Patch Testing With a New Composition of the Mercapto Mix-A Multicenter Study from the International Contact Dermatitis Research Group.

BACKGROUND: Mercaptobenzothiazole compounds are associated with allergic contact dermatitis caused by rubber products. Several screening substances have been used for patch testing. OBJECTIVE: To compare the frequency of positive test reactions to a mercapto mix containing a higher concentration of 2-mercaptobenzothiazole with reactions to the combination of 2-mercaptobenzothiazole 2.0% and mercapto mix 2.0%. METHODS: There were 7103 dermatitis patients in 12 International Contact Dermatitis Research Group dermatology departments who were patch tested with 2-mercaptobenzothiazole 2.0% petrolatum (pet.), mercapto mix 2.0% pet., and mercapto mix 3.5% pet. RESULTS: Contact allergy to the 3 test preparations varied among the 12 centers: 2-mercaptobenzothiazole 2.0% pet. (0-2.4%), mercapto mix 2.0% pet. (0-4.9%), and mercapto mix 3.5% pet. (0-1.4%). 2-Mercaptobenzothiazole 2.0% and mercapto mix 2.0% detected a few more positive patients compared with mercapto mix 3.5%, but the difference was statistically insignificant (mercapto mix 2.0% pet., P = 1.0; 2-mercapto-benzothiazole 2.0% pet., P = 0.66). CONCLUSIONS: Mercapto mix 3.5% pet. is not better than 2-mercaptobenzothiazole 2.0% and mercapto mix 2.0% by a difference that is significant. By using only 1 test preparation (mercapto mix 3.5%), an additional hapten could be tested. No cases of suspected/proven patch test sensitization were registered.

The benefits of latex-free gloves in the operating room environment.

Sterile protective gloves are used to reduce the risk of infection for patients and clinicians in all healthcare settings. This is particularly important in operating theatres, where surgical site infection is a common and serious complication for perioperative patients. These gloves have traditionally been made from natural rubber latex and dusted with cornstarch powder. However, frequent use of latex gloves can lead to a hypersensitivity or allergy to latex. A latex allergy causes discomfort and inconvenience, and it may reduce productivity, impose significant financial burdens and even be life threatening. There has not been sufficient evidence to ban the clinical use of latex; however, in cases of suspected latex allergy, guidelines recommend the use of either latex-free gloves or powder-free, low-protein latex gloves. The use of these alternative gloves has typically been limited to cases of allergy, because they have previously been associated with reduced dexterity and durability compared with latex gloves. This article presents four case studies, in which health professionals in a perioperative setting compare the advantages and disadvantages of using traditional latex surgical gloves with those of latex-free gloves manufactured by Cardinal Health. The findings of these case studies suggest that these latex-free gloves are equal to latex gloves in terms of establishing asepsis and providing comfort and dexterity to the wearer, without presenting the risk of developing latex sensitivity and/or allergy.

Accelerator-free gloves as alternatives in cases of glove allergy in healthcare workers.

BACKGROUND: Accelerators in rubber gloves constitute an important group of contact allergens, particularly in healthcare workers. OBJECTIVES: To assess the efficacy of accelerator-free medical gloves in the secondary prevention of allergic contact dermatitis caused by rubber accelerators in healthcare workers. METHODS: Nine healthcare workers with hand eczema were advised to use accelerator-free rubber gloves after a diagnosis of allergic contact dermatitis caused by rubber accelerators. RESULTS: Switching from conventional medical single-use gloves containing accelerators to accelerator-free medical gloves led to improvement in all cases, and more than two-thirds of the patients were completely free of symptoms. CONCLUSION: The use of accelerator-free medical gloves can be an effective alternative in healthcare workers who are allergic to rubber accelerators.

Development of an Economical Method to Reduce the Extractable Latex Protein Levels in Finished Dipped Rubber Products.

