- Email: [email protected]
Tar
ELSEVIER
Tar W. PETER ARNOLD,
MD, PhD
T
he use of tar as a treatment for cutaneous disorders was described nearly two thousand years ago by Dioscorides. It was not coal tar but “asphalt”, because coal tar was not known at that time. Coal tar was first discovered and described by Becher and Serle in 1681.l Today the efficacy of medical tar preparations is well established in psoriasis, (atopic) dermatitis, dandruff, seborrheic dermatitis, and pruritus. Antifungal activity of shampoos with as low as 0.5% coal tar has been described. The use of tar also has a dark side. In 1775, Sir Percival Pott noticed an increased prevalence of scrotal skin cancer in chimney sweepers.2 It is well known that workers who have been chronically exposed to tar commonly develop spinocellular cancers of skin and airways. Still, tar has proven to be a safe substance in dermatological applications. In this chapter an overview will be presented regarding the method of preparation, modes of action, efficacy, and adverse effects of coal tar in the management of psoriasis.
Method of Preparation Tar is obtained by heating organic materials in the absence of oxygen. This process is called destructive distillation. Several sources can be utilized for the preparation of tar products for dermatological usage. Wood tars (pix liquida) are produced by destructive distillation of birch, beech, pine, or juniper wood, and they are successfully used in the treatment of atopic dermatitis. Wood tar is not phototoxic, but in comparison with coal tar it does have an increased risk of irritation (beware of the Kobner phenomenon in psoriasis!) and sensitization.3,4 Shale tar (ichthyol or ammonium bituminosulfonate) is obtained by destructive distillation of bituminous stone, which contains deposits of fossilized fish. Ichthy01 is not phototoxic, does not have antipsoriatic action of any significance, and has been used earlier in inflammatory processes, for example furunculosis.3 Coal tars (pix lithanthracis) are used mostly for dermatological purposes. In coke ovens, coal is heated in the absence of air. Gases are formed that turn into a From the Department of Dermatology, University Hospitd Nijmegen, Nijmegen, The Netherlands. Address correspondence to Dr. W. P. Arnold, 802 Department of Dermatology, University Hospital Nijmegen, P.O. Box 9101, 6500 H B Nijmegen, The Netherlands.
0 1997 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
black-brown, thick liquid during the cooling-down process. After removal of ammonia, crude coal tar is left. The composition of crude coal tar depends mainly on the temperature of the carbonization.5 In general, coal tars are complex combinations of hydrocarbons; phenols; and heterocyclic oxygen, sulfur, and nitrogen compounds. Probably as many as 10,000 compounds are actually present; low-temperature (400-700°C) coal tars have a higher content of phenols and tar acids, and high-temperature (lOOO-1300°C) coal tars have a higher content of polycyclic aromatic hydrocarbons (PAHs) such as naphthalene, anthracene, and others. The tar bases (for example, quinoline, isoquinoline, and pyridine) have almost identical average weight percentages in comparison to low- and high-temperature coal tar. Crude coal tar can be modified in three ways, as follows: (1) After fractional distillation at different temperatures (loo-450”(Z), tar oils are formed; the remaining residue is called pitch, which was used in building. In the Netherlands medical pix lithantracis is produced by mixing two thirds of pitch of high-temperature sources with one third of tar oils that have been obtained by fractional distillation between 220 and 270°C. (2) Modification has been tried in order to improve the cosmetics of coal tar and to loosen the carcinogenic fractions by fractional distillation at different temperatures; however, it was not possible to separate the carcinogenic from the therapeutic fractions. Besides, a cosmetically better tar product is associated with a loss of efficacy .6,7Comparison of the efficacy of coal tar from high- and low-temperature sources in the treatment of patients suffering from chronic psoriasis showed the tars to be equally effective.8 (3) Extraction of 20 g pix lithantracis with 100 ml alcohol and addition of 5 g Tween 80’s’ produces liquor (solutio) carbonis detergens. Pix lithantracis (l-10%) or solutio carbonis detergens (5-20%) can be manufactured into a greasy ointment, like yellow soft paraffin, white Vaseline, or a mixture of white Vaseline with lanette wax cream ana. Addition of a nonionic surfactant (Tween 80@or 20@‘)improves the dispersion of the tar in its vehicle. For the treatment of acute eruptions it is possible to mix the tar with zinc paste. This vehicle increases the time of absorption of tar. Pharmaceutical and cosmetic industries have developed lotions, gels, and shampoos in which tar has been dissolved. 0738-081X/97/$32.00 PI1 SO738-081X(97)00018-7
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Modes of Action Studies in animals revealed an inhibitory effect of coal tar on sebum secretion,9 the number of mitoses in the basal cells of the epidermis, and scale development.9-11 The xanthenes, monoazoanilines, fluorans, and indigoids, all coal-tar derivatives, proved to be potent comedogens in the rabbit ear assay.]* Comedogenic activity and epidermal growth/differentiation inhibitory capacity are related, because formation of a comedo implies a disturbed balance between sebum secretion on one side and proliferation/differentiation patterns of the follicular epithelium on the other side. Both ichthyol and pix lithanthracis were shown to reduce the number of ATPase-positive epidermal Langerhans cells in the epidermis of BALB/c m.ice;i3 however, pix lithanthracis did not have an effect on MHC class II antigens, nor did it inhibit the induction of contact hypersensitivity, in contrast to psoralen plus ultraviolet-A (PUVA) treatmenti* The explanation of these conflicting data probably lies in differences in systemic absorption of the topically applied contact allergen (sensitization outside the application area). Pyroleum lithanthracis (5%) seemed to give rise to hydrolysis of the triglycerides in human epidermis, as measured by infrared spectroscopy.15 Besides, coal tar proved to reduce the lipid synthesis in the sebaceous gland, and inhibition of mitosis could also be demonstrated in the human scalp.16 DNA synthesis of transformed keratinocytes could be inhibited in vitro from a concentration of 0.35 pg/ml.i7 The growth inhibitory effect showed to be reversible up to the effective dose (ED 50) concentration (1.3 pg coal tar/ml). Comparison of a tar-treated and -untreated group of psoriasispatients revealed a significantly increased chemotactic response to the arachidonic acid lipoxygenase product leukotriene B, in the tar-treated group;ls howzver, the clinical relevance of this observation is not :lear. The same is true for the observation that 100% pix .ithantracis neither inhibited nor induced the rate-lim.ting enzyme of polyamine biosynthesis, ornithine delarboxylase (ODC).19 Almost all antipsoriatic therapies corticosteroids, retinoic acid, vitamin D3) inhibit epilermal ODC induction, except the UVB and dithranol :reatments, which induce ODC per se. The same study 11~0demonstrated that one of the components of coal ar, isoquinoline, did not have any antipsoriatic potenial. These results were disappointing, because isoluinoline promised antipsoriatic characteristics in the nouse-tail model.20 An explanation of how coal tar nfluences the abnormal pattern of keratinocyte growth md differentiation in psoriasis is presented by a group )f investigators. ** They showed a decrease of the elerated levels of transforming growth factor cymRNA in he subcorneal layers of the epidermis during treatment )f psoriasis with coal tar and UVB or PUVA followed
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by tar. Of course, the question remains whether this i> an epiphenomenon or not. In addition to its antimitotic and antiinflammatory effects, coal tar also possessesa photodynamic effect. An investigator determined that anthracene, 3,4-bent pyrene, fluoranthene, and pyrene were responsible for this action.** The clinical relevance of the photodynamic activity of coal tar has never been documented. Many articles describe the efficacy of the so-called Goeckerman’s treatment, the combination of tar with ultraviolet-B (UVB) irradiation, but ultraviolet-A (UVA) light contains the part of the light spectrum that activates coal tar.23 In summary: the antiproliferative and antiinflammatory capacities of coal tar are greater than the sum of the efficacy of the separated ingredients. Its precise mechanism of action remains unknown.
