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Combined set of tests will be needed for final evaluation. It is widely recognised that
alternatives to animal testing cannot be accomplished with a single approach, but rather
will require the integration of results obtained from different in vitro and in silico methods
(Basketter & Kimber 2009; Roberts & Patlewicz 2010). The physicochemical diversity
determines the domains of applicability of the available in vitro tests. An integrated
testing strategy adapted to the diverse chemical categories is required. Questions to
consider:
• Which elements are in place / which steps are further needed and are still missing
• Are the endpoints under study specific enough for sensitisers, how do they relate to
other biological processes such as oxidative stress responses
• What is needed to reduce uncertainties for skin sensitisation testing How to
proceed
To predict risk we need to have information on the dose at which chemicals exert the adverse
biological effect
Potency information enables the establishment of safe levels for human exposure
to chemicals that cannot be regarded as not having any skin sensitising potential.
An important question is whether there is a threshold below which no adverse effects
are to be expected. With respect to the skin, dose-response relationships and
no-effect levels were found for both intradermal and topical induction, as well as for
intradermal and topical elicitation of allergenic responses in epidemiological, clinical,
and animal studies (Arts et al., 2006). It was also shown that repeated exposure
to low doses of contact sensitisers may increase the sensitising potency (Paramasivan
et al., 2009). With the introduction of the murine Local Lymph Node Assay
(LLNA) and the EC3 value (the effective concentration of test substance needed to
induce a stimulation index of three), chemicals could potentially be placed into potency
groups (e.g., extreme/strong, moderate, weak, and non-sensitisers (Basketter
2007). Is potency ranking possible using in vitro assays or computational models
Assays on peptide reactivity, QSARs and cellular systems are attempting potency
classification of skin sensitisers (Gerberick et al., 2008; Van Och et al., 2005; McKim
et al., 2010; Lambrechts et al., 2010). To date, experience has shown that using
a combination of in vitro assays with in silico models might predict hazard classification.
However challenges still exists for risk assessment decision-making. International
efforts of research leaning on a shift of paradigm and relying on human cells
as well as on adverse outcomes pathways are still needed. Another difficulty is the
availability of reliable, preferentially human, in vivo data for potency ranking. Other
drawbacks may be the limited solubility of the compounds for in vitro testing and
the lack of oxidation and metabolism in the alternative assays. Knowledge of the
dose at the target cells is another important issue. Relating in vitro and in vivo expo-
AXLR8-2 WORKSHOP REPORT
Progress Report 2011 & AXLR8-2 Workshop Report
347