Natural rubber latex (NRL) allergy is caused by the extractable latex proteins in dipped rubber products. It is a major concern for the consumers who are sensitive to the allergenic extractable proteins (EP) in products such as NRL gloves. Objective of this research was to develop an economical method to reduce the EP in finished dipped NRL products. In order to reduce the EP levels, two natural proteases, bromelain from pineapple and papain from papaya, were extracted and partially purified using (NH4)2SO4. According to the newly developed method, different glove samples were treated with a 5% solution of each partially purified enzyme, for 2 hours at 60°C. Residual amounts of in treated samples were quantified using the modified Lowry assay (ASTM D5712-10). Bromelain displayed a 54 (±11)% reduction of the EP from the dipped rubber products, whereas it was 58 (±8)% with papain. These results clearly indicate that the selected natural proteases, bromelain, and papain contribute significantly towards the reduction of the total EP in finished NRL products. Application of bromelain enzyme for the aforementioned purpose has not been reported up to date, whereas papain has been used to treat raw NRL towards reducing the EP.

ESSCA results with the baseline series, 2009-2012: rubber allergens.

BACKGROUND: Allergic contact dermatitis caused by rubber allergens is common, and causes significant patient morbidity. Contemporary data are important to allow appropriate preventive measures and identification of contact allergy trends. OBJECTIVES: To describe the pattern of patch test reactivity to rubber allergens, including those in the European baseline series. METHODS: Data collected by the European Surveillance System on Contact Allergies (ESSCA) network between 2009 and 2012 from 12 European countries were analysed. RESULTS: Contact allergy to thiuram mix declined over the studied time period, with an overall prevalence of 1.87%. The prevalence of allergy to carba mix was 2.29%, and was significantly increasing. Prevalence rates of sensitization to other rubber allergens were largely unchanged. Statistical analysis with the MOAHLFA index confirmed the strong links between rubber allergy and occupational hand dermatitis. CONCLUSIONS: Changing patterns of allergy to rubber additives have been identified. Inclusion of carba mix in the European baseline series may be appropriate.

Molecular profile of sensitization in subjects with short occupational exposure to latex.

OBJECTIVES: We examined the prevalence of latex allergy in subjects with occupational exposure to latex allergens for less than 5 years, determining the disease spectrum in symptomatic workers. We identified the most frequent molecular allergens by Immuno- CAP (ICAP), correlating the findings with skin prick test (SPT) results. MATERIAL AND METHODS: Seven hundred twenty-three healthcare students using latex gloves on a regular basis were invited to participate in a baseline questionnaire screening. An ICAP serum test was performed only when a possible latex allergy was indicated by the questionnaire. RESULTS: The total number of participants responding to the baseline survey was 619. Glove-related symptoms were indicated by 4% (N = 25) of the students. The most common symptom was contact dermatitis (N = 18, 72%). In 12 subjects, ICAP revealed a real sensitization to latex, with a recombinant latex allergen profile showing a high frequency for rHev b 6.01 specific immunoglobulin E (sIgE) (N = 9, 67%). In these individuals, skin symptoms were more prevalent than other types (88%). CONCLUSIONS: The combined positivity for rHev b 6.01, rHev 8 and rHev b 5 determined by ICAP identified 92% of latex-allergic subjects with short-term exposure to latex.

Occupational management of type I latex allergy.

BACKGROUND: Although the incidence of type 1 latex allergy has decreased in recent years with the introduction of powder-free low-protein (PFLP) latex gloves, type 1 latex allergy is still commonly found among workers who use natural rubber latex (NRL) gloves at work. AIMS: To elucidate the optimal management of workers with type 1 latex allergy whose work necessitates the use of NRL gloves in the workplace. METHODS: A sensitive electronic search of relevant bibliographic databases was performed with related search terms for articles from 1 January 1990 to 1 September 2010. Relevant abstracts were reviewed, and studies that furnished data on the management of type 1 latex allergy in the workplace were extracted. Articles for inclusion in the review were appraised using the Scottish Intercollegiate Guideline Network methodology. RESULTS: A total of 7041 abstracts were retrieved; 12 articles met the inclusion criteria for the review. We found moderately strong and consistent evidence that avoidance of NRL in the workplace reduces both symptoms and markers of sensitization in latex-allergic individuals. There is limited evidence that latex-allergic workers can continue to use PFLP gloves with no worsening of symptoms, provided that their co-workers also use PFLP latex or non-latex gloves. CONCLUSIONS: Individuals with type 1 latex allergy whose work necessitates them wearing latex gloves may continue in their job provided that adjustments are made to ensure that they are not exposed to powdered latex gloves.

Respiratory and dermal symptoms in Thai nurses using latex products.

