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Background: Alcohol-based hand rub (ABHR) is recommended for hand hygiene, and application on dry skin is generally well tolerated. However, hydration of the skin may lead to increased susceptibility to ABHR., Objectives: To evaluate if increased skin hydration changes skin barrier response to ABHR, as compared to application on dry skin., Methods: Twenty healthy volunteers participated in a 3-day experimental setup. Intervention areas on the forearms were exposed to either water immersion or occlusion followed by repeated exposures to ABHR. Skin barrier function was assessed by measurement of transepidermal water loss (TEWL), electrical conductance, pH, and erythema at baseline and day 3., Results: The area exposed to water immersion preceding ABHR showed a significant increase in TEWL from baseline to day 3 (P = .04), and for the occluded area the same trend was found (P = .11), with an additional decrease in electrical conductance (P = .03). No significant differences were found for the control area. The assessments did not differ significantly between intervention and control sites., Conclusion: Our results indicate that extensive skin hydration may lead to increased susceptibility to ABHR. Further evaluation of this observation is important, since ABHRs are widely used, particularly among health care workers in whom hand eczema is a huge problem., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Dimethylfumarate (DMF) was the cause of a major outbreak of allergic contact dermatitis as a consequence of its use as an antifungal agent in leather products, particularly in furniture, with what became known as 'toxic sofa dermatitis'., Objectives: To determine whether the frequency and severity of reactions to DMF arose as a function of its intrinsic potency and/or the nature and extent of exposure., Methods: The intrinsic potency of DMF was measured with the standard local lymph node assay (LLNA), with determination of an EC3 value, which is the threshold in the LLNA and serves as an indicator of relative skin-sensitizing potency in humans., Results: The EC3 value for DMF was 0.35% when tested in dimethylformamide as a vehicle, indicating that DMF is a strong, but not an extreme, skin sensitizer in this mouse model., Conclusions: DMF appears to have a sensitizing potency in the mouse that is very similar to that of formaldehyde, which is also a strong human skin sensitizer. However, the frequency and intensity of allergic contact dermatitis reactions to DMF suggest that it was the prolonged, repeated and occlusive exposure to this chemical over large skin areas, combined with the strong sensitizing potency, that generated the 'perfect storm' conditions that caused the DMF epidemic., (© 2013 John Wiley & Sons A/S.)

Visual assessment of skin reactions has long been used to evaluate the safety of chemicals and preparations that contact the skin, and to meet regulatory requirements. This article reviews the history of visual grading scales, and the results of investigations into the reliability of the method. Some examples are provided to illustrate the diverse array of protocols that use visual scoring to evaluate skin irritation. Furthermore, as bioengineering methods are developed that can quantitate certain aspects of skin irritant and sensitization reactions, it is important to consider whether such measures should supplement or replace visual assessment. Examples of investigations comparing the outcomes of studies that use visual scoring and those that use bioengineering methods are discussed. These examples provide little evidence that bioengineering measures provide an improvement in overall quality in comparison with current testing methods that rely on visual assessment. In addition, such measuring techniques can add considerably to the complexity of testing protocols. When benefits and cost are weighed in the balance, the visual assessment scales popularized by Draize and others remain an effective, practical method of evaluation., (© 2011 John Wiley & Sons A/S.)

The phenomenon of 'sensitive skin' is a relatively recent complaint in which certain individuals report more intense and frequent adverse sensory effects than the normal population upon use of cosmetic (personal-care) products. Originally defined as a minority complaint, sensitive skin is now claimed by a majority of women in industrialized countries and nearly half of men. Sensitive skin is self-diagnosed and typically unaccompanied by any obvious physical signs of irritation, and the number of individuals who claim sensitivity has risen steadily with the number of consumer products targeted towards this supposedly uncommon group. Believed by many dermatologists, therefore, to be a 'princess and the pea' phenomenon, the problem of sensitive skin has largely avoided focussed research. Over the last few years, however, the evidence of documentable biophysical changes associated with the largely sensory symptoms of this disorder has accumulated, including some gained by improved methods of identifying subclinical signs of skin irritation. Although the understanding of the aetiology of this phenomenon is as yet incomplete, existing research now supports a biophysical origin for this disorder. Effective methods of diagnosis, intrinsic and extrinsic contributors to exaggerated neural sensitivity, and the specific mechanisms of the discomfort associated with the compliant are required, as are appropriate means of prevention and treatment.

