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Biomedical subjects

D A Basketter

Publications and source records attributed to D A Basketter.

At least 19 recordsLinked to original sources
PubMed2006

Proteomic analysis of the response of EpiDerm cultures to sodium lauryl sulphate.

The analysis of EpiDerm cultures treated with the known skin irritant sodium lauryl sulphate (SLS) was performed using 2D-gel electrophoresis in order to understand the mechanism of action and thereby identify novel markers of skin irritation. A range of both broad and narrow pH gradient first-dimension gels were run (pH 4-7, 6-11, 4-5, 5-6 and 6-9) consistently followed by 12% SDS-PAGE in the second-dimension. Following treatment of EpiDerm with SLS, 67 proteins of interest were identified, of which 8 were selected as interesting: calmodulin-like skin protein, involucrin, epithelial cell marker protein, HS1, peroxiredoxin 1, serine protease inhibitor, KIAA0117 and ribosomal protein L17. Involucrin was confirmed as being up-regulated by both ELISA and Western blotting. The use of proteomics has identified a number of proteins which could be used as general markers for skin irritation and which may in particular be of value for the development of in vitro predictive models.

Blotting, Western↗
PubMed2006

Simultaneous sensitivity to fragrances.

BACKGROUND: Cinnamal/cinnamic alcohol and isoeugenol/eugenol are pairs of related fragrance chemicals found in Fragrance Mix I (FM I), and thus are routinely tested in combination with other fragrances in the European standard patch test series. Their close structural similarity makes the occurrence of simultaneous sensitivity within these chemical pairs likely, although at present there are no robust data to support this hypothesis. OBJECTIVES: To establish the frequency of simultaneous reactions to these fragrance chemicals in patients with suspected fragrance allergy attending a contact dermatitis clinic; to provide evidence in support of proposed metabolic pathways; and to determine whether including all four separately in FM I is necessary to avoid missing a diagnosis of fragrance allergy. METHODS: We analysed retrospectively the records of patients patch tested to the European standard series during the 15-year period 1984-98 for positive reactions to FM I. In a subset of patients tested to the constituents of FM I, positive reactions to cinnamal, cinnamic alcohol, isoeugenol and eugenol were sought. Data were analysed using 2x2 contingency tables (Fisher's exact test). RESULTS: During this period, 23,660 patients were tested to the European standard series, of whom 1811 (7.7%) had positive reactions to FM I. Of the 1112 patients tested to the constituents of FM I, 934 had positive reactions to at least one constituent (total 1324 positive reactions to constituents). Of these 934, 826 also had positive reactions to FM I itself; 108 were negative to FM I but reacted to one or more of its constituents. One hundred and seventy-eight patients did not react to any of the breakdown constituents of FM I; 34 of these had positive reactions to FM I itself. Of 139 patients allergic to cinnamic alcohol, 87 were also allergic to cinnamal (63%), compared with 108 (11.1%) of 973 cinnamic alcohol-negative patients (P<0.00001). Of 231 patients allergic to isoeugenol, 50 were also allergic to eugenol (22%), vs. 109 (12.4%) of 881 isoeugenol-negative patients (P=0.0002). CONCLUSIONS: These data support in vitro experiments indicating that cinnamal and cinnamic alcohol may generate a common hapten and are consistent with the view that simultaneous sensitization to isoeugenol and eugenol occurs to a limited extent, despite their being metabolized via different pathways. In view of the substantial number of isolated reactions to each of these fragrance chemicals, all four should continue to be included separately as constituents of FM I.

