PERFUMES: pipeline to extract RNA functional motifs and exposed structures.

MOTIVATION: Up to 75% of the human genome encodes RNAs. The function of many non-coding RNAs relies on their ability to fold into 3D structures. Specifically, nucleotides inside secondary structure loops form non-canonical base pairs that help stabilize complex local 3D structures. These RNA 3D motifs can promote specific interactions with other molecules or serve as catalytic sites. RESULTS: We introduce PERFUMES, a computational pipeline to identify 3D motifs that can be associated with observable features. Given a set of RNA sequences with associated binary experimental measurements, PERFUMES searches for RNA 3D motifs using BayesPairing2 and extracts those that are over-represented in the set of positive sequences. It also conducts a thermodynamics analysis of the structural context that can support the interpretation of the predictions. We illustrate PERFUMES' usage on the SNRPA protein binding site, for which the tool retrieved both previously known binder motifs and new ones. AVAILABILITY AND IMPLEMENTATION: PERFUMES is an open-source Python package (https://jwgitlab.cs.mcgill.ca/arnaud_chol/perfumes).

Sniffing Out the Sustainable Future: The Renewability Revolution in Fragrance Chemistry.

In this review, the impact of the transition from today's resource-wasting petrochemical economy towards a 100/100 renewable and biodegradable future is discussed with respect to the fragrance families: "citrus", "green", "fruity", "floral", "floriental", "oriental", "woody", "chypre" and "fougère". After benchmark data on ingredients usage, definitions on biodegradation and sustainability are given. Celebrating the 150th anniversary of synthetic vanillin, its historic synthesis from renewable starting materials serves as introduction. In the grand scheme of things, citrus scents upcycled from the beverages industry, are already an ideal case for 100/100 with new opportunities for artificial essential oils. In the fruity domain, transparent and lactonic ingredients are available in a sustainable manner. However, in the domain of green odorants, there is a lack of green chemistry for important key materials. In the floral family, renewability is more critical than biodegradability, but cost is an issue. Thanks to Ambrox and maltol, florientals and orientals will persist, while woody notes severely lack an Iso E Super replacer. In the chypre genre, patchouli became the new moss, but more musks are increasingly in demand. With their high percentage of linalool and dihydromyrcenol, the construction of fougères could well become a precedent for other families, despite challenges in vetiver and salicylates. Still, the challenges exemplified here create immense opportunities for new perfumery materials.

The transcriptomic signature of adaptations associated with perfume collection in orchid bees.

Secondary sexual traits can convey information on mate quality with the signal honesty maintained by the costly nature of trait expression. Mating signals are also often underpinned by physiological, morphological, and behavioural adaptations, which may require the evolution of novelty, but the genetic basis in many cases is unknown. In orchid bees, males acquire chemical compounds from the environment that act as pheromone-like bouquets (perfumes) during courtship displays. This process could be costly, potentially due to the cognitive demands of learning and the physiological demands of collecting a mix of extrinsic chemical compounds that may require detoxification. Furthermore, a novel trait, a specialized perfume pouch in the hind leg, is required for compound storage. We studied gene expression in the brain, hind leg, and Malpighian tubules-a tissue involved in detoxification-to investigate changes in gene expression following perfume collection. We detected upregulation of genes enriched in functions related to transcription, odorant binding, and receptor activity in the Malpighian tubules. On the other hand, we did not find any evidence for learning processes following perfume collection, or gene expression changes in the hind leg, perhaps due to constitutive expression, or the age of the sampled bees. We did identify high expression of chemosensory proteins in the hind legs, which we suggest could play a role in perfume collection or storage, with further functional studies necessary to determine their binding properties and potential physiological importance. Los rasgos sexuales secundarios pueden servir como indicadores de calidad de la pareja, y en algunos casos la honestidad de la señal se mantiene por el costo de expresar el rasgo. A menudo las señales sexuales están respaldadas por adaptaciones fisiológicas, morfológicas y de comportamiento por lo tanto pueden requerir la evolución de nuevos rasgos, pero en muchos casos se desconoce la base genética. En las abejas de las orquídeas, los machos recolectan compuestos químicos del medio ambiente, los cuales actúan como feromonas (perfumes) durante el despliegue de cortejo. Este proceso podría ser costoso, posiblemente debido a las demandas cognitivas del aprendizaje y las demandas fisiológicas de recolectar una mezcla de compuestos químicos extrínsecos que pueden requerir desintoxicación. Además, se requiere la evolución de un contenedor para almacenar perfumes en la pata trasera. Para investigar los cambios en la expresión génica después de la recolección de perfume, estudiamos la expresión génica en el cerebro, la pata trasera y los túbulos de Malpighi (tejido involucrado en la desintoxicación). Encontramos varios genes regulados positivamente en los túbulos de Malpighi después de la recolección que están enriquecidos en factores de transcripción, proteínas de fijación de olores, y proteínas con actividad de receptor. Por otro lado, no encontramos ninguna evidencia de procesos de aprendizaje posteriores a la recolección de perfumes, o cambios en la expresión génica en la pata trasera, esto quizás debido a la expresión constitutiva o la edad de las abejas muestreadas. Además, identificamos una alta expresión de proteínas quimio-sensoriales en las patas traseras, que podría desempeñar un papel en la recolección o almacenamiento de perfumes. Más estudios funcionales son necesarios para determinar las propiedades de fijación de las proteínas y su potencial importancia fisiológica.

