Photosensitivity Due to Drugs

General Information

John H. Epstein and Bruce U. Wintroub Department of Dermatology, University of California, and Dermatology Service, Veterans Administration Medical Center, San Francisco

Summllry Photosensitivity reactions induced by drugs may be phototoxic or photoallergic in na ture. Acute phototoxic reactions are by far the more common. and are generally charac terised by erythema and oedema followed by hyperpi gmentation and desquamation. Chronic repeated injury of this type may result in fragility. blistering and milia formation or even actinic keratoses and skin cancers. The photochemical mechanisms involved differ with the chemical photosensitiser involved. They include photoaddition of the chemical to bio logical targets such as DNA. the formation oftoxic products due to absorption ofthe action spectrum by the photosensitising molecule. or the activation oftoxic oxygen species or free radicals. Subsequent activation of the complement pathways may participate in the pho toresponse to certain agents. Photoallergic reactions are uncommon. They represent an acquired altered reactivity dependent on a circulating antibody or a cell-mediated hypersensitivity process. Clinically. they are characterised by an immediate wheal and flare or a delayed papular to ecze matous process. Some of the same drugs which cause phototoxic responses occasionally produce photoallergic reactions.

Sun-induced cutaneous reactions have become or oxygen independent (non-photodynamic) [Blum, increasingly common over the past several dec 1941 a; Epstein, 1971]. Photoallergic reactions may ades, due not only to social causes centred on de be due to immediate antibody-mediated or delayed sires for a golden suntan, but also to the ever-ex cell-mediated (eMI) responses (Epstein, 1972; panding numbers and amounts of photosensitising Morison et aI., 1979). chemicals entering our environment - primarily Whichever type of response occurs, it must fol from cosmetic, pharmaceutical and industrial low the basic law of photochemical absorption sources. This article is concerned primarily with which states that non-ionising radiation must be the photosensitising effects of chemicals that are absorbed to produce a photochemical and subse used as medications therapeutically or as cosmet quently a photobiological reaction. This law then ics. stipulates that the photosensitising molecule must Two types of photosensitivity reactions may be be present at the time of the irradiation for the induced by such chemicals; i.e. they may be pho reaction to occur. In addition, the action spectrum totoxic or photoallergic in nature. Phototoxic re for any specific photoreaction must be included in actions may be oxygen dependent (photodynamic) the absorption spectrum of the photosensitiser. Photosensitivity Due to Drugs 43

1. Phototoxicity diation is the classic example of an acute photo toxic reaction. Phototoxic reactions may be drug-induced or Host effects may influence the natural history may accompany certain metabolic disorders in of drug-induced phototoxic reactions. Several fac which an appropriate photosensitising chemical is tors, including hair, pigment, and thickness of the available in target tissue. In each case, the photo stratum corneum, influence radiation penetration. toxic reaction occurs when enough chromophore Topical photosensitisers are dependent on percu (drug or metabolic product) absorbs sufficient ra taneous absorption and metabolism in the skin diation in reactive tissue. Drug-induced phototoxic (Anderson and Parrish, 1981). Systemic chrom reactions, whether from systemic administration ophores are influenced by gastrointestinal absorp or topical application, can occur in 100% of people tion, distribution and metabolism of the chemicals. on first exposure, and using appropriate experi In addition, increased humidity, temperature and mental conditions a dose-response curve can be wind also enhance phototoxic responses (Levine demonstrated with the incidence of phototoxicity and Harber, 1969; Owens and Knox, 1978). being related to the concentration of sensitisers and Histologically, epidermal cell degeneration may amount of light. This section focuses on the clinical be prominent when the photosensitiser or chrom expression and mechanism of phototoxicity due to ophore is in the epidermis (Epstein, 1971). This is topically or systemically administered drugs. It only most notable when a potent photosensitiser, such briefly considers phototoxicity which accompanies as a psoralen compound, is applied to the skin. In certain metabolic disorders, such as the porphy contrast, if the chromophore reaches the skin rias, in which a photo toxic metabolic product ac through the vasculature, the primary site of injury cumulates in skin as the result of an inborn meta may be in the dermis, with little or no visible epi bolic error. dermal change (Epstein, 1974). In both instances, there is generally little inflammatory cell response l.l Clinical Expressions in the dermis in human skin. When tissue is ex amined at a submicroscopic level, vascular injury 1.1.1 Acute Reactions is associated with protoporphyrin photosensitisa In general, acute phototoxic reactions are char tion (Honigsman et aI., 1976; Schnait et aI., 1975). acterised by erythema, oedema, and at times blister formation, followed by hyperpigmentation and de 1.1.2 Chronic Reactions squamation (Epstein, 1983). These reactions are Lifelong exposure to the sun (most notably UVB confined to sun-exposed skin. Immediate burning, rays) causes clinical cutaneous alterations which stinging sensations are characteristic of photosen include wrinkling, atrophy, hyper- and hypopig sitisation by certain chemicals such as coal tar, de men ted macules, telangiectasia, yellow papules and meclocycline (demethylchlortetracycline), and pro plaques, keratotic growths (actinic keratoses), and toporphyrin (in erythropoietic protoporphyria). The at times skin cancer formation. A distinctive, fur clinical reaction may begin from a few minutes to rowed, leathery appearance may be seen on the nu several hours after the irradiation and reach a peak chal area of fair-complexioned individuals. The from several hours to several days later. Acute ery chronically damaged skin is usually quite fragile, thema is usually associated with stimulation of' rupturing following mild trauma. In addition, the melanin formation, leading to subsequent hyper cutaneous blood vessels rupture easily, leading to pigmentation. areas of purpura; these are due to a loss of struc Since phototoxic injury results in cell death, tural support by the dermal connective tissue. sloughing of the dead epidermal cells presents as Histologically, effacement as well as projections desquamation or peeling. 'Sunburn' reaction in of the rete ridges, a possible thinning of the epi duced by ultraviolet B (UVB; 290 to 320nm) ra- dermis, and the presence of many abnormal ker- Photosensitivity Due to Drugs 44

atinocytes in disorderly arrangement may be seen. 1.2 Mechanisms In the dermis, there is a progressive degeneration in the papillary and subpapillary zones. Specific The interactions of light, phototoxic chemicals changes include the development of vascular ec and their biological targets may result from several tasia, the accumulation of acid mucopolysacchar types of photochemical reactions. In each case,' ides and abnormal-appearing fibrocytes, the loss of damage to biological substrates is initiated by the collagen (but an increase in the soluble compo absorption of light energy by a phototoxic com nent), and the marked increase and degeneration pound. As already noted, phototoxic reactions have of elastic tissue, referred to as actinic elastosis. Al been divided into 2 categories: oxygen-dependent though there is still some question as to the origin (photodynamic) and oxygen-independent (non of the fibres which stain like elastic tissue, bio photodynamic) [Blum, 1941a; Epstein, 1971]. In chemical and electron microscopic studies have the case of drug-induced phototoxicity, recent confirmed that actinic elastosis is due to the ac studies have resulted in a more detailed under cumulation of elastic tissue. standing of the various mechanisms of phototox In general, most drug-induced phototoxic re icity. actions are acute and phototoxicity may necessi At least 3 distinct photochemical mechanisms tate discontinuation of the drug. However, chronic have been described in in vitro systems (Kochevar, actinic changes have been associated with a form 1981). Firstly, the direct reaction between the ex of dermatological psoriasis therapy in which pho cited state of a phototoxic molecule and a biologi tochemotherapy is employed. In a large series of cal target may result in the formation of a covalent psoriatic patients treated with psoralens and ultra photoaddition product which is comprised of the violet A (UV A; 320 to 400nm) radiation (PUV A), compound itself and the biological target. Exam a definite increase in cutaneous cancer formation ples include photoaddition of chlorpromazine to was noted (Stern et aI., 1979). In addition, there is protein or DNA, or the light-induced formation of histological evidence of focal dystrophy of epi a photoadduct of methoxsalen (8-methoxypsora dermal cells, atypical changes in melanocytes, len; 8-MOP) and a pyrimidine base in the DNA and deposition of colloid bodies and amyloid molecule (Song and Tapley, 1979). Secondly, the at the dermoepidermal junction (Abel and Farber, phototoxic molecule absorbs protons to form sta 1980). ble photoproducts which are toxic to biological More recently, an increased cancer incidence in substrates. Such photoproducts are usually de psoriatic patients who had received very extensive tected by irradiation of the phototoxic molecule treatment with coal tar and UVB exposures has prior to exposure to a potential substrate. Exam been reported (Stern et aI., 1980). This may rep ples include erythrocytolysis caused by formation resent an additive carcinogenic effect between tar of a stable photoproduct from chlorpromazine or and UVB energy since the action spectrum for coal protriptyline (Kochevar and Lamola, 1979). tar photosensitisation is the UV A range. Thirdly, irradiation of a phototoxic molecule may A limited form of chronic phototoxic injury oc result in the tranfer of energy to oxygen molecules curs'in porphyria cutanea tarda, variegate porphy with resultant formation of toxic active oxygen ria, hereditary coproporphyria, and low-grade pho species, such as a singlet oxygen, a superoxide an tosensitisation by certain medications such as ion, or an hydroxyl radical. Interaction of these nalidixic acid, tetracycline hydrochloride, and the species with biological targets produces photo-ox sui phones. Clinically, this injury is characterised idised molecules. Examples include toxic oxygen by fragility, blistering, milia formation, and at times species produced by irradiation of protoporphyrin sclerodermoid changes involving the sun-exposed (Lamola and Doleideu, 1980), xanthene dyes (Ito skin. In erythropoietic protoporphyria, the skin and Kobayashi, 1977), and thiazine dyes (Stratigos frequently becomes quite thick. and Magnus, 1968). Photosensitivity Due to Drugs 45

