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Drugs used on the skin and cosmetics
J.P. Nater and A.C. de Groot
15
Drugs used on the skin and cosmetics
Introductory remarks From this Annual onwards, the title of this Chapter has been amended to include not only medicaments in the usual sense of the word but also cosmetics. It should be borne in mind that some of the adverse reactions to the latter are due not to their specifically cosmetic constituents, but to excipients of a type also frequently employed in dermatological remedies.
Contact urticaria (52, 53, 54, 55) Contact urticaria refers to a wheal-andflare response to the application o f chemicals to intact skin. The contact urticaria syndrome covers a broad spectrum o f symptoms, and may manifest itself as urticaria, angioedema, asthma, and even as a lifethreatening anaphylactic reaction. Other symptoms include rhinitis, headache, conjunctivitis, sweating, and gastrointestinal disturbances. The symptoms usually develop within 2 0 - 3 0 minutes after contact with the offending chemical, but 'delayed' reactions after several hours have also been recorded. Most cases o f contact urticaria are o f non-immunological origin, presumably due to a direct release o f histamine, slow-reacting substance o f anaphylaxis (SRS-A), bradykinin, or other vasoactive compounds. Topical drugs that have caused 'non-immunological' contact urticaria are listed in Table 1. Contact urticaria o f immunological origin is apparently less frequent, though many topical drugs have caused this condition in previously sensitized individuals. In a number o f reports positive passive transfer tests were noted, and infrequently specific antibodies have been demonstrated, indicating an immunological phenomenon. Topical drugs that have caused 'immunological'
contact urticaria are listed in Table 2; in most o f these cases, the contact urticaria was o f probable immunological origin, without the possibility o f confirming this fact. Some cases o f contact urticarial reactions can neither be ascribed to 'immunological' nor to 'non-immunological' mechanisms with certainty; the classical example o f this category o f contact urticaria o f uncertain mechanism is that caused by the bleaching agent ammonium persulfate. Also belonging to this category are a number o f topical substances which have caused contact urticaria upon patch-testing, but the clinical significance o f which is uncertain: nickel
sulfate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethyl vanillin, potassium bichromate, parabens and ethylene diamine (54). The diagnosis o f contact urticaria can usually be confirmed by an open test; however, these tests should be performed with great caution, as anaphylactic reactions due to the testing procedure have been described several times.
Contact allergy to topical drugs Newly described contact allergies and updated information concerning contact sensiTable 1. Agents causing non.immunological contact urticaria Balsam of Peru* BenzaMehyde Benzocaine Benzoic acid Camphor Cinnamic acid Cinnamic aldehyde (SED 9, 249) Cinnamon oil
Dimethyl sulfoxide (SED 9, 249) Eugenol * Histamine-free base Parabens Phenol Sodium benzoate Sorbic acid Thurfyl nicotinate
* Simultaneous contact allergy described.
J.P. Nater andA.C, de Groot
160
Table 2. Agents known or believed to cause immunological contact urticaria Acetylsalicylic acid A minophenazone ** A minopyrine Ampicillin Amyl alcohol Arsphenamine Bacitracin * * nenzocaine * * Benzophenone (SED 9, 249)* Benzoyl peroxide (58) Butyl alcohol Caraway seed oil Cephalosporins * * * Cetyl alcohol* Chloramphenicol Clioquinol Denatonium benzoate*** Diethyl toluamMe 1,3-Diiodo-2-hydroxypropane Epoxy resin* Estrogen cream Ethyl alcohol* Fixation fluid (permanent wave) FormaMehyde Gentamycin Hairspray * ** * Hexantriol p-Hydroxybenzoic acid
Isopropyl alcohol Lanolin~alcohol Lindane Mechlorethamine hydrochloride** Menthol Methamizole Monoamyl amine Nail lacquer**** Neomycin* ** Nicotinyl alcohol Nitrofuroxime * Parabens Penicillin * * Perfumes**** Permanent wave* p-Phenylene diamine Phenylmercuric propionate* * * Polyethylene glycol (SED 9, 250} Polysorbate.60 (SED 9, 250) Pristinamycin Promethazine hydrochloride Propyl alcohol Pyrazolone Rouge make-up (40} Stearyl alcohol Streptomycin ** Sulfur
*Simultaneous contact allergy described; **Anaphylactic reaction described as well; ***Asthma reported as well," ****No further details available.
tivity to (ingredients of) topical drugs are summarized in Table 3. Table 4 deals with occupational and/or accidental contact with drugs causing contact allergic reactions.
Contact allergy to cosmetics In a prospective study, 4 8 7 cases o f cosmetic-induced dermatitis were identified by the 11 members o f the North American Contact Dermatitis Group over a 389 year period (56). Eighty per cent o f the adverse reactions were due to contact allergy. The material represented 6% o f the patients tested for contact dermatitis and approximately 0.3% o f the total estimated number o f patients seen in the dermatologists" offices or clinics. In only about half o f the patients who proved to be allergic to one or more cosmetic ingredients did the patient or investigator suspect that the clinically examined cutaneous reaction might have been caused by a cosmetic product.
The skin reactions occurred most often on the face (37%), followed by reactions around the eye (13%), on the lower arm (11%), and in the armpit (8%). Skin care preparations, which may be face, hand, or general body care products, caused the greater number o f adverse reactions (26%), followed by hair preparations other than hair colors (16%) and facial make-up products (12%). Patch testing with the separate ingredients o f suspected cosmetics demonstrated that the majority o f cutaneous reactions were caused by fragrance mixtures or individually identified fragrance ingredients. Preservative ingredients, Le. 2-bromo-2-nitropropane-l,3diol, formaldehyde, imidazolidinyl urea, and Quaternium-15 represented the group with the second highest dermatitis incidence. These were followed by p-phenylenediamine, propylene glycol and lanolin. Other relevant literature data on contact allergy to cosmetic ingredients are listed in Table 5.
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166 PSORALEN PHOTOCHEMOTHERAPY
J.P. Nater and A.C. de Groot test concentration and vehicle are known, control tests are mandatory.
PUVA Carcinoma of the oral mucosa Squamous cell carcinoma o f the oral mucosa developed in a 32-year-old woman on PUVA therapy for vitiligo. The authors speculate on a causal relationship between the photochemotherapy and the observed carcinoma; in our opinion, such a relationship would seem to be rather doubtful (60). The question as to whether this type of treatment can have carcinogenic effects as such is of course a separate one and it is discussed in previous Annuals as well as later in this Chapter.
