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Abstract
Particle inhalation is linked to diseases including cancer, COPD, fibrosis and cardiovascular disease. We propose a biological mechanism-of-action for particle-induced cardiovascular disease causally linking particle exposure to induction of acute phase response, which in turn is a known risk factor for atherosclerosis and cardiovascular disease. Inhalation and pulmonary deposition of particles induce inflammation, which is proportional to the total surface area of the pulmonary-deposited particles. In mice, inflammation is accompanied by an acute phase response, which is long-lasting for insoluble particles. Acute phase protein Serum Amyloid A (SAA) is among the most differentially expressed genes in lung tissue following particle exposure. SAA is causally implicated in atherosclerosis and both overexpression and pulmonary dosing of SAA promote plaque formation in ApoE-/- mice. In mice, we show that both soluble and insoluble metal fume particles induce acute phase response but with different time-dependence. Neutrophil influx, pulmonary Saa expression and SAA blood levels are highly correlated in mice and may be used as biomarkers of each other. In humans, controlled exposure to metal oxides and combustion particles induces dose-dependent increases in blood levels of SAA and C-reactive protein. Blood levels of acute phase proteins SAA and C-reactive protein are risk factors for cardiovascular disease in prospective, epidemiological studies. Nanoparticles have a higher specific surface area than larger particles with similar chemical composition, and consequently, nanoparticles are more hazardous than larger particles of similar chemical composition in relation to cardiovascular disease. This underscores cardiovascular disease as a particle-induced occupational disease.

In the context of the recently finalized H2020 project, NanoReg 2 , a new framework for a more comprehensive assessment of the environmental and human implication for engineered nanomaterials (ENMs) and related nano-enabled products has been developed. The developed framework is based on the integration of Life Cycle Assessment (LCA) and Risk Assessment (RA) methodologies during each stage of the innovation process for ENM products. Following a standard stage model, the framework is structured into four distinct phases: in stage one ("business idea"), the core business idea is described, an initial qualitative scoping of possible potential impacts and risks is established and the main legislative requirements are considered; in stage two ("business concept"), a simplified screening LCA-RA of potential benefits and risks (for workers, consumers and the environment) is performed, allowing a first rough evaluation of the sustainability of the product, based on qualitative/quantitative data from literature; stage three commences as experimental testing starts (stages 3a and 3b-"Prototype ENM/Prototype industrial sector"), and entails the undertaking of an LCA and RA at the lab and industrial scales, providing a first quantitative evaluation of the product; in the fourth and final stage ("validation and market"), REACH, product-related regulations/requirements and labelling requirements are integrated into the assessment. At each stage, different tools (e.g. LICARA, NanoRiskCat, Nanosafer, Swiss precautionary matrix) are used to provide valuable insights into performance to support the company in the process of the evaluation of the risk and sustainability of their product. Thus, our framework serves to help identify and minimise risks at an early stage in the innovation cycle and ensure that safety and sustainability implications are considered from the onset. For emerging products this is of high relevance as it enables risk and product management options to be enacted prior to the nanoproducts entering the market. ...

In the context of the recently finalized H2020 project, NanoReg 2 , a new framework for a more comprehensive assessment of the environmental and human implication for engineered nanomaterials (ENMs) and related nano-enabled products has been developed. The developed framework is based on the integration of Life Cycle Assessment (LCA) and Risk Assessment (RA) methodologies during each stage of the innovation process for ENM products. Following a standard stage model, the framework is structured into four distinct phases: in stage one ("business idea"), the core business idea is described, an initial qualitative scoping of possible potential impacts and risks is established and the main legislative requirements are considered; in stage two ("business concept"), a simplified screening LCA-RA of potential benefits and risks (for workers, consumers and the environment) is performed, allowing a first rough evaluation of the sustainability of the product, based on qualitative/quantitative data from literature; stage three commences as experimental testing starts (stages 3a and 3b-"Prototype ENM/Prototype industrial sector"), and entails the undertaking of an LCA and RA at the lab and industrial scales, providing a first quantitative evaluation of the product; in the fourth and final stage ("validation and market"), REACH, product-related regulations/requirements and labelling requirements are integrated into the assessment. At each stage, different tools (e.g. LICARA, NanoRiskCat, Nanosafer, Swiss precautionary matrix) are used to provide valuable insights into performance to support the company in the process of the evaluation of the risk and sustainability of their product. Thus, our framework serves to help identify and minimise risks at an early stage in the innovation cycle and ensure that safety and sustainability implications are considered from the onset. For emerging products this is of high relevance as it enables risk and product management options to be enacted prior to the nanoproducts entering the market. In this presentation, this stage-based, integrated RA-LCA framework will be presented in more detail and its applicability will be demonstrated through several case studies regarding ENM production and application. In addition to the LCA and RA activities, the feasibility for adding a socio-economic component to this framework will be discussed.

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. ; acceptedVersion ; Peer reviewed