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Utility of integrated non-animal approaches for skin sensitisation for safety assessment of cosmetics
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Abstracts / Toxicology Letters 258S (2016) S2–S10
CEC 1: Integrative Approaches to Testing and Assessment (IATA) for skin sensitization: From theory to practice CEC1-1 How to use non-animal test methods for skin sensitisation in the context of REACH Regulation Laura H. Rossi Evaluation, European Chemicals Agency, Helsinki, Finland Recently several in chemico/in vitro methods for skin sensitisation have been adopted by the OECD. The test methods are based on the key events as described in the OECD Adverse Outcome Pathway (AOP) for skin sensitisation (2012). The recent developments in the area have led to the revision of the standard information requirements for skin sensitisation under REACH. The revised Annex VII, section 8.3 of the REACH Regulation, which anticipated entry into force is in autumn 2016, contains as a first step information generation by non-animal testing methods. New in vivo testing, preferably by using Local Lymph Node Assay, should only be done as a last resort. As the new in chemico/in vitro test methods should not be used as a stand-alone method due to test method specific limitations, a combination of these methods should be used. Additional information obtained from other approaches such as (Q)SARs or read-across may assist in making an adequate conclusion that is suitable for classification and risk assessment. The aim of this session is to explain the changes of the revised information requirements for skin sensitisation and how these non-animal testing methods can be used for REACH purposes. http://dx.doi.org/10.1016/j.toxlet.2016.06.026 CEC1-2 OECD guidance on the reporting of defined approaches and individual information sources to be used within Integrated Approaches to Testing and Assessment (IATA) for skin sensitization Silvia Casati EURL ECVAM, Joint Research Centre, European Commission, Italy With a view to assisting the evaluation of integrated approaches to testing and assessment (IATA) in regulatory decision-making, the OECD developed a guidance document (GD) which provides templates for reporting defined approaches to testing and assessment that can be used as one of the components within IATA. A defined approach to testing and assessment consists of a fixed data interpretation procedure (DIP) applied to data generated with a defined set of information sources (e.g. in silico, in chemico, in vitro methods) to derive a prediction that can either be used on its own, or together with other information sources within an IATA, to satisfy a specific regulatory need. The GD is intended to be used alongside similar guidance aimed at harmonising the reporting of other IATA components such as QSARs, grouping and read-across strategies, and non-guideline in vitro methods. The reporting templates have been used to describe a number of defined approaches to testing and assessment for skin sensitisation hazard and potency prediction and the individual information sources used within these approaches. http://dx.doi.org/10.1016/j.toxlet.2016.06.027
CEC1-3 From theory to practice: Case studies illustrating different defined approaches for testing and assessment for skin sensitization Janine Ezendam National Institute for Public Health and the Environment (RIVM), Netherlands In the last years, different non-animal methods for skin sensitization testing were developed. The OECD has accepted three non-animal test methods as test guidelines. These methods address different key events of the Adverse Outcome Pathway (AOP) for skin sensitization, e.g. protein binding, activation of keratinocytes and activation of dendritic cells. This AOP describes the linkages between the molecular initiating event (protein binding) and subsequent key events that occur at the cellular and organ levels that lead to the adverse outcome (skin sensitization). This AOP is used as a mechanistic framework for the development of defined approaches to test and assess the skin sensitization potential and/or potency of chemicals. In the last years, several different defined approaches for the assessment of skin sensitization were proposed. There are differences in both the construction of these approaches and the procedures for data interpretation to come to a prediction. In this CEC course, examples of such approaches are presented. Attention is given to the rationale underlying the construction of the defined approaches and the information sources used. The data interpretation procedures (DIPs) applied to predict whether a chemical is a skin sensitizer or not, are explained as well. These DIPs can be simple, e.g. a 2 out of 3 approach in which two concordant results addressing