Each of the above photochemical reactions oc viewed with respect to clinical problems and mech curs in vitro in a serum-free environment. Recent anisms of phototoxicity. studies have uncovered a critical role for serum protein-dependent systems in acute, in vivo, pho 1.3.1 Psora/en Phototoxicity totoxic tissue damage due to exogenous agents (Lim Furocoumarins are a class of compounds to et aI., 1983). Evidence suggests that complement which the psoralens belong; these compounds con may participate in the development of phototoxic sist of a double-ringed coumarin moiety with a lesions. Irradiation of normal human serum con furan ring attached. At least 28 different furocou taining added uroporphyrin or protoporphyrin, or marins have been isolated from natural sources, demeclocycline resulted in complement activation but only 4 are used clinically: psoralen, methoxsa and generation of chemotactic activity (Lim et aI., len (8-methoxypsoralen), 5-methoxypsoralen, and 1981, 1983). In vivo activation ofthe complement trioxsalen (4,5,8-trimethylpsoralen). The absorp system was noted after irradiation of patients with tion maxima of psoralens range between 210 and erythropoietic protoporphyria or porphyria cuta 330nm, but the erythema action spectrum is in the nea tarda (Lim et aI., 1982). In addition, normal UVA range from 320 to 370nm, with a probable numbers of polymorphonuclear cells and an intact peak at 360nm. complement system are required for the full de Psoralen combined with sun exposure has been velopment of demeclocycline-induced phototoxic used to treat vitiligo for centuries. The availability lesions in an in vivo guinea-pig model system (Lim of high intensity artificial UV A light sources in the et aI., 1983). Therefore, both serum protein-de past decade has permitted the use of psoralens in pendent pathways and circulating, mobile effector combination with controlled doses of UV A light cells appear to be necessary for certain forms of (Parrish et aI., 1974). The acronym PUVA (psor phototoxic tissue injury. alen and UV A photochemotherapy) is used to in With the exception of the examples outlined dicate this form of dermatological therapy. Three above, the erythrogenic mediators of photo toxic major dermatological diseases are frequently treated reactions are not well understood. Unlike UVB with PUV A; vitiligo, psoriasis and mycosis fun phototoxicity, prostaglandins do not appear to be goides. involved in methoxsalen and UV A photoreactions. Anthracene phototoxic-induced hyperaemia in Mechani~m of Phototoxicity mouse skin appears to be mediated by histamine The mechanism of psoralen photosensitisation (Argenbright et aI., 1980). How this relates to ery has been intensively studied. Non-photodynamic thematous responses to other molecules and in reactions have been described for psoralen pho other animals remains to be seen. In general, much tosensitisation (Pathak et al., 1974). In this in more information is needed to clarify the mech stance certain psoralen compounds intercalate into anisms which lead to the changes we see in and the DNA helix (Song and Tapley, 1979). On pho during phototoxic cutaneous responses. toactivation with UV A radiation, mono- and bi functional adducts may be formed in the DNA, de 1.3 Phototoxic Agents of Special Interest pending on the structure of the psoralen molecule and the wavelengths utilised for irradiation (Par Certain frequently used orally and topically ad sons, 1980; Pathak et aI., 1974; Song and Tapley, ministered agents are known to cause phototoxic 1979). Photoreactions with proteins may also oc ity (table I). In certain cases, phototoxicity is em cur. ployed for therapeutic benefit, as in the case of It should be noted that psoralens can also pro psoralens and tar, while in other cases phototox duce photodynamic responses (Parsons, 1980). icity is a distinctly adverse event. In this section, Psoralen photoinduced singlet oxygen formation those drugs which are commonly used are re- has been correlated with erythema production by Photosensitivity Due to Drugs 46

Table I. Some commonly used drug photosensitisers

Drug Clinical manifestations Action spectrum (nm)

Amiodarone Delayed erythema. slate grey pigmentation

Benoxaprofen Pruritus. delayed erythema. photo-onycholysis 310-340

Coal tar derivatives: 'Tar smarts'. pricking sensation. erythema. melanosis 320-430 anthralene methylanthracene acridine phenanthrene benzo(a)pyrene

Furocoumarins: Delayed erythema. phytophotodermatitis 320-380 psoralen 5-methoxypsoralen 8-methoxypsoralen (methoxasalen) 4.5.8-trimethylpsoralen (trioxsalen)

Halogenated salicylanilides Photoall'3rgic contact dermatitis 320-400

Musk ambrette Eczematous reaction 310-380

Nalidixic acid Bullae. fragility. milia 320-360

Phenothiazines: Delayed erythema. eczematous reaction. slate grey 320-400 chlorpromazine pigmentation thioridazine promethazine trimeprazine

Piroxicam Bullae. delayed erythema

Quinidine Delayed erythema 320-380

Sulphonamides Delayed erythema. eczematous reaction 315-400

Sulphonylureas Delayed erythema. eczematous reaction 315-400

Tetracyclines Delayed erythema; photo-onycholysis. bullae. fragility. 350-420 milia

Thiazides Delayed erythema. eczematous reaction. lichenoid 300-400 eruption. bullae

Quindoxin (quinoxaline lA-dioxide) Eczematous reaction

6-Methylcoumarin Eczematous reaction 320-380

several psoralens, suggesting that these photodyn photosensitivity to chlorpromazine was first re amic responses may be responsible for some of the ported in the 1950s (J.H. Epstein et aI., 1957) and effects of psoralen photosensitisation in human skin the drug is now known to be phototoxic in a variety (Parsons, 1980). of in vitro systems, including red blood cells, bac teria, mammalian cells, bacteriophages and viruses 1.3.2 Chlorpromazine Phototoxicity (Kochevar, 1981). Ciorpromazine is known to cause Chlorpromazine is an antipsychotic drug fre several photodermatoses when taken systemically. quently utilised in psychiatric patients. Clinical An exagerated sunburn reaction (phototoxicity) and Photosensitivity Due to Drugs 47