Efficacy in Psoriasis When itching is extensive or the patient presents an unstable psoriasis guttata/punctata, tar is preferable to dithranol. Erythrodermic and/or pustular psoriasis may be very sensitive to irritating factors, so tar is not recommended as a first-line treatment for these two forms of psoriasis. With renewed applications of coal tar, it is important not to scrub the skin until it loo& clean again. This mechanical irritation may induce the Kobner phenomenon. Before the next application it is possible to inspect the underlying skin by gently clearing with vegetable oil, for example oleum arachidis or olivae. There are several factors concerning the role of tars in the treatment of psoriasis:24(1) Tar alone may be helpful for a subset of individuals with mild-to-moderate psoriasis (the majority of patients with psoriasis). (2) Pix lithantracis is not always more beneficial than modified tar preparations; these latter have much better patient acceptance and compliance because of decreased odor, staining, and messiness.(3) Overall, the potential severity of side effects from tars is less than that from anthralin and much less than that from topical corticosteroids (atrophy, rebound). (4) Clinical experience confirms that tar preparations can be effective when other modalities fail or cannot be used for reasons of adverse effects or otherwise. (5) Tar shampoos are ronsidered useful therapeutic agents for active clearing therapy and for maintenance. (6) When combined with suberythemogenic ultraviolet light B, tar can be an use: ful agent, because it prevents the side effects of maximal erythemogenic UVB monotherapy. One of the first extensive left-right comparison studies regarding the efficacy of pix lithantracis and liquor carbonis detergens as monotherapy for psoriasis has been described by an investigator in 1970.2”Ten percent pix lithantracis in zinc paste proved to be superior; 1%
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pix lithantracis and 20% liquor carbonis detergens were approximately of equal value. A group of investigators investigated in a paired comparison study whether chronic plaque psoriasis improved with daily l-hour applications of 30% pix lithantracis in yellow soft paraffin26 This regime was not as effective as daily 23-hour treatments with 5% pix lithantracis. Another group of investigators found that there appears to be no benefit from exceeding a concentration of 5% pix lithantracis in yellow soft paraffin in the treatment of patients with psoriasis, and that the plateau in the dose-response curve for the action of crude coal tar in psoriasis begins at a point between 1 and 5%.z7 In both studies, the median whole body psoriasis area and severity index (PASI) score fell by approximately 50% during a treatment period of ten days. Unfortunately, no data are available regarding the length of remission after the use of pix lithantracis as a monotherapy for psoriasis. Besides, adequate data to support tar as a cost-effective agent in the treatment of psoriasis are lacking.28 The efficacy of coal tar in the treatment of psoriasis sometimes improves when it is combined with other therapeutic modalities. For example, topical corticosteroids (initially), dithranol (finally), or ultraviolet irradiation. The efficacy of these modes of treatment will be discussed in the last chapter of this issue.
Adverse Effects The main drawbacks in using tar are its messiness, staining, and odor; however, these complaints lessen with the use of modified tar preparations. The other side effects can be classified as allergic, (photo-)toxic, and, finally, aspecific reactions, such as folliculitis and bronchoconstriction. Contact allergy to coal tar is less frequent than intolerance, because coal tar is a well-recognized irritant.29 Therefore, it is important to patch test patients with psoriasis who report intolerance to coal tar. While a positive reaction may be obtained only in a minority, those with a negative result, and a presumably irritant response, could be treated more confidently with lower concentrations rather than abandoning a potentially useful treatment. In a population of patients patch tested for allergic contact dermatitis, a prevalence of 5.4% was seen for wood-tar sensitization.30 In this group, a combined allergy was seen to wood tars and fragrance mix in 43%, and to wood tars and balsam of Peru in 31%. A combined allergy to wood tars and coal tar was seen in 18.5%. Comparison of the test results in atopic and nonatopic subgroups led to the hypothesis that combined “wood-tars-coal-tar” allergy could be the consequence of cross-sensitization rather than due to longterm previous topical treatment with tar derivatives.
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The high percentage of cross-allergy between wood tars and fragrance mix emphasizes the role of wood tars as an important indicator allergen in perfume allergy. Of 13 cases of dithranol allergy reported in the English literature, 4 were noted to be allergic to coal tar as well, and in the other 9 it was not stated whether coal tar was tested.31 This may simply be due to independent sensitization, but it does raise the possibility of an allergen shared between coal tar and dithranol or even the presence of dithranol in minute quantities in coal tar. Besides its use in dermatology, coal tar is also frequently used in other fields. Allergic contact dermatitis to coal tar, therefore, can be the result not of dermatological, but rather of occupational or environmental factors. A man who had been working in a factory where brushes for electrical engines are manufactured had been sensitized by the use of E30 and E40, composed of lamp black, tar, and artificial graphite.s2 And another case report describes a woman with coal-tar sensitivity in whom the source of her dermatitis was shown to be newsprint, a common product containing coal-tar-derived material.33 Several of the polycyclic aromatic hydrocarbons, including anthracene, pyrene, fluoranthene, benzo(a)pyrene, acridine, and phenanthrene, are photosensitizers; and they cause phototoxicity by an oxygendependent mechanism. 34 Exposure to these agents causes intense burning and stinging within minutes of UVA exposure, often precluding further light exposure. If UV exposure is continued, a two-stage process is observed that begins with an immediate wheal and flare that fades within an hour and is followed by an erythema response that peaks from 24 to 48 hours. Since pigmentary changes are a frequent feature of phototoxic reactions (unusual in photoallergy), coal tar may be involved in pigmented cosmetic dermatitis as we11.35 The continuous application of coal tar can induce an acneiform eruption, especially after the use of tar in occlusive ointment bases. In blacks, this is a monomorphous crop of cornedones that are of the open variety from the very start. In whites, the first lesions are papulopustules resulting from toxic disorganization of the follicular epithelium. This inflammatory phase is followed by cornedones. 36Concentrations of coal tar larger than 2% are more likely to induce this follicular irritation than are more dilute preparations. Folliculitis usually occurs on the lower extremities.24 Little is known regarding systemic adverse effects after the topical use of coal tar. A severe symptomatic bronchoconstriction in an atopic asthmatic subject following the application of coal tar bandages had been caused by inhalation of coal tar vapor.s7 In a German study, daily application of a coal tar preparation for the scalp for a period of 8 weeks did not show any pathological change or impairment of renal function.38 In
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1960, an investigator described the case of a female psoriatic patient who suffered a life-threatening intoxication due to extensive topical treatment with tar and salicylic acid.39Her symptoms were attributable to both salicylic-acid intoxication (Kussmaul respiration, hyperthermia, periocular edema, increase of xanthoproteins in serum) and phenol intoxication (Cheyne-Stokes respiration, states of excitement as well as collapse, increase of pulse, secretion of phenol in urine). Carcinogenic and/or teratogenic (systemic) side effects after the topical use of coal tar products will be described in the next section.