Miscellaneous adverse effects Adverse reactions to PUVA therapy have been discussed frequently in this series (SEDA-3, 132; SEDA-4, 104; SEDA-5, 150; SEDA-6, 145). The nature of short- and long-term side effects to PUVA therapy depends on the doses, continuance of therapy and the type of skin disorder treated. In a multicenter study from 18 European cities 3175 psoriasis patients were treated with PUVA; data obtained during a 39-month-period were analyzed (66). The most common side effects observed were erythema (32%), pruritus (26%), and nausea (13%). Conjunctivitis due to accidental exposure to sunlight without appropriate eye protection was noted in several patients. LOCAL SIDE EFFECTS OF TOPICAL DRUGS (contact allergy excepted) Urea cream Irritant patch test reactions The interpretation of patch test reactions is often difficult. In particular it is sometimes very hard, if not impossible, to distinguish irritant and allergic reactions from one another. In 79 patients with eczematous skin disease described by Cramers and Thormann, patch tests were performed with a 10% urea-containing cream. Positive reactions developed in seven (9.9%), but the ingredients tested separately were negative. It is suggested that the 'positive' reactions were irritant, due to the hypertonicity and acidity of the cream (62). This report stresses that when positive patch test reactions are observed to chemicals for which no adequate
5-Fluorouracil 5-Fluorouracil (5-FU) is used for the topical treatment of premalignant keratoses, superficial basal cell carcinomas, and condylomata acuminata. Side effects include irritation, hyperpigmentation, erythema, erosion, and contact allergy (SEDA-5, 155). Three more unusual complications have been reported (67, 68, 69): ( I ) t h e development of telangiectasia, fading away very slowly; (2) the reactivation o f herpes simplex; b o t h this and the previous reaction seem to be due to the inflammation caused by the topical drug; (3) bilateral cicatricial ectropion following the topical administration of 5-FU in a patient treated for multiple facial actinic keratoses. Topical corticosteroids
A trophy and skin fragility of the skin due to local and systemic administration of corticosteroids has been well documented (SED 9, 252). A case has now been presented in which prolonged application of a corticosteroid ointment resulted in the formation of a skin ulcer (71). A recent report from Leonforte (76) seems to show that whereas oral corticosteroids readily caused exacerbation o f pityriasis rosea, even increasing the number and severity of the lesions, topical corticosteroid treatment generally did not do so. Phenol Chemical face peeling with phenol has caused serious systemic adverse reactions, notably cardiac arrhythmias; several cases of acute death have been recorded (SEDA-6, 152). Table 6 lists local side effects of this therapeutic modality (57). Table 6. Local complications of chemical face peeling Hypopigmentation Hyperpigmentation Phenol bleaching Blotchy pigmentation demarcation
Milia Persistent erythema Skin pore prominence Telangiectasia Scarring
Drugs used on the skin and cosmetics
Unusual manifestations of allergic contact sensitivity Unusual manifestations of contact allergy have been discussed elsewhere (65). A case of contact sensitivity to ethylenediamine with unusual lymphomatoid features has been reported (63). The clinical and histological findings were in keeping with early mycosis fungoides. Continued contact with the allergen was traced to its retention in a trouser pocket lining. The eruption cleared with avoidance o f the allergen. The reader is also referred to Table 5 (under perfume) for a report on a fatality attributed to spray cologne.
SYSTEMIC EFFECTS O F TOPICAL DRUGS
Silver sulfadiazine Febrile reaction A child with burns over 10% of the b o d y surface, treated with silver sulfadiazine and oral penicillin, developed a febrile episode. No infection could be demonstrated. After the treatment with silver sulfadiazine had been interrupted, the temperature settled rapidly. The authors suggest that the topical drug may have been responsible for the febrile reaction (61); definite p r o o f is, however, lacking. Transient leukopenia, due to silver sulfadiazine has been discussed previously (SEDA-4, 108; SEDA-5,152). Podophyllum resin
Delirium and psychosis A case has been reported in which the absorption of podophyllum resin, used for the treatment of condylomata acuminata, led to the development of a delirium with florid psychotic features (70). Previously reported side effects to this powerful skin irritant include acute confusional state, peripheral neuropathy, bone marrow depression, vomiting, coma and death (SED 9, 240; SEDA-4, 108; SEDA-6, 152). Topical cortieosteroids Hypertension
It has been well documented
167 that topical application of corticosteroids to the skin may cause systemic adverse reactions (SED 9, 2 4 8 - 2 5 2 ) . In ten patients suffering from chronic rhinitis, mineralocorticoid hypertension could be ascribed to the habitual use o f large doses of nasal spray containing 9c~-fluoroprednisolone and vasoconstrictor agents (74). Immunosuppression During the last 2 - 3 years a considerable number o f national regulatory agencies have released low-concentration hydrocortisone creams (usually 0.5%) for free sale to the public, notably for the relief of mild sunburn or irritation. Neumann in the USA has recently suggested that there may be a link between this development and an upsurge in the incidence of overwhelming infections in homosexuals. He points out that the package instructions for these products in the US recommend the use of the creams for skin irritation o f the anal and genital areas, and that skin irritation and herpes in the anogenital region are common among male homosexuals. A 1-oz. (28 g) tube o f a 0.5% hydrocortisone cream contains 160 mg o f hydrocortisone, and absorption is likely to be pronounced. He adds that the types of infections seen in immunocompromised homosexuals are those known to occur with corticosteroid use: Pneumocystis carinii infections, extensive candidiasis and severe viral infections. In his view, the matter needs further attention since it could be that 0.5% is too high a concentration for free-sale hydrocortisone creams (75r).
Promethazine Systemic toxicity A 16-month-old male (weight 11.5 kg) was treated with 2% promethazine cream for generalized eczema. After approximately 1 5 - 2 0 g of the cream had been applied the clfild fell asleep; a few hours later he awoke with abnormal behavior, loss o f balance, inability to focus, irritability, drowsiness and failure to recognize his mother. One day later all symptoms had spontaneously disappeared. A diagnosis of promethazine toxicity through percutaneous absorption was made (59). Known symptoms of promethazine toxicity include disorientation, hallucinations, hyperactivity, convulsions, and coma, but these are more usually seen after oral intake.
168 CARCINOGENIC EFFECTS OF DERMATOLOGICAL THERAPY
Psoriasis treatment Genetic and carcinogenic hazards (73) An expert group of the International Commission for Protection against Environmental Mutagens and Carcinogens has reviewed and assessed the possible longterm sequelae, both genetic and carcinogenic, of various treatments available for psoriasis. In this section only the topical therapies will be mentioned. Experimental and h u m a n data were assessed on dithranol, coal tar and ultraviolet light, and psoralen photochemotherapy. The following conclusions were drawn: 1. No treatment can be regarded as absolutely safe. Each carries an established or potential risk of genetic or carcinogenic effects. 2. Coal tar o i n t m e n t and U V radiation treatments at high doses create an additional risk of (easily treated) skin cancer, this being 3 - 6 times greater than that in psoriasis patients treated with low doses of these agents or not at all. 3. There is insufficient evidence to evaluate the mutagenieity of dithranol, but the available data do not suggest a mutagenic capability. 4. Dithranol has not been shown to initiate cancer, but is an established promoting agent (cocarcinogen) with at least two chemical carcinogens in the mouse, not only for skin neoplasms but, with one agent, for lymphomas. In man no data are available but the use of dithranol after k n o w n initiating treatments such as UV or photochemotherapy could involve some hazard. The influence of different concentrations of dithranol on epidermal DNA synthesis rates in mice was studied by Lowe and Breeding (72).
