Chloroatranol, an extremely potent allergen hidden in perfumes: a dose-response elicitation study

Oak moss absolute is a long-known, popular natural extract widely used in perfumes. It is reported as the cause of allergic reactions in a significant number of those with perfume allergy. Oak moss absolute has been the target of recent research to identify its allergenic components. Recently, chloroatranol, a hitherto unknown fragrance allergen, was identified in oak moss absolute. The objective was to assess the clinical importance of chloroatranol as a fragrance allergen by characterizing its elicitation profile. 13 patients previously showing a positive patch test to oak moss absolute and chloroatranol were included, together with a control group of 10 patients without sensitization to either of the 2 materials. A serial dilution patch test was performed on the upper back with concentrations ranging from 200 to 0.0063 p.p.m. of chloroatranol in ethanol. Simultaneously, the participant performed an open test simulating the use of perfumes on the volar aspect of the forearms in a randomized and double-blinded design. A solution with 5 p.p.m. chloroatranol was used for 14 days, and, in case of no reaction, the applications were continued for another 14 days with a solution containing 25 p.p.m. All test subjects (13/13) developed an allergic reaction at the site of application of the solution containing chloroatranol. Among them, 12/13 (92%) gave a positive reaction to the 5 p.p.m. solution and 1 to 25 p.p.m. None of the controls reacted (P < 0.001). The use test was terminated at median day 4. The dose eliciting a reaction in 50% of the test subjects at patch testing was 0.2 p.p.m. In conclusion, the hidden exposure to a potent allergen widely used in perfumes has caused a highly sensitized cohort of individuals. Judged from the elicitation profile, chloroatranol is the most potent allergen present in consumer products today.     

Experimental systemic contact dermatitis from nickel: a dose-response study

Systemic contact dermatitis is usually seen as flare-up of previous dermatitis or de novo dermatitis similar to allergic contact dermatitis. Although systemic contact dermatitis from medicaments is a well-established entity, the existence of clinically relevant systemic reactions to oral nickel exposure, in particular systemic reactions to nickel in the daily diet, remains controversial. Several studies have shown that oral exposure to nickel can induce systemic contact dermatitis in nickel-sensitive individuals. In most of these studies, however, the exposure dose of nickel used has been considerably higher than the nickel content in the normal daily diet. The aim of the current investigation was to study dose-response dependency of oral exposure to nickel. In a double-blind, placebo-controlled oral exposure trial, 40 nickel-sensitive persons and 20 healthy (non-nickel-sensitive) controls were given nickel sulfate hexahydrate in doses similar to and greater than the amount of nickel ingested in the normal Danish daily diet. The nickel content in urine and serum before and after oral exposure was measured to determine nickel uptake and excretion. The influence of the amount of nickel ingested on the clinical reactions to oral exposure and on nickel concentrations in serum and urine was evaluated. Among nickel-sensitive individuals, a definite dose-response dependency was seen, following oral exposure to nickel. 7 of 10 nickel-sensitive individuals had cutaneous reactions to oral exposure to 4.0 mg nickel, an amount approximately 10 times greater than the estimated normal daily dietary intake of nickel. 4 of 10 nickel-sensitive individuals had cutaneous reactions to 1.0 mg nickel, a dose which is close to the estimated maximum amount of nickel contained in the daily diet. 4 of 10 nickel-sensitive individuals reacted to 0.3 mg nickel or to the amount equivalent to that contained in a normal daily diet, and 1 of 10 reacted to a placebo. None of the 20 healthy controls had cutaneous reactions to 4.0 mg nickel or to a placebo. Prior to oral exposure, there was no measurable difference in the amount of nickel in the urine or serum of nickel-sensitive persons and healthy controls. Following the oral challenge, the nickel content in the urine and serum of both nickel-sensitive and healthy control individuals was directly related to the dose of nickel ingested.     

Content of oak moss allergens atranol and chloroatranol in perfumes and similar products

Chloroatranol and atranol have been identified as the main allergens in the fragrance material of botanical origin, oak moss absolute. A previous study has shown that nearly all individuals sensitized to chloroatranol will elicit to 5 microg/ml. in a repeated open application test and that 50% will get a reaction to 0.15 micro g/ml under patch test conditions. Thus, chloroatranol is known as a potent allergen. The aim of the current investigation was to quantify exposure to chloroatranol and the chemically related substance atranol in some popular perfumes, eaux de parfum and eaux de toilette available on the European market. In total, 31 products were analysed by liquid chromatography-electrospray ionization-tandemmass spectrometry (LC-ESI-MS-MS) for their contents of atranol and chloroatranol. The 2 substances were found in 87% (n = 27) of the products. The median concentration of atranol in perfumes was 0.502 micro g/ml and 0.012 micro g/ml in eaux de toilette, and 0.235 micro g/ml and 0.006 micro g/ml for chloroatranol, respectively, in perfumes and eaux de toilette. Chloroatranol was found at a maximum concentration of 53 micro g/ml and atranol at one of 190 micro g/ml. The wide exposure to oak moss allergens, together with significant amounts of these potent allergens in at least half of perfumes and some eaux de toilettes explains the high frequencies of oak moss absolute allergy. It is suggested that regulations should be introduced aimed directly at these substances, and not just at oak moss absolute.     