Carcinogenic
and Teratogenic
Effects
A thorough review of the existing literature (in vitro, animal and human studies) on the carcinogenicity of tar has been published recently.40 Some of the polycyclic aromatic hydrocarbons in crude coal tar, especially the photosensitizers benzo(a)pyrene, benz(a)anthracene and dibenz(a,h)anthracene are known to be potent carcinogenic compounds. It has been recognized that both tar and UV light increase the risk of cutaneous cancer in animals; tar may act as a tumor initiator and as a promoter. Polycyclic aromatic hydrocarbons applied on the skin can induce epidermal and hepatic aryl hydrocarbon hydroxylase, a cytochrome P450-dependent enzyme. Aryl hydrocarbon hydroxylase is responsible for the conversion of benzo(a)pyrene to its ultimate carcinogenic metabolites. The synergistic effect of crude coal tar and UV irradiation in carcinogenesis may be due to an enhancement of P450-dependent enzymes. Thus, in summary: the carcinogenicity of coal tar has clearly been demonstrated by in vitro and animal studies, and it appears to be potentiated by concomitant use of ultraviolet radiation. Systemic absorption of mutagens from topically applied tar also has been demonstrated in animals.‘n The percutaneous absorption of mutagens from patients receiving crude coal tar has been demonstrated in urine and blood,41-43 but no data are available as to what extent coal-tar treatment results in an increased risk of cancers such as in the bladder or liver. There is one exception; a group of investigators compared the observed and expected numbers of all cancers occurring in a cohort of 719 psoriasis patients between 1963 and 1982.44All had received topical tar therapy intermittently over a lo-year period between 1953 and 1973. None had received any cytotoxic drug, ionizing radiation, or prescribed ultraviolet radiation therapy. No increase in malignancy was found over that expected in the general population. All the other human clinical studies are restricted to the question of whether therapeutic exposure to coal tar poses an increased risk of developing nor-melanoma skin cancers, as has been proven after occupational exposure.45-47 Besides, data
* 1997;15:739.-7&i
are obfuscated by the fact that in these published studies coal-tar treatment was combined with UV therapy. In four of the five major epidemiologic studies, multivariate analysis was not applied, making it impossible to look at the relative contributions of UV radiation and tar independently of one another. In a 25-year retrospective cohort study reported by a group of investigators, those patients with atopic dermatitis in whom skin cancers developed did not receive tar products any longer while hospitalized than did those without skin cancers, nor were they hospitalized more frequently. 48Besides, the skin cancer casesdid not receive any more coal tar during the follow-up pericld than did the others, and many had received less; how ever, several relative risks are elevated and the confi: dence intervals are wide, indicating that the study had low power to detect increased risks. In a parallel study with psoriatic patients similar results were found, although general population rates were used for comparison. In another study, the prevalence of premalignantr’ malignant skin lesions was 5.9% in the psoriasis group vs 3.0.1% in the control group;sO the cohort was too small, however, to evaluate the risk of skin cancer per se. Previous high exposure to tar (>90 months) and/or sunlamp treatment (>300 treatments) had relative risks of carcinoma of 2.4 (using unmatched controls) and 4.7 (using matched controls) as compared with low or moderate exposure reported in another study,51 Although the number of PUVA treatments was controlled for, unfortunately the number of equally risky UVB treatments was not. In 1993, a group of investigators reported a casecontrol study on 24 PUVA-tested patients with squamous cell cancer of the skin, matched with 96 PUVA~ treated patients.s2 Possible cocarcinogens, such as prior therapy with tar, UVB, ionizing radiation, methotrexate, and arsenic, were also investigated. The only statistically significant association to emerge was that ot prior therapy with methotrexate: relative risk 3.5; 95% confidence interval 1.2-9.9. The greatest limitation of the case-control method, is the fact that information of the potential risk factors may not be available from the subjects’ memory or records. In summary: conclusive evidence for the carcinogenicity of tar used in dermatologic practice is lacking. Further controlled studies are clearly indicated. Suggestions for the criteria those cohort studies have to fulfill have been discussed in a report published recently by a group of investigators.40 Severe teratogenic effects have been described after topical application of coal tar on rodent skin;53 in the literature no data are available regarding possible fetotoxic effects in humans. The use of coal tar during pregnancy is contraindicated in Germany, but in the
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Netherlands advice in medical information leaflets is contradictory;% however, in the European Registration of Congenital Anomalies (and Twins) (EUROCAT) registered children with inborn aberrations, exposure to coal tar products has not been mentioned until now (spring 1996; Dr. M. Cornel, personal communications). Nevertheless, the potential teratogenicity of dermatological coal tar products clearly indicates the need for a well-defined retrospective cohort study. Although prospective studies are more reliable, such studies are prohibited for medically ethical reasons.
11.
Risk/Benefit
12.
Ratio
Coal tar is an important possibility for the treatment of (atopic) dermatitis and psoriasis. Its extensive use for centuries appeared to be safe. In view of the fact that coal tar may pose a potential carcinogenic effect, as has been observed by in vitro and animal studies, and by the proven induction of spinocellular carcinoma in workmen who were chronically and intensively exposed to industrial tar, a certain restriction seems to be appropriate. Long-term treatment with concentrations of pix lithantracis above 5% are therefore undesirable and not recommended. And regarding possible teratogenie effects, the use of coal tar at least has to be restricted to intermittent use, in a low concentration on a relatively small percentage of body surface in the second and third trimesters of pregnancy only. With the treatment of chronic skin diseases, one certainly has to take into account the cumulative toxic potential. Therefore, it is useful to have different effective treatment modalities for the same dermatological disorder. The choice of treatment at a certain moment depends on the individual patient, the acceptance of his or her illness and his or her assessability in relation to the treatment.
References 1. Bechter J, Serle H. British Patent No. 214, 1681. 2. Pott I’. Clinical observation relative to the cataract; the polyp of the nose, the cancer of the scrotum, the different kinds of rupture and the mortification of the toes and feet. London: Haus, Clark & Collins, 1775. 3. Mi.iller SA. Topical treatment of psoriasis with tar. Acta Derm Venereol Suppl (Stockh) 1983;112:7-10. 4. Van der Hoek JCS, van Joost T, Stolz E. Sensibilisatie voor pix liquida (houtteer): een persisterend probleem. Ned Tijdschr Geneeskd 1985;129:205-8. 5. Anonymous. International Agency for Research on Cancer. Polynuclear aromatic compounds: Part 4, Bitumens, coal tars and derived products, shale oil and soots. IARC Monograph, Vol35.1985. 6. Rasmussen JE. The crudeness of coal tar. Prog Dermatol 1978;12:23-9. 7. Wrench R, Britten AZ. Evaluation of coal tar fractions for use in psoriasiform diseases using the mouse tail test.
8. 9.
10.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24. 25.