J.P. Nater and A.C. de Groot 5 . 8 - M e t h o x y p s o r a l e n is weakly mutagenie in bacteria and mammalian cells. It is not considered that the genetic risk from exposure of the human testis to 8-MOP with current therapeutic regimens is likely to be significant. 6. P U V A is a potent mutagen and elastogen in all systems studied, including mammalian somatic cells in culture and circulating lymphocytes in man. 7. P U V A is carcinogenic to the skin of mice and probably carcinogenic or cocarcinogenic to the skin of man. In addition, the possibility exists of malignant disease of the reticulo-endothelial system arising out of the irradiation of circulating stem cells. Benzoyl peroxide Skin tumor-promoting activity Allergic contact sensitivity to benzoyl peroxide has been discussed previously (SEDA-3, 131) and elsewhere in this chapter (Table 3). Recently attention has been drawn to another, possibly more serious, unwanted effect of this compound (64): benzoyl peroxide promoted both papillomas and carcinomas when it was applied to mice after 7,12dimethylbenz(a)anthracene initiation. Benzoyl peroxide was inactive on the skin as a complete carcinogen or as a tumor initiator. A single topical application of benzoyl peroxide provided a marked epidermal hyperplasia and induced a large number of dark keratinocytes, effects similar to those produced by the potent tumor promotor 12-O-tetradecanoylphorbol-13-acetate. Benzoyl peroxide, like other known t u m o r promotors, also inhibited metabolic cooperation (intercellular communication) in Chinese hamster cells. In view of these results the authors recommend caution in the use of this and other free radical-generating compounds, as co-carcinogenic effects cannot be excluded.
REFERENCES 1. Meneghini, C.L. and Angelini, G. (1982): Contact dermatitis from pyrrolnitrin. Contact Dermatitis, 8, 55. 2. Burrows, D. and Irvine, J. (1982): Contact dermatitis to hexylresorcinol. Contact Dermatitis, 8, 71. 3. Valsecchi, R., FoiadeUi, L. and Cainelli, T. (1981): Contact dermatitis from pyrrolnitrin. Contact Dermatitis, 7, 340.
4. Lovell, C.R. and Staniforth, P. (1981): Contact allergy to benzalkonium chloride in plaster of Paris. Contact Dermatitis, 7, 343. 5. Van Hecke, E. and Van Brabandt, S. (1981): Contact sensitivity to imidazole derivatives. Contact Dermatitis, 7, 348. 6. Wahlberg, J.E. and Boman, A. (1981): Contact sensitivity to quinidine sulfate from occupational exposure. Contact Dermatitis, 7, 27.
Drugs used on the skin and cosmetics 7. BjiSrkner, B. and Magnusson, B. (1981): Patch test sensitization to D and C Yellow No. 11 and simultaneous reaction to Quinoline Yellow.
Contact Dermatitis, 7, 1. 8. Ljunggren, B. (1981): Contact dermatitis to estradiol benzoate. Contact Dermatitis, 7, 141. 9. Valsecchi, R., Serra, M., Foiadelli, L. and CaineUi, T. (1981): Contact sensitivity to oxyphenbutazone. Contact Dermatitis, 7, 157. 10. Lindemayr, H. and Drobil, M. (1981): Contact sensitization to benzoyl peroxide. Contact Dermatitis, 7, 137. 11. Waddell, M.M. and Finn, O.A. (1981): Sensitivity to resorcin. Contact Dermatitis, 7, 216. 12. Reiffers, J. (1981): Allergy to 5-lodo-2'desoxyuridine. Contact Dermatitis, 7, 125. 13. Jensen, O. (1981): Contact allergy to propylene oxide and isopropyl alcohol in a skin disinfectant swab. Contact Dermatitis, 7, 148. 14. Lawrence, C.M. and Smith, A.G. (1981): Ichthammol sensitivity. Contact Dermatitis, 7, 335. 15. Van Joost, Th., SiUevis Smitt, J.H. and Van Ketel, W.G. (1981): Sensitization to olive oil (olea europeae). Contact Dermatitis, 7, 309. 16. Roberts, D.L., Summerly, R. and Byrne, J.P.H. (1981): Contact dermatitis due to the constituents of Hibiscrub. Contact Dermatitis, 7, 326. 17. Kroon, S. (1981): Contact dermatitis from oleyl polypeptide in Xerumenex ear drops. Contact Dermatitis, 7, 271. 18. Van Ketel, W.G. and Swain, A.F. (1981): Allergy to clobetasol-17-propionate (Dermovate). Contact Dermatitis, 7, 278. 19. Angelini, G. and Meneghini, C.L. (1981): Contact allergy from propylene glycol. Contact Dermatitis, 7, 197. 20. Jensen, O., Petersen, S.H. and Vesterhager, L. (1980): Contact sensitization to benzoyl peroxide following topical treatment of chronic leg ulcers. Contact Dermatitis, 6,179. 21. G6ransson, K. and Lid6n, S. (1981): Contact allergy to sorbic acid and Unguentum Merck. Contact Dermatitis, 7, 277. 22. Calnan, C.D. (1976): Quinazoline Yellow SS in cosmetics. Contact Dermatitis, 2, 160. 23. Mathias, C.G.T. (1982): Pigmented cosmetic dermatitis from contact allergy to a toilet soap containing chromium. Contact Dermatitis, 8, 29. 24. Kozuka, T., Tashiro, M., Sano, S. et al. (1979): Brilliant Lake Red R as a cause of pigmented contact dermatitis. Contact Dermatitis, 5,297. 25. Dooms-Goossens, A., Degreef, H., VanHee, J. et al. (1981): Chlorocresol and chloracetamide: Allergens in medications, glues, and cosmetics.
Contact Dermatitis, 7, 51. 26. Woods, B. (1981): Dermatitis from Eusolex 8021 sunscreen agent in a cosmetic. Contact Dermatitis, 7, 168. 27. Fisher, A.A. (1982): Cortaid cream dermatitis and the 'Paraben Paradox' (letter). J. Amer.
