Review of Data Sources, QSARs and Integrated Testing Strategies for Skin Sensitisation

This review collects information on sources of skin sensitisation data and computational tools for the estimation of skin sensitisation potential, such as expert systems and (quantitative) structure-activity relationship (QSAR) models. The review also captures current thinking of what constitutes an integrated testing strategy (ITS) for this endpoint. The emphasis of the review is on the usefulness of the models for the regulatory assessment of chemicals, particularly for the purposes of the new European legislation for the Registration, Evaluation, Authorisation and Restriction of CHemicals (REACH), which entered into force on 1 June 2007. Since there are no specific databases for skin sensitisation currently available, a description of experimental data found in various literature sources is provided. General (global) models, models for specific chemical classes and mechanisms of action and expert systems are summarised. This review was prepared as a contribution to the EU funded Integrated Project, OSIRIS.JRC.I.3-Consumer products safety and qualit

Oblicza ormiańsko-azerbejdżańskiego konfliktu o Górski Karabach

Faces of the Armenia-Azerbaijan Conflict in Nagorno-Karabakh The territory of Nagorno-Karabakh had become the matter of Armenian-Azerbaijani disputes long before the establishment of the Soviet power in the Caucasus. Armenian colonization of Muslim territories intensified after each conflict which the Russian Empire was involved in, especially after the Crimean War and the Russo-Turkish War of 1876–1878. Following the conflicts which took place between 1905–1907 and 1918–1920, Karabakh became part of the Armenian national myth. The establishment of the Soviet power in November 1920 resulted in the recognition of Karabakh as part of Armenia, but the decision was reversed the following year and the region was transferred to Azerbaijan. The claim that during the times of the Soviet Union the conflict did not exist can only refer to the military state of affairs. The beginning of its current phase occurred in 1987. The Armenian Supreme Council’s decision of 10 January 1990 to cover Nagorno-Karabakh in the republican budget and grant its citizens the right to vote in Armenian general elections was another step leading to the escalation of the conflict. The authorities in Baku insist that it can only be solved according to the principle of territorial integrity, which means that the solution must assume that Nagorno-Karabakh is part of Azerbaijan. On the other hand, the Armenians invoke the right to self-determination, which, according to them, makes Karabakh’s declaration of independence legitimate. The dispute is still one of the key problems destabilizing the situation in the South Caucasus

On the Usefulness of Graph-theoretic Descriptors in Predicting Theoretical Parameters. Phototoxicity of Polycyclic Aromatic Hydrocarbons (PAHs)

Two main aspects on the use of theoretical approaches in predicting biological endpoints are addressed. The first concerns the appropriateness of theoretical methods and the misbelief that more sophisticated approaches produce better results. We demonstrate that the simple graph theoretic HMO approach produces results as good as »high level« ab initio calculations using only 10–4 to 10–7 of the time. Secondly, we investigate the feasibility of using a priori »mechanistic insights« in order to select the variables to be included in a QSAR model. As the majority of biological response measures are not specific for one particular mechanism, the use of this approach may well produce unrealistic results. The black box approach with its many descriptors and a posteriori interpretation of the results is much more appropriate in such cases where the biological response is the result of several mechanisms involving distribution and metabolism. All these aspects are analysed on the basis of the toxicity of PAHs after photoactivation by UV radiation

A Strategy for Structuring and Reporting a Read-Across Prediction of Toxicity

Category formation, grouping and read across methods are broadly applicable in toxicological assessments and may be used to fill data gaps for chemical safety assessment and regulatory decisions. In order to facilitate a transparent and systematic approach to aid regulatory acceptance, a strategy to evaluate chemical category membership, to support the use of read-across predictions that may be used to fill data gaps for regulatory decisions is proposed. There are two major aspects of any read-across exercise, namely assessing similarity and uncertainty. While there can be an over-arching rationale for grouping organic substances based on molecular structure and chemical properties, these similarities alone are generally not sufficient to justify a read-across prediction. Further scientific justification is normally required to justify the chemical grouping, typically including considerations of bioavailability, metabolism and biological/mechanistic plausibility. Sources of uncertainty include a variety of elements which are typically divided into two main issues: the uncertainty associated firstly with the similarity justification and secondly the completeness of the read-across argument. This article focuses on chronic toxicity, whilst acknowledging the approaches are applicable to all endpoints. Templates, developed from work to prepare for the application of new toxicological data to read-across assessment, are presented. These templates act as proposals to assist in assessing similarity in the 50 context of chemistry, toxicokinetics and toxicodynamics as well as to guide the systematic characterisation of uncertainty both in the context of the similarity rationale, the read across data and overall approach and conclusion. Lastly, a workflow for reporting a read-across prediction is suggested

Ability of non-animal methods for skin sensitisation to detect pre- and pro-haptens: Report and recommendations of an EURL ECVAM expert meeting

Significant progress has been made in the development, validation and regulatory acceptance of in chemico and in vitro test methods for skin sensitisation. Although these methods have been shown to perform relatively well (about 80% accuracy in predicting Local Lymph Node Assay (LLNA) classifications) a concern was raised on the regulatory acceptability of negative results since it was questioned whether these methods are able to predict chemicals that need to be activated to act as sensitisers. In order to inform ongoing discussions at the regulatory level in the EU, EURL ECVAM held an expert meeting on 10-11 November 2015 to analyse the extent to which in chemical and in vitro methods are able to correctly identify chemicals that need to be activated either through abiotic activation (pre-haptens) and/or through biotic (enzyme-mediated) mechanisms (pro-haptens) to acquire skin sensitisation potential. The expert group analysed a list of 127 chemicals, with available LLNA and in vitro data, 22% of which were considered to be pre- and/or pro-haptens. The pre-haptens, constituting the vast majority of chemicals requiring activation, where mostly correctly identified by both the in chemico and in vitro assays whereas the pro-haptens which represent a small subset of sensitising chemicals, were generally identified correctly by one of the cell-based assays. As a result, the expert group recommended that negative in vitro data should be accepted unless there is a compelling scientific argument that a substance is likely to be an exclusively metabolically activated pro-hapten.JRC.I.5-Systems Toxicolog

