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the AOP can be used in qualitative or
quantitative scenarios. The premise
being that if a new compound elicits the
molecular initiating event (and other key
events) it will potentially produce the
adverse effect defined by the AOP.
In the OECD approach, it is considered
critical to be able to gauge the reliability
and robustness of an AOP; this is done
by evaluating the experimental support of
the AOP. Included in this evaluation is:
a) an assessment of the qualitative
understanding of the AOP
b) an assessment of the experimental
evidence or data
c) a statement of confidence in the AOP
d) an assessment of the quantitative
understanding of the AOP.
Results
Skin sensitisation is a well-studied toxic
endpoint of which aspects have been the
subject of many scientific experiments
over the past decade. Skin sensitisation
is a Type IV contact allergy which is
typically described in two phases—
the induction of sensitisation and the
subsequent elicitation. The first phase
includes a sequential set of events that
are described in this AOP. While there
is generally agreement regarding these
events (Karlberg et al., 2008; Aeby et al.,
2010; Adler et al., 2011), understanding
of the underlying biology of many of the
key events remains incomplete. Because
of biological complexity (e.g., multiple
organs and multiple cell types), skin
sensitisation is evaluated with in vivo
tests but alternative methods are under
development (Aeby et al., 2010).
While non-covalent reactions with metals
and redox cycling have been linked to skin
sensitisation, the AOP described here is
designed to address organic chemical
agents that react with thiol (i.e., cysteine)
and primary amines (e.g., lysine). The
earlier work on the molecular basis of skin
sensitisation was reviewed by Lepoittevin et
al. (1998). However, knowledge on the key
events associated with skin sensitisation
has evolved rapidly over the past decade.
This knowledge may be summarised as:
1) The target substance must be
bioavailable (i.e., it must penetrate
the stratum corneum of the skin).
2) The target substance must be a directacting
electrophile, be converted
from a non-reactive substance (proelectrophile)
to a reactive metabolite
via metabolism, or be converted
from a non-reactive substance (preelectrophile)
to a reactive derivative via
an abiotic process, typically oxidation.
3) The molecular sites of action are
targeted nucleophilic sites in proteins
(e.g., cysteine and lysine residues) in
the dermis.
4) The molecular initiating event is the
covalent perturbation of dermal
proteins, which is irreversible (i.e.,
formation of the hapten-protein
complex or complete antigen). In
vivo this event is associated with the
production of a specific memory
T-cell response.
5) Biochemical pathways affected by the
definitive electrophile’s action on the
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AXLR8-2 WORKSHOP REPORT
Progress Report 2011 & AXLR8-2 Workshop Report