Patch testing with aluminium Finn Chambers could give false-positive reactions in patients with contact allergy to aluminium.

BACKGROUND: Earlier laboratory studies have shown that sodium tetrachloropalladate, Myroxylon pereirae, caine mix II, and palladium chloride trigger the release of aluminium (Al) from Finn Chambers (FC). OBJECTIVES: To investigate whether aluminium realease from FC could influence the diagnostic outcome of patch testing with FC. METHOD: A retrospective analysis of patch test results from 2010 to 2019 was performed. A two-sided Fisher's exact test was used to calculate any overrepresentation of contact allergy to Al among patients with positive reactions to sodium tetrachloropalladate, Myroxylon pereirae, caine mix II, and palladium chloride. RESULTS: A total of 5446 patients had been tested with FC during the study period. There was a significant overrepresentation of contact allergy to Al among patients with positive reactions to sodium tetrachloropalladate, Myroxylon pereirae, caine mix II, and palladium chloride. Patients with a strong Al allergy had significantly higher amounts of concomitant reactions to sodium tetrachloropalladate, Myroxylon pereirae, caine mix II, and palladium chloride compared to patients with weak Al allergy. These results were not seen for patients tested with Finn Chambers AQUA. CONCLUSION: In patients with contact allergy to Al, patch testing with Finn chambers could give false-positive reactions to sodium tetrachloropalladate, Myroxylon pereirae, caine mix II, and palladium chloride.

Patch testing with purified and oxidized citronellol.

BACKGROUND: Citronellol is a commonly used fragrance terpene included in fragrance mix II. As with many other fragrance terpenes, citronellol is susceptible to autoxidation. Citronellol hydroperoxides are formed in large amounts and are the only oxidation products identified as sensitizers in oxidized citronellol. AIM: To compare frequencies of contact allergy to purified and oxidized citronellol and to investigate the pattern of concomitant reactions to fragrance markers of the baseline series, oxidized linalool, and oxidized limonene. METHODS: A total of 658 dermatitis patients were patch tested with purified and oxidized citronellol at 2.0%, 4.0%, 6.0%, and 1.0%, 2.0%, 4.0%, 6.0% petrolatum, respectively. The irritant properties of purified and oxidized citronellol were studied before patch testing. RESULTS: Few irritant reactions were observed in the pretest. Purified citronellol detected positive reactions in 0.15%-0.31% of patients, while oxidized citronellol detected positive reactions in 0.61%-4.5%. Among patients reacting to oxidized citronellol, 34%-50% showed concomitant reactions to fragrance markers of the baseline series and 75%-91% to oxidized linalool or oxidized limonene. CONCLUSION: Oxidized citronellol detects more cases of contact allergy than purified citronellol, and these cases are not all detected using fragrance mix II. Patch testing with oxidized citronellol will add to the tools in the diagnosis of fragrance allergy.

Fragrance inhalation and adverse health effects: The question of causation.

The toxicology of fragrance materials is largely well understood. Although most are benign, a minority have the potential to cause adverse health effects, notably allergic contact dermatitis resulting from skin sensitization. As a consequence, industry guidelines have banned certain materials and strictly limited the use of others. Recently, data have been published that have been interpreted to suggest that inhalation of fragrances is associated with the occurrence of a variety of health effects, ranging from headaches to asthma attacks. In this review, the evidence basis for these assertions is examined critically and the biological basis and mechanistic plausibility for causation by fragranced products of these health effects is explored. This review concludes that respiratory effects, including irritation and allergy appear highly unlikely to occur by this route. While some sensory/psychosomatic effects are possible, this does not explain the very high rates of adverse effects reported in the recently published questionnaire studies, which this review concludes are more likely to be attributed to methodological weaknesses. Ultimately, it is concluded that adverse health effects arising from fragrance inhalation are uncommon and remain to be identified and confirmed by methodologically rigorous epidemiological investigations supported by a convincing biological and mechanistic basis.

Allergic contact dermatitis caused by hydroperoxides of limonene and dose-response relationship-A repeated open application test (ROAT) study.