169
Acad. Dermatol., 6, 116. 28. Burrows, D. and Rycroft, R.J.G. (1981): Contact dermatitis from PTBP resin and tricresyl ethyl phthalate in a plastic nail adhesive. Contact Dermatitis, 7, 336. 29. Calnan, C.D. (1981): Quinazoline yellow dermatitis (D and C Yellow 11) in an eye cream. Contact Dermatitis, 7, 271. 30. Calnan, C.D. (1981): Monotertiary butyl hydroquinone in lipstick. Contact Dermatitis, 7, 280. 31. Calnan, C.D., Cronin, E. and Rycroft, R.J.G. (1981): Allergy to phenyl salicylate. Contact Dermatitis, 7, 208. 32. Camarasa, J.G. (1981): Contact dermatitis to thioxolone. Contact Dermatitis, 7, 213. 33. Van Ketel, W.G. and Liem, D.H. (1981): Eyelid dermatitis from nickel contaminated cosmetics. Contact Dermatitis, 7, 217. 34. Brown, R. (1981): Chlorphenesin sensitivity. Contact Dermatitis, 7, 162. 35. Adams, R.M. (1981): Allergic contact dermatitis due to o-phenylphenol. Contact Dermatitis, 7, 332. 36. Osmundsen, P.E. (1982): Contact dermatitis to chlorhexidine. Contact Dermatitis, 8, 81. 37. F6rstr6m, L., Lassus, A., Salde, L. and Niemi, K.M. (1982): Allergic contact eczema from topical corticosteroids. Contact Dermatitis, 8, 128. 38. Lawlor, F. and Hindson, C. (1982): Allergy to dithranol. Contact Dermatitis, 8, 137. 39. Menezes Brandao, F. and Pecegueiro, M. (1982): Contact dermatitis to tromantadine hydrochloride. Contact Dermatitis, 8, 140. 40. De Groot, A.C. (1982): Unpublished observation. 41. Verburgh-Van der Zwan, N. and Van Ketel, W.G. (1981): Contactallergie voor een arseenbevattend intravaginaal toegepast geneesmiddel. Ned. T. Geneesk., 125, 1718. 42. Staniforth, P. and LoveU, C.R. (1981): Contact dermatitis related to constituent of an orthopaedic wool. Brit. reed. J., 283, 1297. 43. Giovinazzo, V.J., Harber, L.C., Bickers, D.R. et at. (1981): Photoallergic contact dermatitis to Musk Ambrette. Arch. Dermatol., 117, 344. 44. Zugerman, C. (1981): Persistent photosensitivity caused by Musk Ambrette. Arch. Derma. tol., 117, 432. 45. Shelley, W.B. (1982): Immediate sunburn-like reaction in a patient with formaldehyde photosensitivity. Arch. Dermatol., 118, 117. 46. Merk, H., Ebert, L. and Goerz, G. (1982): Allergic contact dermatitis due to the fungicide hexetidine. Contact Dermatitis, 8,216. 47. Marks Jr., J.G. (1982): Allergic contact dermatitis to povidone-iodine. J. Amer. Acad. Der-
matol., 6,473. 48. Scott, M.J. and Scott Jr., M.J. (1982): Jojoba oil (letter to the Editor). J. Amer. Acad. Dermatol., 6, 545. 49. Grimalt, F. and Romaguera, C. (1981):
170 Cutaneous sensitivity to benzidine. Dermatosen, 29, 95. 50. Thompson Jr., J.A. and Wansker, B.A. (1981): A case of contact dermatitis, erythema multiforme, and toxic epidermal necrolysis. J. Amer. Acad. Dermatol., 5, 666. 51. Marehand, B., Barbier, P., Ducombs, G. et at. (1982): Allergic contact dermatitis to various salols (phenyl sallcylates). Arch. Dermatol. Res., 272, 61. 52. Nater, J.P. and de Groot, A.C. (1983): Contact urticaria. In: Unwanted Effects o f Cosmetics and Drugs Used in Dermatology, Ch. 7, pp. 105-111. Excerpta Medica, Amsterdam. 53. Von Krogh, G. and Maibach, H.I. (1983): The contact urticaria syndrome. In: Dermatotoxicology, 2ndEd., Ch. 14, pp. 3 0 1 - 3 2 2 . Editors: F.N. Marzulli and H.I. Maibach. Hemisphere Publishing Co., Washington. 54. Warin, R.P. and Smith, R.J. (1982): Chronic urticaria. Investigations with patch and challenge tests. Contact Dermatitis, 8, 117. 55. Von Krogh, G. and Malbach, H.I. (1981): The contact urticaria syndrome - an updated review. J. Amer. Acad. Dermatol., 5, 328. 56. Eiermann, H.J., Larsen, W., Maibach, H.I. and Taylor, J.S. (1982): Prospective study of cosmetic reactions: 1977-1980. J. Amer. Acad.
Dermatol., 6,909. 57. Litton, C. and Trinidad, G. (1981): Complications of chemical face peeling as evaluated by a questionnaire. Piast. reconstr. Surg., 6 7, 738. 58. Tkach, J.R. (1982): Allergic contact urticaria to benzoyl peroxide. Cutis, 29, 187. 59. Bloch, R. and Beysovec, L. (1982): Promethazinc toxicity through percutaneous absorption. On continuing Practice, 9, 28. 60. Krutchkoff, D.J., Eisenberg, E. and Neckritz, A.A. (1981): Epidermoid carcinoma of the gingiva: a possible relationship to PUVA therapy. Oral Surg., 52, 44. 61. Clarke, S.D., Gallur, L. and ThrellfaU, G.N. (1981): Febrile reaction to silver sulphadiazine. Med. J. Aust., 22, 208. 62. Cramers, M. and Thormann, J. (1981): Skin reactions to a urea-containing cream. Contact Dermatitis, 7, 189. 63. Wall, L.M. (1982): Lymphomatoid contact dermatitis due to ethylenediamine dihydrochloride. Contact Dermatitis, 8, 51.
J.P. Nater and A. C. de Groot 64. Siaga, T.J., Klein-Szanto, A.J.P., Triplett, L.L. and Yotti, L.P. (1981): Skin tumor-promoting activity of benzoylperoxide, a widely used free radical-generating compound. Science, 213, 1023. 65. Nater, J.P. and de Groot, A.C. (1983): Unusual manifestations of contact allergy. In:
Unwanted Effects o f Cosmetics and Drugs Used in Dermatology, Ch. 6, pp. 99-104. Excerpta Medica, Amsterdam. 66. Henseler, T., Wolff, K., H6nigsmann, H. and Christophers, E. (1981): Oral 8-methoxypsoralen photochemotherapy of psoriasis. Lancet, I, 853. 67. Burnett, J.W. (1975): TWO unusual complications of topical fluorouracil therapy. Arch.
Dermatol., 111,398. 68. Burnett, J.W. (1982): Further observations on two unusual complications of topical fluorouracil therapy. Arch. DermatoL, 118, 74. 69. Galentine, P., Sloas, H., Hargett, N. and Cupples, H.P. (1981): Bilateral cicatricial ectropion following topical administration of 5fluorouraefl. Ann. Oph thalmol. , 13,575. 70. Stoudemire, A., Baker, N. and Thompson, L. (1981): Delirium induced by topical application of podophyllin: a case report. Amer. J. Psychiat., 138, 1505. 71. Kikuehi, I. and Aoki, Y. (1981): Cortisol skin injuries. Skin injuries in atrophic skin of patients receiving corticosteroid therapy. J. Derm., 8, 419. 72. Lowe, N.J. and Breeding,J. (1981): Anthralin, different concentration effects on epidermal DNA synthesis rates in mice and clinical responses in human psoriasis.Arch. Dermatol., 117, 698. 73. Bridges, B.A., Greaves, M., Polani, P.E. and Wald, N. (1981): Do treatments available for psoriasis patients carry a genetic or carcinogenic risk? Murat. Res., 86, 279. 74. Mantero, F., Armanini, D., Opocher, G. et al. (1981): Mineralocorticoid hypertension due to a nasal spray containing 9a-fluoroprednisolone. Amer. J. Med., 17, 352. 75. Neumann, H.N. (1982): Use of steroid creams as a possible cause of immunosuppression in homosexuals. New Engl. J. Med., 306, 935. 76. Leonforte, J.F. (1981): Pityriasis rosea: exacerbation with cortir treatment. Dermatologica, 163, 480.