Age-dependent perfume development in male orchid bees, Euglossa imperialis.

Male neotropical orchid bees concoct complex perfume blends by collecting exogenous volatiles from various sources, including orchids. These perfumes, stored in specialized hind-leg pouches and released during courtship, serve as inter-sexual signals. It has been hypothesized that male perfumes honestly indicate aspects of male fitness. If perfume traits such as quantity or complexity increase over individual lifetime, perfumes could reflect age (survival) and cumulative foraging success of males. We conducted a two-season mark-recapture study with Euglossa imperialis in Costa Rica, monitoring the balance of perfume uptake and expenditure over individual male lifetime. We sealed one hind-leg pouch upon initial capture, 'freezing' the perfume status on one side, and compared it with the other side at recapture to assess changes in perfume traits over time. Additionally, we used a novel method to estimate individual age by combining two parameters of wing degradation. Contrary to predictions, young to intermediate-aged bees had the highest quantities of perfume and the highest diversity of detected compounds. At the same time, the change in perfume between recaptures was positive (increase in amount and complexity) in young bees, whereas it was neutral to negative in older bees. Although these findings do not disprove an indicator function of male perfume, they shift the emphasis to non-cumulative fitness components such as sensory acuteness or cognitive capacity as likely targets of selection. Females preferring strong perfume signals in mates would maximize speed of foraging in offspring rather than their lifetime cumulative yield.

GC × GC-HRMS with complementary ionization methods in the suspect screening analysis of fragrance allergens: overwhelming or justified?

Modern gas chromatography-mass spectrometry (GC-MS) allows for the analysis of complex samples, such as fragrances. However, identifying all the constituents in natural fragrance mixtures, especially allergens that need to be listed on product labels, is a significant challenge. This is primarily due to the high complexity of the sample and the fact that electron ionization, the most commonly used ionization method in GC-MS, produces numerous nonspecific fragment ions, often resulting in the absence or very low abundance of the molecular ion. These factors affect confidence in assigning the analyte. In this study, we demonstrate that the combination of GC × GC separation, with high mass resolution and accurate mass measurements, as well as chemical ionization in addition to traditional electron ionization, becomes an efficient tool for reliable qualitative analysis of a mixture containing 100 fragrance allergens, even when many of them are closely related species or isomers. The proposed approach expands the applicability of the comprehensive GC × GC-HRMS method, which includes complementary ionization techniques, from studies on anthropogenic priority pollutants and emerging contaminants to the analysis of natural products. Although targeted qualitative and quantitative analysis of allergens in the modern laboratories is well organized, GC × GC-HRMS, being a useful complement to routine quality control of volatile allergens in fragrances, definitely gives an additional contribution to the analytical cases when conventional 1D-GC-MS faces some problems or uncertainties.

Fragrance Contact Allergy - A Review Focusing on Patch Testing.

