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ENPRA was one of the earlier multidisciplinary European Commission FP7-funded projects aiming to evaluate the risks associated with nanomaterial (NM) exposure on human health across pulmonary, cardiovascular, hepatic, renal, and developmental systems. The outputs from this project have formed the basis of this review. A retrospective interpretation of the findings across a wide range of in vitro and in vivo studies was performed to identify the main highlights from the project. In particular, focus was placed on informing what advances were made in the hazard assessment of NM, as well as offering some suggestions on the future of "nanotoxicology research" based on these observations, shortcomings, and lessons learned from the project. A number of issues related to the hazard assessment of NM are discussed in detail and include use of appropriate NM for nanotoxicology investigations; characterization and dispersion of NM; use of appropriate doses for all related investigations; need for the correct choice of experimental models for risk assessment purposes; and full understanding of the test systems and correct interpretation of data generated from in vitro and in vivo systems. It is hoped that this review may assist in providing information in the implementation of guidelines, model systems, validation of assessment methodology, and integrated testing approaches for risk assessment of NM. It is vital to learn from ongoing and/or completed studies to avoid unnecessary duplication and offer suggestions that might improve different aspects of experimental design.

Workers involved in producing nanomaterials or using nanomaterials in manufacturing plants are likely to have earlier and higher exposure to manufactured/engineered nanomaterials (ENM) than the general population. This is because both the volume handled and the probability of the effluence of 'free' nanoparticles from the handled volume are much higher during a production process than at any other stage in the lifecycle of nanomaterials and nanotechnology-enabled products. Risk assessment (RA) techniques using control banding (CB) as a framework for risk transfer represents a robust theory but further progress on implementing the model is required so that risk can be transferred to insurance companies. Following a review of RA in general and hazard measurement in particular, we subject a Structural Alert Scheme methodology to three industrial case studies using ZrO2 , TiO2 , and multi-walled carbon nanotubes (MWCNT). The materials are tested in a pristine state and in a remediated (coated) state, and the respective emission and hazard rates are tested alongside the material performance as originally designed. To our knowledge, this is the first such implementation of a CB RA in conjunction with an ENM performance test and offers both manufacturers and underwriters an insight into future applications., (© 2015 The Authors. WIREs Nanomedicine and Nanobiotechnology published by Wiley Periodicals, Inc.)

Background: To assess the risk of all nanomaterials (NMs) on a case-by-case basis is challenging in terms of financial, ethical and time resources. Instead a more intelligent approach to knowledge gain and risk assessment is required., Methods: A framework of future research priorities was developed from the accorded opinion of experts covering all major stake holder groups (government, industry, academia, funders and NGOs). It recognises and stresses the major topics of physicochemical characterisation, exposure identification, hazard identification and modelling approaches as key components of the current and future risk assessment of NMs., Results: The framework for future research has been developed from the opinions of over 80 stakeholders, that describes the research priorities for effective development of an intelligent testing strategy (ITS) to allow risk evaluation of NMs. In this context, an ITS is a process that allows the risks of NMs to be assessed accurately, effectively and efficiently, thereby reducing the need to test NMs on a case-by-case basis.For each of the major topics of physicochemical characterisation, exposure identification, hazard identification and modelling, key-priority research areas are described via a series of stepping stones, or hexagon diagrams structured into a time perspective. Importantly, this framework is flexible, allowing individual stakeholders to identify where their own activities and expertise are positioned within the prioritisation pathway and furthermore to identify how they can effectively contribute and structure their work accordingly. In other words, the prioritisation hexagon diagrams provide a tool that individual stakeholders can adapt to meet their own particular needs and to deliver an ITS for NMs risk assessment. Such an approach would, over time, reduce the need for testing by increasing the reliability and sophistication of in silico approaches.The manuscript includes an appraisal of how this framework relates to the current risk assessment approaches and how future risk assessment could adapt to accommodate these new approaches. A full report is available in electronic format (pdf) at http://www.nano.hw.ac.uk/research-projects/itsnano.html., Conclusion: ITS-NANO has delivered a detailed, stakeholder driven and flexible research prioritisation (or strategy) tool, which identifies specific research needs, suggests connections between areas, and frames this in a time-perspective.