two different key events indicate the sensitizing potential of a chemical. DIPs that are more complex are used, for example Bayesian or neural networks. Finally, predictive capacity, technical limitations and known uncertainties of the different approaches are discussed. http://dx.doi.org/10.1016/j.toxlet.2016.06.028 CEC1-4 Utility of integrated non-animal approaches for skin sensitisation for safety assessment of cosmetics Sebastian Hoffmann Consultant of Cosmetics Europe/SEH Consulting Services, Germany Current efforts to assess skin sensitisation without animal testing focus on hazard identification. Only a few approaches have attempted to provide information on skin sensitisation potency of chemicals. While of lesser relevance for industrial chemicals, potency information is essential for the safety assessment of cosmetic ingredients. Therefore, Cosmetics Europe’s Skin Tolerance Task Force has set up a multi-phase program to develop an approach that allows skin sensitisation safety assessment of cosmetic ingredients without the need for animal data. In the first phase, 16 individual test methods were assessed. In the second phase, a systematic evaluation of existing testing strategies was conducted using a specifically compiled a highly curated database of 130 substances with test data of several non-animal test methods as well as Local Lymph Node Assay (LLNA) and human reference data. In this evaluation existing integrated approaches have characterised with a pre-defined set of criteria covering basic, practical
Abstracts / Toxicology Letters 258S (2016) S2–S10
S3
and mechanistical aspects. In addition, the predictive performance of approaches, for which all input data were available, has been assessed using the same set of animal and human reference values. As a subset of the 130 substances were not part of the training set of the existing approaches, this independent assessment allowed to challenge these approaches with a test set of substances. Through this programme, Cosmetics Europe aims to identify or develop integrated non-animal approaches tailored for cosmetic ingredients, and to explore ways how to conduct safety assessment with the information provided by these approaches.
opment program. This lecture is designed to cover a number of basic concepts of ADME, pharmacokinetics and concepts applied to non-clinical safety studies in support of early drug R&D.
http://dx.doi.org/10.1016/j.toxlet.2016.06.029
Philip Timmerman
CEC1-5 Computational tools and their role in integrative approaches
Janssen R&D, on Behalf of EBF, Belgium
Steve Enoch School of Pharmacy and Biomolecular Sciences, United Kingdom The aim of this presentation will be to outline the use of computational approaches such as grouping and read-across in regulatory toxicology using skin sensitisation as an example endpoint. The talk will take the form of a workshop and will outline the importance of the Adverse Outcome Pathway (AOP) approach and how chemistry can be used to group chemicals based on knowledge of the Molecular Initiating Event within the AOP paradigm. A discussion of the advantages and limitations of this approach in comparison to other computational methods will also be discussed. The talk will conclude with how this information can be useful in a wider integrated testing and assessment strategy for the non-animal prediction of skin sensitisation. http://dx.doi.org/10.1016/j.toxlet.2016.06.030 CEC 2: Toxicokinetics CEC2-1 Basic ADME in non-clinical drug discovery and development Richard John Weaver Servier Group, 50 rue Carnot, 92284 Suresnes Cedex, France The assessment of physicochemical and pharmacological properties of chemical series is conducted at an early stage of drug discovery for the purpose of accelerating identification of druggable chemistry into qualified candidates for non-clinical development. In particular, in vitro absorption, distribution, metabolism and elimination (ADME) assays and in vivo drug metabolism pharmacokinetic (DMPK) studies are performed throughout the discovery process, from ‘hit’ to ‘lead’ optimization. The goal of these early studies is to reduce attrition rates due to poor ADME and PK before they progress through to subsequent phases of non-clinical assessment. The study of ADME/PK has developed into a relatively mature discipline in drug discovery through the application of wellestablished in vitro and in vivo methodologies in conjunction with bioanalytics to enhance the success of drug leads. The information on ADME/PK is gathered to support pharmacology and non-clinical safety studies as an integral part of any drug discovery and devel-
http://dx.doi.org/10.1016/j.toxlet.2016.06.093 CEC2-2 Applying the right level of bioanalytical method validation for PK analysis in support of preclinical (tox) studies