a hyperpigmentation of purple or slate-grey tone in 1.3.4 Nalidixic Acid Phototoxicity light exposed skin have been described. The wave Nalidixic acid is a bacteriostatic agent com length range required to elicit a clinical reaction monly used to treat urinary tract infections. In as has been a topic of controversy. Chlorpromazine sociation with extensive sun exposure, nalidixic acid has an absorption maximum at 305nm in aqueous has caused characteristic bullous eruptions, fragil solution, but the action spectrum for phototoxicity ity, scarring and milum formation in light-exposed has been reported to be both below (J.H. Epstein areas, particularly the lower legs and feet (Ramsay et aI., 1957) and above (S. Epstein, 1968) 320nm and Obreshkova, 1974). Similar reactions have been in man. For phototoxicity in mice, the action spec noted for tetracycline hydrochloride and sulphones trum has been reported to be 320 to 340nm with (Epstein et aI., 1976). a maximum of 330nm (Hunter et aI., 1970). While the mechanisms of nalidixic acid pho totoxicity are not known, the clinical and histo Mechanisms of Phototoxicity pathological changes are identical to those found The mechanisms of chlorpromazine phototox in a number of porphyrias (Epstein et aI., 1973). icity have been extensively studied and at least two possible mechanisms have been demonstrated in 1.3.5 Phototoxicity Due to Non-Steroidal vitro. Photoaddition of chlorpromazine to protein, Anti-Inflammatory Agents DNA, and cell membranes has been reported (Ro In the past 10 years many new non-steroidal senthal et aI., 1978). In addition, it appears that anti-inflammatory drugs have been introduced and stable photoproducts of chlorpromazine elicit cu are widely used to treat a variety of inflammatory taneous toxicity in animals and haemolyse red and symptomatic musculoskeletal disorders. Two blood cells (Kochevar and Lamola, 1979). In both ofthese agents, benoxaprofen (now withdrawn) and systems, toxicity was detected induced by pre-ir piroxicam, are known to cause clinically important radiated chlorpromazine. In the case of red cell phototoxicity. haemolysis, the stable lysis-producing product did Benoxaprofen is a proprionic acid derivative not require oxygen for activity nor cause lipid ox which was introduced into the European and idation in the presence of oxygen. Thus, chlor United States markets for treatment of rheumatoid promazine has been shown to be phototoxic in arthritis, osteoarthritis, ankylosing spondylitis and many systems, but the route of translation of these psoriasis. The drug was suspended because it caused in vitro effects to human phototoxicity is unclear. instances of fatal cholestatic hepatitis, especially in the elderly. Unlike other non-steroidal anti-inflam 1.3.3 Tetracycline Phototoxicity matory drugs which act principally by inhibiting Of the tetracyclines, demeclocycline (demethyl prostaglandin synthetase, benoxaprofen is primar chlortetracycline), is the most potent phototoxic ily a 5-lipoxygenase inhibitor. Benoxaprofen caused agent. It causes both immediate and delayed re side effects in up to 65% of patients, and cutaneous actions in most individuals, according to reactions were the most common, accounting for dose (Kligman, 1962; Maibach et aI., 1967). Hu 70% of all side effects (Halsey, 1982). The com man studies indicate that the action spectrum for monest cutaneous side effect was photosensitivity, demeclocycline phototoxicity is above 320nm, and which occured in up to 29% of patients on the drug, studies in mice demonstrate an effective radiation the incidence depending on skin type and amount range of 350 to 450nm, with the greatest response of UV exposure. The action spectrum of the pho at 400nm. totoxic reaction is 310 to 340nm. The reaction is Recent experiments have clearly demonstrated manifested as immediate itching, burning and ery a requirement for complement and polymorpho thema (Ferguson, 1982). The mechanism of this nuclear leucocytes as amplifiers or effectors of de phototoxicity is unknown. meclocycline phototoxicity (Lim et aI., 1983). Piroxicam is an oxicam which inhibits prosta- Photosensitivity Due to Drugs 48

glandin synthetase and is used for treatment of matltls. Though vasodilitation and oedema are rheumatoid arthritis, osteoarthritis, gout and an present in the immediate reaction, these are diffi kylosing spondylitis. While the incidence of cutan cult to discern histologically. eous side effects is around 2.4%, a unique photo sensitivity due to piroxicam has been reported in 2.2 Photoallergic Reactions to Exogenous several patients (Stern and Bigby, 1984). The pho Chemicals tosensitivity reaction is usually vesiculobullous and is often pruritic. The spectrum and mechanisms of Photoallergic reactions to drugs and other ex photosensitivity are unknown. ogenous chemicals are almost always of a delayed hypersensitivity or cell-mediated type. An excep 1.4 Testing for Phototoxicity tion was reported by Horio (1975) who studied a patient with clinical expressions of both immediate Agents capable of producing phototoxic effects and delayed reactions induced by chlorpromazine. have been identified by use of a variety of in vitro He was able to reproduce both responses with pho and in vivo systems. However, the ultimate issue topatch and intradermal tests and UV A radiation. concerns the effect these compounds have on hu In addition, he passively transferred the immediate man tissue in vivo (Emmet, 1979; Kligman and wheal reaction with the patient's serum. Masuda Kaidbey, 1982). In general, the following 4 tech et ai. (1971) noted an immediate wheal response niques have been utilised: systemic administration, with photopatch tests in 2 of 44 patients who were topical application with occlusion, topical appli contact-photosensitive to biothionoi. They were cation after the stratum corneum is stripped off, also able to passively transfer the reaction. How and intradermal injection. Each of the techniques ever, the patients did not demonstrate solar urti has disadvantages, among which are lack of dis carial responses clinically. tribution to the skin of the active photosensitising The skin is the site of photoallergic reactions to molecule, metabolism of the chemical to a non exogenous chemicals which may be applied topi photosensitising structure, lack of metabolism to cally or administered systemically. As with pho an active photosensitising structure, lack of pene totoxicity, in the photoallergic reactions to these tration to the appropriate target tissue, lack of ir chemicals the action spectrum usually falls in the radiation with the appropriate wavelengths, and UV A range. The immunological basis for these re lack of irradiation at the appropriate time. actions is supported primarily by studies on con tact photoallergy. 2. Photoallergy 2.1 Definition 2.2.1 Photoallergic Contact Dermatitis Clinical Expression Photoallergic reactions are uncommon. As with Photoallergic contact reactions are clinically allergic responses in general, they are acquired al identical to any other type of allergic contact der tered reactivities presumably dependent on an matitis. Thus the spectrum of the possible re antigen antibody or cell-mediated hypersensitivity sponses may range from a simple erythema to a phenomenon. Clinically, they present as an im severe vesiculobullous eruption. The most com mediate wheal and flare or a delayed papular to mon picture is eczematous in nature. When the eczematous dermatitis (J.H. Epstein, 1971, 1972; process is chronic, lichenification results from re S. Epstein, 1962; Morison et aI., 1979; Storck, 1965). peated mechanical trauma (rubbing and scratch Microscopically, these delayed reactions are char ing). The sun-exposed areas of the skin are in acterised by a dense dermal perivascular round cell volved primarily, as would be expected. However, infiltrate similar to that seen in allergic contact der- the eruption may extend to unexposed parts of the Photosensitivity Due to Drugs 49

body and even become generalised due to condi tocontact reactions to the halogenated salicylani tioned irritability and autoeczematisation reac Iides severe enough to necessitate consultation at tions. Even when this occurs the dermatitis is most medical centres have been persistent light reactors. notable in the exposed sites. In our studies with antibacterial halogenated sali Histologically, there is generally some intercell cylanilides we found two types of persistent light ular oedema in the epidermis with or without ve reactors: a mild variety that loses its reactivity sicle formation, depending on the clinical pattern. within 1.5 years and a severe type that appears to However, the characteristic finding is present in the persist indefinitely (Epstein et aI., 1968). dermis and consists of a dense perivascular round Chemicals other than the antibacterial halogen cell infiltrate, which is identical to that found in ated salicylanilides have induced persistent light any allergic contact dermatitis response. reactions, including the related antifungal com Adults 1I.re much more commonly affected than pound buclosamide (Burry, 1970; Burry and children. Obviously the reactions will occur in Hunter, 1970), chlorpromazine (Amblard et aI., populations that are exposed to sunlight and the 1982; Burdick, 1969; Wiskemann and Wulf, 1959), photocontactants. Thus, reactions to the optical promethazine (Sidi et aI., 1955), musk ambrette brighteners are more likely to be seen in occupa (Giovinazzo et aI., 1980) and epoxy resins (Allen tions where they are used: those to chlorpromazine and Kaidbey, 1979). Persistent light reactions in would more likely occur in people who work in duced in guinea-pigs with sulphonamides have also mental institutions, and so on. Perhaps the most been noted (Schwarz and Speck, 1957), and one of extensive statistical data have been compiled on us has observed a phototoxic persistent light re the eruptions induced by the halogenated salicyl action induced by systemic demeclocycline that has anilides and related antibacterial compounds be persisted 3 years (Epstein, unpublished data). The cause of the large number of people photosensi mechanism or mechanisms of this persistent light tised by these agents between 1960 and 1970 reactivity are not clear. Cross-reactions to un (Herman and Sams, 1972). The reactions occurred known photocontactants have been considered. predominantly in men past the age of 40 years. The Willis and Kligman (l968a) presented evidence reason for this age and sex distribution is un suggesting that the reactions could result from the known. Skin colour and race apparently have little retention of small amounts of the photosensitiser influence on the problem, since the reaction occurs in the dermis. These authors also reported that the readily in Blacks and Orientals as well as Cauca lowered minimal erythema dose in persistent light sians. reactors was a photoallergic reaction, which resem In general, removal of the offending photosen bled a sunburn. sitiser and related compounds will eliminate the Photoinduced covalent binding of tetrachloros problem once the eruption has subsided. A small alicylanilide to the albumin molecule has been percentage of patients who have developed this demonstrated by Kochevar (1979). Other possibil process will become persistent light reactors (Jill ities include: (a) the persistence of a sensitised son and Baughman, 1963). These are people who mononuclear infiltrate in the dermis, which will continue to develop the dermatitis on sun-exposed react on minimal antigenic exposure; (b) hypersen areas without apparent further contact with the of sitivity to the protein component of the complete fending agent or related structures. These patients antigen, which then becomes an independent pho tend to be exquisitely sensitive to the sun and usu toallergen; or (c) the development of clones of cells ally have very low UVB minimal erythema doses. that are persistently sensitive to a number of pho The incidence of this most disturbing problem is toallergens (Herman and Sams, 1972). Also, a pos unknown, but it probably represents only a small sible relationship to the chronic eczematous type percentage of those who become contact photosen of polymorphous light eruption has been reported sitive. However, up to 25% of patients with pho- (Epstein et aI., 1968). Photosensitivity Due to Drugs 50

