| 1. |
- Hagvall, Lina, 1978, et al.
(författare)
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Assessment of cross-reactivity of new less sensitizing epoxy resin monomers in epoxy resin-allergic individuals
- 2016
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Ingår i: Contact Dermatitis. - : Wiley. - 0105-1873. ; 75:3, s. 144-150
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundMeasures to prevent occupational exposure to epoxy resins, including education, medical examination, and voluntary agreements between employers and workers, have not been effective enough to protect against skin sensitization. Therefore, alternatives to the major epoxy resin haptens that have been found to be less sensitizing in the local lymph node assay have been developed. ObjectivesTo study the cross-reactivity of two newly designed epoxy resin monomers, with decreased skin-sensitizing potency and good technical properties as compared with diglycidyl ether of bisphenol A (DGEBA), in subjects with known contact allergy to epoxy resin of DGEBA type. Patients and MethodsEleven individuals with previous positive patch test reactions to epoxy resin of DGEBA participated in the study. The two alternative epoxy resin monomers were synthesized and patch tested in dilution series in parallel with epoxy resin of DGEBA from the baseline series (containing 92% DGEBA). ResultsAll participants reacted to epoxy resin of DGEBA on retesting. Three participants reacted to monomer 1. No reactions were seen to monomer 2. ConclusionsThe alternative monomers studied showed little or no cross-reactivity with epoxy resin of DGEBA. Decreasing the risk of sensitization by using less sensitizing compounds is important, as contact allergy to epoxy resins is common in spite of thorough preventive measures.
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| 2. |
- Delaine, Tamara, 1981, et al.
(författare)
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A structure activity relationship study of geranial derivatives
- 2012
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Ingår i: Contact Dermatitis 11th congress of the European society of contact dermatitis (ESCD) 13-16 june 2012, Malmö, Sweden. - : Wiley. ; 66:Suppl. 2
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Konferensbidrag (refereegranskat)abstract
- Background: Fragrances are common causes of contact allergy. Skin exposure to geranial is frequent since citral (mixture of geranial and neral) is commonly used in fragrances and flavors and is considered as a moderate allergen. Previous studies according to the local lymphnodeassay (LLNA)in micehaverevealed large variations in the sensitizing capacity of different geranial derivatives. Objectives: For a better understanding of these variations, a structure-activity relationship (SAR) study on a series of derivatives of geranial was carried out. Methods: The chemical reactivity of the compounds towards a model peptide was investigated using LC-MS. The adduct formation and the non-reacted peptide depletion were monitored. Adducts formed with model amino acids were investigated and structural determination was performed. Additional derivatives were synthesized and their sensitization potencies were evaluated in relation to their physicochemical and reactivity properties. Results: Most of the derivatives were shown to bind covalently to the cysteine residue of the model peptide. The percentage of depletion of the non-reacted peptide ranged from 0% to 100% after 24 hr, constant rate of depletion revealed a large difference between the fastest and lowest reacting derivatives. These resultswere congruent with the skin sensitization potencies obtained with the LLNA. Conclusions: A good correlation between the reactivity and the sensitizing potency was observed. Small changes in the chemical structure of geranial result in significant differences in sensitizing capacity and chemical reactivity. Conflicts of interest: The authors have declared no conflicts.
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| 3. |
- Delaine, Tamara, 1981, et al.
(författare)
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Epoxyalcohols: bioactivation and conjugation required for skin sensitization.
- 2014
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Ingår i: Chemical research in toxicology. - : American Chemical Society (ACS). - 1520-5010 .- 0893-228X. ; 27:10, s. 1860-70
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Tidskriftsartikel (refereegranskat)abstract
- Allylic alcohols, such as geraniol 1, are easily oxidized by varying mechanisms, including the formation of both 2,3-epoxides and/or aldehydes. These epoxides, aldehydes, and epoxy-aldehydes can be interconverted to each other, and the reactivity of them all must be considered when considering the sensitization potential of the parent allylic alcohol. An in-depth study of the possible metabolites and autoxidation products of allylic alcohols is described, covering the formation, interconversion, reactivity, and sensitizing potential thereof, using a combination of in vivo, in vitro, in chemico, and in silico methods. This multimodal study, using the integration of diverse techniques to investigate the sensitization potential of a molecule, allows the identification of potential candidate(s) for the true culprit(s) in allergic responses to allylic alcohols. Overall, the sensitization potential of the investigated epoxyalcohols and unsaturated alcohols was found to derive from metabolic oxidation to the more potent aldehyde where possible. Where this is less likely, the compound remains weakly or nonsensitizing. Metabolic activation of a double bond to form a nonconjugated, nonterminal epoxide moiety is not enough to turn a nonsensitizing alcohol into a sensitizer, as such epoxides have low reactivity and low sensitizing potency. In addition, even an allylic 2,3-epoxide moiety is not necessarily a potent sensitizer, as shown for 2, where formation of the epoxide weakens the sensitization potential.
