Skin Protection: Practical Applications in the Occupational Setting (Current Problems in Dermatology Vol 34)

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Author: S. Schliemann | Peter Elsner

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Skin Protection

Current Problems in Dermatology Vol. 34

Series Editor

P. Itin, Basel

Skin Protection Practical Applications in the Occupational Setting

Volume Editors

S. Schliemann, Jena P. Elsner, Jena

31 figures and 20 tables, 2007

Basel · Freiburg · Paris · London · New York · Bangalore · Bangkok · Singapore · Tokyo · Sydney

Current Problems in Dermatology

Library of Congress Cataloging-in-Publication Data Skin protection : practical applications in the occupational setting / volume editors, S. Schliemann, P. Elsner. p. ; cm. – (Current problems in dermatology, ISSN 1421-5721 ; v. 34) Includes bibliographical references and indexes. ISBN-13: 978-3-8055-8218-6 (hard cover : alk. paper) ISBN-10: 3-8055-8218-8 (hard cover : alk. paper) 1. Occupational dermatitis. 2. Skin–Safety measures. I. Schliemann, S. (Sybille) II. Elsner, Peter, 1955- III. Series. [DNLM: 1. Skin Diseases–prevention & control. 2. Occupational Exposure–prevention & control. W1 CU804L v.34 2006 / WR 140 S6285 2007] RL241.S55 2006 616.5–dc22 2006035387

Bibliographic Indices. This publication is listed in bibliographic services, including Current Contents® and Index Medicus. Disclaimer. The statements, options and data contained in this publication are solely those of the individual authors and contributors and not of the publisher and the editor(s). The appearance of advertisements in the book is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements. Drug Dosage. The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. © Copyright 2007 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland) www.karger.com Printed in Switzerland on acid-free paper by Reinhardt Druck, Basel ISSN 1421–5721 ISBN-10: 3–8055–8218–8 ISBN-13: 978–3–8055–8218–6

Contents

VII Foreword Schliemann, S., Elsner, P. (Jena) Principles of Skin Protection

1 Skin Protection in the Prevention of Skin Diseases Elsner, P. (Jena)

11 Galenical Principles in Skin Protection Zhang, J.; Smith, E.W. (Columbia, S.C.); Surber, C. (Basel) Efficacy and Safety of Skin Protection

19 Using Skin Models to Assess the Effects of a Pre-Work Cream. Methodological Aspects and Perspective of the Industry zur Mühlen, A.; Klotz, A.; Allef, P.; Weimans, S.; Veeger, M.; Thörner, B.; Eichler, J.-O. (Krefeld)

33 Efficacy and Safety Testing. The Clinical Perspective Fluhr, J.W.; Miteva, M.; Elsner, P. (Jena) Skin Protection from Specific Exposures

47 Protection from Irritants Zhai, H.; Maibach, H.I. (San Francisco, Calif.)

58 Protection from Occupational Allergens Schalock, P.C.; Zug, K.A. (Lebanon, N.H.)

V

76 Protection from Toxicants Brodsky, B.; Wormser, U. (Jerusalem)

87 Evaluation of Skin-Protective Means against Acute and Chronic Effects of Ultraviolet Radiation from Sunlight Kütting, B.; Drexler, H. (Erlangen)

98 Protection from Physical Noxae Schürer, N.Y. (Osnabrück); Dickel, H. (Bochum)

111 Protection from Combination Exposure Elsner, P. (Jena) Practical Applications of Skin Protection

120 Skin Protection in the Healthcare Setting Mahler, V. (Erlangen)

133 Skin Protection for Hairdressers Skudlik, C.; John, S.M. (Osnabrück)

138 Skin Protection in the Food Industry Bauer, A.; Kelterer, D.; Bartsch, R. (Jena); Stadeler, M. (Erfurt); Elsner, P. (Jena)

151 Skin Protection in the Metal Industry Funke, U. (Ingolstadt)

161 Skin Protection Training. The Route to Practical Applications Pohrt, U. (Berlin)

171 Limitations of Skin Protection. Interaction of Gloves and Skin Protection Products Schliemann, S. (Jena)

178 Author Index 179 Subject Index

Contents

VI

Foreword

Occupational dermatology is an exciting and very successful subspecialty of dermatology. While incidence and prevalence are increasing for other skin diseases like skin cancer or allergies, occupational dermatology has successfully developed prevention and secondary intervention programs for occupational skin diseases that have been proven to be successful and cost-effective. The success of these programs is at least partially due to the use of skin protection products. While in the past they had been considered by some dermatologists with scepticism, within the last few years evidence has accumulated that these products may indeed be safe and effective tools of prevention. However, concerns remain, especially considering the possible percutaneous penetration enhancement of noxious work substances by skin protection agents. This underlines that more research is needed before the widespread use of skin protectants in high-risk workplaces can be advocated unequivocally. We hope that the readers, especially dermatologists, occupational physicians and safety engineers, will draw support from this text for their daily work with skin protection products. We are grateful to the international panel of distinguished authors that devoted so much time and effort to make this a useful text, and we would like to thank the staff of Karger AG, especially Ms. Ludwig and Ms. Anyawike, for their kind help with the project. Sibylle Schliemann Peter Elsner Jena, 2006

VII

Principles of Skin Protection Schliemann S, Elsner P (eds): Skin Protection. Curr Probl Dermatol. Basel, Karger, 2007, vol 34, pp 1–10

Skin Protection in the Prevention of Skin Diseases Peter Elsner Department of Dermatology and Allergology, University of Jena, Jena, Germany

Abstract Occupational skin diseases comprise a wide spectrum of conditions. Under epidemiological aspects, occupational contact dermatitis that is usually manifested on the hands is the most frequent occupational skin disease with an estimated average incidence rate of 0.7–1.5 cases per 1,000 workers per year. Irritant dermatitis is due to individual susceptibility and the exposure to irritants such as wet work combined with detergents or other hydrophilic irritants or solvents at the workplace. Chronic irritant dermatitis is a risk factor for delayed-type sensitization and subsequently allergic contact dermatitis. It is therefore the prevention of chronic or cumulative irritant dermatitis that is the decisive factor in the prevention of occupational skin disease. Within prevention programs at the workplace, skin protection plays an important, but limited role. Others are technical and organizational means to avoid or reduce skin exposure to irritants and allergens. Educational measures to increase the awareness of workers for workplace hazards and to motivate them to use skin protection measures appropriately are just as important as the careful selection of skin protection materials. Copyright © 2007 S. Karger AG, Basel

While occupational skin diseases are an old phenomenon associated with the exposures of working life, great progress has been made in the understanding of these conditions within the last two decades. This has led to evidencebased prevention and secondary intervention programs that have found widespread acceptance among dermatologists and occupational physicians. Occupational dermatology is thus at the forefront of preventive dermatology. Spectrum of Occupational Skin Diseases

Skin diseases are among the most frequent occupational diseases in many countries. In Germany, 40% of all notified and acknowledged occupational

Others; 1,747 Vertebral column disorders; 308 Chronic Bronchitis/Emphysema; 336 Infectious diseases; 465

Skin diseases; 9,124

Allergic airway diseases; 585 Asbestosis with cancer; 771 Mesotheliomas; 853 Silicosis; 1,011 Asbestosis; 2,114

Occupational hearing impairments; 5,478

Fig. 1. Notified and acknowledged occupational diseases in Germany 2005 [1].

diseases relate to the skin (fig. 1) [1]. Occupational skin diseases encompass a wide array of conditions, including acne, cancer, connective tissue disorders, contact dermatitis, infectious diseases, pigment changes, urticaria and aggravation of preexisting skin diseases (table 1). Contact dermatitis is the most frequent and epidemiologically relevant occupational skin disease.

Incidence and Prevalence of Occupational Skin Diseases

High-quality epidemiological data on the incidence of occupational skin diseases are rare. Occupational hand dermatitis is the most frequent condition, and an incidence of 0.7–1.5 cases per 1,000 per year as a gross average is estimated (table 2) [11]. The incidence rates are very different between trades (table 3) [12]. Hairdressers are most frequently affected by occupational hand dermatitis. In a questionnaire study in the UK, 38.6% of responding hairdressers reported prevalent hand dermatitis with trainees and persons working 2 years or less in the profession having a significantly increased risk [13].

Consequences of Occupational Hand Dermatitis

Occupational hand dermatitis tends to be a chronic disease, leading to disability, job loss and extended need of dermatological therapy. In a 12-year

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Table 1. Spectrum of occupational skin diseases Infectious diseases [2] Viral infections Parapox virus infections (orf, milker’s node) Poxvirus infections (vaccinia) Human papillomavirus infections (butchers’ warts) Herpesvirus infections Bacterial infections Tuberculosis (in anatomists, pathologists) Atypical mycobacteriosis (in fishermen) Anthrax (in farmers, butchers) Fungal infections (deep mycosis in farmers) Parasitic infections Contact dermatitis Irritant contact dermatitis [3] Allergic contact dermatitis [4] Urticaria [5] Allergic contact urticaria Nonimmunological contact urticaria Connective tissue disorders [6] Scleroderma in silicosis patients Acne [7] Oil acne Halogen acne Pigment changes [8] Hypopigmentations Hyperpigmentations Tumors [9] Nonmelanoma skin cancer Aggravation of preexisting skin disorders [10] Atopic dermatitis Psoriasis

follow-up study in Sweden, only 28% of persons notified with occupational skin disease in 1987 considered themselves healed, and 82% had performed occupational changes. Fifteen percent had left the labor market due to unemployment or disability pension [14]. A recent prognostic study from Denmark found especially patients with atopy to be at risk for a poor prognosis [15]. The economic impact of occupational contact dermatitis is estimated to be very high considering the direct cost of medical care, workers’ compensation or disability payments, indirect costs associated with lost workdays and loss of

Skin Protection in the Prevention of Skin Diseases

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Table 2. Incidence of notified occupational skin diseases per 1,000 per year (data from Diepgen [11]) USA

Bavaria Cooks, bakers, etc. Hairdressers

Services Hospitals Machinery Meat products Grand average of total workforce

0.6 3.1 2.3 5.7 0.8

Nurses Mechanics

Denmark 6.0 24.0 1.5 3.4 0.8

Cooks, bakers Hairdressers Cleaners/household Nurses Mechanics Meat/fish industry

10.0 11.0 13.2 1.5 6.6 10.1 0.8

Table 3. Incidence rate of occupational skin diseases per 10,000 workers per year (data from the Northern Bavaria population-based study [12]) Hairdressers and barbers Bakers Florists Pastry cooks Tile setters and terrazzo workers Electroplaters Solderers Dental technicians Machinists Metal surface processors Healthcare workers Cooks Painters and varnishers Metal processors Mechanics Assemblers Construction and cement workers Leather industry and fur processors Housekeepers, restaurant business and cleaners Food-processing industry and butchers Wood processors Locksmiths and automobile mechanics Unskilled workers Electrical industry

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97.4 33.2 23.9 20.6 19.0 13.3 10.9 10.8 9.0 9.0 7.3 6.6 6.6 6.4 6.0 5.8 5.4 5.0 3.4 2.9 2.6 2.2 2.1 1.2

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productivity, costs of occupational retraining, and costs attributable to the effects on the quality of life [11]. The impact of occupational hand dermatitis on quality of life is significant. A population-based quality of life study from Denmark on 758 persons with occupational eczema showed a reduction of quality of life depending on the severity of the skin diseases and the socioeconomic status [16].

Risk Factors of Occupational Contact Dermatitis

The development of occupational contact dermatitis depends on a combination of endogenous (individual susceptibility) and exogenous factors (exposure). Except for an exposure to strong sensitizing substances, occupational contact dermatitis usually develops in steps, frequently starting with atopic hand dermatitis, followed by irritant dermatitis leading to sensitization and eventually allergic contact dermatitis (multistep eczema). Therefore, susceptibility to irritant dermatitis is of high importance in the natural history of occupational contact dermatitis. The skin of different individuals differs in susceptibility to irritation in a remarkable manner, and a number of individual factors influencing the development of irritant dermatitis that have been identified include age, genetic background, anatomical region exposed and preexisting skin disease. Although experimental studies did not support any sex difference of irritant reactivity, females turned out to be at risk in some epidemiological studies. Probably increased exposure to irritants at home, caring for children under the age of 4 years, lack of a dishwashing machine and preference of high-risk occupations contribute to the higher incidence of irritant contact dermatitis in females. Recent population-based studies correcting for these factors could not confirm a gender-dependent increase in risk [17]. The best established individual risk factor that turned out of several studies about occupational hand eczema is atopic dermatitis [18–20]. Age is related to irritant susceptibility in so far as irritant reactivity declines with increasing age. This is true not only for acute but also for cumulative irritant dermatitis [21]. Fair skin, especially skin type I, is supposed to be the most reactive to all types of irritants, and black skin is the most resistant [22]. The clinical manifestation of irritant contact dermatitis is also influenced by type and concentration of irritant, solubility, vehicle, and length of exposure [3], as well as temperature and mechanical stress. During the winter months, low humidity and low temperature decrease the water content of the stratum corneum and increase irritant reactivity [23].


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Table 4. Prevention strategies in occupational contact dermatitis Technical means Encapsulation of irritants/allergens Exchange of irritants/allergens Organizational means Optimization of workflow to reduce exposure to irritants/allergens Personal skin protection Protective garments Gloves Skin protection products Education Awareness of skin hazards Motivation for avoidance and use of skin protection

Prevention of Occupational Contact Dermatitis

The severe impact of the disease on quality of life, the high costs of retraining and the poor employment prospects once workers lose their job highlight the need for effective primary and secondary preventive measures in occupational contact dermatitis. Successful prevention programs focus not on one aspect, but they employ a combination of measures (table 4). The first step in a prevention program should always be a thorough risk assessment of the workplace. Ideally, the skin exposure to irritants and allergens can be reduced or even removed by technical means. By organizational means, the exposure to damaging substances can be controlled. For instance, if shampooing in hairdressers’ salons is not only limited to one employee (usually the apprentice) but is spread evenly over the whole workforce, the individual exposure time may be limited to acceptable levels. Personal skin protection measures are of great importance when skin contact with irritant or sensitizing substances cannot be avoided. The correct use of personal skin protection measures requires educational efforts; at the same time, the awareness of skin hazards at the workplace should be increased, and the motivation to take responsibility for one’s own skin health should be fostered. The hairdressers’ trade is a paradigm for successful preventive interventions in occupational dermatology. During the 1990s, two legislative regulations concerning hairdressers came into effect in Germany [Technical Rules for Hazardous Substances 530 ‘Hairdressing trade’ and 531 ‘Endangerment of the skin by work in the wet environment (wet work)’]. At the same time, glyceryl

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Cases per 10,000 insured people

250 200 150 100 50 0 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 Year

Fig. 2. Annual incidence (95% confidence interval) of hairdressers with a stated occupational skin disease (from Dickel et al. [24]).

Identification of employees with OD No. 5101 by the occupational insurer

Exposure analysis by the technical expert of the occupational insurer at the individuals’ working place Recording of the sequence of occupational activities and exposures Saving samples Controlling the adherence to legal regulations

Initial consultation of the employee at the OSD clinic Personal and occupational history Re-evaluation and complementation of previous diagnoses and therapies Documentation of the clinical features of the hand dermatitis Preparation of individual concepts for skin protection, cleaning and care Instruction of the affected insured persons

Skin care and protection seminars Teaching of basic medical aspects concerning the skin Teaching of technical-organizational preventative measures Hands-on training in skin care, cleaning and protection Evaluation of the individual concepts for skin protection, cleaning and care

Follow-up consultations at intervals of 3–6 months Controlling efficacy of the recommended prevention measures and therapy

Fig. 3. Skin disease prevention program in the baking, hotel and catering industries [25]. OD ⫽ Occupational disease; OSD ⫽ occupational skin disease.


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5 Fig. 4, 5. Examples of occupational hand dermatitis. 4 Irritant and secondarily allergic contact eczema due to cutting oils; identified allergen: monoethanolamine. 5 Eczema of the fingertips due to atopy and irritation.

monothioglycolate as an important occupational allergen was removed from the market. The German occupational insurance for the hairdressers’ trade (BGW) supported dermatological and educational secondary intervention programs to prevent cases with minor hand dermatitis to progress leading to loss of job and need of retraining. As a result, the annual incidence of cases of hand dermatitis in hairdressers fell significantly from 194 to 18 cases per 10,000 workers between 1990 and 1999 (fig. 2) [24]. Similar positive results were reported from interventions in other trades, such as in the food industry (fig. 3) [25]. Considering these experiences of the last decade, skin protection and skin care measures can be introduced successfully in the daily routine of a skin risk occupation (fig. 4, 5), and high uptake and maintenance rates can be achieved. As the efficacy of preventive intervention programs in occupational dermatology has been proven in an evidence-based approach, it is only consequent that evidence-based proof of efficacy and safety is also demanded for skin protection agents to be used in these programs. The guideline of the German Working Group for Occupational and Environmental Dermatology

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(ABD) for occupational skin protection therefore explicitly demands the testing of these products in practice-oriented controlled clinical studies in humans [26].

References 1 2 3

4

5

6

7

8

9 10

11 12 13 14 15 16

17 18

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HVBG: Geschäfts- und Rechnungsergebnisse der gewerblichen Berufsgenossenschaften, St. Augustin. 2006. Lachapelle JM: Biologic causes of occupational dermatoses; in Kanerva L, Elsner P, Wahlberg JE, Maibach HI (eds): Handbook of Occupational Dermatology. Heidelberg, Springer, 2000, pp 179–192. Wigger-Alberti W, Elsner P: Contact dermatitis due to irritation; in Kanerva L, Elsner P, Wahlberg JE, Maibach HI (eds): Handbook of Occupational Dermatology. Heidelberg, Springer, 2000, pp 99–110. Ale S, Maibach HI: Operational definition of occupational allergic contact dermatitis; in Kanerva L, Elsner P, Wahlberg JE, Maibach HI (eds): Handbook of Occupational Dermatology. Heidelberg, Springer, 2000, pp 344–350. Ale SI, Maibach HI: Occupational contact urticaria; in Kanerva L, Elsner P, Wahlberg JE, Maibach HI (eds): Handbook of Occupational Dermatology. Heidelberg, Springer, 2000, pp 200–216. Haustein UF, Haupt B: Occupational connective tissue disorders; in Kanerva L, Elsner P, Wahlberg JE, Maibach HI (eds): Handbook of Occupational Dermatology. Heidelberg, Springer, 2000, pp 295–314. McDonnell JK, Taylor JS: Occupational and environmental acne; in Kanerva L, Elsner P, Wahlberg JE, Maibach HI (eds): Handbook of Occupational Dermatology. Heidelberg, Springer, 2000, pp 225–233. Wattanakrai P, Miyamoto L, Taylor JS: Occupational pigmentary disorders; in Kanerva L, Elsner P, Wahlberg JE, Maibach HI (eds): Handbook of Occupational Dermatology. Heidelberg, Springer, 2000, pp 280–294. Diepgen TL, Drexler H: Skin cancer and occupational disease. Hautarzt 2004;55:22–27. Kalimo K, Lammintausta K: The role of atopy in working life; in Kanerva L, Elsner P, Wahlberg JE, Maibach HI (eds): Handbook of Occupational Dermatology. Heidelberg, Springer, 2000, pp 356–359. Diepgen TL: Occupational skin-disease data in Europe. Int Arch Occup Environ Health 2003;76: 331–338. Dickel H, Kuss O, Blesius CR, Schmidt A, Diepgen TL: Occupational skin diseases in Northern Bavaria between 1990 and 1999: a population-based study. Br J Dermatol 2001;145:453–462. Perkins JB, Farrow A: Prevalence of occupational hand dermatitis in UK hairdressers. Int J Occup Environ Health 2005;11:289–293. Meding B, Lantto R, Lindahl G, Wrangsjo K, Bengtsson B: Occupational skin disease in Sweden – A 12-year follow-up. Contact Dermatitis 2005;53:308–313. Cvetkovski RS, Zachariae R, Jensen H, Olsen J, Johansen JD, Agner T: Prognosis of occupational hand eczema: a follow-up study. Arch Dermatol 2006;142:305–311. Cvetkovski RS, Zachariae R, Jensen H, Olsen J, Johansen JD, Agner T: Quality of life and depression in a population of occupational hand eczema patients. Contact Dermatitis 2006;54: 106–111. Bryld LE, Hindsberger C, Kyvik KO, Agner T, Menne T: Risk factors influencing the development of hand eczema in a population-based twin sample. Br J Dermatol 2003;149:1214–1220. Berndt U, Hinnen U, Iliev D, Elsner P: Role of the atopy score and of single atopic features as risk factors for the development of hand eczema in trainee metal workers. Br J Dermatol 1999; 140:922–924. Coenraads PJ, Diepgen TL: Risk for hand eczema in employees with past or present atopic dermatitis. Int Arch Occup Environ Health 1998;71:7–13.


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Meding B, Swanbeck G: Predictive factors for hand eczema. Contact Dermatitis 1990;23: 154–161. Suter-Widmer J, Elsner P: Age and irritation; in van der Valk PGM, Maibach HI (ed): The Irritant Contact Dermatitis Syndrome. Boca Raton, CRC Press, 1994, pp 257–261. Berardesca E, Maibach HI: Ethnic skin: overview of structure and function. J Am Acad Dermatol 2003;48:S139–S142. Uter W, Gefeller O, Schwanitz HJ: An epidemiological study of the influence of season (cold and dry air) on the occurrence of irritant skin changes of the hands. Br J Dermatol 1998;138:266–272. Dickel H, Kuss O, Schmidt A, Diepgen TL: Impact of preventive strategies on trend of occupational skin disease in hairdressers: population based register study. BMJ 2002;324:1422–1423. Bauer A, Kelterer D, Bartsch R, Pearson J, Stadeler M, Kleesz P, Elsner P, Williams H: Skin protection in bakers’ apprentices. Contact Dermatitis 2002;46:81–85. Wigger-Alberti W, Diepgen TL, Elsner P, Korting H, Kresken J, Schwanitz HJ: Beruflicher Hautschutz. Dermatol Beruf Umwelt 2003;51:D15–D21.

Peter Elsner, MD Department of Dermatology, Friedrich Schiller University Erfurter Strasse 35 DE–07740 Jena (Germany) Tel. ⫹49 3541 937418, Fax ⫹49 3541 937350, E-Mail [email protected]

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Schliemann S, Elsner P (eds): Skin Protection. Curr Probl Dermatol. Basel, Karger, 2007, vol 34, pp 11–18

Galenical Principles in Skin Protection Jin Zhanga, Eric W. Smitha, Christian Surberb a

College of Pharmacy, University of South Carolina, Columbia, S.C., USA; bInstitute of Hospital Pharmacy, Department of Dermatology, and Department of Pharmacy, University of Basel, Basel, Switzerland

Abstract In recent years, dermatological formulations have progressed from an empirical art form to a more scientific discipline. Historically, clinical observations and controlled studies have demonstrated the markedly variable drug delivery potential of different topical vehicles. More recently, research efforts have focused on the role of drug uptake through appendages and the use of penetration enhancement systems (chemical and physical) to force chemicals through the skin. Much of this research has concerned the delivery of active drug moieties from specifically designed delivery vehicles or transdermal therapeutic systems to treat dermatological or systemic conditions. The complexity of topical dosage forms and of desired skin protection properties makes it difficult to formulate general guidelines for the development and the use of protective topical dermatological formulations. At present it appears that a product is designed for each specific environmental condition or threat. It seems unlikely that this will change until there are considerable advances in the engineering technology of topical formulations. At this point we still do not have a complete understanding of the function of topical products – especially the role of emerging theories like the ‘metamorphosis’ of the vehicle after application to the skin. In the immediate future it seems that totally occlusive vehicles will continue to be used to protect the skin, until chemical penetration enhancer or particulatescavenging topical vehicles have been perfected and their toxicity has been fully evaluated. Copyright © 2007 S. Karger AG, Basel

Topical Formulations

The use of cooling or soothing substances to treat skin conditions has been recorded throughout history. However, only in relatively recent years has dermatology progressed from an empirical art form to a more scientific discipline. The knowledge about drug uptake through the skin is still in its infancy. In the last century, some scientists declared the skin to be totally impermeable [1], but

clinical observations soon dispelled this theory [2] and data on the variable delivery potential of different vehicles soon emerged [3]. Observations confirmed that lipid-soluble chemicals were more likely to penetrate the skin than water-soluble agents, and that ionized species penetrate the skin poorly. Research efforts have also focused on the role of drug uptake through appendages and the use of an electrical potential difference to force charged chemicals through the skin [4–8]. Much of this research has concerned the delivery of active drug moieties from specifically designed delivery vehicles or transdermal therapeutic systems to treat dermatological or systemic conditions [9, 10] – and spurned a branch of pharmaceutical industry that thrives today [11–14]. At this point we still do not have a complete understanding of the function of topical products – especially the role of emerging theories like the ‘metamorphosis’ of the vehicle after application to the skin. However, scientists have begun to use this knowledge to develop vehicles that may be used to protect the skin from the environment.

