift in toxicological studies from describing what happens to explaining how the adverse outcome occurs, thereby enabling a deeper and improved understanding of how biomolecular and mechanistic profiling can inform hazard identification and improve risk assessment. Compared to traditional toxicology methods, which have a heavy reliance on animals, new approaches to generate toxicological data are becoming available for the safety assessment of chemicals, including high-throughput and high-content screening (HTS, HCS). With the emergence of nanotechnology, the exponential increase in the total number of engineered nanomaterials (ENMs) in research, development, and commercialization requires a robust scientific approach to screen ENM safety in humans and the environment rapidly and efficiently. Spurred by the developments in chemical testing, a promising new toxicological paradigm for ENMs is to use alternative test strategies (ATS), which reduce reliance on animal testing through the use of in vitro and in silico methods such as HTS, HCS, and computational modeling. Furthermore, this allows for the comparative analysis of large numbers of ENMs simultaneously and for hazard assessment at various stages of the product development process and overall life cycle. Using carbon nanotubes as a case study, a workshop bringing together national and international leaders from government, industry, and academia was convened at the University of California, Los Angeles, to discuss the utility of ATS for decision-making analyses of ENMs. After lively discussions, a short list of generally shared viewpoints on this topic was generated, including a general view that ATS approaches for ENMs can significantly benefit chemical safety analysis.

Research strategies for safety evaluation of nanomaterials, part V: role of dissolution in biological fate and effects of nanoscale particles.

Dissolution, translocation, and disposition have been shown to play a key role in the fate and effects of inhaled particles and fibers. Concepts that have been applied in the micron size range may be usefully applied to the nanoscale range, but new challenges are presented based on the small size and possible change in the dissolution:translocation relationship. The size of the component molecule itself may be on the nanoscale. Solute concentration, surface area, surface morphology, surface energy, dissolution layer properties, adsorbing species, and aggregation are relevant parameters in considering dissolution at the nanoscale. With regard to the etiopathology caused by these types of particulates, the metrics of dose (particle number, surface area, mass or shape) is not yet well defined. Analytical procedures for assessing dissolution and translocation include chemical assay and particle characterization. Leaching of substituents from particle surfaces may also be important. Compartmentalization within the respiratory tract may add another dimension of complexity. Dissolution may be a critical step for some nanoscale materials in determining fate in the environment and within the body. This review, combining aspects of particle toxicology, material science, and analytical chemistry, is intended to provide a useful basis for developing relevant dissolution assay(s) for nanoscale particles.