Volume 62, Issue 4 , Pages 605-610, April 2010
A 20-year analysis of previous and emerging allergens that elicit photoallergic contact dermatitis
Article Outline
Background
Retrospective chart reviews are periodically needed to update allergen series to detect changes in photoallergic contact dermatitis (PACD) over time.
Objective
We sought to evaluate photopatch test results during a 13-year period and extend the observations to 20 years.
Methods
A retrospective chart review was conducted in patients who were photopatch tested.
Results
In all, 76 patients were evaluated. A total of 69 positive photopatch and 45 positive patch test reactions were detected in 30 and 23 patients, respectively. The frequencies of the positive photopatch test reactions were sunscreens 23.2%, antimicrobial agents 23.2%, medications 20.3%, fragrances 13%, plants and plant derivatives 11.6%, and pesticides 8.7%. Of the positive photopatch reactions to antimicrobial agents, 60% were caused by Fentichlor.
Limitations
This study was a retrospective chart analysis, and the number of patients was small.
Conclusions
Sunscreens and antimicrobial agents were the most frequent allergens eliciting PACD, and there was a decrease in PACD caused by fragrances. The number of reactions to medications increased. This study also demonstrated that pesticides can be a cause of PACD. The detection of reactions to Fentichlor was unexpected and, although they have been attributed in some studies to cross-reactions to sulfanilamides and bithionol, such a robust association was not observed in this study. This study extends our experience of the changes in the allergens that elicit PACD to 20 years.
Key words: antimicrobial agents, Fentichlor, pesticides, photoallergic contact dermatitis, sunscreens
Photoallergic contact dermatitis (PACD) is an uncommon dermatosis that can only be diagnosed with the use of photopatch tests. The eruption presents as an eczematous eruption that occurs in a photodistribution. PACD is a T cell–mediated or delayed-type hypersensitivity reaction of the skin that occurs in response to a photoallergen or photoantigen in an individual who previously has been sensitized to the same chemical or one that cross-reacts with it.1 The pathogenesis of PACD is similar to that of allergic contact dermatitis, with the additional requirement of ultraviolet (UV) light.2 The action spectrum that most commonly elicits a photoallergic response is UVA, which includes wavelengths from 320 to 400 nm.
The allergens that cause PACD change based on product use by a population. The decline in the use of some products and the introduction of new ones have an impact on the prevalence of specific photoallergens that induce PACD. Retrospective chart reviews are one method to assess the prevalence of PACD and the responsible specific photoallergens. With this information, photoallergen series can be altered, and changes in trends over time may be detected. As an extension of our previous 7-year study,3 we sought to evaluate photopatch test results during an additional 13-year period to determine changes in the allergens that elicited PACD in the tested population and to seek potential alterations in the prevalence of PACD during a 20-year period.
Methods
After approval from our institutional review board, a retrospective chart review of patients presenting to our institution with a diagnosis of photosensitivity from October 1993 to December 2006 was performed. The age and sex of all patients, the date of the photopatch tests, and positive photopatch and patch test reactions were recorded.
Light sources
A bank of 47 HO-UVA bulbs (National Biologic Corp, Twinsburg, OH) served as the UVA light source. The output of the UVA light source was monitored monthly with an IL 1700 research radiometer (International Light Inc, Newburyport, MA).
Phototests and photopatch tests
These tests have been described previously.3 On day 1, duplicate sets of photoallergens were applied. The determination of the minimal erythema dose to UVA was performed. A series of 1.5- × 1.5-cm2 areas of the covered, uninvolved skin of the buttocks was exposed to incremental increases of UVA (8-45 J/cm2). On day 2, the minimal erythema dose-A was quantitated, and one set of photoallergens was exposed to UVA (either 10 J/cm2 or 50% of the minimal erythema dose-A, whichever was lower). On days 3 and 5 or 7, the irradiated and nonirradiated photopatch test sites were evaluated. The response was graded using a scoring system recommended by the International Contact Dermatitis Group: 1+, erythema and papules; 2+, edema or vesicles; 3+, bullae and/or erosions; 5, irritant reaction; and 6, negative reaction. A positive response at the irradiated sites, in the absence of a response at the nonirradiated site, was interpreted as PACD. A positive response of equal intensity at both irradiated and nonirradiated sites was interpreted as an allergic contact dermatitis. A response at both sites, in which the reaction was more pronounced at the irradiated site, was interpreted as both photoallergic and allergic contact dermatitis. The photoallergens used were the Charles C. Harris Skin and Cancer Pavilion photoallergen series (Table I). For the purposes of data analysis, the photoallergens used were grouped into 7 categories: sunscreens, antimicrobial agents, medications, fragrances, plants and plant derivatives, pesticides, and other substances.