In this presentation, Philip will give feedback on the progress from the EBF (European Bioanalysis Forum) an in industry on their efforts to provide practical and tangible solutions for a harmonized implementation scientific validation as part of the principles of tiered approach, with focus on early preclinical (Tox) studies. By describing tiered approach as different levels of scientific validation alongside the established regulatory validation, EBF aims at providing the industry an acceptable tool for scientific validation for studies where the Guidance was not the intended scope. The practice of adopting more lean validation requirements, especially in earlier stages of development, suggested in Crystal City III (Viswanathan et al., 2007), further highlighted in recent (draft) Guidance (BioAnalysisForum, 2016; FDA, 2016) and confirmed during discussions at the Crystal City-V meeting (Baltimore, USA, December 2013) stimulated the EBF to seek further alignment and provide practical solutions to bring tiered approach into practice (Timmerman et al., 2014). In 2015, the discussion continued in meetings not only in the EBF community, but also outside Europe (DV-DMDG (January 2015) (Timmerman et al., 2015), JBF (February 2015), CPSA-Shanghai (April 2015), CPSA-US and AAPS (both October 2015). Finally, the EBF published their recommendation on bringing scientific validation into practice for 5 areas/assay types (Anon., 2015). The current presentation will focus on the principles of the recent recommendation and aims at stimulating an open discussion in the toxicokinetic community on the advantages and/or risk associated with a more lean approach to bioanalytical method validation. References Anon., 2015. Tiered approach into practice-scientific validation for chromatographybased assays: a recommendation from the European Bioanalysis Forum. Bioanalysis (in press). http://bioanalysisforum.jp/images/T130918I0020.pdf#zoom=100. http:// www. fda. gov/ downloads/ Drugs/ GuidanceComplianceRegulatory Information/ Guidances/ UCM368107. pdf. Timmerman, P., et al., 2014. Feedback from the European Bioanalysis Forum Workshop: taking tiered approach to the next level. Bioanalysis 7 (7), 815–824. Timmerman, P., et al., 2015. Scientific or regulated validation - a tiered approach? Meeting report from a Joint EBF/DVDMDG Workshop. Bioanalysis 7 (August (14)), 1703–1710. Viswanathan, C.T., et al., 2007. Workshop/Conference Report — Quantitative Bioanalytical Methods Validation and Implementation: Practices for Chromatographic and Ligand Binding Assays. Workshop/Conference Report. AAPS J. 9 (1), E30–E42.
http://dx.doi.org/10.1016/j.toxlet.2016.06.094
Abstracts / Toxicology Letters 258S (2016) S2–S10
CEC 1: Integrative Approaches to Testing and Assessment (IATA) for skin sensitization: From theory to practice CEC1-1 How to use non-animal test methods for skin sensitisation in the context of REACH Regulation Laura H. Rossi Evaluation, European Chemicals Agency, Helsinki, Finland Recently several in chemico/in vitro methods for skin sensitisation have been adopted by the OECD. The test methods are based on the key events as described in the OECD Adverse Outcome Pathway (AOP) for skin sensitisation (2012). The recent developments in the area have led to the revision of the standard information requirements for skin sensitisation under REACH. The revised Annex VII, section 8.3 of the REACH Regulation, which anticipated entry into force is in autumn 2016, contains as a first step information generation by non-animal testing methods. New in vivo testing, preferably by using Local Lymph Node Assay, should only be done as a last resort. As the new in chemico/in vitro test methods should not be used as a stand-alone method due to test method specific limitations, a combination of these methods should be used. Additional information obtained from other approaches such as (Q)SARs or read-across may assist in making an adequate conclusion that is suitable for classification and risk assessment. The aim of this session is to explain the changes of the revised information requirements for skin sensitisation and how these non-animal testing methods can be used for REACH purposes. http://dx.doi.org/10.1016/j.toxlet.2016.06.026 CEC1-2 OECD guidance on the reporting of defined approaches and individual information sources to be used within Integrated Approaches to Testing and Assessment (IATA) for skin sensitization Silvia Casati EURL ECVAM, Joint Research Centre, European Commission, Italy With a view to assisting the evaluation of integrated approaches to testing and assessment (IATA) in regulatory decision-making, the OECD developed a guidance document (GD) which provides templates for reporting defined approaches to testing and assessment that can be used as one of the components within IATA. A defined approach to testing and