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| 4. |
- Delaine, Tamara, 1981, et al.
(författare)
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Structure-Activity Relationship between the in Vivo Skin Sensitizing Potency of Analogues of Phenyl Glycidyl Ether and the Induction of Nrf2-Dependent Luciferase Activity in the KeratinoSens in Vitro Assay.
- 2011
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Ingår i: Chemical research in toxicology. - : American Chemical Society (ACS). - 1520-5010 .- 0893-228X. ; 24:8, s. 1312-8
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Tidskriftsartikel (refereegranskat)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.
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| 5. |
- Hagvall, Lina, 1978, et al.
(författare)
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Can the epoxides of cinnamyl alcohol and cinnamal show new cases of contact allergy?
- 2018
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Ingår i: Contact dermatitis. - : Wiley. - 1600-0536 .- 0105-1873. ; 78:6, s. 399-405
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Tidskriftsartikel (refereegranskat)abstract
- Cinnamyl alcohol is considered to be a prohapten and prehapten with cinnamal as the main metabolite. However, many individuals who are allergic to cinnamyl alcohol do not react to cinnamal. Sensitizing epoxides of cinnamyl alcohol and cinnamal have been identified as metabolites and autoxidation products of cinnamyl alcohol.To investigate the clinical relevance of contact allergy to epoxycinnamyl alcohol and epoxycinnamal.Irritative effects of the epoxides were investigated in 12 dermatitis patients. Epoxycinnamyl alcohol and epoxycinnamal were patch tested in 393 and 390 consecutive patients, respectively. In parallel, cinnamyl alcohol and cinnamal were patch tested in 607 and 616 patients, respectively.Both epoxides were irritants, but no more positive reactions were detected than when testing was performed with cinnamyl alcohol and cinnamal. Late allergic reactions to epoxycinnamyl alcohol were observed. In general, patients with late reactions showed doubtful or positive reactions to cinnamal and fragrance mix I at regular patch testing.The investigated epoxides are not important haptens in contact allergy to cinnamon fragrance. The high frequency of fragrance allergy among patients included in the irritancy study showed the difficulty of suspecting fragrance allergy on the basis of history; patch testing broadly with fragrance compounds is therefore important.
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| 6. |
- Karlsson, Isabella, et al.
(författare)
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Nature-Derived Epoxy Resin Monomers with Reduced Sensitizing Capacity-Isosorbide-Based Bis-Epoxides
- 2023
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Ingår i: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 36:2
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Tidskriftsartikel (refereegranskat)abstract
- Epoxy resin systems (ERSs) are a class of thermosetting resins that become thermostable and insoluble polymers upon curing. They are widely used as components of protective surfaces, adhesives, and paints and in the manufacturing of composites in the plastics industry. The diglycidyl ether of bisphenol A (DGEBA) is used in 75-90% of ERSs and is thus by far the most used epoxy resin monomer (ERM). Unfortunately, DGEBA is a strong skin sensitizer and it is one of the most common causes of occupational contact dermatitis. Furthermore, DGEBA is synthesized from bisphenol A (BPA), which is a petroleum-derived chemical with endocrine-disruptive properties. In this work, we have used isosorbide, a renewable and nontoxic sugar-based material, as an alternative to BPA in the design of ERMs. Three different bisepoxide isosorbide derivatives were synthesized: the diglycidyl ether of isosorbide (1) and two novel isosorbide-based bis-epoxides containing either a benzoic ester (2) or a benzyl ether linkage (3). Assessment of the in vivo sensitizing potency of the isosorbide bis-epoxides in the murine local lymph node assay (LLNA) showed that all three compounds were significantly less sensitizing than DGEBA, especially 2 which was nonsensitizing up to 25% w/v. The peptide reactivity showed the same order of reactivity as the LLNA, i.e., 2 being the least reactive, followed by 3 and then 1, which displayed similar peptide reactivity as DGEBA. Skin permeation of 2 and 3 was compared to DGEBA using ex vivo pig skin and static Franz cells. The preliminary investigations of the technical properties of the polymers formed from 1-3 were promising. Although further investigations of the technical properties are needed, all isosorbide bis-epoxides have the potential to be less sensitizing renewable replacements of DGEBA, especially 2 that had the lowest sensitizing potency in vivo as well as the lowest peptide reactivity.
