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Biomedical subjects

A T Karlberg

Publications and source records attributed to A T Karlberg.

At least 19 recordsLinked to original sources
PubMed2001

Identification and allergenic activity of hydroxyaldehydes - a new type of oxidation product from an ethoxylated non-ionic surfactant.

Ethoxylated alcohols, which are widely used as surfactants, are susceptible to oxidation on air exposure. A complex mixture of oxidation products is formed, among which alkylated aldehydes, alkylated formates, formaldehyde and peroxides have previously been identified by our group. In the present study, we have identified a new class of oxidation product from the nonionic ethoxylated surfactant C12E5. These oxidation products are highly water-soluble hydroxyaldehydes with the general formula HO(CH2CH2O)nCH2CHO, n=1-4. To facilitate the identification of the hydroxyaldehydes in oxidized C12E5, reference compounds were synthesized. The sensitizing potential of 1 of the identified hydroxyaldehydes, HO(CH2CH2O)3CH2CHO, was studied in guinea pigs and was found to be weak. A significant cross-reactivity between this aldehyde and the next shorter homologue, HO(CH2CH2O)2CH2CHO, was observed. Irritant components, present in the oxidation mixture, facilitate the skin penetration of allergens, which further accentuates the importance of controlling the conditions of storage and handling of ethoxylated surfactants, to reduce the formation of allergenic and irritant oxidation products.

Aldehydes↗
PubMed2001

Mechanism of the antigen formation of carvone and related alpha, beta-unsaturated ketones.

In the present study, the mechanism for the antigen formation of alpha, beta-unsaturated ketones was investigated. A series of analogues of carvone ((5R)-5-isopropenyl-2-methyl-2-cyclohexenone) with altered chemical reactivity and with retained overall structure or with retained reactivity and altered three-dimensional structure were synthesized. These analogues were tested for cross-reactivity in carvone-sensitized animals. Cross-reactivity was observed for analogue 3 ((5R)-5-isopropyl-2-methyl-2-cyclohexen-1-one). No cross-reactions were observed for analogues 1 ((2R,5R)-5-isopropenyl-2-methyl cyclohexanone) and 4 ((5R)-2,3-dimethyl-5-isopropenyl-2-cyclohexene-1-one). Both those compounds also failed to induce sensitization. These findings demonstrate that alpha, beta-unsaturated ketones form antigens after a nucleophilic attack at the beta-carbon with soft nucleophiles such as thiol in cysteine and not with the formation of a Schiff's base after a nucleophilic attack at the carbonyl carbon with nitrogen nucleophiles. Furthermore, no cross-reactivity was observed between R- and S-carvone indicating the importance of the 3-dimensional structure of haptens (and antigens) in T-cell recognition. The analogues were also tested for cross-reactivity on patients allergic to carvone. The results from the animal study were confirmed.

Allergens↗
PubMed2000

Skin irritation from air-oxidized ethoxylated surfactants.

Surfactants are known to be skin irritants, but change in their irritant potential due to change in composition during handling and storage has not previously been investigated. The aim of this study was to investigate the influence of oxidation products on the irritant potential of a non-ionic ethoxylated alcohol, C12E5. Pure and oxidized C12E5 were tested, using 2 different patch test procedures; 1 with a single 24 h exposure and 1 with repeated exposures. 18 healthy volunteers participated in each of these studies. Evaluations were made by visual scoring and by measurement of transepidermal water loss and skin blood flow. In the single exposure study, no significant difference in skin irritation was observed between pure C12E5 and a sample of oxidized C12E5 at the concentrations tested (1, 3, 9 and 27%). After repeated exposures, however, the oxidized C12E5 was significantly more irritant than pure C12E5 at the concentrations 9% and 27% (p<0.05). Non-ionic ethoxylated surfactants are known for their weak skin irritant effect and are, due to this, often included in products with prolonged contact with the skin, i.e., skin care products. An increased irritant potential after oxidation might be of importance due to the conditions of use.

Adult↗
PubMed1999

Atmospheric oxidation of poly(oxyethylene) alcohols. Identification of ethoxylated formates as oxidation products and study of their contact allergenic activity.

