Special Issue "Cosmetic Contact Allergens"

In Europe, a cosmetic is defined as any substance or preparation intended to be placed in contact with the various external parts of the human body (epidermis, hair system, nails, lips and external genital organs) or with the teeth and the mucous membranes of the oral cavity with a view exclusively or mainly to cleaning them, perfuming them, changing their appearance and/or correcting body odours and/or protecting them or keeping them in good condition.[...

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

Consensus Report on the Future of Animal-Free Systemic Toxicity Testing

Since March 2013, animal use for cosmetics testing for the European market has been banned. This requires a renewed view on risk assessment in this field. However, in other fields as well, traditional animal experimentation does not always satisfy requirements in safety testing, as the need for human-relevant information is ever increasing. A general strategy for animal-free test approaches was outlined by the US National Research Council’s vision document for Toxicity Testing in the 21st Century in 2007. It is now possible to provide a more defined roadmap on how to implement this vision for the four principal areas of systemic toxicity evaluation: repeat dose organ toxicity, carcinogenicity, reproductive toxicity and allergy induction (skin sensitization), as well as for the evaluation of toxicant metabolism (toxicokinetics) (Fig. 1). CAAT-Europe assembled experts from Europe, America and Asia to design a scientific roadmap for future risk assessment approaches and the outcome was then further discussed and refined in two consensus meetings with over 200 stakeholders. The key recommendations include: focusing on improving existing methods rather than favoring de novo design; combining hazard testing with toxicokinetics predictions; developing integrated test strategies; incorporating new high content endpoints to classical assays; evolving test validation procedures; promoting collaboration and data-sharing of different industrial sectors; integrating new disciplines, such as systems biology and high throughput screening; and involving regulators early on in the test development process. A focus on data quality, combined with increased attention to the scientific background of a test method, will be important drivers. Information from each test system should be mapped along adverse outcome pathways. Finally, quantitative information on all factors and key events will be fed into systems biology models that allow a probabilistic risk assessment with flexible adaptation to exposure scenarios and individual risk factors

ESAC Opinion on the BASF-coordinated Performance Standards-based validation of the LuSens test method for skin sensitisation testing

ESAC, the EURL ECVAM Scientific Advisory Committee, advises EURL ECVAM on scientific issues. Its main role is to conduct independent peer review of validation studies of alternative test methods and to assess their scientific validity for a given purpose. The committee reviews the appropriateness of study design and management, the quality of results obtained and the plausibility of the conclusions drawn. ESAC peer reviews are formally initiated with a EURL ECVAM Request for ESAC Advice, which provides the necessary background for the peer-review and establishes its objectives, timelines and the questions to be addressed. The peer review is normally prepared by specialised ESAC Working Groups. These are typically composed of ESAC members and other external experts relevant to the test method under review. These experts may be nominated by ESAC, EURL ECVAM and partner organisations within the International Cooperation on Alternative Test Methods (ICATM). ESAC ultimately decides on the composition of these Working Groups. ESAC's advice to EURL ECVAM is formally provided as 'ESAC Opinions' and 'Working Group Reports' at the end of the peer review. ESAC may also issue Opinions on other scientific issues of relevance to the work and mission of EURL ECVAM but not directly related to a specific alternative test method. The ESAC Opinion expressed in this report relates to the peer-review of the BASF-coordinated Performance Standards-based validation of the LuSens test method for skin sensitisation testing.JRC.F.3-Chemicals Safety and Alternative Method

Measurement of CD4+ and CD8+ T-Lymphocyte Cytokine Secretion and Gene Expression Changes in p-Phenylenediamine Allergic Patients and Tolerant Individuals

Factors predisposing to individual susceptibility to contact allergic dermatitis are ill defined. This study was designed to characterize the response of allergic and tolerant individuals’ T-lymphocytes after exposure to p-phenylenediamine (PPD). Peripheral blood mononuclear cells (PBMCs) from allergic patients proliferated when treated with PPD and Bandrowski's base (BB) and secreted IL-1α, -1β, -4, -5, -6, -8, -10, and -13; IFN-γ; tumor necrosis factor-α; MIP-1α/β; MCP-1 (monocyte chemotactic protein-1); and RANTES. PBMCs from tolerant individuals were stimulated to proliferate only with BB, and they secreted significantly lower levels of Th2 cytokines. Principal component analysis showed that genes are differentially expressed between the patient groups. A network-based analysis of microarray data showed upregulation of T helper type 2 (Th2) gene pathways, including IL-9, in allergic patients, but a regulatory gene profile in tolerant individuals. Real-time PCR confirmed the observed increase in Th2 cytokine gene transcription in allergic patients. Purified CD4+ and CD8+ T cells from allergic patients were stimulated to proliferate and secrete Th2 cytokines following antigen exposure. Only CD4+ T cells from tolerant individuals were stimulated by BB, and levels of Th2 cytokines were 80% lower. The nature of the antigenic determinant stimulating PBMCs and levels of Th2 cytokines, including IL-9, was confirmed in a validation cohort. These studies show increased activity of Th2 cytokines in CD4+ and CD8+ T cells from individuals with allergic contact dermatitis

Representations of sport in the revolutionary socialist press in Britain, 1988–2012