Table I. Charles C. Harris Skin and Cancer Pavilion photoallergen series
| Allergen | Concentration, diluent |
|---|---|
| Sunscreens | |
 PABA | 5% Alcohol |
| Cinoxate | 1% Pet |
| 2-Hydroxy-4-methoxybenzophenone-5-sulfonic acid (sulisobenzone, BZP-4) | 10% Pet |
| 4-Isopropyl-dibenzoylmethane (Eusolex 8020) | 2% Pet |
| Menthyl anthranilate | 5% Pet |
| 4-Methylbenzylidene camphor (Eusolex 6300) | 10% Pet |
| Octyldimethyl PABA | 5% Alcohol |
| Octyl methoxycinnamate | 7.5% Pet |
| Oxybenzone (BZP-3) | 3% Pet |
| Photoplex (Herbert Laboratories, Irvine, CA) | (Surrogate for Parsol 1789) as is |
| Ti-screen 15 (TI Pharmaceuticals Inc, Irvine, CA) | (Surrogate for Parsol 1789) as is |
| 4-tert-Butyl-4'-methoxydibenzoylmethane (Parsol 1789) | 10% Pet |
| Antimicrobial agents | |
| Bithionol (2, 2'-thiobis [4, 6-dichlorophenol]) | 1% Pet |
| Chlorhexidine diacetate | 0.5% Water |
| Dichlorophen | 1% Pet |
| Fentichlor (2, 2'-thiobis [4-chlorophenol]) | 1% Pet |
| Hexachlorophene | 1% Pet |
| Sulfanilamide | 1% Pet |
| Tribromosalicylanilide | 1% Pet |
| Trichlorocarbanilide | 1% Pet |
| Triclosan | 2% Pet |
| Medications | |
| Chlorpromazine hydrochloride | 0.1% Pet |
| Diphenhydramine hydrochloride | 1% Pet |
| Promethazine | 1% Pet |
| Fragrances | |
| 6-Methylcoumarin | 1% Pet |
| Musk ambrette | 1% Alcohol |
| Musk ambrette | 1% Pet |
| Sandalwood oil | 2% Pet |
| Plants and plant derivatives | |
| Achillea millefolium | 1% Pet |
| Alantolactone | 0.1% Pet |
| Arnica montana | 0.5 Pet |
| Chamomilla romana | 1% Pet |
| Chrysanthemum cinerariaefolium | 1% Pet |
| Diallyldisulfide | 1% Pet |
| Lichen acid mix | 0.3% Pet |
| α-Methylene-γ-butyrolactone | 0.01% Pet |
| Propolis | 10% Pet |
| Pyrethrum | 2% Pet |
| Sesquiterpene lactone mix | 0.1% Pet |
| Tanacetum vulgare | 1% Pet |
| Taraxacum officinal | 2.5% Pet |
| Pesticides | |
| Benomyl | 0.1% Pet |
| Captan | 0.1% Pet |
| Captafol | 0.1% Pet |
| Folpet | 0.1% Pet |
| Maneb | 1% Pet |
| Zineb | 1% Pet |
| Ziram | 1% Pet |
| Other chemicals | |
| Thiourea (thiocarbamide) | 0.1% Pet |
| Pet control | 100% Pet |
Patients with reactions that could be temporally linked to a specific exposure in their work or home that also was congruent, based on the appearance and location of the eruption, were considered currently clinically definite or probable relevant reactions based on the weight of evidence. Only those with currently clinical relevant reactions were included in this group. When both metrics of exposure and appearance were not met, and clinical suspicion remained, a designation of possible relevance was assigned.
Results
Photopatch tests were performed in 76 patients. In all, 35 patients were female and 41 were male. The mean age of the patients was 49.2 years, with a range of 11 to 81 years. Of the patients who were tested, 39.5% had at least one positive photopatch test reaction. In all, 69 positive photopatch test reactions and 45 positive patch test reactions were detected in 30 and 23 patients, respectively. Of the positive photopatch test reactions, 23.2% were caused by sunscreens, 23.2% by antimicrobial agents, 20.3% by medications, 13% by fragrances, 11.6% by plants and plant derivatives, and 8.7% by pesticides (Table II, Table III).
