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The projects constituting the SEURAT-1 research initiative have received funding from the European Union Seventh Framework Programme (FP7/2007-2013). The projects constituting the SEURAT-1 research initiative have received financing from Cosmetics Europe.

Glossary

Glossary:

3Rs   Reduction, replacement, refinement - defined by Russel & Birch 1959

ADME Absorption, Distribution, Metabolism, and Excretion. ADME describes the disposition of a pharmaceuticalcompound within an organism.

Analogue and / or category approach The terms category approach and analogue approach describe techniquesfor grouping chemicals. The term analogue approach is used when the grouping is based on a very limited number of chemicals, where trends in properties are not apparent.

A chemical category is a group of chemicals whose physicochemical and human health and/or environmental toxicologicalproperties and/or environmental fate properties are likely to be similar or follow a regularpattern as a result of structural similarity (or other similarity characteristic). In principle, there should be sufficient members in the chemical category, to enable the detection of trends across endpoints. As the number of chemicals being grouped into a category increases, the potential for developing hypotheses and making generalisations about the trends will also increase, and hence increase the robustness of the evaluation.

AOP An Adverse Outcome Pathway (AOP) describes and formalises the documented, plausible, and testable processes by which a chemical induces molecular perturbations which may lead to a toxic effect. As such it links directly to the associated biological responses which describe how the molecular perturbations cause effects at the subcellular, cellular, tissue, organ, whole animal, and population levels of observation. The AOP can then be used to form chemical categories to allow for read across (if appropriate). The AOP can be supported by knowledge of how chemicals interact with biological systems (i.e., the molecular initiating events) and in vitro and in vivo knowledge of the biological responses.

API Application ProgrammingInterface: a particular set of commands, functions and protocols that programmers can use to develop software programs that interact with services and resources provided by another particular software program that also implements that API.

Authentication: Confirmation of the identity of a user.

Authorisation: Provision of controlled access to resources to a user based on the access permissions they have for the resources.

BAC recombineering: A bacterial artificial chromosome (BAC) is a DNA construct used for transforming and cloning in bacteria, usually Escheria coli. Recombineering (recombination-mediated genetic engineering) is a genetic and molecular biology technique that has been developed in E. coli and now is expanding to other bacteria species and is used to modify DNA in a precise and simple manner.

BAL Bioartificialliver.

Category formation The processof forming a group of chemicals – often termed a category – on a rational basis, suchas having a similar chemical structure or mechanism of action.

Chemical category A chemical category is a group of chemicals whose physico-chemical and human health and/or environmental toxicological properties and/or environmental fate properties are likely to be similar or follow a regular pattern as a result of structural similarity (or other similarity characteristic).

ChIP Chromatin Immuno-Precipitation, antibody based enrichement analysis of genomic regions to analyse the presence or relative distribution of histone-modifications and histone variants at and across genomic regions

             CLP Classification, Labelling and Packaging Regulation, i.e. (EC) No 1272/2008.

CNS: Central nervoussystem.

Computational Chemistry Computational chemistry is a discipline using mathematical methods for the calculation of molecular properties or for the simulation of molecular behaviour.

CSR Chemical Safety Report in the context of EU regulations of chemicals (see REACH, CLP)

CYP Cytochrome-P450

EB Embryoidbody

EC Endothelialcell

ECG Electrocardiogram

ecopa European ConsensusPlatform for 3R Alternatives

ENCODE ENCyclopediaOf DNA Elements, NHGRI programme to identify all functional elements in the human genome sequence in the human genome http://genome.ucsc.edu/ENCODE/

ECVAM EuropeanCentre for the Validation of Alternative Methods

EMEA EuropeanMedicines Agency

ES cells See pluripotentstem cells. ES cells are obtained by derivation from the inner cell mass of the embryo at the blastocyst stage (5.5 to 7.5 days after fertilization in the Human).

EST Embryonicstem cell test

ESTIV European Society of Toxicology In vitro

Expert system for predicting toxicity This is a broadly used term for any formal system, generally computer-based, whichenables a user to obtain rational predictions about the properties or biological activity of chemicals. Expert systems may be classified as knowledge-based (when the rules are based on expert knowledge), induction rule-based (when statistical methods are used to automatically derive the rules) or hybrid (when both approaches are present). One or more databases may additionally be integrated in the system.