Background: Development of cosmetic products and household detergents necessitates comparative study designs to assess the skin tolerance of products. In initial tests, the epicutaneous patch test for irritation is widely used., Objectives: This study was conducted to develop a protocol that would facilitate a comparison of results obtained when tests are conducted by different laboratories., Methods: 'In-house' and standardized patch test protocols were used to assess irritation potentials of surfactant-based products in intra- and interlaboratory studies using defined surfactant samples., Results: The various in-house protocols tested did not consistently produce equivalent results. In order to develop a study design that yields comparable results, various factors were identified and adjusted. The standardized study protocol includes occlusive application of 70 microl of the test substance to the back of 30 subjects, defined reading times and schemes, assessments based mainly on erythema, and inclusion of sodium laureth sulfate and sodium dodecyl sulfate as positive controls as well as water as a negative control., Conclusions: Use of the standardized protocol and training of assessors improved the reliability and consistency of results whereby the irritation potentials of the references and test samples were ranked similarly by the laboratories.

Background: Evaluation of skin sensitization potential is an important part of the safety assessment of cosmetic ingredients and topical drugs. Recently, evaluation of changes in surface marker expression induced in dendritic cells (DC) or DC surrogate cell lines following exposure to chemicals represents one approach for in vitro test methods., Objective: The study aimed to test the change of expression patterns of surface markers on THP-1 cells by chemicals as a predictive in vitro method for contact sensitization., Methods: We investigated the expression of CD54, CD86, CD83, CD80, and CD40 after a 1-day exposure to sensitizers (1-chloro-2,4-dinitrobenzene; 2,4-dinitrofluorobenzene; benzocaine; 5-chloro-2-methyl-4-isothiazolin-3-one; hexyl cinnamic aldehyde; eugenol; nickel sulfate hexahydrate; potassium dichromate; cobalt sulfate; 2-mercaptobenzothiazole; and ammonium tetrachloroplatinate) and non-sensitizers (sodium lauryl sulfate, benzalkonium chloride, lactic acid, salicylic acid, isopropanol, and dimethyl sulphoxide). The test concentrations were 0.1x, 0.5x, and 1x of the 50% inhibitory concentration, and the relative fluorescence intensity was used as an expression indicator., Result and Conclusion: By evaluating the expression patterns of CD54, CD86, and CD40, we could classify the chemicals as sensitizers or non-sensitizers, but CD80 and CD83 showed non-specific patterns of expression. These data suggest that the THP-1 cells are good model for screening contact sensitizers and CD40 could be a useful marker complementary to CD54 and CD86.

Background: Persulfate salts have been associated with both allergic contact dermatitis and bronchial asthma. Because there is currently no experimental data available on the sensitizing properties of persulfate salts (ammonium, sodium, and potassium persulfates), we determined their dermal sensitizing capacity, using the murine local lymph node assay (LLNA)., Material and Methods: For three consecutive days, BALB/c mice were dermally treated with ammonium, sodium, or potassium persulfate or with the vehicle alone (dimethyl sulfoxide) on each ear (2 x 25 microl). On D6, mice were injected intravenously with [(3)H]-methyl thymidine. The draining auricular lymph nodes were removed, and the incorporation of [(3)H]-methyl thymidine was compared with that of vehicle-treated control mice. A stimulation index (SI) relative to the vehicle-treated control value was derived. The sensitizing potency of the chemicals tested was determined by estimating the concentration of chemical required to induce a SI of 3 (EC3)., Results: All three chemicals provoked positive responses in the LLNA, with dose-dependent increases in proliferation. Maximal SIs recorded were 6.8 +/- 1.8, 6.5 +/- 1.2, and 5 +/- 1.0 at 5% for ammonium, sodium or potassium persulfate, respectively. The EC3 values were 1.9%, 0.9%, and 2.4% for ammonium, sodium, and potassium persulfates, respectively., Conclusions: All three persulfate salts need to be considered strong-to-moderate sensitizers according to the murine LLNA.

