Article

Evaluation of Phototoxic Properties of Fragrances

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Abstract

Fragrances are widely used in topical formulations and can cause photoallergic or phototoxic reactions. To identify phototoxic effects, 43 fragrances were evaluated in vitro with a photohaemolysis test using suspensions of human erythrocytes exposed to radiation sources rich in ultraviolet (UV) A or B in the presence of the test compounds. Haemolysis was measured by reading the absorbance values, and photohaemolysis was calculated as a percentage of total haemolysis. Oakmoss caused photohaemolysis of up to 100% with radiation rich in UVA and up to 26% with radiation rich in UVB. Moderate UVA-induced haemolysis (5-11%) was found with benzyl alcohol, bergamot oil, costus root oil, lime oil, orange oil, alpha-amyl cinnamic aldehyde and laurel leaf oil. Moderate UVB-induced haemolysis was induced by hydroxy citronellal, cinnamic alcohol, cinnamic aldehyde, alpha-amyl cinnamic aldehyde and laurel leaf oil. The phototoxic effects depended on the concentration of the compounds and the UV doses administered. We conclude that some, but not all, fragrances exert phototoxic effects in vitro. Assessment of the correlation of the clinical effects of these findings could lead to improved protection of the skin from noxious compounds.

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... • Dermatologic: Allergic hypersensitivity and contact allergic reactions may occur in sensitive individuals [46,50,100,103,108,113,116,151,156,190,222,230,240,267,304,305,315,325,352,353,358,415,417,426,429,465,487,508,521]. Dermatitis, photodermatitis, stomatitis, glossitis, gingivitis, perioral dermatitis, perioral leukoderma (simulating vitiligo), oral lesions, cheilitis, eczema, lip edema, irritation, and depigmentation have been noted in case reports after external application of cinnamon (e.g., cinnamon oils in fragrances or cinnamic aldehyde in deodorant) as well as after the use of flavored chewing gums, mints, or toothpastes [3,12,20,27,31,40,47,50,51,52,59,91,98,100,107,110,112,135,136,137,142,156,157,158,159,163,164,167,170,178,187,188,206,237,242,243,246,247,269,285,286,297,317,323,330,339,340,346,349,350,362,369,370,380,381,403,409,429,432,447,440,451,452,456,459,460,461,484,493,503,515,519,522,539,549,551]. One case of allergic contact dermatitis has been reported as a result of airborne exposure to cinnamon [9]. ...
... Cinnamon extracts have been shown to inhibit tau aggregation and filament formation; a significant portion of the effect is attributed to an A-linked proanthocyanidin trimer molecule [377]. • Phototoxic effects: Alpha-amyl cinnamic aldehyde, cinnamic alcohol, cinnamic aldehyde, and alpha-amyl cinnamic aldehyde have all been identified as increasing phototoxicity [381]. • Pigmentation effects: Cinnamic acid has been shown to reduce melanin production, likely via inhibition of tyrosinase [249,313]. ...
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An evidence-based systematic review of cinnamon (Cinnamomum spp.), including written and statistical analysis of scientific literature, expert opinion, folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse effects, toxicology, and dosing, by the Natural Standard Research Collaboration is discussed in this monograph.
... Oakmoss, lime oil, orange oil, bergamot oil, α-amyl cinnamic aldehyde, and laurel leaf oil can be stimulated by ultraviolet light. The photoreaction generates toxic compounds and causes hemolysis (Placzek et al. 2007). The oakmoss allergens atranol and chloratranol have been identified as strong allergens (Placzek et al. 2007). ...
... The photoreaction generates toxic compounds and causes hemolysis (Placzek et al. 2007). The oakmoss allergens atranol and chloratranol have been identified as strong allergens (Placzek et al. 2007). The pharmacokinetics and bioavailability of essential oils differ. ...
Article
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Synthetic fragrance compounds have become a ubiquitous part of household cleaning products and personal care agents. To improve aesthetics, fragrances are added, but the current research has unveiled detrimental effects of these odorous compounds. The exposure to the synthetic fragrances and musks, which are produced in quantities of thousands of tons per year, has been shown to elicit several pathologies. The fragrance compounds are regarded as toxins by the human immune system, and to eliminate them, cytochrome enzymes, especially aromatases, are overexpressed. These enzymes also convert androgens into estrogens, but excess estrogen production affects the endocrine system in both males and females. Although the estrogenic properties of cosmetics are increasingly being proven, the link between fragrance compounds and a wide variety of modern lifestyle diseases is not known to the majority of the public. It is increasingly being evident that all diseases have common roots, i.e., inflammation. The unprecedented prevalence of diabetes, obesity, cancer, and depression, among others pathologies, is tied to the limitless usage of fragrance compounds. Therefore, it is important to further investigate the dangers associated with fragrance compounds, to inform the regulatory bodies to allow them to better control manufacturers, and to alert consumers. This article is directed for facilitation of that objective.
... Contact allergy to perfume and other consumer products cause dermatitis and asthma [25]. An in vitro study revealed that the fragrances such as oak moss, benzyl alcohol, bergamot oil, lime oil, orange oil, a-amyl cinnamic aldehyde and laurel leaf oil can be stimulated by ultraviolet (UV) A or B. The photo-activation can generate toxic compounds and can cause hemolysis [55]. Incense smoke liberates fumes of toxic gases as CO, CO 2 , NO 2 , SO 2 , benzene, toluene, xylenes, aldehydes, and PAHs (polycyclic aromatic hydrocarbons) along with particulate matters (higher than cigarettes) that mediate airway diseases as well as contact dermatitis [40]. ...
... One should realize that every time an individual gets exposed to a perfume, he/she agitates his/ her hormonal signaling, risking cancer development. Even essential oil generally traded to be ''plant-based, so safe" are not free of risks, as they can cause phototoxicity and skin irritations [55]. The fragrance compounds so ubiquitous in modern times initiate vicious cycles of 'exposure -pathologies -drugs', which must be understood, information disseminated and terminated. ...
Article
In the past few decades, synthetic fragrance compounds have become ubiquitous components of personal care and household cleaning products. Overwhelming consumerism trends have led to the excess usage of these chemicals. It has been observed that this fragrance-laden unhealthy lifestyle runs parallel with the unprecedented rates of diabetes, cancer, neural ailments, teratogenicity, and transgender instances. The link between fragrances as and the multiplicity of pathogens remained latent for decades. However, now this health hazard and its role in homeostasis breakdown is getting attention. The adverse effects of the fragrance constituents as phthalates, paraben, glutaraldehyde, hydroperoxides, oil of turpentine, metals, nitro musks, and essential oils, among others, are being identified. The endocrine-immune-neural axis perturbation pathways of these chemicals are being proven. Despite the revelations of cause-effect nexus, a majority of the vulnerable populations are unaware and unmotivated to avoid these ‘slow poisons’. Hence, the researchers need to further validate the toxicity of fragrance compounds, and raise awareness towards the health risks. In this regard, a number of pathologies triggered by fragrance exposure, yet proven only scantily have been hypothesized. Analysis of the health issues from multiple facets, including the pivotal ‘stressors – extracellular acidosis – aromatase upregulation – estrogen hyperproduction – inflammation’ link has been proposed. Fragrance compounds share configurational similarity with carcinogenic environmental hydrocarbons and they provoke the expression of cytochrome group monooxygenase enzyme aromatase. This enzyme aromatizes androgens to form estrogen, the powerful signaling hormone, which underlies the majority of morbidities. This holistic review with a repertoire of preliminary evidences and robust hypotheses is expected to usher in deserving extent of research on this pervasive health risk.
... Photoallergic reactions are T-cell-mediated immunological reactions, while phototoxic reactions are non-immunological events inducing cell damage. Most substances eliciting photoallergic reactions also have a phototoxic potential (8). Photoactivated drugs may induce DNA damage of skin cells resulting in the increase of skin cancer incidence (9). ...