Skin Protection Strategies

Skin protection strategies with topical agents range from simple emollient products (intended to retain the hydration and homeostasis of the skin) through the myriad of topical therapeutic agents intended to treat infections or dermatoses to the contemporary formulations intended to be potent barriers to external chemicals for use in potentially harmful environments (e.g., in agriculture or warfare). Each strategy requires specific formulation attributes: lipid and moisture delivery, drug delivery or generalized occlusion of large body surfaces, respectively. Treatment by topical (local) application allows intimate contact between the emollient formulation (drug delivery vehicle) and the target tissue – an ideal scenario for treating skin xerosis or dermatoses. Drug delivery to or through the skin is aimed at targeting the drug to three anatomical locations: the skin, the deeper tissues and organs, or for systemic delivery. On the other end of the spectrum, total occlusion of the skin with formulations intended to prevent chemical penetration [15] has added difficulties in that the occlusive vehicle usually also blocks sweat evaporation, disturbing the homeostatic processes of the skin.

The Galenical Vehicle

Topical galenicals vary in physical and chemical nature from powders through semisolids to liquids. Skin protection and dermatological products

Zhang/Smith/Surber

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Active drug e.g. retinoids, corticosteroids

Vehicle Ingredients Structural matrix agents: e.g. hydrocarbons, alcohols, celluloses, silicones Auxiliary agents: e.g. benzoic acid, phenols, benzalkonium chloride, butylated hydroxytoluene

Principle of structural matrix Monophasic systems: e.g. ointments Biphasic systems: e.g. creams Tri-(multi-)phasic systems: e.g. cream pastes

Fig. 1. Principle of topical preparations: example of a topical preparation comprised of individual ingredients that form a structural matrix.

rarely consist of a single chemical entity; almost invariably there are several chemicals formulated together into a stabilized matrix that behaves in a specific manner when applied to the skin. This complex matrix of chemicals, of specific and critical physical and chemical properties, is now known as the vehicle (fig. 1). In a typical formulation, the active principle is incorporated with several inactive ones – although the vehicle constituents may not have intentional pharmacological effects, they may have profound effects on delivery and skin residency of the active principle. Modern vehicles are meticulously engineered for their intended purpose in terms of stability, compatibility, delivery and enduser acceptability. Thus the ‘ideal’ vehicle should fulfill many physical, chemical, pharmaceutical and sensory criteria.

The Vehicle Effect

In classical dermatological treatment, the ideal vehicle is believed to be inert in the therapeutic process of drug delivery. However, both clinicians and consumers expect that the topical product should provide appealing sensory effects in addition to drug delivery. These sensory properties are provided by the vehicle constituents. In skin protection strategies, the topical vehicle often occupies a position of even greater importance in terms of the ‘protective’ effect that it must afford the skin. Protective galenicals usually must supply some form of physical barrier as well as the normal desirable properties of e.g. a cooling sensation or spreadability demanded by consumers. These properties appear to be on opposite ends of the spectrum: a formulation that is easy to apply and

Galenical Principles

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Metamorphosis

%

Water

80

Oil

15

Tensid

5

Excipients

6h 32˚C 60% RH

O/W cream in primary container

%

4

O/W cream immediately after application

Time

Excipients

Vehicle on the skin

Conditions

Vehicle in the primary container

72 24

O/W cream approximately 3 min after application

Fig. 2. In clinical situations most dermatological vehicles (structural matrix and ingredients) undergo considerable changes after they have been removed from the primary container and are applied to the skin. Subsequently, the initial structural matrix of the vehicle will most likely change during and after application of the product and/or evaporation of ingredients. Evaporative concentration first leads to saturation and then to supersaturation that, although generally a transient condition, results in deposition exceeding that achievable with a saturated solution. O/W ⫽ Oil-in-water; RH ⫽ relative humidity.

which ‘vanishes’ into the skin on inunction, yet retains a formidable, superficial, physicochemical barrier to the environment to protect the skin to which it has been applied. These additional performance effects must be engineered into the final product by utilizing appropriate ingredients and compounding strategies. In this process, it is difficult to assign a specific vehicle effect to a particular ingredient or structural feature of a formulation, keeping in mind that the structural matrix changes once it is applied to the skin (metamorphosis; figs. 2, 3). In skin protection formulations, this metamorphosis is critically important because it is the final form of the vehicle, after its transformation, that must form the substantive barrier for the long-term protection of the skin. The vehicle metamorphosis is a complex equilibrating process that results from several interactions between the drug, the formulation and the skin. Vehicle-drug interactions increase the thermodynamic activity of the drug in the vehicle, usually as volatile components evaporate from the formulation after spreading. Vehicle constituents may be absorbed by the skin or may be lost to the atmosphere – this loss must be designed in such a way as to retain the protective nature of the vehicle after metamorphosis. Typically the formulation constituents that contribute most to the physicochemical protective function (such as lipids, silicones or nanostructures)

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a

b

c Fig. 3. Micrographs of commercial corticosteroid lotion metamorphosis showing appearance of the physical vehicle matrix at time 0 (a), 120 (b) and 240 (c) min (thin film of formulation spread on glass slide and exposed to ambient conditions).

are minimally lost following application. The substantivity of these chemicals on the skin surface constitutes the physical barrier for protection.

The Choice of Vehicle

The capability of topical vehicles to alter the physical and chemical status of the skin can be attributed to their influence on the lipid and water content of the skin [16–18]. Vehicles with hydrophilic properties are easily removed from the skin but may be suitable for relatively simple protection strategies such as sunscreen formulations. Here the sunscreen agent must simply be spread over the surface of the skin, often with little regard paid to substantivity. On the other


15

hand, vehicles with lipophilic properties are more substantive and, therefore, more suitable for broad-spectrum protective products. Furthermore, once formulations include silicone derivatives or particulate matter, the formulations become physically stronger (and even more protective). However, with an increase in protective potential there is also usually an increase in occlusiveness and usually stickiness of the skin to which the product is applied. Vehicles that are the best physical barriers to chemicals in the environment are also the best barriers to the evaporation of endogenous sweat. The use of these products is usually associated with a heating or flushing of the skin, especially in environments where the user is physically active (e.g. agriculture or military). The stickiness of the formulation after application creates an additional, uncomfortable sensation that aggravates the flushing reaction. These are highly undesirable properties that induce a use reluctance or avoidance on the part of the user. These adverse properties may be exacerbated by the environmental conditions under which the topical products will be used. Formulation and testing in the controlled climatic conditions of the laboratory [19] often have little bearing on the field use of protective formulations, where temperatures and atmospheric humidity may be much higher (or lower). The physical activity of the end user is often overlooked when assessing products at the developmental stage. Wherever possible the real conditions of usage of the topical preparation should be borne in mind when formulating the vehicle. In all cases the protective function of the formulation must be foremost on the list of design criteria. A formulation intended to treat xerosis must improve the suppleness of the skin, rehydrate the strata and supply the necessary lipids to restore the emollient barrier. Sunscreen products must supply the correct combination of chemical and physical UV-absorbing/blocking species to prevent light-induced damage to the epidermal strata. Chemical protectants must maintain a polymer-like barrier that markedly slows the diffusion of environmental chemicals to the stratum corneum, without the barrier itself acting as a depot for the chemicals that can produce prolonged chemical delivery to the skin once the immediate exposure has passed.

Future Topical Vehicles

Groundbreaking discoveries continue in the design technology for topical vehicles. Chemical and physical strategies are constantly being refined to extend the control of the release and penetration of drugs and chemicals into the skin, or the prevention thereof. In the last decade, terms like vesicular carriers, liposomes [20], transfersomes, ethosomes and microemulsions [21, 22] have become commonplace in dermatopharmaceutical research and development.

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Microsponge delivery systems appear to have some promise in the skin protection arena in that these formulation structures, although primarily used as reservoirs for releasing active ingredients over a prolonged period of time, appear capable of absorbing undesirable chemicals from the skin. Solid lipid nanoparticles equally show some promise of success for topical and cosmetic applications. These particles are composed of biocompatible lipids that often form an occlusive film on the skin surface, reducing transepidermal water loss. The beneficial properties of solid lipid nanoparticles are due to the solid matrix structures of the particles within the skin. Even in very basic applications, solid lipid nanoparticles have apparent physical sunscreen potential by scattering UV light efficiently [23]. As protection environments are identified, researchers will use the technology of these topical vehicle components to address the protection requirements. Clearly there is a modern trend away from the totally occlusive polymer vehicles to more carefully engineered matrices that may utilize nanostructure or penetration retarder technologies to prevent the ingress of unwanted environmental agents. Conclusions

The complexity of this type of dosage form and of the skin protection properties that are desirable makes it difficult to formulate general guidelines for the development and the use of protective topical dermatological formulations. At present it appears that a product is designed for each specific environmental condition or threat to the exposed individual [24, 25]. It seems unlikely that this will change until there are considerable advances in the engineering technology of topical formulations. However, the strides that have been made recently on topical vehicle research are encouraging. In the immediate future it seems that totally occlusive vehicles will continue to be used to protect the skin, until chemical penetration enhancer or particulate-scavenging topical vehicles have been perfected, and their toxicity has been fully evaluated. References 1 2 3 4 5

Fleischer R: Untersuchungen über das Resorptionsvermögen der menschlichen Haut. Erlangen, Verlag von Eduard Besold, 1877. Bourget E: Über die Resorption der Salicylsäure durch die Haut und die Behandlung des acuten Gelenkrheumatismus. Ther Monatsh 1893;7:531–539. Schwenkenbecher A: Das Absorptionsvermögen der Haut. Arch Anat Physiol 1904;I/II:121–127. Reynolds HJ: Eine Methode zur Behandlung der Pilzkrankheiten der Haut. Monatsh Prakt Dermatol 1887;6:945–949. Leduc S: Introduction des substances médicamenteuses dans la profondeur des tissus par le courant électrique. Ann Electrobiol 1900;3:545–560.


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6 7 8 9 10 11 12 13 14 15 16 17 18 19

20 21 22

23 24 25

Turrell WJ: The therapeutic action of the constant current. Proc R Soc Med 1921;14:41–52. Licht S: History of electrotherapy; in Licht S (ed): Therapeutic Electricity and Ultraviolet Radiation. New Haven, Elisabeth Licht Publisher, 1967, pp 1–70. Chien YW, Banga AK: Iontophoretic (transdermal) delivery of drugs: overview of historical development. J Pharm Sci 1989;78:353–354. Porjé IG: En studie över sorbiddinitratets perkutana resorption. Svenska Läkartid 1946;44:923–925. Davis TA, Wiesel BH: The treatment of angina pectoris with a nitroglycerin ointment. Am J Med Sci 1955;230:259–263. Zaffaroni A: Therapeutic adhesive patch. US Patent 3,699,963. 1972, 18. Zaffaroni A: Bandage for the administration of drug by controlled metering through microporous materials. US Patent 3,797,494. 1974, 8. Shaw J, Urquhart J: Programmed, systemic drug delivery by the transdermal route. Trends Pharm Sci 1980;1:208–211. Urquhart J: Rate-controlled drug dosage. Drugs 1982;23:207–226. Zhai H, Willard P, Maibach HI: Evaluating skin protective materials against contact irritants and allergens. Contact Dermatitis 1998;38:155–158. Gabard B: Testing the efficacy of moisturizers; in Elsner P, Berardesca E, Maibach HI (eds): Bioengineering of the Skin: Water and Stratum Corneum. Boca Raton, CRC Press, 1994, pp 147–170. Lodén M: The increase in skin hydration after application of emolients with different amounts of lipids. Acta Derm Venereol (Stockh) 1992;72:327–330. Choudhury TH, Marty JP, Orecchini AM, Seiller M, Wepierre J: Factors in the occlusivity of aqueous emulsions: influence of humectants. J Soc Cosmet Chem 1985;36:255–269. Grimm W: International harmonization of stability tests for pharmaceuticals. the ICH tripartite guideline for stability testing of new drug substances and products. Eur J Pharm Biopharm 1995;41:194–196. Meidan V, Alhaique F, Touitou E: Vesicular carriers for topical delivery. Acta Technol Legis Med 1998;9:1–6. Lehmann L, Keipert S, Gloor M: Effects of microemulsions on the stratum corneum and hydrocortisone penetration. Eur J Pharm Biopharm 2001;52:129–136. Begona Delgado-Charro M, Iglesias-Vilas G, Blanco-Méndez J, Arturo López-Quintela M, Marty JP, Guy RH: Delivery of a hydrophilic solute through the skin from novel microemulsion systems. Eur J Pharm Biopharm 1997;43:37–42. Wissing SA, Muller RH: Solid lipid nanoparticles as carriers for sunscreens: in vitro release and in vivo skin penetration. J Control Rel 2002;81:225–233. Cohen J: Microbicide shuts the door on HIV. Science 2004;306:387. Ledermann M, Veazey R, Offord R, Mosier D, Dufour J, Mefford M, Piatak M, Lifson J, Salkowitz J, Rodriguez B, Blauvelt A, Hartley O: Prevention of vaginal SHIV transmission in rhesus macaques through inhibition of CCR5. Science 2004;306:485–487.

Prof. Dr. phil. nat. Christian Surber Institut für Spital-Pharmazie, Universitätsspital Basel Spitalstrasse 26 CH–4031 Basel (Schweiz) Tel. ⫹41 61 265 2905, Fax ⫹41 61 265 8875, E-Mail [email protected]

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Efficacy and Safety of Skin Protection Schliemann S, Elsner P (eds): Skin Protection. Curr Probl Dermatol. Basel, Karger, 2007, vol 34, pp 19–32

Using Skin Models to Assess the Effects of a Pre-Work Cream Methodological Aspects and Perspective of the Industry

A. zur Mühlena, A. Klotza, P. Allef a, S. Weimansb, M. Veegera, B. Thörnera, J.-O. Eichlerb a

Degussa, Stoko Skin Care, and bLaboratory for Toxicology and Ecology, Degussa Services Krefeld, Krefeld, Germany

Abstract Background: There is a basic necessity to understand the mechanisms of the protective effects of pre-work creams. Additionally a lot of workplace-related irritants cannot be tested with the existing in vivo methods due to their toxicological profile. As a consequence, there is a need for additional in vitro models for testing pre-work creams. Objective: An in vitro skin model test was developed to evaluate the protective mechanism of a pre-work cream. Methods: The efficacy of 3 products was assessed by an in vivo test (repetitive occlusive irritation test) and then 3-dimensional skin model tests were carried out. Results: In vivo test results demonstrate that the best protection against sodium dodecyl sulfate is offered by a multiple emulsion. In the case of a skin model test, sodium dodecyl sulfate led to cell damage, an increase in proinflammatory markers and some barrier lipids. The pre-work cream increased the content of skin lipids, without inducing irritation or cell death. Conclusion: Skin models support the understanding of the interaction of irritants and pre-work creams. Because they are in vitro models, there are no limitations regarding the selection of irritants, which offers numerous opportunities to test a broad range of workplace irritants. Copyright © 2007 S. Karger AG, Basel

Allergic contact dermatitis and irritant contact dermatitis are the common manifestations of occupational skin diseases. This is often linked to mechanical stress and contact with substances which result in damage to the skin barrier. Apart from the real personal problems of those affected, skin diseases also have

a major economic impact because of the loss of working hours, curative treatment, rehabilitation and retraining programs [1]. One of the effective measures and a common practice to reduce or eliminate the cutaneous exposure to hazardous substances are pre-work creams applied before and during work. The protection can be achieved by a pure physical effect – meaning the hazard cannot penetrate the protective layer – and by a regenerative effect of reinforcing the natural barrier function of the skin [2, 3]. Various in vitro and in vivo tests to evaluate the efficacy of pre-work creams are described in the literature [4]. In spite of all efforts, to date no really standardized method for the evaluation of pre-work creams exists. Several reasons account for this situation: a broad range of workplace materials and potential areas of applications for pre-work creams. Especially for the testing of water-based irritants, an appropriate assessment method for protective creams in vivo is the repetitive occlusive irritation test (ROIT) [5]. Such in vivo models have to be seen as the gold standard for the efficacy testing of pre-work creams. However, they also have limitations such as ethical restrictions in the testing of certain irritants and workplace substances. Additionally, this model gives an indication about the efficacy of pre-work creams but does not allow any insights into the mechanism behind. To identify whether the protective effect is caused by a physical or by a regenerative effect, skin biopsies or suction blisters from humans or animals would be necessary. However, due to ethical reasons and especially because of the ban of animal testing in the European Union for cosmetics, this is not applicable. In vitro models based on exercised animal or human skin cannot represent intact human skin, as pretreatment leads to alterations and limited viability following imperfect biochemical reaction to external influences. Other in vitro models like the bovine udder skin model allow testing on fully viable skin for approximately 8 h [6]. None of these in vitro models allow long-term testing and are therefore limited to stronger irritants with short-term effects. Pre-work creams are intended to prevent cumulative irritation, but it is impossible to mimic cumulative effects in these in vitro models. Moreover animal skin differs significantly from human skin [7]. Therefore the main disadvantage of these models is that they cannot reflect realistic workplace conditions. An alternative are 3-dimensional skin models. These are human epidermis reconstituted in vitro using chemically defined tissue culture medium. Advantages are a good correlation between the structure and composition of 3-dimensional skin models and epidermis of human skin, the opportunity of analyzing the whole epidermis and the evaluation of biochemical parameters like release of proinflammatory markers and determination of cytotoxicity

zur Mühlen/Klotz/Allef/Weimans/Veeger/Thörner/Eichler

20

caused by penetrating substances [8, 9]. Regarded as in vitro method, there is no restriction by ethical or legal aspects in the selection of irritants or using of invasive methods. This means a broad range of workplace irritants can be tested [10]. With a lifetime up to 3 weeks, also long-term effects of products and irritants can be evaluated. This allows a good simulation of the real workplace situation. However, some differences to human skin have been noticed, such as the free fatty acid content and profile and the lateral packing of stratum corneum lipids [11–13]. It was speculated that these differences are responsible for the impaired barrier function of 3-dimensional skin models leading to penetration rates 5- to 50-fold higher compared to human skin [14]. So far 3-dimensional skin models are mainly used to investigate skin penetration and irritancy of single substances. The aim of this study was to develop and to use a new 3-dimensional skin model test design to analyze the mode of action of a pre-work cream. In a first step, the efficacy of 3 products was investigated by using the ROIT method. In a second step, 3-dimensional skin model tests were carried out in order to elucidate the mode of action of the product which proved to be most effective in the in vivo test.

Materials and Methods Formulations The ingredients of the formulations are listed according to the declaration of the International Nomenclature of Cosmetic Ingredients. Water-in-oil emulsion: aqua, paraffinum liquidum, panthenol, cera microcristallina, ceresin, glycerin, polyglyceryl-3-diisostearate, isopropyl palmitate, tocopheryl acetate, lanolin alcohol, magnesium sulfate, phenoxyethanol, diammonium citrate, aluminum stearates, citric acid, sodium citrate, potassium sorbate, magnesium stearate, perfume. Petrolatum: petrolatum alone. Multiple (water/oil/water) emulsion: aqua (water), paraffinum liquidum, isopropyl palmitate, cetearyl alcohol, polyglyceryl-2-dihydroxystearate, propylene glycol, cetearyl glucoside, C12–15 alkyl benzoate, stearic acid, bisabolol, petrolatum, PEG-30 dipolyhydroxystearate, PEG-40 stearate, Hamamelis virginiana, alcohol denat. Repetitive Occlusive Irritation Test Fifteen healthy test subjects (6 males, 9 females, ages 18–49 years, average age 25.7 years) were included in this study after obtaining informed consent. The subjects were instructed not to use moisturizers on the volar forearms during and 8 h before the study, and to avoid direct contact with detergents during the study. The test was conducted following the procedure described elsewhere [15]; 200 ␮l 0.5% sodium dodecyl sulfate (SDS, min. 99.0%, Merck, Darmstadt, Germany) was used as irritant.

Skin Models to Assess Pre-Work Cream

21

Measurement of the transepidermal water loss and visual assessment according to the scoring of Frosch and Kligman was carried out every morning before the first application and 15–18 h after the last application on day 5. Transepidermal water loss as an indicator of the epidermal barrier function was measured with the Tewameter TM210 (Courage & Khazaka, Cologne, Germany) following published guidelines [16]. Data of the transepidermal water loss measurement were interpreted by means of linear regression to avoid interpretation errors due to missing data caused by dropouts [5]. Statistical evaluation was performed with the Wilcoxon matched-pairs signed-rank test for the visual score data and the Student t test for transepidermal water loss results. Three-Dimensional Skin Culture Tests Pretreated [17] Epiderm-200-HCF skin cultures (Mattek Corp., Ashland, Mass., USA) were treated with 0.2% SDS (min. 99.0%, Merck) prepared in phosphate-buffered saline (Biochrom, Berlin, Germany) for 40 min. Excess of the SDS was removed by gentle washing of cultures 3 times with phosphate-buffered saline. Medium was exchanged again; skin cultures were elevated on EPI stands and 5 ml EPI-100-MM was added. Afterwards about 5 mg of the multiple emulsion was applied onto the surface of the skin cultures using a sterile swab. Cell culture supernatants were collected 4, 7, 24 and 48 h after the start of the experiment. Three untreated 3-dimensional skin models were used as control. Additionally, 3 skin models were only treated with the pre-work cream. This should also give insights as to what will happen after the cream has been applied. Additionally these data compared to the data obtained with pretreated skin models should serve to circumvent misinterpretations. Cell viability expressed by lactate dehydrogenase (LDH), inflammatory mediators interleukin (IL) 1␣ and prostaglandin E2 (PGE2) as well as skin lipid analysis [17] have been selected to characterize the effects of the pre-work cream. At least 3 tissue cultures per test condition were analyzed. Thus, all parameters were analyzed at least in triplicate. The data presented are expressed as means ⫾ SD. Statistical significance was determined by ANOVA single factor test. Differences were considered significant for at least p ⬍ 0.1.

Results and Discussion

In the ROIT, all 3 test formulations significantly reduced skin irritation (visual score data not shown) and the transepidermal water loss increase caused by 0.5% SDS. The best protection was offered by the multiple emulsion (water/oil/water), followed by petrolatum and the water-in-oil formulation (fig. 1). In theory the protective effect of an emulsion or ointment can be based on a purely physical effect. That means the compounds of the formulations are building up a protecting film on the skin, which cannot be penetrated by the specific hazardous substance. Therefore oil-in-water emulsions are recommended against lipophilic irritants and water-in-oil emulsions or petrolatum against hydrophilic irritants [18].


22

21

⌬TEWL (g/hm2)

18

* 15

** 12

** 9 6 3 W/O/W

Petrolatum

W/O

SDS

Fig. 1. Mean values and SEM on day 5 interpreted by means of regression analysis. TEWL ⫽ Transepidermal water loss; W/O ⫽ water-in-oil emulsion; W/O/W ⫽ multiple emulsion. *p ⬍ 0.05, **p ⬍ 0.001.

