Identification of Substances of Very High Concern (SVHC) under the 'equivalent level of concern' route (REACH Article 57(f)) - neurotoxicants and immunotoxicants as examples

This report analyses whether substances classified for specific target organ toxicity (STOT) according Regulation 1272/2008 on Classification, Labelling and Packaging, in particular those causing immunotoxic or neurotoxic effects, would be eligible to be identified as substances of very high concern (SVHC) under the 'equivalent level of concern' route set out in Article 57(f) of REACH Regulation (EC) No 1907/2006 (Registration, Evaluation, Authorisation and Restriction of Chemicals). This document attempts to identify, characterise and compare the 'level of concern' that exists for immunotoxic and neurotoxic substances with that of CMRs (carcinogens, mutagens and/or reproductive toxicants). The comparison considers the seriousness, irreversibility and delay of hazardous effects, together with other factors, such as the quality of life affected, consequences for society and the possibility to derive a safe concentration.JRC.I.4-Nanobioscience

NANoREG harmonised terminology for environmental health and safety assessment of nanomaterials

Several terms in the field of environmental health and safety (EHS) assessment of chemicals and nanomaterials (hereinafter NMs) have been defined or used by the scientific community and different organisations, including international bodies, European authorities, and industry associations. This is also true for multidisciplinary projects such as NANoREG, which aims at supporting regulatory authorities and industry in dealing with EHS issues of manufactured NMs. The objective of the present JRC technical report is to publish the harmonised terminology that has been developed and used within NANoREG. It has been agreed upon and adopted by all project partners in their activities and related documents. The report specifically includes: i) the methodology used to select key terms that form the harmonised terminology and to develop harmonised definitions; ii) the existing literature definitions that have been used as a starting point to develop for each key term a harmonised definition; and iii) the reason(s) behind the choices that have been made in drafting a definition. As far as possible, the harmonised definition is reproducing (an) already existing definition text(s), thus avoiding the creation of new and unwelcome information. The discussion on the key terms to be considered for the harmonised terminology led to the selection of 43 key terms. The list includes terms with international regulatory relevance, such as those defined at OECD level, as well as terms that have a specific meaning and use under REACH. The 'NANoREG Harmonised Terminology' has already proven very useful in the context of the OECD work, as support document to the April 2016 OECD Expert Meeting on 'Grouping and read-across for the hazard assessment of manufactured nanomaterials', and in a regulatory context, as support document to the work recently released by RIVM, ECHA and JRC on using (eco)toxicological data for bridging data gaps between nanoforms of the same substance (March 2016). For quick access, the 'NANoREG Harmonised Terminology' is reported in Section 3.JRC.I.4-Nanobioscience

Microfluidic genome-wide profiling of intrinsic electrical properties in Saccharomyces cerevisiae

Methods to analyze the intrinsic physical properties of cells – for example, size, density, rigidity, or electrical properties – are an active area of interest in the microfluidics community. Although the physical properties of cells are determined at a fundamental level by gene expression, the relationship between the two remains exceptionally complex and poorly characterized, limiting the adoption of intrinsic separation technologies. To improve our current understanding of how a cell's genotype maps to a measurable physical characteristic and quantitatively investigate the potential of using these characteristics as biomarkers, we have developed a novel screen that combines microfluidic cell sorting with high-throughput sequencing and the haploid yeast deletion library to identify genes whose functions modulate one such characteristic – intrinsic electrical properties. Using this screen, we are able to establish a high-content electrical profile of the haploid yeast gene deletion strains. We find that individual genetic deletions can appreciably alter the electrical properties of cells, affecting [approximately] 10% of the 4432 gene deletion strains screened. Additionally, we find that gene deletions affecting electrical properties in specific ways (i.e. increasing or decreasing effective conductivity at higher or lower electric field frequencies) are strongly associated with an enriched subset of fundamental biological processes that can be traced to specific pathways and complexes. The screening approach demonstrated here and the attendant results are immediately applicable to the intrinsic separations community.Singapore-MIT AllianceNational Science Foundation (U.S.) (NSF IDBR grant DBI-0852654)National Institutes of Health (U.S.) (NIH grant EB005753