Article
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... Oxidized fragrance ingredients can act as potent sensitizers and phototoxic agents (Dubertret 1990). Recent in-vitro studies have suggested that exposure of common fragrance compounds to UV light can cause direct cell damage and cell death (Placzek 2007;Dijoux 2006).] ...
... Moreover, the high levels of oxygen heterocyclic compounds in the non-volatile fraction is of significant interest with regard to their pharmacological properties (Santana, Uriarte, Roleira, Milhazes, & Borges, 2004). The toxicological effects of these compounds are also of concern because photo-toxicity has previously been highlighted by several reports (Placzek, Fromel, Eberlein, Gilbertz, & Przybilla, 2007). Because of the considerable diversity of their constituents, which subsequently results in different physicochemical properties, CPLOs are challenging to analyse with conventional reverse phase (RP) chromatography. ...
... Inhibition of this enzyme prevents oxidative metabolism of certain drugs, resulting in an elevated concentration of a drug in the bloodstream [61]. Bergamot and other chemicals in citrus (e.g., lime, grapefruit, orange, lemon) oils [62] are also phototoxic, causing significant toxicity to the skin when exposed to sunlight [63]. 5-Methoxypsoralen, the most phototoxic constituent of bergamot oil, showed mutagenic activity in bacterial assays and clastogenic effects in mammalian cells in culture when exposed to UV light [64]. ...
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Although many foods contain toxins as a naturally-occurring constituent or, are formed as the result of handling or processing, the incidence of adverse reactions to food is relatively low. The low incidence of adverse effects is the result of some pragmatic solutions by the US Food and Drug Administration (FDA) and other regulatory agencies through the creative use of specifications, action levels, tolerances, warning labels and prohibitions. Manufacturers have also played a role by setting limits on certain substances and developing mitigation procedures for process-induced toxins. Regardless of measures taken by regulators and food producers to protect consumers from natural food toxins, consumption of small levels of these materials is unavoidable. Although the risk for toxicity due to consumption of food toxins is fairly low, there is always the possibility of toxicity due to contamination, overconsumption, allergy or an unpredictable idiosyncratic response. The purpose of this review is to provide a toxicological and regulatory overview of some of the toxins present in some commonly consumed foods, and where possible, discuss the steps that have been taken to reduce consumer exposure, many of which are possible because of the unique process of food regulation in the United States.
... While the UV absorption spectrum for α-amylcinnamaldehyde demonstrates that it absorbs UV light in the 290- 700 nm region (spectra are not suitable for calculating a molar absorption coefficient), no photoallergic or phototoxic effects were observed in guinea pig assays (RIFM, 1988; RIFM, 1988a). Addo et al., 1982; RIFM, 1980; Placzek et al., 2007 ...
... essential oil with ICG and IR diode laser exhibited lethal effect on yeast cells 29 . Placzek and coworkers determined that benzyl alcohol, bergamot oil, costus root oil, lime oil, orange oil, α-amyl cin-namic aldehyde and laurel leaf oil have phototoxic potential depended on the concentration of those on human erythrocytes exposed to ultraviolet (UV) radiation sources 30 . In another study, ethanol extracts of Momordica charantia and Eugenia uniflora, have rich in flavonoids and terpenes, showed antibacterial activity against an E. coli strain when exposed to UV-A light 31 . ...
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Aromatic plants comprise many biologically active compounds such as mainly anti-microbial, anti-oxidant, anti-parasitic, anti-fungal and anti-inflammatory characteristics. The demand for these plants and their derivatives has became popular since they are natural and generally recognized as safe products. Thus, chemical composition of volatile oils, obtained from Myrtus communis (Myrtle), Citrus sinensis (Lemon), Cinnamomum zeylanicum (Cinnamon), Laurus nobilis (Laurel), and Lavandula stoechas (Lavender) were analysed. It was reported that the main components of M. communis were 1,8 cineole (29.68 %), linalool (15.03 %), α-pinene (12.41 %) while volatile components of C. sinensis were found to be limonene (57.78 %), β-pinene (10.38 %). C. zeylanicum contained cinnamaldehyde (34.31 %), propylene glycol acetal (26.82 %), cinnamal (16.54 %). The components of L. nobilis were 1,8 cineole (29.75 %), camphor (9.85 %). In addition, L. stoechas contained camphor (36.69 %), α-thujene (21.37 %), 1,8 cineole (11.96 %). In this study, The minimum inhibitory concentration (MIC) and Minimal Bactericidal Concentration (MBC) were determined by using microbroth dilution technique. In addiition, in vitro, phototoxicity of volatile oil were researched against Escherichia coli (ATCC 25293), Klebsiella pneumoniae (10031), Salmonella thyphimurium, Bacillus subtilis (ATCC 6633), Staphylococcus aureus (ATCC 25925), Enterococcus feacalis (ATCC 29212) by using disc diffusion method. We showed that microoganisms were inhibited by volatile oil photoinduced using a standard LED light. Volatile oils of M. communis, L. nobilis and L. stoechas have significantly phototoxic activity against bacteria (P < 0.05), while minor phototoxicity was induced by C. zeylanicum and C. sinensis Consequently, volatile oils of those plant could be utilized as photosensitizer agent in antimicrobial photodynamic therapy.
... An in vitro photohemolysis test in human erythrocyte suspensions was used to evaluate the phototoxicity of benzyl alcohol and benzyl benzoate. 84 Cells were incubated with either chemical (10 À3 mol/L) for 1 hour and exposed to UVA or short wave ultraviolet light (UVB) radiation. The UVA rich light source was a UVASUN 5000 lamp (320-460 nm; 42 mW/cm 2 ), and the UVB rich light source was a lamp with TL 20 W/12 light bulbs (between 275 and 365 nm; 1 mW/cm 2 [UVB] and 0.4 mW/cm 2 [UVA]). ...
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Benzyl alcohol, benzoic acid and its salts, and benzyl benzoate function mostly as fragrance ingredients/preservatives in cosmetic products. The Cosmetic Ingredient Review Expert Panel previously established concentration limits for benzyl alcohol, benzoic acid, and sodium benzoate in cosmetics and determined that the available data were insufficient to support the safety of these ingredients during inhalation exposure. After reviewing newly available data, it was concluded that benzyl alcohol, benzoic acid and its salts, and benzyl benzoate are safe in the present practices of use and concentration described in this safety assessment.
... Oakmoss (from the lichens Evernia furfuracea and Evernia prunastri), used in perfumery, is an allergen, because of its components atranol (2,6-Dihydroxy-4-methylbenzaldehyde) and chloratranol (3-chloro-2,6-dihydroxy-4-methylbenzaldehyde). Oakmoss is stimulated by ultraviolet (UV) light, which generates toxic compounds and causes hemolysis [11]. Balsam of Peru derived from a tree Myroxylon, has a sweet scent. ...
... This habit is not going to improve vitamin D level, rather will increase estrogen dominance. Some UV filters in the sunscreen are photo-unstable, and they can cause allergies (Placzek et al., 2007). Plant essential oils used in cosmetics are phototoxic (Kejlová et al., 2010). ...
Article
Vitamin D (25(OH)D3 and 1,25-dihydroxycholecalciferol), is known to play role in calcium uptake, bone metabolism, mineral homeostasis, modulation of the innate and adaptive immune systems and the regulation of cell proliferation, among a litany of other functions. If serum level of this vitamin falls below 30-40 ng/mL, its deficiency can occur, predisposing the individual to cancers, cardiovascular disease, autoimmune conditions, and infections. Consequently, the antiproliferative, antifibrotic, immunomodulatory, and anti-estrogenic significance of this vital vitamin is emerging. In this regard, the endocrine functions of vitamin D have been discussed. Vitamin D has innate response to infection but it can prevent the overelaboration of inflammatory adaptive immunity as well. Maintaining right vitamin D level by sensible lifestyle can reduce enormous public health burden.