Ethoxylated alcohols are widely used as surfactants. In the present study we have continued our investigations on the degradation with time upon air exposure of the ethoxylated alcohols at normal storage and handling. As a result, a new group of ethoxylated formates with the general formula C12H25(OCH2CH2)nOCHO (n = 0-4) was identified in C12H25(OCH2CH2)5OH stored and handled at room temperature. To facilitate the identification work, reference compounds were synthesized. The formates showed no allergenic activity in the sensitization studies performed. In previous investigations on the same ethoxylated alcohol, we have identified formaldehyde and ethoxylated aldehydes among the oxidation products formed. Formaldehyde is a common contact allergen, and the ethoxylated aldehydes were shown to have a sensitizing capacity of the same magnitude as formaldehyde. The instability of the ethoxylated alcohols and formation of oxidation products may give an allergenic contribution to hand eczema caused by work with water and surfactants. To investigate the clinical significance in man an appropriate diagnostic patch testing in exposed humans is required.

Allergens↗
PubMed1999

Direct Ni2+ antigen formation on cultured human dendritic cells.

The possible direct antigen formation of Ni2+ on antigen-presenting cells (APCs) was studied with cultured human dendritic cells (DCs) obtained from 10 subjects contact allergic to Ni2+ and six non-allergic control individuals. All contact allergic subjects showed a significantly increased peripheral blood mononuclear cell (PBMC) response in vitro to Ni2+. DCs were expanded from the plastic-adherent cell fraction of PBMCs by culturing with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4) for 7 days to obtain immature DCs, and with the addition of monocyte-conditioned medium for another 4 days, for DC maturation. The DCs were pulsed for 20 min with Ni2+ (50 micrometers) in protein-free Hank's balanced salt solution (HBSS) and added to freshly prepared autologous responder PBMCs. With five allergic subjects, immature DCs pulsed with Ni2+ demonstrated a significant capacity to activate Ni2+-reactive lymphocytes. With the remaining five patients and the six controls no difference in lymphocyte proliferation was observed between Ni2+-pulsed and non-pulsed immature DCs. In contrast, with mature Ni2+-pulsed DCs from both 'positive responder' (n=4) and 'non-responder' (n=4) patients, there was a significantly stimulated PBMC proliferation, whereas with the controls (n=4) still no activation was observed. Our results indicate that direct formation of the antigenic determinant of Ni2+ on APCs is possible and that Ni2+ uptake and processing mechanisms may not play a major role. Differences in the ease of activation of Ni2+-reactive lymphocytes are discussed in terms of a possible heterogeneity in the availability of Ni2+-reactive groups presented on endogenous peptides bound in the antigen binding groove of human leucocyte antigen (HLA) class-II molecules.

Adult↗
PubMed1999

Are contact allergens stable in patch test preparations? Investigation of the degradation of d-limonene hydroperoxides in petrolatum.

Several of the products formed after oxidation of d-limonene exhibit strong contact allergenic properties. Some, e.g., the hydroperoxides, are unstable compounds. In this study, we have examined whether the limonene hydroperoxides are chemically stable in white petrolatum used for patch testing. We found that the stability of the hydroperoxides was strongly dependent on whether or not the petrolatum was stabilized with alpha-tocopheryl acetate. In the presence of this antioxidant, the hydroperoxides were degraded to a greater extent. The hydroperoxides were shown to be directly reduced to the corresponding alcohols by this agent. On the other hand, the compounds where shown to be stable in non-stabilized petrolatum throughout clinical patch testing for a period of 6 weeks, provided that the preparations were stored in a refrigerator when not used. Thus, it is recommended that vehicles without alpha-tocopheryl acetate are used when peroxy or hydroperoxy compounds are patch tested or used in sensitization experiments. However, it is important to limit the storage time so that optimal conditions are at hand. A fast method was developed to enable isolation and quantification of the hydroperoxides in white petrolatum. This analytical method may also be applicable to other compositions of patch test preparations.

Allergens↗
PubMed1999

Sensitizing potential of acetaldehyde and formaldehyde using a modified cumulative contact enhancement test (CCET).