BACKGROUND: Contact allergy to oxidized limonene, with hydroperoxides of limonene (Lim-OOHs) as the main allergens, is common. However, high proportions of weak positive and doubtful patch test reactions have been reported. OBJECTIVES: To determine the clinical relevance, elicitation threshold and dose-response relationship of Lim-OOHs in individuals with a positive or doubtful patch test reaction to standard Lim-OOHs 0.3% pet. METHODS: A multicentre 3-week double-blind vehicle-controlled repeated open application test (ROAT) study with a simulated fine fragrance containing Lim-OOHs at 1260, 420 and 140 ppm, equal to a dose/area per application of Lim-OOHs of 3.0, 0.99 and 0.33 µg/cm2 , was performed. RESULTS: Among 11 subjects allergic to Lim-OOHs, 11 (100%), 7 (64%), and 3 (27%), respectively, reacted to the applied doses. No reactions were seen in 17 healthy controls exposed to the highest dose. This difference in reactivity was statistically significant (P < 0.0001). Among 13 subjects with doubtful patch test reactions to Lim-OOHs, two (15%) had positive ROAT reactions to the highest Lim-OOH dose applied (P = 0.36 as compared with controls). CONCLUSIONS: Contact allergy to Lim-OOHs is of clinical relevance in patients with positive patch test reactions. A doubtful patch test reaction to Lim-OOHs 0.3% pet. can be of clinical relevance.

Fragrance allergens in household detergents.

Consumers are confronted with a large number of fragrance allergens from various sources. Until now, the discussion of exposure sources has mainly addressed cosmetic products and neglected other scented products in households. For the first time, fragrance allergens were evaluated in a complete set of detergents in households. In 131 households, we investigated the prevalence of detergents and searched their lists of ingredients for 26 fragrance allergens liable to be indicated on products according to the European Detergents Regulations. On the ingredient lists of 1447 products, these 26 fragrance substances were named almost 2000 times, most often limonene, linalool and hexyl cinnamal. Benzyl salicylate was used frequently in all-purpose cleaners. Linalool and limonene, hexyl cinnamal and butylphenyl methylpropional and citronellol and linalool co-occurred most often together in products. Fragrance allergens co-occurring together most frequently within households were eugenol, coumarin and cinnamyl alcohol. The study shows that detergents could play a relevant role for the exposure of consumers towards fragrance allergens and that they should not be underestimated as an exposure source during the exposure assessment.

Can the epoxides of cinnamyl alcohol and cinnamal show new cases of contact allergy?

BACKGROUND: Cinnamyl alcohol is considered to be a prohapten and prehapten with cinnamal as the main metabolite. However, many individuals who are allergic to cinnamyl alcohol do not react to cinnamal. Sensitizing epoxides of cinnamyl alcohol and cinnamal have been identified as metabolites and autoxidation products of cinnamyl alcohol. OBJECTIVE: To investigate the clinical relevance of contact allergy to epoxycinnamyl alcohol and epoxycinnamal. METHODS: Irritative effects of the epoxides were investigated in 12 dermatitis patients. Epoxycinnamyl alcohol and epoxycinnamal were patch tested in 393 and 390 consecutive patients, respectively. In parallel, cinnamyl alcohol and cinnamal were patch tested in 607 and 616 patients, respectively. RESULTS: Both epoxides were irritants, but no more positive reactions were detected than when testing was performed with cinnamyl alcohol and cinnamal. Late allergic reactions to epoxycinnamyl alcohol were observed. In general, patients with late reactions showed doubtful or positive reactions to cinnamal and fragrance mix I at regular patch testing. CONCLUSION: The investigated epoxides are not important haptens in contact allergy to cinnamon fragrance. The high frequency of fragrance allergy among patients included in the irritancy study showed the difficulty of suspecting fragrance allergy on the basis of history; patch testing broadly with fragrance compounds is therefore important.

Qualitative and quantitative composition of essential oils: A literature-based database on contact allergens used for safety assessment.

The risks related to the use of essential oils are difficult to ascertain at present, due in part to the large number of different oils available on the market, making it difficult for the risk assessor. Essential oils may contain skin allergens in significant amounts, and could thus pose a risk to the consumer. The aim of our study was to collect as much qualitative and quantitative data as possible on allergens present in essential oils. 11 types of essential oils, with 25 respective subspecies, were taken into account based on a previous survey. Based on the literature, 517 dosages were recorded from 112 publications, providing precious information for probabilistic exposure assessment purposes. 22 substances recognized as established allergens were found in the essential oils we included. Of these, 11 are also found in cosmetics as fragrance components. These results are of major importance regarding co-exposure to fragrance allergens. Moreover, this could lead to regulatory measures for essential oils in the future, as it is the case for cosmetic products, in order to better protect consumers against skin allergy.