... α-Terpineol has anticarcinogenic activity [187]. It is a non-irritant at 1-15%, and non-phototoxic [188]. It is not mutagenic or genotoxic. ...
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Citrus fruits have been a commercially important crop for thousands of years. In addition, Citrus essential oils are valuable in the perfume, food, and beverage industries, and have also enjoyed use as aromatherapy and medicinal agents. This review summarizes the important biological activities and safety considerations of the essential oils of sweet orange (Citrus sinensis), bitter orange (Citrus aurantium), neroli (Citrus aurantium), orange petitgrain (Citrus aurantium), mandarin (Citrus reticulata), lemon (Citrus limon), lime (Citrus aurantifolia), grapefruit (Citrus × paradisi), bergamot (Citrus bergamia), Yuzu (Citrus junos), and kumquat (Citrus japonica).
... In 2005, a review on lavender essential oil reported that lavender is traditionally regarded as a 'safe' oil, whereas skin problems (contact dermatitis) may occur at only a very low frequency [12]. In a study dealing with the relationship between various fragrances and photosensitivity carried out in 2007, it was reported that, even though lavender is known to favour cutaneous photo-toxic reactions, it did not induce photohaemolysis [13]. ...
Article
Full-text available
The aim of the present study was to characterize Lavandula stoechas (Ladastacho) from the region of Saidona by means of physico-chemical parameters, phenolic profile, in vitro antioxidant activity and volatile compounds. Physico-chemical parameters (pH, acidity, salinity, total dissolved solids, electrical conductivity and liquid resistivity) were determined using conventional methods. The phenolic profile was determined using high-performance liquid chromatography electrospray ionization mass spectrometry (HPLC/ESI-MS), whereas a quantitative determination was also accomplished using the total phenolics assay. In vitro antioxidant activity was determined using the 2,2-diphenyl-1-picryl-hydrazyl assay. Finally, volatile compounds were determined using headspace solid phase microextraction coupled to gas chromatography mass spectrometry (HS-SPME/GC-MS). The results showed that Lavandula stoechas aqueous extract had a slightly acidic pH, low salinity content and considerable electrochemical properties (electrical conductivity and liquid resistivity along with electric potential). In addition, aqueous fractions showed a significantly (p < 0.05) higher phenolic content and in vitro antioxidant activity, whereas phenolic compounds, such as caffeic acid, quercetin-O-glucoside, lutelin-O-glucuronide and rosmarinic acid, were identified. Finally, numerous volatile compounds were found to dominate the volatile pattern of this flowering plant, producing a strong, penetrating, cool and menthol-like odour.
... For example, Hans et al. (2008) reported that lipstick and facial cream cosmetic products generated reactive oxygen species, produced hemolysis, and caused lipid peroxidation in human erythrocytes under sunlight exposure [3]. Additionally, ingredients commonly used in personal care and cosmetic products, such as essential oils, fragrance chemicals, and botanicals have been associated with phototoxic effects [4][5][6]. This is an area of rising interest, given the number of personal care and cosmetic products available on the market, as well as the number of personal care and cosmetic products applied per day [7]. ...
Article
Full-text available
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... Embora existam dados limitados de irritação e sensibilização disponíveis para o benzaldeído, os dados de irritação e sensibilização cutânea disponíveis e os dados de absorção e fototoxicidade em ultravioleta (UV) que não demonstram reações adversas aos ácidos benzoicos suportam a segurança do benzaldeído como usado atualmente em produtos cosméticos. 37,38 Leite, T. O. C. ...
... Czynnikami wywołującymi mogą być produkty smołowcowe, leki (fenotiazyny, sulfonamidy), barwniki (antrachinon, eozyna, błękit metylenowy, róż bengalski) i furokumaryny roślin. Część substancji o wybiórczo fototoksycznym działaniu może, po ustąpieniu ostrej reakcji, powodować opóźnione odczyny fototoksyczne w postaci długotrwałych przebarwień (35)(36)(37)(38)(39)(40)(41). ...
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... Indigenous people use the oil on joints to gain relief from pain and for its claimed efficacy against paralysis [259], as well as topically against scalp scabies [262]. However, costus oil is responsible for numerous cases of versatile skin reactions, associated with its high content of sesquiterpene α-methylene-γ-butyrolactones [182,271]. Thus, costus root oil-absolute and concrete have been listened in the IFRA-standards as prohibited fragrance ingredients since 2006 [22]. ...
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Since ancient times, plant roots have been widely used in traditional medicine for treating various ailments and diseases due to their beneficial effects. A large number of studies have demonstrated that—besides their aromatic properties—their biological activity can often be attributed to volatile constituents. This review provides a comprehensive overview of investigations into the chemical composition of essential oils and volatile components obtained from selected aromatic roots, including Angelica archangelica, Armoracia rusticana, Carlina sp., Chrysopogon zizanioides, Coleus forskohlii, Inula helenium, Sassafras albidum, Saussurea costus, and Valeriana officinalis. Additionally, their most important associated biological impacts are reported, such as anticarcinogenic, antimicrobial, antioxidant, pesticidal, and other miscellaneous properties. Various literature and electronic databases—including PubMed, ScienceDirect, Springer, Scopus, Google Scholar, and Wiley—were screened and data was obtained accordingly. The results indicate the promising properties of root-essential oils and their potential as a source for natural biologically active products for flavor, pharmaceutical, agricultural, and fragrance industries. However, more research is required to further establish the mechanism of action mediating these bioactivities as well as essential oil standardization because the chemical composition often strongly varies depending on external factors.
... The cytotoxicity was also similar under both conditions indicating only toxic (but no phototoxic) properties at high concentrations. This result is also consistent with data obtained from a photohaemolysis test [39]. NI induced similar dose-dependent increases of the CD86 expression under both conditions and irradiation had no influence on its relatively weak cytotoxicity. ...
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Photoactivation and binding of photoactive chemicals to proteins is a known prerequisite for the formation of immunogenic photoantigens and the induction of photoallergy. The intensive use of products and the availability of new chemicals, along with an increasing exposure to sun light contribute to the risk of photosensitizing adverse reactions. Dendritic cells (DC) play a pivotal role in the induction of allergic contact dermatitis. Human peripheral blood monocyte derived dendritic cells (PBMDC) were thus perceived as an obvious choice for the development of a novel in vitro photosensitization assay using the modulation of cell surface protein expression in response to photosensitizing agents. In this new protocol, known chemicals with photosensitizing, allergenic or non-allergenic potential were pre-incubated with PBMDCs prior to UVA irradiation (1 J/cm(2)). Following a 48 h incubation, the expression of the cell surface molecules CD86, HLA-DR and CD83 was measured by flow cytometry. All tested photosensitizers induced a significant and dose-dependent increase of CD86 expression after irradiation compared to non-irradiated controls. Moreover, the phototoxicity of the chemicals could also be determined. In contrast, (i) CD86 expression was not affected by the chosen irradiation conditions, (ii) increased CD86 expression induced by allergens was independent of irradiation and (iii) no PBMDC activation was observed with the non-allergenic control. The assay proposed here for the evaluation of the photoallergenic potential of chemicals includes the assessment of their allergenic, phototoxic and toxic potential in a single and robust test system and is filling a gap in the in vitro photoallergenicity test battery.
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The structure of simple linear alkanals from propanal to nonanal was studied utilizing configurational bias Monte Carlo (MC) simulations of the aldehydes modeled according to the transferable potential for phase equilibria-united atom force field (TraPPE-UA) and was compared to experimental small-angle X-ray scattering (SAXS) results. This was done by exploiting a recently developed approach for calculating the scattering intensities from theoretically obtained MC data by utilizing the Debye equation (Tomsic et al. J. Phys. Chem. B 2007, 111, 1738). Similar calculations were also performed utilizing a well-established approach based on the reciprocal lattice. Comparison of the calculated scattering data with the experimental SAXS results in the first instance revealed information on the molecular organization in simple aldehydes and in addition also served as a good structural test of the TraPPE-UA force field used to model the aldehydes studied. However, it turned out that such a structural test is a rather strict test for the model which otherwise showed good agreement with the experimental data from the thermodynamic point of view.
