Contact allergy to oxidised geraniol may be over-represented in individuals with photocontact allergy to ketoprofen.

BACKGROUND: Simultaneous overrepresentations of contact allergies and photocontact allergies are common in individuals with photocontact allergy to ketoprofen. AIMS: To investigate whether contact allergy to oxidised (ox.) geraniol, geraniol, geranial, neral and citral is overrepresented in individuals with photocontact allergy to ketoprofen. METHODS: The contact allergy rates to ox. geraniol, geraniol, geranial, neral and citral in routinely patch tested dermatitis patients were compared with the corresponding rates in individuals with photocontact allergy to ketoprofen. RESULTS: Allergic patch test reactions were noted to ox. geraniol 11% (n = 39, 5.8%), ox. geraniol 6% (n = 12, 1.8%), geraniol 6% (n = 2, 0.3%), geranial (n = 18, 2.7%), neral (n = 7, 1.0%) and citral (n = 15, 2.2%). In those four patients who were diagnosed with photocontact allergy to ketoprofen during the test period, a significant overrepresentation (p = 0.020) of simultaneous contact allergy to ox. geraniol 11% was demonstrated. Overrepresentation of simultaneous contact allergy to various combinations of ox. geraniol, ox. limonene and ox. linalool was also noted in ketoprofen-photoallergic patients. CONCLUSIONS: Contact allergy to ox. geraniol, geranial and citral is common in routinely tested dermatitis patients. There is an overrepresentation of simultaneous contact allergy to ox. geraniol, ox. limonene and ox. linalool in patients with photocontact allergy to ketoprofen.

Non-animal approaches for photoallergenicity safety assessment: Needs and perspectives for the toxicology for the 21st century.

Certain chemicals and/or their byproducts are photoactivated by UV/VIS and trigger a dermal allergenic response, clinically recognized as photoallergic contact dermatitis (PACD). It is important to identify the chemicals which are potentially photoallergenic, not only for establishing the correct differential diagnosis between PACD and other photodermatoses, but also as causative agents which should be avoided as a preventative measure. Moreover, materials with photoallergenic properties need to be correctly identified to allow thorough safety assessments for their use in finished products (e.g. cosmetics). Development of methods for predicting photoallergenicity potential of chemicals has advanced at slow pace in recent years. To date, there are no validated methods for photosensitisation potential of chemicals for regulatory purposes, although it remains a required endpoint in some regions. The purpose of this review is to explore the mechanisms potentially involved in the photosensitisation process and discuss the methods available in the literature for identification of photosensitisers. The review also explores the possibilities of further research investment required to develop human-relevant new approach methodologies (NAMs) and next generation risk assessment (NGRA) approaches, considering the current perspectives and needs of the Toxicology for the 21st Century.

Photopatch testing in Singapore: A 10-year retrospective study.

BACKGROUND: Photopatch testing represents the gold standard for the diagnosis of photoallergic contact dermatitis (PACD). We aimed to identify common photoallergens in our tertiary dermatological referral centre from 2012 to 2021, to compare this to the preceding period studied, and data from other communities. METHODS: We conducted a retrospective review of all 90 patients who underwent photopatch testing at the National Skin Centre, Singapore, between 2012 and 2021. RESULTS: Of 90 patients, 19 (21.1%) were male, and the mean age was 41.6 years. Eighty-four (93.3%) underwent testing to our standard sunscreen series, 10 (11.1%) to our extended series, and 73 (81.1%) to their own items. Seventeen (18.9%) were diagnosed with PACD (i.e., photocontact allergy with present or past relevance), 12 (13.3%) with ACD, and 4 (4.4%) with photoaugmented ACD. Relevant reactions were commonest to oxybenzone (8, 9.5%) and mexenone (3, 3.6%). Eleven (15.1%) had PACD to their own items, with 3 of 4 (75%) tested to ketoprofen diagnosed with PACD and the remaining 1 (25%) with photoaugmented ACD. Age, race, sex, atopy, and site of involvement were not associated with photocontact allergy. Compared to the preceding time period, the overall frequency of photocontact allergy and PACD decreased, but rates of photoallergic reactions to individual photoallergens were not significantly different. CONCLUSION: Organic ultraviolet absorbers such as oxybenzone and mexenone remained the most relevant photoallergens. Personal item testing was valuable, and testing to ketoprofen should be considered.

Shedding a light on the importance of photopatch testing: A 12-year experience in a dermatology unit.

