Ann-Therese Karlberg

University of Gothenburg, Göteborg, Vaestra Goetaland, Sweden

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Publications (77)222.08 Total impact

  • [show abstract] [hide abstract]
    ABSTRACT: Linalool is a commonly used fragrance terpene that forms potent sensitizers upon oxidation. In a recent multicentre study, we found that 7% of 2900 patients showed positive patch test reactions to oxidized linalool at 6.0%. No elicitation studies have been performed. To identify threshold concentrations for elicitation of allergic contact dermatitis caused by oxidized linalool in allergic individuals with repeated exposures. Repeated open application tests were performed in 6 participants previously diagnosed with contact allergy to oxidized linalool. Creams containing 3.0%, 1.0% and 0.30% oxidized linalool (corresponding to 0.56%, 0.19% and 0.056% linalool hydroperoxides, respectively) and 'fine fragrance' containing 1.0%, 0.30% and 0.10% oxidized linalool (corresponding to 0.19%, 0.056% and 0.019% linalool hydroperoxides, respectively) were used twice daily for up to 3 weeks. Patch testing with a dilution series of oxidized linalool was performed. Five of 6 participants reacted to the cream containing 3% oxidized linalool. With 1% oxidized linalool, a reaction was seen in 3 (cream) and 4 (fine fragrance) participants, respectively. With 0.3% oxidized linalool, 2 (cream) and 1 (fine fragrance) participants reacted. Repeated exposure to low concentrations of oxidized linalool can elicit allergic contact dermatitis in previously sensitized individuals.
    Contact Dermatitis 03/2014; 70(3):129-38. · 2.93 Impact Factor
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    ABSTRACT: The fragrance terpene R-limonene is a very weak sensitizer, but forms allergenic oxidation products upon contact with air. The primary oxidation products of oxidized limonene, the hydroperoxides, have an important impact on the sensitizing potency of the oxidation mixture. One analogue, limonene-1-hydroperoxide, was experimentally shown to be a significantly more potent sensitizer than limonene-2-hydroperoxide in the local lymph node assay with non-pooled lymph nodes. To investigate the pattern of reactivity among consecutive dermatitis patients to two structurally closely related limonene hydroperoxides, limonene-1-hydroperoxide and limonene-2-hydroperoxide. Limonene-1-hydroperoxide, limonene-2-hydroperoxide, at 0.5% in petrolatum, and oxidized limonene 3.0% pet. were tested in 763 consecutive dermatitis patients. Of the tested materials, limonene-1-hydroperoxide gave most reactions, with 2.4% of the patients showing positive patch test reactions. Limonene-2-hydroperoxide and oxidized R-limonene gave 1.7% and 1.2% positive patch test reactions, respectively. Concomitant positive patch test reactions to other fragrance markers in the baseline series were frequently noted. The results are in accordance with the experimental studies, as limonene-1-hydroperoxide gave more positive patch test reactions in the tested patients than limonene-2-hydroperoxide. Furthermore, the results support the specificity of the allergenic activity of the limonene hydroperoxide analogues and the importance of oxidized limonene as a cause of contact allergy.
    Contact Dermatitis 02/2014; · 2.93 Impact Factor
  • Johanna Rudbäck, Ahmed Ramzy, Ann-Therese Karlberg, Ulrika Nilsson
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    ABSTRACT: Fragrance monoterpenes are widely used commercially due to their pleasant scent. In previous studies, we have shown that air-exposed monoterpenes form hydroperoxides that are strong skin sensitizers. Methods for detection and quantification of the hydroperoxides in essential oils and scented products are thus desirable. Due to thermolability and low UV-absorbance this is a complicated task. We have recently developed a sensitive LC-ESI-MS method, but with limited structural information and separation efficiency for positional isomers and stereoisomers. In the present study, we investigated derivatization with a trimethyl silyl reagent and subsequent GC with electron ionization MS for the determination of monoterpene hydroperoxides. All investigated monoterpene hydroperoxides could be chromatographed as thermostable trimethylsilyl derivatives and yielded the fragment m/z 89 ([OSi(CH3 )3 ](+) ) at a higher extent compared to corresponding alcohols. Limonene-2-hydroperoxide and four other hydroperoxide isomers of limonene were separated and detected in sweet orange oil autoxidized for two months. The concentration of limonene-2-hydroperoxide isomers was found to be 19 μg/mg in total. Also isomers of linalyl acetate hydroperoxide and linalool hydroperoxide were detected in autoxidized petitgrain oil (two months). The presented GC-MS method showed concentrations in the same order as previous LC-MS/MS analysis of the same type of oils. This article is protected by copyright. All rights reserved.