Mapping Nanomedicine Terminology in the Regulatory Landscape

A common terminology is essential in any field of science and technology for a mutual understanding among different communities of experts and regulators, harmonisation of policy actions, standardisation of quality procedures and experimental testing, and the communication to the general public. It also allows effective revision of information for policy making and optimises research fund allocation. In particular, in emerging scientific fields with a high innovation potential, new terms, descriptions and definitions are quickly generated, which are then ambiguously used by stakeholders having diverse interests, coming from different scientific disciplines and/or from various regions. The application of nanotechnology in health -often called nanomedicine- is considered as such emerging and multidisciplinary field with a growing interest of various communities. In order to support a better understanding of terms used in the regulatory domain, the Nanomedicines Working Group of the International Pharmaceutical Regulators Forum (IPRF) has prioritised the need to map, compile and discuss the currently used terminology of regulatory scientists coming from different geographic areas. The JRC has taken the lead to identify and compile frequently used terms in the field by using web crawling and text mining tools as well as the manual extraction of terms. Websites of 13 regulatory authorities and clinical trial registries globally involved in regulating nanomedicines have been crawled. The compilation and analysis of extracted terms demonstrated sectorial and geographical differences in the frequency and type of nanomedicine related terms used in a regulatory context. Finally 31 relevant and most frequently used terms deriving from various agencies have been compiled, discussed and analysed for their similarities and differences. These descriptions will support the development of harmonised use of terminology in the future. The report provides necessary background information to advance the discussion among stakeholders. It will strengthen activities aiming to develop harmonised standards in the field of nanomedicine, which is an essential factor to stimulate innovation and industrial competitiveness.JRC.F.2-Consumer Products Safet

Regulatory aspects of nanotechnology in the agri/feed/food sector in EU and non-EU countries

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Towards a review of the EC Recommendation for a definition of the term "nanomaterial"; Part 1: Compilation of information concerning the experience with the definition

In October 2011 the European Commission (EC) published a Recommendation on the definition of nanomaterial (2011/696/EU). The purpose of this definition is to enable determination when a material should be considered a nanomaterial for regulatory purposes in the European Union. In view of the upcoming review of the current EC Definition of the term 'nanomaterial' and noting the need expressed by the EC Environment Directorate General and other Commission services for a set of scientifically sound reports as the basis for this review, the EC Joint Research Centre (JRC) prepares three consecutive reports, of which this is the first. This Report 1 compiles information concerning the experience with the definition regarding scientific-technical issues that should be considered when reviewing the current EC definition of nanomaterial. Based on this report and the feedback received, JRC will write a second, follow-up report. In this Report 2 the JRC will provide a detailed assessment of the scientific-technical issues compiled in Report 1, in relation to the objective of reviewing the current EC nanomaterial definition.JRC.I.4-Nanobioscience

Genome-wide single-cell-level screen for protein abundance and localization changes in response to DNA damage in S. cerevisiae

An effective response to DNA damaging agents involves modulating numerous facets of cellular homeostasis in addition to DNA repair and cell-cycle checkpoint pathways. Fluorescence microscopy-based imaging offers the opportunity to simultaneously interrogate changes in both protein level and subcellular localization in response to DNA damaging agents at the single-cell level. We report here results from screening the yeast Green Fluorescent Protein (GFP)-fusion library to investigate global cellular protein reorganization on exposure to the alkylating agent methyl methanesulfonate (MMS). Broad groups of induced, repressed, nucleus- and cytoplasm-enriched proteins were identified. Gene Ontology and interactome analyses revealed the underlying cellular processes. Transcription factor (TF) analysis identified principal regulators of the response, and targets of all major stress-responsive TFs were enriched amongst the induced proteins. An unexpected partitioning of biological function according to the number of TFs targeting individual genes was revealed. Finally, differential modulation of ribosomal proteins depending on methyl methanesulfonate dose was shown to correlate with cell growth and with the translocation of the Sfp1 TF. We conclude that cellular responses can navigate different routes according to the extent of damage, relying on both expression and localization changes of specific proteins.National Cancer Institute (U.S.) (R01-CA055042 (now NIEHS R01-ES022872))Massachusetts Institute of Technology. Center for Environmental Health Sciences (Grant NIEHS P30-ES002109)National Cancer Institute (U.S.) (KI Center Grant U54-CA112967)National Cancer Institute (U.S.) (Cancer Center Support Grant P30-CA14051)National Institute of Environmental Health Sciences (R01-ES022872)MIT Faculty Start-up FundMassachusetts Institute of Technology. Computational and Systems Biology Initiative (Merck & Co. Postdoctoral Fellowship