PARTICLE_RISK was one of the first multidisciplinary projects funded by the European Commission's Framework Programme that was responsible for evaluating the implications of nanomaterial (NM) exposure on human health. This project was the basis for this review which identifies the challenges that exist within the assessment of NM risk. We have retrospectively reflected on the findings of completed nanotoxicology studies to consider what progress and advances have been made within the risk assessment of NMs, as well as discussing the direction that nanotoxicology research is taking and identifying the limitations and failings of existing research. We have reflected on what commonly encountered challenges exist and explored how these issues may be resolved. In particular, the following is discussed (i) NM selection (ii) NM physico-chemical characterisation; (iii) NM dispersion; (iv) selection of relevant doses and concentrations; (v) identification of relevant models, target sites and endpoints; (vi) development of alternatives to animal testing; and (vii) NM risk assessment. These knowledge gaps are relatively well recognised by the scientific community and recommendations as to how they may be overcome in the future are provided. It is hoped that this will help develop better defined hypothesis driven research in the future that will enable comprehensive risk assessments to be conducted for NMs. Importantly, the nanotoxicology community has responded and adapted to advances in knowledge over recent years to improve the approaches used to assess NM hazard, exposure and risk. It is vital to learn from existing information provided by ongoing or completed studies to avoid unnecessary duplication of effort, and to offer guidance on aspects of the experimental design that should be carefully considered prior to the start of a new study.

New developments in technology usually entail some hazard as well as advantage to a society. Hazard of a material translates into risk by exposure of humans and/or their environment to the agent in question, and risk is reduced by control of exposure, usually guided by regulation based on understanding of the mechanisms of harm. We illustrate risks relating to the causation of diseases associated with exposure to aerosols of combustion particles and asbestos, leading to paradigms of particle toxicity, and discuss analogies with potential exposure to manufactured nanoparticles (NPs). We review the current understanding of the hazard of NPs derived from the new science of nanotoxicology and the limited research to date into human exposure to these particles. We identify gaps in knowledge relating to the properties of NPs that might determine toxicity and in understanding the most appropriate ways both to measure this in the laboratory and to assess it in the workplace. Nevertheless, we point out that physical principles governing the behaviour of such particles allow determination of practical methods of protecting those potentially exposed. Finally, we discuss the early steps towards regulation and the difficulties facing regulators in controlling potentially harmful exposures in the absence of sufficient scientific evidence.

Societies worldwide are investing considerable resources into the safe development and use of nanomaterials. Although each of these protective efforts is crucial for governing the risks of nanomaterials, they are insufficient in isolation. What is missing is a more integrative governance approach that goes beyond legislation. Development of this approach must be evidence based and involve key stakeholders to ensure acceptance by end users. The challenge is to develop a framework that coordinates the variety of actors involved in nanotechnology and civil society to facilitate consideration of the complex issues that occur in this rapidly evolving research and development area. Here, we propose three sets of essential elements required to generate an effective risk governance framework for nanomaterials. (1) Advanced tools to facilitate risk-based decision making, including an assessment of the needs of users regarding risk assessment, mitigation, and transfer. (2) An integrated model of predicted human behavior and decision making concerning nanomaterial risks. (3) Legal and other (nano-specific and general) regulatory requirements to ensure compliance and to stimulate proactive approaches to safety. The implementation of such an approach should facilitate and motivate good practice for the various stakeholders to allow the safe and sustainable future development of nanotechnology. [ABSTRACT FROM AUTHOR]

Assessing the safety of engineered nanomaterials (NMs) is paramount to the responsible and sustainable development of nanotechnology, which provides huge societal benefits. Currently, there is no evidence that engineered NMs cause detrimental health effects in humans. However, investigation of NM toxicity usingin vivo, in vitro, in chemico, andin silicomodels has demonstrated that some NMs stimulate oxidative stress and inflammation, which may lead to adverse health effects. Accordingly, investigation of these responses currently dominates NM safety assessments. There is a need to reduce reliance on rodent testing in nanotoxicology for ethical, financial and legislative reasons, and due to evidence that rodent models do not always predict the human response. We advocate thatin vitromodels and zebrafish embryos should have greater prominence in screening for NM safety, to better align nanotoxicology with the 3Rs principles. Zebrafish are accepted for use by regulatory agencies in chemical safety assessments (e.g. developmental biology) and there is growing acceptance of their use in biomedical research, providing strong foundations for their use in nanotoxicology. We suggest that investigation of the response of phagocytic cells (e.g. neutrophils, macrophages)in vitroshould also form a key part of NM safety assessments, due to their prominent role in the first line of defense. The development of a tiered testing strategy for NM hazard assessment that promotes the more widespread adoption of non-rodent, alternative models and focuses on investigation of inflammation and oxidative stress could make nanotoxicology testing more ethical, relevant, and cost and time efficient. [ABSTRACT FROM AUTHOR]