Diagnosis cent tubes, zenon arcs, carbon arcs, and mono The differential diagnosis includes essentially chromatic sources (Harber et aI., 1974). Window any eruption that may involve the sun-exposed glass filtration is necessary if there is a significant skin. However, for practical purposes, allergic con amount ofUVB emitted by the lamp, as in the case tact dermatitis, the eczematous type of polymor of the hot quartz source. 24 hours after the irra phous light eruption, and phototoxic reactions are diation the closed and exposed sites are compared. by far the most important. The reading techniques are identical to those used Airborne allergens will primarily contact ex in evaluation of ordinary patch tests. A positive posed skin. Unlike photocontactant reactions, the reaction to the photopatch tests reproduces the airborne contact eruption will be accentuated in fold clinical lesions morphologically and histologically. areas such as the upper eyelids, antecubital fossae, Certain difficulties with patch testing may occur. and the flexural areas of the wrists, etc., because of If the patient is contact allergic to a chemical it concentration of the airborne material in these may be difficult to determine if he or she is pho areas. Differentiation from allergic contact reac tocontact allergic as well. However, in general, the tions to sunscreens, 'suntanning' lotions and photopatch test site will be much more reactive than creams, and medications used to relieve the dis the patch test area in a patient with dual sensitiv comfort of a sunburn is more difficult since they ity. are confined to the sun-exposed areas and are in Another significant problem concerns identify distinguishable clinically and histologically. The ing the potential photoallergen. The history may same is true for the eczematous type of polymor be helpful in this determination. Unfortunately phous light eruption. patients often do not know what they contacted Phototoxic reactions induced by topical or sys (except for suntan oils or the like). This is espe temic exogenous photosensitisers will have the same cially true of preservatives and ingredients in soaps. distribution as the photoallergic reactions. The We use the following series of compounds rou clinical picture and lack of the dermal round cell tinely and add whatever can be determined from infiltrate histologically will usually serve to make the history: 5% para-aminobenzoic acid (PABA); this differentiation. However, the most useful diag amyl dimethyl PABA; glyceryl PABA; 5% musk nostic tools available are the patch, photopatch, and ambrette; octyl dimethyl PABA; oxybenzone; phototesting procedures. dioxybenzone; 0.25% tetrachlorosalicylanilide: and The diagnosis of photocontact dermatitis is sus 1% tribromosalicylanilide. pected by the clinical picture, including the char We also routinely patch test with the screening acter and distribution of the eruption and the his materials suggested by the North American Con tology. Confirmation and identification of the tact Dermatitis Groups (NACDG, 1974) to eval offending chemical depends on photopatch testing. uate other potential contactants and phototest to This is accomplished by the application in dupli examine for polymorphous light eruption (Epstein, cate of non-irritating concentrations of the poten 1966). tial photosensitisers in appropriate vehicles (i.e. a 1% concentration of halogenated salicylanilides in Photocontactants petrolatum). The use of an extra layer of black pa Photoallergic reactions to a number of topically per· over the patches will help prevent a 'masked' contacted chemicals have been reported. These in positive reaction to the photopatch test (Epstein, clude: sulphonamides (Epstein, 1962; Schwarz and 1963); this is unnecessary with the use of alumin Speck, 1957; Storck, 1965); phenothiazines (Am ium patches. 24 hours later one set of patches is blard et aI., 1982; Burdick, 1969; Epstein, 1960a, irradiated with the UV A rays. Any light source that 1968; Epstein and Rowe, 1957; Ertle, 1982; Horio, emits sufficient amounts of these rays can be util 1975; Polano, 1964; Sidi et aI., 1955; Storck, ised, including the sun, hot quartz lamps, fluores- 1965; Torinuki et aI., 1982); sulphonylcarbamides Photosensitivity Due to Drugs 51

(Burckhardt and Schwarz-Speck, 1957); men's col Plewig, 1982; Giovinazzo et ai., 1980; Raugi et ai., ognes and after-shave lotions (Epstein, 1969; Starke, 1979). In addition, musk ambrette has been re 1967); blankophores (optical brighteners) [Burck ported to be responsible for the induction of a per hardt, 1957]; Persian lime rind (Epstein, 1956); sistent light reactor state similar to that noted with ragweed (Epstein, 1960b); sunscreens (Davies et ai., the halogenated salicylanilides (Giovinazzo et ai., 1982; Fagerlund et ai., 1983; Fitzpatrick et al., 1963; 1980). The action spectrum for the photoallergic Goldman and Epstein, 1969; H6z1e and Plewig, reactions to these fragrances appears to fall in the 1982; Kaidbey and Allen, 1981; Mathias et al., 1978; UVA range (Giovinazzo et ai., 1981; Jackson et ai., Sams, 1956; Satulsky, 1950); diphenhydramine 1980; Kaidbey and Kligman, 1978). (Emmett, 1974); psoralens (Fulton and Willis, 1968; Sidi and Bourgeois-Cavardin, 1953); epoxy resins Mechanisms Involved in Development of (Allen and Kaidbey, 1979); and quindoxin (Scott Photocontact Reactions and Dawson, 1974; Zanoun et aI., 1976). However, The clinical appearance, histology and photo the halogenated salicylanilides and related antibac patch test responses strongly suggest that the pho terial and antifungal compounds represented the toreactions described in this discussion are de most important group of allergic contact photosen pendent on a cell-mediated immunity process. A sitisers. In the 1960s these chemicals were respon number of experimental studies utilising animal and sible for almost an epidemic of photoallergic re human models have supported this concept. actions. Tetrachlorosalicylanilide was perhaps the Herman and Sams (1972), using micro-ouch most potent photosensitiser of this type. Between terlony immune diffusion techniques, could not 1960 and 1961 it was responsible for an estimated demonstrate antibodies to 3,5-dibromosalicylani tO,ooO cases in England (Wilkinson, 1961) before lide (3,5-DBS) protein complexes in the serum of it was removed from general use. Subsequently, a patients photocontact-sensitive to this chemical. No number of related phenolic compounds were in binding of fluorescein-tagged goat antihuman IgG, corporated into soaps and other vehicles to combat IgA, IgM and complement or fibrin was noted in infection, reduce body odour, act as preservatives, positive photopatch test sites with the direct and destroy fungi. Photocontact reactions were in immunofluorescence methods. In addition, im duced by many of these agents, including bi munoglobulins in serum from patients photosen thionol, the brominated salicylanilides, hexachlo sitive to tetrachlorosalicylanilide and 3,5-DBS did rophane, dichlorophen, the carbanilides, fenticlor not bind to cutaneous tissues bathed in these [bis (2-hydroxy-5-chlorophenyl) sulphide], brom chemicals. Thus, no evidence of antibody-me ochlorosalicylanilide, 'Jadit' (a mixture of buclo diated hypersensitivity was discovered in patients samide and salicylic acid) [Epstein, 1972; Herman with photocontact reactions to the halogenated and Sams, 1972], and chloro-2-phenylphenol (Ad salicylanilides. ams, 1972). Photoallergic reactions in human skin charac Since 1968, there has been a rapid decline in the teristic of cell-mediated immunity responses have induction of photocontact dermatitis by the halo been induced by a number of agents including the genated salicylanilides and related compounds sulphonamides (Epstein, 1939), phenothiazines (Smith and Epstein, 1977). This is most likely due (Burdick, 1969), and the halogenated salicylani to the removal of the more potent of these pho lides (Willis and Kligman, 1968b). Perhaps the most tosensitisers from general use. However, within the extensive studies have been performed with the past 5 years, 2 new contactants appear to produce halogenated salicylanilides. Willis and Kligman most, if not all, photoallergic responses. These are utilised UVB as well as UV A exposures plus the the two widely used fragrance compounds 6-meth chemicals to induce photosensitivity, but only UV A ylcoumarin (Jackson et ai., 1980; Kaidbey and and the halogenated salicylanilides were used to Kligman, 1978) and musk ambrette (Galosi and elicit the photocontact allergy. Photosensitivity Due to Drugs 52

