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In silico and in chemico approaches to identify respiratory sensitisers
Abstracts / Toxicology Letters 280S (2017) S60–S61
construction and highlight possible opportunities for testing and assessment of this toxicological endpoint. This abstract does not necessarily represent U.S. EPA policy. http://dx.doi.org/10.1016/j.toxlet.2017.07.152 S25-03 In silico and in chemico approaches to identify respiratory sensitisers Steve Enoch School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, United Kingdom The aim of this presentation will be to outline the use of in silico and in chemico methods for the identification of organic low molecular weight respiratory sensitisers (defined as chemicals with a molecular weight of less than 1000 g/mol). The presentation will outline the importance of considering protein binding towards lysine as the key molecular initiating event for these types of chemicals within the construct of the Adverse Outcome Pathway (AOP) approach. A structure-activity analysis will be presented as support for the lysine hypothesis. In addition, currently available in silico and in chemico methods for identifying such chemicals will also be discussed. The advantages and limitations of these approaches will be outlined. The talk will conclude with a reflection on what science needs to be carried out in the future to fully understand the chemistry of protein binding leading to respiratory sensitisation. http://dx.doi.org/10.1016/j.toxlet.2017.07.153 S25-04 Advances in the development of in vitro airway models as innovative tools to identify chemical respiratory sensitizers Erwin L. Roggen 3Rs Management and Consulting ApS, Lyngby, Denmark In vitro test systems based on human cells or tissue combined with multiple endpoint analysis are believed to provide robust
S61
alternatives for evaluating respiratory sensitization induction. Validated methods or frameworks for identifying and characterizing the hazard for sensitization induction by chemicals are not available yet. The current mechanistic understanding of respiratory sensitization induction to chemicals was collected and structured by Sullivan et al. (https://aopwiki.org/wiki/index.php/Aop:39. Chemical respiratory sensitization involves predominantly innate and adaptive mechanisms which in concert drive Th2 immunological mechanism. Some overlapping cellular events with skin sensitization are well understood, but the full mechanism remains unavailable. Innovative approaches to skin sensitization testing are currently evaluated on respiratory sensitizers. Existing and emerging test methods address the molecular initiation event(s) (MIE(s)) and key events (KEs) identified by the AOP for respiratory sensitization induction: (i) peptide/protein-binding, (ii) epithelial inflammation, (iii) dendritic cell activation, maturation and migration, and finally (iv) T-cell (and (v) B cell (?)) priming. Development of methods and approaches for testing and assessment of chemicals with a potential to induce respiratory sensitization has been complicated by the growing evidence that respiratory sensitization may also occur via dermal exposure. The aim of this presentation is to get closer to an understanding of which sensitization AOP-related test methods would make it possible to determine if the response triggered by a chemical is one of respiratory sensitization induction. http://dx.doi.org/10.1016/j.toxlet.2017.07.154
construction and highlight possible opportunities for testing and assessment of this toxicological endpoint. This abstract does not necessarily represent U.S. EPA policy. http://dx.doi.org/10.1016/j.toxlet.2017.07.152 S25-03 In silico and in chemico approaches to identify respiratory sensitisers Steve Enoch School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, United Kingdom The aim of this presentation will be to outline the use of in silico and in chemico methods for the identification of organic low molecular weight respiratory sensitisers (defined as chemicals with a molecular weight of less than 1000 g/mol). The presentation will outline the importance of considering protein binding towards lysine as the key molecular initiating event for these types of chemicals within the construct of the Adverse Outcome Pathway (AOP) approach. A structure-activity analysis will be presented as support for the lysine hypothesis. In addition, currently available in silico and in chemico methods for identifying such chemicals will also be discussed. The advantages and limitations of these approaches will be outlined. The talk will conclude with a reflection on what science needs to be carried out in the future to fully understand the chemistry of protein binding leading to respiratory sensitisation. http://dx.doi.org/10.1016/j.toxlet.2017.07.153 S25-04 Advances in the development of in vitro airway models as innovative tools to identify chemical respiratory sensitizers Erwin L. Roggen 3Rs Management and Consulting ApS, Lyngby, Denmark In vitro test systems based on human cells or tissue combined with multiple endpoint analysis are believed to provide robust
S61
alternatives for evaluating respiratory sensitization induction. Validated methods or frameworks for identifying and characterizing the hazard for sensitization induction by chemicals are not available yet. The current mechanistic understanding of respiratory sensitization induction to chemicals was collected and structured by Sullivan et al. (https://aopwiki.org/wiki/index.php/Aop:39. Chemical respiratory sensitization involves predominantly innate and adaptive mechanisms which in concert drive Th2 immunological mechanism. Some overlapping cellular events with skin sensitization are well understood, but the full mechanism remains unavailable. Innovative approaches to skin sensitization testing are currently evaluated on respiratory sensitizers. Existing and emerging test methods address the molecular initiation event(s) (MIE(s)) and key events (KEs) identified by the AOP for respiratory sensitization induction: (i) peptide/protein-binding, (ii) epithelial inflammation, (iii) dendritic cell activation, maturation and migration, and finally (iv) T-cell (and (v) B cell (?)) priming. Development of methods and approaches for testing and assessment of chemicals with a potential to induce respiratory sensitization has been complicated by the growing evidence that respiratory sensitization may also occur via dermal exposure. The aim of this presentation is to get closer to an understanding of which sensitization AOP-related test methods would make it possible to determine if the response triggered by a chemical is one of respiratory sensitization induction. http://dx.doi.org/10.1016/j.toxlet.2017.07.154