BACKGROUND: Despite known health risks related to the use of powdered latex gloves (PLGs), they are still widely used in hospitals in developing countries due to the high cost of alternatives. AIMS: To determine the prevalence of dermal and respiratory symptoms associated with latex glove use in nurses in Thailand and evaluate the influence of previously reported occupational risk factors in this population. METHODS: A cross-sectional study in female nurses working in three Thai hospitals. Participants completed a questionnaire on demographics, occupational and personal history, use of latex products at work and dermal and respiratory symptoms attributed to occupational use of latex gloves. RESULTS: Of 899 nurses, 18% reported health effects attributed to the use of latex products. After adjustment for confounding, occupational risk factors associated with increased reporting of dermal symptoms included wearing more than 15 pairs of PLG per day (odds ratio (OR): 2.10, 95% confidence interval (CI): [1.32-3.34]), using chlorhexidine (OR: 2.07, 95% CI: [1.22-3.52]) and being an operating theatre nurse (OR: 2.46, 95% CI: [1.47-4.12]). Being a labour ward nurse (OR: 3.52, 95% CI: [1.26-9.85]) was the only factor associated with increased reporting of respiratory symptoms. CONCLUSIONS: Continuing use of PLGs in Thai nurses is associated with increased prevalence of dermal symptoms compared with data from developed countries. Measures to reduce such health effects are well established and should be considered. Additionally, replacement of chlorhexidine with an alternative detergent seems advisable.

Prevalence and risk factors for latex glove allergy among female clinical nurses: a multicenter questionnaire study in China.

BACKGROUND: Natural rubber latex glove use is widespread in mainland China, but the prevalence and risk factors for latex glove allergy among clinical nurses have previously been unreported. METHODS: A questionnaire was used to collect information on latex glove-related allergy among clinical nursing staff in 35 hospitals of eight provinces in the southern, central southern, and northern regions of China, and the risk factors were calculated with logistic regression analysis. Some subjects with glove dermatitis were patch tested with a modified European standard series of allergens. RESULTS: Among 8485 female nurses in eight provinces of China, overall prevalence of latex glove allergy was 8.8%. Of 743 symptomatic nurses, 573 (77.1%) and 475 (63.9%) reported symptoms suggestive of glove dermatitis and type I latex allergy, respectively. Of 69 randomly selected subjects with glove dermatitis, 18 (26.1%) had a positive patch to rubber additives. Employment seniority, positive family and personal history of allergic diseases, and longer extent of time spent in a single hospital room were associated with latex allergy, while using >5 pairs of gloves per working day may be a protective factor. CONCLUSION: Chinese nurses are at high risk for latex sensitization. Nurses who develop latex-related symptoms after exposure to latex gloves should undergo screening tests for latex allergy. Low-protein, powder-free natural rubber latex gloves, or latex-free gloves should be widely adopted in China, along with other preventive measures.

[Research into sensitization and allergies to latex: results after 10 years of the use of powder-free latex gloves]. / Sensibilisatie en allergie voor natuurrubberlatex: onderzoeksresultaten 10 jaar na introductie van een latexprotocol.

OBJECTIVE: To compare the prevalence of sensitization and allergy to natural rubber latex amongst Erasmus Medical Centre (MC) operating theatre employees before and 10 years after the introduction of powder-free latex gloves. DESIGN: Descriptive study. METHOD: Employees working permanently in the operating theatre were evaluated in 1998 (n = 163) and in 2009 (n = 178) for sensitization and allergies to natural latex by means of questionnaires, serological analyses and skin testing. The prevalence of sensitization and allergies within these 2 groups was then established and compared. RESULTS: The two groups were comparable in terms of gender, smoking habits, job classification, work-related symptoms and the number of individuals who had atopy. In 2009, the prevalence of sensitization to latex was statistically significantly lower than in 1998 (4.5 vs. 14.1%). Allergy to latex was also established a statistically significantly fewer number of times in 2009 than in 1998 (2.8 vs. 9.8%). This same trend could be observed in the subgroup that participated both years (n = 49). Individuals with an atopic constitution had a statistically significant higher risk of developing hypersensitivity to natural latex; the risk of developing an allergy to latex was also higher, but not significantly. CONCLUSION: After the study in 1998, the introduction of sterile, powder-free latex gloves very likely led to a decline in the prevalence of sensitization and allergy to natural latex in 2009.