As noted, animal and human studies have con contrast, the available evidence suggests that the firmed the cell-mediated immunity mechanism for haptens in clinically acquired disease are unstable the photocontact allergy reactions, which appears photoproducts, perhaps free radicals, which must to be identical to the mechanism of contact allergy be in close proximity to the protein carrier at the itself. However, the nature of the antigen has not time of irradiation. been settled. The studies of Burckhardt and Schwarz-Speck (1957), Jung and Schwarz (1965) Experimental Predictive Testing Models and Schwarz and Speck (1957) with sulphonamide Determination of the potential for a chemical and related compounds, those of Epstein and Enta to induce allergic contact sensitisation has de (1965), Jung and Schultz (1968) and Willis and pended on demonstration of such reactions in Kligman (l968b, 1969) with the halogenated sali patients who have clinically developed photocon cylanilides, and those of Fulton and Willis (1968) tact allergies to the chemical. Though animal with methoxypsoralens suggested that the haptens models are readily available for phototoxicity stud were stable photoproducts of these chemicals. In ies, their use in evaluation of photoallergic reac vitro binding studies have also supported this con tions has presented a more complicated problem. cept. Schwarz and Speck (1957) first reported the in An alternative concept was proposed by Jenkins duction of photoallergic contact dermatitis to sul et al. (1964). They concluded that the photoprod phanilamide in guinea-pigs. Subsequently, pho ucts might well be shortlived free radicals, which toallergic contact reactions in guinea-pigs have been would attach to the protein carrier within micro induced by tetrachlorosalicylanilide and related seconds to form the complete antigen. Support for compounds, chlorpromazine, musk ambrette and this theory has developed from clinical observa 6-methylcoumarin (Harber, 1981; Jordan, 1982). tions (Epstein, 1972; Herman and Sams, 1972; Os In vitro and in animals, immunological studies have mundsen, 1969). In addition, Jung's studies of supported the cell-mediated nature of the hyper postirradiation free radical formation and subse sensitivity (Harber et aI., 1959, 1967; Herman and quent binding to albumin and fj-globulin of chlor Sams, 1972; Jung et aI., I 968a,b). More recently, pramazine (Jung, 1970) and triplet state induction mouse models have been shown to be most effi by radiation of triacetyldiphenylisatin with deac cient for experimentally examining this problem tivation by binding to albumin, 'Y-giobulin, and skin (Maguire and Kaidbey, 1982; Miyachi and Taki protein (Jung, 1967) present further evidence in fa gawa, 1983). Using such animals, demonstration of vour of this concept. The studies of Jung et al. the necessity of Langerhans cells apparently to pro (1968a,b) with 'Jadit' (buclosamide/salicylic acid) cess the photoallergen appropriately, the need for were even more supportive of this second theory genetically dependent T cells for the development immunologically. They were able to demonstrate of the reactivity, and the inhibiting influence of protein binding in vitro after irradiation. This in UVB-induced suppressor T cells, have been estab vitro protein complex then acted as a full antigen lished under experimental conditions (Granstein et on· plain patch testing of 'Jadit'-photosensitive aI., 1983; Miyachi and Takigawa, 1982; Takigawa patients. and Miyachi, 1982). However, to date, no animal As can be seen, there is a significant discrepancy models have proved to be predictive for screening between the theories concerning the origin of the the potential for chemicals which had not previ antigen in photocontact reactions. Most probably ously been identified to produce photoallergic con both theories are correct under different circum tact reactions. stances; i.e. it is likely that at least some of the subjects experimentally photosensitised by Willis Human Predictive Testing Models and Kligman (l968b) were actually contact sensi Predictive testing in human skin is even less de tised by stable photoproducts of the chemicals. In finitive. In the I 960s, identification of tetrachlo- Photosensitivity Due to Drugs 53

rosalicylanilide and related phenolic compounds mate (Kobori and Araki, 1966; Lamberg, 1967; was accomplished by photopatch testing clinically Tatsuji and Toshie, 1963), chloroquine (van Weel involved patients. Subsequently, Willis and Klig den et aI., 1982), quinidine (Lang, 1983; Marx et man (1968b) induced contact photoallergy to cer aI., 1983), carprofen (Merot et aI., 1983) and 5- tain of these agents in normal human subjects us fluorocytosine (Beardmore, 1979; Shelley and Sica, ing a modification of the maximisation test devel 1983). oped for evaluating the potential for chemicals to produce contact dermatitis (Kligman, 1966). Clinical Expression Recently, Kaidbey and Kligman (Kaidbey, 1983; The reaction times for these responses appear Kaidbey and Kligman, 1980) modified the pho to be delayed in nature and the clinical eruptions tomaximisation procedure. With the new test they range from lichenoid papules to eczematous were able to photoallergically contact sensitise nor changes. Though the problems are generally short mal human volunteers relatively readily to certain term in nature, occasionally persistent light reac methylated coumarin derivatives, tetrachlorosali tivity may be induced by these systemic photosen cylanilide, 3,5-DBS, chlorpromazine, and sodium sitisers (S. Epstein, 1962). pyrithione. A lesser number of positive induction Histologically, the lichenoid eruptions resemble responses were noted with tribromosalicylanilide lichen planus with a subepidermal band of round contaminated with 47% dibromosalicylanilide, 4, cells. In addition, they have a perivascular round 5-DBS, buclosamide, and bithionoI. However, ne cell infiltrate deeper in the dermis. The eczematous gative results were noted with para-aminobenzoic eruptions show epidermal oedema and a dermal acid and musk ambrette which have produced round cell infiltrate. photoallergic contact reactions clinically. The auth ors considered them weak photosensitisers. Diagnosis Thus, to date there is no proven effective The diagnosis of photoallergy is usually made predictive testing model for photoallergic contact on morphological, histological, and historical dermatitis. grounds. In some instances reproduction of the photoallergic response has been accomplished by 2.2.2 Systemic Drug Photoallergy exposure to the appropriate action spectrum. How Photoallergic reactions to systemic photosensi ever, the use of injections or topical applications tisers are less common than those induced by con with occlusion or after stripping may be useful if tactants and they are less well understood. How the agent itself, and not a metabolite, is responsible ever, a few apparent photoallergic reactions have for the photosensitivity. been reported to a number of agents, including the There is little information concerning the mech antibacterial sulphonamides (Blum, 1941 b; Burck anisms involved in the development of these re hardt, 1941; Epstein, 1939; Schwarz and Speck, actions induced by systemic medications. How 1957; Stevanovic, 1961), sulphonylurea antidi ever, th~y do appear to be delayed hypersensitivity abetic agents (Hitselberger and Foxnaugh, '1962), responses. Thus the principles noted in section 2.2.1 the thiazide diuretics (Harber et aI., 1959) and on photoallergic contact dermatitis should apply. quinethazone (Miller and Beltrani, 1966), pheno thiazines (Calnan et aI., 1962; Schultz et aI., 1956), 3. Therapy of Drug-Induced oral contraceptive hormones (Erickson and Pe Photosensitivity terka, 1968), griseofulvin (Chang, 1965), chlordi azepoxide hydrochloride (Luton and Finchum, Therapy of acute photoallergic or phototoxic re 1965), several antihistamines (Schreiber and Nay sponses is identical to that used for any such in lor, 1962), triacetyldiphenylisatin (Kasuistik and flammatory reactions. This includes the use of top Jung, 1967), the artificial sweetener calcium cycla- ical cool wet dressings, soothing shake lotions, Photosensitivity Due to Drugs 54