    Journal of Separation Science 01/2014; · 2.59 Impact Factor
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    ABSTRACT: Cinnamic alcohol is a frequent contact allergen, causing allergic contact dermatitis (ACD) in a substantial number of individuals sensitized from contacts with fragrances. Hence, cinnamic alcohol is one of the constituents in fragrance mix I (FM I) used for screening of contact allergy in dermatitis patients. Cinnamic alcohol lacks structural alerts for protein reactivity, and must therefore be activated by either air oxidation or bioactivation to be able to act as a sensitizer. In the present study, we have explored the bioactivation of cinnamic alcohol using human liver microsomes (HLM) and the potential pathways for these reactions have been modeled by in silico (DFT) techniques. Subsequently, the reactivity of cinnamic alcohol and its metabolites toward a model hexapeptide were investigated. In addition to cinnamic aldehyde and cinnamic acid two highly sensitizing epoxides, previously unobserved in studies of bioactivation, were detected in the incubations with HLMs. Formation of epoxy cinnamic aldehyde was shown (both by the liver microsomal experiments, in which no depletion of epoxy cinnamic alcohol was observed after initial formation, and by the very high activation energy found for oxidation thereof by calculations) to proceed via cinnamic aldehyde and not epoxy cinnamic alcohol.
    Chemical Research in Toxicology 01/2014; · 3.67 Impact Factor
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    ABSTRACT: Experimental and clinical studies have shown that fragrance substances act as prehaptens or prohaptens. They form allergens that are more potent than the parent substance by activation outside or in the skin via abiotic (chemical and physical factors) and/or biotic activation, thus, increasing the risk of sensitization. In the present review a series of fragrance substances with well documented abiotic and/or biotic activation are given as indicative and illustrative examples of the general problem. Commonly used fragrance substances, also found in essential oils, autoxidize on contact with air, forming potent sensitizers that can be an important source for contact allergy to fragrances and fragranced products. Some of them can act as prohapten and be activated in the skin as well. The experimental findings are confirmed in large clinical studies. When substances with structural alerts for acting as prohaptens and/or prehaptens are identified, the possibility of generating new potent allergens should be considered. Predictive testing should include activation steps. Further experimental and clinical research regarding activation of fragrance substances is needed to increase consumer safety.
    Contact Dermatitis 09/2013; · 2.93 Impact Factor
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    ABSTRACT: Contact allergy to fragrances is still relatively common, affecting ∼ 16% of patients patch tested for suspected allergic contact dermatitis, considering all current screening allergens. The objective of the review is to systematically retrieve, evaluate and classify evidence on contact allergy to fragrances, in order to arrive at recommendations for targeting of primary and secondary prevention. Besides published evidence on contact allergy in humans, animal data (local lymph node assay), annual use volumes and structure-activity relationships (SARs) were considered for an algorithmic categorization of substances as contact allergens. A total of 54 individual chemicals and 28 natural extracts (essential oils) can be categorized as established contact allergens in humans, including all 26 substances previously identified as contact allergens (SCCNFP/0017/98). Twelve of the 54 individual chemicals are considered to be of special concern, owing to the high absolute number of reported cases of contact allergy (> 100). Additionally, 18 single substances and one natural mixture are categorized as established contact allergens in animals. SARs, combined with limited human evidence, contributed to the categorization of a further 26 substances as likely contact allergens. In conclusion, the presence of 127 single fragrance substances and natural mixtures should, owing to their skin sensitizing properties, be disclosed, for example on the label. As an additional preventive measure, the maximum use concentration of 11 substances of special concern should be limited to 100 ppm. The substance hydroxyisohexyl 3-cyclohexene carboxaldehyde and the two ingredients chloroatranol and atranol in the natural extracts Evernia prunastri and Evernia furfuracea should not be present in cosmetic products.
