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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
PubMed1998

Assessment of the skin sensitization potential of topical medicaments using the local lymph node assay: an interlaboratory evaluation.

The murine local lymph node assay (LLNA) is a method for the predictive identification of chemicals that have a potential to cause skin sensitization. Activity is measured as a function of lymph node cell (LNC) proliferative responses stimulated by topical application of test chemicals. Those chemicals that induce a threefold or greater increase in LNC proliferation compared with concurrent vehicle controls are classified as skin sensitizers. In the present investigations we have evaluated further the reliability and accuracy of the LLNA. In the context of an international interlaboratory trial the sensitization potentials of six materials with a history of use in topical medicaments have been evaluated: benzoyl peroxide, hydroquinone, penicillin G, streptomycin sulfate, ethylenediamine dihydrochloride, and methyl salicylate. Each chemical was analyzed in the LLNA by all five laboratories. Either the standard LLNA protocol or minor modifications of it were used. Benzoyl peroxide and hydroquinone, both human contact allergens, elicited strong LLNA responses in each laboratory. Penicillin G, another material shown previously to cause allergic contact dermatitis in humans, was also positive in all laboratories. Streptomycin sulfate induced equivocal responses, in that this material provoked a positive LLNA response in only one of the five laboratories, and then only at the highest concentration tested. Ethylenediamine dihydrochloride dissolved in a 3:1 mixture of acetone with water, or in 4:1 acetone:olive oil (one laboratory), was uniformly negative. However, limited further testing with the free base of ethylene diamine yielded a positive LLNA response when applied in acetone:olive oil (AOO). Finally, methyl salicylate, a nonsensitizing skin irritant, was negative at all test concentrations in each laboratory. Collectively these data serve to confirm that the local lymph node assay is sufficiently robust to yield equivalent results when performed independently in separate laboratories and indicate also that the LLNA is of value in assessing the skin sensitization potential of topical medicaments.

Administration, Topical↗
PubMed1998

Selective induction of type 2 cytokines following topical exposure of mice to platinum salts.

Repeated topical exposure of BALB/c strain mice to organic chemical respiratory allergens, such as trimellitic anhydride (TMA), or contact allergens such as 2,4-dinitrochlorobenzene (DNCB), provokes characteristic cytokine secretion profiles consistent with the divergent activation of discrete T cell subpopulations. Under such conditions, lymph node cells (LNC) isolated from animals exposed to TMA elaborated comparatively large amounts of the type 2 cytokines interleukin 10 (IL-10) and mitogen-inducible interleukin 4 (IL-4), but only low levels of the type 1 product interferon gamma (IFN-gamma). In contrast, DNCB-activated LNC displayed the converse (type 1) cytokine secretion profile. We have now examined cytokine production induced by topical application to mice of respiratory sensitizing platinum salts; ammonium tetrachloroplatinite II, ammonium hexachloroplatinate IV and cis-dichlorodiammine platinum II. Metal salts were dissolved in dimethyl sulfoxide (DMSO). Cytokine secretion profiles were compared with those elicited following concurrent exposure to TMA or DNCB or to the vehicle acetone:olive oil (AOO) alone. All three platinum salts and TMA stimulated vigorous IL-4 and IL-10 production compared with DNCB-activated LNC; vehicle-stimulated LNC failed to elaborate detectable levels of either cytokine. However, DNCB and the DMSO vehicle provoked substantial IFN-gamma expression, whereas exposure to AOO vehicle resulted in a considerably weaker IFN-gamma response. Levels of this cytokine induced by treatment with respiratory allergens were, in the majority of cases, substantially lower than those observed with the relevant vehicle. Indeed, an inverse dose-response relationship for IFN-gamma expression was exhibited by all three platinum salts, suggestive of the elaboration by platinum salt activated LNC of an inhibitory factor or factors for IFN-gamma. These data suggest that it may be possible to identify those metal salts with respiratory sensitizing potential as a function of induced type 2 cytokine secretion patterns.

Administration, Topical↗
PubMed1998

Skin irritation potential of mixed surfactant systems.