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| 7. |
- Niklasson, Ida B, 1982, et al.
(författare)
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Bioactivation of Cinnamic Alcohol Forms Several Strong Skin Sensitizers
- 2014
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Ingår i: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 27:4, s. 568-575
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Tidskriftsartikel (refereegranskat)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 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 explored the bioactivation of cinnamic alcohol using human liver microsomes (HLM), and the potential pathways for these reactions were 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 epoiddes 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 the oxidation thereof by calculations) to proceed via cinnamic aldehyde and not epoxy cinnamic alcohol.
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| 8. |
- Niklasson, Ida B, 1982, et al.
(författare)
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Cinnamyl alcohol oxidizes rapidly upon air exposure
- 2013
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Ingår i: Contact Dermatitis. - : Wiley. - 0105-1873 .- 1600-0536. ; 68:3, s. 129-138
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Tidskriftsartikel (refereegranskat)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 alcoholandtoidentifytheoxidationproductsformedonairexposure.Wealsowantedto evaluate the effect of autoxidation on the sensitization potency of cinnamyl alcohol. Methods. Samples of commercially available cinnamyl alcohol with and without purificationwereexposedtoair,andtheautoxidationwasfollowedbychemicalanalysis. Theanalysiswasperformedwithmassspectrometry(LC/MS/MS).Sensitizationpotencies ofcompoundsweredeterminedwiththemurinelocallymphnodeassay(LLNA)inmice. 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 thefirstautoxidation productsformed. Theepoxy cinnamyl alcohol wasshowntobethe 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. Cinnamylalcoholreadilyautoxidizesuponairexposure,andformsstrong sensitizers as determined by the LLNA. Cinnamal was formed in the largest amounts, showingthatcinnamalisnotonlyformedviabioactivation,ashaspreviouslybeenshown. A highly sensitizing epoxide was also identified and quantified in the oxidation mixture.
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| 9. |
- Niklasson, Ida B, 1982, et al.
(författare)
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Impact of a Heteroatom in a Structure-Activity Relationship Study on Analogues of Phenyl Glycidyl Ether (PGE) from Epoxy Resin Systems.
- 2011
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Ingår i: Chemical research in toxicology. - : American Chemical Society (ACS). - 1520-5010 .- 0893-228X. ; 24:4, s. 542-8
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Tidskriftsartikel (refereegranskat)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.
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| 10. |
- O'Boyle, Niamh M, et al.
(författare)
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Epoxy Resin Monomers with Reduced Skin Sensitizing Potency
- 2014
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Ingår i: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 27:6, s. 1002-1010
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Tidskriftsartikel (refereegranskat)abstract
- Epoxy resin monomers (ERMs), especially diglycidyl ethers of bisphenol A and F (DGEBA and DGEBF), are extensively used as building blocks for thermosetting polymers. However, they are known to commonly cause skin allergy. This research describes a number of alternative ERMs, designed with the aim of reducing the skin sensitizing potency while maintaining the ability to form thermosetting polymers. The compounds were designed, synthesized, and assessed for sensitizing potency using the in vivo murine local lymph node assay (LLNA). All six epoxy resin monomers had decreased sensitizing potencies compared to those of DGEBA and DGEBF. With respect to the LLNA EC3 value, the best of the alternative monomers had a value approximately 2.5 times higher than those of DGEBA and DGEBF. The diepoxides were reacted with triethylenetetramine, and the polymers formed were tested for technical applicability using thermogravimetric analysis and differential scanning calorimetry. Four out of the six alternative ERMs gave polymers with a thermal stability comparable to that obtained with DGEBA and DGEBF. The use of improved epoxy resin monomers with less skin sensitizing effects is a direct way to tackle the problem of contact allergy to epoxy resin systems, particularly in occupational settings, resulting in a reduction in the incidence of allergic contact dermatitis.
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