Usage patterns of aromatherapy among the French general population: A descriptive study focusing on dermal exposure.

Although likely benefits of aromatherapy are well documented, little is known about essential oils consumption and exposure to molecules present in the oils. The aim of our study was to determine usage patterns of 12 types of essential oils among a quite large panel, sorted per sex and quintile of age from birth to 70. A survey was conducted in September 2014 among 1507 French individuals, selected to build a representative panel of the general population. The key point of our study, apart from the fact that it has never been done among general population, was the focus on dermal exposure. Information about types of essential oils used, skin areas exposed, frequencies and quantities were collected. Our work revealed that some sub-populations could be significantly exposed to molecules of toxicological concern, especially in terms of skin sensitization. This work is the first step to assess human exposure to these molecules, and will help safety authorities and risk managers to protect the population.

Correlation between experimental human and murine skin sensitization induction thresholds.

Quantitative risk assessment for skin sensitization is directed towards the determination of levels of exposure to known sensitizing substances that will avoid the induction of contact allergy in humans. A key component of this work is the predictive identification of relative skin sensitizing potency, achieved normally by the measurement of the threshold (the "EC3" value) in the local lymph node assay (LLNA). In an extended series of studies, the accuracy of this murine induction threshold as the predictor of the absence of a sensitizing effect has been verified by conduct of a human repeated insult patch test (HRIPT). Murine and human thresholds for a diverse set of 57 fragrance chemicals spanning approximately four orders of magnitude variation in potency have been compared. The results confirm that there is a useful correlation, with the LLNA EC3 value helping particularly to identify stronger sensitizers. Good correlation (with half an order of magnitude) was seen with three-quarters of the dataset. The analysis also helps to identify potential outlier types of (fragrance) chemistry, exemplified by hexyl and benzyl salicylates (an over-prediction) and trans-2-hexenal (an under-prediction).

Controlled release of encapsulated bioactive volatiles by rupture of the capsule wall through the light-induced generation of a gas.

The encapsulation of photolabile 2-oxoacetates in core-shell microcapsules allows the light-induced, controlled release of bioactive compounds. On irradiation with UVA light these compounds degrade to generate an overpressure of gas inside the capsules, which expands or breaks the capsule wall. Headspace measurements confirmed the light-induced formation of CO and CO2 and the successful release of the bioactive compound, while optical microscopy demonstrated the formation of gas bubbles, the cleavage of the capsule wall, and the leakage of the oil phase out of the capsule. The efficiency of the delivery system depends on the structure of the 2-oxoacetate, the quantity used with respect to the thickness of the capsule wall, and the intensity of the irradiating UVA light.

Fragrance patch tests prepared in advance may give false-negative reactions.

BACKGROUND: Several of the ingredients in fragrance mix I (FM I) have been shown to evaporate from petrolatum preparations applied in test chambers to an extent that can be suspected to affect the patch test result. OBJECTIVES: To compare the reactivity towards FM I and fragrance mix II (FM II) when they are applied in test chambers in advance and immediately prior to the patch test occasion. METHODS: Seven hundred and ninety-five consecutive patients were simultaneously patch tested with duplicate samples of FM I and FM II. One sample was applied in the test chamber 6 days in advance (6D sample), and the other sample was applied immediately before the patients were patch tested (fresh sample). RESULTS: Twenty-two (2.8%) patients reacted exclusively to the fresh sample of FM I, 6 (0.7%) reacted exclusively to the 6D sample, and 22 (2.8%) reacted to both samples. The corresponding numbers for FM II were 9 (1.1%) for the fresh sample, 6 (0.7%) for the 6D sample and 12 (1.5%) for both samples. CONCLUSIONS: There was a statistically significant difference between the numbers of patients reacting to the fresh and 6D samples of FM I. No corresponding difference was observed for FM II. This can probably be explained by differences in volatilities between the ingredients of FM I and FM II.

Adhesion of perfume-filled microcapsules to model fabric surfaces.