FDA U.S. Foodand Drug Administration (TG)

FP 7 Seventh Framework Programme for Research and Technological Development of the European Union

GCCP Good Cell Culture Practice

Gesicles Methodologyfor producing proteins and transferring them to target cells, based upon the introduction in producing cells of the gene encoding the viral fusiogenic protein VSVG. Vesicles (“Gesicles” where the G stands for the G viral protein) formed and released by those producing cells are, then, both much more numerous and very prone to fusion with cell membranes. Engineering producing cells with constructs encoding proteins of interest leads to packing of well translated and processed proteins in gesicles, providing a way to produce and transfer proteins into target cells where normal function has been well demonstrated.

GFP Green fluorescent protein

GLP Good laboratory practice

GMP Good manufacturing practice

Gold Compound: A well characterised compound for toxicity testing.

HBV Hepatitis B virus

HCC Hepatocellular carcinoma

HCV Hepatitis C virus

Hep G2 cells A HCC derivedhuman hepato-carcinoma cell line (ATCC No. HB-8065) from liver tissue of a 15 year old Caucasian American male with a well differentiated hepatocellular carcinoma.

HepaRG cell line  HepaRG is an immortalized cell line of the liver that can be differentiated into hepatocytes which retain many characteristics of primary human hepatocytes.

hES cell Human embryonic stem cell

hiPS cell Human induced pluripotent stem cell

HSC Hepatic stellate cells

HSEC Hepatic sinusoidal endothelial cells

HTS High-Throughput-Screening

In silicomethods for toxicity prediction  The use of computer-based methods e.g. databases, (Q)SARs, read-across etc to retrieve or estimate toxicological effects of chemicals. These do not require the testing of a chemical (and hence can be termed non-testing information).

Intermediate precursors Cells that are committed to a specific lineage but are not terminally fully differentiated and exhibit the capacity to self-renew without changes in phenotype for a number of passageswhen grown in culture with specific cocktails of cytokines (e.g. EGF/FGF2 for neural precursors). Intermediate precursors can be terminally differentiated into discrete populations of their lineage. For SCR&Tox purposes, intermediate precursor populations are currently available in the neural, mesodermal and keratinocyte lineages

Interoperability The abilityof two or more systems or components to exchange information and to correctly use the information that has been exchanged. More generally, it is a property of a system, whose interfaces are completely understood, to work with other systems without any restricted access or implementation.

iPS cells See pluripotent stem cells. iPS cells are most commonly obtained nowadays by transferring into replicative donors’ cells (e.g. dermic fibroblasts) genes encoding 4 transcription factors (in the original technique, designed by S. Yamanaka, c-Myc, Oct4, Klf4, Sox2). Because current techniques rely on transgene expression, they “alter” cell homeostasis, potentially in a definitive manner. Alternative methods – referred to in the SCR&Tox project as “clean reprogrammation” – are therefore actively sought.

ITS  Integrated Testing Strategy. An ITS is an approach that integrates different types of toxicological data and information into a decision-making process for the safety of a chemical. In additionto the information from individual assays, test batteries, and/or tiered test schemes, integrated testing strategies may incorporate approaches such as weight-of-evidence and exposure/ population data into the final risk assessment for a substance.

Lattice-based model Single-cell based model comprising different classes: (i) each lattice site can be occupied by at most one cell (for cells with homogenous size and shape and fixed positions); (ii) a cell may span many lattice sites (for migrating cells with complex shapes); (iii) lattice sites can be occupied by many cells (for growing cell populations). Lattice models are rule based and do not directly represent the physical reality.

Lattice-free model Represent deformable spheres or ellipses. In some approaches each cell is mimicked by an aggregate of many spheres. Compared with lattice-based models, off-lattice models permit to better directly represent the physical reality.

lin-log kinetics Reaction rates are linearly dependent on enzyme concentration and on the logarithm of concentrations. Rates are defined with respect to a reference state.

