Here - Stiftung Forschung 3R

Discussion Summary
• There was a general view among BOG3 participants that progress in the field
of skin sensitisation testing over the last 10 years has been substantial. Several
research groups have unraveled key mechanisms related to chemically-induced skin
sensitisation, which is a complex process, which involves the chemical reactivity
of compounds with the surrounding extracellular matrix of the skin, as well as
reactivity with specific cell types. Structure-activity approaches have defined
key characteristics and an in silico-in vitro strategy is being developed to identify
sensitising chemicals. The initial cellular events at the level of dendritic cells and
keratinocytes are now largely understood. Advanced technologies such as genomics
and proteomics have been introduced and have contributed to the elucidation of
the sensitisation phase in keratinocytes and dendritic cells. This has enabled the
development of a testing strategy based on mechanistic understanding of the
crucial steps leading to skin sensitisation by low-molecular-weight chemicals.
• The current working strategy is largely in line with the pathway-based concept of ‘21 st
century’ toxicology. The process was successful in unraveling basic immunological
processes for skin sensitisation and yielding a test battery that covers the key
essential pathways except for T-cell responses. BOG3 recommends further work
to build on the success in the skin area and to apply a similar approach towards a
testing strategy for respiratory sensitisation.
Challenges for the future:
• The BOG emphasises that a conceptual framework needs to be built on integration
of already available building blocks of assays and computational knowledge. This
integrating framework should not be developed empirically but should be based
on mechanistic insights. New experimental data should be generated that permit
validation of an integrated in silico simulation.
• Better consumer exposure scenarios are needed as an input into the testing framework.
Human exposure pathways and dose patterns are not yet well defined. Information
on the dose range of interest and the likelihood of continuous or repeated
dosing should permit simulation of real-life exposures. These scenarios are needed
to obtain useful results from the in silico/in vitro testing strategy, thereby addressing
thresholds of adverse effects based on mechanistic insights.
• Realistic scenarios should include cost-effective models for topical application, and
should also take into account that exposure to a sensitising chemical occurs typically
in combination with other chemicals. Testing strategies should include the testing
of formulations. Interaction with other ingredients such as irritants or impaired
sensitivity due to damaged or diseased skin should be considered.
• The BOG identified in particular the lack of predictive clinical data as a drawback
AXLR8-2 WORKSHOP REPORT
Progress Report 2011 & AXLR8-2 Workshop Report
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