The retention and adhesion of melamine formaldehyde (MF) microcapsules on a model fabric surface in aqueous solution were investigated using a customised flow chamber technique and atomic force microscopy (AFM). A cellulose film was employed as a model fabric surface. Modification of the cellulose with chitosan was found to increase the retention and adhesion of microcapsules on the model fabric surface. The AFM force-displacement data reveal that bridging forces resulting from the extension of cellulose chains dominate the adhesion between the microcapsule and the unmodified cellulose film, whereas electrostatic attraction helps the microcapsules adhere to the chitosan-modified cellulose film. The correlation between results obtained using these two complementary techniques suggests that the flow chamber device can be potentially used for rapid screening of the effect of chemical modification on the adhesion of microparticles to surfaces, reducing the time required to achieve an optimal formulation.

Disposition and excretion of 14C-AHTN (7-acetyl-1,1,3,4,4,6-hexamethyl-1,2,3,4-tetrahydronaphthalene) and 14c-hhcb (1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethyl-cyclopenta-gamma-2-benzopyran) after intravenous administration to Sprague-Dawley rats and domestic pigs.

7-Acetyl-1,1,3,4,4,6-hexamethyl-1,2,3,4-tetrahydronaphthalene (AHTN ) and 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethylcyclopenta-gamma-2-benzopyran (HHCB) are polycyclic musks widely used as fragrance ingredients in consumer products. Because their metabolic fate following systemic exposure is not fully characterized, disposition and excretion of (14)C-AHTN- and (14)C-HHCB-derived radioactivity were studied in Sprague-Dawley rats and domestic pigs following a single intravenous dose. Rats administered with AHTN or HHCB excreted 21% or 28% of the radioactivity in urine and 67% or 61% in feces, respectively, within 7 days. In pigs administered AHTN or HHCB, 86% or 74% of the dose was excreted in the urine, and 12% or 15% in feces, respectively, during the 14-day collection period. Radioactivity in the whole blood and plasma of both species and tissues of rats declined steadily until the end of the study (28 days) for both the materials. Radioactivity in rat adipose tissue reached peak at 2 hours after dosing, decreasing steadily thereafter. Radioactivity in pig blood declined rapidly from 70 ng equivalents/g at 10 minutes to 1 ng equivalent/g or less by 28 days after administration of either AHTN or HHCB. Radioactivity in pig skin and adipose tissue decreased to below the limit of detection by 28 days for both the materials. Thin-layer chromatography showed multiple radioactive components in both species' urine after administration of either material. Components found in the urine of the 2 species were qualitatively similar but quantitatively different. Both AHTN and HHCB were completely metabolized and excreted. No unchanged parent compound was detected in rat or pig urine.

Slow breathing and emotions associated with odor-induced autobiographical memories.

An important feature of olfactory perception is its dependence on respiratory activity. By inspiration, olfactory information ascends directly to olfactory-related limbic structures. Therefore, every breath with odor molecules activates these limbic areas associated with emotional experience and memory retrieval. We tested whether odors associated with autobiographical memories can trigger pleasant emotional experiences and whether respiration changes during stimulation with these odors. During presentation of odors related to autobiographical memories and control odors, we measured minute ventilation, tidal volume, respiratory frequency, O2 consumption, and end tidal CO2 concentration. Findings showed that autobiographical memory retrieval was associated with increasing tidal volume and decreasing respiratory frequency more than during presentation of control odors. Subjective feelings such as emotional arousal during retrieval of the memory, arousal level of the memory itself, or pleasantness and familiarity toward the odor evoked by autobiographical memory were more specific emotional responses compared with those related to control odors. In addition, high trait anxiety subjects responded with a stronger feeling of being taken back in time and had high arousal levels with tidal volume increases. We discussed assumptions regarding how deep and slow breathing is related to pleasantness and comfortableness of an autobiographical memory.

Allergen fragrance molecules: a potential relief for COVID-19.

