Jurij J. Hostynek

Use tests: ROAT (repeated open application test)/PUT (provocative use test): an overview

As one step in defining the clinical relevance of exposure to an allergen identified with patch testing, use tests (provocative use test (PUT), and repeated open application test (ROAT)) have been used. In 1/2 of the cases of seemingly reliable patch tests, use tests are negative, suggesting that the patients biologic threshold of response had not been reached with open application dosing. Dramatic differences exist in regional skin reactivity and percutaneous penetration. Negative results of use tests on normal skin may become positive on diseased skin. To refine this assay further, more controlled observations and analysis of reaction differences between normal and damaged skin, and among regional anatomic sites might be performed. In addition, we require a standardized measurement for the results. Use testing has significant potential in refinement of the evidence‐based diagnosis of clinical relevance. However, for general validation, we should fill the deficiencies described above.

Copper hypersensitivity: dermatologic aspects.

ABSTRACT:  Reports of immune reactions of both the immediate and delayed types due to cutaneous or systemic exposure to copper have been reviewed, in the endeavor to draw a comprehensive profile of the immunogenic potential of that metal and its compounds. The metals immunotoxic potential is also briefly reviewed. In principle, as noted for other transition metals, the electropositive copper ion is potentially immunogenic due to its ability to diffuse through biological membranes to form complexes in contact with tissue protein. Based on predictive guinea pig test and the local lymph node assay (LLNA), copper has a low sensitization potential. Reports of immune reactions to copper include immunologic contact urticaria (ICU), allergic contact dermatitis (ACD), systemic allergic reactions (SAR) and contact stomatitis (STO), but considering the widespread use of copper IUDs and the importance of copper in coinage, items of personal adornment and industry, unambiguous reports of sensitization to the metal are extremely rare, and even fewer are the cases, which appear clinically relevant. Reports of immune reactions to copper mainly describe systemic exposure from intrauterine devices and prosthetic materials in dentistry, implicitly excluding induction of the hypersensitivity from contact with the skin as a risk factor. We provide a diagnostic algorithm that might clarify the frequency of copper hypersensitivity.

Copper Hypersensitivity: Dermatologie Aspects

Reports of immune hypersensitivity reactions of both the immediate and the delayed type following cutaneous or systemic exposure to copper are reviewed here in an endeavor to draw a comprehensive profile of the immunogenic potential of that metal and its compounds. The immunotoxic potential of the metal is also briefly reviewed. In principle, as noted for other transition metals, the electropositive copper ion is potentially immunogenic because of its ability to diffuse through biological membranes, forming complexes when in contact with tissue protein. Based on the results of the predictive guinea pig test and the local lymph node assay (LLNA), copper has a low sensitization potential. Reports of immune reactions to copper include immunologic contact urticaria (ICU), allergic contact dermatitis (ACD), systemic allergic reactions (SAR) and contact stomatitis (STO), but considering the widespread use of copper intrauterine devices (IUDs) and the importance of copper in coinage, items of personal adornment and industry, unambiguous reports of sensitization to the metal are extremely rare, and even fewer are the cases that appear clinically relevant. Most reports of immune reactions to copper describe systemic exposure as a cause--predominantly to intrauterine devices and to prosthetic materials in dentistry--implicitly excluding the induction of hypersensitivity from contact with the skin as a risk factor.

A quantitative structure-toxicity relationships model for the dermal sensitization guinea pig maximization assay

We have developed quantitative structure-toxicity relationship (QSTR) models for assessing dermal sensitization using guinea pig maximization test (GPMT) results. The models are derived from 315 carefully evaluated chemicals. There are two models, one for aromatics (excluding one-benzene-ring compounds), and the other for aliphatics and one-benzene-ring compounds. For sensitizers, the models can resolve whether they are weak/moderate or severe sensitizers. The statistical methodology, based on linear discriminant analysis, incorporates an optimum prediction space (OPS) algorithm. This algorithm ensures that the QSTR model will be used only to make predictions on query structures which fall within its domain. Calculation of the similarities between a query structure and the database compounds from which the applicable model was developed are used to validate each skin sensitization assessment. The cross-validated specificity of the equations ranges between 81 and 91%, and the sensitivity between 85 and 95%. For an independent test set, specificity is 79%, and sensitivity 82%.

Sensitization to nickel: etiology, epidemiology, immune reactions, prevention, and therapy.