Linked Data A method of publishing structured data, so that it can be interlinked and become more useful. It builds upon standard Web technologies, but rather than using them to serve web pages for human readers, it extends them to share information in a way that can be read automatically by computers. This enables data from different sources to be connected and queried.

Linked Resources Linked Data approach expanded to all resources including for compounds, biomaterials, assays, algorithms, models, analysis, validation and reports.

MEA Microelectrode array

Mechanism of toxic action The mechanism of toxic action is the molecular sequence of events leading fromthe absorption of an effective dose of a chemical to the production of a specific toxicological response in the target organ or organism.

MeDIP profile Methylated DNA immuno-precipitation - a method to analyse the DNA methylation across the genome using antibodies directed against modified cytosines (e.g. 5-methyl-cytosine or 5-hydroxymethylcytosine). Profiling across the genome involved either subsequent next-generation sequencing MeDIP-Seq or array (MeDIP-Chip) technologies.

Meganucleases Endonucleases, either natural or specifically engineered, that are capable of identifying a very discrete region of the DNA and to cut it, resulting in the disruption of a specific sequence with the potential insertion of a construct of interest. One construct used in SCR&Tox is a so-called “landing pad”, i.e. a sequence that has been engineered in order to facilitate homologous recombination of various gene constructs that will be secondarily introduced into cells that carry the “landing pad”. Flanking regions of the “landing pad” have been engineered in order to allow meganucleases to retrieve the entire region, leaving no scar in the host genome.

MID Moulded interconnectdevice

miRNA MicroRNA

MRM: Multiple Reaction Monitoring (MRM), simultaneous quantification of a large number of peptides (several hundreds) in transcriptomics (Toxicoproteomics).

mRNA MessengerRNA

MS Massspectrometry

M.SssI DNA methyltransferase from Spiroplasma sp. with the DNA sequence specificity CpG.

MTT assay Assays for measuring the activity of enzymes that reduce 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) or close dyes (XTT, MTS, WSTs) to formazan dyes, giving a purple color. Used to assess the viability (cell counting) and the proliferation of cells (cell culture assays), as well as cytotoxicity.

NIH reference map Epigenome reference map: A program launched by the NIH to uncover the epigenomic landsacape across human cells

http://www.roadmapepigenomics.org/

NMR Nuclear magneticresonance

NOAEC  No observedadverse effect concentration

NOAEL  No observedadverse effect level

Non-testing information Non-testing data can be generated by three main approaches: a) grouping approaches, whichinclude read-across and chemical category formation; (quantitative) structure-activity relationships ((Q)SARs); and c) expert systems.

OECD Principles for the Validation of (Q)SARs  A series of rules to assist in the evaluation of a (Q)SAR for use for regulatory purposes. These state that to facilitate the consideration of a (Q)SAR model for regulatory purposes, it should be associated with the following information:

i) a defined endpoint

ii) an unambiguous algorithm

iii) a defined domain of applicability

iv) appropriate measures of goodness-of-fit, robustness and predictivity

v) a mechanistic interpretation, if possible (COSMOS)

OECD QSAR Application Toolbox Software tool (under development)  that allows the user to:  a) make (Q)SAR estimations for single chemicals; b) receive summary information on the validation results of the model according to the OECD validation principles; c) receive a list of analogues, together with their (Q)SAR estimates; d) receive estimates for metabolite activation/detoxification information. The Toolbox is freely downloadable from www.qsartoolbox.org

Ontology  An ontology is a formalrepresentation of knowledge as a set of concepts within a domain, and the relationships between those concepts. Domain experts are required to specify an ontology. Computer scientists use ontologies to reason about entities within that domain in the creation of user applications.

PBPK models  Physiologically-based Pharmacokinetic models. These models apply a realistic mathematical descriptionof physiology and biochemistry to simulate ADME (Absorption, Distribution, Metabolism, Excretion) processes and assess the distribution of chemicals and their metabolites in the body throughout time. They are particularly adapted to interspecies extrapolation and can be calibrated based on in vivo, in vitro or in silico data.

Pluripotent stem cell lines These cells are of embryonic origin (ES cells) or induced to pluripotency by genetic re-programmation of somatic cells from donors (iPS cells). They share two main attributes, unlimited self-renewal –which makes them formally immortal- and pluripotency, the ability to differentiate into any cell type of the body at any stage of differentiation.