The contact allergenic activity of acetaldehyde was investigated with a modified cumulative contact enhancement test (CCET) method in guinea pigs. Possible cross-reactivity between acetaldehyde and formaldehyde was also studied. In contrast to the original CCET protocol, we used sham-treated controls and the chemicals were tested with closed epicutaneous application at 1st challenge. The suitability of the method was verified with formaldehyde and the results were comparable with those previously found with the guinea pig maximization test (GPMT). For the 1st time, acetaldehyde was shown to be a contact allergen in predictive tests. No cross-reactivity was observed between acetaldehyde and formaldehyde. Acetaldehyde seems to be a rare sensitizer in man. However, its allergenic activity should be considered, since it might be present as an impurity in ethoxylated surfactants. As the CCET protocol involves topical induction and challenge, we regard the modified version as well suited to evaluation of the contact allergenic potential of chemicals.

Acetaldehyde↗
PubMed1999

Regulatory classification of substances oxidized to skin sensitizers on exposure to air.

Regulatory classification of substances in the European Union (EU) is intended to identify their hazardous toxicological properties in a formal and harmonized manner. In the regulatory work, a specific chemical with its molecular structure is classified as a skin sensitizer. This implies that the compound is stable throughout its lifetime. The purpose of the present paper is to discuss the problem of skin sensitizing oxidation/degradation products formed by air exposure of various materials or substances with very low allergenic activity. In regulatory classification work on skin sensitizers, the intrinsic suspectibility of a chemical to air oxidation (autoxidation) should be taken into consideration. We give examples of natural terpenoid materials, but the concept of allergens formed by air oxidation can apply to other materials widely used in industrial products. If a positive classification is made for a substance with a known chemical structure, a note should indicate that the primary chemical structure of the notified substance is not a skin sensitizer, but that (some of) its oxidation products are. Complex mixtures which inevitably contain sensitizing oxidation products should (on the basis of sufficient evidence) be classified as skin sensitizing.

Allergens↗
PubMed1998

Free radicals as potential mediators of metal-allergy: Ni2+- and Co2+-mediated free radical generation.

The generation of free radicals by Ni(2+) and Co(2+) was studied at physiological pH in H(2)O(2)-containing solutions in the absence and presence of various radical-mediating ligands and in human peripheral blood mononuclear cell (PBMC) cultures. With ESR spectroscopy, free radical species were identified and quantitated by spin trapping with 5,5-dimethyl-1-pyrroline-N-oxide (DMPO). Co(2+) generated hydroxyl radicals from H(2)O(2) in PBS solutions containing glutathione (GSH) or histidine (His). Omission of GSH or His from the reaction mixture significantly reduced the ESR-signal, indicating the importance of metal-chelation in free radical generation. Carnosine did not significantly enhance the reactivity of Co(2+) toward H(2)O(2), whereas cysteine (Cys) and N-acetylcysteine (NAC) suppressed free radical generation. Under identical reaction conditions, Ni(2+) was markedly less reactive toward H(2)O(2) in comparison with Co(2+). GSH, His, Cys and NAC did not enhance free radical generation of Ni(2+) from H(2)O(2). However, in the presence of carnosine weak but significantly enhanced ESR intensities were found. Incubation of PBMC cultures from healthy subjects with Co(2+) (10-50 microM) yielded the DMPO-.OH adduct, suggesting Co(2+)-mediated hydroxyl radical generation. In contrast, incubation of PBMC cultures with Ni(2+) (10-50 microM) did not produce a detectable ESR-signal. Ascorbic acid efficiently inhibited Co(2+)-mediated free radical generation in PBS solutions and PBMC cultures. The observed difference in free radical generating capacity between Ni(2+) and Co(2+) is of interest with respect to the absence of cross-reactivity between the two metal-ions in experimental allergic contact dermatitis.

Acetylcysteine↗
PubMed1998

Contact allergens from surfactants. Atmospheric oxidation of polyoxyethylene alcohols, formation of ethoxylated aldehydes, and their allergenic activity.

