Allergic Contact Sensitization Research Articles

Evaluation of the Primary Skin Irritation and Allergic Contact Sensitization Potential of Transdermal Triprolidine

Evaluation of the Primary Skin Irritation and Allergic Contact Sensitization Potential of Trans-dermal Triprolidine. ROBINSON, M. K.., PARSELL, K. W., BRENEMAN, D. L., AND CRUZE, C. A. (1991). Fundam. Appl. Toxicol. 17, 103–119. A transdermal patch for the OTC antihistamine, triprolidine (TP), might provide benefits in terms of increased efficacy and reduced sedative side effects. However, concerns over potential irritant or allergic contact sensitization (ACS) skin reactions necessitated thorough skin toxicity testing before and during initial dinical development Initial effort was expended on development of a binary vehicle delivery system comprised of TP in 0.5% oleic acid (OA) in propylene glycol (PG). Rabbit skin irritation and Buehler guinea pig skin sensitization testing indicated that this TP/OA/PG formula had both skin irritation and ACS potential. Both tests underestimated, to some degree, the skin toxicities observed in later clinical testing. In clinical tests, skin irritation was due mainly to the OA–PG vehicle, but was enhanced in the presence of high TP concentrations. Of 26 subjects enrolled in a rising dose clinical phar-macokinetics study, one subject exposed twice to TP/OA/PG presented with delayed skin reactions suggestive of ACS. Positive diagnostic patch test results for this subject and four out of five other twice-exposed study subjects suggested that the TP/OA/PG formula had a very high ACS potential. Subsequent predictive clinical patch testing was conducted with a buffered aqueous TP formula which provided in vitro skin penetration of the drug equivalent to the TP/OA/PG formula. These clinical studies demonstrated that TP itself had no significant irritation potential but still induced ACS reactions in a high proportion of test subjects. The incidence of adverse skin reactions to TP was considered to be too high relative to the degree of improved therapeutic benefit of this delivery form. On this basis, all technology development effort was discontinued, © 1991 by the Society of Toxicology

Allergologic Evaluation for Workers Exposed to Toluene Diisocyanate.

A cross-sectional investigation for allergology was performed of 15 painters exposed to high concentrations of toluene diisocyanate (TDI) (0.07-0.17 ppm) during the process of handling polyurethane varnish in a furniture manufacturing factory. Asthmatic reactions such as dyspnea, wheezing related to workshifts and contact dermatitis were observed in four and three cases respectively by questionnaire survey. Lung function tests on the painters showed significant decline in FEV1, %FEV1 and MMF compared to the referents. An increment in mast cell degranulation percentage could be seen in the painters. And also, patch testing with TDI were positive in five cases. From the results, it was suggested that both allergic pulmonary effects and contact sensitization had occurred in TDI-exposed painters in this factory.

Immunosuppressive Effects of Clonidine on the Induction of Contact Sensitization in the Balb/c Mouse

The clonidine transdermal therapeutic system (clonidine-TTS) has been associated with a significant incidence of allergic contact sensitization. This incidence was not predicted by premarket skin sensitization testing in animals or humans. One possible explanation lies in recent findings in guinea pigs that clonidine exposure could inhibit the elicitation of skin reactions to unrelated strong contact sensitizers. However, these studies also showed that clonidine pretreatment did not appear to affect the induction of contact sensitization. On this basis, we sought to specifically evaluate the induction phase of sensitization to clonidine as an alternative means of assessing its sensitization properties. The method selected was the assay of in situ lymphocyte proliferation in lymph nodes draining the sites of clonidine exposure, a method recently promoted as an alternative means to assess contact allergenic potential. Utilizing various induction application techniques and regimens, we were consistently unable to demonstrate clonidine's allergenic potential through such an assessment of lymphocyte proliferation. We were also unable to demonstrate sensitization by in vivo ear swelling or in vitro lymphocyte blastogenesis assay techniques. However, a subsequent assessment of the effect of clonidine exposure on the induction of sensitization to unrelated strong contact allergens demonstrated a consistent 40-70% inhibition of the proliferative response to the contact allergens oxazolone and trinitrochlorobenzene. This was similar to the degree of suppression produced by the corticosteroids fluocinonide and hydrocortisone when they were tested at 80 and 10 times lower concentrations. In addition, we observed a comparable inhibition of the ear swelling response to oxazolone. These data extend our knowledge of the immunomodulatory effects of clonidine and offer additional mechanistic insights into the failure of short-term predictive patch-test methods to detect this chemical's potential to induce allergic contact sensitization.