Acrolein↗
PubMed2006

p-Phenylenediamine allergy: the role of Bandrowski's base.

p-Phenylenediamine (PPD) is a commonly used hair-dye and a potent skin allergen. The mechanism of sensitization is unknown, as PPD is protein unreactive. We studied Bandrowski's base (BB), a PPD trimer, as well as 1,4-benzoquinone (BQ), a PPD hapten. PPD patch-test positive patients were patch-tested to BB and BQ. All tests were negative to 0.01% BQ and 0.01% BB. Five of 14 (35.7%) tested had true positive reactions to 0.1% BQ. One percent BQ was found to be irritant. Seven of 43 tested (16%) were positive to either 0.1% or 1% BB. The positive reactions to BB were weak, even when PPD reactions were strong. Mice lymph node assay gave EC3 values of 0.14% for PPD compared with 0.03% for BB. Therefore, BB is approximately 10 times more potent than PPD, taking into account the molarity. We suggest that while PPD may act as a prohapten, there is probably a spectrum of antigenic determinants in vivo. BB may be bound or metabolized by keratinocytes before it reacts with Langerhans cells.

Animals↗
PubMed2006

The local lymph node assay in practice: a current regulatory perspective.

Following the formal acceptance of the local lymph node assay (LLNA) as an Organization for Economic Cooperation and Development (OECD) guideline in April 2002, the UK Health and Safety Executive (HSE) informed notifiers that this was now the method of choice for the assessment of skin sensitization potential under the EU notification scheme for new industrial chemicals (NONS). This paper summarizes the experience of the HSE for the 2-year period immediately following the issuing of this statement, during which 48 LLNA study reports were assessed for notification purposes. The issues discussed here include adherence to the OECD guideline, interpretation of results, and classification outcomes. Generally, notifying laboratories followed the OECD guideline successfully, with regard to the sex/ strain/numbers of mice used, the precise process used for measurement of cell proliferation, and the use of recommended vehicles and positive controls. Initially, use of the individual animal approach (measuring the cell proliferation in each animal rather than for a pooled dose group) highlighted problems caused by technical inexperience, but these were overcome by practice. Toxicity or irritation were found to be minor factors in dose selection; more important was the choice of vehicle to correctly maximize the test substance concentration, while maintaining appropriate application properties. Contrary to concerns that the LLNA would prove to be less sensitive or more sensitive than the traditionally used Guinea Pig Maximization Test (GPMT), the proportion of new substances classified as skin sensitizers was within the range observed in previous years. Although the sample size is relatively small, the experience of the HSE indicates that the LLNA is satisfactory for routine regulatory use.

Animals↗
PubMed2005

Analysis of para-phenylenediamine allergic patients in relation to strength of patch test reaction.

BACKGROUND: Despite having a positive patch test reaction to para-phenylenediamine (PPD), some patients continue to dye their hair, while others are forced to give up or abandon this practice. This difference in patient behaviour could be due to the degree of sensitization. OBJECTIVES: To establish whether the ability to continue dyeing hair in PPD allergic patients is related to the strength of patch test reaction. To note differences in other clinical features in relation to the strength of patch test reaction. METHODS: We analysed retrospectively the patch test records of 400 sequential PPD-positive patients for the strength of patch test reaction (+, ++, +++) and different clinical features. Data were analysed using Cochran-Mantel-Haenszel chi2 tests. RESULTS: There was a strong linear relationship between the strength of patch test reaction and continuation with hair dyeing. Patients were more likely to report a history of hair dye reaction with increasing strength of patch test reaction. There was no difference in strength of patch test reaction in relation to age, site of rash, occupation (hairdressing) or history of atopic eczema. Overall concomitant reactivity with related aromatic amine allergens (benzocaine, N-isopropyl-N-phenyl-para-phenylenediamine, para-aminobenzoic acid) was infrequent. CONCLUSIONS: Patients with stronger patch test reactions (++, +++) are more likely to have a clear history of reacting to hair dye and are less likely to still be dyeing their hair.

Adolescent↗
PubMed2004

Immediate contact reactions to fragrance mix constituents and Myroxylon pereirae resin.