    Contact Dermatitis 07/2013; · 2.93 Impact Factor
  • Dermatitis 05/2013; · 0.93 Impact Factor
  • Lina Hagvall, Ann-Therese Karlberg, Johanna B Christensson
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    ABSTRACT: Background. Geraniol is a commonly used fragrance terpene, and is tested in the baseline series in fragrance mix I. Geraniol is a pro-hapten and a pre-hapten, and sensitizers are formed in the autoxidation and skin metabolism of geraniol. Previous patch testing with air-exposed (oxidized) geraniol has suggested that oxidized geraniol could be a better marker for contact allergy to geraniol than pure geraniol. Objectives. To find the optimal patch test substance and concentration for detecting contact allergy to geraniol. Patients and methods. Six hundred and fifty-five patients were patch tested with pure and oxidized geraniol at 4.0%, 6.0% and 11.0% in petrolatum. Before patch testing, the irritant properties of pure and oxidized geraniol were studied in 27 patients at 2.5%, 5.0%, 10.0% and 20.0% pet. Results. Pure geraniol detected positive reactions in 0.15-1.1% of the patients, and oxidized geraniol detected positive reactions in 0.92-4.6% of the patients. Reactions to pure geraniol in patients not reacting to oxidized geraniol indicated metabolic activation of geraniol. Neither pure nor oxidized geraniol gave significant irritant reactions. Conclusions. Increasing the test concentrations of pure and oxidized geraniol enables the detection of more cases of contact allergy. Oxidized geraniol detects more patients than pure geraniol, but patch testing with only oxidized geraniol does not detect all cases of contact allergy to geraniol.
    Contact Dermatitis 04/2013; 68(4):224-31. · 2.93 Impact Factor
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    ABSTRACT: Structure-activity relationship (SAR) models are important tools for predicting the skin sensitization potential of new compounds without animal testing. In compounds possessing a structural alert (aldehyde) and an activation alert (double bond), it is important to consider bioactivation/autoxidation (e.g. epoxidation). In the present study we have explored a series of aldehydes with regard to contact allergy. The chemical reactivity of these 6 aldehydes toward a model hexapeptide was investigated and their skin sensitization potencies were evaluated using the local lymph node assay (LLNA). Overall, we observed a similar trend for the in vitro reactivity and the in vivo sensitization potency for the structural analogs in this study. The highly reactive conjugated aldehydes (a,b-unsaturated aldehydes and 2,3-epoxyaldehydes) are sensitizing moieties while non-conjugated aldehydes and non-terminal aliphatic epoxides show low reactivity and low sensitization potency. Our data show the importance not only of double bond conjugation to aldehyde but also epoxide-aldehyde conjugation. The observations indicate that the formation of non-conjugated epoxides by bioactivation or autoxidation is not sufficient to significantly increase the sensitization potency of weakly sensitizing parent compounds.