Mast cell participation in allergic contact sensitivity

Contact DermatitisVolume 23, Issue 4 p. 239-239 Mast cell participation in allergic contact sensitivity Gianni Angelini, Gianni Angelini Departments of Dermatology and Clinical Immunology, University of Ban, ItalySearch for more papers by this authorGino A. Vena, Gino A. Vena Departments of Dermatology and Clinical Immunology, University of Ban, ItalySearch for more papers by this authorRaffaele Filotico, Raffaele Filotico Departments of Dermatology and Clinical Immunology, University of Ban, ItalySearch for more papers by this authorAlfredo Tursi, Alfredo Tursi Departments of Dermatology and Clinical Immunology, University of Ban, ItalySearch for more papers by this author Gianni Angelini, Gianni Angelini Departments of Dermatology and Clinical Immunology, University of Ban, ItalySearch for more papers by this authorGino A. Vena, Gino A. Vena Departments of Dermatology and Clinical Immunology, University of Ban, ItalySearch for more papers by this authorRaffaele Filotico, Raffaele Filotico Departments of Dermatology and Clinical Immunology, University of Ban, ItalySearch for more papers by this authorAlfredo Tursi, Alfredo Tursi Departments of Dermatology and Clinical Immunology, University of Ban, ItalySearch for more papers by this author First published: October 1990 https://doi.org/10.1111/j.1600-0536.1990.tb05017.xCitations: 7AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume23, Issue4October 1990Pages 239-239 RelatedInformation

An investigation of the potential for allergic contact sensitization of several oakmoss preparations

An investigation of the potential for allergic contact sensitization of several oakmoss preparations

Piroxicam-induced photosensitivity and contact sensitivity to thiosalicylic acid

A photocontact dermatitis developed in three patients after the application of gel containing 0.5% piroxicam. Patch tests were positive to thiomersal and thiosalicylic acid. Photopatch tests with piroxicam at several concentrations were positive in the three patients but negative in 62 normal volunteer subjects. Patch tests performed on 14 patients with proved systemic photosensitivity to piroxicam were positive for thiomersal and thiosalicylic acid. Nine of 12 patients previously sensitized to thiosalicylic acid and with no history of exposure to piroxicam showed positive photopatch test reactions to this chemical. These results support a relation between piroxicam-induced photosensitivity and contact sensitivity to thiosalicylic acid. Contact allergic sensitivity to the latter is a marker for patients with a high risk of developing photosensitivity reactions to piroxicam. These reactions may be due to photoproducts of the drug rather than metabolites.

In vitro tests with sensitized lymphocytes—Relevance for predictive allergenicity testing

The main obstacle to routine in vitro tests to identify contact sensitizers is the inappropriate application of the allergens in vitro, even when sufficient antigen-presenting cells are available. Some allergens may need the skin tissue for adequate conjugation with carrier molecules, whereas others may be poorly solubilized or toxic for the cultures. Methods, therefore, which make use of the in vivo system for allergen binding and presentation, but which assess in vitro the subsequent lymphocyte activation are most promising. For this reason, the local lymph node assay deserves more attention as a predictive assay in allergenicity testing and should be validated in more laboratories in the near future. The value of allergen-stimulated in vitro tests for predictive allergenicity screening will remain limited. This type of in vitro test is, however, invaluable for mechanistic studies on contact sensitivity in well defined allergen models. Also for clinical diagnosis of allergic contact sensitivity to selected allergens, the lymphocyte transformation test and macrophage migration inhibition test may be useful, particularly when skin tests fail to be conclusive.

Polyamine sensitization in offshore workers handling drilling muds

Oil-based mud, a complex mixture containing amines in emulsifiers, is used in offshore drilling operations. It is a skin irritant that occasionally gives rise to allergic contact sensitivity. In patch testing patients with allergy to drilling mud, we have identified polyamine (diethylenetriamine and triethylenetetramine) sensitivity in 5 patients. All 5 patients were also allergic to emulsifiers. These emulsifiers are cross-linked fatty acid amido-amines, in which unreacted amine groups are thought to cross-sensitize with these constituent polyamines. Cross-reactivity between ethylenediamine, diethylenetetramine and triethylenetetramine was found in 9 subjects.

Allergic contact dermatitis resulting from sensitivity to citrus peel, geraniol, and citral

A bartender with hand dermatitis had allergic contact sensitivity to the skin of lemon, lime, and orange but not to their juices. Although most reported cases of citrus peel allergy are due to d-limonene, for our patient, reactions to patch tests for geraniol and citral, two minor components of citrus peel oil, were positive, whereas those for d-limonene were negative. Contact allergy to citrus peel oil should be considered in patients with hand dermatitis who are occupationally exposed to citrus fruits.