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High and low temperature tars and their constituents. Br J Dermatol 1975;92:569-74. Chapman RS, Finn OA. An assessment of high and low temperature tars in psoriasis. Br J Dermatol 1976;94:71-4. Gloor M, Kellermann H. Tierexperimentelle Untersuchungen zur sebosuppressiven Wirkung von Steinkohlenteer. Dermatol Monatsschr 1977;163:550-3. Gloor M, Dressel M, Schnyder UW. The effect of coal tar distillate, cadmium sulphide, ichthyol sodium and omadine MDS on the epidermis of the guinea pig. Dermatologica 1978;156:238-43. Wrench R. Scale prophylaxis. A new antiparakeratotic assay. Arch Dermatol 1981;117:213-5. Fulton JE Jr, Pay SR, Fulton JE 3d. Comedogenicity of current therapeutic products, cosmetics, and ingredients in the rabbit ear. J Am Acad Dermatol 1984;10:96-105. Diezel W, Gruner S, Anhalt GJ. ATPase positive epidermale Langerhans-Zellen: Hemmung der ATPase durch Ammonium-bituminosulfonat (Ichthyol) und Pix lithanthracis. Hautarzt 1992;43:22-4. Gruner S, Zwimer A, Strunk D, et al. The influence of topical dermatological treatment modalities on epidermal Langerhans cells and contact sensitization in mice. Contact Dermatitis 1992;26:241-7. Fischmeister I, Hellgren L, Vincent J. Infrared spectroscopy for tracing of topically applied ointment vehicles and active substances on healthy skin. Arch Dermatol Res 1975;253:63-9. Gloor M. Aspekte zur Therapie der Seborrhoea oleosa und der Pityriasis simplex capillitii. Hautarzt 1979;30: 236-41. Bemd A, Wehrenberg 0, Hevert F, et al. Experimenteller und klinischer Nachweis der antiproliferativen Wirkung einer hochgereinigten Steinkohlenteer-Fraction in einer speziellen Gelgrundlage. Arzneimittelforschung 1988;38: 582-6. Green CM, Ferguson J, MacLeod TM, et al. Polymorphonuclear leucocyte chemotaxis in response to leukotriene B, in treated and untreated psoriatics. Dermatologica 1989;178:20-2. Arnold WP, Glade CP, Mier PD, et al. Effects of sphingosine, isoquinoline and tannic acid on the human tapestripping model and the psoriatic lesion. Skin Pharmacol 1993;6:193-9. Foreman MJ, Taylor M, Clark C, et al. Isoquinoline is a possible anti-psoriatic agent in coal tar. Br J Dermatol 1985;112:323-8. Watts I’, Stables GS, Akhurst RJ, et al. Localization of transforming growth factor alpha RNA and protein in the skin of psoriatic patients receiving therapy, Br J Dermatol 1994;131:64-71. Unna PJ. Experimentelle Untersuchungen iiber die photodynamische Wirksamkeit von Steinkohlenteerbestandteilen. Thesis. University of Hamburg, Hamburg, 1957. Tannenbaum L, Parrish JA, Pathak MA, et al. Tar phototoxicity and phototherapy for psoriasis. Arch Dermatol 1975;111:467-70. Dodd WA. Tars. Their role in the treatment of psoriasis. Dermatol Clin 1993;11:131-5. Young E. The external treatment of psoriasis. A controlled
744
26. 27.
28.
29.
30.
31. 32.
33.
34.
35.
36. 37.
38.
39. 40.
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investigation of the effects of coal tar. Br J Dermatol 1970;82:510-5. Finlay AY, Young DW. Short contact crude coal tar therapy for psoriasis. Clin Exp Dermatol 1985;10:371-4. Williams REA, TiIlman DM, White SI, et al. Re-examining crude coal tar treatment for psoriasis. Br J Dermatol 1992; 126:608-10. Stern RS. The benefits, costs and risks of topical tar preparations in the treatment of psoriasis: considerations of cost effectiveness. Ann Acad Med Singapore 1988;17:473-6. Burden AD, Muston H, Beck MH. Intolerance and contact allergy to tar and dithranol in psoriasis. Contact Dermatitis 1994;31:185-6. Roesyanto ID, van den Akker TW, van Joost TW. Wood tars allergy, cross-sensitization and coal tar. Contact Dermatitis 1990;22:95-8. Burden AD, Stapleton M, Beck MH. Dithranol allergy: fact or fiction?. Contact Dermatitis lY92;27:291-3. Conde-Salaaar L, Guimaraens D, Romero LV, et al. Occupational coal tar dermatitis. Contact Dermatitis 1987;16: 231. Illchyshyn A, Cartwright, Smith AG. Contact sensitivity to newsprint: a rare manifestation of coal tar allergy. Contact Dermatitis 1987;17:52-3. Gould JW, Mercurio MG, Elmets CA. Cutaneous photosensitivity diseases induced by exogenous agents. JAAD 3995;33:551-73. Sugai T, Takahashi Y, Kakagi T. Pigmented cosmetic dermatitis and coal tar dyes. Contact Dermatitis 1977;3:24956. Kaidbey KH, Kligman AM. A human model of coal tar acne. Arch Dermatol 1974;109:212-5. Ibbotson SH, Stenton SC, Simpson NB. Acute severe bronchoconstriction precipitated by coal tar bandages. Clin Exp Dermatol 1995;20:58-9. Wright MC, Kaufhold A, Hevert F, et al. Untersuchungen zur miiglichen Nephrotoxizitat eines steinkohlenteerhaltigen Dermatikums. Hautarzt 1992;43:483-6. Roder H. Lebensbedrohliche Vergiftung bei ortlicher Psoriasisbehandlung. Z Hautkr 1960;29:175-80. Pion IA, Koening KL, Lim HW. Is dermatologic usage of coal tar carcinogenic? A review of the literature. Dermatol Surg 1995;21:227-31.
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41. Jongeneelen FJ, Bos RP, Azion RBM, et al. Biologicai monitoring of polycyclic aromatic hydrocarbons. Metabolites in urine. Stand J Work Environ Health 1986;12:137.43. 42. Hansen AM, Paulsen OM, Men& T. Longitudinal Study of excretion of metabolites of polycyclic aromatic hydrocarbons in urine from two psoriatic patients. Acta Derm Venereol (Stockh) 1993;73:188-90. 43. Storer JS, DeLeon I, Millikan LE, et al. Human absorption of crude coal tar products. Arch Dermatol1984;120:874-7. 34. Jones SK, Ma&e RM, Hole DJ, et al. Further evidence of the safety of tar in the management of psoriasis. Br J Dermatol 1985;113:97-101. 45. Everall JD, Hansteen I-L, Lawler SD. Chromosome studies in pitch warts. Br J Dermatol 1967;79:271-7. 46. Brownstein MH, Rabinowitz AD. The precursors of cutaneous squamous cell carcinoma. Int J Dermatol 1979;18: l-16. 47. Emmett EA. Cutaneous and ocular hazards of roofer+ Occup Med 1986;1:307-22. 48. Maughan WZ, Muller SA, Perry HO, et al. Incidence of skin cancers in patients with atopic dermatitis treated with coal tar. A 25-year follow-up study. J Am ,4cad Dermatol 1980;3:612-5. 49. Pittelkow MR, Perry HO, Muller SA, et al. Incidence of skin cancers in psoriatic patients treated with coal tar: a 25-year follow-up study. Arch Dermatol 1981;117:465-8. 50. Larko 0, Swanbeck G. Is UVB treatment safe? A study 01 extensively UVB treated psoriasis patients compared with a matched control group. Acta Derm Venereol (Stockh) 1982;62:502-12. 51. Stern RS, Zierler S, Parrish JA. Skin carcinoma in patients with psoriasis treated with topical tar and artificial ultraviolet radiation. Lancet 1980$732-5. 52. Lindeliif B, Sigurgeirsson B, PUVA and cancer: a casecontrol study. Br J Dermatol 1993;129:39-41. 53. Zangar RC, Springer DL, Buschbom RL, et al. Comparisou of fetotoxic effects of a dermally applied complex organic mixture in rats and mice. Fundam Appl Toxicol 1989;13: 662-9. 54. Arnold WI’, Boelen RE, van de Kerkhof PCM. De lokale behandeling van dermatosen bij zwangere vrouwen. Ned Tijdschr Geneeskd 1995;139:1170-3.