This paper considers how sport presents a dualism to those on the far left of the political spectrum. A long-standing, passionate debate has existed on the contradictory role played by sport, polarised between those who reject it as a bourgeois capitalist plague and those who argue for its reclamation and reformation. A case study is offered of a political party that has consistently used revolutionary Marxism as the basis for its activity and how this party, the largest in Britain, addresses sport in its publications. The study draws on empirical data to illustrate this debate by reporting findings from three socialist publications. When sport did feature it was often in relation to high profile sporting events with a critical tone adopted and typically focused on issues of commodification, exploitation and alienation of athletes and supporters. However, readers’ letters, printed in the same publications, revealed how this interpretation was not universally accepted, thus illustrating the contradictory nature of sport for those on the far left

t4 Workshop Report: Integrated Testing Strategies (ITS) for Safety Assessment

Integrated testing strategies (ITS), as opposed to single definitive tests or fixed batteries of tests, are expected to efficiently combine different information sources in a quantifiable fashion to satisfy an information need, in this case for regulatory safety assessments. With increasing awareness of the limitations of each individual tool and the development of highly targeted tests and predictions, the need for combining pieces of evidence increases. The discussions that took place during this workshop, which brought together a group of experts coming from different related areas, illustrate the current state of the art of ITS, as well as promising developments and identifiable challenges. The case of skin sensitization was taken as an example to understand how possible ITS can be constructed, optimized and validated. This will require embracing and developing new concepts such as adverse outcome pathways (AOP), advanced statistical learning algorithms and machine learning, mechanistic validation and “Good ITS Practices”.JRC.I.5-Systems Toxicolog

Legislative Aspects of Cosmetic Safety in the European Union: The Case of Contact Allergy

For several decades, the European Union (EU) has amongst its many tenets and principles the aim, enshrined in an EU Directive, that cosmetic products should not cause harm to the consumer. To a great extent, this is been successful, although it is noteworthy that the frequency of contact allergy to a number of ingredients commonly found in cosmetics has remained stubbornly high. Perhaps because of this, but certainly because of the drive by the European Commission towards better, more streamlined, regulation, the Directive was recast into a Regulation, usually referred to as the EU Cosmetics Regulation ((EC) No 1223/2009). As with the Directive, for each and every cosmetic product placed on the consumer market in the EU, a safety assessment is required. The Regulation requires that a dossier is prepared detailing the composition of the product, the safety of each of its ingredients, as well as an evaluation of overall product safety. This has to be completed by suitably trained and qualified assessors. Also relevant to cosmetic products are the general regulations pertaining to chemicals used in the EU where again many details of the toxicological profile must be ascertained and reviewed. On this basis, it should be possible to ensure that the extent of contact allergy attributed to cosmetic products declines. However, legislation is one thing, but it is also necessary to ensure that the cosmetic industry safety assessment process is completed in a rigourous manner (or even done at all) and that demands enforcement of the legislation

Dermal Toxicity: skin sensitzation

When one considers the huge spectrum of chemicals that are available in the world today (sometimes estimated at greater than 100,000) the opportunities for adverse health effects following exposure to these chemicals can appear to be very great. However, the reality is that most of the substances do not cause any significant impact on human health. Perhaps the most common effect, and certainly the most common in the field demeanour toxicology, appear to be the allergic responses that arise in susceptible individuals following exposure to chemicals that possess skin sensitising properties. It is not appropriate in this chapter to delve into great detail concerning the mechanistic immunobiology of skin sensitisation nor to provide a detailed account of the substances that are sensitising and the clinical effects known as allergic contact dermatitis (ACD) that they can produce. The mechanisms of skin sensitisation have been extensively reviewed elsewhere (1 - 3). In brief, to behave as a skin sensitiser a chemical must penetrate into the viable layers of the epidermis and once there form a stable association with skin proteins, typically via covalent binding. If this event occurs in the presence of danger signals (4, 5), the dendritic cells of the skin will be triggered to migrate to the draining lymph nodes where, in their mature form, they will interact with T lymphocytes. Those T lymphocytes bearing surface receptors which recognise the chemically modified protein being presented by the dendritic cell will be stimulated into clonal expansion and the daughter cells released back to the systemic circulation. When this process happens to a sufficient extent, the sensitised state has said to be to have been induced. Subsequent exposure to the same chemical by the dermal route can then elicit the characteristic delayed inflammatory response which we recognise as allergic contact dermatitis (ACD). The panoply of substances which can give rise to ACD and are most commonly diagnosed, include transition metals (nickel, chromium and cobalt), fragrance chemicals, preservatives, various topical medicaments, rubber chemicals, epoxy resins, acrylates, plant defence substances (e.g. pentadecylcatechol in poison ivy), and many others. They are fully detailed in current textbooks of contact dermatitis (6, 7) and in guidance concerning diagnosis of this disease (8). From the perspective of the practicing toxicologist what is therefore most important is to have the capacity to identify potential causes of allergic contact dermatitis, i.e. skin sensitizing chemicals, so that such hazards can be characterised and the risks they present to human health the assessed and appropriately managed (9). In the material which follows, a very brief account of in vivo predictive methods will be given so that an appreciation of the information these tests produce and how it is used can be gained. Subsequently, the details of in vitro methods that seem close to successful validation will be offered, together with the discussion concerning the strengths and limitations of the information that the yield. Finally, the focus will be on how we may in the reasonably foreseeable future try to close the remaining gaps so that using only non-animal methods, at least for this endpoint in toxicology, human health can people be protected as, or even more, successfully them in recent yearsJRC.I.5-Systems Toxicolog