Thus, a multiple emulsion should offer the lowest protection compared to the other formulations used in the ROIT. But in contrast this formulation was the most effective formulation in this test. As it has already been shown in other studies, the protective effect of pre-work creams cannot only be based on a physical effect [19, 20]. From these observations an important question arises as to how the protective effect of the multiple emulsion is achieved. Three-dimensional skin models offer the possibility to get more insights into biochemical processes in the skin, which are responsible for skin barrier function. The Epiderm skin model consists of human-derived keratinocytes. During culturing, these cells form a multilayer structure and differentiate. Like the human epidermis, basal, spinous, granular and stratum corneum layers are formed. The Epiderm skin model was chosen, because of the reported reproducibility and reliable results both within and between laboratories [21]. In order to assess the effect of the multiple emulsion on the skin barrier, the following in vitro method was used: In contrast to the ROIT setup, the samples were pretreated with SDS and subsequently the multiple emulsion was applied, in order to exclude physical protection by the nonpolar oils. Additionally in most cases pre-work creams are applied on preirritated skin. Control samples, samples which were only treated with the multiple emulsion and samples which were only treated with SDS were included in the test.


23

Pretests (results not shown) and literature data [22] were used to define the SDS concentration and duration of SDS treatment to avoid severe toxic reactions leading to cell death. In contrast to 3-dimensional skin model tests where the irritancy of formulations and substances are investigated, the compatibility of the chosen treatment conditions was very important, because dead cells or heavily damaged cells cannot influence barrier repair. Thus, an SDS concentration of 0.2% in the subtoxic range was chosen, which caused no substantial decrease in cell viability but induced a measurable formation of inflammatory mediators. Two types of parameter are generally assessed for prediction of cutaneous irritation and barrier disruption: those linked to cell viability and those linked to inflammatory processes. Analyzed were the cell integrity (LDH leakage), proinflammatory markers (PGE2 and IL-1␣) and skin barrier lipids at various times after exposure to SDS. Stratum corneum lipids, especially ceramides, cholesterol and fatty acids play an important role in the formation and maintenance of the barrier function of the skin [23]. Mostly ceramides and especially ceramide 1 are regarded as being the most important skin lipids for the barrier function of the skin. Apart from single compounds, the right mixture of skin lipids is essential [24]. Thus, different lipid classes important for formation of the epidermal barrier were selected to assess the impact of the multiple emulsion on the natural barrier function of the skin. Lactate Dehydrogenase Release of LDH into culture medium is a rapid and simple method for quantification of cell death and cell lysis. No differences were detected between LDH concentration of the control and the sample only treated with the multiple emulsion. This result clearly demonstrates that the multiple emulsion is not cytotoxic (fig. 2). The SDS-irritated skin models showed the highest LDH concentration. In contrast subsequent treatment with the multiple emulsion tends to decrease LDH release 48 h after application compared to the sample only treated with SDS. This suggests that the multiple emulsion reduces cell damage after treatment with SDS. Interleukin 1a Release Keratinocytes are capable of producing and releasing inflammatory mediators in vivo and in vitro when treated with various irritants [25, 26]. IL-1␣ is a major epidermal cytokine and is increased by SDS treatment even at levels that are noncytotoxic [27]. Thus, IL-1␣ provides a sensitive marker for induced


24

60

*

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*

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30 20 10 0 0.7

Control

4

7 Time (h)

Multiple emulsion

SDS

24

48

SDS/multiple emulsion

Fig. 2. LDH release of 3-dimensional skin models into culture medium totalized for each time point (n ⫽ 3). *p ⬍ 0.05, **p ⬍ 0.01.

damage. Further various publications showed that IL-1␣ secretion correlates best with human irritation data [25, 28, 29]. As demonstrated in figure 3, IL-1␣ was secreted in a time-dependent manner with a maximum 48 h after SDS treatment. Application of the multiple emulsion did not result in an IL-1␣ response compared to the control samples. In consideration of the data obtained in the cell viability assay, we conclude that the multiple emulsion is nonirritating and can be graded as well skin compatible. Similar results were observed when the multiple emulsion was applied onto skin models pretreated with SDS. Application of the multiple emulsion did not increase the secretion of IL-1␣ compared to SDS alone, showing that the multiple emulsion does not aggravate the inflammatory response induced by SDS. Prostaglandin E2 Secretion Alterations of plasma membranes can lead to release of arachidonic acid metabolites such as prostaglandins and leukotrienes after activation of lipoxygenases or cyclooxygenases. PGE2 is produced by skin equivalents exposed to SDS [30] as well as in human skin after patch application of SDS [31]. Similar to IL-1␣, release of PGE2 in human keratinocyte cultures can be evoked at nearly noncytotoxic doses of SDS [27].


25

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50

* **

*

40 30

*

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SDS


Fig. 3. IL-1␣ release of 3-dimensional skin models into culture medium (n ⫽ 3). *p ⬍ 0.05, **p ⬍ 0.01.

In vivo elevated PGE2 levels are correlated with induction of erythema and impairment of epidermal barrier after exposure to SDS and benzalkonium chloride [31]. As shown in figure 4, PGE2 was increased 48 h after treatment of skin with SDS compared to the control sample. Application of the multiple emulsion onto SDS-irritated skin models resulted in a marked reduction of PGE2 release after 48 h compared to skin cultures only treated with SDS. This clearly demonstrates that the multiple emulsion possesses antiinflammatory properties and can diminish PGE2 response of keratinocytes after exposure to surfactants. Since it has already been shown that PGE2 is a factor influencing barrier function after treatment with certain surfactants [31], it can be gathered from the data that the multiple emulsion is capable of preventing disturbance of the epidermal barrier by inhibition of PGE2 secretion. However, skin cultures only treated with the multiple emulsion showed a slight increase in the PGE2 level after 7 h compared to the control which can be explained by the fact that the cultures which were randomly chosen for this treatment group exhibited a slightly increased PGE2 secretion from the beginning of the study. Skin Lipids As key indicators for skin barrier function, ceramides 1, 3, 5 and 6, sphingomyelin, cholesterol, cholesterol 3-sulfate and phosphatidylcholine were


26

7,000

*

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6,000

*

5,000 4,000 3,000

(*)

2,000 1,000 0 Start

7

24

48

Time (h) Control

Multiple emulsion

SDS


Fig. 4. PGE2 release of 3-dimensional skin culture samples (n ⫽ 3). (*)p ⬍ 0.1, *p ⬍ 0.05.

selected. In order to exclude that the multiple emulsion is interfering with the lipid analysis, the emulsion was included into the thin-layer chromatography analysis. Compared to the control samples, after 24 h the multiple emulsion led to an increase in ceramide 3 (89%), ceramide 6 (194%) and cholesterol 3-sulfate (fig. 5a). The cholesterol level seems to be slightly increased in the control compared to the samples treated with the multiple emulsion. After 48 h the ceramide 3 and 6 and cholesterol 3-sulfate levels were still higher than the control levels. The ceramide 3 and 6 content was still increased by 72 and 134%. No differences could be observed between ceramide 1, ceramide 5, sphingomyelin, cholesterol and phosphatidylcholine. As shown in figure 5b, exposure to SDS alone enhanced the ceramide 3 (24 h p ⬍ 0.01, 48 h p ⬍ 0.05), cholesterol (24 h p ⬍ 0.05, 48 h p ⬍ 0.05), and cholesterol 3-sulfate (24 h p ⬍ 0.01, 48 h p ⬍ 0.01) content 24 and 48 h after treatment compared to control samples (fig. 5a). Ceramide 5 and 6 contents were similar to the control. Ceramide 1 as well as phosphatidylcholine seem to be decreased after SDS treatment. Treatment with SDS followed by application of the multiple emulsion led to the same lipid pattern from the qualitative point of view. Furthermore, ceramide 1, which is an important ceramide for barrier function, tends to be


27

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* *

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Control 24 h Control 48 h Multiple emulsion 24 h Multiple emulsion 48 h

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e in

te

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SDS 24 h SDS 48 h SDS/multiple emulsion 24 h SDS/multiple emulsion 48 h

*

700 Lipid (␮g/mg protein)

Lipid (␮g/mg protein)

700

Fig. 5. a Lipid content of 3-dimensional skin cultures untreated and after treatment with the multiple emulsion (n ⫽ 3). (*)p ⬍ 0.1, *p ⬍ 0.05, **p ⬍ 0.01. b Lipid content of 3-dimensional skin cultures after treatment with SDS alone and with SDS followed by the multiple emulsion (n ⫽ 3). (*)p ⬍ 0.1, *p ⬍ 0.05.

enhanced after 24 h in samples treated with SDS and the multiple emulsion as compared to SDS alone. It is known that SDS treatment of Epiderm skin models with subtoxic concentration leads to up- and downregulation of a significant number of genes [22] and that SDS induces cell proliferation [32]. Especially the induction of inflammatory mediators such as IL-1␣ and PGE2 by SDS is addressed by many authors [25, 28, 29]. In the literature it was discussed that IL-1␣ might be one signaling pathway which can influence lipid content [33]. Signaling processes induce several metabolic repair responses that are specifically regulated and which can result in lamellar body secretion, lipid synthesis and DNA synthesis response [34, 35]. An in vivo study revealed that the stratum corneum showed regular lamellar arrangements after SDS exposure and only lamellar body secretion abnormalities occur in the lower stratum corneum layers. Damage of the nucleated parts of the epidermis was also described [36]. It is also reported that application of SDS for 2 weeks to the skin has an impact on the ratio of some lipids, but not on the lipid content. The main differences of the lipid profile are that the ceramide and cholesterol content increased [37]. This is well in accordance with our findings, because SDS led to cell damage, an increase in proinflammatory markers like IL-1␣ and to an increase in some ceramides and cholesterol. This shows that 3-dimensional models react similarly to SDS compared to


28

human skin and therefore they seem suitable to study barrier repair after SDS damage. However, further studies have to be done to investigate the sensitivity of the method. The samples treated only with the multiple emulsion also showed a pronounced increase in some barrier lipids but no loss of cell viability, and above all no increase in proinflammatory markers. Other signaling pathways have to be responsible for the increase in barrier lipids. In this context, depletion of calcium after epidermal barrier disruption or participation of other cytokines and growth factors [33], the pH of the skin and thus e.g. free fatty acid content [38, 39], the sphingolipids and ceramides themselves acting as a second messenger [40] have to be considered. It should be emphasized that these pathways are often cross-linked. However, the results show that the multiple emulsion increases the content of skin lipids, which are important for the skin barrier function without inducing irritation or cell death. It is likely that the superior protective effect found with the ROIT is based on the increased amount of skin barrier lipids which can also be responsible for the earlier decrease in PEG2 and the less severe impact on cell viability after SDS treatment. So far it has been reported that the effectiveness of protection creams is mainly caused by a physical effect. Based on the film-forming ingredients, these formulations possess a poor cosmeticity. In a large number of studies, it was investigated whether it is possible to improve the barrier function by lipid supplementation on the skin [2, 41, 42]. In contrast the new skin protection concept is based on the enhancement of the lipid biosynthesis of the skin and thus to render the skin less susceptible to irritants like SDS. It cannot be excluded that to some extent the nonpolar oils also offer a physical protective effect. However, compared to petrolatum or water-in-oil emulsions, the multiple emulsion possesses a much better cosmeticity and therefore an excellent consumer acceptance [43].

Conclusion

In this study a large amount of agreement in barrier response between human skin and 3-dimensional models has been shown. Thus the 3-dimensional skin model seems to be suitable for studying barrier repair mechanisms and to gain insights into the protective and regenerative effects of cosmetic formulations. In this test only SDS was used as irritant, but testing of other irritants as well as workplace materials not applicable for in vivo tests is possible. At the workplace often complex mixtures of irritant substances can be found, making


29

recommendations for skin protection difficult. Therefore 3-dimensional skin models are also a valuable method for even more specific workplace skin protection recommendations.

References 1 2

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Diepgen TL, Coenraads PJ: The epidemiology of occupational contact dermatitis. Int Arch Occup Environ Health 1999;73:496–506. Kucharekova M, Schalkwijk J, van de Kerkhof PCM, van der Valk PGM: Effect of a lipid-rich emollient containing ceramide 3 in experimentally induced skin barrier dysfunction. Contact Dermatitis 2002;46:331–338. Kresken J, Klotz A: Occupational skin protection products – A review. Int Arch Occup Environ Health 2003;76:355–358. Zhai H, Maibach H: Efficacy of barrier creams; in Maibach H, Elsner P (eds): Cosmeceuticals. New York, Decker, 2000, pp 249–264. Schnetz E, Diepgen TL, Elsner P, Frosch PJ, Klotz AJ, Kresken J, Kuss O, Merk H, Schwanitz HJ, Wigger-Alberti W, Fartasch M: Multicentre study for the development of an in vivo model to evaluate the influence of topical formulations on irritation. Contact Dermatitis 2000;42:336–343. Klotz A, zur Mühlen A, Thörner B, Kietzmann M, Holtmann W, Pittermann W: Testing the efficacy of skin protection products in vivo and in vitro. SÖFW J 2003;9:10–16. Wertz P, Downing DT: Ceramides of pig epidermis: structure determination. J Lipid Res 1983;24: 759–765. Roguet R: The use of standardized human skin models for cutaneous pharmatoxicology studies. Skin Pharmacol Appl Skin Physiol 2002;15:1–3. Ponec M, Boelsma E, Gibbs S, Mommaas M: Characterization of reconstructed skin models. Skin Pharmacol Appl Skin Physiol 2002;15:4–17. Eichler JO, Hey S: Das humane 3D Hautmodell als Testsystem für das Reizpotential von Arbeitsstoffen. Internationaler Hautschutztag 2006, available from www.krefelder-hautschutztag.de. Ponec M, Weerheim A, Mulder A, Gooris G, Bouwstra J, Mommaas M: The formation of competent barrier lipids in the reconstructed epidermis requires the prevalence of vitamin C. J Invest Dermatol 1997;109:348–355. Ponec M, Boelsma E, Weerheim A: Covalent bound lipids in reconstructed human epithelia. Acta Derm Venereol 2000;80:89–93. Bouwstra J, Gooris G, Weerheim A, Kempenaar J, Ponec M: Characterisation of stratum corneum structure in reconstructed epidermis by X-ray diffraction. J Lipid Res 1995;36:496–504. Ponec M, Gibbs S, Pilgram G, Boelsma E, Koerten H, Bouwstra J, Mommaas M: Barrier function in reconstructed epidermis and its resemblance to native human skin. Skin Pharmacol Appl Skin Physiol 2001;14:63–71. Kresken J, Klotz A, Rosenberger V: Gewerblicher Hautschutz: Wirksamkeitsprüfung nichtwassermischbarer Hautschutzsalben im repetitiven Irritationstest (RIT); in Braun-Falco O, Gloor M, Korting HC (eds): Nutzen und Risiko von Kosmetika. Berlin, Springer, 2000, pp 41–46. Pinnagoda J, Tupker RA, Agner T, Serup J: Guidelines for transepidermal water loss (TEWL) measurements. Contact Dermatitis 1990;22:164–178. zur Muehlen A, Klotz A, Veeger M, Thörner B, Weimans S, Diener B, Hermann M, Coppotelli A: Using skin models to assess the effects of a skin care emulsion on skin barrier function. Cosmet Toiletries 2004;119:81–85. Greif C, Wigger-Alberti W, Elsner P: Emollients and barrier creams in the prevention of hand eczema; in Maibach HI, Menné T (eds): Hand Eczema. Boca Raton, CRC Press, 2000, pp 323–331.


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Ramsing DW, Agner T: Preventive and therapeutic effects of a moisturizer: an experimental study of human skin. Acta Derm Venereol 1997;77:335–337. De Paepe K, Hachem JP, Vanpee E, Goossens A, Germaux MA, Lachapelle JM, Lambert J, Matthieu L, Roseeuw D, Suys E, Hecke EV, Rogiers V: Beneficial effects of a skin tolerancetested moisturizing cream on the barrier function in experimentally elicited irritant and allergic contact dermatitis. Contact Dermatitis 2001;44:337–343. Faller C, Bracher M: Reconstructed skin kits: reproducability of cutaneous irritancy testing. Skin Pharmacol Appl Skin Physiol 2002;15:74–91. Fletcher ST, Baker VA, Fentem JH, Basketter DA, Kelsell DP: Gene expression analysis of Epiderm following exposure to SLS using cDNA microarrays. Toxicol In Vitro 2001;15:393–398. Feingold KR, Elias PM: The environmental interface: regulation of permeability barrier homeostasis; in Loden M, Maibach (eds): Dry Skin and Moisturizers. Boca Raton, CRC Press, 2000, pp 45–58. Bouwstra JA, Gooris GS, Dubbelaar FER, Weerheim AM, Ijzerman AP, Ponec M: Role of ceramide 1 in the molecular organization of the stratum corneum lipids. J Lipid Res 1998;39:186–196. Perkins MA, Osborne R, Rana FR, Ghassemi A, Robinson MK: Comparison of in vitro and in vivo human skin responses to consumer products and ingredients with a range of irritancy potential. Toxicol Sci 1999;48:218–229. Roguet R: Use of skin cell cultures for in vitro assessment of corrosion and cutaneous irritancy. Cell Biol Toxicol 1999;15:63–75. Cohen C: Measurement of inflammatory mediators produced by human keratinocytes in vitro: a predictive assessment of cutaneous irritation. Toxicol In Vitro 1991;5:407–410. Bernhofer LP, Barkovic S, Appa Y, Martin KM: IL-1 alpha and IL-1 ra secretion from epidermal equivalents and the prediction of the irritation of mild soap and surfactant-based consumer products. Toxicol In Vitro 1999;13:231–239. Bernhofer LP, Seiberg M, Martin KM: The influence of the response of skin equivalent systems to topically applied consumer products by epithelial-mesenchymal interactions. Toxicol In Vitro 1999;13:219–229. Gay R, Swidderek M, Nelson D, Ernesti A: The living skin equivalent as a model in vitro for ranking the toxic potential of dermal irritants. Toxicol In Vitro 1992;6:303–315. Müller-Decker K, Heinzelmann T, Fürstenberger G, Kecskes A, Lehmann WD, Marks F: Arachidonic acid metabolism in primary irritant dermatitis produced by patch testing of human skin with surfactants. Toxicol Appl Pharmacol 1998;153:59–67. Bloom E, Sznitowska M, Polansky J, Ma D, Maibach: Increased proliferation of skin cells by sublethal doses of sodium lauryl sulfate. Dermatology 1994;188:263–268. Elias PM, Feingold KR: Coordinate regulation of epidermal differentation and barrier homeostasis. Skin Pharmacol Appl Skin Physiol 2001;14:28–34. Elias PM, Ansel JC, Woods LC, Feingold KR: Signalling networks in barrier homeostasis: the mystery widens. Arch Dermatol 1996;132:1505–1506. Elias PM, Woods LC, Feingold KR: Epidermal pathogenesis of inflammatory dermatoses. Am J Contact Dermatitis 1999;10:119–126. Fartasch M, Schnetz E, Diepgen TL: Characterization of detergent-induced barrier alterations – Effect of barrier cream on irritation. J Invest Dermatol Symp Proc 1998;3:121–127. Fulmer AW, Kramer GJ: Stratum corneum lipid abnormalities in surfactant-induced dry scaly skin. Soc Invest Dermatol 1986;86:598–602. Fluhr JW, Elias PM: Stratum corneum pH: formation and function of the ‘acid mantle’. Exog Dermatol 2002;1:163–175. Fluhr JW, Kao J, Jain M, Ahn SK, Feingold KR, Elias PM: Generation of free fatty acids from phospholipids regulates stratum corneum acidification and integrity. Soc Invest Dermatol 2001;117:44–51. Geilen CC, Barz S, Bektas M: Sphingolipid signaling in epidermal homeostasis. Skin Pharmacol Appl Skin Physiol 2001;14:261–271. Coderch L, de Pera M, Fonollosa J, de la Maza A, Parra JL: Efficacy of stratum corneum lipid supplementation on human skin. Contact Dermatitis 2002;47:139–146.


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Zellmer S: Hautlipide, Vesikel aus Hautlipiden und ceramidhaltige Liposomen. SÖFW J 2000;126:37–40. Klotz A, Zur Mühlen A, Röcher W, Kirchhof R, Veeger M: Neue Wirkprinzipien für Hautschutzmittel. Berufsgenossenschaft 2002;9:460–463.

Annette zur Mühlen Degussa, Stoko Skin Care Bäkerpfad 25 DE–47805 Krefeld (Germany) Tel. ⫹49 2151 381399, Fax ⫹49 2151381648, E-Mail [email protected]


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Efficacy and Safety Testing The Clinical Perspective

J.W. Fluhr, M. Miteva, P. Elsner Department of Dermatology, Friedrich Schiller University, Jena, Germany

Abstract The number of workplace substances is uncountable, and technical progress enforces the adaptation of substances such as cutting fluids to the new demands. For that reason new substances can hardly be tested in in vivo studies. In vitro models are widely used to test the effects of barrier creams since they are simple, rapid and safe. Since no animal model could perfectly mimic human percutaneous absorption, these tests are particularly recommended as screening procedures for barrier cream candidates. A number of in vivo methods exist whereupon conventional, non-invasive bioengineering methods, along with clinical scoring, provide the most accurate, highly reproducible assessment of the inflammatory response to irritants and allergens. Nevertheless, no general accepted procedure for the evaluation of skin protection products exists. It is essential that all the products applied to the skin (protective creams inclusive) should be clinically tested in order to verify their propensity for causing cutaneous reactions. Safety testing is a stepwise approach, comprising various in vitro and in vivo test models. The nature of the plausible biological or even toxic reactions that might occur and the types of tests designed to determine the safety of the topical formulations in men are described in this chapter. Copyright © 2007 S. Karger AG, Basel

The stratum corneum (SC), being the outer permeability barrier of the skin, is permanently exposed to contacts with physical and chemical agents from the environment, which in turn may cause a continuous loss of water and proteins. As a highly specialized structure, it is essentially impermeable for water, except for a small but vital flux, serving to maintain its hydration and its flexibility [1]. Besides, the SC is a very resilient tissue, determined by the integrity of the cornified envelope of the corneocytes (which is highly resistant to both physical and chemical assault) and by the interdigitation of adjacent corneocytes. The riveting of adjacent corneocytes via specialized desmosomes (corneodesmosomes) as well as the presence of an interconnected network of structural

proteins, dispersing the force of external physical insults laterally throughout the skin, are also of paramount importance for maintaining the epidermal structural integrity. The physical barrier, located in the SC, resides in long-chain lipids, organized as bilamellar structures stacked on top of each other and filling the intercellular spaces among the horny layer corneocytes, thus developing a brick (corneocytes)-and-mortar (continuous matrix of specialized lipids) organization. To account for such barrier properties and for the hydrophilic and hydrophobic pathways through the skin barrier, an alternative model – the domain mosaic model of the skin barrier – has been proposed [2]. This model envisages the barrier lipids as existing predominantly in crystalline domains, surrounded by grain borders of lipids in a liquid crystalline state. The latter provide an effective barrier which allows a minute, but controlled water loss through the liquid interdomains, which is sufficient to keep the SC keratin hydrated. Perturbation in the barrier due to the use of organic solvents, detergents or mechanical abrogation leads to an altered water flux and sets in motion a cascade of events within the underlying epidermis to promote barrier recovery. The principal response to minor repeated or severe barrier disruption comprises a temporary increase in the biosynthesis of all major lipid species in the epidermis as well as an enhanced cytokine production within the ranges of the inflammatory events, involving also the deeper layers of the skin and the endothelium, epidermal hyperplasia and abnormal keratinization.

Risk Factors for Occupational Skin Diseases: Examples

Skin protection products are designed to protect the skin against exogenous risk factors occurring at the workplace. Among the most frequent non-toxic, non-cancerogenous and non-sensitizing low-grade hazards in the occupational field, water, wet work, detergents, solvents and cutting fluids seem to play an important role [3]. Regular skin cleansing with washing substances is one of the probable potential ways by which skin irritation might be induced [4]. The surfactants in modern cleansing products are anionics, non-ionics and amphoters, each with a specific active profile. The dermatological effects of surfactants on skin can be attributed to four fundamental mechanisms, finally affecting barrier homoeostasis of the skin and other physiological factors: (1) adsorption to the skin surface; (2) removal of skin components; (3) penetration into deeper skin layers, and (4) cytotoxic effects on living cells in the epidermis. Consequences of this interaction with the skin, particularly with the SC, are the clinically well-studied symptoms of erythema, scaling, swelling and dryness,

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which can be nowadays documented and quantified by using a clinical assessment approach and biophysical instrumentation (measurements of transepidermal water loss, SC hydration, epidermal perfusion, roughness of the skin surface and skin colour). In addition, subjective perceptions of sensorial discomfort such as tension, burning or itching might occur alone or in combination with pathological cutaneous symptoms.