topical corticosteroids and systemic antipruritic Burdick, K.H.: Prolonged sensitivity to intradermal chlorprom azine. Cutis 5: 1113-1114 (1969). agents. Burry, J.N.: Persistent light reactions from buclosamide. Archives If the process is severe enough, systemic cor of Dermatology 101: 95-97 (1970). Burry, J.N. and Hunter, G.A.: Photocontact dermatitis from Jadit. ticosteroids may be indicated. As with any topical British Journal of Dermatology 82: 244-249 (1970). or systemic drug-induced eruption, removal of the Calnan, e.D.; Frain-Bell, W. and Cuthbert, W.I.: Occupational dermatitis from chlorpromazine. Transactions of the St John offending agent is essential to the cure of the al Hospital Dermatological Society 48: 49-72 (1962). lergic process. In the case of photoallergy or pho Chang, T.W.: Cold urticaria and photosensitivity due to griseo fulvin. Journal ofthe American Medical Association 193: 848- totoxicity, either the sun or the chemical could be 850 (1965). removed. The radiant energy is more difficult to Davies, M.G.; Hawk, J.L. and Rycroft, R.J.: Acute photosensi tivity from the sunscreen 2-ethoxyethyl-P-methoxycinnamate. control; therefore removal of the chemical is usu Contact Dermatitis 8: 190-200 (I982l. ally the most appropriate approach since the patient Emmet, E.A.: Diphenhydramine photoallergy. Archives of Der matology 110: 249-251 (1974). frequently is made exquisitely sensitive by the Emmet, E.A.: Phototoxicity from exogenous agents. Photochem drugs. At times, the medication may be indispen ical Photobiology 38: 429-436 (1979). Epstein, E.: Persome dermatitis in men. Journal of the American sable and avoidance of the sun is essential. Medical Association 209: 911-913 (1969). As noted previously, some patients may de Epstein, J.H.: Polymorphous light eruption. Annals of Allergy 24: 397-405 (1966). velop persistent light eruptions which persist after Epstein, J.H.: Adverse cutaneous reactions to the sun; in Malk discontinuing use of the offending agent. When this inson and Pearson (Eds) Yearbook of Dermatology, pp. 5-43 (Yearbook Medical Publishers, Chicago 1971). occurs, the patient usually becomes markedly pho Epstein, J.H.: Photoallergy: A review. Archives of Dermatology tosensitive. Long term anti-inflammatory therapy 106: 741-748 (1972). Epstein, J.H.: Phototoxicity and photoallergy; in Pathak et al. (Eds) and avoidance of any sun exposure may be neces Sunlight and Man, pp. 459-477 (University of Tokyo Press, sary to control such a process. Tokyo 1974). Epstein, J.H.: Phototoxicity and photoallergy in man. Journal of the American Academy of Dermatology 8: 141-147 (1983). Epstein, J.H.; Brunsting, L.A.; Petersen, M.e. et al.: A study of References photosensitivity occurring with chlorpromazine therapy. Jour nal oflnvestigative Dermatology 28: 329-338 (1957). Abel. E.A. and Farber, E.M.: Photochemotherapy; in Rook and Epstein, J.H.; TufTanelli, D.L. and Epstein, W.L.: Cutaneous Savin (Eds) Recent Advances in Dermatology, pp. 259-283 changes in the porphyrias: A microscopic study. Archives of (Churchill Livingstone, Edinburgh 1980). Dermatology 107: 689-698 (1973). Adams, R.M.: Photoallergic contact dermatitis to chloro-2-phen Epstein, J.H.; TufTanelli, D.L.; Seibert, J.S. and Epstein, W.L.: ylphenol. Archives of Dermatology 106: 711-714 (1972). Porphyria-like cutaneous changes induced by tetracycline Allen, H. and Kaidbey, K.H.: Persistent photosensitivity follow hydrochloride photosensitization. Archives of Dermatology 112: ing occupational exposure to epoxy resin. Archives of Der 661-666 (1976). matology 115: 1307-1310 (1979). Epstein, J.H.; Wuepper, K.D. and Maibach, H.I.: Photocontact Amblard, P.; Beani, J.e. and Reymond, J.L.: Persistent light re dermatitis to halogenated compounds and related compounds. action due to phenothiazines in atopic disease. Annals of Der Archives of Dermatology 97: 236-244 (1968). matology and Venereology 109: 225-228 (1982). Epstein, S.: Photoallergy and primary phototoxicity to sulfanila Anderson, R.R. and Parrish, J.A.: Optics of human skin. Journal mide. Journal of Investigative Dermatology 2: 43-51 (1939). oflnvestigative Dermatology 77: 13-19 (1981). Epstein, S.: Discussion of paper by Sams, W.M. Archives of Der Argenbright, L.W.; Forbes, P.D. and Stewart, G.J.: Quantitation matology 73: 142-148 (1956). of phototoxic hyperemia and permeability. II. Inhibition of Epstein, S.: Allergic photocontact dermatitis from promethazine histamine (HI and H2) receptor antagonists in mouse skin. (Phenergan). Archives of Dermatology 81: 175-180 (1960a). Journal oflnvestigative Dermatology 75: 417-420 (1980). Epstein, S.: Role of dermal sensitivity in ragweed contact der Beardmore, G.L.: Recalcitrant sporotrichosis: A report of a patient matitis. Archives of Dermatology 82: 48-55 (1960b). treated with various therapies, including oral miconozole and Epstein, S.: Photoallergy versus phototoxicity; in Rees (Ed.) Der 5-fluorocytosine. Australasian Journal of Dermatology 20: 10- matoses Due to Environmental and Physical Factors, pp. 119- 13 (1979). 135 (Thomas, Springfield 1962). Blum, H.F.: Photodynamic Action and Diseases Caused by Light Epstein, S.: 'Masked' photopatch tests. Journal of Investigative (Rhinehold, New York 194Ia). Dermatology 41: 369-370 (1963). Blum, H.F.: Studies ofphotosensivity due to sulfanilamide. Jour Epstein, S.: Chlorpromazine phQtosensitivity: Phototoxic and nal of Investigative Dermatology 4: 159-173 (l94Ib). photoallergic reactions. Archives'of Dermatology 98: 354-3.63 Burckhardt, W.: Photoallergy eczema due to blankophores (optic (1968). brightening agents). Hautarzt 8: 486-488 (1957). Epstein, S. and Enta, T.: Photoallergic contact dermatitis. Journal Burckhardt, W.: Untersuchungen uber die Photoaktivitat einiger of the American Medical Association 194: 1016-1017 (1965). Sulfanilamide. Dermatologica 83: 63-83 (1941). Epstein, S. and Rowe, RJ.: Photoallergy and photocross-sensitiv Burckhardt, W. and Schwarz-Speck, M.: Photoallergische Ekzeme ity to Phenergan. Journal of Investigative Dermatology 29: 319- durch Nadisan. Schweizerische Medizinische Wochenschrift 326 (1957). 87: 954-956 (1957). Erickson, L.R. and Peterka, E.S.: Sunlight sensitivity from oral Photosensitivity Due to Drugs 55