    Chemical Research in Toxicology 03/2013; · 3.67 Impact Factor
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    ABSTRACT: Background. Cinnamyl alcohol and cinnamal are frequent fragrance contact allergens. Both are included in the European baseline fragrance mix I, which is used for screening of contact allergy in dermatitis patients. Objectives. The aim of this study was to investigate the autoxidation of cinnamyl alcohol and to identify the oxidation products formed on air exposure. We also wanted to evaluate the effect of autoxidation on the sensitization potency of cinnamyl alcohol. Methods. Samples of commercially available cinnamyl alcohol with and without purification were exposed to air, and the autoxidation was followed by chemical analysis. The analysis was performed with mass spectrometry (LC/MS/MS). Sensitization potencies of compounds were determined with the murine local lymph node assay (LLNA) in mice. Results. Chemical analysis showed that the concentration of cinnamyl alcohol in the air-exposed samples decreased rapidly over time, and that autoxidation products were formed. Cinnamal, epoxy cinnamyl alcohol and cinnamic acid were identified as oxidation products. According to our study, cinnamal and epoxy cinnamyl alcohol were the first autoxidation products formed. The epoxy cinnamyl alcohol was shown to be the oxidation product with the highest sensitization potency. The analysis of our samples of commercially available cinnamyl alcohol showed that there was already a content of 1.5% cinnamal at the start of the autoxidation experiments. Conclusion. Cinnamyl alcohol readily autoxidizes upon air exposure, and forms strong sensitizers as determined by the LLNA. Cinnamal was formed in the largest amounts, showing that cinnamal is not only formed via bioactivation, as has previously been shown. A highly sensitizing epoxide was also identified and quantified in the oxidation mixture.
    Contact Dermatitis 03/2013; 68(3):129-38. · 2.93 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Different compositions of monoterpenes are utilized for their pleasant scent in cosmetics and perfumes. However, the most commonly used fragrance terpenes easily oxidize upon contact with air, forming strongly skin-sensitizing hydroperoxides. Due to their thermolability and low UV absorbance, detection methods for hydroperoxides are scarce. For the first time, a simple and sensitive method using liquid chromatography/electrospray ionization-tandem mass spectrometry was developed to quantitatively determine hydroperoxides from the common fragrance compounds linalool, linalyl acetate, and limonene. The method was applied to autoxidized petitgrain oil and sweet orange oil. A separation was accomplished using a C(3) column. The method limit of detection for the investigated hydroperoxides in the essential oils was below 0.3 μg/mL, corresponding to 0.3 ppm. For prevention purposes and according to EU regulations, concentrations in cosmetics exceeding 100 ppm in "rinse-off" and 10 ppm in "stay-on" products of linalool and limonene must be labeled. However, the products may still contain allergens, such as hydroperoxides, formed by oxidative degradation of their parent terpenes. The sensitivity and selectivity of the presented LC/MS/MS method enables detection of hydroperoxides from the fragrance terpenes linalool, linalyl acetate, and limonene. However, for routine measurements, the method requires further validation.
    Journal of Separation Science 02/2013; · 2.59 Impact Factor
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    ABSTRACT: Allergic contact dermatitis (ACD) is caused by low-molecular weight compounds called haptens. It has been shown that the potency of haptens can depend on the formulation in which they are applied on the skin. Specifically the sensitization potency of isothiocyanates, a group of haptens which can be released from e.g. adhesive tapes and neoprene materials, increases with the presence of phthalates; however, the underlying mechanisms are not clear. A better understanding of the mechanisms governing the potency of haptens is important, e.g. to improve the risk assessment and the formulation of chemicals in consumer products. In this study we have explored phthalate-induced effects on the sensitization potency, skin distribution, and reactivity of fluorescent model isothiocyanate haptens using non-invasive two-photon microscopy to provide new insights regarding vehicle effects in ACD. The data presented in this paper indicate that the sensitization potency of isothiocyanates increases when applied in combination with dibutylphthalate due to a specific uptake via the pilosebaceous units. The results highlight the importance of shunt pathways when evaluating the bioavailability of skin sensitizers. The findings also indicate that vehicle-dependent hapten reactivity towards stratum corneum proteins regulates the bioavailability, and thus the potency, of skin sensitizers.