Table II. Positive photopatch test reactions
| n (%) | |
|---|---|
| Patients with at least one positive photopatch test reaction | 30 (39.5) |
| Positive photopatch test reactions and relevance | |
| Sunscreens | 16 (23.2) |
| Probable relevance | 9 (56.3) |
| Possible relevance | 7 (43.7) |
| Antimicrobial agents | 16 (23.2) |
| Definite relevance | 1 (6.3) |
| Unknown relevance | 15 (93.7) |
| Medications | 14 (20.3) |
| Possible relevance | 3 (21.4) |
| Unknown relevance | 11 (78.6) |
| Fragrances | 9 (13) |
| Definite relevance | 2 (22.2) |
| Probable relevance | 4 (44.4) |
| Possible relevance | 1 (11.2) |
| Unknown relevance | 2 (22.2) |
| Plants and plant derivatives | 8 (11.6) |
| Definite relevance | 4 (50) |
| Probable relevance | 2 (25) |
| Possible relevance | 1 (12.5) |
| Unknown relevance | 1 (12.5) |
| Pesticides | 6 (8.7) |
| Possible relevance | 2 (33.3) |
| Unknown relevance | 4 (66.7) |
Table III. Allergens eliciting positive photopatch test reactions
| Sunscreens | Antimicrobial agents | Medications | Fragrances | Plants and plant derivatives | Pesticides |
|---|---|---|---|---|---|
| PABA 4 (5.8%) | Fentichlor 9 (13%) | Promethazine 9 (13%) | Musk ambrette 6 (8.7%) | Diallyldisulfide 3 (4.3%) | Folpet 3 (4.3%) |
| Oxybenzone 3 (4.3%) | Bithionol 3 (4.3%) | Chlorpromazine 4 (4.3%) | 6-Methylcoumarin 2 (3.0%) | Alantolactone 1 (1.4%) | Captan 2 (3.0%) |
| Benzophenone-4 3 (4.3%) | Sulfanilamide 2 (3.0%) | Diphenhydramine 1 (1.4%) | Sandalwood oil 1 (1.4%) | Arnica montana 1 (1.4%) | Captafol 1 (1.4%) |
| Parsol 1789 3 (4.3%) | Chlorhexidine 1 (1.4%) | Pyrethrum 1 (1.4%) | |||
| Octyldimethyl PABA 2 (3.0%) | Dichlorophen 1 (1.4%) | Sesquiterpene lactone mix 1 (1.4%) | |||
| Padimate O 1 (1.4%) | Tanacetum vulgare 1 (1.4%) |
Relevance was assessed for each positive photopatch test reaction by class. Of the photopatch test reactions to sunscreens, 56.3% were of probable relevance and 43.7% of possible relevance; to antimicrobial agents, 6.3% were of definite relevance and 93.7% of unknown relevance; to medications, 21.4% were of possible relevance and 78.6% of unknown relevance; to fragrances, 22.2% were of definite relevance, 44.4% of probable relevance, 11.2% of possible relevance, and 22.2% of unknown relevance; to plants and plant derivatives, 50% were of definite relevance, 25% of probable relevance, 12.5% of possible relevance, and 12.5% of unknown relevance; and to pesticides, 33.3% were of possible relevance and 66.7% of unknown relevance. Of the total number of reactions, 11.2% were of definite relevance, 25.4% of probable relevance, 16.9% of possible relevance, and 45.5% of unknown relevance.
Of the positive patch test reactions, 53.3% were caused by sunscreens, 28.9% by plants and plant derivatives, 11.1% by pesticides, 2.2% by antimicrobial agents, 2.2% by fragrances, and 2.2% by medications.
Discussion
Definite relevant causes of PACD were detected in 11.2% of individuals with a photosensitivity disorder. This finding is consistent with a previous study3 at our institution, which showed a prevalence of 12%, and with another study,4 which also was conducted in New York, that showed a prevalence of 11%. The prevalence of PACD and of the specific allergens that induce PACD can vary widely, change over time, and depend on the population tested. In the 1960s and 1970s, antimicrobial agents, such as salicylanilides, were causes; in the 1970s and 1980s, fragrances, such as musk ambrette and 6-methylcoumarin, were causes; and in the 1980s and 1990s, sunscreens and topical nonsteroidal anti-inflammatory drugs became prominent causes. The topical use of nonsteroidal anti-inflammatory agents in Europe has been associated with an increase in PACD to these agents (Table IV).16
Table IV. Summary of photopatch test studies
| Location | n | Study period | Most frequent allergens |
|---|---|---|---|
| Scandinavia5 | 1993 | 1980-1985 | Musk ambrette, PABA, promethazine, chlorpromazine |
| United States6 (Minnesota) | 70 | 1980-1985 | Chlorpromazine, musk ambrette, promethazine |
| United Kingdom7 | 2715 | 1983-1998 | Sunscreens, chlorpromazine, promethazine, musk ambrette |
| United States4 (New York) | 187 | 1985-1990 | Sunscreens, antimicrobial agents, fragrances |
| Austria, Germany, Switzerland8 | 1129 | 1985-1990 | Tiaprofenic acid, Fentichlor, carprofen, 4-isopropyl-dibenzoylmethane |
| United States3 (New York) | 138 | 1986-1993 | Sunscreens, fragrances, antimicrobials agents |
| Netherlands9 | 44 | 1989-1994 | Chlorpromazine, promethazine, musk ambrette |
| Austria, Germany, Switzerland10 | 1261 | 1991-1997 | Fentichlor, carprofen, chlorpromazine, 2-hydroxy-4-methoxybenzophenone |
| Australia11 | 81 | 1991-1999 | Oxybenzone, benzophenone-4 |
| France12 | 2067 | 1991-2001 | Sesquiterpene lactone, ketoprofen, benzophenone, dibenzoylmethane |