Skin Protection and Skin Care: Definitions

Occupational skin protection products against noxious chemicals from the workplace are designed to be used before and during work. This distinguishes them from the skin-conditioning formulations normally used after work. According to Kresken and Klotz [5], skin protection creams are special products that protect the skin against hazards at the workplace or against skin-irritating influences from the workplace surroundings. Skin-conditioning products are used mainly after work or before longer work interruptions to increase moisture and smoothness of the skin. Skin regeneration products are aimed at restoring the natural barrier function of the skin. Elsner and Wigger-Alberti [6] have classified the protection products at the workplace into pre-exposure barrier creams, mild skin cleansers and postexposure skin care products such as emollients and moisturizers. While barrier creams are designed to prevent damage due to irritant contact, skin cleaning should remove harmful substances from the skin and skin care is intended to enhance epidermal barrier regeneration. The term invisible glove is incorrect in relation to skin protection products and should be avoided due to its misinterpretation as providing extreme safety for the user. A perfect protection against whatever workplace substances cannot be assured by any protective formulation. The term barrier cream indicates that the product builds up a diffusion barrier between the skin and the irritant applied. The effectiveness of many skin protection products is however conditioned by their composition, including active ingredients such as astringents, UV absorbers, complexing agents etc., and not only by setting up a physical diffusion barrier. Thus, some authors suggest that the term ‘barrier cream’ should also be avoided and be replaced by a more appropriate one – a protective cream (PC) [5]. The distinction between skin protection and skin care is also raising discussion as it is not always obvious. For example, in nurses a PC was compared with its vehicle for assessing their effects on clinical improvement. Interestingly, both clinical skin status as well as SC hydration improved significantly in each treatment group, without evidence of a difference between the vehicle and the barrier cream groups [7]. Correct instructions for the consumer use should be

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stressed with regard to regular and frequent application of a protection product in order to be effective [8]. Furthermore, a recent study discussed whether claims could be made with respect to protective and preventive properties of topically applied body lotions and barrier creams. In this particular study, enhanced SC hydration improved barrier function as well as a faster barrier recovery were reported after sodium lauryl sulphate (SLS) barrier disruption [9].

Specific Effects of Topical Formulations

Dermatological creams and PCs exert a number of effects, in and on the skin, including skin hydration, skin cooling and barrier effect [10]. The relative cooling effect of a PC can be attributed to the amount of water and/or alcohol in the emulsion system(s) and to water ‘activity’, more precisely the amount of freely evaporating water that is liberated in the early phase after topical application. Moreover, the emulsion structure (e.g. liquid crystals) and the presence of hydrotopes determine the water liberation properties. This effect is more pronounced when the vehicle is formed by an aqueous or hydro-alcoholic phase or when these are present within the external phase of the formulation, e.g. lotions, hydrogels or oil-in-water emulsions. PCs are also well known to influence the hydration of the SC, for which at least three different mechanisms have been proposed: First, the cosmetic vehicle can exert a direct hydrating effect by liberating water from the formulation itself [11]. In this way moisturizers actively increase the water content of the skin. Second, the occlusive effect of the formulation can influence SC hydration, especially in long-term applications. Emollients are designed to smooth the skin and to increase the water content indirectly by creating an occlusive film on the skin surface, which traps the water in the upper layers of the SC. A third mechanism by which PCs influence skin hydration is evident when highly hygroscopic compounds like glycerol or hydrotropes like hyaluronic acid or trimethylglycine are applied. By absorbing water either from the vehicle itself, from surface water or from water evaporation, these agents are then able to increase SC hydration [12]. In addition, vehicles can exert an emollient (re-lipidizing or re-greasing effect), which is of great importance in the postexposure treatment of skin conditions, where a cracked, rigid or rough skin surface is the main problem to be considered. Furthermore, some moisturizers, in their capacity of postexposure skin care products, release anti-inflammatory and epithelial growth-promoting substances.

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Evidence-Based Medicine and Skin Protection

Although barrier creams are one of the most commonly recommended measures to prevent occupational dermatoses such as irritant contact dermatitis and allergic contact dermatitis, their actual benefit at the workplace is still lively debated [13]. Nevertheless, there is a lack of placebo-controlled, randomized clinical studies, evaluating the benefit of skin protection products in the prevention of occupational diseases under real workplace conditions. Moreover, the literature data are controversial – some publications report on positive results after applying skin protection, whereas others disclose negative ones. In a worldwide survey of international experts, 98% considered protective creams to be no more effective than bland emollients in the prevention of contact dermatitis [14]. In the past decade evidence-based medicine has become a generally accepted method for bringing the results of the research and medical practice together. It uses the following five steps: (1) formulation of a clear clinical question, (2) searching through the literature for relevant articles, (3) assessing (clinical appraisal) the evidence for its validity and usefulness, (4) implementation of useful findings in the clinical practice, and (5) evaluation one’s own performance [15]. Proceeding from the discrepancy between the wide propagation of ‘the 3-step skin protection concept’ (including pre-exposure barrier creams, cleaning and postexposure skin care) in the last few years and the relatively high, persisting level of occupational skin diseases, Kütting and Drexler [16] raised the question as to what extent this ‘3-step programme of skin protection’ is really evidence based. Their work, aimed at assessing critically the evidence for the recommendation of skin protection products in the practice, was based upon the methods of evidence-based medicine – searching the available literature, critically appraising the results and interpolating the results to certain questions. The authors reached the conclusion that, even though a huge number of in vitro and in vivo methods for evaluation of barrier creams have been described and many clinical trials related to the subject of skin protection have been performed, for the evidencebased recommendation of skin protection, further studies are needed particularly under daily working conditions. The latter should be focused on evaluating the contribution of each single element of a skin care programme – products, frequency of application and education programmes.

Proof of Efficacy: Test and Evaluation Methods

The number of workplace substances is uncountable and technical progress enforces the adaptation of substances such as cutting fluids to the new


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demands. For that reason every new substance can hardly be tested in in vivo studies. Thus, testing of the efficacy of skin protection products, by both in vitro and in vivo models, is limited to a certain number of model irritants such as SLS as a hydrophilic model irritant. However, for some substance classes like lipophilic irritants, model irritants are controversial, although toluene has been used in many studies. Based on the test results with the above-mentioned model irritants, products are recommended for hydrophilic, lipophilic or varying substances [5]. In vitro models, which mimic the reaction of in vivo skin, are widely used to test the effects of barrier creams since they are simple, rapid and safe. They are particularly recommended as screening procedures for barrier cream candidates. For example, radiolabelled methods may determine the accurate protective and penetration results even with the lower levels of chemicals because of the sensitivity of radiolabelled counting, whereas animal experiments may be used to generate kinetic data, due to the closer similarity between humans and some animals (pigs and monkeys) in percutaneous absorption and penetration for definite compounds. However, there is no animal existing which could perfectly simulate the penetration of all topical products in humans [17], and since skin protection products are cosmetics, animal testing has been banned by the Cosmetic Directive. In vitro studies, as the sole proof of efficacy of skin protection products, should be rejected as long as no significant correlation between reliable in vivo and selected in vitro methods has been proven [5]. Herein, we would like to allude briefly to some of the methods, falling into this category of models: Boman et al. [18] measured the blood concentration of a solvent in animals after percutaneous absorption through a barrier cream as a tool for validation of PC efficacy. For the same purpose, histological assessment of skin inflammation after skin irritation has been performed in mice [19]. Goffin et al. [20] assessed the efficacy of PCs to surfactants and organic solvents with shielded variants of the corneosurfametry and corneoxenometry methods. Frosch et al. [21] first used a guinea pig model for performing the repetitive irritation test to evaluate the efficacy of barrier creams. Over a 2-week period, cumulative irritation with standard irritants was performed. Irritation of pretreated sites was compared with irritation of untreated control sites [21]. In vivo methods determine the most objective estimation of human percutaneous absorption. Histological assessment may define which layers of skin are damaged or protected and may provide insight into PC mechanisms. Conventional noninvasive bioengineering methods ensure accurate, highly reproducible observations in quantifying the inflammatory response to numerous irritants and allergens. They are capable of assessing subtle distinctions, thus assisting the interpretation of results from traditional clinical studies [17]. Therefore bioengineering methods, along with clinical scoring, seem to be the

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most adequate assay for monitoring the complex interaction between an irritant, a skin protection product and the human skin [22]. Different test procedures have been developed: (1) 1-time occlusive test (exposing the skin for 24 h to high concentrations of different irritants), (2) repeated open tests (using multiple non-occlusive application of the irritant and the skin PC), (3) repeated occlusive tests (also called repetitive irritation tests – PC and irritants being applied on the back of the volunteers once daily over 2 weeks). In general, the repetitive exposure is considered to be more adequate in mimicking the real life situation, as it is more common to develop an occupational skin disease triggered by repeated short-time contacts with low-concentration irritants than by a single long-lasting exposure. One disadvantage of the bioengineering methods is that in the presence of skin barrier cream, the results obtained might be influenced by methodological difficulties [23]. In vivo models are based on the assessment of the reduction either of a known contact sensitization or of irritant and inflammatory alterations in the skin when a barrier cream or moisturizer is used before the application of the irritant or the allergen. The results are compared to an untreated area. Hereby, a few examples are listed: Zhai and Maibach [24] developed an in vivo method to measure the effectiveness of a PC against two dye indicator solutions, methylene blue in water and oil red O in ethanol, representative of model hydrophilic and lipophilic compounds. The solutions were applied to untreated and PCpretreated skin areas, using occlusive chambers. Subsequently materials were removed and skin surface biopsies were obtained. The amount of dye penetrating into each strip was determined by colorimetry, with the cumulative amount representing the amount of permeation of each solution at each time point, therefore submitting a marker for the efficacy of the PC. De Fine Olivarius et al. [25] introduced a method based on the evaluation of colour intensities to prove the water-protective effects of PC. If the skin is pretreated with a waterrepellent cream, the penetration of an aqueous solution of crystal violet is impaired, leading to less binding to the keratin and to a less intense colour. The relative efficacy of various creams may therefore be assessed visually by comparing the different colour intensities, which in turn are quantified by measurement of skin reflectance. Elsner et al. [26] and Schliemann-Willers et al. [27] evaluated perfluoropolyether-containing PCs against a set of 4 irritants: 10% SLS, 0.5% NaOH, 15% lactic acid and undiluted toluene in the repetitive irritation test on the person’s back. Irritation was assessed by visual scoring, transepidermal water loss and colorimetry. All perfluoropolyether preparations substantially suppressed irritation induced by SLS and NaOH. However, only the 4% perfluoropolyether preparation was significant against lactic acid and toluene. Sun et al. [28] used laser-induced breakdown spectroscopy to evaluate the effect of PCs on human


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skin. Three representatives of commercial barrier creams (proclaimed as being effective against lipophilic and hydrophilic substances) were evaluated by measuring zinc absorbed through the SC. Four consecutive skin surface biopsies were taken from the biceps of the forearms of 6 volunteers at time intervals of 0.5 and 3 h after PC application. The cream provided appreciable protection against the penetration of both ZnCl2 and ZnO into the skin when compared with control skin. Not only do test methods vary in their design, but also the evaluation methods vary among visual scoring system, histological findings, bioengineering approach or a combination of them all. However, no generally accepted procedure for the evaluation of skin protection products exists [29]. To find a standardized, reproducible test procedure for the evaluation of skin protection products, a multicentre study was performed, evaluating a multiple repeated short-time occlusive irritation method. The irritation was monitored by bioengineering methods and by clinical scoring. The assessment showed that significant results could already be achieved with the 5-day protocol [22]. No matter whether the data are generated from in vitro or in vivo models, the testing quality and the reproducibility of results still remain incompletely developed. Furthermore, even extensive laboratory testing cannot simulate the complex workplace situation. In order to obtain an evidence-based recommendation of the use of the 3-step concept of skin protection, further field tests with occupational skin care products under daily working conditions are warranted. Kütting and Drexler [16] emphasized the fact that people being educated about skin care regimens might have a more careful behaviour than those not being trained. In line with this, it could be concluded that the reduced burden of exposure by an educational plan might play an important role in the field of skin protection. The effectiveness of a skin care programme is conditioned not only by the effectiveness of the product itself, but also by the frequency and the elaboration of the application (re-application over a certain time, spreading of steady, adequate amounts of the PC on all skin areas that need protection), and finally by the effectiveness of the education in reducing skin-damaging exposure. A simple method to verify and quantify how exactly the self-application of a PC is performed at the workplace was introduced by Wigger-Alberti et al. [8]. The authors proceeded from the assumption that certain areas of the hands are usually skipped on self-application of a PC – a fact that might contribute to the discrepancy between promising experimental efficacy data and the practical benefit after PC application. With the use of a fluorescent technique, it was shown that the application was mostly insufficient among patients with hand eczema (falling into different professional groups), particularly on the dorsal aspects of the hands and in the interdigital spaces. The findings indicate that not

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only when washing their hands do many people miss certain areas, but also when applying the PC. Educational demonstrations of the most common mistakes should be performed in order to ensure complete skin protection [30].

Safety Testing: General Aspects

Safety testing of topically applied products is recommended by health authorities. It is assumed that all chemical substances, when coming into contact with the skin surface, have the potential to be absorbed at least in small amounts, thus exerting biological or even toxic effects. It is essential that all the products applied to the skin are clinically tested in order to verify their propensity for causing cutaneous reactions. As outlined above, for a new dermatological or cosmetic product to be launched, a toxicity testing in the course of the product’s various developmental phases should be performed [31]. The latter is a stepwise procedure, commencing with collecting data about the raw materials. The next step is the toxicity testing that supports the first clinical trials with preliminary formulations of the test product. The final step consists of toxicity testing that either supports phase III clinical trials with the final formulations of the product and fulfills the preconditions for the registration of a new drug or allows the marketing of a new cosmetic, respectively. The main objective of the safety testing is to provide answers to the following questions [31]: (1) Which are the plausible side-effects of the new product? (2) Are any local or systemic effects to be expected? (3) What are the exposure levels in the different animal species when compared with the ones expected in men? (4) Is there a margin of safety between the lowest effective levels in animal models and the maximal estimated exposure levels in men? (5) Are the toxicokinetic properties of the compound in animals comparable with the ones assumed in men? To get a new angle on the process of safety assessment as a whole, the latter might be regarded as a multistep approach, comprising a number of stages [32]: (1) hazard identification – this step essentially collects all the adverse data pertaining to the product and its ingredients in order to identify the hazards; (2) risk characterization – the hazard data are compared with the anticipated exposure conditions to determine which hazards might constitute risks to human health, i.e. which hazards are relevant for further consideration; (3) risk evaluation – a detailed information regarding the actual exposure is required, as this step represents a further refinement of the risk characterization (potential risks are quantified and gauged against known risks); (4) safety assessment – in this final step the safety assessor has to conclude whether the potential risks could be considered as acceptable and therefore safe to the market.


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Preclinical Toxicology The major requirement for a novel topical product is that the material applied is neither an acute poison nor a corrosive agent or allergen. As far as skin protection products are within the scope of this book chapter, it must be taken into account that it is most unlikely that potentially irritative ingredients are included in the preliminary manufacturer’s formulation of the product. In spite of this, such information should be obtained for safety reasons. Much of the data about the preclinical toxic properties of a product can be provided by using various in vitro models: (1) mammalian cell culture systems are widely used as screening systems during development [33]; (2) an epidermal-slice technique has been used successfully for identifying strong irritants [34]. A more complex cell culture system, the skin equivalent, has also been proposed as a screening procedure for topically applied materials – a 3-dimensional reconstruction of human skin is prepared using epidermis cells layered on a collagen lattice containing fibroblasts. After 2–3 weeks, a structure resembling SC is formed and the materials could be applied directly to this surface. The release of inflammatory mediators can also be monitored [35]. Skin Irritation Tests Possible irritant effects of the substance on the skin should be assessed. In most cases, the material being tested is not novel and is similar in structure to materials for which human data are already available. The irritant potential can then be determined by performing simple patch tests such as the 48-hour irritancy test or the cumulative-irritancy test [36]. The 48-hour irritancy test consists of 2 sequential 24-hour applications of a material under occlusion to the same site. The change to fresh material at 24 h allows the assessment and possible termination of the experiment if severe reactions occur. The interpretation of the 48-hour irritancy test is important as a negative result does not mean that the product is safe (sometimes irritants reveal their potential only after repeated application). The primary function of this test is therefore screening and is aimed to identify the products with a high potential for skin irritancy. The cumulative irritancy test is designed to enable the comparison and classification of the weaker types of irritants – the product is applied repeatedly to the same site under occlusion to ensure greater penetration of the potential irritants. In this way an exaggerated exposure is provided. It is assumed that the information obtained from a relatively small panel of individuals (a total of 20–30 subjects) is indicative for the plausible behaviour of the product under everyday conditions in the population at large. Predicting Photo-Irritancy All the methods available require the skin to be irradiated with UVA following application of the test substance. The method of Kaidbey and Kligman [37]

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for assessing the phototoxic potential of topically applied drugs, chemicals, transdermal agents and skin care products is widely used. Skin assessments are accomplished immediately following irradiation 24 and 48 h after photo-exposure. The irradiated sites should be compared in each subject to the unirradiated site. If the response at the irradiated site is more intense than the one at the unirradiated site, then the product is deemed a photo-irritant. Testing for Sensitization and Photosensitization Sensitization and, increasingly, photosensitization data (whether a substance is capable of absorbing UV light) are required if the sensitizing potential of a product is to be estimated [32]. On one hand, the various in vitro tests developed over the years to model aspects of the sensitization process are still not able to completely replace in vivo studies. On the other hand, in order to reduce the severity of the in vivo procedures, the murine local lymph node test is at the present time accepted as a fully validated alternative to the more stressful guinea pig maximization methods [38]. The photosensitization data should be taken into consideration wherever ingredients are envisaged to be included in certain products such as sunscreens. Subchronic Toxicity These studies provide valuable information about any toxic effects which occur following repeated exposure to a substance [32], thus substantiating the safety of the substance for the population exposed. Investigations normally involve post-mortem examination of all major organ systems as well as numerous in vivo investigations (a 90- or 28-day study in rats is usually used). Ideally, the results of a repeated exposure study would allow the identification of doses which could be termed the no-effect level, no-adverse-effect level, noobserved-effect level or no-observed-adverse-effect level. The endpoint of the subchronic toxicity studies is the no-adverse-effect level to be obtained. Mutagenicity and Genotoxicity To exclude the substances with mutagenic effects (having the capacity to induce mutation) or genotoxic potential (affecting the individuals’ genome by expressing a mutagenic or cancerogenic effect), special in vitro tests are designed. The latter should detect all 3 mutation endpoints, namely gene mutation, clastogenicity and aneuploidy. Nevertheless, there is currently no single, validated test to provide sufficient information. In general, absence of activity in an in vitro study is taken as encouraging, whereby a positive effect is not proof of a potential human hazard – it confirms only the necessity of further investigation to be carried out. The underlying principle is to see if activity observed in vitro can be expressed in vivo – if not, less emphasis should be laid on the in vitro results.


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Phototoxicity and Photomutagenicity Information related to these endpoints is needed when the proposed conditions of use would include prolonged exposure to sunlight, as would be the case with the UV filters present in skin protection cosmetics [32]. Toxicokinetics Toxicokinetics refers to the absorption, distribution, metabolism and excretion of the substance. Knowledge of the toxicokinetics allows an estimation of the concentration and duration profile of the substance and its metabolites at the tissue site of interest, respectively. Long-Term Toxicity and Carcinogenicity When pre-existing data are available, their trustworthiness and relevance to the proposed use of the product should be taken into account. The need for studies to generate such data should be carefully considered. Human Data They are extremely valuable for the safety evaluation of both the substances and the products later. Human data could be collected from different sources [32], such as: (1) previous market experience – a history of safe use of the substance in similar products; (2) human volunteer studies (in-use or preference data trials of the market research kind, efficacy trials under clinical conditions or clinical trials to determine kinetic data); (3) accidents and industrial exposure (recorded incidents in the literature); (4) epidemiological studies (require particular attention during interpretation). In conclusion, it should be emphasized that, due to the differences between animal and human skin and due to the differences between in vitro and in vivo studies [39], it is recommended to include well-known reference substances in the toxicity tests. Regardless of the benefits provided by a protection product, it is of basic importance that no damage to human health is eventually induced. Postmarket surveillance is always warranted.

References 1 2 3

4

Harding C: The stratum corneum: structure and function in health and disease. Dermatol Ther 2004;17:6–15. Forslind B: A domain mosaic model of the skin barrier. Acta Derm Venereol 1994;74:1–6. Bornkessel A, Flach M, Arens-Corell M, Elsner P, Fluhr JW: Functional assessment of a washing emulsion for sensitive skin: mild impairment of stratum corneum hydration, pH, barrier function, lipid content, integrity and cohesion in a controlled washing test. Skin Res Technol 2005;11:53–60. Fluhr JW, Ennen J: Standardized washing models: facts and requirements. Skin Res Technol 2004;10:141–143.

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5 6 7 8 9

10 11

12 13 14 15 16

17 18

19 20 21 22

23 24 25 26 27 28 29 30

Kresken J, Klotz A: Occupational skin-protection products – A review. Int Arch Occup Environ Health 2003;76:355–358. Elsner E, Wigger-Alberti W: Skin-conditioning products in occupational dermatology. Int Arch Occup Environ Health 2003;76:351–354. Berndt U, Wigger-Alberti W, Gabard B, Elsner P: Efficacy of a barrier cream and its vehicle as a protective measure against irritant contact dermatitis. Contact Dermatitis 2000;42:77–80. Wigger-Alberti W, Walter MD, Maraffio B, Wernli M, Elsner P: Self-application of a protective cream: pitfalls of occupational skin protection. Arch Dermatol 1997;133:861–864. De Paepe K, Drede MP, Roseeuw D, Rogiers V: Incorporation of ceramide 3B in dermatocosmetic emulsions: effect on the transepidermal water loss of sodium lauryl sulphate-damaged skin. J Eur Acad Dermatol Venereol 2000;14:272–279. Fluhr JW, Rigano L: Clinical effects of cosmetic vehicles on skin. J Cosmet Sci 2004;55:189–205. Blichmann CW, Serup J, Winther A: Effects of single application of a moisturizer: evaporation of emulsion water, skin surface temperature, electrical conductance, electrical capacitance, and skin surface (emulsion) lipids. Acta Derm Venereol 1989;69:327–330. Fluhr JW, Goor M, Lehmann L, Lazzerini S, Distante F, Berardesca E: Glycerol accelerates recovery of barrier function in vivo. Acta Derm Venereol 1999;79:418–421. Wigger-Alberti W, Elsner P: Do barrier creams and gloves prevent or provoke contact dermatitis? Am J Contact Dermatitis 1998;9:100–106. Hogan DJ, Dannaker CJ, Lal S, Maibach HI: An international survey on the prognosis of occupational contact dermatitis of the hands. Dermatosen 1990;38:143–147. Rosenberg A, Donald A: Evidence-based medicine, an approach to clinical problem-solving. Br Med J 1995;310:1122–1126. Kütting B, Drexler H: Effectiveness of skin protection creams as a preventive measure in occupational dermatitis: a critical update according to criteria of evidence-based medicine. Int Arch Occup Environ Health 2003;76:253–259. Zhai H, Maibach HI: Testing and efficacy of barrier creams; in Fluhr JW, Elsner P, Berardesca E, Maibach HI (eds): Bioengineering of the Skin. Boca Raton, CRC Press, 2005. Boman A, Wahlberg JE, Johansson G: A method for the study of the effect of barrier creams and protective gloves on the percutaneous absorption of solvents. Dermatologica 1982;164: 157–160. Mahmoud G, Lachapelle JM, van Neste D: Histological assessment of skin damage by irritants: its possible use in evaluation of a ‘barrier cream’. Contact Dermatitis 1984;11:179–185. Goffin V, Piérard-Franchimont C, Piérard GE: Shielded corneosurfametry and corneoxenometry: novel bioassays for the assessment of skin barrier products. Dermatology 1998;196:434. Frosch PJ, Schulze-Dirks A, Hoffmann M, Axthelm I, Kurte A: Efficacy of skin barrier creams. I. The repetitive irritation test (RIT) in the guinea pig. Contact Dermatitis 1993;28:94–100. Schnetz E, Diepgen TL, Elsner P, Frosch PJ, Klotz AJ, Kresken J, Kuss O, Merk H, Schwanitz HJ, Wigger-Alberti W, Fartasch M: Multicentre study for the development of an in vivo model to evaluate the influence of topical formulations on irritation. Contact Dermatitis 2000;42:336–433. Jemec GB, Na R, Wulf HC: The inherent capacitance of moisturizing creams: a source of falsepositive results? Skin Pharmacol Appl Skin Physiol 2000;13:182–187. Zhai H, Maibach HI: Effect of barrier creams: human skin in vivo. Contact Dermatitis 1996; 35:92. De Fine Olivarius F, et al: Water protective effects of barrier creams and moisturizing creams: a new in vivo test method. Contact Dermatitis 1996;35:219–225. Elsner P, Wigger-Alberti W, Pantini G: Perfluoropolyethers in the prevention of irritant contact dermatitis. Dermatology 1998;197:141. Schliemann-Willers S, Wigger-Alberti W, Elsner P: Efficacy of a new class of perfluoropolyethers in the prevention of irritant contact dermatitis. Acta Derm Venereol 2001;81:392–394. Sun Q, Tran M, Smith B, Winefordner JD: In-situ evaluation of barrier cream performance on human skin using laser-induced breakdown spectroscopy. Contact Dermatitis 2000;43:259. Löffler H, Effendy I: Prevention of irritant contact dermatitis. Eur J Dermatol 2002;12:4–9. Kelterer D, Fluhr JW, Elsner P: Application of protective creams: use of a fluorescence-based training system decreases unprotected areas on the hands. Contact Dermatitis 2003;49:159–160.