BACKGROUND: Photopatch testing has been standardized for diagnosing photoallergic contact dermatitis but is still infrequently used. OBJECTIVES: To characterize photopatch test (PPT) results and their clinical relevance. METHODS: We collected retrospective data from patients photopatch tested in our Dermatology Unit (2010-2021), using the European PPT 'baseline' series, other allergens, and patient's own products, when appropriate. RESULTS: Out of 223 patients, 75 patients (33.6%) were reactive with 124 positive PPT reactions, considered relevant in 56/223 patients (25.1%) and in 72/124 reactions (58.1%). Most reactions were caused by topical drugs (n = 33; 45.8%), such as ketoprofen or promethazine, and 7 (9.8%) by systemic drugs, such as hydrochlorothiazide and fenofibrate. 'Classical' ultraviolet filters were responsible for six positive PPT reactions whereas there was only three relevant PPT to the 'newer' UV filters. Patients' sunscreens/cosmetics or plant extracts caused 10 positive PPT each. Additional patch test reactions were observed, mostly to Tinosorb® M. CONCLUSION: Contrary to the trend in ACD, most positive PPT reactions were caused by topical drugs, outweighing ultraviolet filters and cosmetics. We stress the low reactivity to the 'newer' UV filters included in the PPT series. PPT was occasionally positive in systemic drug photosensitivity, but overall PPT reactivity was low.

Sunscreens: A Review of UV Filters and Their Allergic Potential.

Abstract Active ingredients of sunscreens, or UV filters, have increased in use because public awareness of sun safety has risen. In addition to this intentional use, unintentional exposures to UV filters also occur through application of personal care products, where the filters are incorporated into the product. There are 2 main types of UV filters: organic (chemical) filters and the 2 inorganic (mineral) filters, titanium dioxide and zinc oxide. Both allergic contact dermatitis (ACD) and photoallergic contact dermatitis (PACD) have been caused by organic filters; oxybenzone (benzophenone-3) is the most frequently reported contact and photocontact allergen compared with all other UV filters. There are no reports of ACD or PACD to the inorganic (physical) UV filters. Here, we review the categories of sunscreens available, currently marketed UV filters, and their corresponding ACD and PACD.

Photosensitivity is an important cause of refractory facial erythema in atopic dermatitis: A retrospective study of 82 Chinese patients.

BACKGROUND: Ultraviolet radiation can aggravate facial erythema in atopic dermatitis (AD) patients. OBJECTIVE: To investigate the photobiological testing results of Chinese AD patients with refractory facial erythema. METHODS: We conducted a retrospective analysis of 82 AD patients with refractory facial erythema who visited our department during 2004-2021. All of them completed phototesting and photopatch testing. RESULTS: 82 patients were enrolled in the study, and 53 (64.6%) were between 18 and 30 years old. 51.2% (42/82) had positive phototesting results and were considered photosensitive AD (PhAD) patients. One-third of them were both allergic to ultraviolet A and ultraviolet B. 65.9% (54/82) suffered from photoallergic contact dermatitis. Chlorpromazine (50.7%), potassium dichromate (13.2%), and thimerosal (11.8%) were the top three common photoallergens. Overall, 86.3% of AD patients with refractory facial erythema had direct photoallergy or photocontact allergy. PhAD patients had fewer allergic comorbidities than the other group (p = .007). More non-PhAD patients (55.0%) suffered from AD at 2-14 years old (p = .015). CONCLUSIONS: Photosensitivity contributes a lot to the facial lesions of AD patients, especially in their 20s. 86.3% of these patients had direct photoallergy or photocontact allergy. Therefore, AD patients with facial erythema should undergo phototesting and photopatch testing routinely.

A new case of photoallergic contact dermatitis caused by benzophenones in magazine covers.

BACKGROUND: Allergic contact dermatitis (ACD) and photoallergic contact dermatitis (PACD) to benzophenone present in printing ink have been reported. However, precise chemical analyses and extended photo-patch tests have not been performed in these cases. OBJECTIVES: To determine which components present in a magazine cover are responsible for a patient's skin reaction, to determine the primary sensitizer, and precisely diagnose ACD and PACD. METHODS: After initial photo-patch tests were performed on a patient with a history of reaction to magazine covers after sun exposure, gas chromatography-mass spectrometry and high-performance liquid chromatography analyses of the magazine covers, and additional photo-patch tests were performed. RESULTS: The first photo-patch test results confirmed PACD to ketoprofen and fenofibrate and evoked PACD to the magazine covers. 4-methyl benzophenone (4-MBP) and 1-hydroxy-cyclohexyl-phenyl-ketone (1-HCPK) were found in the magazine cover. Additional photo-patch tests confirmed PACD to 1-HCPK and to benzophenone, and photo-aggravated ACD to 4-MBP. The primary sensitizer was ketoprofen. CONCLUSIONS: Benzophenones are present in a wide variety of products, without always being listed on the packaging. Patients previously sensitized to other ketones, such as ketoprofen, may react to benzophenones without being able to avoid contact with these molecules. New regulations may be needed for more efficient eviction advice.

