Danail Hristozov

Concern-driven integrated approaches to nanomaterial testing and assessment - report of the NanoSafety Cluster Working Group 10

Abstract Bringing together topic-related European Union (EU)-funded projects, the so-called “NanoSafety Cluster” aims at identifying key areas for further research on risk assessment procedures for nanomaterials (NM). The outcome of NanoSafety Cluster Working Group 10, this commentary presents a vision for concern-driven integrated approaches for the (eco-)toxicological testing and assessment (IATA) of NM. Such approaches should start out by determining concerns, i.e., specific information needs for a given NM based on realistic exposure scenarios. Recognised concerns can be addressed in a set of tiers using standardised protocols for NM preparation and testing. Tier 1 includes determining physico-chemical properties, non-testing (e.g., structure–activity relationships) and evaluating existing data. In tier 2, a limited set of in vitro and in vivo tests are performed that can either indicate that the risk of the specific concern is sufficiently known or indicate the need for further testing, including details for such testing. Ecotoxicological testing begins with representative test organisms followed by complex test systems. After each tier, it is evaluated whether the information gained permits assessing the safety of the NM so that further testing can be waived. By effectively exploiting all available information, IATA allow accelerating the risk assessment process and reducing testing costs and animal use (in line with the 3Rs principle implemented in EU Directive 2010/63/EU). Combining material properties, exposure, biokinetics and hazard data, information gained with IATA can be used to recognise groups of NM based upon similar modes of action. Grouping of substances in return should form integral part of the IATA themselves.

Risk assessment of engineered nanomaterials: a review of available data and approaches from a regulatory perspective

Abstract It has been largely recognised that substantial limitations and uncertainties make the conventional risk assessment (RA) of chemicals unfeasible to apply to engineered nanomaterials (ENMs) today, which leaves the regulators with little support in the near term. The aim of this paper is to discuss the state of the art in the area of the RA of nanomaterials, focusing on the available data and approaches. There is a paucity of reliable information in the online safety databases and the literature is dominated by (eco)toxicity studies, while the nano-exposure research lags behind. Most of the reviewed nano-RA approaches are designed to serve as preliminary risk screening and/or research prioritisation tools and are not intended to support regulatory decision making. In this context, we recommend to further study the possibilities to apply complementary/alternative tools for near-term RA of ENMs in order to facilitate their timely regulation, using the data that are currently available in the literature.

Common strategies and technologies for the ecosafety assessment and design of nanomaterials entering the marine environment.

The widespread use of engineered nanomaterials (ENMs) in a variety of technologies and consumer products inevitably causes their release into aquatic environments and final deposition into the oceans. In addition, a growing number of ENM products are being developed specifically for marine applications, such as antifouling coatings and environmental remediation systems, thus increasing the need to address any potential risks for marine organisms and ecosystems. To safeguard the marine environment, major scientific gaps related to assessing and designing ecosafe ENMs need to be filled. In this Nano Focus, we examine key issues related to the state-of-the-art models and analytical tools being developed to understand ecological risks and to design safeguards for marine organisms.

Considerations of Environmentally Relevant Test Conditions for Improved Evaluation of Ecological Hazards of Engineered Nanomaterials

Engineered nanomaterials (ENMs) are increasingly entering the environment with uncertain consequences including potential ecological effects. Various research communities view differently whether ecotoxicological testing of ENMs should be conducted using environmentally relevant concentrations-where observing outcomes is difficult-versus higher ENM doses, where responses are observable. What exposure conditions are typically used in assessing ENM hazards to populations? What conditions are used to test ecosystem-scale hazards? What is known regarding actual ENMs in the environment, via measurements or modeling simulations? How should exposure conditions, ENM transformation, dose, and body burden be used in interpreting biological and computational findings for assessing risks? These questions were addressed in the context of this critical review. As a result, three main recommendations emerged. First, researchers should improve ecotoxicology of ENMs by choosing test end points, duration, and study conditions-including ENM test concentrations-that align with realistic exposure scenarios. Second, testing should proceed via tiers with iterative feedback that informs experiments at other levels of biological organization. Finally, environmental realism in ENM hazard assessments should involve greater coordination among ENM quantitative analysts, exposure modelers, and ecotoxicologists, across government, industry, and academia.

Grouping and Read-Across Approaches for Risk Assessment of Nanomaterials

Physicochemical properties of chemicals affect their exposure, toxicokinetics/fate and hazard, and for nanomaterials, the variation of these properties results in a wide variety of materials with potentially different risks. To limit the amount of testing for risk assessment, the information gathering process for nanomaterials needs to be efficient. At the same time, sufficient information to assess the safety of human health and the environment should be available for each nanomaterial. Grouping and read-across approaches can be utilised to meet these goals. This article presents different possible applications of grouping and read-across for nanomaterials within the broader perspective of the MARINA Risk Assessment Strategy (RAS), as developed in the EU FP7 project MARINA. Firstly, nanomaterials can be grouped based on limited variation in physicochemical properties to subsequently design an efficient testing strategy that covers the entire group. Secondly, knowledge about exposure, toxicokinetics/fate or hazard, for example via properties such as dissolution rate, aspect ratio, chemical (non-)activity, can be used to organise similar materials in generic groups to frame issues that need further attention, or potentially to read-across. Thirdly, when data related to specific endpoints is required, read-across can be considered, using data from a source material for the target nanomaterial. Read-across could be based on a scientifically sound justification that exposure, distribution to the target (fate/toxicokinetics) and hazard of the target material are similar to, or less than, the source material. These grouping and read-across approaches pave the way for better use of available information on nanomaterials and are flexible enough to allow future adaptations related to scientific developments.