15
Drugs used on the skin and cosmetics
Introductory remarks From this Annual onwards, the title of this Chapter has been amended to include not only medicaments in the usual sense of the word but also cosmetics. It should be borne in mind that some of the adverse reactions to the latter are due not to their specifically cosmetic constituents, but to excipients of a type also frequently employed in dermatological remedies.
Contact urticaria (52, 53, 54, 55) Contact urticaria refers to a wheal-andflare response to the application o f chemicals to intact skin. The contact urticaria syndrome covers a broad spectrum o f symptoms, and may manifest itself as urticaria, angioedema, asthma, and even as a lifethreatening anaphylactic reaction. Other symptoms include rhinitis, headache, conjunctivitis, sweating, and gastrointestinal disturbances. The symptoms usually develop within 2 0 - 3 0 minutes after contact with the offending chemical, but 'delayed' reactions after several hours have also been recorded. Most cases o f contact urticaria are o f non-immunological origin, presumably due to a direct release o f histamine, slow-reacting substance o f anaphylaxis (SRS-A), bradykinin, or other vasoactive compounds. Topical drugs that have caused 'non-immunological' contact urticaria are listed in Table 1. Contact urticaria o f immunological origin is apparently less frequent, though many topical drugs have caused this condition in previously sensitized individuals. In a number o f reports positive passive transfer tests were noted, and infrequently specific antibodies have been demonstrated, indicating an immunological phenomenon. Topical drugs that have caused 'immunological'
contact urticaria are listed in Table 2; in most o f these cases, the contact urticaria was o f probable immunological origin, without the possibility o f confirming this fact. Some cases o f contact urticarial reactions can neither be ascribed to 'immunological' nor to 'non-immunological' mechanisms with certainty; the classical example o f this category o f contact urticaria o f uncertain mechanism is that caused by the bleaching agent ammonium persulfate. Also belonging to this category are a number o f topical substances which have caused contact urticaria upon patch-testing, but the clinical significance o f which is uncertain: nickel
sulfate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethyl vanillin, potassium bichromate, parabens and ethylene diamine (54). The diagnosis o f contact urticaria can usually be confirmed by an open test; however, these tests should be performed with great caution, as anaphylactic reactions due to the testing procedure have been described several times.
Contact allergy to topical drugs Newly described contact allergies and updated information concerning contact sensiTable 1. Agents causing non.immunological contact urticaria Balsam of Peru* BenzaMehyde Benzocaine Benzoic acid Camphor Cinnamic acid Cinnamic aldehyde (SED 9, 249) Cinnamon oil
Dimethyl sulfoxide (SED 9, 249) Eugenol * Histamine-free base Parabens Phenol Sodium benzoate Sorbic acid Thurfyl nicotinate
* Simultaneous contact allergy described.
J.P. Nater andA.C, de Groot
160
Table 2. Agents known or believed to cause immunological contact urticaria Acetylsalicylic acid A minophenazone ** A minopyrine Ampicillin Amyl alcohol Arsphenamine Bacitracin * * nenzocaine * * Benzophenone (SED 9, 249)* Benzoyl peroxide (58) Butyl alcohol Caraway seed oil Cephalosporins * * * Cetyl alcohol* Chloramphenicol Clioquinol Denatonium benzoate*** Diethyl toluamMe 1,3-Diiodo-2-hydroxypropane Epoxy resin* Estrogen cream Ethyl alcohol* Fixation fluid (permanent wave) FormaMehyde Gentamycin Hairspray * ** * Hexantriol p-Hydroxybenzoic acid
Isopropyl alcohol Lanolin~alcohol Lindane Mechlorethamine hydrochloride** Menthol Methamizole Monoamyl amine Nail lacquer**** Neomycin* ** Nicotinyl alcohol Nitrofuroxime * Parabens Penicillin * * Perfumes**** Permanent wave* p-Phenylene diamine Phenylmercuric propionate* * * Polyethylene glycol (SED 9, 250} Polysorbate.60 (SED 9, 250) Pristinamycin Promethazine hydrochloride Propyl alcohol Pyrazolone Rouge make-up (40} Stearyl alcohol Streptomycin ** Sulfur
*Simultaneous contact allergy described; **Anaphylactic reaction described as well; ***Asthma reported as well," ****No further details available.
tivity to (ingredients of) topical drugs are summarized in Table 3. Table 4 deals with occupational and/or accidental contact with drugs causing contact allergic reactions.
Contact allergy to cosmetics In a prospective study, 4 8 7 cases o f cosmetic-induced dermatitis were identified by the 11 members o f the North American Contact Dermatitis Group over a 389 year period (56). Eighty per cent o f the adverse reactions were due to contact allergy. The material represented 6% o f the patients tested for contact dermatitis and approximately 0.3% o f the total estimated number o f patients seen in the dermatologists" offices or clinics. In only about half o f the patients who proved to be allergic to one or more cosmetic ingredients did the patient or investigator suspect that the clinically examined cutaneous reaction might have been caused by a cosmetic product.
The skin reactions occurred most often on the face (37%), followed by reactions around the eye (13%), on the lower arm (11%), and in the armpit (8%). Skin care preparations, which may be face, hand, or general body care products, caused the greater number o f adverse reactions (26%), followed by hair preparations other than hair colors (16%) and facial make-up products (12%). Patch testing with the separate ingredients o f suspected cosmetics demonstrated that the majority o f cutaneous reactions were caused by fragrance mixtures or individually identified fragrance ingredients. Preservative ingredients, Le. 2-bromo-2-nitropropane-l,3diol, formaldehyde, imidazolidinyl urea, and Quaternium-15 represented the group with the second highest dermatitis incidence. These were followed by p-phenylenediamine, propylene glycol and lanolin. Other relevant literature data on contact allergy to cosmetic ingredients are listed in Table 5.
Drugs used on the skin and cosmetics
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166 PSORALEN PHOTOCHEMOTHERAPY
J.P. Nater and A.C. de Groot test concentration and vehicle are known, control tests are mandatory.
PUVA Carcinoma of the oral mucosa Squamous cell carcinoma o f the oral mucosa developed in a 32-year-old woman on PUVA therapy for vitiligo. The authors speculate on a causal relationship between the photochemotherapy and the observed carcinoma; in our opinion, such a relationship would seem to be rather doubtful (60). The question as to whether this type of treatment can have carcinogenic effects as such is of course a separate one and it is discussed in previous Annuals as well as later in this Chapter.
