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molecular targets are incompletely
known but often include the mitogenactivated
protein signaling pathway
and the oxidative stress response
pathway, especially in keratinocytes.
6) The cellular-level outcomes are
incompletely known but include
immune recognition of chemical
allergens by Langerhans cells
(specialised epidermal dendritic cells)
and dermal dendritic cell. Responses
in the form of expression of specific
cell surface markers, chemokines,
and cytokines are typically taken as
evidence of dendritic cell maturation.
7) The organ-level responses include:
a. dendritic cell migration to the
lymph node, and
b. differentiation and proliferation
of allergen-specific memory
T-cells.
8) The target organ(s) are the skin and
required intact local lymph nodes;
the target cell populations are the
immune cells, especially T-cells.
9) The key physiological response is
acquisition of sensitivity.
10) The key organism response is dermal
inflammation upon receiving the
substance challenge in the elicitation
phase. This response is associated
with stimulation of specific memory
T-cell produced in the induction phase.
11) The overall effect on mammals is
allergic contact dermatitis in humans
or its rodent equivalent, contact
hypersensitivity.
An assessment of the qualitative
understanding of the AOP should include
a listing of the key events, as well as
the documentation of the experimental
support for each event and an evaluation of
the strength of scientific evidence for that
event. For this case study the information
is summarised in Table 1.
A second part of the OECD approach is
to answer a series of questions designed
to summarise the current experimental
evidence supporting the proposed AOP. An
AOP may be considered either plausible
or probable, depending upon the extent
(i.e., depth and breadth) of the available
scientific evidence supporting the AOP,
and the extent to which the key events have
been experimentally tested and found to
be consistent with empirical data. In this
regard, an AOP can be thought of as an
evolving entity. With regards to this case
study for skin sensitisation, the following
questions are asked and answered:
• How well characterised is the AOP
The skin sensitisation AOP is at least
qualitatively well characterised, as the
seminal events are generally accepted
by the scientific community.
• How well are the initiating, and key
events causally linked to the outcome
The molecular initiating event (protein
binding reactions) is based on
long-standing, well-studied organic
chemical mechanisms and reactions.
T-cell proliferation and to a lesser
extent dendritic cell activation/
maturation, as well as keratinocytebased
gene expression, are causally
linked to sensitisation.
• What are the limitations in the evidence
in support of the AOP While there is
general agreement that the AOP for
AXLR8-2 WORKSHOP REPORT
Progress Report 2011 & AXLR8-2 Workshop Report
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