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.

[Current problems of polypharmacy in geriatric patients when taking drugs with a risk of photosensitivity.]

The article presents an overview of the current problems of polypharmacy in geriatric patients when taking drugs with a risk of photosensitivity. The article contains information about emerging adverse drug reactions, as well as methods for diagnosing, correcting and preventing phototoxic and photoallergic reactions in patients of older age groups. The main aspects of dermatological support in the system of long-term care for geriatric patients when taking drugs with a risk of photosensitivity are outlined. Clinical signs of senile xerosis and skin manifestations of adverse drug reactions were studied when taking drugs with the risk of photosensitization before and after the use of a photoprotector in elderly patients.

Anticancer treatments and photosensitivity.

Drug-induced photosensitivity is associated with a wide range of anticancer treatments, including conventional chemotherapeutic agents, targeted anticancer therapies, and immune checkpoint inhibitors. These dermatologic adverse events can have a major impact on the well-being and quality of life of cancer patients, leading to dose modifications and interruption or discontinuation of anticancer treatments in severe cases. However, the heterogeneous nature of the photosensitive reactions induced by these agents, as well as the common concomitant use of other potentially photosensitizing drugs (antibiotics, voriconazole, nonsteroidal anti-inflammatory drugs, etc.), can make the diagnosis and, therefore the prevention, of these adverse events particularly challenging. The aim of this review is to describe the most characteristic forms of photosensitivity observed in patients being treated with anticancer treatments, including phototoxicity and photoallergy, and other potentially photo-induced manifestations such as UV recall, exaggerated sunburn reactions associated with treatment-related vitiligo, drug-induced cutaneous lupus erythematosus, and UV-induced hyperpigmentation. We also discuss the photosensitive reactions recently reported with new-generation targeted anticancer therapies and immune checkpoint inhibitors and highlight the importance of continued surveillance to identify photosensitizing agents, and of educating patients on the need for preventive UVA/UVB photoprotective measures.

Photosensitizing drug reactions.

Photosensitizing drug reactions are cutaneous eruptions that occur after exposure to ultraviolet radiation in patients using photosensitizing medications. The reactions can be broadly classified into phototoxic and photoallergic, with the former being much more common and well documented. There is an extensive list of photosensitizing medications, especially in the case of phototoxicity. The most common are amiodarone, chlorpromazine, doxycycline, hydrochlorothiazide, nalidixic acid, naproxen, piroxicam, tetracycline, thioridazine, vemurafenib, and voriconazole. Most of the medications implicated in photosensitivity share an action spectrum within the ultraviolet A range. Distinguishing between phototoxicity and photoallergy can be difficult, because some clinical overlap exists between the two disorders. It is often done based on pathogenesis, clinical presentation, and diagnosis. Management is similar for both types of reactions, with the gold standard being prevention. This review provides an overview of the photosensitizing drug reactions and highlights the similarities and differences between phototoxicity and photoallergy, as well as other photosensitizing drug reactions in the phototoxicity family including lichenoid reactions and pseudoporphyria.

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.

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 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.

Standard photopatch test battery? Proposal based on current epidemiology and experience in our Skin Allergy Unit.

BACKGROUND: The diagnosis of photoallergic contact dermatitis (PACD) is confirmed by photopatch testing (PPT). In Spain, the latest recommendation on which allergens to test in PPT dates from 1995. METHODS: In the last 4 years, we studied 455 patients with epicutaneous tests and performed PPT on 33 of those patients (7.3%). RESULTS: The most prevalent allergens in PPT were as follows: non-steroidal anti-inflammatory drugs (NSAIDs) (46%), fragrances (21%), and solar filters (18%). DISCUSSION: In our country, the most common photoallergens continue to be NSAIDs (ketoprofen). The increasingly common use of sunscreens has led to a growing involvement of solar filters in PACD, which can be also contained in other cosmetics. In our experience, PACD due to fragrances is nonetheless at least similar in frequency. CONCLUSIONS: The PPT battery must adapt to the prescription, use, and exposure habits of each country. We propose a diagnostic model to guide which allergens to test in PPT, which in our experience should also include fragrances.

Photopatch Testing in New Zealand: A 12-Year Retrospective Review.

BACKGROUND: Little is known about the common photoallergens in New Zealand, where ultraviolet exposure is particularly high. Availability of photopatch testing is limited because of it being performed in very few tertiary referral and contact dermatitis clinics. OBJECTIVE: To review the photopatch testing experience in New Zealand. METHOD: A retrospective review of all patients who underwent photopatch testing at a tertiary referral center in Auckland from 2008 to 2019 was performed. RESULTS: Seventy patients had photopatch testing over the 12-year period. Of the 58 patients tested using the photoallergen series, 6 (10%) patients had a positive photopatch test reaction, of which 4 were to promethazine and 2 were to benzophenone-3. The most common postpatch diagnosis was endogenous dermatitis (54%), followed by allergic contact dermatitis (21%), photoallergic contact dermatitis (9%), and chronic actinic dermatitis (4%). CONCLUSIONS: Both patch and photopatch testing are important investigations in patients with suspected photoallergic contact dermatitis. Promethazine and benzophenone-3 were the most frequent and only photoallergens in our population. Promethazine sensitization was via oral exposure, supporting a mechanism of systematized photoallergy to promethazine.

Photopatch testing in a tropical country, Thailand: 20 years' experience.

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.

Thoughts on the interpretation of positive photopatch test reactions.

BACKGROUND: Positive photopatch test reactions are classified according to the International Contact Dermatitis Group. The various reaction patterns are interpreted to represent patterns such as contact allergy, photocontact allergy, photoaugmentation, and photoinhibition. OBJECTIVE: To investigate whether there are any weaknesses in the interpretation of reaction patterns. MATERIALS & METHODS: A dermatitis patient with photoallergic contact dermatitis due to ketoprofen was photopatch tested with serial dilutions of ketoprofen in ethanol. The reaction patterns for the various concentrations were used as a basis for discussion on weaknesses regarding the present interpretations of positive photopatch test reactions. RESULTS: The reaction patterns to the ketoprofen photopatch at various concentrations were interpreted as (i) contact allergy, (ii) contact allergy with photoaugmentation, (iii) contact allergy and photocontact allergy, and (iv) photocontact allergy. CONCLUSION: The present interpretation of positive photopatch test reactions is unreliable and therefore insufficient regarding appropriate advice for patients.