Miscellaneous adverse effects Adverse reactions to PUVA therapy have been discussed frequently in this series (SEDA-3, 132; SEDA-4, 104; SEDA-5, 150; SEDA-6, 145). The nature of short- and long-term side effects to PUVA therapy depends on the doses, continuance of therapy and the type of skin disorder treated. In a multicenter study from 18 European cities 3175 psoriasis patients were treated with PUVA; data obtained during a 39-month-period were analyzed (66). The most common side effects observed were erythema (32%), pruritus (26%), and nausea (13%). Conjunctivitis due to accidental exposure to sunlight without appropriate eye protection was noted in several patients. LOCAL SIDE EFFECTS OF TOPICAL DRUGS (contact allergy excepted) Urea cream Irritant patch test reactions The interpretation of patch test reactions is often difficult. In particular it is sometimes very hard, if not impossible, to distinguish irritant and allergic reactions from one another. In 79 patients with eczematous skin disease described by Cramers and Thormann, patch tests were performed with a 10% urea-containing cream. Positive reactions developed in seven (9.9%), but the ingredients tested separately were negative. It is suggested that the 'positive' reactions were irritant, due to the hypertonicity and acidity of the cream (62). This report stresses that when positive patch test reactions are observed to chemicals for which no adequate
5-Fluorouracil 5-Fluorouracil (5-FU) is used for the topical treatment of premalignant keratoses, superficial basal cell carcinomas, and condylomata acuminata. Side effects include irritation, hyperpigmentation, erythema, erosion, and contact allergy (SEDA-5, 155). Three more unusual complications have been reported (67, 68, 69): ( I ) t h e development of telangiectasia, fading away very slowly; (2) the reactivation o f herpes simplex; b o t h this and the previous reaction seem to be due to the inflammation caused by the topical drug; (3) bilateral cicatricial ectropion following the topical administration of 5-FU in a patient treated for multiple facial actinic keratoses. Topical corticosteroids
A trophy and skin fragility of the skin due to local and systemic administration of corticosteroids has been well documented (SED 9, 252). A case has now been presented in which prolonged application of a corticosteroid ointment resulted in the formation of a skin ulcer (71). A recent report from Leonforte (76) seems to show that whereas oral corticosteroids readily caused exacerbation o f pityriasis rosea, even increasing the number and severity of the lesions, topical corticosteroid treatment generally did not do so. Phenol Chemical face peeling with phenol has caused serious systemic adverse reactions, notably cardiac arrhythmias; several cases of acute death have been recorded (SEDA-6, 152). Table 6 lists local side effects of this therapeutic modality (57). Table 6. Local complications of chemical face peeling Hypopigmentation Hyperpigmentation Phenol bleaching Blotchy pigmentation demarcation
Milia Persistent erythema Skin pore prominence Telangiectasia Scarring
Drugs used on the skin and cosmetics
Unusual manifestations of allergic contact sensitivity Unusual manifestations of contact allergy have been discussed elsewhere (65). A case of contact sensitivity to ethylenediamine with unusual lymphomatoid features has been reported (63). The clinical and histological findings were in keeping with early mycosis fungoides. Continued contact with the allergen was traced to its retention in a trouser pocket lining. The eruption cleared with avoidance o f the allergen. The reader is also referred to Table 5 (under perfume) for a report on a fatality attributed to spray cologne.
SYSTEMIC EFFECTS O F TOPICAL DRUGS
Silver sulfadiazine Febrile reaction A child with burns over 10% of the b o d y surface, treated with silver sulfadiazine and oral penicillin, developed a febrile episode. No infection could be demonstrated. After the treatment with silver sulfadiazine had been interrupted, the temperature settled rapidly. The authors suggest that the topical drug may have been responsible for the febrile reaction (61); definite p r o o f is, however, lacking. Transient leukopenia, due to silver sulfadiazine has been discussed previously (SEDA-4, 108; SEDA-5,152). Podophyllum resin
Delirium and psychosis A case has been reported in which the absorption of podophyllum resin, used for the treatment of condylomata acuminata, led to the development of a delirium with florid psychotic features (70). Previously reported side effects to this powerful skin irritant include acute confusional state, peripheral neuropathy, bone marrow depression, vomiting, coma and death (SED 9, 240; SEDA-4, 108; SEDA-6, 152). Topical cortieosteroids Hypertension
It has been well documented
167 that topical application of corticosteroids to the skin may cause systemic adverse reactions (SED 9, 2 4 8 - 2 5 2 ) . In ten patients suffering from chronic rhinitis, mineralocorticoid hypertension could be ascribed to the habitual use o f large doses of nasal spray containing 9c~-fluoroprednisolone and vasoconstrictor agents (74). Immunosuppression During the last 2 - 3 years a considerable number o f national regulatory agencies have released low-concentration hydrocortisone creams (usually 0.5%) for free sale to the public, notably for the relief of mild sunburn or irritation. Neumann in the USA has recently suggested that there may be a link between this development and an upsurge in the incidence of overwhelming infections in homosexuals. He points out that the package instructions for these products in the US recommend the use of the creams for skin irritation o f the anal and genital areas, and that skin irritation and herpes in the anogenital region are common among male homosexuals. A 1-oz. (28 g) tube o f a 0.5% hydrocortisone cream contains 160 mg o f hydrocortisone, and absorption is likely to be pronounced. He adds that the types of infections seen in immunocompromised homosexuals are those known to occur with corticosteroid use: Pneumocystis carinii infections, extensive candidiasis and severe viral infections. In his view, the matter needs further attention since it could be that 0.5% is too high a concentration for free-sale hydrocortisone creams (75r).
Promethazine Systemic toxicity A 16-month-old male (weight 11.5 kg) was treated with 2% promethazine cream for generalized eczema. After approximately 1 5 - 2 0 g of the cream had been applied the clfild fell asleep; a few hours later he awoke with abnormal behavior, loss o f balance, inability to focus, irritability, drowsiness and failure to recognize his mother. One day later all symptoms had spontaneously disappeared. A diagnosis of promethazine toxicity through percutaneous absorption was made (59). Known symptoms of promethazine toxicity include disorientation, hallucinations, hyperactivity, convulsions, and coma, but these are more usually seen after oral intake.
168 CARCINOGENIC EFFECTS OF DERMATOLOGICAL THERAPY
Psoriasis treatment Genetic and carcinogenic hazards (73) An expert group of the International Commission for Protection against Environmental Mutagens and Carcinogens has reviewed and assessed the possible longterm sequelae, both genetic and carcinogenic, of various treatments available for psoriasis. In this section only the topical therapies will be mentioned. Experimental and h u m a n data were assessed on dithranol, coal tar and ultraviolet light, and psoralen photochemotherapy. The following conclusions were drawn: 1. No treatment can be regarded as absolutely safe. Each carries an established or potential risk of genetic or carcinogenic effects. 2. Coal tar o i n t m e n t and U V radiation treatments at high doses create an additional risk of (easily treated) skin cancer, this being 3 - 6 times greater than that in psoriasis patients treated with low doses of these agents or not at all. 3. There is insufficient evidence to evaluate the mutagenieity of dithranol, but the available data do not suggest a mutagenic capability. 4. Dithranol has not been shown to initiate cancer, but is an established promoting agent (cocarcinogen) with at least two chemical carcinogens in the mouse, not only for skin neoplasms but, with one agent, for lymphomas. In man no data are available but the use of dithranol after k n o w n initiating treatments such as UV or photochemotherapy could involve some hazard. The influence of different concentrations of dithranol on epidermal DNA synthesis rates in mice was studied by Lowe and Breeding (72).