Topical Cyclosporine and Contact Dermatitis in Guinea Pig and Man

To the Editor.— A recent article in theArchivesshowed that topical cyclosporine applied to the test site of guinea pigs previously sensitized with 2,4-dinitrochlorobenzene (DNCB) inhibits the elicitation reaction of contact sensitivity.1Similar reports showing that topical cyclosporine is capable of inhibiting allergic and/or irritant contact sensitivity reactions in guinea pigs2,3have suggested the use of topical cyclosporine in patients with contact allergy. In a recent report, topical cyclosporine showed some inhibitory effect in patch test reactions to nickel in patients with nickel contact dermatitis.4 To study whether topical cyclosporine has an effect in human DNCB-induced contact hypersensitivity, we applied topical cyclosporine in eight separate rechallenge experiments to test sites on three male volunteer subjects who had been previously sensitized with 600 μg of DNCB in a 60-μL Finn chamber. Pretreatment with topical cyclosporine on a tape-stripped skin area used for rechallenge was also studied. For

Induction of hair growth in alopecia totalis with diphencyprone sensitization.

The therapeutic use of the induction of an allergic contact sensitivity to diphencyprone in alopecia areata has been studied. Fourteen subjects had alopecia totalis and four had extensive and long-standing alopecia areata. Topical diphencyprone was capable of inducing an allergic contact sensitivity in 16 subjects (89%), and 13 of these agreed to proceed to repeated intermittent applications to the left side of the scalp, the right side acting as an untreated control; six subjects achieved cosmetically useful regrowth of normally pigmented terminal hair. No clinical features seemed to distinguish those who showed a favourable response from those who did not.

Allergic contact sensitivity to quinophthalone

A 73-year-old patient, diagnosed as having seborrheic dermatitis, was patch tested with his hair preparations. The hair stick gave a positive reaction. Among its ingredients, D & C Yellow No. 11, from 0.0001% to 0.1%, and perfume showed positive reactions. D & C Yellow No. 11 was found to consist only of quinophthalone by chemical analyses. The concentration of quinophthalone in the hair stick was determined as 9.41 ppm w/w by high-performance liquid chromatography.

A risk assessment process for allergic contact sensitization

This review describes an approach that has been used to assess the skin sensitization risk of new chemicals and product formulations prior to launching the new chemical or product on the market. The risk assessment process utilizes a comparative toxicological approach, in which data on the inherent toxicity of a material, and the exposure to it through manufacturing or consumer use or foreseeable misuse, are integrated and compared with data generated by ‘benchmark’ materials of similar chemistry or product application, or both. This approach has been valuable in providing an accurate assessment of the skin sensitization potential for a wide range of consumer products and pharmaceuticals, ranging from products with a very transient skin exposure (e.g. some paper products), to cosmetics, to products whose ingredients may be deposited on fabrics and thus result in chronic skin exposure. The risk assessment process described includes both guinea-pig (Buehler) and human skin sensitization test methodologies to evaluate inherent toxicity under relevant epicutaneous exposure conditions. Alternative guinea-pig test methods have been reported to be more sensitive than the Buehler method, particularly those employing intradermal injection of the test material in Freund's complete adjuvant (e.g. maximization test). However, by bypassing the skin barrier at induction, these methods can overstate the sensitization risk of epicutaneous exposure to weak sensitizers (Andersen and Hamann, 1983 and 1984; Matsushita et al., 1975a,b), and can understate the risk to very strong sensitizers possibly through tolerance induction (Buehler, 1985). In addition, materials are tested and classified at concentrations that may not be relevant to anticipated human exposure. The Buehler guinea-pig test data are important in assessing skin sensitization risk in the early phases of product development, where human exposure can be limited, controlled and monitored (e.g. manufacturing employees). The Buehler test can often define consumer skin sensitization risk; however, the ultimate consumer skin safety assessment should in general be developed through a series of controlled human tests; the human repeat insult patch test and, when necessary, the provocative or extended product use tests. Post-market monitoring of skin-related consumer comments is the final phase of the data gathering process. These results can be used to assess further each product and to provide valuable feedback to confirm the validity of the overall risk assessment process. Risk assessment for skin sensitization potential is seldom a simple process. Unexpected results, for example clinical patch test reactions that resemble allergic contact dermatitis, but are poorly reproducible, can lead to the expenditure of considerable effort. Fortunately, the various assessment tools, such as the provocative use test, can greatly aid in the resolution of such cases. Thus the knowledge that people reacting under exaggerated patch test exposure conditions (regardless of the nature of the reaction) can safely use the product, increases the assurance that consumers will suffer no adverse reactions from long-term product use. The risk assessment approach outlined is of value from two perspectives. First, it provides manufacturing and product development employees with safer working conditions, and it provides the consumer with safer products from a skin sensitization standpoint. Secondly, it provides an extensive database on skin sensitization potential from predictive animal testing, predictive human testing, clinical use testing and long-term worker and consumer exposure. It thus strengthens the confidence we have in extrapolating data obtained from each phase of skin sensitization testing for a new chemical or product in order to protect the well-being of the skin.