Applying Adverse Outcome Pathways (AOPs) to support Integrated Approaches to Testing and Assessment (IATA)

Chemical regulation is challenged by the large number of chemicals requiring assessment for potential human health and environmental impacts. Current approaches are too resource intensive in terms of time, money and animal use to evaluate all chemicals under development or already on the market. The need for timely and robust decision making demands that regulatory toxicity testing becomes more cost-effective and efficient. One way to realize this goal is by being more strategic in directing testing resources; focusing on chemicals of highest concern, limiting testing to the most probable hazards, or targeting the most vulnerable species. Hypothesis driven Integrated Approaches to Testing and Assessment (IATA) have been proposed as practical solutions to such strategic testing. In parallel, the development of the Adverse Outcome Pathway (AOP) framework, which provides information on the causal links between a molecular initiating event (MIE), intermediate key events (KEs) and an adverse outcome (AO) of regulatory concern, offers the biological context to facilitate development of IATA for regulatory decision making. This manuscript summarizes discussions at the Workshop entitled “Advancing AOPs for Integrated Toxicology and Regulatory Applications” with particular focus on the role AOPs play in informing the development of IATA for different regulatory purposes.publishedVersio

Navigating through the minefield of read-across frameworks: A commentary perspective

Read-across is a popular data gap filling technique used within analogue and category approaches for both regulatory and product stewardship purposes. In recent years there have been many efforts focused on the challenges involved in read-across development, its scientific justification and documentation for both chemical hazard and risk assessment purposes. Here, we summarise a selection of the read-across frameworks published in technical guidance documents or in the literature, and review their respective similarities and differences. There was a great deal of consensus between the different frameworks in terms of the general steps outlined and the similarity contexts considered although the terminology, decision context (chemical hazard and/or risk assessment purposes) and scope varied. A harmonised hybrid framework is proposed to help reconcile the common guiding principles and steps of the read-across process which should be helpful in expanding the scope and decision context of the existing frameworks. This harmonised framework is also intended to illustrate where generalised and systematic read-across approaches taking into consideration new approach methodology (NAM) information can be applied

Global QSAR models of skin sensitisers for regulatory purposes

Abstract Background The new European Regulation on chemical safety, REACH, (Registration, Evaluation, Authorisation and Restriction of CHemical substances), is in the process of being implemented. Many chemicals used in industry require additional testing to comply with the REACH regulations. At the same time EU member states are attempting to reduce the number of animals used in experiments under the 3 Rs policy, (refining, reducing, and replacing the use of animals in laboratory procedures). Computational techniques such as QSAR have the potential to offer an alternative for generating REACH data. The FP6 project CAESAR was aimed at developing QSAR models for 5 key toxicological endpoints of which skin sensitisation was one. Results This paper reports the development of two global QSAR models using two different computational approaches, which contribute to the hybrid model freely available online. Conclusions The QSAR models for assessing skin sensitisation have been developed and tested under stringent quality criteria to fulfil the principles laid down by the OECD. The final models, accessible from CAESAR website, offer a robust and reliable method of assessing skin sensitisation for regulatory use.</p

AMBIT RESTful web services: an implementation of the OpenTox application programming interface

The AMBIT web services package is one of the several existing independent implementations of the OpenTox Application Programming Interface and is built according to the principles of the Representational State Transfer (REST) architecture. The Open Source Predictive Toxicology Framework, developed by the partners in the EC FP7 OpenTox project, aims at providing a unified access to toxicity data and predictive models, as well as validation procedures. This is achieved by i) an information model, based on a common OWL-DL ontology ii) links to related ontologies; iii) data and algorithms, available through a standardized REST web services interface, where every compound, data set or predictive method has a unique web address, used to retrieve its Resource Description Framework (RDF) representation, or initiate the associated calculations

Addressing a bottle neck for regulation of nanomaterials: quantitative read-across (Nano-QRA) algorithm for cases when only limited data is available

The number and variety of engineered nanoparticles have been growing exponentially. Since the experimental evaluation of nanoparticles causing public health concerns is expensive and time consuming, efficient computational tools are amongst the most suitable approaches to identifying potential negative impacts, to the human health and the environment, of new nanomaterials before their production. However, developing computational models complimentary to experiments is impossible without incorporating consistent and high quality experimental data. Although there are limited available data in the literature, one may apply read-across techniques that seem to be an attractive and pragmatic alternative way of predicting missing physico-chemical or toxicological data. Unfortunately, the existing methods of read-across are strongly dependent on the expert's knowledge. In consequence, the results of estimations may vary dependently on personal experience of expert conducting the study and as such cannot guarantee the reproducibility of their results. Therefore, it is essential to develop novel read-across algorithm(s) that will provide reliable predictions of the missing data without the need to for additional experiments. We proposed a novel quantitative read-across approach for nanomaterials (Nano-QRA) that addresses and overcomes a basic limitation of existing methods. It is based on: one-point-slope, two-point formula, or the equation of a plane passing through three points. The proposed Nano-QRA approach is a simple and effective algorithm for filling data gaps in quantitative manner providing reliable predictions of the missing data. © The Royal Society of Chemistry