Ketoprofen-induced Photoallergic Reaction.

Dear Editor, Photoallergic reactions are classic T-cell-mediated or delayed-type hypersensitivity reactions of the skin in response to a photoallergen (or a cross-reacting chemical) to which a subject was sensitized in the past (1). The immune system recognizes the changes caused by ultraviolet (UV) radiation; it produces antibodies and causes inflammation of the skin in the exposed areas (2). Common photoallergic drugs and ingredients are included in some sunscreens, aftershave lotions, antimicrobials (especially sulfonamides), non-steroidal anti-inflammatory drugs (NSAIDs), diuretics, anticonvulsants, chemotherapy drugs, fragrances, and other hygiene products (1,3,4). A 64-year-old female patient was admitted to the Department of Dermatology and Venereology with erythema and underlining edema on her left foot (Figure 1). A few weeks earlier, the patient had had a fracture of the metatarsal bones and since then she had been taking NSAIDs systemically every day to suppress pain. Five days before being admitted to our Department, the patient started applying 2.5% ketoprofen gel to her left foot twice daily and was frequently exposed to the sun. For the last twenty years, the patient had been struggling with chronic back pain and was frequently taking different NSAIDs (ibuprofen, diclofenac, etc.). The patient also suffered from essential hypertension and was regularly taking ramipril. She was advised to discontinue ketoprofen application, avoid sunlight, and apply betamethasone cream twice daily for 7 days, which lead to complete resolution of the skin lesions in a few weeks. Two months later, we performed patch and photopatch tests to baseline series and topical ketoprofen. Only the irradiated side of the body where ketoprofen-containing gel was applied showed positive reaction to ketoprofen. Photoallergic reactions manifest as eczematous, pruritic lesions, which may spread to involve other areas of the skin that were not previously exposed to the sun (4). Ketoprofen is a nonsteroidal anti-inflammatory drug composed of a benzoylphenyl propionic acid that is commonly used both topically and systemically for the treatment of musculoskeletal diseases because of its analgesic and anti-inflammatory effects and low toxicity, but it is one of the most frequent photoallergens (1,5,6). Ketoprofen-induced photosensitivity reactions usually present as photoallergic dermatitis characterized as acute dermatitis with edema, erythema, papulovesicles, blisters, or erythema exsudativum multiforme-like lesions at the application site 1 week to 1 month after the initiation of use (7). Depending on the frequency and intensity of sun exposure, ketoprofen photodermatitis may continue or reoccur up to 1 to 14 years after discontinuing the medication (6,8). Moreover, ketoprofen contaminates clothing, shoes, and bandages, and some cases of photoallergy relapses have been reported that were induced by ketoprofen-contaminated objects after they were used again in the presence of UV radiation (5,6). Due to their similar biochemical structure, patients with ketoprofen photoallergy should avoid using some drugs such as some NSAIDs (suprofen, tiaprofenic acid), antilipidemic agent (fenofibrate) and sunscreens based on benzophenones (6,9). Physicians and pharmacists should advise patients of the potential risks when topical NSAIDs are applied on the photoexposed skin.

Photoallergic Contact Dermatitis: No Fun in the Sun.

Photoallergic contact dermatitis (PACD) is a form of allergic contact dermatitis that occurs due to the interaction between a topically applied chemical and exposure to UV radiation. It can be difficult to identify and requires photopatch testing (PPT) for definitive diagnosis. In this article, we provide an overview of PACD, including clinical features, the most common photoallergens, and why cases may go undiagnosed.

In chemico sequential testing strategy for assessing the photoallegic potential.