Chemical warfare: Cutaneous lesions from mustard gas

Cutaneous lesions of eight patients evacuated from the Iran-Iraq war zone are reported. The patients were exposed to mustard gas, and there was a spectrum of dermatologie lesions. In the mild cases only there was a sunburnlike erythema, but in the most severe cases this erythema was followed by large and disseminated bullae, which histologically showed a subepidermal location with full-thickness epidermal necrosis. The resorption of these blisters was followed by hyperpigmentation, which was more evident in the intertriginous areas. In these last cases there also were ocular, respiratory, and gastrointestinal manifestations. In the skin this mustard gas seems to act through a primary irritant mechanism and without allergic contact sensitization.

Trends in allergic contact sensitization.

A standard patch test series was tested for 7 years (1977-1983) in a total of 11,962 patients. The annual frequency of positive reactions to the compounds tested was assessed for the total and for males and females separately. During the observation period, there were significant increases in positive reactions in the total group from 6.2% to 12.7% for nickel sulphate, from 5.3% to 7.0% for balsam of Peru and from 3.8% to 6.5% for potassium dichromate, reflecting significant changes in both sexes. The frequency of positive reactions to wool alcohols, formaldehyde, neomycin sulphate, paraben mix and gentamycin sulphate significantly increased, while that of positive reactions to clioquinol, mercuric chloride and turpentine peroxide significantly decreased in either males or females, sometimes leading to significant changes in the total group.

Allergic contact sensitization potential of hydroxycitronellal in humans

Hydroxycitronellal, an important ingredient in fragrances, was studied for its sensitizing potential in human skin. Fifteen human maximization tests were conducted with hydroxycitronellal obtained from four different sources at induction concentrations from 5 to 12%. No reactions were induced at 5% in two separate panels while 10% sensitized 2/25 panelists in one test but none in a second. Induction at 12% produced sensitization in 8 of 11 tests. Impurities do not appear to be a sensitizing factor. There is some evidence that the l-stereoisomer is a less potent sensitizer than the d-stereoisomer. In an initial modified human repeat-insult patch-test two positive reactions to challenge were observed among 197 panelists, one at a concentration of 5% and the other at 7.5%. When 100 of the non-reacting panelists were re-exposed in the same way, allergic sensitization reactions appeared during the induction period with concentrations as low as 2.5%. When 28 sensitized panelists were exposed to 1% concentrations in a simulated use test, there were three reactors. A no-effect level for sensitization has not been determined although the lowest concentrations tested were in the product usage range.

Persistence of allergic contact sensitivity in subjects with photosensitivity dermatitis and actinic reticuloid syndrome.

We report the maintenance of allergic contact sensitivity in 20 subjects with photosensitivity dermatitis and actinic reticuloid syndrome. Positive patch test reactions were demonstrated some years after the initial diagnosis and after significant maintained improvement of the photodermatosis had occurred.

Epidermal langerhans cell density and contact sensitivity in young and aged BALB/c mice

The loss of tissue and organ function with age may depend on the inability of old cells to carry out specialized functions. Like other systems in the body, the immune system deteriorates with age. Over the past 10 years it has become clear that the skin can play an active role in immunological processes. In this report we evaluated changes in murine cutaneous immunity with age. Studies in humans had shown a decreased Langerhans cell density with age, but it is difficult to control for the effect of ultraviolet light in human studies. Since ultraviolet light has a significant effect on Langerhans cells, we chose to evaluate the effect of age on Langerhans cell density using inbred mice not exposed to ultraviolet light. Cutaneous immunity was examined phenotypically by studying Langerhans cell density and functionally by studying allergic contact sensitivity. Langerhans cell density was assessed in epidermal sheets prepared from ear skin of mice and examined by ATPase histochemistry and fluoresceinated anti-la staining. With both methods, aged (18 months old) mice had approximately two-thirds the number of Langerhans cells that young (10–12 weeks old) animals did. Allergic contact sensitivity response to trinitrochlorobenzene (TNCB) was compared between aged and young animals. Although the aged animals demonstrated increased variability in their responsiveness, there was no overall difference in this example of cutaneous immunoreactivity between the two age groups.