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Maurer T: Guidelines and methods on safety testing for dermatics and cosmetics; in Elsner P, Gabard B, Surber C, Treffel P (eds): Dermatopharmacology of Topical Preparations: A ProductDevelopment Orientated Approach. Berlin, Springer, 2000. Flower C: Safety assessment of cosmetic product; in Leyden JJ, Rawlings AV (eds): Skin Moisturization. New York, Dekker, 2002. Duffy PA, Flint PO: In vitro dermal irritancy tests; in Steele C, Atterwill C (eds): In vitro Methods in Toxicology. Cambridge, Cambridge University, 1987. Oliver GJA, Pemberton MA: An in vitro epidermal slice technique for identifying chemicals with potential for severe cutaneous effects. Food Chem Toxicol 1985;23:229–232. Dykes P, Edwards MJ, O’Donovan MR, Merrett V, Morgan HE, Marks R: In vitro reconstruction of human skin: the use of skin equivalents as potential indicators of cutaneous toxicity. Toxicol In Vitro 1991;5:1–8. Dykes PJ, Pearse AD: Basics on clinical safety testing; in Elsner P, Gabard B, Surber C, Treffel P (eds): Dermatopharmacology of Topical Preparations: A Product-Development Orientated Approach. Berlin, Springer, 2000, pp 79–94. Kaidbey KH, Kligman AM: Identification of topical photosensitizing agents in humans. J Invest Dermatol 1978;70:149–151. Draize JH, Woodward G, Galvery HO: Methods for the study of the irritation and toxicity of substances applied topically to the skin and mucous membranes. J Pharmacol Exp Ther 1994;83: 377–390. Spilker B: Extrapolation of preclinical safety data to humans. Drug News 1991;4:211–216.

Joachim W. Fluhr, MD Head of the Skin Physiology Laboratory, Department of Dermatology Friedrich Schiller University Jena, Erfurter Strasse 35 DE–07740 Jena (Germany) Tel. ⫹49 3641 937399, Fax ⫹49 3641 937435, E-Mail [email protected]

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Skin Protection from Specific Exposures Schliemann S, Elsner P (eds): Skin Protection. Curr Probl Dermatol. Basel, Karger, 2007, vol 34, pp 47–57

Protection from Irritants Hongbo Zhai, Howard I. Maibach Department of Dermatology, University of California, School of Medicine, San Francisco, Calif., USA

Abstract Contact dermatitis is a common skin disease in the workplace and at home. The theoretically optimal way to minimize this problem is to use skin protection products such as barrier creams and moisturizers. Numerous ingredients have been formulated into the skin protection products in the marketplace. However, the US Food and Drug Administration only issued 13 skin protectants for over-the-counter products. Definition, reasons, mechanism of action and duration, application methods as well as efficacy of using skin protection products are extensively reviewed in this article. We conclude that the use of skin protection products may help people to reduce the intensity of skin irritations caused by irritants at home and at the workplace. We should remind the public not to use them as a primary protection against high-risk substances such as corrosive agents. Additionally, careful selection of appropriate skin protection products in the specific situations/environments is suggested. Copyright © 2007 S. Karger AG, Basel

Contact dermatitis (CD), including irritant contact dermatitis (ICD) and allergic CD, comprises 90–95% of work-related dermatoses [1]. ICD results from contact with irritants, while allergic CD is an immunological reaction from contact with allergens in sensitized individuals [1–5]. To reduce the risk of CD developing, skin protection products such as barrier creams (BCs) and moisturizers have been used [6–16]. Though BCs and moisturizers are not identical, probably, due to the ambiguous definition, the terms of BC and moisturizer are often mixed in the literature and marketplace. The target of a BC is the prevention of external noxious substances penetrating the skin, used usually in an occupational setting [6–13], and moisturizers are frequently used for ‘dry’ skin conditions as well as to maintain healthy skin [10, 14–17]. However, moisturizers and BCs may share characteristics [14]; to strictly distinguish between them may be difficult. This chapter focuses on the skin protection of both BCs and moisturizers from irritants.

Irritant Reaction

ICD is the result of an unspecific damage due to contact to chemical substances that cause an inflammatory skin reaction [1–3, 5]. Exposure of human beings to irritants such as solvents, detergents and even water [18], at home and in work environments, leads to damage to the stratum corneum and hence skin barrier impairment [14]. The exact mechanisms of irritant action are incompletely understood, but it seems likely that there is an ‘immunologic-like’ component to the irritant response [3]. The clinical appearance of ICD varies depending on multiple external and internal factors [2, 3, 5]. Airborne ICD may develop in uncovered skin areas, mostly in the face and neck after exposure to volatile irritants or vapor. Avoidance of these irritants may not be practical for persons whose occupation or daily activities require them. Prophylactic measures reduce the risk of developing ICD: BCs and moisturizers may play a role in this strategy. Barrier Creams

Definition and Terms A BC, in theory, is designed to prevent or reduce the penetration of harmful agents [6–13, 19–21]. BCs are also called ‘skin-protective creams’ or ‘protective creams’ as well as ‘protective ointments’, ‘invisible glove’, ‘barrier’, ‘protective’ or ‘pre-work’ creams and/or gels (lotions), ‘antisolvent’ gels and so on [19, 21–25]. Frosch et al. [19] consider ‘skin-protective creams’ a more appropriate terminology since most creams do not provide a real barrier, at least not comparable to the stratum corneum. Kresken and Klotz [21] believe that the term BC is incorrect for these formulations and suggest instead the term ‘skin protection cream/product’. We still use the term BC here because of its wide usage in industry. Reasons to Use Barrier Creams Protective clothing and other personal devices may provide protective effects in industry [26, 27]. But protective clothing may trap moisture and occlude potentially damaging substances next to the skin for prolonged periods and increase the likelihood that dermatitis will develop [26, 27]. In practice, BCs are recommended only for low-grade irritants (water, detergents, organic solvents, cutting oils) [6, 7, 21, 28–31]. The first line of defense against hand dermatitis is to wear gloves, but in many professions it is impossible to wear them because of dexterity loss. In some instances, an alternative could be to apply a BC. Many workers prefer a BC instead of gloves because they do not want the hand continuously sealed inside a glove. Furthermore, gloves can inhibit skin barrier function [7]. Another reason to minimize wearing gloves is

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glove intolerance [32–35]. Furthermore, due to continuous glove wearing, workers can develop serious symptoms (i.e. contact urticaria syndrome) including generalized urticaria, conjunctivitis, rhinitis, asthma etc. [7, 36]. Mechanism of Action and Duration The information on the mechanisms of BC action is limited. The frequently quoted general rule is that water-in-oil emulsions are effective against aqueous solutions of irritants and oil-in-water emulsions are effective against lipophilic materials [6, 19, 27]. Some studies have demonstrated exceptions to this rule [37, 38]. BCs may contain active ingredients that are presumed to work by trapping or transforming irritants [12, 38]. Most believe they interfere with absorption and penetration of the irritants by physical blocking – forming a thin film that protects the skin [6, 12, 38–40]. In order to avoid frequent interruptions for reapplication, BCs are expected to remain effective for 3 or 4 h. Most manufacturers claim that their products last around 4 h. Others suggest use ‘as often as necessary’ [6, 21, 27]. Several studies document the duration of action – with varying results [28, 31, 41, 42]. Application Methods and Efficacy BC effectiveness may be influenced by application methods [43–45]. Wigger-Alberti et al. [44] determined which areas of the hands were likely to be skipped on self-application of a BC by a fluorescence technique at the workplace; BC application was incomplete, especially on the dorsal aspects of the hands. Most manufacturers suggest rubbing thoroughly onto the skin, to pay special attention to cuticles and the skin under the nails, to let it dry approximately 5 min and to apply a thin layer of BC to all appropriate skin surfaces 3–4 times daily. Presumably, these controlled experiments are indicated. BC efficacy in preventing or reducing ICD has been documented in many experimental environments [for reviews, see 6, 8–13, 19–21]. However, some reports document that inappropriate BC application may exacerbate rather than ameliorate [12, 19, 31, 37, 46–48]. US Food and Drug Administration Monograph on Skin Protectants The US Food and Drug Administration defines 13 skin protectants for overthe-counter products [49]. These ingredients and concentrations are listed in table 1. Moisturizers

Definition and Terms The term ‘moisturizer’ was generated by Madison Avenue marketers [15]. The definition of ‘moisturizers are substances used to reduce the signs and

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Table 1. The US Food and Drug Administration identified 13 skin protectants and their concentrations Ingredients

Concentrations (%)

Allantoin Aluminum hydroxide gel Calamine Cocoa butter Dimethicone Glycerin Kaolin Petrolatum Shark liver oil White petrolatum Zinc acetate Zinc carbonate Zinc oxide

0.5–2 0.15–5 1–25 50–100 1–30 20–45 4–20 30–100 3 30–100 0.1–2 0.2–2 1–25

symptoms of dry, scaly skin, making the rough surface soft and smooth’ may lack specificity. Also, the term ‘dry skin’ is not generally accepted [15, 16]. However, no consensus exists regarding the definition of a moisturizer [15]. Moisturizers are used daily to alleviate or improve ‘dry’ skin symptoms such as chapped hands and heels, ichthyosis, asteatosis, atopic dermatitis, atopic dry skin etc. [14–17]. Application of moisturizers may increase skin hydration and therefore may modify the skin surface’s physical and chemical nature, so as to smooth, soften and make more pliable [14, 16]. Effect of Moisturizers on the Skin Natural moisturizing factors, stored in the stratum corneum, aid horny layer hydration and flexibility and consist of a mixture of low-molecular-weight soluble hygroscopic substances [15, 16]. They include amino acids, lactic acid, pyrrolidone carboxylic acid and urea. A deficiency of natural moisturizing factors is linked to dry skin conditions [16]. Skin function maintenance is important in protecting the skin against many disorders which cause dry, chapped and cracked skin, sensitivity, irritation or inflammation and also against the repeated use of water, detergents and other irritants. Moisturizers often contain humectants of low molecular weight and lipids. Humectants, such as urea, glycerin, lactic acid, pyrrolidone carboxylic acid and salts, are absorbed into the stratum corneum and there, by attracting water, increase hydration [16, 17, 50]. Lipids, for instance petrolatum, beeswax, lanolin and various oils in moisturizers, have traditionally been considered to exert

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Table 2. Effects of moisturizers in the prevention of ICD Irritants

Moisturizers

Results

Authors and references

Liquid dishwashing detergent

Eight commercial moisturizers (3 oil-in-water creams; 1 skin oil; 4 double emulsions)

Significantly prevented ICD; also significantly enhanced the healing process

Hannuksela and Kinnunen [63]

Water and detergents

Locobase®

The moisturizer prevented the development of skin dryness

Halkier-Sørensen and Thestrup-Pedersen [64]

Dermatitis of premature newborns

Water-in-oil emollient

Statistically decreased dermatitis

Lane and Drost [65]

SLS

Three cream emulsions, 3 gels

5% urea increased TEWL, Lodén [61] whereas treatment with 10% urea for 10 and 20 days decreased TEWL

SLS

Hydrocortisone cream; fish oil; borage oil; petrolatum; canola oil; canola USF; shea butter; shea butter USF; sunflower oil

Canola oil and its sterolenriched fraction reduced the degree of SLS-induced irritation

Lodén and Andersson [66]

Water

Plutect 22®; Kerodex 71®; Locobase®

The test moisturizers showed a certain protective effect against water

de Fine Olivarius et al. [67]

Soap

Vaseline Intensive Care Lotion®

Significantly decreased dryness grades and scaling

El Gammal et al. [68]

SLS

Locobase®

The moisturizer showed significantly preventive and therapeutic effects

Ramsing and Agner [69]

SLS

Canoderm®

Skin hydration was significantly increased by the treatment and also reduced skin susceptibility to irritants

Lodén et al. [70]

SLS

A moisturizer

The moisturizer accelerated regeneration of the skin barrier function

Held and Agner [71]

SLS

A moisturizer

The moisturizer under an occlusive glove diminished irritation from exposure to a detergent followed by glove wearing

Held and Jorgensen [72]


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Table 2. (continued) Irritants

Moisturizers

Results

Authors and references

SLS

Six moisturizers

All 6 moisturizers accelerated regeneration of the skin barrier function when compared to irritated nontreated skin; the most lipid-rich moisturizers improved barrier restoration more rapidly than the less lipidrich moisturizers

Held et al. [73]

The emulsion minimized glove-induced ICD and decreased dry skin

Zhai et al. [74]

Occlusive A model lipid emulsion glove-induced ICD

SLS ⫽ Sodium lauryl sulfate; TEWL ⫽ transepidermal water loss; USF ⫽ unsaponifiable lipids.

their effects on the skin solely by forming an inert, epicutaneous, occlusive membrane. They are, therefore, incorporated into formulations on the basis of their technical and sensory properties rather than on their possible epidermal impact [50, 51]. However, topically applied lipids may also penetrate to the living cells of normal epidermis, enter into the metabolism and significantly modify endogenous epidermal lipids [52]. In normal skin, a single application of a moisturizer did not cause long-lasting effects expressed as skin capacitance and conductance [53, 54] whereas repeated applications of a moisturizer twice daily for 1 week produced a significant increase in the skin conductance for at least 1 week after treatment [55]. Urea, a unique physiological, nonallergic substance [56, 57], has been used in dermatological therapy for decades. Urea can decrease reversibly the turnover of epidermal cells [58] and may enhance the penetration of other substances into the skin [56, 59, 60]. Other effects include binding water in the horny layer, being antipruritic and reducing CD from irritant stimuli [56, 57, 61, 62]. Notable, high concentrations of urea can be irritating and therefore cause the irritant dermatitis and sensory irritation [15]. Moisturizers in Preventing Irritant Contact Dermatitis This topic has been extensively reviewed previously [14, 58]. Table 2 summarizes the effects of moisturizers in the prevention of ICD.

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Conclusion

The use of skin protection products such as BCs and moisturizers may help people to avoid or reduce the intensity of skin irritations caused by irritants at home and at the workplace. We should clearly educate people that BCs should be not used as a primary protection against high-risk substances as well as corrosive agents. It is recommended to provide the protection against low-grade irritants. However, wet workers utilizing water, soaps and detergents daily may benefit by applying BCs frequently. Furthermore, BCs may also shield the skin from chemicals, oils and other substances and make them easier to clean at the end of the workday [27]. To achieve optimal protective effects, BCs should be used with careful consideration of the types of substances they are designed to protect against based on a specific exposure condition; also, the proper education in use is essential [44, 45]. Inappropriate BC application may exacerbate irritation [12, 19, 31, 37, 46–48]; using BC on diseased skin may lead to increased irritation [12, 26]. The efficacy of moisturizers in the prevention of ICD has been well documented [14, 58]. Application of appropriate moisturizers may also accelerate the rate of healing on damaged skin [63, 68, 69, 71, 73, 74]. The use of a moisturizer under an occlusive glove may diminish irritation from exposure to a detergent [72], and it also minimized glove-induced ICD as well as decreased skin dryness [74]. Individuals regularly exposed to irritants should be encouraged to apply moisturizers frequently to reduce such dermatitides. However, controversial results have indicated that daily use of moisturizers on normal skin might increase the skin susceptibility to irritants even for 5 consecutive daily applications [75, 76]. The potential irritating effect of moisturizers may also need to be evaluated [77]. Optimal BC and moisturizer use not only prevents, but also treats mild ICD. Mixture of water-binding ingredients in the formulations may provide beneficial synergy [78]. Furthermore, cosmetically functional BCs or moisturizers, in particular containing cosmetic active components are more acceptable to the public [79, 80]. The optimum time to dose moisturizers remains to be determined. In industries and for individuals at low risk, dosing will probably be started after dermatitis development; conversely, in some industries and for individuals at high risk, prophylaxis such as BC may be applied prior to work. The ideal skin protection formulations should be nontoxic, noncomedogenic, nonirritating, nongreasy foam and colorless. They should keep high efficacy but not interfere with the user’s manual dexterity or sensitivity. They should be easy to apply and remove, cosmetically acceptable and economical. We believe that optimal multiple-function skin protection products will be developed with modern technology in the near future.


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43 44 45

46 47 48 49

Mahmoud G, Lachapelle JM: Evaluation of the protective value of an antisolvent gel by laser Doppler flowmetry and histology. Contact Dermatitis 1985;13:14–19. Loden M: The effect of 4 barrier creams on the absorption of water, benzene, and formaldehyde into excised human skin. Contact Dermatitis 1986;14:292–296. Mathias CGT: Prevention of occupational contact dermatitis. J Am Acad Dermatol 1990;23: 742–748. Davidson CL: Occupational contact dermatitis of the upper extremity. Occup Med 1994;9:59–74. Boman A, Wahlberg JE, Johansson G: A method for the study of the effect of barrier creams and protective gloves on the percutaneous absorption of solvents. Dermatologica 1982;164:157–160. McClain DC, Storrs F: Protective effect of both a barrier cream and a polyethylene laminate glove against epoxy resin, glyceryl monothioglycolate, frullania, and tansy. Am J Contact Dermatitis 1992;13:201–205. Mellström GA, Johansson S, Nyhammar E: Barrier effect of gloves against cytostatic drugs; in Elsner P, Lachapelle JM, Wahlberg JE, Maibach HI (eds): Prevention of Contact Dermatitis. Curr Probl Dermatol. Basel, Karger, 1996, pp 163–169. Zhai H, Maibach HI: Effect of barrier creams: human skin in vivo. Contact Dermatitis 1996;35: 92–96. Birmingham D: Prevention of occupational skin disease. Cutis 1969;5:153–156. Estlander T, Jolanki R, Kanerva L: Rubber glove dermatitis: a significant occupational hazard prevention; in Elsner P, Lachapelle JM, Wahlberg JE, Maibach HI (eds): Prevention of Contact Dermatitis. Curr Probl Dermatol. Basel, Karger, 1996, pp 170–176. Boman A, Estlander T, Wahlberg JE, Maibach HI (eds): Protective Gloves for Occupational Use, ed 2. Boca Raton, CRC Press, 2005. Chowdhury MMU, Maibach HI (eds): Latex Intolerance: Basic Science, Epidemiology, and Clinical Management. Boca Raton, CRC Press, 2005. Amin S, Maibach HI: Immunologic contact urticaria definition; in Amin S, Lahti A, Maibach HI (eds): Contact Urticaria Syndrome. Boca Raton, CRC Press, 1997, pp 11–26. Frosch PJ, Schulze-Dirks A, Hoffmann M, Axthelm I: Efficacy of skin barrier creams. II. Ineffectiveness of a popular ‘skin protector’ against various irritants in the repetitive irritation test in the guinea pig. Contact Dermatitis 1993;29:74–77. Frosch PJ, Kurte A: Efficacy of skin barrier creams. IV. The repetitive irritation test (RIT) with a set of 4 standard irritants. Contact Dermatitis 1994;31:161–168. Orchard S: Barrier creams. Dermatol Clin 1984;2:619–629. Marks JG Jr, Fowler JF Jr, Sheretz EF, Rietschel RL: Prevention of poison ivy and poison oak allergic contact dermatitis by quaternium-18 bentonite. J Am Acad Dermatol 1995;33:212–216. Reiner R, Rossmann K, van Hooidonk C, Ceulen BI, Bock J: Ointments for the protection against organophosphate poisoning. Arzneimittelforschung/Drug Res 1982;32:630–633. Zhai H, Buddrus DJ, Schulz AA, Wester RC, Hartway T, Serranzana S, Maibach HI: In vitro percutaneous absorption of sodium lauryl sulfate (SLS) in human skin decreased by quaternium-18 bentonite gels. In Vitr Mol Toxicol 1999;12:11–15. Packham CL: Evaluation of barrier creams: an in vitro technique on human skin (letter). Acta Derm Venereol 1994;74:405–406. Wigger-Alberti W, Maraffio B, Wernli M, Elsner P: Self-application of a protective cream: pitfalls of occupational skin protection. Arch Dermatol 1997;133:861–864. Wigger-Alberti W, Maraffio B, Wernli M, Elsner P: Training workers at risk for occupational contact dermatitis in the application of protective creams: efficacy of a fluorescence technique. Dermatology 1997;195:129–133. Goh CL: Cutting oil dermatitis on guinea pig skin. I. Cutting oil dermatitis and barrier cream. Contact Dermatitis 1991;24:16–21. Frosch PJ, Schulze-Dirks A, Hoffmann M, Axthelm I, Kurte A: Efficacy of skin barrier creams. I. The repetitive irritation test (RIT) in the guinea pig. Contact Dermatitis 1993;28:94–100. Treffel P, Gabard B, Juch R: Evaluation of barrier creams: an in vitro technique on human skin. Acta Derm Venereol 1994;74:7–11. Federal Register: Skin protectant drug products for over-the-counter human use. Fed Regist 1983;48:6832.