Background: Simultaneous contact allergies to the reactive diluent phenyl glycidyl ether (PGE) and epoxy resins based on diglycidyl ether of bisphenol A (DGEBA) or epoxy resins of the bisphenol F-type have been reported. The latter epoxy resins contain three isomers of diglycidyl ether of bisphenol F (DGEBF). PGE, DGEBA, and DGEBF are chemically similar with respect to the reactive glycidyl group and an aromatic ring, making cross-reactivity one of the possible explanations to simultaneous reactions., Aim: To investigate the sensitizing capacity of PGE and the cross-reactivity of PGE versus the epoxy resin monomers DGEBA and the three DGEBF monomers and vice versa., Method: The guinea-pig maximization test., Results: PGE is a strong sensitizer. Induction with DGEBA resulted in a statistically significant number of animals reacting to PGE, but when induced with PGE, the animals did not react significantly to DGEBA., Conclusions: When the results are applied to humans, it can be assumed that patients sensitized primarily to DGEBA react to PGE, but when sensitized exclusively to PGE, they do not react to DGEBA. Both reactive diluents and epoxy resins should be tested when contact allergy to epoxy resin systems are suspected.

Background: Eliminating animal testing for skin sensitization is a significant challenge in consumer safety risk assessment. To be able to perform resilient risk assessments in the future, one will need alternative approaches to fill the data gaps., Objectives: To this end, we propose a subcategory-based read-across approach to estimate and rank skin sensitization potential of chemicals. The example described here is for the mechanism of Michael-type nucleophilic addition with subcategories being limited to carbonyl-containing compounds., Patients/methods: In this approach, in silico tools based on structural alerts were used to determine both the mechanism of protein binding and the relative subcategories within that mechanism., Results: Fifty compounds previously evaluated in the in vivo mouse local lymph node assay (LLNA) were placed in 10 subcategories defined by their polarized alpha,beta-unsaturated substructure. To offset the limitations and skewness of the published in vivo data, in chemico glutathione (GSH) depletion data also were included., Conclusions: It was shown that the read-across approach can be successfully used to rank qualitatively skin sensitization potential of an untested carbonyl-containing Michael acceptor chemical by using subcategories. Moreover, the use of the more resilient in chemico GSH depletion data added further support to the read-across result.

In evaluating the safety of a novel cosmetic product or a new chemical, it is important to assess susceptible population. One group of subjects is known to stingers who are more likely to experience sensory effects such as stinging and burning after contacting with cosmetics. The purpose of the study is to measure skin biophysical parameters noninvasively in stingers and non-stingers and to see their correlations with stinging responses. 298 women were evaluated by modified lactic acid stinging test with 5% lactic acid solution rather than classic 10% solution because of strong reaction in Asian populations. Transepidermal water loss (TEWL), skin hydration, sebum content, and pH were measured using the bioengineering instruments in an environment-controlled room. Correlations between stinging responses and skin biophysical parameters were statistically analysed. There was a positive correlation between stinging responses and TEWL evaluation. However, no correlations was observed between stinging responses and other parameters such as skin hydration, sebum content, and pH. Our data indicate that there is a relationship between the degree of stinging and the skin barrier function. However, we believe that various additional studies are necessary to characterize skin of stingers and the pathogenesis.

