Donna Jefferies

Predictive identification of human skin sensitization thresholds.

For years, methods have been available for the predictive identification of chemicals that possess the intrinsic potential to cause skin sensitization. However, many have proven less suitable for the determination of relative sensitizing potency. In this respect, the local lymph node assay (LLNA) has been shown to have a number of important advantages. Through interpolation of LLNA dose–response data, the concentration of a chemical required to produce a threshold positive response (a 3‐fold increase in activity compared with concurrent vehicle controls, the EC3 value) can be measured. The robustness of this parameter has been demonstrated rigorously in terms of inter‐ and intralaboratory reproducibility. Additionally, the relationship between potency estimates from the LLNA and an appreciation of human potency based on clinical experience has been reported previously. In the present investigations, we have sought to consolidate further our understanding of the association between EC3 values and human skin‐sensitization potency by undertaking a thorough and extensive analysis of existing human predictive assays, particularly where dose–response information is available, from historical human repeated insult patch tests (HRIPTs). From these human data, information on the approximate threshold for the induction of skin sensitization in the HRIPT was determined for 26 skin‐sensitizing chemicals. These data were then compared with LLNA‐derived EC3 values. The results from each assay, expressed as dose per unit area (μg/cm2), revealed a clear linear relationship between the 2 values, thereby substantiating further the utility of LLNA EC3 values for prediction of the relative human sensitizing potency of newly identified skin sensitizers.

The impact of exposure variables on the induction of skin sensitization.

Whereas many investigations of the variables associated with the elicitation of allergic contact dermatitis have been undertaken, to the point where we can begin to predict the likelihood of elicitation occurring in a given situation, the same is not true for the induction of skin sensitization. Studies have demonstrated that increasing dose has an impact; in an experimental setting, a number of variables received attention some decades ago. However, in the work reported here, the relative importance of the frequency and the duration of exposure is highlighted. In an investigation using a human repeated insult patch test, it was demonstrated that reduction of the exposure duration from 48 hr to 5 min decreased the rate of sensitization to 1% p‐phenylenediamine (PPD) from 54% to 3%. However, in an extended clinical study, it was observed that infrequent but longer duration and higher concentration exposure to PPD was significantly less likely to induce sensitization compared to more frequent, short duration, and lower concentration exposure. Detailed statistical analysis of the results indicated that the most important factor driving the induction of skin sensitization was the number of exposures.

Patch test frequency to p‐phenylenediamine: follow up over the last 6 years

While the frequency of patch test reactivity to many cosmetic allergens has decreased over the last 20 years, we have previously shown that in our clinic, the patch test reactivity to p‐phenylenediamine (PPD) has remained stubbornly high between 2.5% and 4.2% in the years when patch testing was performed with 1% PPD. Further retrospective analysis of the PPD patch test frequency over the last 6 years shows an increasing rate of PPD patch test frequency, showing an upward linear trend. This increasing trend cannot be fully explained by any increase in patch testing of Southern Asian patients or of sensitization caused by PPD exposure from ‘temporary henna tattoos’. An alternative explanation may be the increasing use of permanent hair dyes.