NANO(materials): EHS, Research, INnovation, ReGulation

This collection contains data, results, information and tools derived from research and institutional activities regarding the environment, health and safety matters for supporting sustainable innovation for regulatory purposes, with a focus on nanomaterials.JRC.F.2-Consumer Products Safet

Genomic phenotyping of the essential and non-essential yeast genome detects novel pathways for alkylation resistance

Background: A myriad of new chemicals has been introduced into our environment and exposure to these agents can damage cells and induce cytotoxicity through different mechanisms, including damaging DNA directly. Analysis of global transcriptional and phenotypic responses in the yeast S. cerevisiae provides means to identify pathways of damage recovery upon toxic exposure. Results: Here we present a phenotypic screen of S. cerevisiae in liquid culture in a microtiter format. Detailed growth measurements were analyzed to reveal effects on ~5,500 different haploid strains that have either non-essential genes deleted or essential genes modified to generate unstable transcripts. The pattern of yeast mutants that are growth-inhibited (compared to WT cells) reveals the mechanisms ordinarily used to recover after damage. In addition to identifying previously-described DNA repair and cell cycle checkpoint deficient strains, we also identified new functional groups that profoundly affect MMS sensitivity, including RNA processing and telomere maintenance. Conclusions: We present here a data-driven method to reveal modes of toxicity of different agents that impair cellular growth. The results from this study complement previous genomic phenotyping studies as we have expanded the data to include essential genes and to provide detailed mutant growth analysis for each individual strain. This eukaryotic testing system could potentially be used to screen compounds for toxicity, to identify mechanisms of toxicity, and to reduce the need for animal testing.National Institutes of Health (U.S.) (NIH grant CA055042)National Institutes of Health (U.S.) (Grant ES002109)Swedish Research Council (Fellowship)Spain. Ministerio de Ciencia e Innovación (Fellowship)American Cancer Society (Research Professor

Nanomaterials in Food – Current and Future Applications and Regulatory Aspects

Nanotechnology can contribute to the development of innovative applications in the agriculture, food and feed sector by e.g. enabling improved delivery of nutrients or increased efficacy of agrichemicals. It is expected that applications will increase in the near future and may therefore become a relevant source of human exposure to nanomaterials (NM). To gain more up-to date information, RIKILT and the Joint Research Centre (JRC) were commissioned by the European Food Safety Authority (EFSA) to prepare an inventory of currently used and reasonably foreseen applications of NM in agriculture and food/feed production and carried out a review of regulatory aspects concerning NM in both EU and non-EU countries. An analysis of the information records in the inventory shows that nano-encapsulates, silver and titanium dioxide are the most frequent type of NM listed and that food additives and food contact materials are the most frequent types of application. A comparison between marketed applications and those in development indicates a trend from inorganic materials (e.g. silver) towards organic materials (nano-encapsulates, nanocomposites). Applications in novel food, feed additives, biocides and pesticides are currently mostly at a developmental stage. The review of EU and non-EU legislation shows that currently a few EU legal acts incorporate a definition of a nanomaterial and specific provisions for NM, whereas in many non-EU countries a broader approach is applied, which mainly builds on guidance for industry.JRC.I.5-Systems Toxicolog