Several non-animal testing methods to assess photoallergic potential have been developed so far, while none of them have yet to be validated and regulatory accepted. Currently, some photoreactivity assays such as UV-VIS spectral analysis and ROS assay are generally used for initial photosafety assessments because of their high sensitivity. However, they have a low specificity, generating a high percentage of false positive results, and the development of a follow-up assessment method is desired. Therefore, this study aimed to develop an in chemico photoallergy testing method, photo-direct peptide reactivity assay (photo-DPRA). Based on photosafety information, 34 photoallergens and 16 non-photoallergens were selected and subjected to UV-VIS spectral analysis, ROS/micellar ROS assays, photo-DPRA, sequential testing strategy (STS) consisting of all three methods, and 3T3 neutral red uptake phototoxicity testing (3T3 NRU PT). Combination of the methods addressing the key events of photoallergy exhibited high prediction performance. Our results showed the proposed strategy would be useful to predict the photoallergic potential of chemicals as the follow-up assessment for false positive chemicals by UV/VIS spectral analysis and ROS assay.

Contact allergy to fragrance mix I and its components in individuals with photocontact allergy to ketoprofen.

BACKGROUND: Contact allergy to fragrance mix I (FM I) is over-represented in patients photoallergic to ketoprofen. The prevalence of contact allergy to two components of FM I, cinnamal and cinnamyl alcohol, in ketoprofen-photoallergic patients is higher than in dermatitis patients. OBJECTIVE: To explore the prevalence of contact allergy to FM I and its individual components in patients with photocontact allergy to ketoprofen, and to compare with a dermatitis and the general population. METHODS: Data on patch and photopatch tests performed between 2009-2018 were collected. Ketoprofen-photoallergic patients were compared with dermatitis patients and published data on the general population regarding the prevalence and the distribution of contact allergy to FM I and its components. RESULTS: A higher prevalence of contact allergy to cinnamyl alcohol compared with cinnamal (23.3% vs 10.0%), and eugenol compared with isoeugenol (23.3% vs 6.7%), was observed in ketoprofen-photoallergic patients, while the relationship was the opposite in the dermatitis group (0.7% vs 1.05%; 0.4% vs 0.9%). The overall prevalence of contact allergy to several components of FM I was significantly higher in ketoprofen-photoallergic patients. CONCLUSIONS: Contact allergy to FM I and many of its components is over-represented in patients photoallergic to ketoprofen compared with dermatitis patients and the general population.

Assessment of Skin Photoallergy Risk in Cosmetics Containing Herbal Extract Ingredients.

BACKGROUND/OBJECTIVE: In recent years, herbal extracts are becoming increasingly popular ingredients added in cosmetics; however, the assessment of their potential adverse effects on the skin remains unclear. As Coptis, Phellodendron amurense, curcumin, and shikonin are herbs currently used in cosmetic ingredients, the aim of this study was to assess their skin photoallergy (PA) potential and the concentrations at which they could safely be used. METHODS: In the patch test, Coptis, P. amurense, curcumin, and shikonin with 5, 10, 25, and 50% concentration were applied on 33 healthy Chinese subjects using the T.R.U.E. TEST® patch test system for 48 h. Photopatch testing was performed on 206 Chinese subjects with predisposed photosensitivity history using the Scandinavian photopatch series, and subjects were irradiated by 50% UVA minimum erythema dose. Photopatch testing of herbal extracts was then performed on subjects diagnosed with PA. RESULTS: Thirty-three subjects (14 with type III skin and 19 with type IV skin) completed contact patch testing of herbal extracts. Coptis induced a contact allergy (CA) reaction on 2 subjects at 25% concentration and on 2 subjects at 10% concentration. P. amurense induced a CA reaction on 1 subject at 10% concentration and on 1 subject at 5% concentration. Shikonin induced a stimulating reaction on 1 subject at 10% concentration. Curcumin induced a stimulating reaction on 1 subject at 10% concentration. Of the 206 Chinese subjects predisposed for photosensitivity, 10.19% had PA, 16.5% showed CA, and 1.45% had both PA + CA. PA-induced substances were promethazine hydrochloride (15%, n = 31), chlorpromazine hydrochloride (10.84%, n = 19), perfume mix (5.82%, n = 12), atranorin (3.39%, n = 7), 6-methyl coumarine (3.39%, n = 7), balsam Peru (1.94%, n = 4), fentichlor (1.94%, n = 4), 3,3',4',5-tetrachloro salicylanilide (0.97%, n = 2), hexachlorophene (0.97%, n = 2), chlorhexidine digluconate (0.97%, n = 2), and 4-aminobenzoic acid 2-hydroxy-4-methoxybenzophenone (0.97%, n = 2). Coptis at 25, 10, and 5% concentration and P. amurense, shikonin, and curcumin each at 10 and 5% concentration induced negative photopatch test results in all 10 photosensitive subjects. CONCLUSION: We have shown that Coptis, shikonin, or curcumin at 5% concentration in cosmetics could be applied safely without inducing contact allergic and photosensitive reactions on the skin. These findings advance the understanding of herbal extract use in cosmetic ingredients as related to the fields of dermatopharmacology and dermatotoxicology.