Different particle types cause excessive lung inflammation that is thought to play a role in the various types of pathology they produce. Recently attention has been focused on nanoparticles due to their presence in environmental particulate air pollution, their use and exposure in occupational settings, and their potential use in nanotechnology and novel therapeutics. We have shown previously that the surface area metric drives the overload response. We have instilled a number of low-toxicity dusts of various particle sizes and assessed neutrophil influx into the lung at 18-24 h postinstillation. The extent of inflammation was demonstrated as being a function not of the mass dose instilled but interestingly of the surface area dose instilled. Since low-toxicity nanoparticles present a "special" case of high surface area, they are relatively inflammogenic. We tested whether we could use this approach to model the reactivity of highly toxic dusts. Rats were instilled with either DQ12 quartz or aluminum lactate-treated DQ12 and, as anticipated, the high specific surface toxicity of DQ12 meant that it was much more inflammogenic (63 times more) than the surface area alone would have predicted. By contrast, aluminum lactate-treated DQ12 fell into the line of "low-toxicity" dusts. In addition, as an in vitro testing alternative to that of in vivo testing, interleukin (IL)-8 production in A549 cells exposed to the panel of various particles clearly demonstrated the ability to also identify a relationship between surface area dose and reactivity. These approaches present the possibility of modelling potential toxicity of nanoparticles and nuisance dusts based on the inflammatory response of a given instilled surface area dose. [ABSTRACT FROM AUTHOR]

The celebrated physicist and Nobel laureate Richard Feynman was the first to predict the opportunities presented by the manipulation of matter at the level of individual atoms and molecules. Today, almost 50 years after his classic lecture on the wonders of the small world, the evolving nanotechnologies have the potential to bring about major changes in the lives of citizens. However, the very same properties that make engineered nanomaterials so promising from a technological perspective, such as their high degree of reactivity and the ability to cross biological barriers, could also make these novel materials harmful to human health and the environment. Therefore, exploitation of the full potential of the nanotechnologies requires close attention to safety issues. The 1st Nobel Forum mini-symposium on nanotoxicology was recently held in Stockholm, Sweden, and the program was devoted to the topic of definitions and standardization in nanotoxicological research, as well as nano-specific risk assessment and regulatory/legislative issues. Examples of recent and ongoing studies of carbon-based nanomaterials, including single-walled carbon nanotubes, using a wide range of in vitro and in vivo model systems were also presented. The current review will provide some highlights and conclusions from this exciting meeting. [ABSTRACT FROM AUTHOR]

Commercialization of nanotechnologies entails a regulatory requirement for understanding their environmental, health and safety (EHS) risks. Today we face challenges to assess these risks, which emerge from uncertainties around the interactions of manufactured nanomaterials (MNs) with humans and the environment. In order to reduce these uncertainties, it is necessary to generate sound scientific data on hazard and exposure by means of relevant frameworks and tools. The development of such approaches to facilitate the risk assessment (RA) of MNs has become a dynamic area of research. The aim of this paper was to review and critically analyse these approaches against a set of relevant criteria. The analysis concluded that none of the reviewed frameworks were able to fulfill all evaluation criteria. Many of the existing modelling tools are designed to provide screening-level assessments rather than to support regulatory RA and risk management. Nevertheless, there is a tendency towards developing more quantitative, higher-tier models, capable of incorporating uncertainty into their analyses. There is also a trend towards developing validated experimental protocols for material identification and hazard testing, reproducible across laboratories. These tools could enable a shift from a costly case-by-case RA of MNs towards a targeted, flexible and efficient process, based on grouping and read-across strategies and compliant with the 3R (Replacement, Reduction, Refinement) principles. In order to facilitate this process, it is important to transform the current efforts on developing databases and computational models into creating an integrated data and tools infrastructure to support the risk assessment and management of MNs. [ABSTRACT FROM AUTHOR]