Current tests available for assessment of the skin sensitization potential of chemicals include the murine local lymph node assay, and guinea pig assays. Despite the wide acceptance of these methods, there are reports of false positives and false negatives and of some discrepancies between the tests. Application of modern technologies, e.g. toxicogenomics, may provide opportunities to identify novel markers that are mechanistically linked to the acquisition of skin sensitization, and possibly provide improved readouts for the existing assays. Improved assays are desirable in particular to assess chemistries that have proven difficult to test using the current protocols, to distinguish between irritants and sensitizers, or to identify different types of chemical allergens, i.e. skin and respiratory allergens.
The objectives of this research are to:
”¢ Identify and investigate novel markers, anchored to traditional toxicological readouts, for the identification of skin sensitizing chemicals;
”¢ Determine whether any such novel markers correlate quantitatively with the acquisition of skin sensitization and can be used for assessment of relative potency;
”¢ Address limitations of the current assays with respect to improved discrimination between contact allergens and skin irritants and, ideally, for the assessment of complex mixtures;
”¢ Determine whether novel markers facilitate discrimination between skin sensitizing chemicals and chemical respiratory allergens;
”¢ Evaluate whether the identified novel markers are robust and reproducible.
The proposal should include examination of well-characterized chemical sensitizers spanning a range of potencies, as well as non-sensitizing chemicals. Dose-response data should be generated as a means to characterize sensitization potency. The approaches should be evaluated with respect to their sensitivity and specificity. Further, the potential for the development of in vitro-based models should be considered.
Whilst it is expected that the first part of the study will include a broad analysis of markers for the steps involved in inducing sensitization, it is envisioned that subsequent investigations will focus on a smaller number of candidate markers that are mechanistically and biologically relevant for skin sensitization and have a strong predictive potential. It is also envisioned that a battery of markers may offer the best predictive capacity for sensitization. Finally, it will be necessary to provide a critical evaluation of any of the identified novel markers with respect to hazard identification and risk assessment.
The principal investigator will be required to submit a progress report at six-monthly intervals and a detailed review of the results at the end of the project. It is expected that the results will be published in peer-reviewed journals, and the investigators are encouraged to present their preliminary findings at appropriate scientific meetings.