We have studied patients who have positive-patch test reactions to fragrance-allergic screening substances fragrance mix (FM) or Myroxylon pereirae resin (balsam of Peru) for immediate contact reactions to the standard FM, the constituents of the FM and Myroxylon pereirae resin. In the fragrance-positive subjects (n = 60), there were positive immediate contact reactions to Myroxylon pereirae resin in 56.6% and to FM in 11.6%. In a control group (n = 50) of eczematous, patch test-negative patients there were positive immediate reactions to Myroxylon pereirae resin in 58.0% subjects and to FM in 12.0%. The absence of a significant difference between the fragrance-allergic group and control group is in keeping with a non-immunological basis for the majority of the immediate reactions seen.

Adult↗
PubMed2004

Intra-individual variation of irritant threshold and relationship to transepidermal water loss measurement of skin irritation.

Irritant susceptibility studies have used either visual assessment or transepidermal water loss (TEWL) to determine subject response. We have developed a visual assessment method which determines subject irritant threshold. We examined the relationship between sodium lauryl sulfate (SLS) irritant threshold and TEWL measurements from normal skin and SLS patch tests. 19 subjects were recruited. The irritant threshold of each subject was measured and TEWL measurements made from the applied SLS patch tests. Individuals with a lower irritant threshold (easily irritated skin) had elevated TEWL levels compared to those with higher thresholds. The irritant threshold test had a low intraindividual variation. This study showed that the 2 methods grouped patients in a similar manner. The variation seen may reflect the different outcomes measured: irritant threshold visually assesses the skin inflammatory response while TEWL measures skin barrier modification.

Adult↗
PubMed2003

Classification of contact allergens according to potency: proposals.

It is clear that contact allergens vary substantially with regard to the relative potency with which they are able to induce skin sensitisation. Considerations of potency will in the future become a significant factor in the classification of skin sensitising chemicals. It is therefore appropriate to establish what is known of potency and thresholds in the induction of skin sensitisation and the elicitation of allergic contact dermatitis, and to identify approaches that might be available for assessment of relative potency for the purposes of categorising chemical allergens. This paper was prepared by an ECETOC (European Centre for Ecotoxicology and Toxicology) Task Force that had the objective of recommending approaches for the measurement of potency and definition of thresholds for both the induction and elicitation of contact sensitisation. The deliberations recorded here build upon recommendations made previously by an ECETOC Task Force that considered the conduct of standard skin sensitisation test methods for the purposes of hazard identification and risk assessment (ECETOC, Monograph No. 29, Brussels, 2000). The emphasis in this present paper is also on standard and accepted methods for the assessment of skin sensitisation, and for which OECD guidelines are available: the local lymph node assay (LLNA), the guinea pig maximisation test and the occluded patch test of Buehler. For various reasons, discussed in detail herein, attention focused primarily upon consideration of categorisation of chemical allergens and the identification of thresholds with respect to the induction of skin sensitisation, rather than the elicitation of allergic contact dermatitis. It is concluded that although the LLNA is the method of choice for the determination of skin sensitisation potency for the purposes of categorisation, if data are already available from appropriate guinea pig tests then their judicious interpretation may provide information of value in determinations of potency and categorisation. Included here are detailed and specific recommendations for how best the results of the three test methods considered can be used for the categorisation of chemical allergens as a function of skin sensitisation potency.

Allergens↗
PubMed2003

Evaluation of protein allergenic potential in mice: dose-response analyses.