Occupational contact allergy caused by rubber gloves--nothing has changed.

BACKGROUND: Allergic contact dermatitis caused by rubber gloves is not infrequent, and has almost exclusively been attributed to contact sensitization to accelerators. Thiurams have been the most frequent allergens, followed by dithiocarbamates. OBJECTIVES: To describe the current allergen pattern in patients with occupational allergic contact dermatitis caused by rubber gloves. METHODS: This study was a retrospective analysis of data from the Information Network of Departments of Dermatology (IVDK), 2002-2010. RESULTS: Of 93 615 patients patch tested in the IVDK, 3448 both suffered from occupational dermatitis and were tested because of suspected glove allergy. Among these, healthcare workers were the largest group (n = 1058). Of all occupational dermatitis patients, 13% were sensitized to thiurams, 3.5% to dithiocarbamates, 3% to mercaptobenzothiazole and/or its derivatives, and 0.4% to thioureas. Positive test reactions to 1,3-diphenylguanidine were seen in 3.0%. Reaction frequencies varied with the years, but showed no uniform time trend. CONCLUSIONS: As compared with a former IVDK data analysis (1995-2001), there was no change in sensitization pattern and no decline in sensitization frequencies. This is in line with data from the literature. Particularly in healthcare, there is a need for (i) allergen declaration on the glove package, and (ii) gloves with reduced accelerator content.

Reação anafilática induzida por látex em paciente submetido à apendicectomia aberta: relato de caso / Latex-induced anaphylactic reaction in a patient undergoing open appendectomy: case report / Reacción anafiláctica inducida por el látex en paciente sometido a la apendicectomía abierta: relato de caso

JUSTIFICATIVA E OBJETIVOS: Embora crescente a incidência de alergia ao látex na população em geral, eventos graves de anafilaxia durante alguns procedimentos cirúrgicos felizmente ainda são raros, porém com morbidade e mortalidade elevados. Não apenas a prevenção, mas o diagnóstico, o pronto tratamento e o acompanhamento dos pacientes acometidos por esse evento representam um desafio para o anestesiologista. O presente relato teve por objetivo descrever um caso de anafilaxia grave ao látex e discutir seu diagnóstico e tratamento. RELATO DO CASO: Paciente do sexo feminino, 39 anos, branca com suspeita diagnóstica de apendicite, é levada para procedimento de urgência sob raquianestesia. Aproximadamente 30 minutos após o início da cirurgia, apresentou quadro de anafilaxia com parada cardiorrespiratória, revertida após tratamento. Um dos cuidados foi o isolamento de eventuais agentes causais, sendo que, posteriormente, a paciente foi encaminhada para unidade de terapia intensiva e evoluiu sem sequelas. A dosagem de IgE-RAST (Radioallergosorbent Test) específico para o látex mostrou-se positiva. A paciente foi encaminhada para acompanhamento com o alergologista. CONCLUSÕES: O anestesiologista deve concentrar esforços na anamnese, mesmo em procedimentos de urgência, estando consciente das limitações que se apresentam nessas ocasiões. O prognóstico de anafilaxia depende do pronto início do tratamento adequado e o diagnóstico não se limita ao momento do evento, mas sim à determinação do fator causal. Criar um meio de acompanhar esses pacientes, a exemplo de outros centros internacionais, parece ser o caminho a ser seguido.

BACKGROUND AND OBJECTIVE: Despite the increase of latex allergy in general population, severe anaphylactic events during some surgical procedures are still rare; however, they are associated with increased morbidity and mortality. Prevention, diagnosis, treatment, and follow-up of patients affected by this event represent a challenge for anesthesiologists. The objective of this report was to describe a case of severe latex-induced anaphylactic reaction and discuss its diagnosis and treatment. CASE REPORT: This is a 39-year-old Caucasian female patient, with a diagnostic suspicion of appendicitis, who underwent an emergency surgery under spinal anesthesia. Approximately 30 minutes after beginning the surgery, the patient developed an anaphylactic reaction with cardiorespiratory arrest, which was reversed after treatment. Possible causative agents were isolated and, posteriorly, the patient was transferred to the intensive care unit, evolving without sequelae. Latex-specific IgE-RAST (Radioallergosorbent Test) was positive. The patient was referred to an allergist for follow-up. CONCLUSIONS: Anesthesiologists should focus on patient's history, even in urgent procedures, being aware of the limitations arising on these situations. The prognosis of anaphylaxis depends on prompt initiation of adequate treatment; diagnosis is not limited to the event occasion, but to the determination of the causative factor. Creating the means of following-up these patients, similar to other international centers, seems to be the example to be followed.