    Toxicology and Applied Pharmacology 07/2012; 264(1):114-20. · 3.98 Impact Factor
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    ABSTRACT: The fragrance terpene geraniol forms sensitizing compounds via autoxidation and skin metabolism. Geranial and neral, the two isomers of citral, are the major haptens formed in both of these activation pathways. To investigate whether testing with oxidized geraniol detects more cases of contact allergy than testing with pure geraniol. The pattern of reactions to pure and oxidized geraniol, and metabolites/autoxidation products, was studied to investigate the importance of autoxidation or cutaneous metabolism in contact allergy to geraniol. Pure and oxidized geraniol were tested at 2.0% petrolatum in 2227 and 2179 consecutive patients, respectively. In parallel, geranial, neral and citral were tested in 2152, 1626 and 1055 consecutive patients, respectively. Pure and oxidized geraniol gave positive patch test reactions in 0.13% and 0.55% of the patients, respectively. Eight of 11 patients with positive patch test reactions to oxidized geraniol also reacted to citral or its components. Relevance for the positive patch test reactions in relation to the patients' dermatitis was found in 11 of 14 cases. Testing with oxidized geraniol could detect more cases of contact allergy to geraniol. The reaction pattern of the 14 cases presented indicates that both autoxidation and metabolism could be important in sensitization to geraniol.
    Contact Dermatitis 07/2012; 67(1):20-7. · 2.93 Impact Factor
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    ABSTRACT: The monoterpene α-terpinene is used as a fragrance compound and is present in different essential oils. It is one of the components responsible for the antioxidant activity of tea tree oil. α-Terpinene is structurally similar to other monoterpenes, e.g., limonene, known to autoxidize on air exposure and form allergenic compounds. The aim of the present study was to investigate the possible autoxidation of α-terpinene at room temperature. To investigate the sensitization potency of air-exposed α-terpinene and the oxidation products formed, the murine local lymph node assay was used. Chemical analysis showed that α-terpinene degrades rapidly, forming allylic epoxides and p-cymene as the major oxidation products and also hydrogen peroxide. Thus, the oxidation pathway differs compared to that of, e.g., limonene, which forms highly allergenic hydroperoxides as the primary oxidation products on autoxidation. The sensitization potency of α-terpinene was increased after air-exposure. The allylic epoxides and a fraction, in which only an α,β-unsaturated aldehyde could be identified, were shown to be strong sensitizers in the local lymph node assay. Thus, we consider them to be the major contributors to the increased sensitization potency of the autoxidized mixture. We also investigated the presence of α-terpinene and its oxidation products in four different tea tree oil samples of various ages. α-Terpinene and its oxidation products were identified in all of the tea tree oil samples. Thus, from a technical perspective, α-terpinene is a true antioxidant since it autoxidizes rapidly compared with many other compounds, preventing these from degradation. However, as it easily autoxidizes to form allergens, its suitability can be questioned when used in products for topical applications, e.g., in tea tree oil but also in cosmetics and skin care products.
    Chemical Research in Toxicology 02/2012; 25(3):713-21. · 3.67 Impact Factor
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    ABSTRACT: Diglycidyl ethers of bisphenol A (DGEBA) and bisphenol F (DGEBF) are widely used as components in epoxy resin thermosetting products. They are known to cause occupational and nonoccupational allergic contact dermatitis. The aim of this study is to investigate analogues of DGEBF with regard to contact allergy and cytotoxicity. A comprehensive knowledge of the structural features that contribute to the allergenic and cytotoxic effects of DGEBF will guide the development of future novel epoxy resin systems with reduced health hazards for those coming into contact with them. It was found that the allergenic effects of DGEBF were dependent on its terminal epoxide groups. In contrast, it was found that the cytotoxicity in monolayer cell culture was dependent not only on the presence of epoxide groups but also on other structural features.
