Embedding Ethical Impact Assessment in Nanosafety Decision Support.

Nanotechnology is a key enabling technology, which is developing fast and influences many aspects of life. Nanomaterials are already included in a broad range of products and industrial sectors. Nanosafety issues are still a matter of concern for policy makers and stakeholders, but currently, there is no platform where all stakeholders can meet and discuss these issues. A comprehensive overview of all the issues in one single dashboard presenting the output of a decision support system is also lacking. This article outlines a strategy for developing one innovative part of a modular decision support system, designed to support the work of a new Risk Governance Council (RGC) for nanomaterials which will be established through the combined efforts of the GOV4NANO, NANORIGO, and RiskGONE H2020 projects. This new module will consist of guidelines for Ethical Impact Assessment (EIA) for nanomaterials and nanoenabled products. This article offers recommendations for adapting the European Committee for Standardization (CEN) prestandard on Ethical Impact Assessment CWA (CEN Workshop Agreement) 17145-2:2017 (E), to fit into the more-encompassing decision support system for risk governance of nanomaterials within the RiskGONE project.

Risk Governance of Emerging Technologies Demonstrated in Terms of its Applicability to Nanomaterials.

Nanotechnologies have reached maturity and market penetration that require nano-specific changes in legislation and harmonization among legislation domains, such as the amendments to REACH for nanomaterials (NMs) which came into force in 2020. Thus, an assessment of the components and regulatory boundaries of NMs risk governance is timely, alongside related methods and tools, as part of the global efforts to optimise nanosafety and integrate it into product design processes, via Safe(r)-by-Design (SbD) concepts. This paper provides an overview of the state-of-the-art regarding risk governance of NMs and lays out the theoretical basis for the development and implementation of an effective, trustworthy and transparent risk governance framework for NMs. The proposed framework enables continuous integration of the evolving state of the science, leverages best practice from contiguous disciplines and facilitates responsive re-thinking of nanosafety governance to meet future needs. To achieve and operationalise such framework, a science-based Risk Governance Council (RGC) for NMs is being developed. The framework will provide a toolkit for independent NMs' risk governance and integrates needs and views of stakeholders. An extension of this framework to relevant advanced materials and emerging technologies is also envisaged, in view of future foundations of risk research in Europe and globally.

Governance of advanced materials: Shaping a safe and sustainable future.

The past few decades of managing the uncertain risks associated with nanomaterials have provided valuable insights (knowledge gaps, tools, methods, etc.) that are equally important to promote safe and sustainable development and use of advanced materials. Based on these insights, the current paper proposes several actions to optimize the risk and sustainability governance of advanced materials. We emphasise the importance of establishing a European approach for risk and sustainability governance of advanced materials as soon as possible to keep up with the pace of innovation and to manage uncertainty among regulators, industry, SMEs and the public, regarding potential risks and impacts of advanced materials. Coordination of safe and sustainable advanced material research efforts, and data management according to the Findable, Accessible, Interoperable and Reusable (FAIR) principles will enhance the generation of regulatory-relevant knowledge. This knowledge is crucial to identify whether current regulatory standardised and harmonised test methods are adequate to assess advanced materials. At the same time, there is urgent need for responsible innovation beyond regulatory compliance which can be promoted through the Safe and Sustainable Innovation Approach. that combines the Safe and Sustainable by Design concept with Regulatory Preparedness, supported by a trusted environment. We further recommend consolidating all efforts and networks related to the risk and sustainability governance of advanced materials in a single, easy-to-use digital portal. Given the anticipated complexity and tremendous efforts required, we identified the need of establishing an organisational structure dedicated to aligning the fast technological developments in advanced materials with proper risk and sustainability governance. Involvement of multiple stakeholders in a trusted environment ensures a coordinated effort towards the safe and sustainable development, production, and use of advanced materials. The existing infrastructures and network of experts involved in the governance of nanomaterials would form a solid foundation for such an organisational structure.

Testing ethical impact assessment for nano risk governance.