BACKGROUND: With the increasing interest in novel foods derived from transgenic crop plants, there is a growing need for the development of approaches for the characterization of the allergenic potential of proteins. Whereas immunogenicity is a common property of foreign proteins, including food proteins, relatively few are significant dietary allergens with the inherent capacity to provoke IgE antibody production and immediate-type hypersensitivity responses. OBJECTIVE: In order to evaluate an approach for the measurement of the allergenic potential of proteins, detailed dose-response analyses of humoral immune responses induced following systemic exposure of BALB/c strain mice to proteins known to differ in terms of sensitizing activity have been conducted. RESULTS: Mice were exposed to a range of concentrations of ovalbumin, a major allergenic constituent of hen's egg, a purified peanut allergen, Arachis hypogea agglutinin, or to the milk allergen bovine serum albumin, and to materials considered to lack significant allergenicity: a crude potato protein extract and a purified potato protein, potato agglutinin. The specific IgE antibody was measured by homologous passive cutaneous anaphylaxis assay, and the specific IgG antibody was measured by enzyme-linked immunosorbent assay. Each of the five proteins was immunogenic in mice, inducing IgG antibody responses at all doses tested, although there was some variation with respect to the vigour of IgG responses. Marked differences in the capacity of these proteins to induce IgE responses were observed, however, with relatively high-titre IgE antibody provoked by all three allergens over the dose ranges examined, whereas the potato proteins stimulated low-titre IgE antibody at the highest dose (10%) only. Importantly, differences in IgE antibody production have been observed against a background of equivalent immunogenicity (IgG antibody responses). CONCLUSION: The data presented here suggest that the measurement of antibody (IgE) responses in BALB/c mice appears to identify allergens accurately and to distinguish them from those materials that apparently lack allergenicity.

Allergens↗
PubMed2003

Contact allergy: the role of skin chemistry and metabolism.

Chemical reactivity plays the driving role in the biological processes that result in the induction of allergic contact dermatitis. This paper presents an overview of the chemical basis of allergic contact dermatitis, including the physicochemical parameters governing skin penetration, chemical reaction mechanisms associated with haptenation of skin proteins, (quantitative) structure-activity relationships (Q)SARs for contact allergens and prohaptens/skin metabolism of contact allergens. Despite the complexities and poor understanding of some of the metabolic processes leading to skin sensitization, it is possible to describe some of the relationships between chemical structures and the ability to form covalent conjugates with proteins. This knowledge, which relates chemical structure to a specific endpoint, can be programmed into an expert system. The Deductive Estimation of Risk from Existing Knowledge (DEREK) is one such expert system which is described in further detail.

Allergens↗
PubMed2003

Contact allergy: the local lymph node assay for the prediction of hazard and risk.

The prospective identification of potential contact allergens and their subsequent safety assessment are pivotal in successful management of this risk to human health. Although much can be learned from the chemical and physical properties of a substance, the definitive information in respect of sensitizing hazard/risk derives from an assessment of the integrated response of the immune system. In recent years, the focus for such assessments has begun to switch from the guinea pig to the mouse, notably to the local lymph node assay (LLNA). In this paper, the current value of the LLNA for hazard identification is reviewed and its regulatory status defined. Once a potential contact allergen has been identified, however, the vital clue to accurate safety evaluation is the assessment of the potency of the allergen. How this can be achieved using the LLNA and employed in safety evaluation is discussed in detail, together with practical suggestions for the deployment of such processes in regulatory toxicology.

Allergens↗
PubMed2003

Citral a fragrance allergen and irritant.

Citral is a well known contact allergen and a contact irritant. Routine patch testing in the past may have been restricted because of possible irritant (IR) patch test responses. 586 consecutive patients, with hand eczema, were patch tested with a selection of fragrances including citral 2% petrolatum and the European standard series. 28 of the patients showed a positive patch test reaction (+ to +++) to citral and 82 at least 1 IR patch test reaction and no positive patch test reaction to citral. A statistically significant association between a positive patch test reaction to citral and positive patch test reactions to other fragrances compared with IR reactions (n = 82) was established. The difference regarding fragrance history found between those with IR and positive reactions to citral was not significant. Citral could be an allergen and/or irritant, worthy of further more extensive studies.

Acyclic Monoterpenes↗
PubMed2003

Utility of historical vehicle-control data in the interpretation of the local lymph node assay.

