TRAAC framework to improve regulatory acceptance and wider usability of tools and methods for safe innovation and sustainability of manufactured nanomaterials.

There has been an increasing use of advanced materials, particularly manufactured nanomaterials, in industrial applications and consumer products in the last two decades. It has instigated concerns about the sustainability, in particular, risks and uncertainties regarding the interactions of the manufactured nanomaterials with humans and the environment. Consequently, significant resources in Europe and beyond have been invested into the development of tools and methods to support risk mitigation and risk management, and thus facilitate the research and innovation process of manufactured nanomaterials. The level of risk analysis is increasing, including assessment of socio-economic impacts, and sustainability aspects, moving from a conventional risk-based approach to a wider safety-and-sustainability-by-design perspective. Despite these efforts on tools and methods development, the level of awareness and use of most of such tools and methods by stakeholders is still limited. Issues of regulatory compliance and acceptance, reliability and trust, user-friendliness and compatibility with the users' needs are some of the factors which have been traditionally known to hinder their widespread use. Therefore, a framework is presented to quantify the readiness of different tools and methods towards their wider regulatory acceptance and downstream use by different stakeholders. The framework diagnoses barriers which hinder regulatory acceptance and wider usability of a tool/method based on their Transparency, Reliability, Accessibility, Applicability and Completeness (TRAAC framework). Each TRAAC pillar consists of criteria which help in evaluating the overall quality of the tools and methods for their (i) compatibility with regulatory frameworks and (ii) usefulness and usability for end-users, through a calculated TRAAC score based on the assessment. Fourteen tools and methods were assessed using the TRAAC framework as proof-of-concept and for user variability testing. The results provide insights into any gaps, opportunities, and challenges in the context of each of the 5 pillars of the TRAAC framework. The framework could be, in principle, adapted and extended to the evaluation of other type of tools & methods, even beyond the case of nanomaterials.

Toward Rigorous Materials Production: New Approach Methodologies Have Extensive Potential to Improve Current Safety Assessment Practices.

Advanced material development, including at the nanoscale, comprises costly and complex challenges coupled to ensuring human and environmental safety. Governmental agencies regulating safety have announced interest toward acceptance of safety data generated under the collective term New Approach Methodologies (NAMs), as such technologies/approaches offer marked potential to progress the integration of safety testing measures during innovation from idea to product launch of nanomaterials. Divided in overall eight main categories, searchable databases for grouping and read across purposes, exposure assessment and modeling, in silico modeling of physicochemical structure and hazard data, in vitro high-throughput and high-content screening assays, dose-response assessments and modeling, analyses of biological processes and toxicity pathways, kinetics and dose extrapolation, consideration of relevant exposure levels and biomarker endpoints typify such useful NAMs. Their application generally agrees with articulated stakeholder needs for improvement of safety testing procedures. They further fit for inclusion and add value in nanomaterials risk assessment tools. Overall 37 of 50 evaluated NAMs and tiered workflows applying NAMs are recommended for considering safer-by-design innovation, including guidance to the selection of specific NAMs in the eight categories. An innovation funnel enriched with safety methods is ultimately proposed under the central aim of promoting rigorous nanomaterials innovation.

Quantitative human health risk assessment along the lifecycle of nano-scale copper-based wood preservatives.

The use of nano-scale copper oxide (CuO) and basic copper carbonate (Cu2(OH)2CO3) in both ionic and micronized wood preservatives has raised concerns about the potential of these substances to cause adverse humans health effects. To address these concerns, we performed quantitative (probabilistic) human health risk assessment (HHRA) along the lifecycles of these formulations used in antibacterial and antifungal wood coatings and impregnations by means of the EU FP7 SUN project's Decision Support System (SUNDS, www.sunds.gd). The results from the risk analysis revealed inhalation risks from CuO in exposure scenarios involving workers handling dry powders and performing sanding operations as well as potential ingestion risks for children exposed to nano Cu2(OH)2CO3 in a scenario involving hand-to-mouth transfer of the substance released from impregnated wood. There are, however, substantial uncertainties in these results, so some of the identified risks may stem from the safety margin of extrapolation to fill data gaps and might be resolved by additional testing. Our stochastic approach successfully communicated the contribution of different sources of uncertainty in the risk assessment. The main source of uncertainty was the extrapolation from short to long-term exposure, which was necessary due to the lack of (sub)chronic in vivo studies with CuO and Cu2(OH)2CO3. Considerable uncertainties also stemmed from the use of default inter- and intra-species extrapolation factors.

