A 20-year analysis of previous and emerging allergens that elicit photoallergic contact dermatitis

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.

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

BZP, Benzophenone; PABA, p-aminobenzoic acid; pet, petrolatum.

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%)

PABA, p-Aminobenzoic acid. No of positive patch test reactions (percent of total).

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

PABA, p-Aminobenzoic acid.

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.