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2-acetonaphthone (2-ACN) is a synthetic fragrance material used in various cosmetics, as an adulterant. Due to its frequent use, we have conducted an in-depth study to understand the photosensitizing potential of 2-ACN. Results of this study illustrate that 2-ACN showed photodegradation in 4 hrs under ambient UVR (UV radiations) and sunlight exposure. It generated (1-25µg/ml) superoxide anion radical (O2·‒) and singlet oxygen (¹O2) in the presence of UVR/sunlight through in-chemico and in-vitro test systems. 2-ACN (10 µg/ml) showed 43.9 % and 57.4 % reduction in cell viability under UVA and sunlight, respectively. Photosensitized 2-ACN generated intracellular ROS (6 folds in UVA; 8 folds in sunlight), which compromises the endoplasmic reticulum and mitochondrial membrane potential leading to cell death. Acridine orange/ethidium bromide dual staining and annexin-V/PI uptake showed cell death caused via 2-ACN under UVR exposure. The above findings signify the role of ROS via Type-I & Type-II photodynamic pathways in photosensitization of 2-ACN that ultimately promotes photodamage of important cellular organelles leading to cell death. The study advocates that solar radiation should be avoided by the users after the application of cosmetic products contain 2-ACN.
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This is a comprehensive review of extracts from the lichen Pseudevernia furfuracea (treemoss) that are used in the fragrance industry. Qualitative and quantitative analytical aspects are critically reviewed and the results are compared to those of the related oakmoss extracts. It is shown that more than 90 constituents have been identified so far in treemoss extracts, including 42 depsides, depsidones or depside-derived compounds, and 42 triterpenes or steroids. Constituents of certain host trees, mainly Pinus species, generate specific analytical and toxicological issues which need to be considered in addition to those related to the known degradation products of lichen compounds. A new classification of lichen extracts used as raw materials in fragrance compounding is proposed. Copyright © 2009 John Wiley & Sons, Ltd.
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A comprehensive review is presented on extracts of a lichen, oakmoss (Evernia prunastri), that are used in the fragrance industry. Analytical aspects are discussed in detail, from both qualitative and quantitative standpoints, mainly in relation to the industrial processing of the lichen. It is shown that more than 170 constituents have been identified so far in oakmoss extracts, including 47 depsides or depside-derived compounds and 25 triterpenes or steroids. A survey of industrially relevant synthetic products with an oakmoss odour is included. Toxicology issues related to the use of oakmoss extracts in cosmetics and fragrance formulations are critically reviewed. Copyright © 2009 John Wiley & Sons, Ltd.
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The second edition of this book is virtually a new book. It is the only comprehensive text on the safety of essential oils, the first review of essential oil/drug interactions, and it provides detailed essential oil constituent data not found in any other text. Much of the existing text has been re-written, and 80% of the text is completely new. There are 400 comprehensive essential oil profiles and almost 4000 references. There are new chapters on the respiratory system, the cardiovascular system, the urinary system, the digestive system and the nervous system. For each essential oil there is a full breakdown of constituents, and a clear categorization of hazards and risks, with recommended maximum doses and concentrations. There are also 206 Constituent Profiles. There is considerable discussion of carcinogens, the human relevance of some of the animal data, the validity of treating an essential oil as if it was a single chemical, and the arbitrary nature of uncertainty factors. There is a critique of current regulations.
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The anti-proliferative potential of vanillin isolated from an ethnomedicine Flacourtia indica bark was evaluated in an acute lymphoblastic leukemia cell line (Jurkat) in our previous study, but its molecular mechanisms of action are not yet revealed. The present work investigated the pharmacokinetic properties & cellular uptake of vanillin, in addition to evaluating the effect of vanillin treatment on cell morphology, mitochondrial membrane potential, DNA fragmentation, and cell survival & pro-apoptotic proteins in Jurkat cells. High absorption, good oral bioavailability, and safety of vanillin were recorded through in silico pharmacokinetic studies. In vitro study results indicate that 24.07% of vanillin was absorbed by Jurkat cells within 120 min. The IC50 dose of vanillin reduced the mitochondrial membrane potential up to 77.05% and also caused 60.94% of DNA fragmentation in Jurkat cells. Further, inhibition of cell survival proteins such as H-RAS, K-RAS, N-RAS, & BCL-2 and activation of pro-apoptotic proteins like p-38, BAX, pro-caspase-9, pro-caspase-3, and caspase-3 by vanillin was confirmed through molecular docking and western blotting studies. Thus, the current study revealed the pharmacokinetic properties and anti-proliferative mechanisms of vanillin in Jurkat cells. Therefore vanillin could be further investigated to develop a safe and alternative phytopharmaceutical to treat acute lymphoblastic leukemia.
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Background Photoallergic contact dermatitis is one of the important parts of photodermatoses. The investigation of choice is photopatch testing. However, reports with photopatch test results from Asian countries are scarce. The objective of this study was to determine the prevalence of positive photopatch test reactions and to ascertain the common photoallergens among Thai patients during 1998–2018. Methods We retrospectively reviewed the records of 339 patients who were clinically suspected of having photoallergic contact dermatitis and had undergone photopatch testing. Results A total of 44 photoallergic contact reactions in 38 patients (11.2%) were found. The positive photoallergic reactions were mainly found with organic ultraviolet filters and fragrances. Conclusions Organic ultraviolet filter chemicals especially benzophenone‐3 and fragrances were found to have a high prevalence of photoallergic contact reactions. Monitoring of the photoallergens employed in photopatch tests should be conducted periodically to provide the best patient care.
Article
Use of sunscreens has increased dramatically worldwide, and some sunscreen chemicals may be allergens. Ultraviolet (UV) filters are added to various cosmetic products. Cinnamate UV filters are structurally related to cinnamon-related fragrances. The purpose of this study was to determine if 'cinnamon-sensitive' patients show positive photopatch tests to cinnamate UV filters and, therefore, should avoid these UV filters. We photopatch tested cinnamon-sensitive patients (n = 18) with cinnamon, cinnamon-related fragrances, Myroxylon pereirae, and two cinnamate UV filters. No positive photopatch test to cinnamate UV filters was found (95% confidence interval 0-13%). The risk of developing unwanted allergic contact dermatitis because of cinnamate UV filters in cinnamon-sensitive patients seems to be low, but our study population was small. Therefore, we recommend cinnamon-sensitive patients to perform a use test, for example the repeated open application test, before using cosmetic products containing cinnamate UV filters. In addition, physicians and patients should be aware that many sunscreens contain (cinnamon-related) fragrances and could, therefore, elicit allergic contact dermatitis in cinnamon-sensitive patients, independently from other potential sensitizing components of the sunscreen.
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In phase I of a joint prevalidation study six laboratories from COLDPA (the European Cosmetic, Toiletry and Perfumery Association) as well as FRAME (England) and ZEBET (Germany) have evaluated the most promising in vitro methods for phototoxicity testing. Twenty chemicals with known photoirritation properties [11 phototoxins (PT), 5 UV-ab-sorbing non-PT, and 4 non-UV absorbing non-PT] were tested under identical UVA exposure conditions (sun simulation: 5 J/cm2 UVA) in a cytotoxicity assay with 3T3 fibroblasts (endpoint: neutral red uptake, NRU) in all of the laboratories. The chemicals were also tested with in vitro phototoxicity assays established in laboratories of the European cosmetic industry, e.g., photohemolysis and hemoglobin oxidation in red blood cells (RBC), histidine oxidation, a Candida albicans assay, a human lymphocyte assay, a human keratinocyte assay, and, in addition, also in two recently developed commercial assays (SO-LATEX PI ™, Skin2™ PI). Development and standardization of the 3T3 NRU phototoxicity test and of the Skin2 phototoxicity .assay were carried out at ZEBET's laboratory and are described in detail. During phase I of the EU/COIIPA in vitro phototoxicity study, the 3T3 NRU phototoxicity test, the combined RBC hemolysis and hemoglobin oxidation test, and the Skin2 phototoxicity assay showed the best overall correlation with in vivo data. These assays are currently undergoing a formal validation in phase n of the study, which is conducted in 11 laboratories in Europe and the United States as a blind trial with 30 chemicals carefully selected according to high quality human data.