Changes in Expression of Ia, Thy-1, and Ly-5 Antigens in Epidermal Cells During Delayed Contact Sensitivity Reactions in Mice: Flow Cytometric Analysis

Ia antigen-bearing (Ia+) Langerhans cells have attained an important position as immunocompetent cells in the epidermis. Recently there have been successive reports on other new possible candidates for immunocompetent cells in the epidermis, i.e., Ia+ keratinocytes and dendritic Thy-1 antigen-bearing (Thy-1+) epidermal cells which also express Ly-5 antigen and asialo-GM1. Based on our previous findings that in allergic contact sensitivity reactions, keratinocytes express Ia antigen 3-9 days postchallenge, in this report, we have attempted to define more clearly the dynamic changes of Ia+ keratinocytes and dendritic Thy-1+ epidermal cells by enumeration of the precise percentages of Ia+, Thy-1+, and Ly-5 antigen-bearing (Ly-5+) cells in epidermal cells at various times of the challenge phase in allergic contact sensitivity reactions by use of a fluorescence-activated cell sorter. By 24 h postchallenge, the percentages of Ia+, Thy-1+, and Ly-5+ cells showed hardly any change. There were approximately 2% Ia+ cells, 50% Thy-1+ cells which consist of 2 populations (i.e., 45% weakly Thy-1 antigen-positive cells and 4% strongly Thy-1 antigen-positive cells), and 3.5% Ly-5+ cells. From 48 h postchallenge, however, the percentage of Ia+ cells and that of Thy-1+ cells began to increase and reached a plateau, with approximately 20% Ia+ cells and 70% Thy-1+ cells, respectively, at 120 h postchallenge. The change of the percentages of Ly-5+ cells appears to correspond to that of strongly Thy-1 antigen-positive cells. Only at 48 h postchallenge, Ly-5+ cells and strongly Thy-1 antigen-positive cells showed a small increase in number, comprising approximately 10% of the epidermal cells. These data suggest that among Thy-1+ epidermal cells, strongly Thy-1 antigen-positive cells correspond to dendritic Thy-1+ epidermal cells, and in contact sensitivity reactions in mice, dendritic Thy-1+ epidermal cells show only a minor dynamic change in contrast to Ia+ cells, in which more than 15% of keratinocytes express Ia antigen from 48 h postchallenge.

TNP-specific Lyt-2+ cytolytic T cell clones preferentially respond to TNP-conjugated epidermal cells.

A most effective method for the induction of hapten-specific allergic contact sensitivity (CS) is via epicutaneous application of the hapten. Another effective method is by the administration of haptenated epidermal cells (EC) subcutaneously. The latter method induces more intense and longer lasting CS than does the subcutaneous administration of haptenated spleen cells (SC). Thus, there may be something unique about EC which, when haptenated, allows them to generate effector cells more effectively than do SC. We therefore attempted to generate T cell clones that were both hapten- and epidermal-specific. Four days after painting mice with 7% trinitrochlorobenzene, draining lymph node cells were obtained and T cells were purified. These cells were co-cultured with trinitrophenylated (TNP) Langerhans cell-enriched EC. After 4 days, cells were harvested and rested on non-TNP-conjugated EC. The cells were restimulated and rested three times, and were then cloned by limiting dilution with added interleukin 2, which was then continually added. Proliferation of T cells was assessed by [3H]-thymidine incorporation. Cytotoxicity assays utilized TNP-conjugated concanavalin A SC blasts or EC as targets. Clones A-2 and E-4 are Thy-1+, Lyt-2+, and L3T4-, and TNP-specific. In contrast to noncloned TNP-specific T cells, the clones proliferate preferentially in response to TNP-EC rather than TNP-SC. Also in contrast to noncloned T cells, the clones were preferentially cytotoxic for TNP-EC; compared to TNP-SC, there was an eight- to 32-fold increase in killing when TNP-EC were used as targets. Clones A-2 and E-4 therefore exhibit hapten and epidermal specificity. The epidermal-specific epitope that is recognized is unknown, but genetic restriction and antibody inhibition studies indicate that it is co-recognized with H-2K.