Nickel is a contact allergen causing Type I and Type IV hypersensitivity, mediated by reagins and allergen-specific T lymphocytes, expressing in a wide range of cutaneous eruptions following dermal or systemic exposure. As such, nickel is the most frequent cause of hypersensitivity, occupational as well as among the general population. In synoptic form, the many effects that nickel has on the organism are presented to provide a comprehensive picture of the aspects of that metal with many biologically noxious, but metallurgically indispensable characteristics. This paper reviews the epidemiology, the prognosis for occupational and non-occupational nickel allergic hypersensitivity, the types of exposure and resulting immune responses, the rate of diffusion through the skin, and immunotoxicity. Alternatives toward prevention and remediation, topical and systemic, for this pervasive and increasing form of morbidity are discussed. The merits and limitations of preventive measures in industry and private life are considered, as well as the effectiveness of topical and systemic therapy in treating nickel allergic hypersensitivity.

Gold: an allergen of growing significance

Gold moved into the limelight of medical literature thanks to the anti-inflammatory activity and effectiveness of gold compounds in the treatment of rheumatoid arthritis, but more recently also because of the growing incidence of hypersensitivity induced by it which is expressed in cutaneous and mucosal reactions. This review discusses dermatotoxicity associated with gold. In some countries gold has moved into second place as allergen, following nickel. Such recognition is mainly due to improved diagnostic methods and to its inclusion in routine dermal patch testing. Some unconventional manifestations of hypersensitivity are associated with use patterns which involve intimate contact with the metal as a component of jewelry. In-depth analysis of the growing number of cases of allergy has revealed various immunological idiosyncrasies as being characteristic of this metal. These include late reactions to challenge, extraordinary persistence of clinical effects, formation of intracutaneous nodules and immunogenic granuloma unresponsive to conventional steroid therapy, the occurrence of eczema at sites distant from the site of contact, and flare-ups of eczema upon systemic provocation with allergen which are characteristic of drug induced allergy. These manifestations demand investigations at the molecular level of the unusual mechanisms of action involved.

Provocative use test of nickel coins in nickel‐sensitized subjects and controls

Summary  Background Consensus exists on levels of nickel release that are well tolerated in exposure to nickel‐containing items in direct and continuous contact with skin (e.g. watches). The clinical relevance of nickel‐containing coins eliciting nickel dermatitis associated with extensive occupational exposure (e.g. coins handled by cashiers) has not been determined.

Skin Penetration by Metal Compounds with Special Reference to Copper

The process of diffusion into and across the different structures of the skin by chemicals is reviewed, with particular attention given to copper compounds. The scarce data available from the literature indicate that, in contact with the skin, metallic copper will oxidize, and the compounds resulting will penetrate it. Results from our lab confirm that copper compounds formed with skin exudates penetrate the human stratum corneum in a time-dependent fashion. The only quantitative diffusion rates for copper compounds given in the literature so far refer to experiments performed on the cat in vitro and in vivo. Transformation of data from that study, based on certain assumptions, lead to estimated Kp values of 10−6 to 10−5 cm/h for the copper salts tested, values that lie at the lower end of skin diffusivity rates measured for transition metal salts. Permeability coefficients for aqueous copper sulfate and acetate through human epidermis in vitro measured in our laboratory are of the order of 10−6 cm/h. For copper compounds formulated in combination with zinc compounds for therapeutic purposes, applied on dermatomed human skin in vitro in various vehicles, the apparent penetration coefficients Kp were in the range of 3.2 × 10−6 and 1.6 × 10−5 cm/h.

Skin irritation potential of copper compounds.

Data on the dermal irritation by copper and its compounds is scant, and its irritancy has not been determined, e.g., in terms of an irritant dose ID50. Irritancy of copper can only be comparatively characterized in relation to other metal salts. A rank order for the irritancy of metal compounds can be inferred from the patch test concentrations recommended as non-irritating for the purpose of cutaneous allergy testing: potassium dichromate 0.5% in petrolatum; copper sulfate, cobalt chloride and palladium chloride ex equo: 1% in aqueous solution, and nickel sulfate: 5% in petrolatum.

Nickel content of standard patch test materials

The nickel sulfate content in standard patch test materials currently used in the US, Europe and Japan was determined by inductively‐coupled plasma atomic emission spectroscopy, a state‐of‐the‐art microanalytical method which allows nickel detection to levels of 7 ppb (μg/l). In 2 materials with a nominal concentration of 5% nickel sulfate hexahydrate in pet., the range (calculated averages of triplicate analyses of 3 different batches) was from 4.72 to 4.87% and 4.97 to 5.39%, respectively. In 1 material with a 2.5% nominal concentration in pet., the values ranged from 2.41 to 2.48%. The range seen in a 5% NiSO4 hexahydrate aq. material was 4.95 to 5.03%. The range for 2.5% NiSO4 anh. in pet. was 2.39 to 2.49%. This data suggest a significant improvement in quality control compared to our previously published data.