BACKGROUND: The latest coronavirus SARS-CoV-2, discovered in China and rapidly spread Worldwide. COVID-19 affected millions of people and killed hundreds of thousands worldwide. There are many ongoing studies investigating drug(s) suitable for preventing and/or treating this pandemic; however, there are no specific drugs or vaccines available to treat or prevent SARS-CoV-2 as of today. METHODS: Fifty-eight fragrance materials, which are classified as allergen fragrance molecules, were selected and used in this study. Docking simulations were carried out using four functional proteins; the Covid19 Main Protase (MPro), Receptor binding domain (RBD) of spike protein, Nucleocapsid, and host Bromodomain protein (BRD2), as target macromolecules. Three different software, AutoDock, AutoDock Vina (Vina), and Molegro Virtual Docker (MVD), running a total of four different docking protocol with optimized energy functions were used. Results were compared with the five molecules reported in the literature as potential drugs against COVID-19. Virtual screening was carried out using Vina, molecules satisfying our cut-off (- 6.5 kcal/mol) binding affinity was confirmed by MVD. Selected molecules were analyzed using the flexible docking protocol of Vina and AutoDock default settings. RESULTS: Ten out of 58 allergen fragrance molecules were selected for further docking studies. MPro and BRD2 are potential targets for the tested allergen fragrance molecules, while RBD and Nucleocapsid showed weak binding energies. According to AutoDock results, three molecules, Benzyl Cinnamate, Dihydroambrettolide, and Galaxolide, had good binding affinities to BRD2. While Dihydroambrettolide and Galaxolide showed the potential to bind to MPro, Sclareol and Vertofix had the best calculated binding affinities to this target. When the flexible docking results analyzed, all the molecules tested had better calculated binding affinities as expected. Benzyl Benzoate and Benzyl Salicylate showed good binding affinities to BRD2. In the case of MPro, Sclareol had the lowest binding affinity among all the tested allergen fragrance molecules. CONCLUSION: Allergen fragrance molecules are readily available, cost-efficient, and shown to be safe for human use. Results showed that several of these molecules had comparable binding affinities as the potential drug molecules reported in the literature to target proteins. Thus, these allergen molecules at correct doses could have significant health benefits.

Experimental inhalation of fragrance allergens in predisposed subjects: effects on skin and airways.

BACKGROUND: Exposure to fragrances is increasingly encountered in the environment. Some fragrances are known to be important skin and potential airway sensitizers. OBJECTIVES: We investigated whether patients with contact allergy to isoeugenol (ISO) or hydroxyisohexyl-3-carboxaldehyde (HICC) would react to inhalation exposure at the level of the airways and skin. METHODS: Eleven patients sensitized to ISO and 10 patients sensitized to HICC were exposed for 60 min to 1000 microg m(-3) of these compounds in an exposure chamber at rest, and to geraniol 1000 microg m(-3) as a control. Patients wore protective clothing to prevent skin exposure. Assessments were performed prior to exposure, and immediately, 2, 5, 24 and 72 h afterwards. RESULTS: There were no significant changes in lung function but a tendency towards an increased bronchial hyper-responsiveness after exposure to any of the compounds. Laboratory parameters of inflammation did not indicate responses. Single patients reported respiratory symptoms unrelated to objective measures. In contrast, the observed skin symptoms corresponded to the patients' specific sensitization. Four patients reported symptoms compatible with delayed-type hypersensitivity, and two demonstrated a flare after ISO. On re-exposure they did not respond to a lower, more realistic level of ISO. CONCLUSION: Inhalation of high concentrations of fragrance contact allergens apparently poses a risk for some patients of developing manifest haematogenic contact dermatitis, while the changes in the respiratory tract are limited to symptoms in some subjects without objective changes.

The dose-response relationship between the patch test and ROAT and the potential use for regulatory purposes.

BACKGROUND: Allergic contact dermatitis is common and can be prevented. The relationship between thresholds for patch tests and the repeated open application test (ROAT) is unclear. It would be desirable if patch test and ROAT data from already sensitized individuals could be used in prevention. OBJECTIVES: The aim was to develop an equation that could predict the response to an allergen in a ROAT based on the dose-response curve derived by patch testing. MATERIALS/METHODS: Results from two human experimental elicitation studies with non-volatile allergens, nickel and the preservative methyldibromo glutaronitrile (MDBGN), were analysed by logistic dose-response statistics. The relation for volatile compounds was investigated using the results from experiments with the fragrance chemicals hydroxyisohexyl 3-cyclohexene carboxaldehyde and isoeugenol. RESULTS: For non-volatile compounds, the outcome of a ROAT can be estimated from the patch test by: ED(xx)(ROAT) = 0.0296 ED(xx)(patch test). For volatile compounds, the equation predicts that the response in the ROAT is more severe than the patch test response, but it overestimates the response. CONCLUSIONS: This equation may be used for non-volatile compounds other than nickel and MDBGN, after further validation. The relationship between the patch test and the ROAT can be used for prevention, to set safe levels of allergen exposure based on patch test data.