An approach to evaluate metabolite-related phototoxicity with combined use of photochemical properties and skin deposition.

Some chemicals have been reported to cause metabolite-related phototoxicity, and this study aimed to verify the applicability of photosafety assessment based on photochemical and pharmacokinetic properties to evaluate the metabolite-related phototoxicity risk. The phototoxic risk of imipramine (IMI) and its metabolite, desipramine (DMI), was evaluated by photochemical and pharmacokinetic analyses. IMI and DMI were found to have similar photoreactivities based on the generation of reactive oxygen species. The skin concentrations of IMI and DMI reached maximal levels at approximately 1 and 4 h, respectively, after oral administration of IMI (10 mg/kg), and DMI showed high skin deposition compared with IMI. According to the results, DMI was identified as a contributor to phototoxicity induced by orally-taken IMI. In in vivo phototoxicity testing, ultraviolet A irradiation from 3 to 6 h after oral administration of IMI (100 mg/kg) caused more potent phototoxic reactions compared with that from 0 to 3 h, and DMI yielded by metabolism of IMI would be associated with phototoxic reactions caused by orally-administered IMI. In addition to the data on IMI, a parent chemical, photochemical and pharmacokinetic profiling of its metabolite, DMI, led to reliable phototoxicity prediction of orally-administered IMI. Thus, characterization of the photosafety of metabolites would generate reliable information on the phototoxicity risk of parent chemicals, and the proposed strategy may facilitate comprehensive photosafety assessment of drug candidates in pharmaceutical development.

Contact Allergy to Oxidized Linalool and Oxidized Limonene is Over-represented in Individuals with Photocontact Allergy to Ketoprofen.

Simultaneous contact allergies are common in individuals with photocontact allergy to ketoprofen. The rate of contact allergy to the fragrance substances oxidized linalool and oxidized limonene in ketoprofen-photo-allergic individuals were investigated in comparison with the corresponding rates in individuals without photo-contact allergy to ketoprofen, using Fisher's exact test. A total of 4,021 patients were routinely tested with oxidized linalool; of whom 190 (4.7%) tested positively. For oxidized limonene the numbers were 3,797 patients and 111 positive reactions (2.9%). A total of 19 contact allergic reactions to oxidized linalool were noted in 29 patients (65.5%) who also had photocontact allergy to ketoprofen (p < 0.0001). The corresponding figures for oxidized limonene were 10 positive reactions in 24 ketoprofen-photoallergic individuals (41.7%) (p < 0.0001). Contact allergy to oxidized linalool and/or oxidized limonene is common in routinely tested patients with dermatitis and, particularly, in those patients who are photoallergic to ketoprofen.

The presence of benzophenone in sunscreens and cosmetics containing the organic UV filter octocrylene: A laboratory study.

BACKGROUND: The reason why patients photosensitized to the drug ketoprofen (KP) may develop severe photoallergic skin reactions to octocrylene (OCT), an organic ultraviolet filter in sunscreens and cosmetics, remains largely unknown. OCT can be synthesized by using unsubstituted benzophenone (BP), a possible human carcinogen. OBJECTIVES: To verify if, and to what extent, BP residues are present in OCT-containing consumer products. METHODS: The raw material of OCT and 39 skincare products, of which 28 contain OCT, were chemically analysed for the presence of BP by means of liquid chromatography. RESULTS: In the OCT raw material and in all 28 OCT-containing products the presence of BP could be demonstrated, mostly in concentrations above 10 ppm (0.001%), whereas a majority of OCT-free products (8/11, 73%) did not contain BP. Moreover, BP concentrations significantly increased, in a time- and temperature-dependent manner, likely due to the additional degradation of OCT. CONCLUSIONS: Photoallergic contact dermatitis from OCT in patients photosensitized to KP might rely on residual BP impurities. Toxicological and ecological studies that evaluate the safety of OCT might also need to consider the concomitant presence of BP.