JUSTIFICATIVA Y OBJETIVOS: Aunque exista un aumento en la incidencia de alergia al látex en la población en general, los eventos graves de anafilaxia durante algunos procedimientos quirúrgicos por suerte todavía son raros, aunque con un nivel de morbilidad y mortalidad elevados. La prevención, el diagnóstico, el rápido tratamiento y el seguimiento de los pacientes afectados por ese evento, representan un reto para el anestesiólogo. El presente relato intentó describir un caso de anafilaxia grave al látex y discutir su diagnóstico y tratamiento. RELATO DEL CASO: Paciente del sexo femenino, 39 anos, blanca y con sospecha diagnóstica de apendicitis, que fue derivada a quirófano para un procedimiento urgente bajo raquianestesia. Aproximadamente 30 minutos después del inicio de la cirugía, presentó un cuadro de anafilaxia con parada cardiorrespiratoria, revertida posteriormente al tratamiento. Uno de los cuidados tomados fue el aislamiento de eventuales agentes causales, siendo que, posteriormente, la paciente fue derivada a la Unidad de Cuidados Intensivos y evolucionó sin secuelas. La dosificación de IgE-RAST (Radioallergosorbent Test), específico para el látex fue positiva. La paciente fue derivada para seguimiento con el alergista. CONCLUSIONES: El anestesiólogo debe concentrar sus esfuerzos en la anamnesis, aunque en los procedimientos de urgencia, sea consciente de las limitaciones que se presentan en esas ocasiones. El pronóstico de anafilaxia depende del rápido inicio del tratamiento adecuado, y el diagnóstico no se restringe al momento del evento, sino a la determinación del factor causal. Crear un medio de seguimiento para esos pacientes, como lo hacen otros centros internacionales, parece ser el camino que debe ser secundado.

[Latex-induced anaphylactic reaction in a patient undergoing open appendectomy. Case report]. / Reacción anafiláctica inducida por el látex en pacientesometido a la apendicectomía abierta. relato de caso.

BACKGROUND AND OBJECTIVE: Despite the increase of latex allergy in general population, severe anaphylactic events during some surgical procedures are still rare; however, they are associated with increased morbidity and mortality. Prevention, diagnosis, treatment, and follow-up of patients affected by this event represent a challenge for anesthesiologists. The objective of this report was to describe a case of severe latex induced anaphylactic reaction and discuss its diagnosis and treatment. CASE REPORT: This is a 39-year-old Caucasian female patient, with a diagnostic suspicion of appendicitis, who underwent an emergency surgery under spinal anesthesia. Approximately 30 minutes after beginning the surgery, the patient developed an anaphylactic reaction with cardiorespiratory arrest, which was reversed after treatment. Possible causative agents were isolated and, posteriorly, the patient was transferred to the intensive care unit, evolving without sequelae. Latex-specific IgE-RAST (Radioallergosorbent Test) was positive. The patient was referred to an allergist for follow-up. CONCLUSIONS: Anesthesiologists should focus on patient's history, even in urgent procedures, being aware of the limitations arising on these situations. The prognosis of anaphylaxis depends on prompt initiation of adequate treatment; diagnosis is not limited to the event occasion, but to the determination of the causative factor. Creating the means of following-up these patients, similar to other international centers, seems to be the example to be followed.