Virtually all current detergent formulations contain mixtures of surfactants. Our experience and test data on these formulations, which is in agreement with that of many others, has shown that in use the formulations exhibit lower acute irritation potential than predicted by simple summation of the irritation potential of the individual actives. Using the criteria of the Dangerous Preparations Directive (EC Directive 88/379/EEC), many of these formulations classify as irritant in the neat state, with consequent labelling requirements. Such classification is based on addition of irritant components giving a total concentration which exceeds a nominal threshold. In this study, mixtures of surfactants were tested by application to a panel of 31 human volunteers for up to 4 hr, using the technique established for the assessment of acute skin irritation potential. The positive control, sodium dodecyl sulfate (SDS) at 20% concentration, gave an 84% positive response. Dimethyl dodecyl amido betaine (DDAB) at the same concentration gave a 94% response. However, a combination of 20% of each of these surfactants in the same panellists gave a response of only 44%--a significant reduction in the irritation potential. A further test conducted with a mixture of 10% SDS and 10% DDAB in a second panel gave a 31% positive response compared with a 94% positive response to the 20% SDS control in that panel. These results clearly demonstrate that the acute irritation potential of mixed surfactants cannot be predicted by simple summation of the irritation potential of the component substances. Initial results of the mechanistic investigation indicate that the reduced irritation induced by the mixed surfactant systems correlates with a reduced critical micelle concentration (CMC). However, the reduced CMC itself seems not to be responsible for the lowered irritation, since these experiments were conducted at concentrations well above the CMC. It is proposed that the critical event leading to skin irritation is binding to skin protein and that in mixed surfactant systems, the individual surfactants exhibit less affinity for this protein.

Betaine↗
PubMed1998

Strategies for identifying false positive responses in predictive skin sensitization tests.

It is important that predictive toxicological test methods are selective for their intended endpoint and that their limitations are understood and acknowledged. The local lymph node assay (LLNA) is a relatively new predictive test for skin sensitization potential that can replace traditional guinea pig tests and offers significant scientific and animal welfare advantages. However, there has been some concern that certain irritant materials may yield false positive results, although it must be emphasized that false positives also occur in guinea pig methods. Consequently, we have examined the performance in the LLNA of a range of skin irritants, from varying chemical classes and covering a range of irritation potency. The results presented here demonstrate clearly that the majority of skin irritants are negative in the LLNA. These results are reviewed in the context of the occurrence of false positive reactions in the guinea pig maximization test and the strategies for dealing with such results are discussed. The need for careful scientific evaluation of the results in all predictive tests for sensitization is thus emphasized. In terms of specificity, the LLNA has been more fully evaluated than other predictive test methods and is at least as accurate. In terms of animal welfare, objectivity, reproducibility and reliability it is superior to other methods. In summary, all predictive skin sensitization test results should be evaluated in a scientifically rigorous manner and the additional data provided herein further support the adoption of the LLNA as a complete replacement for the traditional guinea pig methods.

Animals↗
PubMed1998

Susceptibility to skin stinging, non-immunologic contact urticaria and acute skin irritation; is there a relationship?

Adverse skin reactions cover many types of response: toxic, irritant, allergic, urticarial, sensory, etc. The relationships between an individual's tendency to develop different types of skin response are not well-described. We examined whether those who perceive stinging might be more likely to experience urticarial, sensory and irritation reactions in skin. A panel of 86 volunteers was tested with 10% lactic acid in the nasolabial fold to assess their ability to perceive stinging. At the same time, their capacity to develop non-immunologic contact urticaria was evaluated using chemicals of different structural type and urticant ability: methyl nicotinate, benzoic acid, cinnamic acid, cinnamaldehyde and dimethyl sulfoxide (DMSO). DMSO was also used to assess sensory effects and skin irritation. 44 were classes as "stingers" and 42 as "non-stingers". The pattern of urticant reactivity in the stingers and non-stingers was essentially the same, with neat DMSO generating the strongest reactions in both groups. Sensory reactions to DMSO (stinging, itching, tingling or burning) were similar in stingers and non-stingers; although the former may have reacted more quickly, a smaller proportion reacted (64% versus 76%). The skin irritation response to DMSO was also identical in stingers and non-stingers and the intensity of the urticant response in an individual did not correlate with the intensity of their subsequent irritant reaction. In conclusion, this study demonstrated that an individual's ability to perceive skin stinging does not give a general indication of their susceptibility to other types of non-immunologic skin response. Indeed, there appeared to be little evidence of correlations between any of the skin effects studied.

Acrolein↗
PubMed1998

Acute irritation thresholds in subjects with type I--type VI skin.