Ethoxylated surfactants are susceptible to oxidation upon air exposure. We have previously studied the rate of peroxidation and formaldehyde formation in the chemically well-defined ethoxylated alcohol C12H25(OCH2CH2)5OH. Formaldehyde is a common cause of contact allergy. The aim of the present study was to identify other oxidation products that could be formed upon air exposure of the ethoxylated alcohol and to determine their allergenic activity. It was shown that air oxidation of C12H25(OCH2CH2)5OH gave all the theoretically possible aldehydes of the general formula C12H25(OCH2CH2)nOCH2CHO (n = 0-4) and that the major oxidation product was C12H25(OCH2CH2)4OCH2CHO, dodecyltetraoxyethyleneoxyacetaldehyde. The structure elucidation and synthesis of these aldehydes are here presented for the first time. The major aldehyde was shown to be a contact allergen with the same sensitizing capacity as that of formaldehyde. A dose-response relationship was observed in the sensitization studies. The allergens were formed from the surfactant itself and the skin reactions cannot be explained due to any impurities that may be present in a technical quality of the surfactant. Cases of allergic contact dermatits to ethoxylated surfactants have been reported. To avoid the formation of allergenic oxidation products it is important to control the conditions for storage, handling, and transportation of ethoxylated surfactants.

Alcohols↗
PubMed1998

Free radicals as potential mediators of metal allergy: effect of ascorbic acid on lymphocyte proliferation and IFN-gamma production in contact allergy to Ni2+ and Co2+.

A possible free radical mechanism in metal allergy was investigated in peripheral blood mononuclear cell (PBMC) cultures from 6 subjects, contact allergic to Ni2+ and Co2+, and 6 control individuals. Ni2+ and Co(2+)-mediated free radical generation was studied with electron spin resonance spectroscopy. The immune response was characterized by cellular [methyl-3H]thymidine uptake and interferon-gamma (IFN-gamma) production Ni2+ and Co2+ (10-50 microM) significantly increased lymphocyte proliferation and IFN-gamma production in PBMC cultures from contact allergic subjects in comparison with cultures from controls. Inhibition of Co(2+)-mediated free radical generation by ascorbic acid did not influence cellular [methyl-3H]thymidine uptake and IFN production. Detectable amounts of free radicals were not obtained with Ni2+. We therefore conclude that it is unlikely that free radicals are involved in contact allergy to Ni2+ and Co2+.

Adult↗
PubMed1998

A method for quantification of formaldehyde in the presence of formaldehyde donors in skin-care products.

Reliable and uncomplicated methods for detection of free formaldehyde in products preserved with formaldehyde donors are desirable to decrease the risk of allergic contact dermatitis. The aim of this study was to develop a method that could be used in clinics and workplaces for quantification of free formaldehyde in products preserved with formaldehyde donors. The method developed is named the closed container diffusion (CCD) method. Formaldehyde in a sample is allowed to evaporate in a closed container and react with 2,4-dinitrophenylhydrazine coated on a glass fibre filter. The hydrazone formed is analyzed with HPLC. The method was tested on 3 different formaldehyde donors, imidazolidinyl urea, diazolidinyl urea and 2-bromo-2-nitropropane-1,3-diol, using 4 different cream bases. The results obtained with this method accord, with those obtained with the official method within the European Union (EU). The method is sensitive enough for analysis of patients' products and for control of labelled amounts of formaldehyde in technical products without solvent extraction. As a result of our studies, we observed a risk of exceeding the labelling limit for free formaldehyde in cosmetic products when using the highest amount of diazolidinyl urea allowed within the EU.

Dermatitis, Allergic Contact↗
PubMed1998

Lack of antagonism to Ni2+ and Co2+ contact allergy from other essential divalent metal ions.

