Chemical reactivity indices and mechanism‐based read‐across for non‐animal based assessment of skin sensitisation potential

Abstract

The skin sensitisation potential of chemicals is currently assessed using in vivo methods where the murine local lymph node assay (LLNA) is typically the method of first choice. Current regulatory initiatives are driving the impetus for the use of in vitro/in silico alternative approaches to provide the relevant information needed for the effective assessment of skin sensitisation, for both hazard characterisation and risk assessment purposes. A chemical must undergo a number of steps for it to induce skin sensitisation but the main determining step is formation of a stable covalent association with carrier protein. The ability of a chemical to react covalently with carrier protein nucleophiles relates to both its electrophilic reactivity and its hydrophobicity. This paper focuses on quantitative indices of electrophilic reactivity with nucleophiles, in a chemical mechanism-of-action context, and compares and contrasts the experimental approaches available to generate reactivity data that are suitable for mathematical modelling and making predictions of skin sensitisation potential, using new chemistry data correlated against existing in vivo bioassay data. As such, the paper goes on to describe an illustrative example of how quantitative kinetic measures of reactivity can be usefully and simply applied to perform mechanism-based read-across that enables hazard characterisation of skin sensitisation potential. An illustration of the types of quantitative mechanistic models that could be built using databases of kinetic measures of reactivity, hydrophobicity and existing in vivo bioassay data is also given.

Read-across approaches - misconceptions, promises and challenges ahead

“…Skin sensitization, for example: there is an abundance of mechanistic knowledge about the induction of skin sensitization as summarized in the adverse outcome pathway (AOP) recently published by the OeCD (2012). In turn, much of this information has been encoded into software tools such as tIMeS (Patlewicz et al, 2014a) or the OECD (Q)SAR Toolbox, as well as into QSARs published in the literature (Roberts et al, 2008;Patlewicz and Worth, 2008).…”

Integrating non-animal test information into an adaptive testing strategy – skin sensitization proof of concept case

“…In parallel, several groups are pursuing a different route to explain skin sensitization effects in vivo (e.g., Roberts and Patlewicz, 2009). Roberts et al (2008) explore the concept of a molecular initiating event that is represented by covalent chemical binding with "protein" and focus on interpretation of this step to explain sensitization, considering cell-based assays only for stages downstream of the reactivity step. there is no consensus on the relative merits of different proposed frameworks.…”

The Adverse Outcome Pathway for Skin Sensitisation Initiated by Covalent Binding to Proteins

“…Since the 1930's, there has been growing evidence that the main potency-determining step in skin sensitisation of industrial organic compounds is the formation of a stable hapten-protein conjugate (see Roberts and Aptula, 2008;Karlberg et al, 2008). Consequently, the molecular initiating event leading to skin sensitisation is postulated in this AOP to be covalent binding of electrophilic chemical species with selected nucleophilic molecular sites of action in skin proteins Karlberg et al, 2008).…”

“…Reactivity in general, and measurements and estimations of reactivity, have recently been reviewed (see Roberts et al, 2008;OECD, 2011b;. For skin sensitisation and other toxicological endpoints for which protein binding is important, the biological nucleophile is assumed to be selected amino acids.…”