assessment consists of a fixed data interpretation procedure (DIP) applied to data generated with a defined set of information sources (e.g. in silico, in chemico, in vitro methods) to derive a prediction that can either be used on its own, or together with other information sources within an IATA, to satisfy a specific regulatory need. The GD is intended to be used alongside similar guidance aimed at harmonising the reporting of other IATA components such as QSARs, grouping and read-across strategies, and non-guideline in vitro methods. The reporting templates have been used to describe a number of defined approaches to testing and assessment for skin sensitisation hazard and potency prediction and the individual information sources used within these approaches. http://dx.doi.org/10.1016/j.toxlet.2016.06.027
CEC1-3 From theory to practice: Case studies illustrating different defined approaches for testing and assessment for skin sensitization Janine Ezendam National Institute for Public Health and the Environment (RIVM), Netherlands In the last years, different non-animal methods for skin sensitization testing were developed. The OECD has accepted three non-animal test methods as test guidelines. These methods address different key events of the Adverse Outcome Pathway (AOP) for skin sensitization, e.g. protein binding, activation of keratinocytes and activation of dendritic cells. This AOP describes the linkages between the molecular initiating event (protein binding) and subsequent key events that occur at the cellular and organ levels that lead to the adverse outcome (skin sensitization). This AOP is used as a mechanistic framework for the development of defined approaches to test and assess the skin sensitization potential and/or potency of chemicals. In the last years, several different defined approaches for the assessment of skin sensitization were proposed. There are differences in both the construction of these approaches and the procedures for data interpretation to come to a prediction. In this CEC course, examples of such approaches are presented. Attention is given to the rationale underlying the construction of the defined approaches and the information sources used. The data interpretation procedures (DIPs) applied to predict whether a chemical is a skin sensitizer or not, are explained as well. These DIPs can be simple, e.g. a 2 out of 3 approach in which two concordant results addressing two different key events indicate the sensitizing potential of a chemical. DIPs that are more complex are used, for example Bayesian or neural networks. Finally, predictive capacity, technical limitations and known uncertainties of the different approaches are discussed. http://dx.doi.org/10.1016/j.toxlet.2016.06.028 CEC1-4 Utility of integrated non-animal approaches for skin sensitisation for safety assessment of cosmetics Sebastian Hoffmann Consultant of Cosmetics Europe/SEH Consulting Services, Germany Current efforts to assess skin sensitisation without animal testing focus on hazard identification. Only a few approaches have attempted to provide information on skin sensitisation potency of chemicals. While of lesser relevance for industrial chemicals, potency information is essential for the safety assessment of cosmetic ingredients. Therefore, Cosmetics Europe’s Skin Tolerance Task Force has set up a multi-phase program to develop an approach that allows skin sensitisation safety assessment of cosmetic ingredients without the need for animal data. In the first phase, 16 individual test methods were assessed. In the second phase, a systematic evaluation of existing testing strategies was conducted using a specifically compiled a highly curated database of 130 substances with test data of several non-animal test methods as well as Local Lymph Node Assay (LLNA) and human reference data. In this evaluation existing integrated approaches have characterised with a pre-defined set of criteria covering basic, practical
Abstracts / Toxicology Letters 258S (2016) S2–S10
S3
and mechanistical aspects. In addition, the predictive performance of approaches, for which all input data were available, has been assessed using the same set of animal and human reference values. As a subset of the 130 substances were not part of the training set of the existing approaches, this independent assessment allowed to challenge these approaches with a test set of substances. Through this programme, Cosmetics Europe aims to identify or develop integrated non-animal approaches tailored for cosmetic ingredients, and to explore ways how to conduct safety assessment with the information provided by these approaches.
opment program. This lecture is designed to cover a number of basic concepts of ADME, pharmacokinetics and concepts applied to non-clinical safety studies in support of early drug R&D.