A weight of evidence approach for hazard screening of engineered nanomaterials

Abstract 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.

Demonstrating approaches to chemically modify the surface of Ag nanoparticles in order to influence their cytotoxicity and biodistribution after single dose acute intravenous administration

Abstract With the advance in material science and the need to diversify market applications, silver nanoparticles (AgNPs) are modified by different surface coatings. However, how these surface modifications influence the effects of AgNPs on human health is still largely unknown. We have evaluated the uptake, toxicity and pharmacokinetics of AgNPs coated with citrate, polyethylene glycol, polyvinyl pyrolidone and branched polyethyleneimine (Citrate AgNPs, PEG AgNPs, PVP AgNPs and BPEI AgNPs, respectively). Our results demonstrated that the toxicity of AgNPs depends on the intracellular localization that was highly dependent on the surface charge. BPEI AgNPs (ζ potential = +46.5 mV) induced the highest cytotoxicity and DNA fragmentation in Hepa1c1c7. In addition, it showed the highest damage to the nucleus of liver cells in the exposed mice, which is associated with a high accumulation in liver tissues. The PEG AgNPs (ζ potential = −16.2 mV) showed the cytotoxicity, a long blood circulation, as well as bioaccumulation in spleen (34.33 µg/g), which suggest better biocompatibility compared to the other chemically modified AgNPs. Moreover, the adsorption ability with bovine serum albumin revealed that the PEG surface of AgNPs has an optimal biological inertia and can effectively resist opsonization or non-specific binding to protein in mice. The overall results indicated that the biodistribution of AgNPs was significantly dependent on surface chemistry: BPEI AgNPs > Citrate AgNPs = PVP AgNPs > PEG AgNPs. This toxicological data could be useful in supporting the development of safe AgNPs for consumer products and drug delivery applications.

Organ burden and pulmonary toxicity of nano-sized copper (II) oxide particles after short-term inhalation exposure

Abstract Introduction: Increased use of nanomaterials has raised concerns about the potential for undesirable human health and environmental effects. Releases into the air may occur and, therefore, the inhalation route is of specific interest. Here we tested copper oxide nanoparticles (CuO NPs) after repeated inhalation as hazard data for this material and exposure route is currently lacking for risk assessment. Methods: Rats were exposed nose-only to a single exposure concentration and by varying the exposure time, different dose levels were obtained (C × T protocol). The dose is expressed as 6 h-concentration equivalents of 0, 0.6, 2.4, 3.3, 6.3, and 13.2 mg/m3 CuO NPs, with a primary particle size of 10 9.2–14 nm and an MMAD of 1.5 μm. Results: Twenty-four hours after a 5-d exposure, dose-dependent lung inflammation and cytotoxicity were observed. Histopathological examinations indicated alveolitis, bronchiolitis, vacuolation of the respiratory epithelium, and emphysema in the lung starting at 2.4 mg/m3. After a recovery period of 22 d, limited inflammation was still observed, but only at the highest dose of 13.2 mg/m3. The olfactory epithelium in the nose degenerated 24 h after exposure to 6.3 and 13.2 mg/m3, but this was restored after 22 d. No histopathological changes were detected in the brain, olfactory bulb, spleen, kidney and liver. Conclusion: A 5-d, 6-h/day exposure equivalent to an aerosol of agglomerated CuO NPs resulted in a dose-dependent toxicity in rats, which almost completely resolved during a 3-week post-exposure period.

Sustainable nanotechnology decision support system: bridging risk management, sustainable innovation and risk governance

The significant uncertainties associated with the (eco)toxicological risks of engineered nanomaterials pose challenges to the development of nano-enabled products toward greatest possible societal benefit. This paper argues for the use of risk governance approaches to manage nanotechnology risks and sustainability, and considers the links between these concepts. Further, seven risk assessment and management criteria relevant to risk governance are defined: (a) life cycle thinking, (b) triple bottom line, (c) inclusion of stakeholders, (d) risk management, (e) benefit–risk assessment, (f) consideration of uncertainty, and (g) adaptive response. These criteria are used to compare five well-developed nanotechnology frameworks: International Risk Governance Council framework, Comprehensive Environmental Assessment, Streaming Life Cycle Risk Assessment, Certifiable Nanospecific Risk Management and Monitoring System and LICARA NanoSCAN. A Sustainable Nanotechnology Decision Support System (SUNDS) is proposed to better address current nanotechnology risk assessment and management needs, and makes. Stakeholder needs were solicited for further SUNDS enhancement through a stakeholder workshop that included representatives from regulatory, industry and insurance sectors. Workshop participants expressed the need for the wider adoption of sustainability assessment methods and tools for designing greener nanomaterials.

Frameworks and tools for risk assessment of manufactured nanomaterials.

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.