contraceptives. Journal of the American Medical Association oftetrachlorosalicylanilide. Nature 201: 827-828 (1964). 203: 980-981 (1968). Jillson. V.F. and Baughman, R.D.: Contact dermatitis from bi Ertle, T.: Work-related contact and photocontact allergy in a farmer thionol. Archives of Dermatology 88: 409-418 (1963). caused by chlorpromazine. Dermatosen in Berufund Umwelt Jordan Jr. W.P.: The guinea pig model for predicting photoal 30: 120-122 (1982). lergic contact dermatitis. Contact Dermatitis 8: 109-116 (1982). Fagerlund, V.L.; Kalimo, K. and Jansen, c.: Photocontact allergy Jung, E.G.: Photoallergie durch Triacetyldiphenolisatin (TOI). II. from sunscreens. Duodecim 99: 146-150 (1983). Photochemische Untersuchungen zur Pathogenese. Archiv fur Ferguson, J.: A study of benoxaprofen-induced photosensitivity. K1inische und Experimentelle Dermatologie 231: 39-49 (1967). British Journal of Dermatology 107: 429-442 (1982). Jung, E.G.: In vitro-Untersuchungen zur Chlorpromazine (CPZ) Fitzpatrick, T.B.; Pathak, M.A.; Magnus, LA. et al.: Abnormal Photoallergie. Archiv fur K1inische und Experimentelle Der reactions of man to light. Annual Reviews of Medicine 14: matologie 237: 501-506 (1970). 195-214 (1963). Jung, E.G.; Dummler, U. and Immich, H.: Photoallergie durch Fulton Jr, J.E. and Willis, I.: Photoallergy to methoxsalen. Ar 4-Chlor-2-hydroxy-benzoesaure-n-butylamid. I. Lichtbiolo chives of Dermatology 98: 445-450 (1968). gische Untersuchungen zur Antigenbildung. Archiv fur K1in Galosi, A. and Plewig, G.: Photoallergic eczema caused by musk ische und Experimentelle Dermatologie 232: 403-412 (l968a). ambrette. Hautarzt 33: 589-594 (l982). Jung, E.G.; Hornke, J. and Hajde, P.: Photoallergie durch 4-Chlor- Giovinazzo, V.J.; Harber, L.c.; Bickers, D.R.; Armstrong, R.B. 2-hydroxy-benzoesaure-n-butylmid. II. Photochemische Un and Silvers, D.N.: Photoallergic contact dermatitis to musk tersuchungen. Archiv fur K1inische und Experimentelle Der ambrette. Journal of the American Academy of Dermatology atologie 233: 287-295 (1968b). 3: 384-393 (1980). Jung, E.G. and Schultz, R.: Kontakt und Photoallergien durch Giovinazzo, V.J.; Ichikawa, H.; Kochevar, I.E.; Armstrong, R.B. Desinfizienzen. Dermatologica 137: 216-226 (1968). and Harber, L.c.: Photoallergic contact dermatitis to musk Jung, E.G. and Schwarz, K.: Photoallergy to 'Jadit' with photo ambrette: Action spectrum in guinea pigs and man. Photo cross-reactions to derivatives of sulfanilamide. International chemical Photobiology 33: 773-777 (1981). Archives of Allergy and Applied Immunology 27: 313-317 Goldman, G.c. and Epstein Jr, E.: Contact photosensitivity der (1965). matitis from a sun-protective agent. Archives of Dermatology Kaidbey, K.H.: The evaluation of photoallergic contact sensitiz 100: 447-449 (1969). ers in humans; in Marzulli and Maibach (Eds) Dermatotoxi Granstein, R.D.; Morison, W.L. and Kripke, M.L.: The role of cology, 2nd ed., pp. 405-414 (Hemisphere Publishers, Wash suppressor cells in the induction of murine photoallergic con ington 1983). tact dermatitis and in its suppression by prior UVB irradia Kaidbey, K.H. and Allen, H.: Photocontact allergy to benzocaine. tion. Journal of Immunology 130: 2099-2103 (1983). Archives of Dermatology 117: 77-79 (1981). Halsey, J.: Benoxaprofen: Side-effect profile in 300 patients. Brit Kaidbey, K.H. and Kligman, A.M.: Contact photoallergy to 6- ish Medical Journal 284: 1365 (1982). methyl coumarin in proprietary sunscreens. Archives of Der Harber, L.c.: Current status of mammalian and human models matology 114: 1709-1710 (1978). for predicting drug photosensitivity. Journal of Investigative Kaidbey, K.H. and Kligman, A.M.: Photo-maximization test for Dermatology 77: 65-70 (1981). identifying photoallergic contact sensitizers. Contact Derma Harber, L.c.; Bickers, D.R.; Epstein, J.H.; Pathak, M.A. and Ur titis 6: 161-169 (1980). bach, F.: Report on ultraviolet light sources. Archives of Der Kasuistik, I. and Jung, E.G.: Photoallergie durch Triacetyldi matology 109: 833-839 (1974). phenolisatin (TOI) Archiv fur K1inische und Experimentelle Harber, L.c.; Lashinsky, A.M. and Baer, R.L.: Photosensitivity Dermatologie 229: 170-173 (1967). due to chlorothiazide and hydrochlorothiazide. New England Kligman, A.M.: Identification of contact allergens by human as Journal of Medicine 261: 1378-1381 (1959). say. III. The maximization test. A procedure for screening and Harber, L.c.; Targovnik, S.E. and Baer, R.L.: Contact photosen rating contact sensitizers. Journal of Investigative Dermatol sitivity patterns to halogenated salicylanilides in man and guinea ogy 47: 393-409 (1966). pigs. Archives of Dermatology 96: 646-656 (1967). Kligman, A.M.: Declomycin compendium. (Lederle Laboratories, Herman, P.S. and Sams Jr, W.M.: Soap photodermatitis. (Tho Pearl River, New York 1962). mas, Springfield 1972). Kligman, A.M. and Kaidbey, K.H.: Human models for identifi Hitselberger, J.F. and Foxnaugh, R.P.: Photosensitivity due to cation of photosensitizing chemicals. Journal of the National chlorpropamide. Journal of the American Medical Association Cancer Institute 69: 264-272 (1982). 180: 142-143 (1962). Kobori, T. and Araki, H.: Photoallergy in dermatology. Journal Hbzle, E. and Plewig, G.: Photoallergic contact dermatitis by ben of Asthma Research 3: 213-215 (1966). zophenone containing sunscreening preparations. Hautarzt 33: Kochevar, I.E.: Photoallergic responses to chemicals. Photochem 391-393 (1982). istry and Photobiology 30: 437-442 (1979). Hbnigsman, H.; Scnait, G.S.; Konrad, R.A.; Stingl, G. and Wolff, Kochevar, I.E.: Phototoxicity mechanisms: Chlorpromazine pho K.: Mouse model for protoporphyria. Journal of Investigative tosensitized damage to DNA and cell membranes. Journal of Dermatology 66: 188-195 (1976). Investigative Dermatology 77: 59-64 (1981). Horio, T.: Chlorpromazine photoallergy. Archives of Dermatol Kochevar. I.E. and Lamola, A.A.: Chlorpromazine and protrip ogy II: 1469-1471 (1975). tyline phototoxicity: Photosensitized oxygen-independent red Hunter, J.A.; Bhutani, L.K. and Magnus, LA.: Chlorpromazine cell hemolysis. Photochemistry and Photobiology 29: 1177-1197 photosensitivity in mice; Its action spectrum and effect of anti (1979). inflammatory agents. British Journal of Dermatology 82: 157- Lamberg, S.I.: A new photosensitizer: The artificial cyclamate. 168 (1970). J.A.M.A. 201: 121-124 (1967). Ito. T. and Kobayashi, K.: A survey of in vivo photodynamic Lamola. A.A. and Doleideu. F.H.: Cross-linking of membrane activity of xanthenes, thiazines and acridines in yeast cells. proteins and protoporphyrin-sensitized photohemolysis. Pho Photochemical Photobiology 26: 581-587 (1977). tochemistry and Photobiology 31: 597-60 I (1980). Jackson, R.T.; Nesbit, L.T. and Deleo, V.A.: 6-Methyl coumarin Lang Jr. P.G.: Quinidine-induced photodermatitis confirmed by photocontact dermatitis. Journal of the American Academy of photopatch testing. Journal of the American Academy of Der Dermatology 2: 124-127 (1980). matology 91: 124-128 (1983). Jenkins. F.P.; Welti, D. and Baines, D.: Photochemicals reactions Levine. G.M. and Harber. L.c.: The effect of humidity on the Photosensitivity Due to Drugs 56

