The circumventricular organs of the brain are fenestrated capillaries that permit direct interaction of circulating chemicals with neuronal elements. Phylogenetically old aggregates of specialised nervous tissue, the CVOs are unique in their anatomical relationship to both the systemic blood and cerebrospinal fluid circulations. It is known that these fenestrated capillaries provide a pathway for the direct feedback action of peptide hormones on the central nervous system.
In chemico methods such as the in vitro direct peptide reactive assay (DPRA) or a kinetic version of it, the reaction kinetics of a chemical with a synthetic cysteine-containing peptide are evaluated and used to predict whether the chemical is a sensitiser or non-sensitiser. The prediction is combined with predictions from two in vivo cell-based assays to identify the sensitisation hazard of chemicals using a consensus procedure.
These assays depend on the assumption that potency is a single increasing function of the chemical’s reactivity. However, this assumption is not valid for all chemicals. Phthalic and trimellitic anhydrides are two examples that demonstrate this. Both are very similar in their reactivity to the peptide and have similar logkmax values, but they differ significantly in their hydrophobicity.
Using a true rate constant to assign a chemical as a sensitiser or non-sensitiser or to predict its potency is thus problematic. Similarly, the use of DPRA or kDPRA to classify chemicals into GHS sub-categories 1A and 1B is problematic because the results are based on an implicit assumption that the chemical’s potency is solely related to its reactivity.direct peptides