    Chemical Research in Toxicology 01/2012; 25(11):2469-2478. · 3.67 Impact Factor
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    ABSTRACT: Because of regulatory constraints and ethical considerations, research on alternatives to animal testing to predict the skin sensitization potential of novel chemicals has become a high priority. Ideally, these alternatives should not only predict the hazard of novel chemicals but also rate the potency of skin sensitizers. Currently, no alternative method gives reliable potency estimations for a wide range of chemicals in differing structural classes. Performing potency estimations within specific structural classes has thus been proposed. Detailed structure-activity studies for the in vivo sensitization capacity of a series of analogues of phenyl glycidyl ether (PGE) were recently published. These studies are part of an investigation regarding the allergenic activity of epoxy-resin monomers. Here we report data on the same chemicals in the KeratinoSens in vitro assay, which is based on a stable transgenic keratinocyte cell line with a luciferase gene under the control of an antioxidant response element. A strong correlation between the EC3 values in the local lymph node assay (LLNA) and both the luciferase-inducing concentrations and the cytotoxicity in the cell-based assay was established for six analogues of PGE. This correlation allowed the potency in the LLNA of two novel structurally closely related derivatives to be predicted by read-across with errors of 1.4- and 2.6-fold. However, the LLNA EC3 values of two structurally different bifunctional monomers were overpredicted on the basis of this data set, indicating that accurate potency estimation by read-across based on in vitro data might be restricted to a relatively narrow applicability domain.
    Chemical Research in Toxicology 08/2011; 24(8):1312-8. · 3.67 Impact Factor
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    ABSTRACT: The autoxidation of geranial with O(2) was studied both experimentally and using density functional theory. Computational results were used to interpret experimentally observed product ratios. Geranial was found to autoxidize, forming 6,7-epoxygeranial as the main oxidation product. Hydroperoxides corresponding to those identified as important skin sensitizers in previous studies of fragrance terpenes could not be detected. Instead, a dioxolan derivative and its corresponding hydroperoxide were identified and detected in high concentrations. The distribution of products in autoxidation generally depends on the stabilities of the intermediate peroxyl radicals. In this study, the formation of a peracyl radical was found to be highly favored. This radical forms peracid which epoxidizes geranial. The epoxide thus produced can react with acyl radical to yield the dioxolan hydroperoxide. The dioxolan derivative is believed to form in an acid catalyzed closed shell reaction between 6,7-epoxygeranial and geranial. The dioxolan hydroperoxide and 6,7-epoxygeranial are strong sensitizers and are considered to be the compounds mainly responsible for the skin sensitization potency of air-exposed geranial.
    Chemical Research in Toxicology 08/2011; 24(9):1507-15. · 3.67 Impact Factor
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    ABSTRACT: Epoxy resins are among the most common causes of occupational contact dermatitis. They are normally used in so-called epoxy resin systems (ERS). These commercial products are combinations of epoxy resins, curing agents, modifiers, and reactive diluents. The most frequently used resins are diglycidyl ethers based on bisphenol A (DGEBA) and bisphenol F (DGEBF). In this study, we have investigated the contact allergenic properties of a series of analogues to the reactive diluent phenyl glycidyl ether (PGE), all with similar basic structures but with varying heteroatoms or with no heteroatom present. The chemical reactivity of the compounds in the test series toward the hexapeptide H-Pro-His-Cys-Lys-Arg-Met-OH was investigated. All epoxides were shown to bind covalently to both cysteine and proline residues. The percent depletion of nonreacted peptide was also studied resulting in ca. 60% depletion when using either PGE, phenyl 2,3-epoxypropyl sulfide (2), or N-(2,3-epoxypropyl)aniline (3), and only 15% when using 1,2-epoxy-4-phenylbutane (4) at the same time point. The skin sensitization potencies of the epoxides using the murine local lymph node assay (LLNA) were evaluated in relation to the observed physicochemical and reactivity properties. To enable determination of statistical significance between structurally closely related compounds, a nonpooled LLNA was performed. It was found that all investigated compounds containing a heteroatom in the α-position to the epoxide were strong sensitizers, congruent with the reactivity data, indicating that the impact of a heteroatom is crucial for the sensitizing capacity for this type of epoxides.
