Biomedical subjects

G Frank Gerberick

Publications and source records attributed to G Frank Gerberick.

22 records · Page 2Linked to original sources

PubMed2002

Allergic contact dermatitis.

Allergic contact dermatitis (ACD) is a common occupational and environmental health issue. In common with other forms of allergy the disease progresses in two stages; an initial phase during which sensitization is acquired, followed later (after subsequent exposure to the same chemical allergen) by elicitation of a cutaneous inflammatory reaction. The development of skin sensitization is associated with, and requires, the activation and clonal expansion of allergen responsive T lymphocytes and it is these cells that orchestrate the cutaneous allergic reaction. In recent years, much has been learned of the characteristics of immune responses to skin sensitizing chemicals and of the roles played by dendritic cells, cytokines and chemokines. Some of the more interesting cellular and molecular mechanisms are reviewed briefly in this article. A more detailed appreciation of responses induced by chemical allergens has in turn facilitated the design of novel approaches to the toxicological evaluation of skin sensitization. Real progress has been made, not only in the development of improved methods for hazard identification and characterization, but also in the application of new paradigms for risk assessment. The newer methods now available and the opportunities that exist for further advances are considered. Finally, progress has been made in the characterization of skin sensitization in humans and in the clinical management of ACD. This article seeks to consider skin sensitization and ACD in holistic fashion, bridging experimental observations with clinical disease and basic mechanisms with practical toxicology.

Allergens↗

PubMed2002

Factors affecting thresholds in allergic contact dermatitis: safety and regulatory considerations.

Although it is now well understood that thresholds exist for both the induction and the elicitation of allergic responses, such as those of allergic contact dermatitis, it must also be appreciated that for any given allergen, these thresholds are not absolute values. They will vary between individuals, and according to the conditions of exposure to the allergen. Therefore, it is necessary for the purposes both of risk assessment and regulatory toxicology to appreciate the variables involved and to adopt strategies that incorporate this understanding. In this short article, the nature of thresholds in allergic contact dermatitis and the factors affecting them are reviewed. In particular, thresholds will vary according to whether skin exposure is transient or prolonged, open or occluded and single or repeated. The condition of the skin, the presence of inflammation and the matrix in which a chemical sensitizer comes into contact with the skin also are important. However, the scale of these variables frequently is quantifiable. Thus, recommendations can be made concerning how these considerations can be embraced by those responsible for safety evaluation and for the shaping of regulations for skin sensitizing chemicals/formulations.

Allergens↗

PubMed2002

A review of the scientific basis for uncertainty factors for use in quantitative risk assessment for the induction of allergic contact dermatitis.

Safety evaluations for chemicals which possess the ability to cause sensitization by skin contact have traditionally been done using an ad hoc comparative risk assessment technique. Recently, several papers have been published supporting the use of an alternative, and potentially better, quantitative risk assessment approach. While they represent a relatively new approach to risk assessment for sensitizers, quantitative methods have been used for decades to support risk assessments for systemic toxicity. Historically, these methods have involved the extrapolation of toxicity data - generally from studies in laboratory animals at relatively high doses to human exposures at lower doses. For toxicity endpoints with a threshold, this process has traditionally involved the use of uncertainty factors. For example, uncertainty factors are commonly used to extrapolate from laboratory animals to humans, and from 'average' humans to sensitive subpopulations. In the absence of data to support a different value, a default factor of 10 is widely accepted for each of these areas. Recent papers have advocated the use of a similar approach to characterize the risk of the induction of skin sensitization by allergens of varying potency and potential for skin contact. As with other forms of toxicity, a quantitative assessment of risk for allergic skin reactions can be approached by identifying a NOAEL (no observed adverse effect level) and applying appropriate uncertainty factors. Three major areas of data extrapolation have been identified: inter-individual susceptibility, the influence of vehicle or product matrix, and exposure considerations. This paper provides an overview of each of these areas with an evaluation of the available scientific database to support an uncertainty factor in the range of 1-10 for each area.

Data Interpretation, Statistical↗

PubMed2002

Use of a B cell marker (B220) to discriminate between allergens and irritants in the local lymph node assay.

It has been shown that exposure of mice to contact allergens induces B cell activation in the draining lymph nodes (DLN), as seen by an increase in the percentage of B220+ or IgG/IgM+ cells. We have now examined whether the measurement of the percentage of B220+ cells could be used as an alternative or supplementary endpoint for the local lymph node assay (LLNA) to differentiate between allergenic responses and those few irritants that induce low-level proliferation in the DLN. Mice were treated on the ears, daily for 3 consecutive days, with various allergens (1-chloro-2,4-dinitrobenzene, alpha-hexylcinnamaldehyde, trinitrochlorobenzene, isoeugenol, and eugenol) or irritants (benzalkonium chloride, methyl salicylate, salicylic acid, and sodium lauryl sulfate). The DLN were excised 72 h following the final topical treatment, and the cells were prepared for B220 analysis using flow cytometry. The percentage of B220+ cells in lymph nodes derived from test and vehicle-treated animals was determined for 5 allergens and 4 irritants tested in multiple experiments (n = 3 to 17). As expected, the percentage of B220+ B cells was increased with each of the allergens tested, whereas irritant treatment did not cause similar increases. Moreover, the method was reproducible. For example, the strong allergen, 1-chloro-2,4-dinitrobenzene and the weak allergen, alpha-hexylcinnamaldehyde were identified as allergens in 17 of 17 and in 12 of 13 experiments, respectively. The percentage of B220 values for each chemical treatment (41 observations for allergens; 28 observations for irritants) versus the percentage of B220 values for the concurrent vehicle controls were plotted, and a classification tree model was developed that defined a B220 test:vehicle ratio cutoff of 1.25 for discriminating between allergens (>1.25) and irritants (<1.25). Using this B220 test:vehicle ratio of 1.25 in 93% of the 69 independent observations made, the allergens and irritants tested were identified correctly. Finally, to evaluate the performance of this model in a second independent laboratory, 3 allergens and 2 irritants were tested. Each of the allergens and irritants were classified correctly using the B220 test:vehicle ratio cutoff of 1.25. These data demonstrate that analysis of B220 expression in DLN may be useful in differentiating between allergen and irritant responses induced in chemically treated mice.

Allergens↗