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The human three-dimensional in vitro model Skin(2) ZK 1350(TM) [Advanced Tissue Sciences (ATS), La Jolla, USA] was tested for two in vitro toxicology applications, prediction of phototoxicity and classification of skin corrosivity. For phototoxicity testing chemicals were applied topically for 1 or 24 hr followed by 30 min of irradiation with a non-irritating dose of UVA. Phototoxicity was assessed 24 hr later by comparing cytotoxicity of UVA-exposed and non-exposed tissue in the MTT assay. In a European EC/COLIPA in vitro phototoxicity validation trial with 20 test chemicals (11 phototoxic and nine non-phototoxic), the best result was obtained with the Skin(2) ZK 1350 assay in the 24-hr exposure protocol where nine of the 11 phototoxins were classified correctly both at ATS and ZEBET. 6-Methylcoumarin could only be identified as a phototoxin when applied through the medium to the dermis side of the skin model for 24 hr. All of the nine non-phototoxic chemicals were identified correctly with either 1- or 24-hr preincubation. To classify chemicals as corrosive to the skin with an in vitro assay, ZEBET and two other laboratories tested 50 chemicals under blind conditions in the Skin(2) ZK 1350 model within a European ECVAM validation trial. The results obtained with the ZK 1350 assay showed a satisfactory classification of skin corrosive/non-corrosive chemicals and a sufficient prediction of the three UN Packing Groups for corrosive chemicals. Predictions obtained at ZEBET with the Skin(2) ZK 1350 model (sensitivity: 64%, specificity: 76%; positive and negative predictive values: 68%) compared with a sensitivity of 81% and a specificity of 77% as mean values for the three laboratories testing the model.
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The ability of fluoroquinolones to cause light-induced adverse effects has been established in experimental studies and clinical observations. The formation of active oxygen species appears to be responsible for this activity. Photomutagenicity tests with bacterial, lower eukaryotic and mammalian cells were performed with three fluoroquinolones (Fleroxacin, Ciprofloxacin and Lomefloxacin). After concomitant irradiation with simulated solar light (with a reduced UVB component), weak increases in the number of revertants were observed in Salmonella typhimurium TA104 and TA100. No photomutagenic activity was detected in Saccharomyces cerevisiae D7. In the chromosomal aberration (CA) test with Chinese hamster V79 cells the number of aberrant metaphases was markedly increased. In the Comet assay with mouse lymphoma cells, evidence of extensive DNA breakage was obtained. All three compounds showed similar potencies in the Comet and Ames assays while there was a clear gradation of potencies in the CA assay (Lomefloxacin > Fleroxacin > Ciprofloxacin), which conformed with reports on the relative potencies regarding phototoxicity. The oxygen radical scavengers catalase, superoxide dismutase and N, N'-dimethylurea modulated the photoclastogenicity and phototoxicity but had no influence on the effects in the Comet and Ames tests. It thus appears that different kinds of mechanism are responsible for toxicity and clastogenicity on the one side and DNA breakage and gene mutation on the other side. Pre-irradiation of the test articles did not lead to enhanced genotoxicity, indicating the involvement of very short lived genotoxic agents. The results endorse the advice to avoid excessive light exposure during antibiotic therapy with fluoroquinolones.
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Hairless mice were exposed orally to antibiotics of the fluoroquinolone group alone and in combination with irradiation with UVA over an extended period of time to determine the possible skin carcinogenicity in comparison with that with 8-methoxypsoralen, i.e. a known photochemical skin carcinogen. Animals exposed to UVA and fleroxacin, ciprofloxacin, nalidixic acid and ofloxacin exhibited an increase in the number of benign skin tumors when compared with animals exposed to UVA alone. Animals exposed to lomefloxacin and UVA exhibited a specific type of neoplastic progression. In addition to benign papillomas and solar keratoses, a number of cystic squamous cell carcinomas were observed. In the positive control group, which was given 8-methoxypsoralen and UVA, a number of papillomas and superficial squamous cell carcinomas were found. In animals exposed to UVA alone, only a few benign tumors were seen; in unexposed animals, no cutaneous neoplasms were observed. It is concluded that fluoroquinolones warrant further study, because they have potential photocarcinogenic properties.
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In a joint project six laboratories from the European cosmetics industry (COLIPA) as well as from FRAME (England) and ZEBET (Germany) are validating in vitro methods to be incorporated into new international guidelines for photoirritancy testing. During the first stage of the study it was attempted to select the most promising in vitro photoirritancy tests for further validation. Twenty chemicals with known photoirritation properties (12 phototoxins (PT), 4 non-PTs and 4 UV absorbing non-PTs) were tested under identical UV exposure conditions (5 J/cm2, UV-A sun simulator) in a standardized cytotoxicty assay using 3T3 fibroblasts (endpoint): Neutral red uptake, NRU). The chemicals were also tested with in vitro phototoxicity assays established in industrial laboratories, e.g. the photohaemolyses (Pape et al, 1993), histine oxidation, candida albicans (Johnson et al, 1986), and, furthermore two commercial tests (SOLATEX PItrade mark and Skin2trade mark). Data from the 3T3 NRU photoirritancy test, the red blood cell photohaemolysis test and the Skin2trade mark assay showed a better overall correlation to human in vivo data than results from the other tests. These simple assays therefore, seem very promising for further validation under blind conditions. The protocols of the other tests have to be improved and standardized to permit better interlaboratory comparison.
Article
The effects of UV irradiation on the cytotoxicities of selected chemicals were investigated in cultures of Balb/c 3T3 cells, normal human keratinocytes and Jurkat cells. The chemicals were chosen according to their reported photoirritancy, or lack thereof, and the abilities of the in vitro tests to distinguish between these photoirritants and non-photoirritants were assessed. The data obtained suggest that the neutral red uptake assay with Balb/c 3T3 cells can be used to provide some indication of the potential photoirritancy of these particular chemicals. However, similar results were also obtained using the human keratinocytes and these should provide a more relevant in vitro model for investigating mechanisms of chemical-induced photoirritation.
Article
Chronic irradiation of mice with ultraviolet (UV) light produces a systemic alteration of an immunologic nature. This alteration is detectable in mice long before primary skin cancers induced by UV light begin to appear. The alteration results in the failure of UV-irradiated mice to reject highly antigenic, transplanted UV-induced tumors that are rejected by unirradiated syngeneic recipients. The immunologic aspect of this systemic alteration was demonstrated by transferring lymphoid cells from UV-irradiated mice to lethally x-irradiated recipients. These recipeints were unable to resist a later challenge with a syngeneic UV-induced tumor, whereas those given lymphoid cells from normal donors were resistant to tumor growth. Parabiosis of normal mice with UV-irradiated mice, followed by tumor challenge of both parabionts with a UV-induced tumor, resulted in the growth of the challenge tumors in both UV-irradiated and unirradiated mice. Splenic lymphocytes from tumor-implanted UV-treated mice were not cytotoxic in vitro against UV-induced tumors, whereas under identical conditions cells from tumor-implanted, unirradiated mice were highly cytotoxic. Our findings suggest that repeated UV irradiation can circumvent an immunologic mechanism that might otherwise destroy nascent UV-induced primary tumors that are strongly antigenic.