55

50 51 52 53

54 55 56

57 58

59 60 61 62

63 64

65 66 67 68

69 70

71 72 73

Lodén M: Barrier recovery and influence of irritant stimuli in skin treated with a moisturizing cream. Contact Dermatitis 1997;36:256–260. Lodén M: Biophysical properties of dry atopic and normal skin with special reference to effects of skin care products. Acta Derm Venereol Suppl 1995;192:1–48. Wertz PW, Downing DT: Metabolism of topically applied fatty acid methyl esters in BALB/C mouse epidermis. J Dermatol Sci 1990;1:33–37. Blichmann CW, Serup J, Winther A: Effects of single application of a moisturizer: evaporation of emulsion water, skin surface temperature, electrical conductance, electrical capacitance, and skin surface (emulsion) lipids. Acta Derm Venereol 1989;69:327–330. Lodén M, Lindberg M: The influence of a single application of different moisturizers on the skin capacitance. Acta Derm Venereol 1991;71:79–82. Serup J, Winther A, Blichmann CW: Effects of repeated application of a moisturizer. Acta Derm Venereol 1989;69:457–459. Serup J: A double-blind comparison of two creams containing urea as the active ingredient: assessment of efficacy and side-effects by non-invasive techniques and a clinical scoring scheme. Acta Derm Venereol Suppl 1992;177:34–43. Swanbeck G: Urea in the treatment of dry skin. Acta Derm Venereol Suppl 1992;177:7–8. Hannuksela A: Moisturizers in the prevention of contact dermatitis; in Elsner P, Lachapelle JM, Wahlberg JE, Maibach HI (eds): Prevention of Contact Dermatitis. Curr Probl Dermatol. Basel, Karger, 1996, pp 214–220. Feldmann RJ, Maibach HI: Percutaneous penetration of hydrocortisone with urea. Arch Dermatol 1974;109:58–59. Wohlrab W: Effect of urea on penetration kinetics of vitamin A acid in human skin. Z Hautkr 1990;65:803–805. Lodén M: Urea-containing moisturizers influence barrier properties of normal skin. Arch Dermatol Res 1996;288:103–107. Serup J: A three-hour test for rapid comparison of effects of moisturizers and active constituents (urea): measurement of hydration, scaling and skin surface lipidization by noninvasive techniques. Acta Derm Venereol Suppl 1992;177:29–33. Hannuksela A, Kinnunen T: Moisturizers prevent irritant dermatitis. Acta Derm Venereol 1992;72: 42–44. Halkier-Sørensen L, Thestrup-Pedersen K: The efficacy of a moisturizer (Locobase) among cleaners and kitchen assistants during everyday exposure to water and detergents. Contact Dermatitis 1993;29:266–271. Lane AT, Drost SS: Effects of repeated application of emollient cream to premature neonates’ skin. Pediatrics 1993;92:415–419. Lodén M, Andersson AC: Effect of topically applied lipids on surfactant-irritated skin. Br J Dermatol 1996;134:215–220. de Fine Olivarius F, Hansen AB, Karlsmark T, Wulf HC: Water protective effect of barrier creams and moisturizing creams: a new in vivo test method. Contact Dermatitis 1996;35:219–225. El Gammal C, Pagnoni A, Kligman AM, el Gammal S: A model to assess the efficacy of moisturizers – The quantification of soap-induced xerosis by image analysis of adhesive-coated discs (D-Squames®). Clin Exp Dermatol 1996;21:338–343. Ramsing DW, Agner T: Preventive and therapeutic effects of a moisturizer: an experimental study of human skin. Acta Derm Venereol 1997;77:335–337. Lodén M, Andersson AC, Lindberg M: Improvement in skin barrier function in patients with atopic dermatitis after treatment with a moisturizing cream (Canoderm®). Br J Dermatol 1999;140:264–267. Held E, Agner T: Comparison between 2 test models in evaluating the effect of a moisturizer on irritated human skin. Contact Dermatitis 1999;40:261–268. Held E, Jorgensen LL: The combined use of moisturizers and occlusive gloves: an experimental study. Am J Contact Dermatitis 1999;10:146–152. Held E, Lund H, Agner T: Effect of different moisturizers on SLS-irritated human skin. Contact Dermatitis 2001;44:229–234.

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74

75 76 77 78

79 80

Zhai H, Schmidt R, Levin C, Klotz A, Maibach HI: Prevention and therapeutic effects of a model emulsion on glove-induced irritation and dry skin in man. Dermatol Beruf Umwelt/Occup Environ Dermatol 2002;4:134–138. Held E, Sveinsdóttir S, Agner T: Effect of long-term use of moisturizer on skin hydration, barrier function and susceptibility to irritants. Acta Derm Venereol 1999;79:49–51. Held E, Agner T: Effect of moisturizers on skin susceptibility to irritants. Acta Derm Venereol 2001;81:104–107. Agner T, Held E, West W, Gray J: Evaluation of an experimental patch test model for the detection of irritant skin reactions to moisturizers. Skin Res Technol 2000;6:250–254. Miettinen H, Johansson G, Gobom S, Swanbeck G: Studies on constituents of moisturizers: waterbinding properties of urea and NaCl in aqueous solutions. Skin Pharmacol Appl Skin Physiol 1999;12:344–351. Kobayashi R, Takisada M, Suzuki T, Kirimura K, Usami S: Neoagarobiose as a novel moisturizer with whitening effect. Biosci Biotechnol Biochem 1997;61:162–163. Jemec GB, Wulf HC: Correlation between the greasiness and the plasticizing effect of moisturizers. Acta Derm Venereol 1999;79:115–117.

Hongbo Zhai, MD Department of Dermatology, University of California School of Medicine San Francisco, CA 94143–0989 (USA) Tel. ⫹1 415 514 1537, Fax ⫹1 415 753 5304, E-Mail [email protected]


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Protection from Occupational Allergens Peter C. Schalock, Kathryn A. Zug Dermatology Unit, Department of Medicine, Dartmouth Medical School, Lebanon, N.H., USA

Abstract Occupational skin disease (OSD) is an important and costly problem within occupational medicine. Ten to 15% of all occupational illness is caused by skin disease with contact dermatitis being the cause of up to 95% of all OSD. While irritant contact dermatitis is the most frequent cause of OSD, allergic contact dermatitis (ACD) is an important cause of chronic skin disease. In this chapter, various methods of protecting a worker from workrelated allergy, including immediate and delayed-type hypersensitivities, are considered and reviewed. Concepts such as elimination of harmful exposures and allergen identification are considered. Personal protective equipment is an important component of prevention, including barrier creams, gloves and protective clothing. Methods for preventing allergy are discussed including prevention of sensitization, prevention of skin barrier breakdown, postexposure skin care and the role of educational programs. Protecting a worker from initial sensitization is the primary goal in prevention, but this is challenging considering the small amounts of an allergen needed to initiate and potentiate dermatitis. Patients diagnosed as having ACD can have symptoms that are more persistent, despite accurate diagnosis and therapy. With the high prevalence of contact dermatitis in the occupational setting, prevention is a key to healthy skin. Copyright © 2007 S. Karger AG, Basel

Occupational skin disease (OSD) is an important and costly problem. Ten to 15% of all occupational illness is caused by skin disease with contact dermatitis being the cause of up to 95% of all OSD. Contact dermatitis can be divided into irritant contact dermatitis (ICD), which makes up 80% of cases, and allergic contact dermatitis (ACD), which makes up 20% of cases [1]. Exposed areas such as the hands and arms are most commonly affected. Occupational hand dermatitis is a common cause of OSD, with an estimated annual cost in 1984 of 222 million to 1 billion USD in the USA [1]. In 1995, the Netherlands had an annual cost of 42 million EUR [2].

The incidence of OSD appears to be similar, whether data from Europe or the USA are examined. Rates from the USA, Germany and Denmark are estimated at 0.8 per 1,000 workers per year [2]. In 1993, 60,200 OSD cases were reported in the USA. Seventy percent of these cases were diagnosed as dermatitis and 21% required time away from work. In 2000, 41,800 cases of OSD were reported in the US workforce, though the actual number of cases is presumed to be 10–50 times higher due to underreporting [1]. Once occupational contact dermatitis is established, many patients are unable to obtain complete resolution of their skin condition, despite aggressive treatment and leaving the dermatitis-provoking job [3]. Interestingly, leaving a job due to an occupational allergy has been associated with a significantly worse quality of life compared to those who elected to keep their current position [4]. The prognosis for patients with ACD is thought to be worse than those with ICD. Meding and Swanbeck [5] examined 1,238 patients with hand eczema in Sweden by questionnaire. They found that patients with ACD had more frequent changes in occupation, take a greater number of sick days and have more medical appointments when compared to other causes of hand dermatitis [5]. Patients with a diagnosis of ACD can have symptoms that are more persistent, despite an accurate diagnosis and therapy. With the high prevalence of contact dermatitis in the occupational setting, prevention is a desirable goal. While the majority of patients with occupational contact dermatitis have ICD, which most people will develop when exposed to an irritant at a sufficient concentration, there are two other types of skin disease due to exposure to allergenic compounds. Immediate-type hypersensitivity (type I) can occur in an occupational setting, most recently made prominent by allergy to natural rubber latex (NRL) proteins found in latex/rubber gloves. Fish, shellfish, meat and other proteins can also cause relevant IgE-mediated type I allergies in workers. Type IV delayed-type hypersensitivity can occur from a variety of allergens found in the workplace. A list of likely allergens can often be associated with a particular workplace or job. For instance, there are a number of chemicals commonly associated with the professions of dentistry, the machinist trade or hairdressing. In this chapter, protection of the worker from ACD will be discussed with a focus on delayed-type hypersensitivities. The relevant data concerning methods of protection from occupational allergens will be presented in detail. Concepts such as elimination of harmful exposures and allergen identification are considered and personal protective equipment is reviewed, including barrier creams, gloves and protective clothing. Methods for preventing allergy are discussed including prevention of sensitization, prevention of barrier breakdown, postexposure skin care and workplace educational programs.

Protection from Occupational Allergens

59

Table 1. Top allergens in occupational ACD Germany [9]

North America (NACDG allergens) [10]

North America (True Test allergens) [10]

(1) (2) (3) (4)

(1) (2) (3) (4) (5) (6) (7) (8) (9) (10)

(1) (2) (3) (4) (5) (6) (7) (8) (9) (10)

(5) (6) (7) (8)

Thiuram mix Epoxy resin p-Phenylenediamine free base p-Phenylenediamine-black-rubber mix/N-isopropyl-N⬘-phenylp-phenylenediamine Potassium dichromate Formaldehyde Chloromethylisothiazolinone/ methylisothiazolinone Mercapto mix/mercaptobenzothiazole

Nickel Thiuram Carba mix Formaldehyde Quaternium-15 Neomycin Cobalt Thimerosal Bacitracin Balsam of Peru

Nickel Thimerosal Formaldehyde Quaternium-15 Carba mix Fragrance mix Ethylenediamine Cobalt Epoxy resin Thiuram

Allergens in the Workplace

So-called universal precautions resulted in the marked increase in use of latex gloves as personal protective equipment. Since then, the rate of NRL allergy, especially type I allergy, has increased. While approximately 1% of the general population is sensitized to latex, it is now believed that 10–17% of healthcare workers have a type I allergy to NRL allergenic proteins [6, 7]. However, these numbers may be inflated by self-reported allergy assessments. In a study by Allmers [8], it was found that 63% of healthcare workers selfreporting sensitivity to NRL had negative results (hives, pruritus etc.) when exposed to NRL in an occupational use type of situation. Many other professions use gloves on a daily basis for the perceived benefit of protection from irritant and allergy-provoking exposures. While protecting themselves to some degree, individuals using latex gloves may be exposed to other glove additive allergens (i.e. thiurams and carbamates) that result in delayed-type hypersensitivity. The most common occupationally relevant causes of ACD in a 10-year study in Germany and recent data from the North American Contact Dermatitis Group reporting the top occupational allergens seen by their group are summarized in table 1 [9, 10]. Professions associated with exposure to these and other allergens and recommended gloves for protection are summarized in table 2. A comparison between the top occupations effected by occupational ACD is presented in table 3. Skoet et al. [11] examined the rates

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Table 2. Glove penetration of allergens by profession Profession

Allergen

Use

Protective

Not protective

Hairdresser

Glyceryl monothioglycolate/ ammonium thioglycolate Epoxy resin Acrylates

Permanent wave solution

Neoprene household gloves, 4H

Butadiene polymer, NRL, V

Adhesive Adhesive/ plastic appliances Hair dye Nail polishes

N, SR, P, 4H 4H

NRL NRL, N, V

V ?

?

Metal finishes

P, polyethylene, neoprene

Cement additive/ leather tanning Adhesive Automobile paints

Some BC

p-Phenylenediamine Tosylamide formaldehyde resin Nickel Cement/ construction industry Healthcare/ dentistry

Chromates Epoxy resins Aliphatic isocyanates

NRL Glove material Rubber accelerators Rubber production (carba, thiuram, mercaptobenzothiazole) Chlorhexidine Antibacterial/surgical scrub Bacitracin/neomycin/ Antibacterial polymyxin Formaldehyde Preservative Acrylates Adhesive/plastic appliances Epoxy resin Adhesive Glutaraldehyde Cold sterilization

NRL

N, SR, P, 4H 4H

NRL NRL

P

BC NRL, N

NRL, SR ?NRL (neomycin) SR, 4H 4H N, SR, P, 4H N, P, SR, 4H

NRL NRL, N NRL NRL

BC ⫽ Barrier cream; N ⫽ nitrile; P ⫽ plastic; SR ⫽ synthetic rubber; 4H ⫽ Silvershield/4H; ? ⫽ not known.

of occupational hand dermatitis both from irritant and allergic eczema in Denmark in 2004. Women were more likely to be allergic to rubber additives (from gloves) and biocides such as methylchloroisothiazolinone/ methylisothiazolinone, Euxyl K400 and quaternium-15 (from skin care products). Men reacted at significantly higher rates than women to chromates (from leather gloves), but at similar rates to rubber additives and nickel (from tools) [11].


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Table 3. Risk of ACD by profession Germany [9]

North America [10]

(1) (2) (3) (4) (5) (6) (7)

(1) (2) (3) (4) (5) (6) (7) (8) (9) (10)

Hairdressers/barbers Florists Tile setters/terrazzo workers Bakers Dental technicians Healthcare workers Machinists/metal surface processors

Registered nurses Assemblers Nurses aides/orderlies Machinists Students Hairdressers Machine operators Auto mechanics Compressing/compacting Cooks

Table 4. Methods of protection from occupational ACD [12, 13] Identification of potential allergens Elimination/replacement of harmful exposures Personal protective equipment Personal and environmental hygiene Educational programs Prevention of skin barrier breakdown (ICD) Postexposure skin care Regulatory controls Preemployment screening

Methods of Skin Protection

Prevention from allergic sensitization and subsequent ACD is an important goal of occupational dermatology. When this statement is made, what is meant by the word prevention? There are three types of prevention, primary, secondary and tertiary. In primary prevention, the goal is to keep the healthy individual without skin problems in that disease-free state. Secondary prevention targets a diseased patient in an attempt to prevent a disease relapse. Rehabilitation or tertiary prevention is aimed at treating a chronically diseased individual and attempts to help return him/her to the workplace. Primary prevention is highly desirable but for a variety of economical and practical reasons is often not accomplished. Nine important concepts in worker protection from allergens and irritants are summarized in table 4 (modified from Mathias [12] and Wigger-Alberti and Elsner [13]). These critical concepts are explored further individually.

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Identification of Allergens

An awareness and understanding of the chemicals that a worker is exposed to in the workplace are of the utmost importance for protecting the worker from exposures to substances that may induce ACD. Predictive tests such as the Draize test and the open epicutaneous test use animal models to help predict allergenic compounds. Other tests available use adjuncts, such as Freund’s complete adjuvant test, the optimization test, the split adjuvant test and the guinea pig optimization test [13]. Allergens identified by these processes should be used with caution in the workplace. Chemical tests that can be used by the worker to determine if an object or contact contains a particular allergen are not widely available for most allergens. However, nickel and chromate can be detected simply using the dimethylglyoxime and diphenylcarbazide tests, respectively. The dimethylglyoxime test for nickel is used by applying the solution onto a cotton applicator and then rubbing the item suspected of containing nickel. A positive test is indicated by a pink color on the applicator. One version of this test, the ‘Allertest Ni’, is available commercially from Allerderm Laboratories (www.allerderm.com).

Elimination/Replacement of Harmful Exposures

Elimination or replacement of known sensitizing allergens can be a useful method to prevent ACD. Successful identification of a common allergen, chromate, and replacement with another nonsensitizing agent is well described in Denmark. In 1981, at manufacture, the chromate content of cement in Denmark was lowered to less than 2 parts per million of water-soluble chromate. This was accomplished by replacing chromate with ferrous sulfate at an added cost of approximately 1%. By this substitution, hand eczema decreased from 11.7 to 4.4% of workers [14]. Chromate allergy also decreased from 10.5 to 2.6% of workers examined. Irritant dermatitis rates did not change [14]. In a separate study, Avnstorp [15] compared the workers sensitized to chromate prior to the change in 1981 with younger workers who were employed after the decrease in cement chromate concentration. The older workers with chromate allergy appeared to show no improvement after 6 years, despite the reduction of chromate in the cement. Older workers also required more medical services and topical corticosteroids and took retirement at a younger age than non-chromatesensitized workers. Workers with concomitant allergy to cobalt and rubber chemicals had a worse prognosis. The younger workers were able to continue working, and their employment status was not influenced by their skin problems [15]. A change as seemingly simple as the substitution of one nonallergenic


63

metal for an allergenic metal was enough to decrease the rate of ACD by 7.9% over the course of 6 years! The benefit of this change has recently been confirmed by Bock et al. [16], who examined the rates of ACD in the construction industry, finding potassium dichromate (chromium VI) to be the most prevalent allergen in cement workers in Germany, where the chromium VI content of the cement has not been decreased. The rate of sensitization was unchanged during the 1990s using the cement products with a higher chromium VI content [16]. This example of elimination of a known allergen illustrates the concept of primary prevention with excellent results for workers. Decreasing the rate of sensitization makes for better outcomes for workers and potentially reduces costs associated with worker compensation insurance and healthcare expenses for affected workers.

Personal Protective Equipment

Barrier creams are used as both primary and secondary prevention from exposure to allergens in the workplace. Their functional intent is to provide a nonpermeable barrier, separating the skin from potential irritating, noxious and/or allergenic substances to which a worker may be exposed. There are three types of nonspecific barrier creams, water repellant, oil repellant and silicone based. Water-repellant barrier creams contain hydrophobic substances. They are used in wet work professions and to prevent exposure to water-soluble irritants and allergens. Oil-repellant barrier creams contain lipophobic substances, which are intended for use by individuals exposed to oils, greases or other oilsoluble substances. Silicone-based creams are useful for general protection from both water-soluble and organic agents. The controversy about whether barrier creams are effective at doing what they claim is well illustrated by the title of a recent article, ‘Barrier creams: fact or fiction’ [17]. Protecting the worker from exposure to allergens and irritants is a large task. An established ACD in a sensitized individual can be elicited with only a minimal exposure quantity and concentration of allergen, thus complete protection is necessary at all times. Practical matters such as the need for frequent barrier cream reapplication and patient acceptance to use may also hinder obtaining the best possible protection from ACD. Despite these issues, there have been a few reported successes in the development and use of barrier creams specifically for ACD. Studies evaluating barrier cream efficacy for protection from various allergens are summarized in table 5. Urushiol contact dermatitis (poison oak/ivy) has been prevented with the application of quaternium-18 bentonite, an organoclay. Quaternium-18 bentonite blocks the development of dermatitis by physically blocking the urushiol

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Table 5. Protective creams by allergen Allergen

Active agent or name

Reference

Comment

Available

Urushiol

Quaternium-18 bentonite

[46]

Ivy Block (www.ivyblock.com)

Stokogard

[47]

‘Very effective’, absent or very reduced dermatitis 52% reduction in dermatitis severity 52% reduction 48% reduction

Hollister moisture barrier Hydropel

Epoxy resins

Teflon-like polymer in perfluoroalkylpolyether

[18]

‘Highly effective’

Kerodex 77 and Dermotect

[19]

Barrier creams – decreased reaction intensity

Nobecutane and Organon

Nickel

EDTA

Methacrylate wound spray, decreased reaction intensity/area [20]

5-Chloro-7-iodoquinolin8-ol (clioquinol)

Cream based on ion exchange resin Spray containing dexamethasone and isopropyl myristate DTPA

[48]


Not available Yes (www.hollister.com) Yes (www.genesispharm.com) Not available Kerodex 77 – yes (www.arsima.dk) Dermotect – yes (www.procar.nl) Nobecutane – no Organon – no

Various formulations of EDTA effective Most effective topical Ni ligand, cutaneously absorbed; is a potential neurotoxin ‘Very effective’

Compounded cream

Not available

‘very effective’

Not available

Oil-in-water emulsion; 96% with reduction of ⫹ reaction in patch test trial

DTPA compounded with Hydrocream HY/Excipial

Various formulations commercially available

65

Table 5. (continued) Allergen

Active agent or name

Reference

Comment

Available

Potassium dichromate

1.8% Na2H2EDTA ⫹ 5.4% CaNa2EDTA

[20]

Effective in reducing dermatitis

Compounded cream

Cream compound: silicone, glyceryl lactate, glycine, tartaric acid and base

[49]

60% effective in 60 workers

Compounded cream

Cobalt

DTPA

[48]

70% effective in patch test trial


Copper

DTPA

[48]

64% effective in patch test trial


DTPA ⫽ Diethylenetriaminepentaacetic acid; EDTA ⫽ ethylenediaminetetraacetic acid.

oil from reaching the skin. Another intriguing barrier cream is a ‘topical skin protectant’ developed by the US military for protection against chemical warfare agents. This is a specially formulated emulsion of a Teflon-like (Teflon, Dupont, Wilmington, Del., USA) polymer in perfluoroalkylpolyether which was shown to protect from urushiol dermatitis in sensitive individuals [20]. However, this product is not commercially available. Other protective creams against urushiol contact allergy are summarized in table 5, with comments regarding efficacy. Protection from epoxy resin ACD was evaluated with 4 barrier creams and 2 methacrylate spray coatings using an artificial, patch testing method [21]. Both of the barrier creams were applied in a thin layer and rubbed in for 1 min. The methacrylate sprays were sprayed on and allowed to dry for 1 min. Patch tests to epoxy resin were applied. They were not reapplied during the 24 h the patch tests were in place. The methacrylate wound sprays both significantly reduced the intensity and surface area of epoxy patch test reactions when compared to control by patch testing. Two of 4 barrier creams decreased the intensity of ACD reactions only. Unfortunately, the application schedule and efficacy of these sprays in an actual working environment are not known. Metal allergy is a significant problem for several professions, specifically concrete workers who become sensitized to hexavalent chromium present in wet cement and hairdressers who use nickel-plated instruments. There have been multiple attempts to create a cream to chelate metal ions, making them unavailable for percutaneous penetration. A review of successes and failures

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has recently been published [22]. The most effective compounded cream for protection against nickel ACD contained 5-chloro-7-iodoquinolin-8-ol (clioquinol). However, clioquinol is readily absorbed through the skin and can itself be a contact allergen. There are also reports of clioquinol causing neurotoxicity in the form of subacute myeloopticoneuropathy. This has limited the development of such a cream for barrier protection. Other formulations showing some protection against nickel, cobalt and copper allergic dermatitis used diethylenetriaminepentaacetic acid, ethylenediaminetetraacetic acid (EDTA) or a blend of dexamethasone and isopropyl myristate. Several creams have been suggested to reduce or eliminate dermatitis in workers exposed to hexavalent chromium including a blend of 1.8% Na2H2EDTA ⫹ 5.4% CaNa2EDTA and a compounded cream containing silicone, glyceryl lactate, glycine, tartaric acid and base. Loden found that 3 of 4 barrier creams tested had no effect on formaldehyde absorption, while 1 reduced absorption by 40%. None of these creams were effective at decreasing exposure to benzene [25]. While barrier creams may in some situations be helpful adjuncts to protecting workers from dermatitis, there are potential negative effects of barrier cream use. Any cream base containing water will need to have some type of preservative. ACD to preparation ingredients can result as an unwanted and unidentified side effect of frequent application of the very agent expected to protect from dermatitis. Lanolin, emulsifiers, fragrances and formaldehyde releasers such as diazolidinyl urea, imidazolidinyl urea and quaternium-15 can be found in some creams. Hachem et al. [26] presented interesting findings regarding skin barrier damage. A poorly hydrating cream was compared to a hydrating cream in nickel-allergic individuals exposed to nickel after 21 days of application of the creams. They concluded that long-term use of an inadequate moisturizer increased skin barrier damage due to ACD [26]. If this conclusion can be extended to other types of ACD, barrier creams may, in fact, be damaging over time if they are not adequately moisturizing the skin. Barrier creams have been examined in patients with type I allergy to NRL. Baur et al. [27] found that barrier cream use increased the uptake of latex allergens from the tested gloves, causing a higher rate of skin reactions when compared to the use of gloves alone. There seem to be many barrier creams that appear to be potentially useful in research situations in preventing dermatitis in workers, but these creams do not seem to be in general use in the workplace. The reasons for this are multiple. Lack of cosmetic acceptance, the frequency of application necessary for protection, decreases in perceived and actual tactile stimulus, and potential damage to the product being manufactured are all reasons why workers have not used barrier creams in the past. The ideal barrier cream would address all of the above issues; unfortunately such a barrier cream does not exist [17].