Fragrance materials are widely used in various types of products in daily life and many of them can be contact sensitizers. Contact allergy to fragrances has been reported to be common worldwide. Unlike other groups of contact allergens such as metals and preservatives, fragrance materials in consumer products can be present as single fragrance chemicals or in the form of mixtures known as natural complex substances. Due to the complexity of the fragrance materials and the high number of fragrance substances known to cause contact sensitization, selecting suitable materials for patch testing is challenging. Emerging fragrance markers have been additionally introduced in different baseline series for screening to enhance the rate of fragrance contact allergy detection. Moreover, there have been continual updates on basic knowledge, clinical perspectives, sources of exposure, and regulations on the use of fragrance materials. Avoiding pitfalls while performing patch testing with fragrance test materials is also crucial and should not be overlooked. Therefore, this review aims to update knowledge to provide a high-quality holistic approach to fragrance contact allergy diagnosis and management.

Do hypoallergenic skincare products contain fewer potential contact allergens?

Personal care products (PCPs) commonly cause allergic contact dermatitis (ACD). Skincare companies often market their products as 'hypoallergenic'; however, this term is not regulated by industry standards. To determine whether PCPs marketed as hypoallergenic are truly less likely to precipitate ACD, we conducted a study of ingredients found in 'hypoallergenic PCPs' from two major UK retailers in 2022. Of 208 products meeting the inclusion criteria, 153 (73.6%) contained at least 1 allergen or related chemical from the British Society for Cutaneous Allergy baseline series, 21 (10.1%) had 2 potential allergens and 4 PCPs (1.9%) had 3 allergens. Cetearyl alcohol was the most common -allergen identified in leave-on PCPs and parabens in rinse-off products; fragrance was the most frequent related chemical found in 85 PCPs (40.1%). A high prevalence of common allergens was found in hypoallergenic PCPs, suggesting that dermatologists and consumers should be cautious of product ingredients.

GARDskin dose-response assay and its application in conducting Quantitative Risk Assessment (QRA) for fragrance materials using a Next Generation Risk Assessment (NGRA) framework.

Development of New Approach Methodologies (NAMs) capable of providing a No Expected Sensitization Induction Level (NESIL) value remains a high priority for the fragrance industry for conducting a Quantitative Risk Assesment (QRA) to evaluate dermal sensitization. The in vitro GARDskin assay was recently adopted by the OECD (TG 442E) for the hazard identification of skin sensitizers. Continuous potency predictions are derived using a modified protocol that incorporates dose-response measurements. Linear regression models have been developed to predict human NESIL values. The aim of the study was to evaluate the precision and reproducibility of the continuous potency predictions from the GARDskin Dose-Response (DR) assay and its application in conducting QRA for fragrance materials using a Next Generation Risk Assessment (NGRA) framework. Results indicated that the GARDskin Dose-Response model predicted human NESIL values with a good degree of concordance with published NESIL values, which were also reproducible in 3 separate experiments. Using Isocyclocitral as an example, a QRA was conducted to determine its safe use levels in different consumer product types using a NGRA framework. This study represents a major step towards the establishment of the assay to derive NESIL values for conducting QRA evaluations for fragrance materials using a NGRA framework.

Detailed aggregate exposure analysis shows that exposure to fragrance ingredients in consumer products is low: Many orders of magnitude below thresholds of concern.

The Research Institute for Fragrance Materials (RIFM) and Creme Global Cremeglobal.com partnered to develop an aggregate exposure model for fragrance ingredients. The model provides a realistic estimate of the total exposure of fragrance ingredients to individuals across a population. The Threshold of Toxicological Concern (TTC) and Dermal Sensitization Threshold (DST) were used to demonstrate the magnitude of low exposure to fragrance materials. The total chronic systemic, inhalation, and dermal 95th percentile exposures on approximately 3000 fragrance ingredients in RIFM's inventory were compared to their respective TTC or DST. Additionally, representative fragrance ingredients were randomly selected and analyzed for exposure distribution by product type (i.e., cosmetic/personal care, household care, oral care, and air care) and route of exposure. It was found that 76 % of fragrance ingredients fall below their respective TTC limits when compared to 95th percentile systemic exposure, while 99 % are below inhalation TTC limits. The lowest 95th percentile aggregate exposure by product type was from household care products, then air care, and oral care products. The highest exposure was from personal care/cosmetic products. The volume of use for most fragrance ingredients (63 %) was <1 metric ton, estimating that environmental exposure to fragrance ingredients is likely low.