Tar W. PETER ARNOLD,
MD, PhD
T
he use of tar as a treatment for cutaneous disorders was described nearly two thousand years ago by Dioscorides. It was not coal tar but “asphalt”, because coal tar was not known at that time. Coal tar was first discovered and described by Becher and Serle in 1681.l Today the efficacy of medical tar preparations is well established in psoriasis, (atopic) dermatitis, dandruff, seborrheic dermatitis, and pruritus. Antifungal activity of shampoos with as low as 0.5% coal tar has been described. The use of tar also has a dark side. In 1775, Sir Percival Pott noticed an increased prevalence of scrotal skin cancer in chimney sweepers.2 It is well known that workers who have been chronically exposed to tar commonly develop spinocellular cancers of skin and airways. Still, tar has proven to be a safe substance in dermatological applications. In this chapter an overview will be presented regarding the method of preparation, modes of action, efficacy, and adverse effects of coal tar in the management of psoriasis.
Method of Preparation Tar is obtained by heating organic materials in the absence of oxygen. This process is called destructive distillation. Several sources can be utilized for the preparation of tar products for dermatological usage. Wood tars (pix liquida) are produced by destructive distillation of birch, beech, pine, or juniper wood, and they are successfully used in the treatment of atopic dermatitis. Wood tar is not phototoxic, but in comparison with coal tar it does have an increased risk of irritation (beware of the Kobner phenomenon in psoriasis!) and sensitization.3,4 Shale tar (ichthyol or ammonium bituminosulfonate) is obtained by destructive distillation of bituminous stone, which contains deposits of fossilized fish. Ichthy01 is not phototoxic, does not have antipsoriatic action of any significance, and has been used earlier in inflammatory processes, for example furunculosis.3 Coal tars (pix lithanthracis) are used mostly for dermatological purposes. In coke ovens, coal is heated in the absence of air. Gases are formed that turn into a From the Department of Dermatology, University Hospitd Nijmegen, Nijmegen, The Netherlands. Address correspondence to Dr. W. P. Arnold, 802 Department of Dermatology, University Hospital Nijmegen, P.O. Box 9101, 6500 H B Nijmegen, The Netherlands.
0 1997 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
black-brown, thick liquid during the cooling-down process. After removal of ammonia, crude coal tar is left. The composition of crude coal tar depends mainly on the temperature of the carbonization.5 In general, coal tars are complex combinations of hydrocarbons; phenols; and heterocyclic oxygen, sulfur, and nitrogen compounds. Probably as many as 10,000 compounds are actually present; low-temperature (400-700°C) coal tars have a higher content of phenols and tar acids, and high-temperature (lOOO-1300°C) coal tars have a higher content of polycyclic aromatic hydrocarbons (PAHs) such as naphthalene, anthracene, and others. The tar bases (for example, quinoline, isoquinoline, and pyridine) have almost identical average weight percentages in comparison to low- and high-temperature coal tar. Crude coal tar can be modified in three ways, as follows: (1) After fractional distillation at different temperatures (loo-450”(Z), tar oils are formed; the remaining residue is called pitch, which was used in building. In the Netherlands medical pix lithantracis is produced by mixing two thirds of pitch of high-temperature sources with one third of tar oils that have been obtained by fractional distillation between 220 and 270°C. (2) Modification has been tried in order to improve the cosmetics of coal tar and to loosen the carcinogenic fractions by fractional distillation at different temperatures; however, it was not possible to separate the carcinogenic from the therapeutic fractions. Besides, a cosmetically better tar product is associated with a loss of efficacy .6,7Comparison of the efficacy of coal tar from high- and low-temperature sources in the treatment of patients suffering from chronic psoriasis showed the tars to be equally effective.8 (3) Extraction of 20 g pix lithantracis with 100 ml alcohol and addition of 5 g Tween 80’s’ produces liquor (solutio) carbonis detergens. Pix lithantracis (l-10%) or solutio carbonis detergens (5-20%) can be manufactured into a greasy ointment, like yellow soft paraffin, white Vaseline, or a mixture of white Vaseline with lanette wax cream ana. Addition of a nonionic surfactant (Tween 80@or 20@‘)improves the dispersion of the tar in its vehicle. For the treatment of acute eruptions it is possible to mix the tar with zinc paste. This vehicle increases the time of absorption of tar. Pharmaceutical and cosmetic industries have developed lotions, gels, and shampoos in which tar has been dissolved. 0738-081X/97/$32.00 PI1 SO738-081X(97)00018-7
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Modes of Action Studies in animals revealed an inhibitory effect of coal tar on sebum secretion,9 the number of mitoses in the basal cells of the epidermis, and scale development.9-11 The xanthenes, monoazoanilines, fluorans, and indigoids, all coal-tar derivatives, proved to be potent comedogens in the rabbit ear assay.]* Comedogenic activity and epidermal growth/differentiation inhibitory capacity are related, because formation of a comedo implies a disturbed balance between sebum secretion on one side and proliferation/differentiation patterns of the follicular epithelium on the other side. Both ichthyol and pix lithanthracis were shown to reduce the number of ATPase-positive epidermal Langerhans cells in the epidermis of BALB/c m.ice;i3 however, pix lithanthracis did not have an effect on MHC class II antigens, nor did it inhibit the induction of contact hypersensitivity, in contrast to psoralen plus ultraviolet-A (PUVA) treatmenti* The explanation of these conflicting data probably lies in differences in systemic absorption of the topically applied contact allergen (sensitization outside the application area). Pyroleum lithanthracis (5%) seemed to give rise to hydrolysis of the triglycerides in human epidermis, as measured by infrared spectroscopy.15 Besides, coal tar proved to reduce the lipid synthesis in the sebaceous gland, and inhibition of mitosis could also be demonstrated in the human scalp.16 DNA synthesis of transformed keratinocytes could be inhibited in vitro from a concentration of 0.35 pg/ml.i7 The growth inhibitory effect showed to be reversible up to the effective dose (ED 50) concentration (1.3 pg coal tar/ml). Comparison of a tar-treated and -untreated group of psoriasispatients revealed a significantly increased chemotactic response to the arachidonic acid lipoxygenase product leukotriene B, in the tar-treated group;ls howzver, the clinical relevance of this observation is not :lear. The same is true for the observation that 100% pix .ithantracis neither inhibited nor induced the rate-lim.ting enzyme of polyamine biosynthesis, ornithine delarboxylase (ODC).19 Almost all antipsoriatic therapies corticosteroids, retinoic acid, vitamin D3) inhibit epilermal ODC induction, except the UVB and dithranol :reatments, which induce ODC per se. The same study 11~0demonstrated that one of the components of coal ar, isoquinoline, did not have any antipsoriatic potenial. These results were disappointing, because isoluinoline promised antipsoriatic characteristics in the nouse-tail model.20 An explanation of how coal tar nfluences the abnormal pattern of keratinocyte growth md differentiation in psoriasis is presented by a group )f investigators. ** They showed a decrease of the elerated levels of transforming growth factor cymRNA in he subcorneal layers of the epidermis during treatment )f psoriasis with coal tar and UVB or PUVA followed
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by tar. Of course, the question remains whether this i> an epiphenomenon or not. In addition to its antimitotic and antiinflammatory effects, coal tar also possessesa photodynamic effect. An investigator determined that anthracene, 3,4-bent pyrene, fluoranthene, and pyrene were responsible for this action.** The clinical relevance of the photodynamic activity of coal tar has never been documented. Many articles describe the efficacy of the so-called Goeckerman’s treatment, the combination of tar with ultraviolet-B (UVB) irradiation, but ultraviolet-A (UVA) light contains the part of the light spectrum that activates coal tar.23 In summary: the antiproliferative and antiinflammatory capacities of coal tar are greater than the sum of the efficacy of the separated ingredients. Its precise mechanism of action remains unknown.