Characterization of lymphocyte subpopulations and cytokine profiles in peripheral blood of nickel-sensitive individuals with systemic contact dermatitis after oral nickel exposure

Several studies have shown that oral nickel exposure can elicit systemic contact dermatitis (SCD) in nickel-sensitive individuals. The current study describes some of the immunological mechanisms underlying such nickel-allergic reactions elicited by oral exposure to nickel. Following oral exposure to graded concentrations of nickel or placebo, blood samples were taken from nickel-sensitive individuals and from non-nickel-sensitive controls. T-cell subtypes (CD3+, CD4+, CD8+ and CD45RO+), expression of skin-homing receptor, cutaneous lymphocyte-associated antigen (CLA) and cytokine profiles [interleukin (IL)-2, IL-4, IL-5, IL-6, IL-10, interferon-gamma and tumour necrosis factor-alpha] were investigated. A definite dose-response reaction pattern to oral nickel exposure was observed among nickel-sensitive individuals. Nickel-sensitive individuals whose dermatitis flared after oral challenge with nickel showed significant decreases in fractions of CD3+ CD45RO+ CLA+ and CD8+ CD45RO+ CLA+ blood lymphocytes, suggesting migration of CD8+ 'memory' CLA+ T lymphocytes from the blood to peripheral tissues. Only those nickel-sensitive individuals who clinically reacted to oral challenge with nickel (4 mg) had elevated levels of IL-5 in the serum, indicating an activation of type 2 T lymphocytes in the peripheral blood. In conclusion, the study indicates that CD8+ CD45RO+ CLA+ T lymphocytes and T lymphocytes with a type 2 cytokine profile are involved in SCD elicited by nickel.     

Heritability of hand eczema is not explained by comorbidity with atopic dermatitis

Genetic factors have been shown to influence the risk of hand eczema, and may theoretically influence the frequency of eruptions as well as age at onset of the disease. However, the result may be confounded by atopic dermatitis, which is a major risk factor for development of hand eczema and is known to be influenced by genetic factors. In this study, the importance of genetic and environmental risk factors in the etiology of hand eczema, independent of atopic dermatitis, was investigated in a population-based twin cohort. In addition, any possible genetic influence on frequency of hand eczema eruptions and age at onset was explored. In all, 4,128 twin individuals (response rate 82%) answered a questionnaire on self-reported hand eczema. Similarity within twin pairs was estimated and quantitative genetic modelling performed. Controlling for age and atopic dermatitis, the effect of genetic risk factors was moderate and explained 41% of the variance in liability to develop hand eczema, leaving 59% of the variance to be caused by environmental factors. Genetic factors accounted for 31% of the variance in liability regarding frequency of eruptions. Environmental factors explained the variance in liability concerning age at onset.     

Retesting with the TRUE Test in a population-based twin cohort with hand eczema - allergies and persistence in an 8-year follow-up study

Population-based studies on contact allergy with retesting of individuals are infrequently performed. Variable degrees of persistence are reported when individuals with contact allergy are retested with years in between. The patch test results of 270 individuals tested in 2005-2006 are presented and the pattern and frequency of sensitization discussed. Persistence when compared with patch test results from 1997-1998 is reported. 270 twin individuals with and without hand eczema underwent patch testing with the TRUE Test((R)) (Mekos Laboratories AS, Hilleroed, Denmark) in 1997-1998 and again in 2005-2006 as part of a larger study. In 2005-2006, a total of 74 (27.4%) of the 270 individuals had at least 1 positive patch test and 20 (7.4%) of the 270 had 2. The frequency in men and women was 9/90 (10%) and 65/180 (36.1%), respectively. The frequency of contact allergy in individuals with and without hand eczema was 59/185 (31.3%) and 15/85 (17.6%), respectively. The most prevalent contact allergies were to nickel, thiomersal, and fragrance mix I. All together, 74% of the positive reactions were reproduced. The frequency of contact allergy in this population-based cohort with hand eczema was comparable with previous reports. Persistence of contact allergy after many years was confirmed.     

Severe allergic hair dye reactions in 8 children

Serious adverse skin reactions to permanent hair dyes and temporary black tattoos have been reported. As temporary tattoos have become fashionable among adolescents, the risk profile for p-phenylenediamine (PPD) sensitization of the population has changed simultaneously with an increasing use of hair dyes in this age group. This investigation reports PPD sensitization in children with regard to cause of sensitization, clinical presentation and consequences. Clinical history and patch test results for consecutive children below 16 years of age with suspected hair dye allergic reactions and positive patch tests to PPD were collected over 2 years in 2 Danish dermatology clinics. 8 children aged 12-15 years were collected, and they all reacted to several hair dye ingredients. 5 of the patients were hospitalized, 1 in the intensive care unit. 6 of the patients gave a history of prior reaction to temporary black tattoos. These children showed simultaneous positive patch reactions to N-isopropyl-N-phenyl-p-phenylenediamine and local anaesthetics, while such reaction patterns were not seen in children with hair dye reactions only. The clinical consequences of these reactions are unknown. A re-evaluation of the risk assessment/risk management for hair dyes is required.     

Cross-reactivity between thiurams

Retesting with an allergen at a site with previous allergic contact dermatitis has been shown to enhance reactivity. It has been suggested that retesting with a cross-reactive allergen will also induce hyperreactivity. Concurrent sensitization to more than 1 thiuram is common, but whether this is due to concomitant primary sensitization or cross-reactivity is uncertain. The aim of this study was to investigate the use of retesting to distinguish between concomitant sensitization and cross-reactivity in the rubber chemicals tetraethylthiuram disulphide (TETD) and tetramethylthiuram disulphide (TMTD). There was a non-significant trend towards enhanced reactivity for both TETD and TMTD when testing in an area with previous allergic contact dermatitis due to TETD. Cross-reactivity between the 2 chemicals is likely, but a definite conclusion from this pilot study is not possible.