J.P. Nater and A.C. de Groot 5 . 8 - M e t h o x y p s o r a l e n is weakly mutagenie in bacteria and mammalian cells. It is not considered that the genetic risk from exposure of the human testis to 8-MOP with current therapeutic regimens is likely to be significant. 6. P U V A is a potent mutagen and elastogen in all systems studied, including mammalian somatic cells in culture and circulating lymphocytes in man. 7. P U V A is carcinogenic to the skin of mice and probably carcinogenic or cocarcinogenic to the skin of man. In addition, the possibility exists of malignant disease of the reticulo-endothelial system arising out of the irradiation of circulating stem cells. Benzoyl peroxide Skin tumor-promoting activity Allergic contact sensitivity to benzoyl peroxide has been discussed previously (SEDA-3, 131) and elsewhere in this chapter (Table 3). Recently attention has been drawn to another, possibly more serious, unwanted effect of this compound (64): benzoyl peroxide promoted both papillomas and carcinomas when it was applied to mice after 7,12dimethylbenz(a)anthracene initiation. Benzoyl peroxide was inactive on the skin as a complete carcinogen or as a tumor initiator. A single topical application of benzoyl peroxide provided a marked epidermal hyperplasia and induced a large number of dark keratinocytes, effects similar to those produced by the potent tumor promotor 12-O-tetradecanoylphorbol-13-acetate. Benzoyl peroxide, like other known t u m o r promotors, also inhibited metabolic cooperation (intercellular communication) in Chinese hamster cells. In view of these results the authors recommend caution in the use of this and other free radical-generating compounds, as co-carcinogenic effects cannot be excluded.
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4. Lovell, C.R. and Staniforth, P. (1981): Contact allergy to benzalkonium chloride in plaster of Paris. Contact Dermatitis, 7, 343. 5. Van Hecke, E. and Van Brabandt, S. (1981): Contact sensitivity to imidazole derivatives. Contact Dermatitis, 7, 348. 6. Wahlberg, J.E. and Boman, A. (1981): Contact sensitivity to quinidine sulfate from occupational exposure. Contact Dermatitis, 7, 27.
Drugs used on the skin and cosmetics 7. BjiSrkner, B. and Magnusson, B. (1981): Patch test sensitization to D and C Yellow No. 11 and simultaneous reaction to Quinoline Yellow.
Contact Dermatitis, 7, 1. 8. Ljunggren, B. (1981): Contact dermatitis to estradiol benzoate. Contact Dermatitis, 7, 141. 9. Valsecchi, R., Serra, M., Foiadelli, L. and CaineUi, T. (1981): Contact sensitivity to oxyphenbutazone. Contact Dermatitis, 7, 157. 10. Lindemayr, H. and Drobil, M. (1981): Contact sensitization to benzoyl peroxide. Contact Dermatitis, 7, 137. 11. Waddell, M.M. and Finn, O.A. (1981): Sensitivity to resorcin. Contact Dermatitis, 7, 216. 12. Reiffers, J. (1981): Allergy to 5-lodo-2'desoxyuridine. Contact Dermatitis, 7, 125. 13. Jensen, O. (1981): Contact allergy to propylene oxide and isopropyl alcohol in a skin disinfectant swab. Contact Dermatitis, 7, 148. 14. Lawrence, C.M. and Smith, A.G. (1981): Ichthammol sensitivity. Contact Dermatitis, 7, 335. 15. Van Joost, Th., SiUevis Smitt, J.H. and Van Ketel, W.G. (1981): Sensitization to olive oil (olea europeae). Contact Dermatitis, 7, 309. 16. Roberts, D.L., Summerly, R. and Byrne, J.P.H. (1981): Contact dermatitis due to the constituents of Hibiscrub. Contact Dermatitis, 7, 326. 17. Kroon, S. (1981): Contact dermatitis from oleyl polypeptide in Xerumenex ear drops. Contact Dermatitis, 7, 271. 18. Van Ketel, W.G. and Swain, A.F. (1981): Allergy to clobetasol-17-propionate (Dermovate). Contact Dermatitis, 7, 278. 19. Angelini, G. and Meneghini, C.L. (1981): Contact allergy from propylene glycol. Contact Dermatitis, 7, 197. 20. Jensen, O., Petersen, S.H. and Vesterhager, L. (1980): Contact sensitization to benzoyl peroxide following topical treatment of chronic leg ulcers. Contact Dermatitis, 6,179. 21. G6ransson, K. and Lid6n, S. (1981): Contact allergy to sorbic acid and Unguentum Merck. Contact Dermatitis, 7, 277. 22. Calnan, C.D. (1976): Quinazoline Yellow SS in cosmetics. Contact Dermatitis, 2, 160. 23. Mathias, C.G.T. (1982): Pigmented cosmetic dermatitis from contact allergy to a toilet soap containing chromium. Contact Dermatitis, 8, 29. 24. Kozuka, T., Tashiro, M., Sano, S. et al. (1979): Brilliant Lake Red R as a cause of pigmented contact dermatitis. Contact Dermatitis, 5,297. 25. Dooms-Goossens, A., Degreef, H., VanHee, J. et al. (1981): Chlorocresol and chloracetamide: Allergens in medications, glues, and cosmetics.