Risk governance of nanomaterials and nanotechnologies is traditionally mainly limited to risk assessment, risk management and life cycle assessment. Recent approaches have experimented with widening the scope and including economic, social, and ethical aspects. This paper reports on tests and stakeholder feedback on the use of ethical impact assessment guidelines and tools adapting CEN Workshop Agreement part 2 CWA 17145-2:2017 (E)) to support risk governance of nanomaterials, in the RiskGONE project.

An In Vitro Dosimetry Tool for the Numerical Transport Modeling of Engineered Nanomaterials Powered by the Enalos RiskGONE Cloud Platform.

A freely available "in vitro dosimetry" web application is presented enabling users to predict the concentration of nanomaterials reaching the cell surface, and therefore available for attachment and internalization, from initial dispersion concentrations. The web application is based on the distorted grid (DG) model for the dispersion of engineered nanoparticles (NPs) in culture medium used for in vitro cellular experiments, in accordance with previously published protocols for cellular dosimetry determination. A series of in vitro experiments for six different NPs, with Ag and Au cores, are performed to demonstrate the convenience of the web application for calculation of exposure concentrations of NPs. Our results show that the exposure concentrations at the cell surface can be more than 30 times higher compared to the nominal or dispersed concentrations, depending on the NPs' properties and their behavior in the cell culture medium. Therefore, the importance of calculating the exposure concentration at the bottom of the cell culture wells used for in vitro arrays, i.e., the particle concentration at the cell surface, is clearly presented, and the tool introduced here allows users easy access to such calculations. Widespread application of this web tool will increase the reliability of subsequent toxicity data, allowing improved correlation of the real exposure concentration with the observed toxicity, enabling the hazard potentials of different NPs to be compared on a more robust basis.

NanoSolveIT Project: Driving nanoinformatics research to develop innovative and integrated tools for in silico nanosafety assessment.

Nanotechnology has enabled the discovery of a multitude of novel materials exhibiting unique physicochemical (PChem) properties compared to their bulk analogues. These properties have led to a rapidly increasing range of commercial applications; this, however, may come at a cost, if an association to long-term health and environmental risks is discovered or even just perceived. Many nanomaterials (NMs) have not yet had their potential adverse biological effects fully assessed, due to costs and time constraints associated with the experimental assessment, frequently involving animals. Here, the available NM libraries are analyzed for their suitability for integration with novel nanoinformatics approaches and for the development of NM specific Integrated Approaches to Testing and Assessment (IATA) for human and environmental risk assessment, all within the NanoSolveIT cloud-platform. These established and well-characterized NM libraries (e.g. NanoMILE, NanoSolutions, NANoREG, NanoFASE, caLIBRAte, NanoTEST and the Nanomaterial Registry (>2000 NMs)) contain physicochemical characterization data as well as data for several relevant biological endpoints, assessed in part using harmonized Organisation for Economic Co-operation and Development (OECD) methods and test guidelines. Integration of such extensive NM information sources with the latest nanoinformatics methods will allow NanoSolveIT to model the relationships between NM structure (morphology), properties and their adverse effects and to predict the effects of other NMs for which less data is available. The project specifically addresses the needs of regulatory agencies and industry to effectively and rapidly evaluate the exposure, NM hazard and risk from nanomaterials and nano-enabled products, enabling implementation of computational 'safe-by-design' approaches to facilitate NM commercialization.

"AMORE" Decision Support System for probabilistic Ecological Risk Assessment - Part II: Effect assessment of the case study on cyanide.

Ecotoxicological data are highly important for risk assessment processes and are used for deriving environmental quality criteria, which are enacted for assuring the good quality of waters, soils or sediments and achieving desirable environmental quality objectives. Therefore, it is of significant importance the evaluation of the reliability and relevance of available data for analysing their possible use in the aforementioned processes. In this context, a new methodology which has been developed based on Multi-Criteria Decision Analysis (MCDA) techniques, is being used, demonstrated and tested for analysing the reliability and relevance of ecotoxicological data of cyanide (which are produced through laboratory biotests for individual effects). The proposed methodology is also used for the production of Weighted by Data Quality Species Sensitivity Distributions (SSD-WDQ), as a component of the Ecological Risk Assessment of chemicals in aquatic systems. The SSD-WDQ production resulted in the estimation of environmental quality criteria (hazard concentration affecting 5% and 50% of the species). The proposed work is part of the development of the AMORE Decision Support System (DSS) for the application of probabilistic Ecological Risk Assessment (ERA), presented in the companion paper (Isigonis et al., 2019). The DSS has been tested through a case study on ERA of cyanide in the watershed of river Selune in France. The paper presents the 'Effect Assessment' of cyanide, based on the aforementioned methodologies. The main results presented in the paper are the probabilistic analysis of the estimated species sensitivity on cyanide (Effect Assessment) and the calculation of Hazardous Concentration (HCx) of the same contaminant in the Selune river area, based on the functionalities of the DSS. The results are described and discussed in detail, with the use of various graphs and indices. The indices are calculated for all the available ecotoxicological data, as well as for the data on trophic levels or taxonomic groups separately. An effect comparison is presented between the innovative methodologies included in the DSS and the currently existing methodologies.

