Standardisation of defined approaches for skin sensitisation testing to support regulatory use and international adoption: position of the International Cooperation on Alternative Test Methods

Abstract

Skin sensitisation is the regulatory endpoint that has been at the centre of concerted efforts to replace animal testing in recent years, as demonstrated by the Organisation for Economic Co-operation and Development (OECD) adoption of five non-animal methods addressing mechanisms under the first three key events of the skin sensitisation adverse outcome pathway. Nevertheless, the currently adopted methods, when used in isolation, are not sufficient to fulfil regulatory requirements on the skin sensitisation potential and potency of chemicals comparable to that provided by the regulatory animal tests. For this reason, a number of defined approaches integrating data from these methods with other relevant information have been proposed and documented by the OECD. With the aim to further enhance regulatory consideration and adoption of defined approaches, the European Union Reference Laboratory for Alternatives to Animal testing in collaboration with the International Cooperation on Alternative Test Methods hosted, on 4–5 October 2016, a workshop on the international regulatory applicability and acceptance of alternative non-animal approaches, i.e., defined approaches, to skin sensitisation assessment of chemicals used in a variety of sectors. The workshop convened representatives from more than 20 regulatory authorities from the European Union, United States, Canada, Japan, South Korea, Brazil and China. There was a general consensus among the workshop participants that to maximise global regulatory acceptance of data generated with defined approaches, international harmonisation and standardisation are needed. Potential assessment criteria were defined for a systematic evaluation of existing defined approaches that would facilitate their translation into international standards, e.g., into a performance-based Test Guideline. Informed by the discussions at the workshop, the ICATM members propose practical ways to further promote the regulatory use and facilitate adoption of defined approaches for skin sensitisation assessments.

Computational approaches for skin sensitization prediction

“…When used on their own, modern theoretical and experimental AATs do not yet reach the regulatory acceptance requirements for skin sensitization risk assessment (Casati et al 2018). Therefore, organizations such as the OECD encourage the development of integrated approaches to testing and assessment (IATAs), which can be described as human expert-led, non-formalized weight of evidence approaches amalgamating results obtained from different experimental models and theoretical approaches (e.g.…”

“…Animal experiments by nature cover the whole process of skin sensitization described in the AOP, including enzymatic or physiological activation of the sensitizer. In contrast, nonanimal testing methods focus on single key events of the AOP (Ezendam et al 2016;Casati et al 2018). Therefore, the combination of different non-animal testing methods and integration with in silico methods is recommended, in particular for the task of potency prediction (Raunio 2011;Mehling et al 2012;Ezendam et al 2016;Goebel et al 2017;OECD 2017a;Casati et al 2018).…”

“…In contrast, nonanimal testing methods focus on single key events of the AOP (Ezendam et al 2016;Casati et al 2018). Therefore, the combination of different non-animal testing methods and integration with in silico methods is recommended, in particular for the task of potency prediction (Raunio 2011;Mehling et al 2012;Ezendam et al 2016;Goebel et al 2017;OECD 2017a;Casati et al 2018). Recent studies indicate that such strategies can yield higher prediction accuracies in human hazard estimation than animal experiments (van der Veen et al 2014;Urbisch et al 2015;Benigni et al 2016;Ezendam et al 2016).…”

Integrated Approaches to Testing and Assessment

“…The need to evaluate the variability of the in vivo reference data (animal and human) for the assessment of defined approaches was also discussed. From the discussions, it became evident that the certainty required by end‐users and regulatory authorities to facilitate deployment and acceptance of defined approaches may only be guaranteed if they attain the same regulatory status as the standard in vivo method(s) .…”

Contact Allergy to Fragrances: In Vitro Opportunities for Safety Assessment

“…org/10.1787/9789264229709-en) for KE1; the Keratinosens TM and LuSens TM assays (OECD TG 442D, https://doi.org/10.1787/9789264229822-en) for KE2; the human Cell Line Activation Test (h-CLAT), the U937 cell line activation test (U-SENS TM ), and the Interleukin-8 Reporter Gene assay (IL-8 Luc assay) (OECD TG 442E, https://doi.org/10.1787/9789264264359-en) for KE3. Recently published reviews provide the state of the art of data integration and best practices for implementation of defined approaches to skin sensitization testing and labeling [7][8][9]. While these methods are useful for hazard identification, classification, and labeling, they are of limited value for quantitative risk assessment and their applicability for final products is questionable due to the intrinsic limitations of the assays themselves, i.e., aqueous culture media used for cell cultures are not compatible with hydrophobic products, limited metabolic capacity, etc.…”