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.

Strong irritants masquerading as skin allergens: the case of benzalkonium chloride.

Chemicals may possess a number of hazards to human health including the ability to cause skin irritation and contact allergy. Identification and characterization of these properties should fall within predictive toxicology, but information derived from human exposure, including clinical experience, is also of importance. In this context, it is of interest to review the case of benzalkonium chloride, a cationic surfactant. This chemical is a well-known skin irritant, but on occasions it has also been reported to have allergenic properties, typically on the basis of positive diagnostic patch test data. Because the accumulated knowledge concerning the properties of a chemical is employed as the basis for its regulatory classification (e.g. in Europe), as well as for informing the clinical community with respect to the diagnosis of irritant versus allergic contact dermatitis (ACD), it is important to distinguish properly which chemicals are simply irritants from those which are both irritant and allergenic on skin. A review of the information on benzalkonium chloride confirms that it is a significant skin irritant. However, both predictive test results and clinical data lead to the conclusion that benzalkonium chloride is, at most, an extremely rare allergen, except perhaps in the eye, but with many supposed cases of ACD being likely to arise from the misinterpretation of patch test data. As a consequence, this substance should not normally be regarded as, or classified as, a significant skin sensitizer.

High frequency of simultaneous sensitivity to Disperse Orange 3 in patients with positive patch tests to para-phenylenediamine.

Cross-sensitization between para-phenylenediamine (PPD) and Disperse Orange 3 (DO3), among other textile dyes, has frequently been reported. We evaluated the frequency of simultaneous patch test reactions to PPD and a range of textile dyes. Retrospectively, we studied 128 patients who were patch test positive to PPD and who had also been tested to textile dyes. The dyes that most commonly also reacted were DO3 (46.1%) followed by Disperse Yellow 3 (21.9%). 80% of 55 patients who had a + + or stronger reaction to PPD also reacted to DO3. Dyes that were least likely also to react were Bismarck Brown (0%), Naphthol AS (1.06%), Disperse Yellow 9 (1.06%), Disperse Blue 3 (1.56%) and Disperse Red 11 (2.13%). We interpreted the simultaneous patch test reactions to PPD and DO3 as due either to cross-sensitivity proper, or to metabolic conversion of textile dyes in the skin to PPD.

Application of the risk assessment paradigm to the induction of allergic contact dermatitis.

The National Academy of Science (NAS) risk assessment paradigm has been widely accepted as a framework for estimating risk from exposure to environmental chemicals (NAS, 1983). Within this framework, quantitative risk assessments (QRAs) serve as the cornerstone of health-based exposure limits, and have been used routinely for both cancer and noncancer endpoints. These methods have focused primarily on the extrapolation of data from laboratory animals to establish acceptable levels of exposure for humans. For health effects associated with a threshold, uncertainty and variability inherent in the extrapolation process is generally dealt with by the application of "uncertainty factors (UFs)." The adaptation of QRA methods to address skin sensitization is a natural and desirable extension of current practices. Based on our chemical, cellular and molecular understanding of the induction of allergic contact dermatitis, one can conduct a QRA using established methods of identifying a NOAEL (No Observed Adverse Effect Level) or other point of departure, and applying appropriate UFs. This paper describes the application of the NAS paradigm to characterize risks from human exposure to skin sensitizers; consequently, this method can also be used to establish an exposure level for skin allergens that does not present an appreciable risk of sensitization.

Chemical allergy: considerations for the practical application of cytokine profiling.

Chemical respiratory allergy is an important occupational health problem, but there are currently available no validated methods for hazard identification. This is due in part to the fact that the relevant cellular and molecular mechanisms of sensitization of the respiratory tract have been unclear, with particular controversy regarding the role of IgE. There is now increasing evidence that respiratory sensitization is associated with the preferential activation of type 2 T lymphocytes and the expression of type 2 cytokines interleukin (IL)-4, IL-5, IL-10, and IL-13. Type 2 cell products favor immediate type hypersensitivity reactions, serving as growth and differentiation factors for mast cells and eosinophils, the cellular effectors of the clinical manifestations of the allergic responses, and promoting IgE antibody production. There has been considerable interest in the application of cytokine profiling for the characterization of chemical allergens, with cytokine phenotypes analyzed in freshly isolated tissue, or following culture in the presence or absence of mitogen at the level of protein secretion or mRNA expression. Experience to date suggests that the measurement of induced cytokine secretion profiles shows promise for the hazard identification and characterization of chemical respiratory allergens. The purpose of this brief review article is to consider the approaches available and to highlight key procedural issues.