    Chemical Research in Toxicology 03/2011; 24(4):542-8. · 3.67 Impact Factor
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    ABSTRACT: The growing focus on nanotechnology and the increased use of nano-sized structures, e.g. vesicles, in topical formulations has led to safety concerns. We have investigated the sensitizing capacity and penetration properties of a fluorescent model compound, rhodamine B isothiocyanate (RBITC), when administered in micro- and nano-scale vesicle formulations. The sensitizing capacity of RBITC was studied using the murine local lymph node assay (LLNA) and the skin penetration properties were compared using diffusion cells in combination with two-photon microscopy (TPM). The lymph node cell proliferation, an indicator of a compounds sensitizing capacity, increased when RBITC was applied in lipid vesicles as compared to an ethanol:water (Et:W) solution. Micro-scale vesicles showed a slightly higher cell proliferative response compared to nano-scale vesicles. TPM imaging revealed that the vesicle formulations improved the skin penetration of RBITC compared to the Et:W solution. A strong fluorescent region in the stratum corneum and upper epidermis implies elevated association of RBITC to these skin layers when formulated in lipid vesicles. In conclusion, the results indicate that there could be an elevated risk of sensitization when haptens are delivered in vehicles containing lipid vesicles. Although the size of the vesicles seems to be of minor importance, further studies are needed before a more generalized conclusion can be drawn. It is likely that the enhanced sensitizing capacity is a consequence of the improved penetration and increased formation of hapten-protein complexes in epidermis when RBITC is delivered in ethosomal formulations.
    Toxicology and Applied Pharmacology 02/2011; 252(3):221-7. · 3.98 Impact Factor
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    ABSTRACT: Diphenylthiourea (DPTU) is a known skin sensitizer commonly used as a vulcanization accelerator in the production of synthetic rubber, for example, neoprene. The versatile usage of neoprene is due to the multifaceted properties of the material; for example, it is stretchable, waterproof, and chemical- and abrasion-resistant. The wide application of neoprene has resulted in numerous case reports of dermatitis patients allergic to DPTU. The mechanism by which DPTU works as a contact allergen has not been described; thus, the aim of the present study was to investigate if DPTU is a prohapten that can be activated by skin metabolism. The metabolic activation and covalent binding of (14)C-labeled DPTU to proteins were tested using a skinlike cytochrome P450 (P450) cocktail containing the five most abundant P450s found in human skin (CYP1A1, 1B1, 2B6, 2E1, and 3A5) and human liver microsomes. The incubations were carried out in the presence or absence of the metabolite trapping agents glutathione, methoxylamine, and benzylamine. The metabolism mixtures were analyzed by LC-radiochromatography, LC-MS, and LC-MS/MS. DPTU was mainly metabolically activated to reactive sulfoxides resulting in desulfurated adducts in both enzymatic systems used. Also, phenylisothiocyanate and phenylisocyanate were found to be metabolites of DPTU. The sensitizing capacity of the substrate (DPTU) and three metabolites was tested in the murine local lymph node assay. Two out of three metabolites tested were strong skin sensitizers, whereas DPTU itself, as previously known, was negative using this mouse model. In conclusion, DPTU forms highly reactive metabolites upon bioactivation by enzymes present in the skin. These metabolites are able to induce skin sensitization and are probable causes for DPTU allergy. To increase the possibilities of diagnosing contact allergy to DPTU-containing items, we suggest that suitable metabolites of DPTU should be used for screening testing.
    Chemical Research in Toxicology 11/2010; 24(1):35-44. · 3.67 Impact Factor

Publication Stats

678 Citations
474 Downloads
222.08 Total Impact Points

Institutions

  • 2002–2013
    • University of Gothenburg
      • • Institutionen för kemi och molekylärbiologi
      • • Department of Physics
      Göteborg, Vaestra Goetaland, Sweden
  • 2006–2010
    • Sahlgrenska University Hospital
      Goeteborg, Västra Götaland, Sweden
  • 2007–2009
    • RWTH Aachen University
      • • Interdisciplinary Center for Clinical Research
      • • Hautkliniken
      Aachen, North Rhine-Westphalia, Germany
    • Mid Sweden University
      Härnösand, Västernorrland, Sweden
  • 2008
    • Stockholm University
      • Department of Analytical Chemistry
      Stockholm, Stockholm, Sweden
  • 2003
    • Karolinska Institutet
      • Institutionen för medicin, Huddinge
      Solna, Stockholm, Sweden