Article
A cooperative photopatch test study was conducted by 45 dermatologic centers in Austria, Germany, and Switzerland. Results obtained from 1985 to 1990 are presented. A standard photopatch test tray of 32 substances was applied to the back of patients with suspected photosensivity. After applications for 24 hours, test sites were irradiated with 10 joules/cm2UVA. Unirradiated controls were included. Readings were performed immediately and 24, 48, and 72 hours after irradiation; responses were qualitatively graded on a 4-point scale. All data were stored and processed by a computer. With computer-assisted analysis of reaction patterns photoallergic reactions were identified and distinguished from phototoxic reactions. Data of 1129 patients were evaluated. Among a total of 2859 positive test reactions in 870 patients, 2041 in 778 patients were found to be photoinduced and 818 in 413 patients were contact reactions; 108 reactions in 83 patients were classified as photoallergic. Nonsteroidal anti-inflammatory drugs, disinfectants, sunscreens, phenothiazines, and fragrances caused most often photoallergic reactions. Many unspecific phototoxic reactions were induced by tiaprofenic acid, promethazine, carprofen, chlorpromazine, fenticolar, wood balsam of Peru, and perfumes. Despite the distinction between photoallergic and phototoxic responses, many test reactions lacked relevance for the patients' dermatoses.
Article
The 'first-generation' quinolones cinoxacin, nalidixic acid, oxolinic acid, pipemidic acid and rosoxacin and the newly developed quinolones ciprofloxacin, enoxacin, fleroxacin, norfloxacin and ofloxacin were screened in vitro at 10(-5), 10(-4) and 10(-3) M concentrations for ultraviolet (UV)-induced phototoxic effects in a photohemolysis test. At 10(-3) M, photodependent effects of norfloxacin could not be evaluated, as hemolysis occurred without irradiation. All other compounds with the exception of ciprofloxacin were found to be phototoxic at 10(-3) M and some also at 10(-4) M. Hemolysis was UV dose dependent and for all compounds most prominent after exposure to UVA-rich radiation except for fleroxacin which was most active in the UVB range. Besides fleroxacin, also oxolinic acid, pipemidic acid and rosoxacin induced hemolysis with irradiations rich in UVB. It is concluded that quinolones have to be regarded as potentially phototoxic substances. Therefore intense light exposure should be avoided during treatment with these agents.
Article
Plants are nature's most efficient factories for producing a variety of chemicals. Of the more than half million known plant species, only about 12,000 have been investigated, with isolation and identification of about 11,000 naturally occurring compounds. 1,2 Most plant species are considered harmless, and only about 500 are reported to be harmful because of their topical or systemic toxicity.Adverse reactions of skin to plants, referred to as phytodermatitis, resulting from mechanical injury, toxicologie effects (eg, alkaloids), pharmacologic effects (eg, stinging nettle causing liberation of histamine and acetylcholine), contact dermatitis by irritant chemicals, and delayed hypersensitivity reactions involving immunologie mechanisms are discussed in other chapters. Phytophotodermatitis, evoked by several furocoumarins (psoralens) produced by such plant families as Umbelliferae, Leguminosae, Rutaceae, occurs only after contact with a plant (sap, leaves, etc.) and subsequent exposure of the skin to long-wave ultraviolet radiation. There is a considerable overlap because phytodermatitis may result from mechanical injury, chemical irritation, or sensitizing substances.The subject and literature concerning dermatitis and allergic plant dermatitis is voluminous, and our knowledge of the chemical nature of allergens present in plants still is limited. Existing data gathered from the published reports do not necessarily establish that the plants mentioned in the literature are indeed capable of inducing phytophotodermatitis; some plants may concomitantly produce reactions of the skin by direct mechanical trauma, contact irritation, allergic sensitization, photosensitization, or any combination of these factors.1–11This chapter is concerned primarily with plants that contain certain photosensitizing agents that may induce photodermatitis only when skin is exposed to sunlight either inadvertently or deliberately. The reactions are mostly phototoxic in nature1,2: they are invariably not dependent on an antigen-antibody relationship or a cell-mediated hypersensitivity reaction. Following the review of phytophotodermatitis in humans, this chapter also includes a brief survey of phytophotodermatosis in animals.
Article
Lemon oil contains furocoumarin derivatives and is known to cause phototoxicity. In this study, lemon oil was fractionated, and its phototoxic activity was measured by means of a biological assay. The substances producing phototoxicity were identified by high-performance liquid chromatography as being oxypeucedanin and bergapten. The phototoxic potency of oxypeucedanin was only one-quarter of that of bergapten. However, the amounts of these two phototoxic compounds present in lemon oils produced in different regions of the world varied by a factor of more than 20 (bergapten, 4-87 ppm; oxypeucedanin, 26-728 ppm), and their ratio was not constant. The two compounds accounted for essentially all of the phototoxic activity of all lemon-oil samples. Among various other citrus-essential oils investigated, lime oil and bitter-orange oil also contained large amounts of oxypeucedanin. Oxypeucedanin was found to elicit photopigmentation on colored-guinea-pig skin without preceding visible erythema.
Article
Delayed contact allergies and the clinical course of the skin disease were investigated in 14 patients with photosensitivity dermatitis/actinic reticuloid and 145 patients with polymorphous light eruption type eczema. Hypersensitivity to chromium and rubber chemicals was encountered in photosensitivity dermatitis more often than in polymorphous light eruption eczema and in the comparison series of 1714 patients with other types of dermatitis. In the eczema group, delayed contact allergies to chromium, rubber chemicals, neomycin, clioquinol, balsam of Peru, fragrance and colophonium were more frequent than in the comparison group, suggesting that at least delayed contact allergy to chromium and rubber chemicals may be of significance in the development of photosensitivity in many patients who suffer eczematous reaction to sunlight.
Article
A quantitative in vitro method for phototoxic evaluation of chemicals has been developed and validated. The assay uses Saccharomyces cerevisiae, seeded in an agar overlay on top of a plate count agar base. 8-Methoxy psoralen is used as a reference standard against which materials are measured. Activity is quantified by cytotoxicity measured as zones of inhibition. Several known phototoxins (heliotropine, lyral, phantolid, and bergamot oil) and photoallergens (6-methyl coumarin and musk ambrette) are used to validate the assay. An excellent correlation is observed between in vivo studies employing Hartley albino guinea pigs and the in vitro assay for several fragrance raw materials and other chemicals. The in vitro assay exhibits a greater sensitivity from 2-500 fold. For three fragrance oils, the in vitro assay detects low levels of photobiological activity while the in vivo assay is negative. Although the in vitro assay does not discriminate between phototoxins and photoallergens, it can be used for screening of raw materials so that reduction in animal usage can be achieved while maintaining the protection of the consumer.
Article
Contact allergic sensitivity to allergens such as plants of the Compositae family is a feature of the chronic skin reaction seen in the photosensitivity dermatitis with actinic reticuloid syndrome. In fifty patients with this syndrome an increased incidence of contact allergic sensitivity to some common fragrance materials was demonstrated. Evidence is also presented, both by in vitro and in vivo studies, which indicates that a phototoxic mechanism is involved. The relevance of continued exposure to common allergens and their involvement in photosensitization mechanisms is discussed in an attempt to explain the state of 'persistent light reaction'.
Article
Cutaneous photosensitivity diseases may be idiopathic, produced by endogenous photosensitizers, or associated with exogenous photosensitizers. Those caused by exogenous agents include phototoxicity, photoallergy, and the exacerbation or induction of systemic disorders in which photosensitivity is a prominent clinical manifestation. Phototoxic disorders have a high incidence, whereas photoallergic reactions are much less frequent. The action spectra for most phototoxins and photoallergens lie in the UVA range. Phototoxic and photoallergic reactions can be distinguished on the basis of pathogenesis, clinical characteristics, diagnosis, and management. Drugs capable of causing phototoxic reactions include psoralens, porphyrins, coal tar, antibiotics, and nonsteroidal antiinflammatory agents. Drugs capable of causing photoallergic reactions include topical antimicrobial agents, fragrances, sunscreens, nonsteroidal antiinflammatory agents, plants, and psychiatric medications. Drug-induced systemic diseases in which photosensitivity is a prominent component include drug-induced lupus erythematosus, porphyria, and pellagra.