The accepted approach to the interpretation of local lymph node assay (LLNA) data requires comparison of responses in the test groups with background activity found in concurrent vehicle-treated controls. However, of established value in the interpretation of toxicity test data is the use of historical control values that provide one criterion against which to judge the integrity of individual experiments. Specifically, the availability of robust and relevant historical control data permits examination of whether, in any individual experiment, control values fall within the expected range. With the most commonly used vehicle employed in the LLNA, acetone/olive oil (4 : 1) (v/v), the mean values, standard deviations and normal ranges are increasingly well established for a given laboratory, although there is some variation between laboratories, particularly with regard to expected ranges. Against this background, it is possible to identify (and, if appropriate, eliminate) a concurrent vehicle-control value that falls well outside the expected range. To explore critically the potential merits of this approach, one specific example is examined in detail.

Animals↗
PubMed2003

Designation of substances as skin sensitizing chemicals: a commentary.

During the last 10 years there have been several attempts to define criteria for the integration of experimental and clinical data into schemes that can be used for the designation of chemicals as skin sensitizers (and in some instances respiratory allergens). The last such proposal was made recently in this journal by Schnuch and colleagues (Hum Exp Toxicol 2002; 2: 439-44) who invited critical discussion and debate of the area. In this present article we have sought to build upon and refine further those previous recommendations and suggest here a modified scheme for the classification of chemicals as confirmed or probable skin sensitizers. This new scheme we believe provides a realistic framework within which informed decisions can be reached about likely skin sensitizing activity based upon judicious consideration of clinical and experimental information.

Allergens↗
PubMed2002

Local lymph node assay - validation, conduct and use in practice.

The validation of alternative methods is a relatively new activity in toxicology. The local lymph node assay (LLNA), a novel method for the identification of chemicals that have the potential to cause skin sensitization, was the first test to pass through the formal regulatory validation process established in the USA under the auspices of ICCVAM, the Interagency Coordinating Committee on the Validation of Alternative Methods. ICCVAM approved the LLNA as an alternative to guinea pig tests for the identification of skin sensitisation hazards. In this report, we explore the nine recommendations made by ICCVAM and discuss their interpretation in relation to the new OECD Guideline 429, which describes the LLNA. In particular, the value and limitations of the use of statistical evaluation of data and of the inclusion of routine positive controls is examined. It is concluded that the OECD Guideline as currently written embodies the necessary flexibility to permit conduct of the LLNA in a manner necessary to meet the varying needs of regulatory agencies and toxicologists around the world.

Animals↗
PubMed2002

Immunogenic properties of rapidly digested food proteins following gavage exposure of mice: a comparison of ovalbumin with a potato acid phosphatase preparation.

The ability of food proteins to resist digestion in simulated gastric fluid (SGF) correlates with allergenic potential. The purpose of the current investigations was to determine whether this association is due solely to the failure of unstable proteins to elicit an immune response when administered orally. We have examined immune responses induced in BALB/c mice by gavage administration of ovalbumin (OVA) and a crude potato protein extract (PPE) containing acid phosphatase activity. The stability of OVA and PPE in SGF was measured using sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis. The ability of these proteins to stimulate specific IgG and IgE antibody production in mice following parenteral (intraperitoneal; ip) or oral (gavage) exposure was compared using enzyme-linked immunosorbent and homologous passive cutaneous anaphylaxis assays, respectively. Both OVA and PPE induced specific IgG antibody responses when administered either by gavage or by ip injection. Parenteral, but not gavage, exposure to OVA was associated with robust IgE antibody responses. Administration of PPE failed to stimulate strong IgE production via either route of exposure. Differential stability in SGF was observed, with PPE being digested extremely rapidly (within 1 min), whereas OVA was more resistant. The strong association reported by others between stability in SGF and allergenic potential is unlikely to be solely due to orally-ingested labile proteins failing to provoke immune responses due to degradation in the stomach.

Acid Phosphatase↗