Exposure of cinnamyl alcohol in co-culture of BEAS-2B and dendritic cells: Interaction between CYP450 and cytokines.

The prevalence of fragrances in various hygiene products contributes to their sensorial allure. However, fragrances can induce sensitization in the skin or respiratory system, and the mechanisms involved in this process are incompletely understood. This study investigated the intricate mechanisms underlying the fragrance's effects on sensitization response, focusing on the interplay between CYP450 enzymes, a class of drug-metabolizing enzymes, and the adaptive immune system. Specifically, we assessed the expression of CYP450 enzymes and cytokine profiles in culture of BEAS-2B and mature dendritic cells (mDC) alone or in co-culture stimulated with 2 mM of a common fragrance, cinnamyl alcohol (CA) for 20 h. CYP1A1, CYP1A2, CYP1B1, CYP2A6, and CYP2A13 were analyzed by RT-PCR and IL-10, IL-12p70, IL-18, IL-33, and thymic stromal lymphopoietin (TSLP) by Cytometric Bead Array (CBA). Through RT-PCR analysis, we observed that CA increased CYP1A2 and CYP1B1 expression in BEAS-2B, with a further increased in BEAS-2B-mDC co-culture. Additionally, exposure to CA increased IL-12p70 levels in mDC rather than in BEAS-2B-mDC co-culture. In regards to IL-18, level was higher in BEAS-2B than in BEAS-2B-mDC co-culture. A positive correlation between the levels of IL-10 and CYP1B1 was found in mDC-CA-exposed and between IL-12p70 and CYP1A1 was found in BEAS-2B after CA exposure. However, IL-12p70 and CYP1A2 as well as IL-18, IL-33, and CYP1A1 levels were negative, correlated mainly in co-culture control. These correlations highlight potential immunomodulatory interactions and complex regulatory relationships. Overall, exposure to CA enhances CYP450 expression, suggesting that CA can influence immune responses by degrading ligands on xenosensitive transcription factors.

Patterns of simultaneous contact allergies in patients with contact sensitization to oxidised linalool and oxidised limonene.

BACKGROUND: Contact allergy rates of linalool and limonene hydroperoxides (HPs) have increased. OBJECTIVES: To demonstrate the patterns of simultaneous positive patch test (PT) reactions and prevalences of multiple contact allergies (MCAs) in patients with contact allergy to linalool and/or limonene HPs. METHODS: A retrospective analysis of consecutive dermatitis patients in 2015-2020 was performed. RESULTS: Of all 4192 patients, 1851 had at least one positive PT reaction. Of these, 410 (22.2%) had MCAs, significantly related to a higher age (p-value = 0.003). Patients with an exclusively positive reaction to linalool HPs but not limonene HPs were shown to have MCAs (p-value <0.001, odds ratio (95% confidence interval) = 4.15 (3.01-5.73)). Patients with simultaneous contact allergies to both linalool and limonene HPs had contact allergies to many other screening and fragrance allergens. CONCLUSIONS: Simultaneous positive PT reactions to allergens in baseline series and fragrances are common in patients with the HPs contact allergy, especially linalool HPs. The pattern of simultaneous PT reactions principally suggested the co-sensitization of the cosmetic allergens.

Results of patch testing with five fragrance materials hitherto not tested: A dose-finding study in the clinical population.

BACKGROUND: Quantitative risk assessment (QRA) for skin sensitization is used to derive safe use levels of sensitising fragrance ingredients in products. Post-marketing surveillance of the prevalence of contact allergy to these ingredients provides relevant data to help evaluate the performance of these measures. OBJECTIVES: To determine a suitable patch test concentration for five fragrance materials that had hitherto not been tested on a regular basis. These concentrations are then to be used in a surveillance study with patch testing consecutive patients over an extended monitoring period. MATERIALS AND METHODS: Furaneol, CAS.3658-77-3; trans-2-hexenal, CAS.6728-26-3; 4,8-dimethyl-4,9-decadienal, CAS.71077-31-1; longifolene, CAS.475-20-7; benzaldehyde, CAS.10052-7, were patch tested with other fragrance allergens in four clinics. Patch testing was conducted in three rounds, starting with the lowest concentrations of the five ingredients. The doses were increased in the subsequent rounds if no late-appearing positive reactions and virtually no irritant reactions were reported. RESULTS: Overall, 373 patients were tested. No positive allergic reaction was reported to the five ingredients. Patch test results of other fragrance allergens are reported. CONCLUSIONS: The highest test concentrations are each considered safe for patch testing consecutive patients. Further surveillance based on these preparations will evaluate the hypothesis that QRA-driven consumer product levels of these fragrances can prevent sensitization.