Article
As some fibric acid derivatives have been reported to exhibit photosensitizing effects in vivo, the antilipemic drugs fenofibrate, bezafibrate, clofibrate, and gemfibrozil were tested for their phototoxic potential in vitro by a photohemolysis test using human erythrocytes and different irradiation sources. In this system only fenofibrate revealed strong phototoxic properties, which were dependent both on the drug concentration and the irradiation doses. Above a surface dose of 40 J/cm2 UVA of an UVA (320-400 nm)-rich irradiation source or 1.6 J/cm2 UVB/0.8 J/cm2 UVA of an UVB (280-320 nm)-rich irradiation source human red blood cells were completely photohemolysed in the presence of fenofibrate. Bezafibrate- and gemfibrozil-induced photohemolysis remained beneath 10%, and clofibrate showed no phototoxicity at all. As the phototoxic potential of fenofibrate lies in the UVB and UVA range, this might be of relevance with regard to clinical photosensitivity.
Article
Fluoroquinolone antibacterials are known to be phototoxic, both in vivo and in vitro. The action spectrum for the phototoxicity of the quinolones lies mainly in the UVA region. During studies of systemic drug phototoxicity, Johnson et al. (Dundee) induced dose-dependent phototoxicity in Swiss albino mice, and severe phototoxic reactions were followed by the development of skin tumors. The present study was designed to compare the ability of several quinolones to produce photobiologic effects following chronic, subphototoxic UVA radiation. To compare the activities of different quinolones (lomefloxacin, fleroxacin, ciprofloxacin, ofloxacin and nalidixic acid), doses that result in similar plasma and skin levels of drug were administered by gavage to slightly pigmented Skh-1 hairless mice for up to 78 weeks. 8-Methoxypsoralen (8-MOP) was used as a positive control, and unirradiated, drug-treated and irradiated and unirradiated drug-free controls were also used. No signs of phototoxicity were seen, except for minimal-to-slight erythema and swelling of the skin in animals of the lomefloxacin-UVA group. Skin tumors (1 mm in diameter or larger) were observed in all the irradiated groups and the incidence was increased in all the groups treated with the test articles. The cumulative tumor prevalence was accelerated, the median latent periods were shortened and tumor onset was significantly enhanced by 8-MOP plus UVA, lomefloxacin plus UVA and fleroxacin plus UVA, as compared with vehicle plus UVA-exposed animals. The majority of skin tumors (with the exception of lomefloxacin and 8-MOP) were benign. The majority of squamous cell carcinomas in the lomefloxacin group were of a histologic type different from those previously reported in UVA-exposed animals. Thus, all the fluoroquinolone antibiotics studied have the capability of enhancing UVA-induced phototumorigenesis, but only lomefloxacin caused the development of cystic squamous cell carcinomas in the majority of treated animals.
Article
Photo-induced eruptions are well-known adverse effects of some neuroleptic drugs, particularly chlorpromazine. By a photohemolysis test we assessed in vitro the phototoxic properties of 12 phenothiazines (chlorpromazine, dixyrazine, fluphenazine, levomepromazine, perazine, perphenazine, promazine, promethazine, prothipendyl, thioridazine, trifluoperazine, triflupromazine) and 5 thioxanthenes (chlorprothixene, clopenthixol, flupenthixol, thiothixene, zuclopenthixol). Human erythrocytes from 3 donors were incubated with the compounds and irradiated with light sources rich in UVA or UVB, respectively. Doses were up to 100 J/cm2 UVA or up to 1,600 mJ/cm2 UVB. Photo-induced hemolysis was calculated as percentage of complete hemolysis. Photo-induced hemolysis >10% due to radiation rich in UVA was found with chlorpromazine (maximal median: 98%), dixyrazine (100%), fluphenazine (84%), perazine (100%), perphenazine (100%), promazine (16%), promethazine (25%), prothipendyl (96%), trifluoperazine (100%), triflupromazine (76%), chlorprothixene (100%) and thiothixene (31%). UVB-rich radiation induced hemolysis only with chlorpromazine (73%), dixyrazine (45%) and perazine (60%). Most neuroleptics are strongly phototoxic in vitro indicating a potential risk for photo-induced reactions also to occur in patients treated with these drugs.
Article
This review summarizes published and unpublished data of our 15-year experience with sunscreen allergy and photoallergy. From 1981-1996, 402 patients with suspected clinical photosensitivity were patch and photopatch tested with the commercial sunscreens and facial cosmetics that they had used and with chemical UV absorbers, fragrance materials, preservatives, and emollients. 80 patients (20%) (28 men, 52 women) demonstrated allergic and/or photoallergic contact dermatitis to 1 or more UV absorber(s). In 47 patients with photodermatoses or photo-aggravated dermatoses and in 33 subjects with normal photosensitivity, 91 allergic and 84 photoallergic reactions to UV filters were observed. Over the years sunscreens were added to the test series, which since 1989 comprised the following 10 UV absorbers and which induced allergic (a) and photoallergic (pa) reactions (number, type of reaction): 4 UVA absorbers--isopropyldibenzoylmethane (30a/32pa); butyl methoxydibenzoyl-methane (15a/13pa); benzophenone-3 (3a/9pa); benzophenone-4 (0a/0pa); and 6 UVB absorbers--PABA (2a/2pa); octyl dimethyl PABA (1a/2pa); methylbenzylidene camphor (32a/5pa); octyl methoxycinnamate (3a/4pa); isoamyl p-methoxycinnamate (4a/10pa); and phenylbenzimidazole sulfonic acid (1a/7pa). The frequent (photo)sensitization to isopropyldibenzoylmethane was the reason that its production was discontinued in 1993. 47 patients reacted to fragrance materials, 11 to preservatives and 2 to lanolin alcohol. These constituents were contained in the commercial sunscreens and cosmetics that they had used. Continuous revision of the UV absorber photopatch test series was necessary to be closer to the real frequency of exposure and of reported (photo)allergy to newer sunscreens. Clinicians should consider contact and photocontact allergy, especially in patients with photodermatoses and photo-aggravated dermatoses, and they should perform photopatch testing. Once the culprit has been identified, its INCI (International Nomenclature Cosmetic Ingredients) designation should be given to the patient, who must be warned to avoid products containing the (photo)allergen.
Article
To the Editor: Actinic (or solar) keratosis is a potential precursor of squamous-cell carcinoma of the skin. Its development is related to the cumulative exposure to ultraviolet radiation from the sun and the sensitivity of people to this radiation. Many drugs have photosensitizing effects,1–3 and some, such as psoralens4 and fluoroquinolones,5 augment photocarcinogenesis. We hypothesized that other photosensitizing drugs could also act in this way. We studied 68 consecutive patients more than 60 years of age who were attending our dermatology clinic for various skin conditions other than actinic keratosis. We asked each patient if he or she had . . .
Article
Over 2000 different ingredients are used in the manufacture of fragrances. The majority of these ingredients have been used for many decades. Despite this long history of use, all of these ingredients need continued monitoring to ensure that each ingredient meets acceptable safety standards. As with other large databases of existing chemicals, fulfilling this need requires an organized approach to identify the most important potential hazards. One such approach, specifically considering the dermal route of exposure as the most relevant one for fragrance ingredients, has been developed. This approach provides a rational selection of materials for review and gives guidance for determining the test data that would normally be considered necessary for the elevation of safety under intended conditions of use. As a first step, the process takes into account the following criteria: quantity of use, consumer exposure, and chemical structure. These are then used for the orderly selection of materials for review with higher quantity, higher exposure, and the presence of defined structural alerts all contributing to a higher priority for review. These structural alerts along with certain exposure and volume limits are then used to develop guidelines for determining the quality and quantity of data considered necessary to support an adequate safety evaluation of the chosen materials, taking into account existing data on the substance itself as well as on closely related analogs. This approach can be considered an alternative to testing; therefore, it is designed to be conservative but not so much so as to require excessive effort when not justified.