It has long been recognized that human skin can be subdivided into simple categories based on their sensitivity to sunlight--from Type I, never tans, always burns, to Type VI, marked constitutive pigmentation. There is also evidence that the more readily sunburnt type of skin is also more susceptible to the effect of irritants. In the present work, the irritancy threshold for sodium lauryl sulfate (SLS) has been assessed using a recently described 4-h acute skin irritation patch test. A total of 110 subjects covering all 6 skin types were examined and their threshold for acute irritancy defined as the lowest concentration of SLS, applied under 4-h occlusion, which would induce a clinically detectable irritant response. The SLS dose response generated using a range of concentrations (0.1%-20%) demonstrated that there was no significant difference between the groups under these test conditions. Even for Type VI skin (n = 25), the dose-response curve fell within the general pattern. These results reinforce the general applicability of predictions of acute irritant potential made in groups of human volunteers.

Acute Disease↗
PubMed1998

Application of a 4-h human patch test method for comparative and investigative assessment of skin irritation.

A human 4-h patch test has recently been developed for testing the irritation hazard potential of chemicals. The original method was developed for comparative irritation assessments relative to benchmark irritants using simple statistical tests. In this context, the method has been shown to be robust in intralaboratory testing over time. Recent interlaboratory testing has also established the consistency of the method in assessment of the relative irritation potential of selected chemicals. These data help to position the method as a suitable replacement for animal test methods in assessment of skin irritation hazard. In addition, the method has great utility for investigating different parameters of clinical skin irritation. Using kinetic response patterns and curve fitting analysis, we have compared the relative irritation potential of chemicals in greater detail, using as a basis the time required for test subjects to respond as well as the incidence of positive responses. Also, using the response to 20% sodium dodecyl sulfate (SDS) as a benchmark, we've been able to examine the intersubject variation in clinical skin irritation responses. In general, subjects most reactive to 20% SDS, in terms of the exposure time required to produce a positive response, were relatively more sensitive to a 2nd irritant chemical as well. However, this was not an absolute correlation in that some test subjects showed divergent patterns of response. The method was also used to compare directly the relative skin reactivity of different populations, based on race (Caucasian versus Asian) or on neurosensory skin sensitivity. Our results using this acute exposure test method indicate little difference in visually assessed skin irritation among these diverse human subpopulations.

Acetic Acid↗
PubMed1998

Acute irritant reactivity to sodium lauryl sulfate in atopics and non-atopics.

Predictive testing of chemicals to assess their acute skin irritation potential is an important part of the assessment of their toxicological profile. It is possible, where safety and ethical considerations can be met, to do this work in groups of human volunteers. Previously, the relative responsiveness of atopics and non-atopics has been evaluated. The results showed that atopics (defined broadly by high IgE reactivity) were a little more susceptible to skin irritation, but not significantly so. In the present work, the relative reactivity of a skin atopic group versus a non-atopic group was examined in more detail. Sodium lauryl sulfate (SLS) was applied at a range of concentrations and exposure times, such that a fairly constant degree of skin irritation was produced. At various time points, the irritation response was measured by visual assessment, chromametry, laser Doppler flowmetry and transepidermal water loss. Using all of the methods of assessment, the reactions in atopics were similar to or a little less than those seen in non-atopics. The conclusion is that atopics and non-atopics will give similar results in a predictive human test for acute skin irritation. Furthermore, the pattern of response obtained from short duration exposure should be predictive of that following longer durations of (single) exposure.

Acute Disease↗
PubMed1998

Cutaneous reactivity of the hands in nickel-sensitive patients with hand eczema.

This study compares the cutaneous reactivity between the hand and the back for 7 female patients with active hand eczema, who were found to be nickel-sensitive on routine patch testing with the European standard series. Patients were patch tested to a dilution series of nickel sulfate on the back in order to determine the threshold concentration for elicitation of allergic contact dermatitis, and based upon this result a lower concentration of nickel was then used for patch tests on the hand. We found that in the majority of patients (6/7) the cutaneous responsiveness of the hand was not increased compared with that of the back. However, the hand of 1 patient was more sensitive to nickel and patch testing was accompanied with a flare of her eczema, which suggests that cutaneous hyperreactivity may be important in individual patients with hand eczema.

Adolescent↗
PubMed1998

The effect of patch duration on the elicitation of para-phenylenediamine contact allergy.

To study the length of exposure time required to elicit para-phenylenediamine (PPD) allergic reactions, patients known to be allergic to PPD were recruited and patch tested. A group of 7 patients were patch tested with 1% PPD in pet. for 15 min, 30 min and for 120 min. The remaining 9 patients were patch tested with 1%, 0.3%, 0.1% and 0.01% PPD for 15 min, 30 min and for 120 min each. With exposure for 120 min, 11 of 16 subjects reacted to 1% PPD and 2 of 9 reacted to 0.01%. With exposure of 15 min, 6 of 16 reacted to 1% PPD and 0 of 9 reacted to 0.01% PPD. This study showed marked inter-individual variability in eliciting a reaction to the PPD molecule on patch testing, with regard to both the exposure time and the concentration required.