Analysis of preservatives and fragrances in topical medical devices: The need for more stringent regulation.

INTRODUCTION: Medical devices (MDs) have a long history of use, and come with regulatory frameworks to ensure user safety. Although topically applied MDs in the form of gels and creams might be used on damaged skin, their composition is often similar to that of cosmetic products applicable to intact skin, especially in terms of preservatives and fragrances. However, unlike cosmetics, these products are not subject to compound-specific restrictions when used in MDs. OBJECTIVE: This study aimed to identify and quantify preservatives and fragrances in topically applied MDs and assess their safety towards the Cosmetic Regulation (EC) 1223/2009. METHOD: Sixty-nine MDs available on the EU market were subjected to previously validated liquid chromatography tandem mass spectrometry (LC-MS/MS) and gas chromatography-mass spectrometry (GC-MS) methods to identify and quantify occurring preservatives and fragrances. RESULTS: Findings revealed that 32% of the examined MDs did not provide comprehensive ingredient lists, leaving users uninformed about potential risks associated with product use. Furthermore, 30% of these MDs would not meet safety standards for cosmetic products and, most significantly, 13% of the analysed samples contained ingredients that are prohibited in leave-on cosmetics. CONCLUSION: Results highlight the pressing demand for more stringent requirements regarding the labelling and composition of MDs to enhance patient safety. Improved regulation and transparency can mitigate potential risks associated with the use of topically applied MDs.

Declining frequency of sensitization to fragrance mixes I and II: IVDK-data of the years 2012-2021.

BACKGROUND: EU Commission Regulation 2017/1410 prohibits using atranol and chloroatranol, the main allergens in Evernia prunastri (oakmoss), and hydroxyisohexyl 3-cyclohexene carboxaldehyde (HICC) in cosmetic products. Oakmoss absolute is contained in fragrance mix (FM) I and HICC in FM II which are patch tested as screening mixtures in the baseline series. OBJECTIVE: To describe the time trends of reaction frequencies to both FMs as well as to their components in FM-positive patients. METHODS: Retrospective analysis of data from the Information Network of Departments of Dermatology (IVDK), 2012-2021. RESULTS: Positive reactions to FM I (FM II) declined from 9.1% (4.7%) in 2012 to 4.6% (3.0%) in 2021. Full breakdown tests were performed in 24% (FM I) and 31% (FM II), respectively, of the mix-positive patients. From this data, frequencies of sensitization to the 14 single fragrances of FM I and FM II were calculated. For the majority, a decline was noted from 2012/2013 to 2020/2021, for oakmoss absolute 1.9%-0.8% and for HICC 1.8%-0.9%. CONCLUSION: EU Commission Regulation 2017/1410 was an effective measure. However, our data have some limitations, possibly causing underestimation of sensitization frequencies to fragrances.

Contact sensitization to fragrance mix I and fragrance mix II among European dermatitis patients: A systematic review.

BACKGROUND: Fragrance substances are a frequent cause of contact allergy worldwide. Fragrance exposure varies by sex, age and possibly country, influenced by cosmetic availability, environmental conditions and cultural practices. OBJECTIVES: To systematically review and gather prevalence of sensitization to fragrance mix I (FM I) and fragrance mix II (FM II) in consecutively patch tested European dermatitis patients. METHOD: A total of 4134 publications on patch test results of European dermatitis patients, published from 1981 to 2022, were systematically reviewed according to a previously registered and published PROSPERO protocol. RESULTS: Eighty-four eligible original articles were analysed. Overall prevalence of sensitization to fragrance mix I (FM I) was 6.81% (95% CI: 6.37-7.28), and FM II was 3.64% (95% CI: 3.3-4.01). Sensitization to FM I was most prevalent in Central and Eastern Europe and to FM II in Western Europe. No clear time trends were observed. Among paediatric dermatitis patients, sensitization prevalence for FM I and FM II was 4.09% (95% CI: 3.37-4.96) and 2.17% (95% CI: 1.53-3.07). CONCLUSION: The frequency of positive patch test results for both FMI and FMII remains high. Sensitization is also prevalent among children. Enhanced regulation and labelling of cosmetic products play a vital role in averting exposure and sensitization to fragrance allergens.