Efficacy in Psoriasis When itching is extensive or the patient presents an unstable psoriasis guttata/punctata, tar is preferable to dithranol. Erythrodermic and/or pustular psoriasis may be very sensitive to irritating factors, so tar is not recommended as a first-line treatment for these two forms of psoriasis. With renewed applications of coal tar, it is important not to scrub the skin until it loo& clean again. This mechanical irritation may induce the Kobner phenomenon. Before the next application it is possible to inspect the underlying skin by gently clearing with vegetable oil, for example oleum arachidis or olivae. There are several factors concerning the role of tars in the treatment of psoriasis:24(1) Tar alone may be helpful for a subset of individuals with mild-to-moderate psoriasis (the majority of patients with psoriasis). (2) Pix lithantracis is not always more beneficial than modified tar preparations; these latter have much better patient acceptance and compliance because of decreased odor, staining, and messiness.(3) Overall, the potential severity of side effects from tars is less than that from anthralin and much less than that from topical corticosteroids (atrophy, rebound). (4) Clinical experience confirms that tar preparations can be effective when other modalities fail or cannot be used for reasons of adverse effects or otherwise. (5) Tar shampoos are ronsidered useful therapeutic agents for active clearing therapy and for maintenance. (6) When combined with suberythemogenic ultraviolet light B, tar can be an use: ful agent, because it prevents the side effects of maximal erythemogenic UVB monotherapy. One of the first extensive left-right comparison studies regarding the efficacy of pix lithantracis and liquor carbonis detergens as monotherapy for psoriasis has been described by an investigator in 1970.2”Ten percent pix lithantracis in zinc paste proved to be superior; 1%
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pix lithantracis and 20% liquor carbonis detergens were approximately of equal value. A group of investigators investigated in a paired comparison study whether chronic plaque psoriasis improved with daily l-hour applications of 30% pix lithantracis in yellow soft paraffin26 This regime was not as effective as daily 23-hour treatments with 5% pix lithantracis. Another group of investigators found that there appears to be no benefit from exceeding a concentration of 5% pix lithantracis in yellow soft paraffin in the treatment of patients with psoriasis, and that the plateau in the dose-response curve for the action of crude coal tar in psoriasis begins at a point between 1 and 5%.z7 In both studies, the median whole body psoriasis area and severity index (PASI) score fell by approximately 50% during a treatment period of ten days. Unfortunately, no data are available regarding the length of remission after the use of pix lithantracis as a monotherapy for psoriasis. Besides, adequate data to support tar as a cost-effective agent in the treatment of psoriasis are lacking.28 The efficacy of coal tar in the treatment of psoriasis sometimes improves when it is combined with other therapeutic modalities. For example, topical corticosteroids (initially), dithranol (finally), or ultraviolet irradiation. The efficacy of these modes of treatment will be discussed in the last chapter of this issue.
Adverse Effects The main drawbacks in using tar are its messiness, staining, and odor; however, these complaints lessen with the use of modified tar preparations. The other side effects can be classified as allergic, (photo-)toxic, and, finally, aspecific reactions, such as folliculitis and bronchoconstriction. Contact allergy to coal tar is less frequent than intolerance, because coal tar is a well-recognized irritant.29 Therefore, it is important to patch test patients with psoriasis who report intolerance to coal tar. While a positive reaction may be obtained only in a minority, those with a negative result, and a presumably irritant response, could be treated more confidently with lower concentrations rather than abandoning a potentially useful treatment. In a population of patients patch tested for allergic contact dermatitis, a prevalence of 5.4% was seen for wood-tar sensitization.30 In this group, a combined allergy was seen to wood tars and fragrance mix in 43%, and to wood tars and balsam of Peru in 31%. A combined allergy to wood tars and coal tar was seen in 18.5%. Comparison of the test results in atopic and nonatopic subgroups led to the hypothesis that combined “wood-tars-coal-tar” allergy could be the consequence of cross-sensitization rather than due to longterm previous topical treatment with tar derivatives.
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The high percentage of cross-allergy between wood tars and fragrance mix emphasizes the role of wood tars as an important indicator allergen in perfume allergy. Of 13 cases of dithranol allergy reported in the English literature, 4 were noted to be allergic to coal tar as well, and in the other 9 it was not stated whether coal tar was tested.31 This may simply be due to independent sensitization, but it does raise the possibility of an allergen shared between coal tar and dithranol or even the presence of dithranol in minute quantities in coal tar. Besides its use in dermatology, coal tar is also frequently used in other fields. Allergic contact dermatitis to coal tar, therefore, can be the result not of dermatological, but rather of occupational or environmental factors. A man who had been working in a factory where brushes for electrical engines are manufactured had been sensitized by the use of E30 and E40, composed of lamp black, tar, and artificial graphite.s2 And another case report describes a woman with coal-tar sensitivity in whom the source of her dermatitis was shown to be newsprint, a common product containing coal-tar-derived material.33 Several of the polycyclic aromatic hydrocarbons, including anthracene, pyrene, fluoranthene, benzo(a)pyrene, acridine, and phenanthrene, are photosensitizers; and they cause phototoxicity by an oxygendependent mechanism. 34 Exposure to these agents causes intense burning and stinging within minutes of UVA exposure, often precluding further light exposure. If UV exposure is continued, a two-stage process is observed that begins with an immediate wheal and flare that fades within an hour and is followed by an erythema response that peaks from 24 to 48 hours. Since pigmentary changes are a frequent feature of phototoxic reactions (unusual in photoallergy), coal tar may be involved in pigmented cosmetic dermatitis as we11.35 The continuous application of coal tar can induce an acneiform eruption, especially after the use of tar in occlusive ointment bases. In blacks, this is a monomorphous crop of cornedones that are of the open variety from the very start. In whites, the first lesions are papulopustules resulting from toxic disorganization of the follicular epithelium. This inflammatory phase is followed by cornedones. 36Concentrations of coal tar larger than 2% are more likely to induce this follicular irritation than are more dilute preparations. Folliculitis usually occurs on the lower extremities.24 Little is known regarding systemic adverse effects after the topical use of coal tar. A severe symptomatic bronchoconstriction in an atopic asthmatic subject following the application of coal tar bandages had been caused by inhalation of coal tar vapor.s7 In a German study, daily application of a coal tar preparation for the scalp for a period of 8 weeks did not show any pathological change or impairment of renal function.38 In
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1960, an investigator described the case of a female psoriatic patient who suffered a life-threatening intoxication due to extensive topical treatment with tar and salicylic acid.39Her symptoms were attributable to both salicylic-acid intoxication (Kussmaul respiration, hyperthermia, periocular edema, increase of xanthoproteins in serum) and phenol intoxication (Cheyne-Stokes respiration, states of excitement as well as collapse, increase of pulse, secretion of phenol in urine). Carcinogenic and/or teratogenic (systemic) side effects after the topical use of coal tar products will be described in the next section.