Clinical significance of cross-reactivity between tobacco and latex

Background: Allergen cross-reactivity between tobacco and other species of Solanaceae family (tomato, potato, aubergine and eggplant) have been reported. We have recently studied IgE response to tobacco in asthmatic patients sensitised to Lolium perenne (Perennial rye grass pollen) and have found that 30% of the tobacco responsive patients also have latex sensitisation. Objective: The aim of our study was to investigate the possibility of cross-reactivity between tobacco and latex in asthmatic patients with IgE response to latex. Methods: A study was performed on tobacco and latex exposure in 15 patients who suffered from asthma and latex sensitisation and who were randomly chosen from our database of latex-sensitive patients. To identify tobacco and latex as possible allergens that might cause clinical specific responses, all these patients were tested with prick-tests, specific IgE to tobacco, latex and related allergens, bronchial challenge, and patch tests with tobacco, latex and nicotine. Immunological response was evaluated with immunoblotting, immunoblotting-inhibition and EAST-inhibition tests. Results: Positive prick and bronchial challenge with specific IgE>0.35kU/L to tobacco was demonstrated in 11 asthmatics who were also sensitised to rye grass. Tobacco IgE level was related with sensitisation to latex (p<0.002), but not to other vegetables belonging to the Solanaceae family. EAST-inhibition and immunoblotting-inhibition showed the existence of cross-reactivity between tobacco and latex. Conclusions: Cross-reactivity exists between latex and tobacco allergens. Smoker patients with IgE response to tobacco may be a risk population for latex sensitisation

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Anaphylactic reaction to phuk-waan-ban in a patient with latex allergy.

Phuk-waan-ban, Euphorbiaceae Sauropus androgynus (Linn) Merr, belongs to the family Euphorbiaceae, which is the same as the rubber tree, Euphorbiaceae Hevea brasiliensis. The young leaves are edible. To the best of the authors knowledge, this is the first report of anaphylactic reaction to Phuk-waan-ban in latex allergic patients. Contact urticaria and anaphylactic reactions to latex-containing rubber products are being recognized with increasing frequency in all kinds of medical disciplines. The prevalence and incidence are both increasing. Recently, a number of reports have been published describing anaphylactic reactions to food items in patients with latex allergy. The authors present a patient with occupational natural rubber allergy who developed an anaphylactic reaction with urticarial rash 20-30 minutes after ingestion of phuk-waan-ban. The diagnostic work up showed specific IgE to latex (CAP class 3). Positive skin prick tests to latex and cooked and raw phuk-waan-ban crude extract confirmed allergic reactions. Moreover, the cross-reaction between phuk-waan-ban and latex can be confirmed by using IgE inhibition test.

Clinical patterns of hand and foot dermatitis: emphasis on rubber and chromate allergens.

The anatomic distribution of dermatitis affecting the hands and feet can provide clues to the likelihood that a contact allergen is provoking the dermatitis. Dermatitis presenting on the hands or feet, but not both, is more likely because of allergic contact dermatitis, whereas dermatitis affecting both the hands and feet is more likely a result of a systemic cause. Exceptions are reviewed in this article. When allergic contact dermatitis affects only the hands and feet, rubber chemicals and chromates are the most common allergens. Pattern recognition can assist with choice of patch test allergens, counseling regarding routes of exposure, and selection of alternative contactants.

Cross-reactions between xanthates and rubber additives.

BACKGROUND: We previously described allergic contact dermatitis from xanthates used in the recovery of metals from mining ores. We observed cross-reactions with carbamates, believed to be due to the common "dithio" nucleus shared by both groups. OBJECTIVE: The present study was undertaken to establish the rate of cross-reactions between xanthates and rubber additives. METHODS: Between November 2002 and December 2005, 1,220 consecutive patients were patch-tested with sodium isopropyl xanthate 10% in petrolatum (pet) and with potassium amyl xanthate 10% pet and later 5% pet, in addition to the North American Contact Dermatitis Group standard series and other series as required by their conditions. RESULTS: Fifty-one patients reacted to xanthates, carbamates, or thiurams; 26 reacted to xanthates only, and these reactions were felt to be irritant. Twenty-five patients reacted to xanthates and/or to one or more of the rubber additives, 12 had positive reactions to xanthates and to either carba mix or thiuram mix, 10 reacted to xanthates and carba mix, 9 reacted to xanthates and thiuram mix, and 8 showed positive reactions to xanthates and both mixes. However, 13 patients had positive reactions to carba mix and thiuram mix but did not react to xanthates. Six patients reacted to other rubber additives such as mercaptobenzothiazole, black rubber mix, and mixed dialkyl thioureas. Five of these patients also reacted to xanthates, 4 reacted to xanthates and carba mix, and 3 reacted to xanthates, carba mix, and thiuram mix. CONCLUSIONS: Of patients sensitized to carbamates, thiurams, or mercaptobenzothiazole, 50% exhibit cross-reactions with xanthates. Xanthates are irritants, and their patch-test concentrations should be lowered to 5% or less.