Contact with metal working fluids (MWF) is an important factor in the development of occupational hand dermatitis in patients working in the metal processing industry. Biocides are added to MWF as preservatives and are known sensitizers. We analysed 318 patch test reactions to N,N-methylene-bis-5-methyl-oxazolidine 1% in petrolatum (5-methyloxazolidine, Grotan OX, CAS no. 66204-44-2, a formaldehyde releasing biocide) present in coolant oils in patients exposed to MWF and with suspected occupational dermatitis (OD). Positive allergic reactions were noted in 15 (4.7%) cases. In 7 (47%) cases, we were able to confirm relevance by examining the material safety data sheets and these showed that N,N-methylene-bis-5-methyl-oxazolidine was present in the oils used by the patients. No certain relevance could be proved in 8 cases, but in these instances, further information on the biocides used in the oils could not be obtained. Positive reactions to formaldehyde were seen in 11 (73%) patients. Sensitization either to this biocide and/or formaldehyde allergy was considered to have been likely to have made a contribution to the workers' dermatitis.

Sodium lauryl sulfate (SLS) has often been chosen as a model for irritant contact dermatitis (ICD) to study the effect of irritants in combination (1-14). Recently 'tandem', or sequential, exposures with SLS have been performed to study the mechanism of skin barrier impairment in ICD (1-6, 15). The assessment of reactions have been documented with visual scoring, transepidermal water loss (TEWL), skin colour reflectance measurements, skin blood flow; among which TEWL has been noted as the most sensitive value (16). The matched control groups were treated with either a single exposure to a single irritant or in tandem with the same irritant repeatedly. Synergistic and additive effects have been reported for various tandem pairs of irritants, however, the mechanism for both remains unclear. The results of tandem irritation studies were evaluated to define and investigate the responses produced and deduce a possible mechanism of action. Clinical ramifications, albeit complex, are discussed.

Testing for potential adverse skin effects is a key part of both the overall safety assessment for many consumer products and the evaluation of potential product improvements in mildness. Whilst modern tissue and paper products (i.e. facial tissues, catamenial products, baby wipes and baby and adult diapers) are inherently very mild to skin, current test methodology may not be robust enough to evaluate future improvements in such products. This article provides a commentary on several technologies we have been exploring to improve the sensitivity of test methods for tissue and paper products. The focus has been on three approaches: (i) further exaggerating exposure conditions using novel approaches to sample application, (ii) increasing the sensitivity of the manner in which we score for irritant effects, either visually or via instrumentation and (iii) quantitatively measuring additional endpoints, i.e. subjective sensory effects.

In view of the wide variety of components currently used in metalworking fluids (MWF), relevant contact sensitizations may be overlooked, because commercially available MWF test series cannot cover the full spectrum. Hence, patch testing with MWF from the patient's workplace is an important additional diagnostic tool. However, recommendations on how to perform such patch tests vary. We retrospectively analyzed patch test data of the Department of Dermatology in Dortmund, 1992-2003. In 141 metalworkers tested because of suspected occupational contact dermatitis due to MWF, 829 patch tests with 306 samples of MWF were performed. Water-based MWF (wb MWF) were mainly tested in 2 dilution series, i.e. pure (workplace concentration), 10% aq. and 1% aq., and pure, 50% aq. and 10% aq. Positive reactions to wb MWF occurred in 27 patients. Patch testing with wb MWF at workplace concentration resulted in 16.1% (39/242) positive reactions, with a positivity ratio of 69% and a reaction index of 0. From the analysis of reaction patterns and concomitant reactions, we conclude that most of these positive reactions indicated true contact allergy. With lower concentrations, relevant allergic reactions may be missed. Neat oils were tested as is or diluted from 1 to 50% in olive oil, but no reactions at all were observed. For optimum benefit of patch testing with MWF from the patient's workplace, breakdown testing is recommended. To overcome the time-consuming difficulties associated with this procedure, we propose a centre for information and documentation of contact allergies due to occupational exposure. Furthermore, full declaration of MWF ingredients is desirable.

