Further investigation of the prohapten concept: reactions to benzene derivatives in man.

p-Phenylenediamine (PPDA) is a strong contact sensitizer which is included in the standard patch test tray and which can also act as an indicator of allergy to related substances by virtue of cross-reactions. In a previous study, the pattern of cross-reactions between PPDA and related substances was investigated in the guinea pig to evaluate the prohapten concept. The results provided some support for this concept, but also indicated that a number of reactive intermediates might be behaving as haptens. This work has now been extended to an examination of the prohapten concept in man in PPDA-allergic subjects. These subjects were tested with 7 substituted benzenes, plus PPDA. Of these, the 1,4-substituted benzenes hydroquinone, Metol, PPDA and p-aminophenol are all capable theoretically of giving rise to benzoquinone by oxidation (after demethylation in the case of Metol). However, as had been the case in the guinea pig, only a limited degree of cross-reaction was observed. Only one of the subjects allergic to PPDA gave a clearly positive allergic reaction to benzoquinone. The data provided only limited support for the prohapten concept in terms of benzoquinone as the ultimate hapten for a range of 1,4-substituted benzenes. As indicated in the guinea pig, a range of reaction intermediates or indeed other oxidation products may be involved. So, for each molecule, the sensitizing activity and potential to give rise to cross-reactions may depend on the balance between routes of skin metabolism.