Association between positive patch tests to epoxy resin and fragrance mix I ingredients.

BACKGROUND: Both epoxy resin (diglycidyl ether of bisphenol A) and fragrance mix I are included in the European baseline series of contact allergens. A significant association between positive reactions to epoxy resin and fragrance mix has been reported by others. OBJECTIVE: To investigate and possibly reproduce this association with the use of TRUE((R)) test data and supplementary tests with fragrance mix ingredients from the Department of Dermatology, Odense University Hospital. MATERIALS AND METHODS: Six thousand one hundred and fifteen consecutive eczema patients tested from 1995 to 2007 were included, and test results from all patients tested with fragrance mix ingredients were analysed. RESULTS: One hundred and forty-five (2.4%) were positive to epoxy resin and 282 (4.6%) were positive to fragrance mix I. Nineteen were positive to both giving an odds ratio of 3.3, which is significant (95% CI 2.0-5.4). Analysis of association to individual fragrance mix ingredients showed a significant association to alpha-amyl cinnamal and isoeugenol. CONCLUSIONS: The significant association between positive reactions to epoxy resin and fragrance mix I was reproduced. However, the clinical implications are not clarified, and even though the association may be coincidental, the fact that it can be reproduced with a different patch test system and in a different population speaks against a random result. Further studies may help to interpret the association.

Atopy and contact allergy to fragrance: allergic reactions to the fragrance mix I (the Larsen mix).

BACKGROUND: The relationship between an atopic diathesis and contact sensitization to fragrances is unclear. OBJECTIVE: To investigate whether there is an association between atopy and allergy to fragrance mix I (FM I). PATIENTS/METHODS: The computerized files of patients patch tested to FM I at St John's Institute of Dermatology (1980-2004) were reviewed. Demographic details recorded for all patch-tested patients included age, sex, date of testing, history of current or previous atopic eczema (AE), history of current or previous asthma nor hay fever (A/HF), family history (FH) of any type of atopy, and any positive patch tests. RESULTS: About 8.4% of females (1713/20 338) and 6.6% of males (903/13 734) were allergic to FM I. About 8.95% (101/1129) of females with AE were allergic to FM I versus 8.63% (619/7171) of females who had neither AE and A/HF nor FH (non-atopics) (P = 0.72). About 5.6% (40/710) of males with AE were positive to FM I versus 6.9% (427/6201) of male non-atopics (P = 0.23). There was a striking increase in AE and A/HF during this 25-year period (P < 0.0001). CONCLUSIONS: We found no association between atopy and allergy to FM I. There has been a marked increase in atopy in individuals referred for patch testing in the past 25 years.

Relevance of positive patch-test reactions to fragrance mix.

BACKGROUND: Fragrances are an important cause of allergic contact dermatitis. We presume that the traditional fragrance mix (FM) detects 70 to 80% of fragrance-allergic patients. FM has an irritant potential. Weak positive reactions may have a greater chance of being irrelevant than strong reactions. OBJECTIVE: To improve the appraisal of FM patch-test reactions, we studied the relevance of reactions of different strength. We also studied the predictive value of the following on the relevance of the initial FM patch-test results: patch-test results of a repeated FM test; results of patch tests with balsam of Peru, colophony, and ingredients of the mix; and (history of) atopic dermatitis. METHODS: One hundred thirty-eight patients who had doubtful positive (?+) or positive (+ to +++) reactions were included in the study. We determined relevance by history taking, location and course of the dermatitis, and additional patch testing. Patients were retested with FM and with each ingredient separately. RESULTS: The relevance of reactions to FM increases with the strength of the reactions. Predictors of relevance are the results of retesting with FM, the results of tests with the ingredients, and a history and/or present symptoms of atopic dermatitis. CONCLUSION: Retesting with FM and its ingredients may add to the benefit of patch testing.