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169
Acad. Dermatol., 6, 116. 28. Burrows, D. and Rycroft, R.J.G. (1981): Contact dermatitis from PTBP resin and tricresyl ethyl phthalate in a plastic nail adhesive. Contact Dermatitis, 7, 336. 29. Calnan, C.D. (1981): Quinazoline yellow dermatitis (D and C Yellow 11) in an eye cream. Contact Dermatitis, 7, 271. 30. Calnan, C.D. (1981): Monotertiary butyl hydroquinone in lipstick. Contact Dermatitis, 7, 280. 31. Calnan, C.D., Cronin, E. and Rycroft, R.J.G. (1981): Allergy to phenyl salicylate. Contact Dermatitis, 7, 208. 32. Camarasa, J.G. (1981): Contact dermatitis to thioxolone. Contact Dermatitis, 7, 213. 33. Van Ketel, W.G. and Liem, D.H. (1981): Eyelid dermatitis from nickel contaminated cosmetics. Contact Dermatitis, 7, 217. 34. Brown, R. (1981): Chlorphenesin sensitivity. Contact Dermatitis, 7, 162. 35. Adams, R.M. (1981): Allergic contact dermatitis due to o-phenylphenol. Contact Dermatitis, 7, 332. 36. Osmundsen, P.E. (1982): Contact dermatitis to chlorhexidine. Contact Dermatitis, 8, 81. 37. F6rstr6m, L., Lassus, A., Salde, L. and Niemi, K.M. (1982): Allergic contact eczema from topical corticosteroids. Contact Dermatitis, 8, 128. 38. Lawlor, F. and Hindson, C. (1982): Allergy to dithranol. Contact Dermatitis, 8, 137. 39. Menezes Brandao, F. and Pecegueiro, M. (1982): Contact dermatitis to tromantadine hydrochloride. Contact Dermatitis, 8, 140. 40. De Groot, A.C. (1982): Unpublished observation. 41. Verburgh-Van der Zwan, N. and Van Ketel, W.G. (1981): Contactallergie voor een arseenbevattend intravaginaal toegepast geneesmiddel. Ned. T. Geneesk., 125, 1718. 42. Staniforth, P. and LoveU, C.R. (1981): Contact dermatitis related to constituent of an orthopaedic wool. Brit. reed. J., 283, 1297. 43. Giovinazzo, V.J., Harber, L.C., Bickers, D.R. et at. (1981): Photoallergic contact dermatitis to Musk Ambrette. Arch. Dermatol., 117, 344. 44. Zugerman, C. (1981): Persistent photosensitivity caused by Musk Ambrette. Arch. Derma. tol., 117, 432. 45. Shelley, W.B. (1982): Immediate sunburn-like reaction in a patient with formaldehyde photosensitivity. Arch. Dermatol., 118, 117. 46. Merk, H., Ebert, L. and Goerz, G. (1982): Allergic contact dermatitis due to the fungicide hexetidine. Contact Dermatitis, 8,216. 47. Marks Jr., J.G. (1982): Allergic contact dermatitis to povidone-iodine. J. Amer. Acad. Der-
matol., 6,473. 48. Scott, M.J. and Scott Jr., M.J. (1982): Jojoba oil (letter to the Editor). J. Amer. Acad. Dermatol., 6, 545. 49. Grimalt, F. and Romaguera, C. (1981):
170 Cutaneous sensitivity to benzidine. Dermatosen, 29, 95. 50. Thompson Jr., J.A. and Wansker, B.A. (1981): A case of contact dermatitis, erythema multiforme, and toxic epidermal necrolysis. J. Amer. Acad. Dermatol., 5, 666. 51. Marehand, B., Barbier, P., Ducombs, G. et at. (1982): Allergic contact dermatitis to various salols (phenyl sallcylates). Arch. Dermatol. Res., 272, 61. 52. Nater, J.P. and de Groot, A.C. (1983): Contact urticaria. In: Unwanted Effects o f Cosmetics and Drugs Used in Dermatology, Ch. 7, pp. 105-111. Excerpta Medica, Amsterdam. 53. Von Krogh, G. and Maibach, H.I. (1983): The contact urticaria syndrome. In: Dermatotoxicology, 2ndEd., Ch. 14, pp. 3 0 1 - 3 2 2 . Editors: F.N. Marzulli and H.I. Maibach. Hemisphere Publishing Co., Washington. 54. Warin, R.P. and Smith, R.J. (1982): Chronic urticaria. Investigations with patch and challenge tests. Contact Dermatitis, 8, 117. 55. Von Krogh, G. and Malbach, H.I. (1981): The contact urticaria syndrome - an updated review. J. Amer. Acad. Dermatol., 5, 328. 56. Eiermann, H.J., Larsen, W., Maibach, H.I. and Taylor, J.S. (1982): Prospective study of cosmetic reactions: 1977-1980. J. Amer. Acad.
Dermatol., 6,909. 57. Litton, C. and Trinidad, G. (1981): Complications of chemical face peeling as evaluated by a questionnaire. Piast. reconstr. Surg., 6 7, 738. 58. Tkach, J.R. (1982): Allergic contact urticaria to benzoyl peroxide. Cutis, 29, 187. 59. Bloch, R. and Beysovec, L. (1982): Promethazinc toxicity through percutaneous absorption. On continuing Practice, 9, 28. 60. Krutchkoff, D.J., Eisenberg, E. and Neckritz, A.A. (1981): Epidermoid carcinoma of the gingiva: a possible relationship to PUVA therapy. Oral Surg., 52, 44. 61. Clarke, S.D., Gallur, L. and ThrellfaU, G.N. (1981): Febrile reaction to silver sulphadiazine. Med. J. Aust., 22, 208. 62. Cramers, M. and Thormann, J. (1981): Skin reactions to a urea-containing cream. Contact Dermatitis, 7, 189. 63. Wall, L.M. (1982): Lymphomatoid contact dermatitis due to ethylenediamine dihydrochloride. Contact Dermatitis, 8, 51.
J.P. Nater and A. C. de Groot 64. Siaga, T.J., Klein-Szanto, A.J.P., Triplett, L.L. and Yotti, L.P. (1981): Skin tumor-promoting activity of benzoylperoxide, a widely used free radical-generating compound. Science, 213, 1023. 65. Nater, J.P. and de Groot, A.C. (1983): Unusual manifestations of contact allergy. In:
Unwanted Effects o f Cosmetics and Drugs Used in Dermatology, Ch. 6, pp. 99-104. Excerpta Medica, Amsterdam. 66. Henseler, T., Wolff, K., H6nigsmann, H. and Christophers, E. (1981): Oral 8-methoxypsoralen photochemotherapy of psoriasis. Lancet, I, 853. 67. Burnett, J.W. (1975): TWO unusual complications of topical fluorouracil therapy. Arch.
Dermatol., 111,398. 68. Burnett, J.W. (1982): Further observations on two unusual complications of topical fluorouracil therapy. Arch. DermatoL, 118, 74. 69. Galentine, P., Sloas, H., Hargett, N. and Cupples, H.P. (1981): Bilateral cicatricial ectropion following topical administration of 5fluorouraefl. Ann. Oph thalmol. , 13,575. 70. Stoudemire, A., Baker, N. and Thompson, L. (1981): Delirium induced by topical application of podophyllin: a case report. Amer. J. Psychiat., 138, 1505. 71. Kikuehi, I. and Aoki, Y. (1981): Cortisol skin injuries. Skin injuries in atrophic skin of patients receiving corticosteroid therapy. J. Derm., 8, 419. 72. Lowe, N.J. and Breeding,J. (1981): Anthralin, different concentration effects on epidermal DNA synthesis rates in mice and clinical responses in human psoriasis.Arch. Dermatol., 117, 698. 73. Bridges, B.A., Greaves, M., Polani, P.E. and Wald, N. (1981): Do treatments available for psoriasis patients carry a genetic or carcinogenic risk? Murat. Res., 86, 279. 74. Mantero, F., Armanini, D., Opocher, G. et al. (1981): Mineralocorticoid hypertension due to a nasal spray containing 9a-fluoroprednisolone. Amer. J. Med., 17, 352. 75. Neumann, H.N. (1982): Use of steroid creams as a possible cause of immunosuppression in homosexuals. New Engl. J. Med., 306, 935. 76. Leonforte, J.F. (1981): Pityriasis rosea: exacerbation with cortir treatment. Dermatologica, 163, 480.