Large-scale data comparing reactions to surfactants between scalp and back and arm are lacking. The sensitivity of responses between scalp and back and arm were explored utilizing an open-application model for testing the potential irritancy of sodium lauryl sulphate (SLS). 10 bald male Caucasians (mean age 56 +/- 9 years) were enrolled. We conducted 5 successive washings: for each wash, the technician pipetted 1 ml of 20% SLS solution into a glass cylinder placed on the designated area with hand pressure that prevented the cylinder leaking. The test area was then rubbed with a Teflon Policeman scrubber for 1 min. Post scrubbing, the solution was absorbed dry with a plastic pipette and blotted by gently applying paper tissues. After a 5-min rest, the procedure was repeated for 4 more times for a total of 5 times. Skin-irritancy assessments by visual scoring and instrumental measurements were made at 30 min and 24 h thereafter and squamometry at the end of last washing. Results indicated that most param- eters revealed that the back was most sensitive to the SLS challenge. Thus, these data support the current standard skin-compatibility testing procedure, employing the back for potential irritation testing of hair care products.

Frequent exposure to water and surfactants is considered to be the main cause of hand eczema from wet work. Ethoxylated surfactants are susceptible to oxidation and some of the oxidation products formed have proved to be contact sensitizers in guinea pigs. The question of human sensitization to oxidized surfactants was addressed in a multicentre study in the Stockholm region. 528 consecutive dermatitis patients were patch tested with widely used ethoxylated surfactants in oxidized and non-oxidized form as well as certain identified oxidation compounds. 61 patients presented with mild, clearly irritant reactions to some of the surfactants tested. 18 patients showed not only erythema but also oedema and/or papules and vesicles, using a morphologic descriptive system for reading the patch test reactions. These reactions occurred mostly to oxidized surfactants and oxidation products. When retesting 9 of these 18 patients only an allergic reaction to acetaldehyde was confirmed. We conclude that oxidized ethoxylated surfactants have increased irritant potential compared to non-oxidized material. Our working hypothesis is that oxidized surfactants of technical quality exert a lower risk of sensitization than do oxidized homologous pure surfactants. Among the potential allergens formed during autoxidation, formaldehyde and acetaldehyde must be considered as a source of unexpected exposure.

Vulvar tissue is more permeable than exposed skin due to differences in structure, occlusion, hydration and susceptibility to friction. The safety assessment of products that contact the vulva should account for this potentially heightened permeability. Standard clinical patch tests may not sufficiently mimic vulvar exposures. Because testing on the vulva is not routinely feasible, we are investigating new and modified cutaneous test methods to increase the degree of conservatism of the safety assessment. To this end, we have 1) developed a method to assess chemical and frictional effects by means of repeated application to the popliteal fossa (the behind-the-knee test); 2) modified the quantitative risk assessment for the induction of allergic contact dermatitis; and 3) proposed a modified human repeat insult patch test for assessing materials intended for vulvar contact. Modification of the traditional 4-day, irritation patch test by using wet samples or compromized skin sites failed to enhance test sensitivity. Future studies will evaluate testing in subjects with heightened susceptibility to chemical and sensory irritation, in order to increase test sensitivity to chemical irritants. These approaches can be employed to augment the margin of safety when cutaneous test methods are applied to agents that contact the vulva.

Recently adopted legislation in Europe has increased the focus that must be placed on the development of in vitro alternatives to the traditional toxicology tests employed to identify the human health hazards associated with chemicals. Included in these is the rabbit skin-irritation test which is used to discriminate those substances which possess significant acute skin irritation potential from those which are of more limited irritation potential. So far, the considerable efforts to replace this assay with in vitro alternatives have not been successful, which may in part be due to the relatively poor quality of the existing in vivo dataset. To help address this problem, we have elected to present our complete database of information on the skin irritation potential of some 65 substances, all of which have been tested in a standard human 4-h patch test. These provide a high quality dataset, generated in man (the goal of toxicologists' health protection-related activities). The data are presented in the context of results with a concurrent positive skin irritation control to ensure that results from individual experiments can be correlated. Consequently, in vitro or in silico alternatives which can identify the significant acute human skin irritants in this group may well represent suitable alternatives to the rabbit.