http://dx.doi.org/10.1016/j.toxlet.2016.06.029
Philip Timmerman
CEC1-5 Computational tools and their role in integrative approaches
Janssen R&D, on Behalf of EBF, Belgium
Steve Enoch School of Pharmacy and Biomolecular Sciences, United Kingdom The aim of this presentation will be to outline the use of computational approaches such as grouping and read-across in regulatory toxicology using skin sensitisation as an example endpoint. The talk will take the form of a workshop and will outline the importance of the Adverse Outcome Pathway (AOP) approach and how chemistry can be used to group chemicals based on knowledge of the Molecular Initiating Event within the AOP paradigm. A discussion of the advantages and limitations of this approach in comparison to other computational methods will also be discussed. The talk will conclude with how this information can be useful in a wider integrated testing and assessment strategy for the non-animal prediction of skin sensitisation. http://dx.doi.org/10.1016/j.toxlet.2016.06.030 CEC 2: Toxicokinetics CEC2-1 Basic ADME in non-clinical drug discovery and development Richard John Weaver Servier Group, 50 rue Carnot, 92284 Suresnes Cedex, France The assessment of physicochemical and pharmacological properties of chemical series is conducted at an early stage of drug discovery for the purpose of accelerating identification of druggable chemistry into qualified candidates for non-clinical development. In particular, in vitro absorption, distribution, metabolism and elimination (ADME) assays and in vivo drug metabolism pharmacokinetic (DMPK) studies are performed throughout the discovery process, from ‘hit’ to ‘lead’ optimization. The goal of these early studies is to reduce attrition rates due to poor ADME and PK before they progress through to subsequent phases of non-clinical assessment. The study of ADME/PK has developed into a relatively mature discipline in drug discovery through the application of wellestablished in vitro and in vivo methodologies in conjunction with bioanalytics to enhance the success of drug leads. The information on ADME/PK is gathered to support pharmacology and non-clinical safety studies as an integral part of any drug discovery and devel-
http://dx.doi.org/10.1016/j.toxlet.2016.06.093 CEC2-2 Applying the right level of bioanalytical method validation for PK analysis in support of preclinical (tox) studies
In this presentation, Philip will give feedback on the progress from the EBF (European Bioanalysis Forum) an in industry on their efforts to provide practical and tangible solutions for a harmonized implementation scientific validation as part of the principles of tiered approach, with focus on early preclinical (Tox) studies. By describing tiered approach as different levels of scientific validation alongside the established regulatory validation, EBF aims at providing the industry an acceptable tool for scientific validation for studies where the Guidance was not the intended scope. The practice of adopting more lean validation requirements, especially in earlier stages of development, suggested in Crystal City III (Viswanathan et al., 2007), further highlighted in recent (draft) Guidance (BioAnalysisForum, 2016; FDA, 2016) and confirmed during discussions at the Crystal City-V meeting (Baltimore, USA, December 2013) stimulated the EBF to seek further alignment and provide practical solutions to bring tiered approach into practice (Timmerman et al., 2014). In 2015, the discussion continued in meetings not only in the EBF community, but also outside Europe (DV-DMDG (January 2015) (Timmerman et al., 2015), JBF (February 2015), CPSA-Shanghai (April 2015), CPSA-US and AAPS (both October 2015). Finally, the EBF published their recommendation on bringing scientific validation into practice for 5 areas/assay types (Anon., 2015). The current presentation will focus on the principles of the recent recommendation and aims at stimulating an open discussion in the toxicokinetic community on the advantages and/or risk associated with a more lean approach to bioanalytical method validation. References Anon., 2015. Tiered approach into practice-scientific validation for chromatographybased assays: a recommendation from the European Bioanalysis Forum. Bioanalysis (in press). http://bioanalysisforum.jp/images/T130918I0020.pdf#zoom=100. http:// www. fda. gov/ downloads/ Drugs/ GuidanceComplianceRegulatory Information/ Guidances/ UCM368107. pdf. Timmerman, P., et al., 2014. Feedback from the European Bioanalysis Forum Workshop: taking tiered approach to the next level. Bioanalysis 7 (7), 815–824. Timmerman, P., et al., 2015. Scientific or regulated validation - a tiered approach? Meeting report from a Joint EBF/DVDMDG Workshop. Bioanalysis 7 (August (14)), 1703–1710. Viswanathan, C.T., et al., 2007. Workshop/Conference Report — Quantitative Bioanalytical Methods Validation and Implementation: Practices for Chromatographic and Ligand Binding Assays. Workshop/Conference Report. AAPS J. 9 (1), E30–E42.
http://dx.doi.org/10.1016/j.toxlet.2016.06.094