"AMORE" Decision Support System for probabilistic Ecological Risk Assessment - Part I: Exposure and risk assessment of the case study on cyanide.

Ecological Risk Assessment of chemicals in fluvial systems is a highly researched topic, but its importance for the environmental protection of our planet is vital. Thus, new developments and improvements to existing methodologies are proposed constantly, for providing more advanced tools and more accurate results to researchers and other interested parties. In the field of probabilistic Ecological Risk Assessment, a new Decision Support System is proposed, developed, tested and evaluated. The AMORE DSS is a modular DSS, which incorporates a series of new methodologies, and is built upon the notions of 'Exposure Assessment', 'Effect Assessment' and 'Risk Assessment'. The AMORE Decision Support System has been developed as part of the AMORE research project (French National Research Agency project). The DSS provides a set of tools for analysing and integrating both exposure and effect information in order to evaluate the risk for species living on a given contaminated aquatic system in terms of the Potentially Affected Fraction. The DSS has been tested through a case study on ERA of cyanide in the watershed of river Selune in France. The paper presents the 'Exposure Assessment' and 'Risk Assessment' of the cyanide case study, as well as the complete functionalities of the AMORE DSS. The main results presented in the paper are the statistical analysis of the measured environmental concentrations of cyanide (Exposure Assessment) and the probabilistic 'Risk assessment' of the same contaminant in the area of interest, based on the functionalities of the DSS. The results are described and discussed in detail with the use of various graphs and risk indices. The risk indices are calculated for all the available ecotoxicological data, as well as for the data on trophic levels or taxonomic groups separately. A risk comparison is presented between the innovative methodologies included in the DSS and the currently existing methodologies.

Risk Governance of Nanomaterials: Review of Criteria and Tools for Risk Communication, Evaluation, and Mitigation.

Nanotechnologies have been increasingly used in industrial applications and consumer products across several sectors, including construction, transportation, energy, and healthcare. The widespread application of these technologies has raised concerns regarding their environmental, health, societal, and economic impacts. This has led to the investment of enormous resources in Europe and beyond into the development of tools to facilitate the risk assessment and management of nanomaterials, and to inform more robust risk governance process. In this context, several risk governance frameworks have been developed. In our study, we present and review those, and identify a set of criteria and tools for risk evaluation, mitigation, and communication, the implementation of which can inform better risk management decision-making by various stakeholders from e.g., industry, regulators, and the civil society. Based on our analysis, we recommend specific methods from decision science and information technologies that can improve the existing risk governance tools so that they can communicate, evaluate, and mitigate risks more transparently, taking stakeholder perspectives and expert opinion into account, and considering all relevant criteria in establishing the risk-benefit balance of these emerging technologies to enable more robust decisions about the governance of their risks.

Demonstration of a modelling-based multi-criteria decision analysis procedure for prioritisation of occupational risks from manufactured nanomaterials.