The potential antagonistic effects of Ca2+, Cu2+, Fe2+, Mg2+, Mn2+ and Zn2+ on contact allergy to Co2+ and Ni2+ were studied. The immune response was characterized by the Co2+ or Ni2+ mediated cellular [methyl-3H]thymidine uptake in peripheral blood mononuclear cell (PBMC) cultures from 6 subjects contact-allergic to Co2+ and Ni2+ and 6 non-allergic control individuals. Results from the in vitro experiments were further evaluated with Co2+-sensitized guinea pigs according to the modified Freund's complete adjuvant test. Ni2+ and Co2+ (10-50 microM) significantly increased the lymphocyte proliferation in PBMC cultures from contact-allergic subjects in comparison with those from control individuals. Pretreatment of the PBMCs with Ca2+, Fe2+, Mg2+ (10-100 microM) or Mn2+ (1-10 microM) did not influence, while Zn2+ (100 microM) enhanced, and Cu2+ (5 and 10 microM) markedly reduced the Ni2+ and Co2+ mediated cellular [methyl-3H]thymidine uptake. The inhibition of the Ni2+- and Co2+-induced cell proliferation by Cu2+ in vitro was probably related to toxicity, since the viability of the cells was significantly reduced by applied combinations of Ni2+ or Co2+ with Cu2+. Topical pretreatment of Co2+-sensitized guinea pigs with maximum non-irritating doses of CuCl2 x 2H2O (0.8%) did not affect the challenge testing to CoCl2 x 6H2O (0.1 and 0.3%). In conclusion, our combined in vitro and in vivo results indicate that Ca2+, Cu2+, Fe2+, Mg2+, Mn2+ and Zn2+ are not able to antagonise the formation of Ni2+ and Co2+ antigens.

Adult↗
PubMed1998

Formation of formaldehyde and peroxides by air oxidation of high purity polyoxyethylene surfactants.

Ethoxylated alcohols are non-ionic surfactants. The majority are used in household cleaners, laundry products, toiletries and in industrial and institutional cleaners. In previous studies, an ethoxylated non-ionic surfactant of technical quality showed allergenic activity in guinea pig experiments. Chemical analysis revealed a content of formaldehyde, a well-known contact allergen, and peroxides in the surfactant. Most cases of occupational contact dermatitis are considered to be of irritant origin, caused by contact with water and surfactants, but if allergenic autoxidation products can be formed, allergic contact dermatitis cannot be excluded. The sensitizing potential of a chemically defined high purity ethoxylated alcohol was investigated and oxidation under various storage and handling conditions was studied for this and a homologous product. The pure surfactant showed no significant allergenic activity on predictive testing in guinea pigs. When ethoxylated alcohols were stored in the refrigerator, their deterioration was limited. At room temperature, their content of peroxides and formaldehyde increased with time. Levels of formaldehyde above those capable of causing positive patch test reactions were found. Since such surfactants have wide applications, resulting exposure to formaldehyde could be more frequent than is generally realized, contributing to persistence of dermatitis in individuals allergic to formaldehyde.

Aerobiosis↗
PubMed1997

Skin sensitization to linalyl hydroperoxide: support for radical intermediates.

In order to better understand the skin sensitization mechanism of allylic hydroperoxides, linalyl hydroperoxide (1) and several of its potential rearrangement products-epoxylinalool (2), epoxynerol (3), epoxygeraniol (4), and furan (5) and pyran (6) derivatives-were synthesized. The sensitizing properties of these molecules have been screened on mice using the local lymph node assay (LLNA) and further evaluated on guinea pigs using the Freund's complete adjuvant test (FCAT). Linalyl hydroperoxide (1) and linalyl epoxide (2) were found to be sensitizers, while the other compounds were classified as mild sensitizers or nonsensitizers. In the guinea pigs, no cross-reactions were observed between skin sensitizers 1 and 2. Radical-trapping experiments were carried out on linalyl hydroperoxide (1) using TTBP as trapping agent and Fe(3+)-TPP as radical inducer. The major reaction taking place is the formation of a furan ring by intramolecular reaction of the oxygen-centered radical with the isoprenyl double bond with the formation of a tertiary radical. Reaction of this intermediate with radicals derived from TTBP gave compounds 10a,b in 25% yield. The second important reaction, accounting for 14%, is taking place on the allylic double bond with the formation of a less stable primary radical which is not trapped by a TTBP-derived radical but by a hydroxy radical to give a mixture of epoxides 3 and 4. These results are in favor of the formation of a carbon-centered reactive radical as intermediate in the skin sensitization to linalyl hydroperoxide.

Animals↗