Adolescent↗
PubMed1998

Estimation of relative skin sensitizing potency using the local lymph node assay: a comparison of formaldehyde with glutaraldehyde.

BACKGROUND: Chemicals vary considerably in their intrinsic ability to cause allergic contact dermatitis. Presently, there are no experimental methods available for the quantitative assessment of the relative sensitizing potency of chemical allergens. OBJECTIVE: The objective of the investigations described here was to evaluate the use of the local lymph node assay for determining the relative skin sensitizing potential of chemicals. This has been addressed by comparing the sensitizing potency of formaldehyde with glutaraldehyde. METHODS: Dose responses induced by formaldehyde and glutaraldehyde in the local lymph node assay, using either acetone or dimethylformamide (DMF) as the application vehicle, have been measured. Relative skin sensitizing potency was estimated as a function of the amount of chemical required to induce a threefold increase in lymph node cell proliferative activity, a mathematically derived EC3 value (estimated concentration required to induce a stimulation index of 3). RESULTS: In both vehicles, glutaraldehyde induced substantially more vigorous responses in the local lymph node assay (EC3 values of 0.006mol/L in acetone and 0.002mol/L in DMF) than did formaldehyde (EC3 values of 0.18mol/L in acetone and 0.11mol/L in DMF). CONCLUSIONS: These results demonstrate that glutaraldehyde has a considerably greater potential to induce skin sensitization than does formaldehyde; the data are consistent with what is known of the ability of these chemicals to cause allergic contact dermatitis in humans. Using formaldehyde and glutaraldehyde as examples, the results here illustrate the utility of EC3 values derived from local lymph node assay responses for the estimation of the relative potency of skin sensitizing chemicals.

Allergens↗
PubMed1998

Chemistry of contact allergens and irritants.

Understanding the nature and causes of contact dermatitis is as much a problem of chemistry as it is of biology. Many of the characteristics of an individual's reaction to a particular chemical, whether it be an irritant or allergen or both, depend very much on that person. From a more general perspective, however, the ability of a chemical to irritate and/or sensitize is a primary function of its chemical properties. The human biological system simply responds to the nature of the chemical perturbation it perceives; thus within the human population there is normal distribution in terms of the intensity of a reaction to a defined stimulus. This article reviews the present state of knowledge regarding the relationships between the ability of a chemical to cause contact dermatitis and its physicochemical properties, with close attention paid to how this knowledge may be used in a predictive sense to assist in risk assessment.

Allergens↗
PubMed1997

A re-appraisal of the skin-sensitizing activity of 2,4-dinitrothiocyanobenzene.

A debate continues regarding the immunological properties of 2,4-dinitrothiocyanobenzene (DNTB). In some investigations this chemical was shown not to cause skin sensitization when applied topically but to induce instead hyporesponsiveness or immunological tolerance. In other studies DNTB was found to cause skin sensitization, but not tolerance. However, this chemical continues to be used to discriminate between the properties of skin sensitizing and non-sensitizing chemicals. This study demonstrates that topical exposure of mice to DNTB induces skin sensitization in mice and that this is associated with the accumulation of dendritic cells in draining lymph nodes and the stimulation of lymph node cell proliferation; the latter responses being of equivalent magnitude to those stimulated by 2,4-dinitrochlorobenzene (DNCB), a chemical known to cause contact sensitization. Moreover, exposure of mice to DNTB, as with exposure to DNCB, resulted in the development of a cytokine secretion pattern by draining lymph node cells (LNC) characteristic of contact allergens. Thus, DNTB and DNCB each induced the production by LNC of high levels of interferon-gamma, but little or no interleukin 4 or interleukin 10. Finally, DNTB was shown in the guinea pig maximization test to behave as an extreme skin sensitizer. These results confirm that DNTB should not be regarded as a universal tolerogen and that it possesses a significant potential to induce contact sensitization. The use of this chemical as a presumptive non-sensitizer and/or tolerogen for the evaluation of the selectivity of new predictive test methods for the identification of contact allergens is therefore considered to be inappropriate.

Administration, Topical↗
PubMed1997

Interlaboratory evaluation of a human patch test for the identification of skin irritation potential/hazard.