Article
A combination of psoralens and ultraviolet A radiation is widely used to treat psoriasis. Long-term, high-dose exposure to psoralen + ultraviolet A is associated with an increased risk of nonmelanoma skin cancer, particularly squamous cell carcinoma. In this study, we used p53 mutations as a molecular marker to determine the separate contributions of psoralen + ultraviolet A and other ultraviolet exposures, such as ultraviolet B for skin cancer development in psoralen + ultraviolet A-treated psoriasis patients. The results indicated that of 69 tumors analyzed, 37 (54%) tumors had one or more p53 mutations. Of 37 tumors with mutations, 17 (46%) tumors had only ultraviolet-type mutations, two (5%) tumors had only psoralen + ultraviolet A-type mutations, and 18 (49%) tumors had both types of mutations. Interestingly, psoralen + ultraviolet A-type p53 mutations were more frequent than ultraviolet type in tumors arising in patients with high-dose exposure to psoralen + ultraviolet A. Field cancerization and tumor heterogeneity appeared to occur frequently in the same patient and even in the same tumor. This study's data suggest that psoralen + ultraviolet A-induced p53 mutations may play an important part in the development of nonmelanoma skin cancer in psoralen + ultraviolet A-treated patients, but these mutations are likely to act in concert with the effects of other carcinogenic exposures, particularly ultraviolet B, in the development of skin cancer.
Article
Ultraviolet (UV) radiation induces a specific tolerance toward UV-induced skin tumors. This phenomenon has been known and studied for more than 25 years, but the mechanisms by which protective tumor immunity or tumor tolerance is induced are still largely obscure. In parallel with these studies, short-term assays on UV-induced immunosuppression and tolerance toward simple chemicals (e.g., dinitrochlorobenzene) have been analyzed, particularly with respect to the role of cytokines (most notably, interleukin (IL)-10 vs IL-12). However, these short-term assays are not likely to be fully adequate models of the long-term UV-induced tumor tolerance. The important nodal points of action in these immune reactions appear to be the T cells and the antigen-presenting cells (APCs) that prime them. The main focus should probably be on CD8(+) T cells as the ultimate effector of the cytotoxic response against UV-induced skin cancers. APC-mediated activation of these cells depends strongly on cosignaling of CD4(+) T cells. In a tumor tolerant state the activity of the cytotoxic CD8(+) T cells appears to be inhibited through CTLA-4(+) and natural killer T cells. The latter cells are CD1-restricted, which indicates the importance of "unconventional" antigens to UV-induced tumor tolerance.
Article
Chronic irradiation of mice with ultraviolet (UV) light produces a systemic alteration of an immunologic nature. This alteration is detectable in mice long before primary skin cancers induced by UV light begin to appear. The alteration results in the failure of UV-irradiated mice to reject highly antigenic, transplanted UV-induced tumors that are rejected by unirradiated syngeneic recipients. The immunologic aspect of this systemic alteration was demonstrated by transferring lymphoid cells from UV-irradiated mice to lethally x-irradiated recipients. These recipients were unable to resist a later challenge with a syngeneic UV-induced tumor, whereas those given lymphoid cells from normal donors were resistant to tumor growth. Parabiosis of normal mice with UV-irradiated mice, followed by tumor challenge of both parabionts with a UV-induced tumor, resulted in the growth of the challenge tumors in both WV-irradiated and unirradiated mice. Splenic lymphocytes from tumor-implanted UV-treated mice were not cytotoxic in vitro against UV-induced tumors, whereas under identical conditions cells from tumor-implanted, unirradiated mice were highly cytotoxic. Our findings suggest that repeated UV irradiation can circumvent an immunologic mechanism that might otherwise destroy nascent UV-induced primary tumors that are strongly antigenic.
Article
Increasing frequencies of sensitization to the fragrance mix (FM) have been acknowledged as a serious problem for many years. It is well known that the single compounds (SCs) of the FM contribute differently to the FM patch rest reactions. In this study, we were interested in the time trends of the FM, the SCs, Myroxylon pereirae resin (MP; balsam of Peru) and oil of turpentine (OT) as possible further indicators of perfume allergy and analysed the data collected by the Information Network of Departments of Dermatology multicentre project from 1996 to 2002. During the study period (1996-2002), the FM [8% petrolatum (pet.)], MP (25% pet.) and OT (1% pet.) were tested in 59,298, 59,334 and 59,478 patients, respectively. SCs were tested in a selected group of patients, ranging from n = 1083 to n = 1924 per year. A significant increase in the proportions of patients with positive reactions to FM, MP and OT between 1996 and 1998 is noted, and a significant decline from 1999 to 2002 (Cochrane Armitage trend test, P < 0.0001). The highest frequency of sensitization to the FM was 13.1% in 1999, and the lowest 7.8% in 2002. The number of concomitant reactions to OT, a surrogate marker for terpenes, in FM-positive patients was significantly increased between 1997 and 1999. Reactions to SCs in FM-positive patients were observed in 29.9% (oak moss absolute) to 5.9% (geraniol). There was no time trend in reactions to SCs, although the relative share was increased for isoeugenol, cinnamic aldehyde and geraniol in 1999. In summary, we report for the first time, a significant decline in sensitization to the FM, very probably due to a reduced exposure (less potent allergens used in fine fragrances, possibly less use of natural ingredient-based cosmetics and lowered use concentration of important fragrance allergens). The differences in ranking of SCs could stimulate (a) a redefinition of the FM and (b) a differentiated preventive and regulatory approach, with oak moss and isoeugenol being regulated strictly by prohibition, concentration limits further reconsidered and/or health warnings and clearly less noxious substances like geraniol treated less restrictively.
Article
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.
Article
Antimicrobials are widely used in topical formulations as preservatives or as therapeutically active agents. Photosensitization by such compounds has not yet been studied systematically. To identify possible phototoxic properties, antimicrobials (benzyl alcohol, bronopol, chloracetamide, clioquinol, diazolidinyl urea, ethylenediamine dihydrochloride, formaldehyde, glutaraldehyde, imidazolidinyl urea, sodium benzoate, propylene glycol) were evaluated in vitro by means of a photohaemolysis test using suspensions of human erythrocytes. Irradiations were performed with UVA- and UVB-rich light sources. In the presence of bronopol or clioquinol, there was photohaemolysis up to 78.1% or 48.5% with UVA and up to 100% or 34.3% with UVB, respectively. The phototoxic effect depended on the concentration of the compounds and the UV doses administered. None of the other substances tested caused significant photohaemolysis. It is concluded that bronopol and clioquinol exert phototoxic effects in vitro and thus might also cause photosensitization when used on the skin. The clinical significance of this has to be established by further work.
Contact and photocontact sensitivity to sunscreens Review of a 15-year experience and of the literature Freund E. Über bisher noch nicht beschriebene künstliche Hautverfärbungen
  • S Schauder
  • Ippen
Schauder S, Ippen H. Contact and photocontact sensitivity to sunscreens. Review of a 15-year experience and of the literature. Contact Dermatitis 1997; 37: 221–232. 11. Freund E. Über bisher noch nicht beschriebene künstliche Hautverfärbungen. Dermatolog. Wochenschrift 1916; 63: 931–933.
Quinolone antibacterials: a new class of photochemical carcinogens
  • M Mäkinem
  • Pd Forbes
  • F Sternbäck
Mäkinem M, Forbes PD, Sternbäck F. Quinolone antibacterials: a new class of photochemical carcinogens. J Photochem Photobiol B Biol 1997; 37: 182-187.