Carcinogenic
and Teratogenic
Effects
A thorough review of the existing literature (in vitro, animal and human studies) on the carcinogenicity of tar has been published recently.40 Some of the polycyclic aromatic hydrocarbons in crude coal tar, especially the photosensitizers benzo(a)pyrene, benz(a)anthracene and dibenz(a,h)anthracene are known to be potent carcinogenic compounds. It has been recognized that both tar and UV light increase the risk of cutaneous cancer in animals; tar may act as a tumor initiator and as a promoter. Polycyclic aromatic hydrocarbons applied on the skin can induce epidermal and hepatic aryl hydrocarbon hydroxylase, a cytochrome P450-dependent enzyme. Aryl hydrocarbon hydroxylase is responsible for the conversion of benzo(a)pyrene to its ultimate carcinogenic metabolites. The synergistic effect of crude coal tar and UV irradiation in carcinogenesis may be due to an enhancement of P450-dependent enzymes. Thus, in summary: the carcinogenicity of coal tar has clearly been demonstrated by in vitro and animal studies, and it appears to be potentiated by concomitant use of ultraviolet radiation. Systemic absorption of mutagens from topically applied tar also has been demonstrated in animals.‘n The percutaneous absorption of mutagens from patients receiving crude coal tar has been demonstrated in urine and blood,41-43 but no data are available as to what extent coal-tar treatment results in an increased risk of cancers such as in the bladder or liver. There is one exception; a group of investigators compared the observed and expected numbers of all cancers occurring in a cohort of 719 psoriasis patients between 1963 and 1982.44All had received topical tar therapy intermittently over a lo-year period between 1953 and 1973. None had received any cytotoxic drug, ionizing radiation, or prescribed ultraviolet radiation therapy. No increase in malignancy was found over that expected in the general population. All the other human clinical studies are restricted to the question of whether therapeutic exposure to coal tar poses an increased risk of developing nor-melanoma skin cancers, as has been proven after occupational exposure.45-47 Besides, data
* 1997;15:739.-7&i
are obfuscated by the fact that in these published studies coal-tar treatment was combined with UV therapy. In four of the five major epidemiologic studies, multivariate analysis was not applied, making it impossible to look at the relative contributions of UV radiation and tar independently of one another. In a 25-year retrospective cohort study reported by a group of investigators, those patients with atopic dermatitis in whom skin cancers developed did not receive tar products any longer while hospitalized than did those without skin cancers, nor were they hospitalized more frequently. 48Besides, the skin cancer casesdid not receive any more coal tar during the follow-up pericld than did the others, and many had received less; how ever, several relative risks are elevated and the confi: dence intervals are wide, indicating that the study had low power to detect increased risks. In a parallel study with psoriatic patients similar results were found, although general population rates were used for comparison. In another study, the prevalence of premalignantr’ malignant skin lesions was 5.9% in the psoriasis group vs 3.0.1% in the control group;sO the cohort was too small, however, to evaluate the risk of skin cancer per se. Previous high exposure to tar (>90 months) and/or sunlamp treatment (>300 treatments) had relative risks of carcinoma of 2.4 (using unmatched controls) and 4.7 (using matched controls) as compared with low or moderate exposure reported in another study,51 Although the number of PUVA treatments was controlled for, unfortunately the number of equally risky UVB treatments was not. In 1993, a group of investigators reported a casecontrol study on 24 PUVA-tested patients with squamous cell cancer of the skin, matched with 96 PUVA~ treated patients.s2 Possible cocarcinogens, such as prior therapy with tar, UVB, ionizing radiation, methotrexate, and arsenic, were also investigated. The only statistically significant association to emerge was that ot prior therapy with methotrexate: relative risk 3.5; 95% confidence interval 1.2-9.9. The greatest limitation of the case-control method, is the fact that information of the potential risk factors may not be available from the subjects’ memory or records. In summary: conclusive evidence for the carcinogenicity of tar used in dermatologic practice is lacking. Further controlled studies are clearly indicated. Suggestions for the criteria those cohort studies have to fulfill have been discussed in a report published recently by a group of investigators.40 Severe teratogenic effects have been described after topical application of coal tar on rodent skin;53 in the literature no data are available regarding possible fetotoxic effects in humans. The use of coal tar during pregnancy is contraindicated in Germany, but in the
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Netherlands advice in medical information leaflets is contradictory;% however, in the European Registration of Congenital Anomalies (and Twins) (EUROCAT) registered children with inborn aberrations, exposure to coal tar products has not been mentioned until now (spring 1996; Dr. M. Cornel, personal communications). Nevertheless, the potential teratogenicity of dermatological coal tar products clearly indicates the need for a well-defined retrospective cohort study. Although prospective studies are more reliable, such studies are prohibited for medically ethical reasons.
11.
Risk/Benefit
12.
Ratio
Coal tar is an important possibility for the treatment of (atopic) dermatitis and psoriasis. Its extensive use for centuries appeared to be safe. In view of the fact that coal tar may pose a potential carcinogenic effect, as has been observed by in vitro and animal studies, and by the proven induction of spinocellular carcinoma in workmen who were chronically and intensively exposed to industrial tar, a certain restriction seems to be appropriate. Long-term treatment with concentrations of pix lithantracis above 5% are therefore undesirable and not recommended. And regarding possible teratogenie effects, the use of coal tar at least has to be restricted to intermittent use, in a low concentration on a relatively small percentage of body surface in the second and third trimesters of pregnancy only. With the treatment of chronic skin diseases, one certainly has to take into account the cumulative toxic potential. Therefore, it is useful to have different effective treatment modalities for the same dermatological disorder. The choice of treatment at a certain moment depends on the individual patient, the acceptance of his or her illness and his or her assessability in relation to the treatment.
References 1. Bechter J, Serle H. British Patent No. 214, 1681. 2. Pott I’. Clinical observation relative to the cataract; the polyp of the nose, the cancer of the scrotum, the different kinds of rupture and the mortification of the toes and feet. London: Haus, Clark & Collins, 1775. 3. Mi.iller SA. Topical treatment of psoriasis with tar. Acta Derm Venereol Suppl (Stockh) 1983;112:7-10. 4. Van der Hoek JCS, van Joost T, Stolz E. Sensibilisatie voor pix liquida (houtteer): een persisterend probleem. Ned Tijdschr Geneeskd 1985;129:205-8. 5. Anonymous. International Agency for Research on Cancer. Polynuclear aromatic compounds: Part 4, Bitumens, coal tars and derived products, shale oil and soots. IARC Monograph, Vol35.1985. 6. Rasmussen JE. The crudeness of coal tar. Prog Dermatol 1978;12:23-9. 7. Wrench R, Britten AZ. Evaluation of coal tar fractions for use in psoriasiform diseases using the mouse tail test.
8. 9.
10.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24. 25.