The human 4 hr patch test provides an opportunity to identify substances with significant skin irritation potential without recourse to the use of animals. To demonstrate the validity of the method it must be relevant and reliable. It is self-evident that the method is relevant to the identification of skin irritation hazards to humans. However, it is essential that the results be reproducible. This paper presents data on a number of substances tested by different laboratories. Eight substances were tested by two or more laboratories and the data compared with a standard positive control, 20% sodium dodecyl sulfate. In almost all cases, the outcome of this comparison was identical. Thus, despite the fact that there is known variability among human subjects in terms of skin reactivity to irritants, this simple method showed good reproducibility for the classification of acute skin irritation potential. Therefore, it is argued that this human 4-hr patch test is a valid alternative to the equivalent rabbit test for the assessment of skin irritation hazard to humans.

Adult↗
PubMed1997

The classification of skin irritants by human patch test.

The human 4 hour patch test provides an opportunity to identify substances with significant skin irritation potential without recourse to the use of animals. The protocol is designed to avoid the production of more than mild irritant reactions and meets the highest ethical standards. This paper provides the background to the development of the method and comments on its performance in the light of recent intra- and inter-laboratory investigations. In particular, the value of the method in providing 'gold standard' data for the identification of those substances (or preparations) which should, or should not, be classified as irritant to skin in European legislation is discussed. On the basis of the published data and supplementary investigations, recommendations are made on both the conduct and interpretation of the human 4 hour patch test. Finally, the lack of any necessity for formal validation of this assay is addressed.

Health Planning Guidelines↗
PubMed1997

Characteristics of antibody responses induced in mice by protein allergens.

Whereas many foreign proteins are immunogenic, only a proportion is also allergenic, having the capacity to induce the quality of immune response necessary to support the production of IgE antibody. We have demonstrated previously that intraperitoneal administration to mice of proteins such as ovalbumin (OVA) or the industrial enzyme A. oryzae lipase, which possess significant allergenic potential, stimulates the production of both IgG and IgE antibody. Identical exposure to bovine serum albumin (BSA), a protein with limited potential to cause immediate respiratory or gastrointestinal hypersensitivity reactions, induced IgG responses only. In the current investigations, the quality of immune responses induced following exposure to these proteins via mucosal tissue (intranasal) has been compared with those provoked following administration via a non-mucosal (intraperitoneal) route of exposure. Intranasal or intraperitoneal administration of BSA, OVA or A. oryzae lipase elicited in each case vigorous IgG and IgG1 antibody responses. For all three proteins, at every concentration tested, and via both routes of exposure, IgG1 antibody titres paralleled closely IgG titres. However, the three materials displayed a differential potential to provoke IgE responses and this correlated with their known allergenic potential in humans. Thus, OVA and A. oryzae lipase stimulated strong IgE antibody responses, whereas BSA provoked low titre IgE only at the highest concentration tested (5% administered intraperitoneally). The quality of induced responses was not affected by the route of exposure. It would appear, therefore, that the stimulation of IgG and IgG1 antibody responses is a reflection of protein immunogenicity whereas protein allergenicity is associated with the induction of strong IgE responses.

Administration, Intranasal↗
PubMed1997

Skin sensitization to eugenol and isoeugenol in mice: possible metabolic pathways involving ortho-quinone and quinone methide intermediates.

With the aim of providing further mechanistic insights into the mode of action of eugenol (4-allyl-2-methoxyphenol) and isoeugenol (4-propenyl-2-methoxyphenol), we have synthesized two series of modified compounds which were tested in the mouse local lymph node assay for their skin sensitizing potential. The replacement of the methoxy group by an isopropoxy group led to a complete loss of sensitization for the eugenol derivative 6a, while no significant effect was observed for the isoeugenol derivative 6b. In the eugenol series, when methyl groups were present in the 3-, 5-, or 6-position a significant reduction in sensitization potential was observed while in the isoeugenol series only methyl substitution in the 3- and 5-position had a discernable effect. Introduction of three methyl groups on the aromatic ring of eugenol (3,5,6-trimethyl-4-allyl-2-methoxyphenol, 7) and of a tert-butyl substituent at the gamma-position of the alkyl chain of isoeugenol (4-[3',3',3'-trimethylpropenyl]-2-methoxyphenol, 8) led to a strong decrease of the sensitizing capacity. Our findings indicate that, at least in the mouse, eugenol could sensitize via a demethylation pathway followed by oxidation to the o-quinone which could act directly as a hapten even if we cannot exclude a reaction via its tautomeric p-quinone methide. Isoeugenol, on the other hand, could act via a mechanism not involving demethylation and for which the evidence is consistent with a direct oxidation to the p-quinone methide.

Animals↗