| India13 | 50 | 1994-1999 | Musk ambrette, chlorpromazine, promethazine, balsam of Peru |
| Netherlands9 | 55 | 1995-1999 | Eusolex 8020, Parsol 1789, benzophenone-3 |
| United Kingdom and Europe14 | 1155 | 2000-2002 | Benzophenone-3 |
| United States15 | 182 | 2000-2005 | Medications, sunscreens, fragrances, antiseptics |
| Italy16 | 1082 | 2004-2006 | Ketoprofen, piroxicam, promethazine, octocrylene |
In this study, sunscreens continued to be the most common allergens that elicited photopatch test reactions. As some of the tested sunscreens contained multiple agents (ie, Photoplex, Herbert Laboratories, Irvine, CA), internal controls were used to determine the specific allergen that was responsible for the positive photopatch test reactions. p-Aminobenzoic acid and its related esters and benzophenones were the most common sunscreen allergens. The prevalence of positive photopatch test reactions to sunscreens reflects their widespread use. Antimicrobial agents also have increased as a cause of PACD. Although their relevance is unclear, there was an increase in the number of reactions to medications. These observations are in contrast to the results obtained with fragrances, such as musk ambrette and sandalwood oil, which decreased in prevalence in the study. Plants and plant derivatives and pesticides were the next most common allergens to elicit positive photopatch test reactions. The majority of positive photopatch test reactions to plants were of definite relevance; however, almost all of the reactions caused by pesticides were of unknown relevance. Nine of 15 (60%) of the positive photopatch test reactions to antibacterial agents were caused by Fentichlor.
When the reactions to Fentichlor are excluded, the percentage of reactions to antimicrobial agents did not increase. Fentichlor was a component of antibacterial creams in the 1960s; however, it is no longer present in topical preparations in the United States. Although PACD to Fentichlor was detected in retrospective studies in Europe in the 1980s and 1990s,8, 10 reports of PACD to Fentichlor have been rare. In a report in 1979, 4 patients with PACD to Fentichlor became persistent light reactors.17 Three of the exposures were caused by a hair cream that contained Fentichlor; the fourth exposure was caused by an industrial exposure. Additional cases were reported in an individual in France, who was exposed to soap,18 and in a service engineer in the United Kingdom, who was exposed to a cooling system liquid.19 Although cross-reactivity between bithionol and Fentichlor has been documented,20, 21 bithionol accounted for 3 of 16 (19%) of the positive photopatch test reactions to antimicrobial agents in our study. Only one of our patients had positive reactions to both Fentichlor and bithionol. In a study in 2002,22 patients who had photoallergy to ketoprofen were tested to Fentichlor and halogenated salicylanilides among other allergens. Of the 9 patients tested, all had positive reactions to Fentichlor, and 4 had positive reactions to the halogenated salicylanilides. The positive reactions to ketoprofen, Fentichlor, and the salicylanilides were interpreted by the authors as cross-reactions to a common metabolite. This hypothesis is not readily applicable to our patient population, owing to the infrequent use of topical nonsteroidal anti-inflammatory drugs in the United States. Although one of our patients had positive reactions to both Fentichlor and bithionol, the importance of photoallergy to Fentichlor in our patients is unclear. A World Wide Web site search for commercial products currently available in the United States that contain Fentichlor yielded only a product from Nipa Hardwicke Inc (Wilmington, DE) that is used in water cooling systems. It remains unknown if positive test reactions to Fentichlor represent a primary allergic response or a cross-reaction with other chemical compounds. A recent study from the United States showed that 9% of the PACD reactions were caused by Fentichlor.15 Our study demonstrates both the changing nature of reactions to photoallergens and the fact that continued and vigilant observation is necessary to maximize the relevance of photopatch test allergen series.
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- . Photoallergic de contact au Fentichlor présent dans un savon d'hygiènc pour les mains. Ann Dermatol Venereol. 1992;119:983–985
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- . Cross sensitivity between Fentichlor and bithionol. Arch Dermatol. 1968;97:497–502
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Funding sources: None.
Conflicts of interest: None declared.
PII: S0190-9622(09)00940-2
doi:10.1016/j.jaad.2009.06.084
© 2009 American Academy of Dermatology, Inc. Published by Elsevier Inc All rights reserved.
Volume 62, Issue 4 , Pages 605-610, April 2010