Clinical relevance of doubtful reactions in patch testing: A single-centre retrospective study.

BACKGROUND: Doubtful reactions in patch testing are infrequently reported in the literature; however, recent reports have suggested they be assessed with the same scrutiny as stronger reactions. OBJECTIVE: Assess the clinical relevance of doubtful reactions in patch testing. METHODS: Retrospective study of 1514 patients comprehensively patch tested via the NACDG standard series and additional allergens based on history. The clinical relevance of each reaction was graded based on the NACDG scale: definite, probable, possible, past, unknown and irritant. Reactions were considered 'unique' if an additional mild-to-strong reaction to the same chemical at a different concentration was not observed. RESULTS: 68.9% (1043) of patients demonstrated at least 1 doubtful reaction. Of 4453 total doubtful reactions, 92.2% (4106) were unique. Only 3.3% (137) and 12.2% (500) of these were determined to be of definite or probable clinical relevance respectively. 'Fragrance' was the most common allergen family present among the unique definite doubtful reactions (37). However, 24 (64.9%) of these also had a stronger reaction to another fragrance. Cocamidopropyl betaine was the second most frequent allergen demonstrating definite doubtful reactions (27) and unique in 85.2% (23) of cases. Methylchloroisothiazolinone/methylisothiazolinone (MCI/MI) was most prevalent (36) but less frequently unique (58.3%, 21). CONCLUSIONS: Doubtful reactions may not be as impactful to clinical decision making as theorised in the literature. Few demonstrate definite clinical significance, and many have related stronger reactions that capture them for clinical purposes. Identification of doubtful reactions to cocamidopropyl betaine and MCI/MI may be of greatest significance as they most frequently were not supported by stronger reactions.

Allergen content of popular chemical hair relaxers: A product analysis.

BACKGROUND: Chemical hair relaxers are widely utilized by black women, yet little research exists on the allergens present in these products. OBJECTIVE: This study aims to investigate allergen prevalence in the most popular chemical hair relaxers. METHODS: We analysed 41 products from five major retailers, identifying allergens through ingredient lists and comparing them to the 2020 American Contact Dermatitis Group Core allergen series. RESULTS: The most common contact allergens in chemical relaxers include propylene glycol, cetyl steryl alcohol, fragrance, D/L-a-tocopherol, tea tree oil and cocamidopropyl betaine. CONCLUSION: Understanding allergen exposure in products used by individuals with textured hair is needed for managing contact dermatitis in diverse populations. This analysis underscores the presence of potential allergens in hair relaxers, emphasizing the importance of dermatologists' awareness and patient scrutiny of ingredient lists.

Contact allergy in Swedish professional ice hockey players.

BACKGROUND: Professional ice hockey players may contract irritant and allergic contact dermatitis. AIMS: To investigate the presence of contact allergy (CA) in professional ice hockey players in Sweden. METHODS: Ten teams from the two top leagues were assessed for potential occupational exposure to sensitizers. Exactly 107 players were patch tested with an extended baseline series and a working series, in total 74 test preparations. The CA rates were compared between the ice hockey players and controls from the general population and dermatitis patients. RESULTS: One out of 4 players had at least one contact allergy. The most common sensitizers were Amerchol L 101, nickel and oxidized limonene. CA was as common in the ice hockey players as in dermatitis patients and significantly more common than in the general population. Fragrances and combined sensitizers in cosmetic products (fragrances + preservatives + emulsifier) were significantly more common in ice hockey players compared with the general population. CONCLUSION: The possible relationship between CA to fragrances and cosmetic products on the one hand and the presence of dermatitis on the other should be explored further.