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Gloves as Barrier Protection

Many workers use gloves, believing that they are protecting themselves from allergy-provoking chemicals and skin irritation. However, protection from gloves is not always the case. Skin irritation can be a significant problem from occlusion, sweating and maceration that occurs with prolonged glove use. Gloves themselves can produce ICD from bacterial endotoxins from gamma radiation used in sterilization and due to ethylene oxide [28, 29]. Surprisingly, allergens can penetrate many types of gloves in minutes to hours after exposure to the glove surface. Additionally, gloves themselves are the source of sensitizing chemicals other than latex, which may be erroneously blamed. In many patients, ACD caused by glove exposure is secondary to exposure to rubber accelerators, antioxidants and vulcanizing agents used in NRL and nitrile glove production. These agents are added to shorten production time, optimize glove quality and reduce effects of weathering and aging of the glove [30]. Von Hintzenstern et al. [30] examined the frequency of rubber allergy during a 5-year period. Of the 55% of rubber-additive-allergic patients who had an occupational source of exposure, 84% were labeled as sensitized by glove exposure, as this was the only likely source of sensitization. The remaining 16% with occupational rubber allergy were sensitized by rubber products such as cables, rubber grips or tools, tires and latex-coated papers. The top 4 professions associated with glove additive allergy were: health and laboratory services, homemaking, building industry and the metal industry [30]. The most frequent glove allergens are thiurams, carbamates and mercaptobenzothiazole. Carbamates are the most commonly used accelerator in NRL gloves and they may cross-react with thiurams. Thiurams were positive in 72% and carbamates in 25% of patch tests in patients with occupationally related ACD to gloves [30]. It is important to differentiate between glove ingredient ACD and the type I allergy seen with NRL. Many patients are convinced that they are ‘latex allergic’ when in actuality, on prick testing and patch testing, they are allergic to the rubber additive components only. It is important to mention here that the proper and complete testing of patients with suspected allergy is a critical aspect of care for the worker suspected of having an occupational dermatitis. Many allergens have been shown to penetrate gloves without causing obvious damage to the glove structure. Frequently encountered workplace allergens such as nickel, epoxy resins, acrylic monomers, glutaraldehyde and glyceryl monothioglycolate are discussed below. Neomycin, organic solvents, diallyl disulfide (the allergen in garlic) and methylparabens have also been shown to cross some brands of gloves [31–33].

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Glove Protection from Nickel

Nickel sulfate has been shown to penetrate NRL gloves but not polyvinyl chloride gloves after 48 h of patch testing in nickel-allergic patients. A dimethylglyoxime test was positive, both from NRL glove surfaces and from the skin [34]. While this is important information, it is not how nickel exposure usually occurs in an occupational setting. Exposure is frequently of short duration with nickel-plated objects. There are no other reports of nickel allergens penetrating gloves.

Glove Protection from Epoxy Resins

Epoxy resins are two-part adhesives used commonly in industry; allergy to epoxy resins can be a significant dermatological problem. The bisphenol A type resins are low-molecular-weight oligomers that are frequent contact sensitizers [21]. Workers exposed to epoxy resins in a wind turbine factory were more likely to be epoxy sensitive with longer durations of work. In these workers, 3 layers of protective gloves were mandatory (cotton on the skin, thin nitrile gloves and thick black rubber gloves on the outside). Despite protective measures of gloves and personal protective clothing, 20% of workers were patch test positive to an epoxy chemical found in their work environment [35]. In this situation, exposure through gloves and failure of the protective clothing both could play a role in allowing sensitization. In a separate study, Blanken et al. [36] examined 10 workers with allergy to bisphenol A epoxy resins. Each was patch tested with controls and samples of 6 different gloves (rubber, neoprene, polyvinyl chloride, nitrile-butatoluene-rubber and nitrile) with epoxy resin in a chamber with each glove type placed over, between the skin and the allergen. Six of 10 patients reacted with a 2⫹ or greater reaction through the NRL glove. One patient also reacted through the neoprene and polyvinyl chloride gloves [36]. Neoprene, polyvinyl chloride, nitrilebutatoluene-rubber and nitrile gloves were protective from the development of epoxy ACD after 48 h of exposure. The North Silvershield/4H glove (www. northsafety.com) does claim to provide protection from epoxy resins [37]. These results suggest that NRL gloves are not protective for epoxy resins, but other synthetic gloves may be helpful in preventing epoxy sensitization and exposure.

Glove Protection from Acrylic Resins

Acrylates are frequent allergens in the healthcare field, especially for dentists and orthopedic surgeons. Mono- and dimethacrylates are components of


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bonding systems, resins and sealants frequently used in dentistry, especially 2-hydroxyethyl methacrylate (HEMA) and triethylene glycol dimethacrylate (TEGDMA). Methyl methacrylate (MMA) is a frequently used bone cement to which orthopedic surgeons are often exposed [38]. Munksgaard [38] examined the rates at which HEMA and TEGDMA pass through latex and nitrile gloves in concentrated, diluted in ethanol and diluted in acetone forms. NRL gloves provided protection for approximately 5 min for the concentrated and diluted in ethanol forms and nitrile gloves for 15.7 and 9.9 min, respectively. Dilute acetone solutions decreased the penetration time to 2.8 min for both NRL and nitrile gloves [38]. Vinyl gloves have a breakthrough time of 1–3 min and NRL gloves one of 5–8 min for HEMA and TEGDMA [39]. MMA has been shown to penetrate gloves in 1–2.5 min [40]. Darre et al. [41] have reported a 3-layer glove made of polyethylene outside, a middle layer of ethylene vinyl alcohol copolymer and an inner layer of polyethylene (the PVP glove) that was impervious to MMA for 20 min. This glove does not seem to be commercially available at this time. Acrylate monomers pass through a variety of gloves at an extremely rapid rate, especially when the actual time a glove would be used in a procedure is considered. The North Silvershield/4H glove claims to provide greater than 240 min protection from a variety of acrylic resins [42]. These may be used under other types of gloves, but due to their nonanatomic fit may be harder to use when fine dexterity is needed. For adequate protection, gloves that show longer times before penetration must be used and frequently changed. For economical and practical reasons, this is very difficult.

Glove Protection from Glutaraldehyde

Glutaraldehyde is commonly used in cold sterilization of medical and dental equipment. It is well known that NRL gloves do not protect from glutaraldehyde exposure. Glove breakthrough with NRL materials has been estimated at 45 min for glutaraldehyde, though there are conflicting data regarding this figure. Mäkelä et al. [43] examined multiple NRL surgical gloves and did not find any glutaraldehyde penetration at 4 and 8 h of exposure to the glove. Whether or not the penetration occurs at a fast or slow rate, the Occupational Safety and Health Administration in the USA prohibits the use of NRL gloves with glutaraldehyde and has fined hospitals for allowing workers to use them [44]. The Occupational Safety and Health Administration’s concern is both for exposure to the allergen and glove deterioration that would allow exposure of the wearer to blood-borne pathogens through undetected pores in the glove. Gloves made of butyl rubber, nitrile rubber or polyethylene have been suggested to be safe for glutaraldehyde exposures for up to 8 h [44].

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Glove Protection from Glyceryl Monothioglycolate

Glyceryl monothioglycolate (GMTG) is found in acid permanent wave solutions used in beauty salons and in home permanent wave kits. Storrs [45] examined hairdressers sensitive to GMTG by patch testing for 48 h through a variety of gloves at varying concentrations of GMTG. Many of these patients were sensitive to GMTG 0.25% through butadiene polymer, NRL and vinyl gloves. Neoprene household gloves were uniformly protective [45].

Protective Clothing

Protective or barrier clothing is often used by workers exposed to irritant or allergy-provoking chemicals. Materials used in these protective barriers include cloth, vinyl and rubber materials. As noted in the glove section above, many allergens are capable of passing through rubber or vinyl materials. These allergens, in small amounts, may be capable of producing ACD in the worker without any obvious degradation of the protective material. With exposure to allergens known to pass through these materials, double gloving and frequent changing has been suggested in some cases to obtain the desired level of protection. Irritants usually do not penetrate these types of materials in amounts sufficient to provoke an irritant skin response without first causing noticeable degradation of the material. Allergy may also occur due to the protective material itself or, more importantly, due to allergen trapping beneath the barrier clothing [12].

Personal and Environmental Hygiene

Personal and environmental hygiene is an important concept in the prevention of ICD and ACD. In three auto body shops which used aliphatic isocyanates in paint, Liu et al. [46] examined environmental surfaces and the workers’ skin for exposure and for breakthrough of personal protective equipment. The study found that surfaces such as workbenches, spray equipment and cleaning tools were contaminated with isocyanates. The workers had frequent unprotected exposures to these surfaces. Moderate to heavy contamination with isocyanates was found on the skin of many workers. Latex gloves used for personal protective equipment showed significant breakthrough, even after a single use [46]. This report is an illustrative example of a failure in occupational hygiene measures. While a worker may be protected from an allergen while actually working with the product, this protection is in vain if the working environment is not


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kept clean and free of the allergen. Use of proper ventilation in closed systems and automation that leads to a no-touch technique can be part of a successful primary prevention strategy. These methods and immediate cleaning after spills or personal exposures can help prevent contamination of the workplace and sensitization of the worker. If the allergen can be found on surfaces that the workers contact without protection, it is challenging to prevent sensitization and allergic reactions. Education of the worker and simple efforts and methods of re-education are also a critical aspect of avoiding or minimizing environmental contamination and subsequent unintended exposures.

Educational Programs

A variety of worker educational programs have been shown to be successful in reducing the incidence of OSD. In general, these educational sessions have focused on the prevention of ICD in various populations, including baking apprentices and new hairdressing trainees [47]. ‘Eczema school’ in an occupational dermatology clinic in Finland was found to improve results for both irritant and allergic dermatitis. In this clinic, a trained dermatology nurse educated patients about skin care, allergen avoidance and skin protection [48]. Patients with ICD had significantly better outcomes after education (p ⬍ 0.008) compared to patients with ACD. Within the ACD groups, those who were educated did not have continuous dermatitis versus 13% of the noneducated group. Education also seemed to enhance avoidance of allergens such as metals or synthetic resins. Pre-employment screening was used in a study by Macan et al. [49] to evaluate rates of atopy and contact sensitization in a group of 351 subjects applying for work at a pharmaceutical company. A patch test, prick test and a health questionnaire were administered. According to the medical history, 69% of women and 77% of men were asymptomatic. Of these asymptomatic individuals, 24% of women and 28% of men showed evidence of atopy and/or contact sensitization. While this information would not be used to exclude someone from a certain occupation, it could be extremely beneficial knowledge for preemptive secondary prevention of OSD.

Prevention of Skin Barrier Breakdown/Postexposure Skin Care

Postexposure skin care is especially important for workers chronically exposed to irritating substances, but is also important for workers known to be allergic to substances with which they come into contact. ICD is the most common cause of occupational skin disease and can play a role in the development

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and perpetuation of allergic skin reactions. Skin barrier breakdown allows greater penetration of allergenic substances, thus increasing the opportunity for sensitization. Good skin care such as the use of appropriate barrier creams, bland emollients and avoidance of wet work or macerating gloves all can decrease skin irritation and transepidermal water loss in experimental settings. Good skin care and prevention of irritation should be an integral part of preventing ACD in the worker. Prevention of allergic skin disease in the worker continues to be a challenge. Primary prevention by identification and substitution of allergen, barriers in the form of gloves or creams, protective clothing and education of the worker are all important strategies to implement. Good basic skin care and prevention of irritant dermatitis may also help reduce the decrease in barrier function of the skin and subsequent sensitization and ACD. References 1 2 3 4 5 6 7 8 9

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11 12 13 14 15 16

Lushniak BD: Occupational contact dermatitis. Dermatol Ther 2004;17:272–277. Diepgen TL: Occupational skin disease data in Europe. Int Arch Occup Environ Health 2003;76: 331–338. Holness DL, Nethercott JR: Work outcome in workers with occupational skin disease. Am J Ind Med 1995;27:807–815. Kadyk DL, McCarter K, Achen F, Belsito DV: Quality of life in patients with allergic contact dermatitis. J Am Acad Dermatol 2003;49:1037–1048. Meding B, Swanbeck G: Consequences of having hand eczema. Contact Dermatitis 1990;23: 6–14. Charous BL, Tarlo SM, Charous MA, Kelly K: Natural rubber latex allergy in the occupational setting. Methods 2002;27:15–21. Wigger-Alberti W, Elsner: Do barrier creams and gloves prevent or provoke contact dermatitis? Am J Contact Dermat 1998;9:100–106. Allmers H: Wearing test with 2 different types of latex gloves with and without the use of a skin protection cream. Contact Dermatitis 2001;44:30–33. Dickel H, Kuss O, Schmidt A, Diepgen TL: Occupational relevance of positive standard patch-test results in employed persons with an initial report of an occupational skin disease. Int Arch Occup Environ Health 2002;75:423–434. Rietschel RL, Mathias CG, Taylor JS, Storrs FJ, Sherertz EF, Pratt M, Marks JG Jr, Maibach HI, Fransway AF, Fowler JF Jr, DeLeo VA, Belsito DV: A preliminary report of the occupation of patients evaluated in patch test clinics. Am J Contact Dermat 2001;12:72–76. Skoet R, Olsen J, Mathiesen B, Iversen L, Johansen JD, Agner T: A survey of occupational hand eczema in Denmark. Contact Dermatitis 2004;51:159–166. Mathias CG: Prevention of occupational contact dermatitis. J Am Acad Dermatol 1990;23: 742–748. Wigger-Alberti W, Elsner P: Preventive measures in contact dermatitis. Clin Dermatol 1997;15: 661–665. Avnstorp C: Prevalence of cement eczema in Denmark before and since addition of ferrous sulfate to Danish cement. Acta Derm Venereol 1989;69:151–155. Avnstorp C: Follow-up of workers from the prefabricated concrete industry after the addition of ferrous sulphate to Danish cement. Contact Dermatitis 1989;20:365–371. Bock M, Schmidt A, Bruckner T, Diepgen TL: Occupational skin disease in the construction industry. Br J Dermatol 2003;149:1165–1171.


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24 25 26 27 28 29 30 31 32 33 34 35

36 37 38 39 40 41 42 43

Lushniak B, Mathias CG, Taylor JS: Barrier creams: fact or fiction. Am J Contact Dermat 2003;14:97–99. Marks JG Jr, Fowler JF Jr, Sherertz EF, Rietschel RL: Prevention of poison ivy and poison oak allergic contact dermatitis by quaternium-18 bentonite. J Am Acad Dermatol 1995;33:212–216. Grevelink SA, Murrell DF, Olsen EA: Effectiveness of various barrier preparations in preventing and/or ameliorating experimentally produced Toxicodendron dermatitis. J Am Acad Dermatol 1992;27:182–188. Vidmar DA, Iwane MK: Assessment of the ability of the topical skin protectant (TSP) to protect against contact dermatitis to urushiol (Rhus) antigen. Am J Contact Dermat 1999;10:190–197. Blanken R, Nater JP, Veenhoff E: Protection against epoxy resins with glove materials. Contact Dermatitis 1987;16:46–47. Gawkrodger DJ, Healy J, Howe AM: The prevention of nickel contact dermatitis: a review of the use of binding agents and barrier creams. Contact Dermatitis 1995;32:257–265. Wohrl S, Kriechbaumer N, Hemmer W, Focke M, Brannath W, Gotz M, Jarisch R: A cream containing the chelator DTPA (diethylenetriaminepenta-acetic acid) can prevent contact allergic reactions to metals. Contact Dermatitis 2001;44:224–228. Romaguera C, Grimalt F, Vilaplana J, Carreras E: Formulation of a barrier cream against chromate. Contact Dermatitis 1985;13:49–52. Loden M: The effect of 4 barrier creams on the absorption of water, benzene, and formaldehyde into excised human skin. Contact Dermatitis 1986;14:292–296. Hachem JP, De Paepe K, Vanpee E, Kaufman L, Rogiers V, Roseeuw D: The effect of two moisturisers on skin barrier damage in allergic contact dermatitis. Eur J Dermatol 2002;12:136–138. Baur X, Chen Z, Allmers H, Raulf-Heimsoth M: Results of wearing test with two different latex gloves with and without the use of skin-protection cream. Allergy 1998;53:441–444. Shmunes E, Darby T: Contact dermatitis due to endotoxin in irradiated latex gloves. Contact Dermatitis 1984;10:240–244. Fisher AA: Burns of the hands due to ethylene oxide used to sterilize gloves. Cutis 1988;42:267–268. von Hintzenstern J, Heese A, Koch HU, Peters KP, Hornstein OP: Frequency, spectrum and occupational relevance of type IV allergies to rubber chemicals. Contact Dermatitis 1991;24:244–252. Moursiden HT, Faber O: Penetration of protective gloves by allergens and irritants. Trans St Johns Hosp Dermatol Soc 1973;59:230–234. Moyle M, Frowen K, Nixon R: Use of gloves in protection from diallyl disulphide allergy. Australas J Dermatol 2004;45:223–225. van der Bijl P, Gareis A, Lee H, van Eyk AD, Stander IA, Cilliers J: Effects of two barrier creams on the diffusion of benzo[a]pyrene across human skin. SADJ 2002;57:49–52. Wall LM: Nickel penetration through rubber gloves. Contact Dermatitis 1980;6:461–463. Ponten A, Carstensen O, Rasmussen K, Gruvberger B, Isaksson M, Bruze M: Epoxy-based production of wind turbine rotor blades: occupational dermatoses. Contact Dermatitis 2004;50: 329–338. Blanken R, Nater JP, Veenhoff E: Protective effect of barrier creams and spray coatings against epoxy resins. Contact Dermatitis 1987;16:79–83. Cahill J, Keegel T, Dharmage S, Nugriaty D, Nixon R: Prognosis of contact dermatitis in epoxy resin workers. Contact Dermatitis 2005;52:147–53. Munksgaard EC: Permeability of protective gloves by HEMA and TEGDMA in the presence of solvents. Acta Odontol Scand 2000;58:57–62. Munksgaard EC: Permeability of protective gloves to (di)methacrylates in resinous dental materials. Scand J Dent Res 1992;100:189–192. Waegemaekers TH, Seutter E, den Arend JA, Malten KE: Permeability of surgeons’ gloves to methyl methacrylate. Acta Orthop Scand 1983;54:790–795. Darre E, Vedel P, Jensen JS: Skin protection against methylmethacrylate. Acta Orthop Scand 1987;58:236–238. North Safety Silvershield/4H glove Chemical Protection Guide. http://www.northsafety.com (accessed April 30, 2005). Mäkelä EA, Vainiotalo S, Peltonen K: The permeability of surgical gloves to seven chemicals commonly used in hospitals. Ann Occup Hyg 2003;47:313–323.

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44 45 46 47

48 49

Notarianni G: Do your gloves really protect you from glutaraldehyde? Mater Manag Health Care 1995;4:104, 106. Storrs FJ: Permanent wave contact dermatitis: contact allergy to glyceryl monothioglycolate. J Am Acad Dermatol 1984;11:74–85. Liu Y, Sparer J, Woskie SR, Cullen MR, Chung JS, Holm CT, Redlich CA: Qualitative assessment of isocyanate skin exposure in auto body shops: a pilot study. Am J Ind Med 2000;37:265–274. Bauer A, Kelterer D, Stadeler M, Schneider W, Kleesz P, Wollina U, Elsner P: The prevention of occupational hand dermatitis in bakers, confectioners and employees in the catering trades: preliminary results of a skin prevention program. Contact Dermatitis 2001;44:85–88. Kalimo K, Kautiainen H, Niskanen T, Niemi L: ‘Eczema school’ to improve compliance in an occupational dermatology clinic. Contact Dermatitis 1999;41:315–319. Macan J, Kanceljak-Macan B, Milkovic-Kraus S: Pre-employment evaluation of atopy and contact sensitisation in the prevention of allergy-related diseases. Arh Hig Rada Toksikol 2002;53: 119–124.

Kathryn A. Zug, MD Dartmouth-Hitchcock Medical Center Department of Medicine (Dermatology), 1 Medical Center Drive Lebanon, NH 03756 (USA) Tel. ⫹1 603 653 9400, Fax ⫹1 603 650 6499, E-Mail [email protected]


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Protection from Toxicants Berta Brodsky, Uri Wormser Department of Pharmacology, School of Pharmacy, Faculty of Medicine, Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem, Israel

Abstract Exposures to skin irritants frequently occur in daily life at the workplace, in laboratories and during housekeeping. Apart from the physical protective countermeasures, there is a need for pharmacological preparations for the topical treatment of the exposed skin to prevent the development of burns. Exposure of the skin to a chemical irritant initiates an inflammatory response which progressively intensifies, leading to epidermal and dermal lesions. Topical treatment with povidone-iodine (PI) or iodine ointment significantly reduced skin damage induced by mustard gas (sulfur mustard), hydrofluoric acid and other chemical irritants. Human studies showed the efficacy of PI and iodine against thermal burns. The combination of anti-inflammatory agents and iodine increased the counterirritating activity. Both human and experimental animal studies demonstrated that the ointment should be immediately applied after occurrence: the earlier the treatment, the better the therapeutic effect. In addition, the ointment should be left on the skin long enough for achieving the therapeutic effect. This simple topical treatment can prevent suffering, skin transplantation and complications associated with skin burns. Copyright © 2007 S. Karger AG, Basel

Numerous chemical irritants are used in daily life at the workplace and in the household. They include acids such as hydrochloric acid and hydrofluoric acid (HF), alkalis like sodium hydroxide, disinfectants such as sodium hypochlorite and phenol, and other toxic chemicals including ammonia, calcium oxide, ethylene oxide, white phosphorous and toluene diisocyanate. In addition, an important group of skin irritants is chemical warfare agents, among them mustard gas, lewisite and chlorine. Unfortunately, there is no specific pharmacological preparation for the topical treatment of burns. The only known and well-accepted treatments in case of skin exposure are decontamination with water or adsorbing agents such as Fuller’s earth in mustard gas exposure. Apart from these physical decontaminating tools and protecting measures such as

gloves, glasses and coats, no pharmacological antidotes for the prevention of skin burns are known among physicians and first-aid personnel. In the vast majority of cases, the patient, upon admission to the hospital or medical center, has been exposed to the noxious stimulus at least tens of minutes before. In most cases, it is too late to treat successfully with topical preparations that can reduce the severity of the skin damage. In case of heat burns or corrosive agents, most of the initial skin lesions have already occurred before the admission to the hospital; thus, preventive measures are useless. In this view, a topical pharmacological preparation should be applied at the very early stages of the burn, namely at the site of occurrence and before admission to the hospital. This implies that such a preparation should be available at home or at the workplace with immediate accessibility. As mentioned, there are no topical preparations for the pharmacological treatment of early stages of chemical-induced burns. Nevertheless, there are newly discovered topical formulations that showed a protective effect against skin irritants. Their activity has been described in experimental animal models, and also a limited experience in humans is documented. Prior to this description, some central pathological aspects of skin irritation are given as a background.

Pathological Aspects of Skin Irritation

Exposure to skin irritants such as heat and ultraviolet light causes an inflammatory response initiated by erythema (local vasodilation) followed by blister formation and/or dermal and epidermal ulceration and necrosis. In general, this is a feature common to the pathology of skin irritants; however, they differ from each other by the kinetics of the evolution of the tissue response. For instance, heat burns develop rapidly: there is an immediate burning sensation, and the appearance of erythema and blisters within minutes or tens of minutes following exposure depends on the severity of the burn. In general, strong acids and alkalis induce skin damage rapidly after exposure although they are somewhat slower [1] than thermal burns. In contrast, the known chemical warfare mustard gas (sulfur mustard, SM) operates at a much slower kinetics. Slight erythema may start at least 20–30 min after exposure and in some cases this period may be extended to several hours, depending on the susceptibility of the individual [2]. Thereafter edema and blisters may develop within 1–9 days after exposure [3]. Experimental animals do not develop blisters, but skin ulceration may appear within 24 h after exposure [4]. Due to its relatively slow toxicokinetics, SM is a convenient tool for skin burn research and development of topical antidotes for preventing skin lesions caused by irritants.