Probabilistic risk assessment of emerging materials: case study of titanium dioxide nanoparticles.

The development and use of emerging technologies such as nanomaterials can provide both benefits and risks to society. Emerging materials may promise to bring many technological advantages but may not be well characterized in terms of their production volumes, magnitude of emissions, behaviour in the environment and effects on living organisms. This uncertainty can present challenges to scientists developing these materials and persons responsible for defining and measuring their adverse impacts. Human health risk assessment is a method of identifying the intrinsic hazard of and quantifying the dose-response relationship and exposure to a chemical, to finally determine the estimation of risk. Commonly applied deterministic approaches may not sufficiently estimate and communicate the likelihood of risks from emerging technologies whose uncertainty is large. Probabilistic approaches allow for parameters in the risk assessment process to be defined by distributions instead of single deterministic values whose uncertainty could undermine the value of the assessment. A probabilistic approach was applied to the dose-response and exposure assessment of a case study involving the production of nanoparticles of titanium dioxide in seven different exposure scenarios. Only one exposure scenario showed a statistically significant level of risk. In the latter case, this involved dumping high volumes of nano-TiO2 powders into an open vessel with no personal protection equipment. The probabilistic approach not only provided the likelihood of but also the major contributing factors to the estimated risk (e.g. emission potential).

In vitro assessment of engineered nanomaterials using a hepatocyte cell line: cytotoxicity, pro-inflammatory cytokines and functional markers.

Effects on the liver C3A cell line treated with a panel of engineered nanomaterials (NMs) consisting of two zinc oxide particles (ZnO; coated 100 nm and uncoated 130 nm), two multi-walled carbon nanotubes (MWCNTs), one silver (Ag < 20 nm), one 7 nm anatase, two rutile TiO2 nanoparticles (10 and 94 nm) and two derivatives with positive and negative covalent functionalisation of the 10 nm rutile were evaluated. The silver particles elicited the greatest level of cytotoxicity (24 h LC50 - 2 µg/cm(2)). The silver was followed by the uncoated ZnO (24 h LC50 - 7.5 µg/cm(2)) and coated ZnO (24 h LC50 - 15 µg/cm(2)) particles with respect to cytotoxicity. The ZnO NMs were found to be about 50-60% soluble which could account for their toxicity. By contrast, the Ag was <1% soluble. The LC50 was not attained in the presence of any of the other engineered NMs (up to 80 µg/cm(2)). All NMs significantly increased IL-8 production. Meanwhile, no significant change in TNF-α, IL-6 or CRP was detected. Urea and albumin production were measured as indicators of hepatic function. These markers were only altered by the coated and uncoated ZnO, which significantly decreased albumin production.

Conceptual model for assessment of inhalation exposure to manufactured nanoparticles.

As workplace air measurements of manufactured nanoparticles are relatively expensive to conduct, models can be helpful for a first tier assessment of exposure. A conceptual model was developed to give a framework for such models. The basis for the model is an analysis of the fate and underlying mechanisms of nanoparticles emitted by a source during transport to a receptor. Four source domains are distinguished; that is, production, handling of bulk product, dispersion of ready-to-use nanoproducts, fracturing and abrasion of end products. These domains represent different generation mechanisms that determine particle emission characteristics; for example, emission rate, particle size distribution, and source location. During transport, homogeneous coagulation, scavenging, and surface deposition will determine the fate of the particles and cause changes in both particle size distributions and number concentrations. The degree of impact of these processes will be determined by a variety of factors including the concentration and size mode of the emitted nanoparticles and background aerosols, source to receptor distance, and ventilation characteristics. The second part of the paper focuses on to what extent the conceptual model could be fit into an existing mechanistic predictive model for ''conventional'' exposures. The model should be seen as a framework for characterization of exposure to (manufactured) nanoparticles and future exposure modeling.