Ian R. Jowsey

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.

A review of critical factors in the conduct and interpretation of the human repeat insult patch test

This paper reviews key factors that are critical to the conduct and interpretation of Human Repeat Insult Patch Tests (HRIPTs). A methodology for HRIP testing is described and general guidelines for evaluation of responses indicative of induction and elicitation of skin sensitization and skin irritation are detailed. Understanding and applying these key factors is crucial to the design of such studies and reliability of the resulting data when used in the overall risk assessment process.

The biocide polyhexamethylene biguanide remains an uncommon contact allergen

Polyhexamethylene biguanide (PHMB) is used as a preservative in cosmetics and personal care products. Previous studies had shown a frequency of sensitization to PHMB of 0.5% and 0.4% in unselected dermatitis patients. The objective of this study was to determine the current frequency of sensitization to PHMB. From July 2005 until December 2005, a total of 1975 consecutive patients were patch tested with PHMB. 10 patients (0.5%) had positive patch test reactions to PHMB 2.5% aq. (9+ and 1++) and 16 patients (0.8%) to PHMB 5.0% aq. (12 +, and 4 ++). The test reaction pattern (reaction index and positivity ratio) of both preparations and a limited concordance between results from both concentrations (Cohen’s kappa = 0.35) are probably indicative of a substantial number of false positive reactions. Potential causal exposures were assessed by a case by case analysis and by referring to surrogate markers of exposure in terms of concomitant reactions. Occupational exposures were identified as a probable cause of sensitization. Further risk factors included leg dermatitis and old age. The frequency of sensitization remains low. It is very unlikely that exposure to cosmetics or personal care products may have played a role in the few cases sensitized.

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

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.

The skin sensitization potential of resorcinol: experience with the local lymph node assay

Resorcinol is a simple aromatic chemical (1,3‐benzenediol) that has found widespread use, particularly as a coupler in hair dyes. Clinical experience clearly shows that resorcinol is a (albeit uncommon) skin sensitizer. By contrast, predictive methods, both animal and human, have previously failed to identify resorcinol as such. Here, we describe the outcome of a recent local lymph node assay performed in accordance with Organisation for Economic Co‐operation and Development guideline 429, which correctly identified resorcinol as a skin sensitizer. Clear evidence of a dose response was apparent, and an EC3 value of approximately 6% was calculated. This suggests that the skin‐sensitizing potency of resorcinol is approximately 2 orders of magnitude lower than that of p‐phenylenediamine but similar to that of hexyl cinnamic aldehyde. These data show the importance of adherence to test guidelines and aligns the clinical experience with resorcinol with that obtained in predictive animal methods.

Oral tolerance to contact allergens: A common occurrence? A review

Experimental and clinical oral tolerance to contact allergens has been reported sporadically, most notably in respect of nickel, and is generally assumed to be an uncommon phenomenon. There has recently been increased understanding of the immunological mechanisms inducing and maintaining oral tolerance. There are several contact allergens, including fragrance, antioxidant, and preservative chemicals, to which subjects are exposed through both cutaneous and oral routes. We examine the possibility that oral tolerance to contact allergens may be more common than previously thought. Animal models of oral tolerance to contact allergens indicate that cutaneous exposure to small, subsensitizing doses of contact allergens might negate any subsequent attempts to induce tolerance by oral administration. Extrapolating these observations to common human practises raises the possibility that application of contact allergens (fragrances, preservatives and antioxidants) in consumer products used by children could prevent or inhibit the later acquisition of specific tolerance resulting from ‘natural’ dietary exposure after weaning. Existing data on formaldehyde may conflict with this theory, though this could be explained by allergen specificity. We propose that further work in this area is needed.

Identification and classification of skin sensitizers: identifying false positives and false negatives

The first step in regulatory evaluation of substances involves the identification of their intrinsic hazards, including the potential for skin sensitization. This is, quite properly, entirely different from assessment of the risks to human health, which might arise from incorporation of substances in products. EU guidance on regulations concerning the classification of skin sensitizers suggests a range of sources of information be deployed in the hazard identification process. These include chemical structure, predictive animal tests, and various types of human data. Where the information is clear‐cut, then uncertainties rarely arise. However, for some materials, discordant information arises, perhaps because the substance is on the borderline of test sensitivity and classification (sensitizing materials of insufficient potency do not classified according to the EU scheme), due to conflicting results in predictive tests or for other reasons. In this study, we review data on a number of substances where a classification decision is complicated by such discordances and seek to use these examples to demonstrate how best to make a weight of evidence decision on whether a substance should, or should not, be classified as a skin sensitizer.

The impact of vehicle on the relative potency of skin-sensitizing chemicals in the local lymph node assay

The identification and characterization of chemicals that possess skin-sensitizing potential are typically performed using predictive tests. However, human exposure to skin-sensitizing chemicals often occurs via a matrix (vehicle) that differs from that used in these tests. It is thus important to account for the potential impact of vehicle differences when undertaking quantitative risk assessment for skin sensitization. This is achieved through the application of a specific sensitization assessment factor (SAF), scaled between 1 and 10, when identifying an acceptable exposure level. The objective of the analysis described herein is to determine the impact of vehicle differences on local lymph node assay (LLNA) EC3 values (concentrations of test chemical required to provoke a 3-fold increase in lymph node cell proliferation). Initially, the inherent variability of the LLNA was investigated by examining the reproducibility of EC3 values for 14 chemicals that have been tested more than once in the same vehicle (4:1 acetone:olive oil, AOO). This analysis reveals that the variability in EC3 value for these chemicals following multiple assessments is <5-fold. Next, data from the literature and previously unpublished studies were compiled for 18 chemicals that had been assessed in the LLNA using at least 2 of 15 different vehicles. These data demonstrate that often the variability in EC3 values observed for a given chemical in different vehicles is no greater than the 5-fold inherent variability observed when assessing a chemical in the same vehicle on multiple occasions. However, there are examples where EC3 values for a chemical differ by a factor of more than 10 between different vehicles. These observations were often associated with an apparent underestimation of potency (higher EC3 values) with predominantly aqueous vehicles or propylene glycol. These data underscore the need to consider vehicle effects in the context of skin-sensitization risk assessments.

Elicitation response characteristics to permanent hair dye in paraphenylenediamine-allergic volunteers

Background:  Elicitation response characteristics to complete permanent hair dye products in paraphenylenediamine (PPD)‐allergic volunteers have not previously been explored in detail.

Proactive surveillance of contact allergies: an important component of the risk management strategy for skin sensitizers

Risk assessment serves to ensure that dermal exposure to skin sensitizers does not result in the acquisition of allergic skin disease. Traditionally, the approach adopted was one of comparative analysis, involving benchmarking against other allergens of known potency. More recently, efforts have been made to embrace a quantitative risk assessment (QRA) approach. However, the accuracy of any risk assessment is reflected in the extent to which it meets the fundamental objective stated above. Thus, clinical experience is of key importance. There exists the possibility for the originators of risk assessments relating to chemicals that possess skin‐sensitizing potential to work directly with the clinical community to proactively obtain this experience through specific surveillance programmes. This forms the focus of this review article. The current status of the QRA approach is considered initially. A recently published example of one such surveillance programme that was undertaken as a collaborative initiative between industry and the clinical community is then reviewed. Finally, a possible strategy for the future is presented, in which it is suggested that surveillance strategies might be deployed in certain situations as an adjunct to the initial risk assessment. It is hoped that such a framework might further improve the efficacy of future approaches to skin sensitization risk assessment.