phototoxic response to 8-methoxypsoralen in guinea pigs. Acta Ramsay, e.A. and Obreshkova, E.: Photosensitivity from nali Dermatologica Venereologica 49: 82-86 (1969). dixic acid. British Journal of Dermatology 91: 523-528 (1974). Lim, H.W.; Novotny, H. and Gigli, I.: Role of complement and Rosenthal, I.; Ben-Hur, E.; Prager, A. and Riklis, E.: Photochem polymorphonuclear cells in demethylchlortetracycline-induced ical reactions of chlorpromazine: Chemical and biochemical phototoxicity in guinea pigs. Journal of Clinical Investigation implications. Photochemical Photobiology 28: 591-594 (1978). 71: 1326-1335 (1983). Sams, W.M.: Contact photodermatitis. Archives of Dermatology Lim, H.W.; Perez, H.D.; Goldstein, I.M. and Gigli, I.: Comple 73: 142-148 (1956). ment-derived chemotactic activity is generated in human serum Satulsky, E.M.: Photosensitization induced by monoglycerol par containing uroporphyrin after irradiation with 405 nm light. aminobenzoate. Archives of Dermatology 62: 711-713 (1950). Journal of Clinical Investigation 67: 1072-1077 (1981). Scott, K.W. and Dawson, T.A.J.: Photocontact dermatitis arising Lim, H.W.; Poh-Fitzpatrick, M.B. and Gigli, I.: Activation of the from the presence of quindoxin in animals seeding stuffs. Brit complement system and generation of hemotactic activity in ish Journal of Dermatology 90: 543-546 (1974). vivo in patients with porphyrias. (Abstract). Clinical Research Schnait, F.G.; Wolff, K. and Konrad, K.: Erythropoietic proto 30: 488a (1982). porphyria-submicroscopic events during the acute photosen Luton E.F. and Finchum, R.N.: Photosensitivity reaction to sitivity flare. British Journal of Dermatology 92: 545-557 (1975). chlordiazepoxide. Archives of Dermatology 91: 362-363 (1965). Schreiber, M.M. and Naylor, L.l.: Antihistamine photosensitiv Maguire Jr, H.C. and Kaidbey, K.H.: Experimental photoallergic ity. Archives of Dermatology 86: 58-62 (1962). contact dermatitis: A mouse model. Journal of Investigational Schultz, K.H.; Wickemann, A. and Wulf, K.: K1inische and ex Dermatology 79: 147-152 (1982). perimentelle untersuchungen uber die photodynamische Wirk Maibach, H.I.; Sams Jr, N.M. and Epstein, J.H.: Screening for samkeit von Phenothiazin Derivaten, insbesondere von Ma drug toxicity by wave lengths greater than 3,IOOA. Archives gaphen. Archiv fur K1inische und Experimentelle Dermatologie of Dermatology 95: 12-15 (1967). 202: 285-298 (1956). Mathias, e.G.T.; Maibach, H.1. and Epstein, J.H.: Allergic con Schwarz, K. and Speck, M.: Experimentelle Untersuchungen zur tact photodermatitis to para-aminobenzoic acid. Archives of Frage der Photoallergie der Sulfonamide. Dermatologica 114: Dermatology 114: 1665-1666 (1978). 232-243 (1957). Marx, J.L.; Eisenstat, B.A. and Gladstein, A.H.: Quinidine pho Shelley, W.B. and Sica, P.A.: Disseminate sporotrichosis of skin tosensitivity. Archives of Dermatology 119: 39-43 (1983). and bone cured with 5-flurocytosine: Photosensitivity as a Masuda, T.; Honda, S.; Nakauchi, Y. et al.: Photocontact der complication. Journal of the American Academy of Derma matitis to bithionol, TBS, diaphene, and hexachlorophene. tology 8: 229-235 (1983). Japanese Journal of Dermatology, Series B 81: 238-244 (1971). Sidi, E. and Bourgeois-Cavardin, J.: Mise au point du traitement Merot, Y.; Harms, M. and Saurat, 1.H.: Photosensitivity associ du vitiligo par I'Ammi Majus. Presse Medicale 61L436-440 ated with carprofen (Imadyl) a new non-steroidal anti-inflam (1953). matory drug. Dermatologica 116: 301-307 (1983). Sidi, E.; Hincky, M. and Gervais, A.: Allergic sensitization and Miller, R.e. and Beltrani, V.S.: Quinethazone photosensitivity photosensitization to Phenergan cream. Journal of Investiga dermatitis. Archives of Dermatology 93: 346-347 (1966). tive Dermatology 24: 345-352 (1955). Miyachi, Y. and Takigawa, M.: Mechanisms of contact photo Smith, S.l. and Epstein, J.H.: Photocontact dermatitis to halo sensitivity in mice. III. Predictive testing of chemicals with genated salicylanilides and related compounds. Archives of photoallergic potential in mice. Archives of Dermatology 119: Dermatology 113: 1372-1374 (1977). 736-739 (1983). Song, P. and Tapley Jr, K.J.: Photochemistry and photobiology Miyachi, Y. and Takigawa, M.: Mechanisms of contact photo of psoralens. Photochemistry and Photobiology 29: 1177-1197 sensitivity in mice. II. Langerhan cells are required for suc (1979). cessful induction of contact photosensitivity to TCSA. Journal Stern, R.S. and Bigby, M.: An expanded profile of cutaneous re of Investigative Dermatology 78: 363-365 (1982). actions to nonsteroidal anti-inflammatory drugs. Journal of Morison, W.L.; Parrish, J.A. and Epstein, J.H.: Photoimmunol American Medical Association 252: 1433-1437 (1984). ogy. Archives of Dermatology 115: 350-354 (1979). Stern, R.S.; Thibodeau, L.A.; K1einerman, R.A.; Parrish, J.A.; NACDG (North American Contact Dermatitis Group) ofthe Na Fitzpatrick, T.B. et al.: Risk of cutaneous carcinoma in patients tional Program for Dermatology: The Role of Patch Testing treated with oral methoxsalen photochemotherapy for psori in Allergic Contact Dermatitis (Johson and Johson, New asis. New England Journal of Medicine 300: 809-813 (1979). Brunswick 1974). Stern, R.B.; liebler, S. and Parrish, J.A.: Skin carcinoma in patients Jsmundsen, P.E.: Contact photoallergy to tribromsalicylanilide. treated with topical tar and artificial ultraviolet radiation. Lancet British Journal of Dermatology 81: 429-434 (1969). I: 732-735 (1980). Jwens, D.W. and Knox, J.M.: Influence of heat, wind, and hu Stevanovic, D.V.: Photosensitivity due to certain drugs. British midity on ultraviolet radiation injury; Kripke and Sass (Eds) Journal of Dermatology 73: 233-237 (1961). ultraviolet Carcinogenesis. National Cancer Institute Mono Storck, H.: Photoallergy and photosensitivity: Due to systemically graphs 50: 161-167 (1978). administered drugs. Archives of Dermatology 91: 469-482 Parrish. J.A.: Fitzpatrick, T.B.: Tannenbaum, L. and Pathak, M.A.: (1965). Photochemistry of psoriasis with oral methoxsalen and long Stratigos, J.D. and Magnus, LA.: Photosensitivity by demethylch wave ultraviolet light. N. Eng. J. Med. 291: 1207-1211 (1974). lortetracycline and sulphanilamide. British Journal of Der Parsons, B.1.: Psoralen photochemistry. Photochemistry and Pho matology 80: 391-405 (1968). tobiology 32: 813-821 (1980). Takigawa, M. and Miyachi, Y.: Mechanisms of contact photo Pathak, M.A.; Kramer, D.M. and Fitzpatrick, T.B.: Photochem sensitivity in mice: I. T cell regulation of contact photosensi istry and photobiology of furocoumarins (psoralens); in Pathak tivity to tetrachlorosalicylanilide under genetic restrictions of et al. (Eds) Sunlight and Man pp. 335-368 (University of To the major histocompatibility complex. Journal of Investigative kyo Press, Tokyo 1974). Dermatology 79: 108-115 (1982). Polano, J.K.: Photosensitivity due to drugs. Exerpta Med. Int. Tatsuji, K. and Toshie, A.: Photoallergic dermatitis probably due Congr. Ser. 85: 102-107 (1964). to artificial sweetening agents. Med. Culture 5: 795-800 (1963). Raugi. G.1.: Storrs, F.J. and Larsen, W.G.: Photoallergic contact Torinuki, W.; Kumai, N. and Miura, T.: Chronic photosensitive dermatitis to men's perfume. Contact Dermatitis 5: 251-260 dermatitis due to phenothiazines. Tohoku Journal of Experi (1979). mental Medicine 138: 223-226 (1982). Photosensitivity Due to Drugs 57

van Weelden. H.; Bolling, H.H.; Baart de la Faille, H. and van Wiskemann. A. and Wulf. K.: Untersuchungen uber den auslo der Leun, J .c.: Photosensitivity caused by chloroquine. (Ab senden Spektralbereich und die direkte Lichtpigmentierung bei stract) Archives of Dermatology 118: 290 (1982). chronischen und akuten Lichtauschhigen. Archiv fur Klinische Wilkinson. D.S.: Photodermatitis due to tetrachlorosalicylanilide. und Experimentelle Dermatologie 209: 443-453 (1959). British Journal of Dermatology 73: 213-219 (1961). Zanoun. S.; Johnson. B.E. and Frain-Bell. W.: The investigation Willis. I. and Kligman. A.M.: The mechanism of the persistent of quindoxin photosensitivity. Contact Dermatitis 2: 342-352 light reactor. Journal of Investigative Dermatology 51: 385-394 (1976). (1968a). Willis. I. and Kligman, A.M.: The mechanism of photoallergic contact dermatitis. Journal of Investigative Dermatology 51: 378-384 (1968b). Willis. I. and Kligman, A.M.: Photocontact allergic reactions: Address for correspondence and reprints: Dr John H. Epstein. Elicitation by low doses ultraviolet rays. Archives of Derma Department of Dermatology A-432. University of California, San tology I 10: 535-539 (1969). Francisco. CA 94143 (USA).

Royal Microscopical Society

International Symposium on the Toxicological Applications of Cytochemistry, Histochemistry and Immunohistochemistry

Date: 24-27 September 1985 Venue: Jesus College, UniverSity of Cambridge, Cambridge

The appropriate application of cyto-, histo- and immunohistochemical techniques in toxicology - the dichotomy between cellular structure and function - identification of early degenerative changes - quantification of repair processes - definition of aspects of the biochemical events which produce pathological response - safety evaluation of chemicals - understanding of toxic lesions - improved detection of lesions - better interpretation of risk assessment in response to chemical exposure - toxicity testing - molecular events associated with chemically induced changes.

For technical information please write to: Abstract and registration forms are available from: The Scientific Organiser, The Administrator, Dr P.H. Bach, Royal Microscopical SOCiety, Robens Institute for Health and Safety, 37/38 St Clements, University of Surrey, Oxford, OX4 lAJ, Surrey GU2 5XH, England. England.