Does Irritation Potency Contribute to the Skin Sensitization Potency of Contact Allergens?

Abstract

Chemicals that possess the capacity to cause skin sensitization have long been recognized to be reactive (electrophilic) or at least the precursor of an electrophile. The chemical species (hapten) covalently bound to skin protein then forms the antigen to which the immune system responds, with sufficient exposure ultimately leading to skin sensitization. However, for this process to occur, many have also considered that in addition to haptenation of skin protein, secondary stimuli (danger signals) are also necessary. Such signals might reasonably be expected to derive from keratinocytes and/or Langerhans cells perturbed by the chemical sensitizer. Whether this disturbance comes from the haptenation process itself or from other properties of the chemical is unknown. We hypothesized that chemicals that were stronger sensitizers might appear so, in part, as a consequence not only of greater (pro)electrophilic reactivity, but also if they were more able to produce inflammatory (danger) signals. To assess this, the sensitizing potency of 55 chemicals in the local lymph node assay was compared with their ability to produce pro-inflammatory signal release, measured as a function of their relative skin irritancy in guinea pigs. A limited trend was demonstrated, consistent with the hypothesis, but indicating that either skin irritation is a poor measure of danger signals, or that such signals are perhaps no more than a necessary requirement for the acquisition of skin sensitization rather than a key determinant of the relative potency of a skin sensitizing chemical. In addition, it is possible that irritancy alone does not represent a complete surrogate marker for the ability of a chemical to produce danger signals relevant to the induction of skin sensitization.

Assessment of the sensitizing potential of textile disperse dyes and some of their metabolites by the loose-fit coculture-based sensitization assay (LCSA)

“…4). Statistical analysis of a larger set of 55 substances using data from LLNA and GPMT was also not conclusive (Basketter et al 2007).…”

Comparison of the skin sensitization potential of 3 red and 2 black tattoo inks using interleukin‐18 as a biomarker in a reconstructed human skin model

“…Furthermore, the irritant potency of a chemical has been shown in vivo and in vitro to be directly related to sensitization potency, and it has also been shown that skin irritation is related to the development and severity of allergic contact dermatitis 29, 30, 31, 32. In this study, we have shown that the inks vary considerably in their irritant potency, as illustrated by the broad range of EC50 values obtained after addition of inks to the culture medium of RHS (EC50 0.04% to EC50 not reached).…”

An epidermal equivalent assay for identification and ranking potency of contact sensitizers

“…Reconstructed epidermal models (EE) using primary human keratinocytes are currently used to test whether a chemical has irritant/corrosive properties or not (Fentem et al, 1998;Liebsch et al, 2000;Spielmann et al, 2007). The initial protocol for the potency classification was based on the clinical observation that there is a clear role of irritancy in contact sensitization due to the irritant property of many allergens (Agner et al, 2002;Basketter et al, 2007;Bonneville et al, 2007;McLelland et al, 1991). Chemicals must cause sufficient local trauma to increase cutaneous cytokine production.…”