Several tools to facilitate the risk assessment and management of manufactured nanomaterials (MN) have been developed. Most of them require input data on physicochemical properties, toxicity and scenario-specific exposure information. However, such data are yet not readily available, and tools that can handle data gaps in a structured way to ensure transparent risk analysis for industrial and regulatory decision making are needed. This paper proposes such a quantitative risk prioritisation tool, based on a multi-criteria decision analysis algorithm, which combines advanced exposure and dose-response modelling to calculate margins of exposure (MoE) for a number of MN in order to rank their occupational risks. We demonstrated the tool in a number of workplace exposure scenarios (ES) involving the production and handling of nanoscale titanium dioxide, zinc oxide (ZnO), silver and multi-walled carbon nanotubes. The results of this application demonstrated that bag/bin filling, manual un/loading and dumping of large amounts of dry powders led to high emissions, which resulted in high risk associated with these ES. The ZnO MN revealed considerable hazard potential in vivo, which significantly influenced the risk prioritisation results. In order to study how variations in the input data affect our results, we performed probabilistic Monte Carlo sensitivity/uncertainty analysis, which demonstrated that the performance of the proposed model is stable against changes in the exposure and hazard input variables.

A Multi-Criteria Decision Analysis based methodology for quantitatively scoring the reliability and relevance of ecotoxicological data.

Ecotoxicological data are highly important for risk assessment processes and are used for deriving environmental quality criteria, which are enacted for assuring the good quality of waters, soils or sediments and achieving desirable environmental quality objectives. Therefore, it is of significant importance the evaluation of the reliability of available data for analysing their possible use in the aforementioned processes. The thorough analysis of currently available frameworks for the assessment of ecotoxicological data has led to the identification of significant flaws but at the same time various opportunities for improvement. In this context, a new methodology, based on Multi-Criteria Decision Analysis (MCDA) techniques, has been developed with the aim of analysing the reliability and relevance of ecotoxicological data (which are produced through laboratory biotests for individual effects), in a transparent quantitative way, through the use of expert knowledge, multiple criteria and fuzzy logic. The proposed methodology can be used for the production of weighted Species Sensitivity Weighted Distributions (SSWD), as a component of the ecological risk assessment of chemicals in aquatic systems. The MCDA aggregation methodology is described in detail and demonstrated through examples in the article and the hierarchically structured framework that is used for the evaluation and classification of ecotoxicological data is shortly discussed. The methodology is demonstrated for the aquatic compartment but it can be easily tailored to other environmental compartments (soil, air, sediments).

A weight of evidence approach for hazard screening of engineered nanomaterials.

Hazard identification is an important step in assessing nanomaterial risk and is required under multiple regulatory frameworks in the US, Europe and worldwide. Given the emerging nature of the field and complexity of nanomaterials, multiple studies on even basic material properties often result in varying data pointing in different directions when data interpretation is attempted. Weight of evidence (WOE) evaluation has been recommended for nanomaterial risk assessment, but the majority of WOE frameworks are qualitative in nature and do not satisfy the growing needs for objectivity and transparency that are necessary for regulatory decision making. This paper implements a quantitative WOE framework that utilizes multi-criteria decision analysis methodology for integrating individual studies on nanomaterial hazard resulting from physico-chemical and toxicological properties of nanomaterials. For the first time, a WOE approach explicitly integrates expert evaluation of data quality of available information. Application of the framework is illustrated for titanium dioxide nanoparticles (nano-TiO2), but the approach is designed to compare the relative hazard of several nanomaterials as well as emerging stressors in general.

Application of a quantitative weight of evidence approach for ranking and prioritising occupational exposure scenarios for titanium dioxide and carbon nanomaterials.

Substantial limitations and uncertainties hinder the exposure assessment of engineered nanomaterials (ENMs). The present deficit of reliable measurements and models will inevitably lead in the near term to qualitative and uncertain exposure estimations, which may fail to support adequate risk assessment and management. Therefore it is necessary to complement the current toolset with user-friendly methods for near-term nanosafety evaluation. This paper proposes an approach for relative exposure screening of ENMs. For the first time, an exposure model explicitly implements quantitative weight of evidence (WoE) methods and utilises expert judgement for filling data gaps in the available evidence-base. Application of the framework is illustrated for screening of exposure scenarios for nanoscale titanium dioxide, carbon nanotubes and fullerenes, but it is applicable to other nanomaterials as well. The results show that the WoE-based model overestimates exposure for scenarios where expert judgement was substantially used to fill data gaps, which suggests its conservative nature. In order to test how variations in input data influence the obtained results, probabilistic Monte Carlo sensitivity analysis was applied to demonstrate that the model performs in stable manner.