743
High and low temperature tars and their constituents. Br J Dermatol 1975;92:569-74. Chapman RS, Finn OA. An assessment of high and low temperature tars in psoriasis. Br J Dermatol 1976;94:71-4. Gloor M, Kellermann H. Tierexperimentelle Untersuchungen zur sebosuppressiven Wirkung von Steinkohlenteer. Dermatol Monatsschr 1977;163:550-3. Gloor M, Dressel M, Schnyder UW. The effect of coal tar distillate, cadmium sulphide, ichthyol sodium and omadine MDS on the epidermis of the guinea pig. Dermatologica 1978;156:238-43. Wrench R. Scale prophylaxis. A new antiparakeratotic assay. Arch Dermatol 1981;117:213-5. Fulton JE Jr, Pay SR, Fulton JE 3d. Comedogenicity of current therapeutic products, cosmetics, and ingredients in the rabbit ear. J Am Acad Dermatol 1984;10:96-105. Diezel W, Gruner S, Anhalt GJ. ATPase positive epidermale Langerhans-Zellen: Hemmung der ATPase durch Ammonium-bituminosulfonat (Ichthyol) und Pix lithanthracis. Hautarzt 1992;43:22-4. Gruner S, Zwimer A, Strunk D, et al. The influence of topical dermatological treatment modalities on epidermal Langerhans cells and contact sensitization in mice. Contact Dermatitis 1992;26:241-7. Fischmeister I, Hellgren L, Vincent J. Infrared spectroscopy for tracing of topically applied ointment vehicles and active substances on healthy skin. Arch Dermatol Res 1975;253:63-9. Gloor M. Aspekte zur Therapie der Seborrhoea oleosa und der Pityriasis simplex capillitii. Hautarzt 1979;30: 236-41. Bemd A, Wehrenberg 0, Hevert F, et al. Experimenteller und klinischer Nachweis der antiproliferativen Wirkung einer hochgereinigten Steinkohlenteer-Fraction in einer speziellen Gelgrundlage. Arzneimittelforschung 1988;38: 582-6. Green CM, Ferguson J, MacLeod TM, et al. Polymorphonuclear leucocyte chemotaxis in response to leukotriene B, in treated and untreated psoriatics. Dermatologica 1989;178:20-2. Arnold WP, Glade CP, Mier PD, et al. Effects of sphingosine, isoquinoline and tannic acid on the human tapestripping model and the psoriatic lesion. Skin Pharmacol 1993;6:193-9. Foreman MJ, Taylor M, Clark C, et al. Isoquinoline is a possible anti-psoriatic agent in coal tar. Br J Dermatol 1985;112:323-8. Watts I’, Stables GS, Akhurst RJ, et al. Localization of transforming growth factor alpha RNA and protein in the skin of psoriatic patients receiving therapy, Br J Dermatol 1994;131:64-71. Unna PJ. Experimentelle Untersuchungen iiber die photodynamische Wirksamkeit von Steinkohlenteerbestandteilen. Thesis. University of Hamburg, Hamburg, 1957. Tannenbaum L, Parrish JA, Pathak MA, et al. Tar phototoxicity and phototherapy for psoriasis. Arch Dermatol 1975;111:467-70. Dodd WA. Tars. Their role in the treatment of psoriasis. Dermatol Clin 1993;11:131-5. Young E. The external treatment of psoriasis. A controlled
744
26. 27.
28.
29.
30.
31. 32.
33.
34.
35.
36. 37.
38.
39. 40.
ARNOLD
investigation of the effects of coal tar. Br J Dermatol 1970;82:510-5. Finlay AY, Young DW. Short contact crude coal tar therapy for psoriasis. Clin Exp Dermatol 1985;10:371-4. Williams REA, TiIlman DM, White SI, et al. Re-examining crude coal tar treatment for psoriasis. Br J Dermatol 1992; 126:608-10. Stern RS. The benefits, costs and risks of topical tar preparations in the treatment of psoriasis: considerations of cost effectiveness. Ann Acad Med Singapore 1988;17:473-6. Burden AD, Muston H, Beck MH. Intolerance and contact allergy to tar and dithranol in psoriasis. Contact Dermatitis 1994;31:185-6. Roesyanto ID, van den Akker TW, van Joost TW. Wood tars allergy, cross-sensitization and coal tar. Contact Dermatitis 1990;22:95-8. Burden AD, Stapleton M, Beck MH. Dithranol allergy: fact or fiction?. Contact Dermatitis lY92;27:291-3. Conde-Salaaar L, Guimaraens D, Romero LV, et al. Occupational coal tar dermatitis. Contact Dermatitis 1987;16: 231. Illchyshyn A, Cartwright, Smith AG. Contact sensitivity to newsprint: a rare manifestation of coal tar allergy. Contact Dermatitis 1987;17:52-3. Gould JW, Mercurio MG, Elmets CA. Cutaneous photosensitivity diseases induced by exogenous agents. JAAD 3995;33:551-73. Sugai T, Takahashi Y, Kakagi T. Pigmented cosmetic dermatitis and coal tar dyes. Contact Dermatitis 1977;3:24956. Kaidbey KH, Kligman AM. A human model of coal tar acne. Arch Dermatol 1974;109:212-5. Ibbotson SH, Stenton SC, Simpson NB. Acute severe bronchoconstriction precipitated by coal tar bandages. Clin Exp Dermatol 1995;20:58-9. Wright MC, Kaufhold A, Hevert F, et al. Untersuchungen zur miiglichen Nephrotoxizitat eines steinkohlenteerhaltigen Dermatikums. Hautarzt 1992;43:483-6. Roder H. Lebensbedrohliche Vergiftung bei ortlicher Psoriasisbehandlung. Z Hautkr 1960;29:175-80. Pion IA, Koening KL, Lim HW. Is dermatologic usage of coal tar carcinogenic? A review of the literature. Dermatol Surg 1995;21:227-31.
Clhzics in Dermatology
l
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41. Jongeneelen FJ, Bos RP, Azion RBM, et al. Biologicai monitoring of polycyclic aromatic hydrocarbons. Metabolites in urine. Stand J Work Environ Health 1986;12:137.43. 42. Hansen AM, Paulsen OM, Men& T. Longitudinal Study of excretion of metabolites of polycyclic aromatic hydrocarbons in urine from two psoriatic patients. Acta Derm Venereol (Stockh) 1993;73:188-90. 43. Storer JS, DeLeon I, Millikan LE, et al. Human absorption of crude coal tar products. Arch Dermatol1984;120:874-7. 34. Jones SK, Ma&e RM, Hole DJ, et al. Further evidence of the safety of tar in the management of psoriasis. Br J Dermatol 1985;113:97-101. 45. Everall JD, Hansteen I-L, Lawler SD. Chromosome studies in pitch warts. Br J Dermatol 1967;79:271-7. 46. Brownstein MH, Rabinowitz AD. The precursors of cutaneous squamous cell carcinoma. Int J Dermatol 1979;18: l-16. 47. Emmett EA. Cutaneous and ocular hazards of roofer+ Occup Med 1986;1:307-22. 48. Maughan WZ, Muller SA, Perry HO, et al. Incidence of skin cancers in patients with atopic dermatitis treated with coal tar. A 25-year follow-up study. J Am ,4cad Dermatol 1980;3:612-5. 49. Pittelkow MR, Perry HO, Muller SA, et al. Incidence of skin cancers in psoriatic patients treated with coal tar: a 25-year follow-up study. Arch Dermatol 1981;117:465-8. 50. Larko 0, Swanbeck G. Is UVB treatment safe? A study 01 extensively UVB treated psoriasis patients compared with a matched control group. Acta Derm Venereol (Stockh) 1982;62:502-12. 51. Stern RS, Zierler S, Parrish JA. Skin carcinoma in patients with psoriasis treated with topical tar and artificial ultraviolet radiation. Lancet 1980$732-5. 52. Lindeliif B, Sigurgeirsson B, PUVA and cancer: a casecontrol study. Br J Dermatol 1993;129:39-41. 53. Zangar RC, Springer DL, Buschbom RL, et al. Comparisou of fetotoxic effects of a dermally applied complex organic mixture in rats and mice. Fundam Appl Toxicol 1989;13: 662-9. 54. Arnold WI’, Boelen RE, van de Kerkhof PCM. De lokale behandeling van dermatosen bij zwangere vrouwen. Ned Tijdschr Geneeskd 1995;139:1170-3.