Polycomb changes Polycomb proteins are involved in setting and maintenance of epigenetic marks at developmentally regulated genes (such as HOX genes). Changes in the patterns of polycomb genes are indicative of changes in the epigenetic programs set across the genome.

QC Quality control

qRT-PCR  Quantitativereal-time polymerase chain reaction

QSAR A Quantitative Structure-Activity Relationship (QSAR) is a quantitative relationship between a biological activity (e.g., toxicity) and one or more molecular descriptors that are used to predict the activity. A molecular descriptor is a structural or physicochemical property of a molecule, or part of a molecule, which specifies a particular characteristic of the molecule and is used as an independent variable in a QSAR.

QT interval: The duration of ventricular depolarization and subsequent repolarization.

REACH Regulationon Registration, Evaluation, Authorisation and Restriction of Chemicals.

Read-across  A method for filling data gaps in either the analogue or category approaches. Endpoint informationfor one chemical is used to make a prediction of the endpoint for another chemical, which is considered to be similar in some way. In principle, read-across can be used to assess physicochemical properties, environmental fate and (eco)toxicity effects, and it may be performed in a qualitative or quantitative manner.

In qualitative read-across, the potential of a chemical to exhibit a property is inferred from the established potential of one or more analogues.

In quantitative read-across, the numerical value of a property (or potency of an endpoint) of a chemical is inferred from the quantitative data of one or more analogues.

RNA Ribonucleic acid

RTD Research and technical development

SAR Structure Activity Relationships (SARs) are theoretical models that can be used to predict in a qualitative manner the physicochemical, biological (e.g., toxicological) and fate properties of molecules from knowledge of chemical structure. More specifically, a SAR is a qualitative relationship (i.e. association) between a molecular (sub)structure and the presence or absence of a given biological activity, or the capacity to modulate a biological activity imparted by another substructure.

The term substructure refers to an atom, or group of adjacently connected atoms, in a molecule. A substructure associated with the presence of a biological activity is sometimes called a structural alert.

A SAR can also be based on the ensemble of steric and electronic features considered necessary to ensure the intermolecular interaction with a specific biological target molecule, which results in the manifestation of a specific biological effect. In this case, the SAR is sometimes called a 3D SAR or pharmacophore.

SCCSScientific Committee on Consumer Safety. This EU Committee provides opinions on health and safety risks (chemical, biological, mechanical and other physical risks) of non-food consumer products (e.g. cosmetic products and their ingredients, toys, textiles, clothing, personal care and household products) and services (e.g. tattooing, artificial sun tanning).

shRNA Short hairpin RNA

siRNA  Short interfering RNA

SOP Standard Operating Procedure

Tanimoto criteria  Molecular Similaritycriteria for chemicals based upon Tanimoto Coefficients.

TBBB The ToxBank BioBank (TBBB) will establish a banking information resource for access to qualified cells, cell lines(including stem cells and stem cell lines), tissues and reference materials to be used for in vitro predictive toxicology research and testing activities.

TBCR The ToxBank Chemical Repository will ensure the availability of test compounds to researchersof the SEURAT-1 Research Initiative.

TBDW  The ToxBank Data Warehouse will establish a centralised compilation of data for systemic toxicity.

TBGCD  The ToxBank Gold Compound Database will provide a information resource servicing the selection and use of test compounds.

Toxicological data Data relating to the harmful (toxicological) effects of chemicals. This may include information from animal, human or non-animal (in vitro) tests.

TTC Thresholds of toxicological concern (TTCs) have been developed for risk assessment of compounds of knownchemical structure for which no compound-specific toxicity data are available. Below the TTC value the risk to human health is assumed to be negligible. The TTC may be used as a substitute for substance-specific information in situations where there is limited or no information on the toxicity of a compound, and where human exposure is so low, i.e. below the corresponding TTC, that adverse effects are not to be expected.

VE-cadherin Vascular endothelialcadherin

Web Service A method of communication between two electronic devices over a network.

ZFN-HR Zinc finger nuclease homologous recombination.