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Topical Iodine as a Potential Antidote – the Experimental Approach

SM [S(CH2CH2Cl)2] is an alkylating agent which chemically attacks macromolecules such as DNA, RNA and proteins. The alkylation process is based on the conversion of the chloroethyl group of SM to the highly electrophilic cyclic ethylene episulfonium derivative [3] which attacks nucleophilic sites in the macromolecules. Oxidation of the sulfur atom to form SM sulfoxide [OS(CH2CH2Cl)2] results in the loss of vesicating activity [5], presumably due to its inability to undergo cyclization to the ethylene episulfonium form. Since oxidizing agents like iodine and povidone-iodine (PI) are widely used as antiseptic agents, the primary approach was to employ them to neutralize SM by oxidizing its sulfur atom to the less active sulfoxide form [5]. As shown later, topical treatment with PI or iodine protected against SM-induced skin lesions [4, 6]. Further analysis revealed that SM was not chemically affected by iodine [4], indicating that it operates by a different mechanism of action. Furthermore, the fact that iodine was effective against skin irritants that cannot be oxidized such as iodoacetate [6] or HF [1] is an additional support for the pharmacological effect rather than the chemical activity of iodine. Finally, its beneficial effect on thermal burns in both humans [7] and animals [1] strongly indicates an influence of iodine on pathophysiological processes occurring in the skin upon exposure to noxious stimuli. In the following, we describe the therapeutic effects of topical PI and iodine preparations in both chemical and thermal skin burns.

Iodine versus Povidone-Iodine

Iodine and PI differ in the amount of free iodine in the solution or ointment. PI is an iodophor, a complex of polyvinylpyrrolidone and iodine from which iodine is released in a semicontrolled manner. The iodine content is about 10% of the total PI, namely 10% PI contains 1% available iodine of which 2.1–22 ppm are free, depending on the type of preparation [8]. In contrast, 1% iodine solution contains 1% free iodine. Due to its relatively low free iodine concentrations, PI is considered nonirritating to the skin, while retaining its antiseptic and counterirritating efficacies. It should be noted that the type of formulation is crucial for the pharmacological and toxicological properties; thus, several preparations of PI and iodine are dermatotoxic and should not be employed. Nevertheless, the new formulations of iodine and PI (described below) have no toxic effects on the skin.

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Effect of Commercial Povidone-Iodine Ointment on Sulfur-Mustard-Induced Burns

The real emergency scenario is exposure to a chemical irritant followed by treatment with a protecting agent. Therefore, most of the studies describing the effect of topical PI- or iodine-induced protection are designed as postexposure treatment rather than prophylactic regimen. The degree of protection caused by a commercial PI ointment (Fischer Pharmaceuticals, Tel Aviv, Israel) was shown to be related to the time interval between SM exposure and PI treatment (fig. 1). Application of PI up to 10 min following SM exposure conferred a high degree of protection [6]. A longer interval of 20 min between exposure and treatment also reduced the skin lesion but to a lesser extent than that observed in the shorter intervals.

Optimization of the Protective Effect against Sulfur Mustard Toxicity

In order to improve its efficacy, iodine replaced PI and was formulated with tetraglycol (TG). Topical treatment with this preparation significantly protected the skin at an interval of 30 min between SM exposure and iodine treatment (fig. 2, 3) [4]. The histopathological findings [4] are quantified in figure 4. At the interval of 15 min between exposure and treatment, a significant reduction was observed in dermal parameters indicative of acute tissue damage such as acute inflammation, hemorrhage and necrosis (fig. 4b). In addition, the epidermal healing markers, acanthosis and hyperkeratosis, were significantly increased (fig. 4a). These healing parameters are the most reliable histological proof for the effectiveness of iodine. At the longer interval of 30 min between SM exposure and iodine treatment, a significant therapeutic effect was conferred, albeit to a lesser extent than that observed with the shorter interval. Although the epidermal healing markers were not elevated, the parameters indicative of acute tissue damage such as subepidermal microblister formation, epidermal ulceration and dermal markers including acute inflammation, hemorrhage and necrosis were significantly reduced. Longer intervals of 45 and 60 min between SM exposure and iodine treatment showed weaker antidotal activity. This was observed both in the gross and histopathological evaluation [4].


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B

A

D

C

F

E

H G

1

2 Fig. 1. Protective effect of PI against SM-induced skin toxicity. A shaved guinea pig was topically treated with 1 ␮l (1.2 mg) neat SM. PI was applied after SM treatment at the indicated time intervals as shown in the following scheme: A, E ⫽ 5 min; B, F ⫽ 10 min; C, G ⫽ 20 min; D, H ⫽ without PI. The photo was taken 4 days after treatment. Reprinted from Wormser et al. [6] with kind permission of Springer Science and Business Media. Fig. 2. Macroscopic appearance of the protective effect of iodine against SM-induced skin lesions. Six sites of a shaved guinea pig back were exposed to 1 ␮l (1.2 mg) neat SM. The 3 left-side sites were treated topically with an iodine formulation 30 min after exposure. The photograph was taken 2 days after treatment. Reprinted from Wormser et al. [4] with permission from Elsevier.

Possible Explanation of the Beneficial Effect of the Tetraglycol Formulation

The superiority of this iodine formulation stems from its ability to dissolve molecular iodine in an aqueous environment. Molecular iodine (I2) is practically water insoluble unless iodide (sodium or potassium salts) is present in the solution to form the water-soluble ion I⫺ 3 . Molecular iodine can be dissolved in organic solvents such as ethanol or polyethyleneglycol 400, but the presence of

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Ulceration area (cm2)

1.00

0.75

0.50

0.25

0

Cont.

*

*

15

30

V

Time interval between exposure and treatment (min)

Fig. 3. Gross pathology quantification of the protective effect of iodine. Guinea pigs were exposed to 1.2 mg SM (1 ␮l) and were treated topically with an iodine formulation. The ulcerated area was measured 2 days following exposure. The time intervals between exposure and treatment were 15 (n ⫽ 9) and 30 (n ⫽ 18) min as indicated. Cont. ⫽ Control, SMexposed skin without iodine treatment (n ⫽ 57); V ⫽ vehicle applied 15 min after SM exposure (n ⫽ 9). Results are expressed as means ⫾ SE using the Kruskal-Wallis test and Dunnett’s multiple comparison posttest for statistical evaluation of the differences between the experimental groups. * p ⬍ 0.001 at comparison between 15- and 30-min intervals and control, p ⬍ 0.05 at comparison between 15-min interval and vehicle. Reprinted from Wormser et al. [4] with permission from Elsevier.

water precipitates the iodine; thus, an iodine tincture which contains ethyl alcohol and water must also contain iodide in the form of I3⫺ for proper dissolution. Experiments conducted in our laboratory showed that the iodine tincture exhibited a weaker protective effect than the iodine formulation described in the present study (data not shown). A possible explanation is that the negatively charged I3⫺ penetrates poorly through biological membranes and barriers, thus reducing its efficacy as a protectant. The TG-containing solvent system that dissolves I2 without the addition of iodide, thus keeping the molecular iodine in its noncharged form I2, might be more penetrable and a stronger oxidizer than the negatively charged I3⫺ and more efficient in its protecting activity. This explanation may also account for the superiority of the TG-containing formulation over the iodide-containing formulations for therapy of thermal burns and for its bactericidal effect [9]. Such an assumption must be experimentally proven by physicochemical and biochemical experiments.


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3

Pathological score

***

a

4 3

** **

2

0

M

2

** ***

**** ** ***

1

**

*

1

Pathological score

5

* U

N

A

H

E

GA

b

0 AI

SI

H

N

F

Fig. 4. Histopathology quantification of the protective effect of iodine at intervals of 15 and 30 min between exposure and treatment. Skin sections (stained with HE) from guinea pigs exposed to 1.2 mg SM (1 ␮l), treated topically with iodine formulation and sacrificed 2 days after treatment. Twelve parameters were determined, 7 epidermal (a) and 5 dermal (b). The epidermal markers were subepidermal microvesicles (M), ulceration (U), necrosis (N), acanthosis (A), hyperkeratosis (H), encrustation (E) and grade of area of epidermal acanthosis (GA). The dermal markers were acute inflammation (AI), subacute inflammation (SI), hemorrhage (H), necrosis (N) and fibrosis (F). The following types of treatment were evaluated: skin exposed to SM only (dotted bars, n ⫽ 57), skin exposed to SM followed by iodine treatment 15 min (open bars, n ⫽ 9) or 30 min (hatched bars, n ⫽ 18) later. Results are expressed as means ⫾ SE using the Kruskal-Wallis test and Dunnett’s multiple comparison posttest for statistical evaluation of the differences between controls (SM only) and 15- or 30-min intervals between exposure and treatment. *p ⬍ 0.05, **p ⬍ 0.01, ***p ⬍ 0.001. Reprinted from Wormser et al. [4] with permission from Elsevier.

Other Chemical Irritants

Commercial PI ointment was also effective against mustard derivatives such as the difunctional nitrogen mustard mechlorethamine [6] which is used as anticancer drug. A significant degree of protection was observed when the skin was treated with PI within 20 min after mechlorethamine exposure. Longer intervals of 60 and 180 min between nitrogen mustard exposure and PI application were also effective but to a lesser extent [6]. Skin toxicity of nonmustard alkylators, such as iodoacetate and cantharidine, was strongly inhibited when PI was applied immediately after the toxic agents. The toxicity of the skin irritant divinylsulfone was also blocked by PI treatment [6]. These findings may indicate that PI-induced protection is not specific for a chemical or group of chemicals. It seems that PI possesses a general counterirritating activity as will be further evidenced below.

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A special focus was directed at skin burns caused by exposure to HF. This is a highly reactive compound and a strong acid which is used in various industries including hi-tech and chemical manufacturers. Due to its high reactivity, it might be a model for other strong acids. The currently used preparation for the treatment of HF burns is calcium gluconate [10–12] which was reported to be efficient in such cases. Nevertheless, animal experiments with guinea pigs did not show any beneficial effect of calcium gluconate. However, topical iodine ointment reduced skin ulceration at intervals of 5, 10 and 15 min between exposure and treatment [1]. Combination of Iodine and Anti-Inflammatory Agents

The evolution of a chemical burn involves a variety of inflammatory processes including production of inflammatory mediators [4, 13–19] and dermal infiltration of polymorphonuclear cells [4]. This was supported by the beneficial effect of anti-inflammatory agents such as olvanil and indomethacin against SM in the mouse ear edema model [14]. A combination of iodine with steroidal (clobetasol) and nonsteroidal (piroxicam) anti-inflammatory agents led to improved therapeutic activity in the guinea pig skin irritation and mouse ear edema models [20]. This kind of preparation also showed a beneficial effect in HF burns in guinea pigs (data not shown). Effect of Iodine and Povidone-Iodine against Thermal Burns in Humans

Case Study No. 1: Topical Treatment with Iodine A 9-year-old girl was exposed by accident to soup of about 75–80⬚C. The dorsal side of the left femur (area of 7 ⫻ 7 cm) and the dorsal side of the left wrist (about 4 ⫻ 4 cm) were involved. The patient suffered from a strong burning sensation and severe erythema at the sites of exposure. About 8 min after exposure, the affected skin areas were topically treated with iodine ointment. The burning sensation was dramatically reduced 2–3 min after iodine application. About 30 min later, the ointment was removed, and both skin areas seemed normal without toxicity signs. The follow-up during the next days did not show pathological changes. Case Study No. 2: Combination of Oral Anti-Inflammatory Agent and Topical Povidone-Iodine A 12-year-old boy touched a hot oven. A blister was formed within minutes at the junction of the proximal phalanx and metacarpal of finger No. 4. Pain sensation was reported in the area of the dorsum of the hand including all fingers. The skin was immediately washed with cold tap water. A commercial


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liquid PI preparation was applied about 3 min after exposure. After 7 min, pain still persisted and a commercial PI ointment was applied (moderate layer, about 1 mm). Acetaminophen (250 mg) was given 10 min after occurrence. The ointment was reapplied 40, 50 and 60 min after exposure with immediate pain relief after each application. About 1.5 h following exposure the patient was painless, and after an additional hour the ointment was washed off with water. About 5 min after ointment removal the pain sensation restarted; PI ointment was reapplied and left on the skin for an additional 3 h. After removal of the ointment, no pain was reported except while moving finger 4. At that stage erythema was observed on fingers 2, 3 and 5 and a blister on finger 4. The patient was given an additional acetaminophen tablet (250 mg). On the following day, the patient was painless and there was no need for PI or acetaminophen treatment. These case reports are representatives of tens of cases in which burns were successfully treated with topical PI or iodine preparations, most of them without supportive anti-inflammatory agents. It should be noted that a few patients were refractory to the beneficial effect of iodine/PI, but this rarely occurred. There are two crucial rules for the treatment: (a) the earlier the treatment, the better therapeutic effect can be obtained; (b) the ointment should be left on the skin long enough for having the therapeutic effect. A delay in the treatment or removal of the preparation too early can dramatically reduce its efficacy [7]. In addition to these human reports, studies with guinea pigs demonstrated the beneficial effect of iodine on thermal burns [1]. Mechanism of Action of Iodine A logical explanation for the beneficial effect of iodine is suppression of the inflammatory events elicited by the chemical or thermal stimuli. The antiinflammatory effect of iodine was characterized by reduction in inflammatory cells [4] and tumor-necrosis-factor-␣-positive cells [21] in the exposed skin. The suppressive effect of iodine on the oxidative burst of activated neutrophils [21] might also be an explanation for its anti-inflammatory activity. However, no information is available on iodine concentrations within the epidermal/ dermal layers, and whether these amounts of iodine correspond to those required for the suppression of the oxidative burst of activated neutrophils. Future investigations are necessary to unravel the mechanism of action of iodine and its influence on other cytokines and inflammatory mediators. Acknowledgements The present study was supported by the USAMRMC Cooperative Agreement No. DAMD17–03–2-0013 and the Binational Science Foundation Research Project 2001186. The authors thank Dr. Michal Raphael for reporting case study No. 2.

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References 1

2 3 4 5 6

7 8 9

10 11 12

13

14

15

16

17

18

19

Wormser U, Sintov A, Brodsky B, Amitai Y, Nyska A: Protective effect of topical iodine preparations upon heat-induced and hydrofluoric acid-induced skin lesions. Toxicol Pathol 2002;30: 552–558. Somani SM, Babu SR: Toxicodynamics of sulfur mustard. Int J Clin Pharmacol Ther Toxicol 1989;27:419–435. Wormser U: Toxicology of mustard gas. Trends Pharmacol Sci 1991;12:164–167. Wormser U, Sintov A, Brodsky B, Nyska A: Topical iodine preparation as therapy against sulfur mustard-induced skin lesions. Toxicol Appl Pharmacol 2000;169:33–39. Dixon M, Needham DM: Biochemical research on chemical warfare agents. Nature 1946;158: 432–438. Wormser U, Brodsky B, Green BS, Arad-Yellin R, Nyska A: Protective effect of povidone-iodine ointment against skin lesions induced by sulphur and nitrogen mustards and by non-mustard vesicants. Arch Toxicol 1997;71:165–170. Wormser U: Early topical treatment with povidone-iodine ointment reduces, and sometimes prevents, skin damage following heat stimulus. Burns 1998;24:383. Atemnkeng MA, Plaizier Vercammen JA: Comparison of free iodine as a function of the dilution of two commercial povidone-iodine formulations. J Pharm Belg 2006;61:11–13. Tam A, Shemesh M, Wormser U, Sintov A, Steinberg D: Effect of different iodine formulations on the expression and activity of Streptococcus mutans glucosyltransferase and fructosyltransferase in biofilm and planktonic environments. J Antimicrob Chemother 2006;57:865–871. Gupta R: Intravenous calcium gluconate in the treatment of hydrofluoric acid burns. Ann Emerg Med 2001;37:734–735. Ohata U, Hara H, Suzuki H: Seven cases of hydrofluoric acid burn in which calcium gluconate was effective for relief of severe pain. Contact Dermatitis 2005;52:133–137. Yasuda H, Honda S, Yamamoto O, Asahi M: Therapeutic effect of topical calcium gluconate for hydrofluoric acid burn – Time limit for the start of the treatment. J UOEH 1999;21: 209–216. Dannenberg AMJ, Pula PJ, Liu LH, Harada S, Tanaka F, Vogt RFJ, Kajiki A, Higuchi K: Inflammatory mediators and modulators released in organ culture from rabbit skin lesions produced in vivo by sulfur mustard. I. Quantitative histopathology; PMN, basophil, and mononuclear cell survival; and unbound (serum) protein content. Am J Pathol 1985;121:15–27. Babin MC, Ricketts K, Skvorak JP, Gazaway M, Mitcheltree LW, Casillas RP: Systemic administration of candidate antivesicants to protect against topically applied sulfur mustard in the mouse ear vesicant model (MEVM). J Appl Toxicol 2000;20(suppl 1):S141–S144. Tsuruta J, Sugisaki K, Dannenberg AMJ, Yoshimura T, Abe Y, Mounts P: The cytokines NAP-1 (IL-8), MCP-1, IL-1␤, and GRO in rabbit inflammatory skin lesions produced by the chemical irritant sulfur mustard. Inflammation 1996;20:293–318. Abe Y, Sugisaki K, Dannenberg AMJ: Rabbit vascular endothelial adhesion molecules: ELAM-1 is most elevated in acute inflammation, whereas VCAM-1 and ICAM-1 predominate in chronic inflammation. J Leukoc Biol 1996;60:692–703. Nakamura M, Rikimaru T, Yano T, Moore KG, Pula PJ, Schofield BH, Dannenberg AMJ: Fullthickness human skin explants for testing the toxicity of topically applied chemicals. J Invest Dermatol 1990;95:325–332. Woessner JFJ, Dannenberg AMJ, Pula PJ, Selzer MG, Ruppert CL, Higuchi K, Kajiki A, Nakamura M, Dahms NM, Kerr JS: Extracellular collagenase, proteoglycanase and products of their activity, released in organ culture by intact dermal inflammatory lesions produced by sulfur mustard. J Invest Dermatol 1990;95:717–726. Harada S, Dannenberg AMJ, Vogt RFJ, Myrick JE, Tanaka F, Redding LC, Merkhofer RM, Pula PJ, Scott AL: Inflammatory mediators and modulators released in organ culture from rabbit skin lesions produced in vivo by sulfur mustard. III. Electrophoretic protein fractions, trypsininhibitory capacity, ␣1-proteinase inhibitor, and ␣1- and ␣2-macroglobulin proteinase inhibitors of culture fluids and serum. Am J Pathol 1987;126:148–163.


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Wormser U, Sintov A, Brodsky B, Casillas RP, Nyska A: Protective effect of topical iodine containing anti-inflammatory drugs against sulfur mustard-induced skin lesions. Arch Toxicol 2004;78:156–166. Wormser U, Brodsky B, Proscura E, Foley JF, Jones T, Nyska A: Involvement of tumor necrosis factor-␣in sulfur mustard-induced skin lesion: effect of topical iodine. Arch Toxicol 2005;79: 660–670.

Uri Wormser Berman Building, Institute of Life Sciences, Givat Ram Hebrew University of Jerusalem IL–91904 Jerusalem (Israel) Tel. ⫹972 2 658 4073, Fax ⫹972 2 658 4250, E-Mail [email protected]

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Evaluation of Skin-Protective Means against Acute and Chronic Effects of Ultraviolet Radiation from Sunlight Birgitta Kütting, Hans Drexler Institute and Outpatient Clinic of Occupational, Social and Environmental Medicine of the Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany

Abstract Apart from erythema, sunlight triggers many biological processes such as photoaging, immune suppression and mutation of skin cells. Numerous epidemiological investigations have shown that sunlight is carcinogenic to humans, and the IARC classifies sunlight within group 1, which includes human carcinogens. Hereby, the UVB component of the solar spectrum presents the greatest degree of risk to the development of cutaneous neoplasms, but a certain carcinogenic potential of UVA has also been discussed. Practical steps to achieve optimal sun protection include avoidance of the sun during the peak hours of radiation, avoidance of photosensitizing drugs, use of photoprotective clothes and diligent application of broadspectrum sunscreens. Of all recommended protective measures, sunscreens are often the most feasible to use, particularly during outdoor leisure, sport or aquatic activities. Therefore, the following chapter focuses mainly on the biological activity and efficacy of short- and long-term use of sunscreen products, but other recommended strategies of UV protection (such as intake of ␤-carotene or application of liposomes) are critically evaluated as well. Although the shortterm efficacy of sunscreens in the prevention of sunburn is undisputed, there is also some evidence that long-term use of sunscreens prevents the appearance of certain forms of skin cancer. Copyright © 2007 S. Karger AG, Basel

Background

Sunlight is indispensable for organisms living on earth and there is no doubt about the beneficial effects of sunrays on human beings. On the other hand, sunlight is biologically harmful. Numerous epidemiological investigations have shown that sunlight is carcinogenic to humans, and the IARC classifies sunlight within group 1, which includes human carcinogens [1].

Practical steps to achieve optimal sun protection include avoidance of the sun during the peak hours of radiation, avoidance of photosensitizing drugs, use of photoprotective clothes, hats and sunglasses and at last the diligent application of broad-spectrum sunscreens. Shade-seeking behavior strategies have recently been publicly disseminated. The American Academy of Dermatology has advanced the concepts of increasing the availability of shade and the building of sun-safe play areas for children [2]. The spectral distribution of solar UV radiation reaching the surface of the earth encompasses wavelengths between 285 and 400 nm. Commonly defined ranges for specific bands of the terrestrial UV spectrum are UVB (290–320 nm) and UVA (320–400 nm). In addition, the UVA waveband is often further divided into UVA2 (320–340 nm) and UVA1 (340–400 nm), generally reflecting the higher erythematogenic efficiency of shorter UVA wavelengths (UVA2). While there is a greater prevalence of UVA radiation in the sun’s spectrum compared with UVB, the intensity is not constant during the day or during the year. Data from Central New Jersey have shown that in winter the UVA daily doses are only half that of a summer, spring or fall day. The UVB radiation changes more dramatically than the UVA radiation during the daytime as well as over the seasons as it is absorbed preferentially by the ozone in the stratosphere (longer path length during the winter and at low sun angles at the beginning and end of the day, resulting in a lower UVB dose reaching the earth’s surface) [3]. Photobiological processes are wavelength dependent, and these wavebands of radiation have significantly different biological effects. The UVB component of the solar spectrum presents the greatest degree of risk to the development of cutaneous neoplasms; hereby the cumulative lifetime dose of UVB radiation seems to be the most important factor for the carcinogenic potential. The melanin synthesis is stimulated by UVB radiation as well. An acute overdose of UVB radiation results in a solar erythema. On the other hand, photoaging (genesis of solar elastosis) is attributed to chronic UVA radiation. Additionally, UVA is the major waveband responsible for polymorphic light eruption, the most common form of the idiopathic photodermatoses. The immediate darkening of the skin is an acute effect related to UVA, but a certain carcinogenic potential of UVA is also discussed [4]. Furthermore, UVB and especially UVA2 (290–320 and 320–340 nm) have been associated with the exacerbation of autoimmune dermatosis, e.g. subacute cutaneous lupus erythematosus [5]. Solar-stimulated UV radiation, particularly UVA2 (320–340 nm) applied after immunization in mice has been shown to suppress immunological memory and the elicitation of delayed-type hypersensitivity [6].

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UVC radiation (200–290 nm) is nearly completely absorbed by the atmosphere and especially by the ozone layer of the stratosphere, only wavelengths ⬎285 nm reach the earth’s surface. Of all recommended protective measures such as sun avoidance during the peak hours of radiation and the use of protective clothes, broad-brimmed hats and sunglasses, sunscreens are often the most feasible to use, particularly during outdoor leisure, sport or aquatic activities [7]. Especially with the rapid rise in occurrence of skin cancer, presumably due to increased recreational exposure to sunlight and to increasing solar UVB radiation reaching the earth’s surface, it is important to investigate the possible means of decreasing photocarcinogenesis. Recommended forms of terrestrial UV protection with special focus on the use of sunscreen products are critically evaluated in this review; advantages and limitations of different measures are discussed.

Sunscreens

In the early 1970s, the first true sunscreens became generally available. However, high-intensity (sun protection factor, SPF, 15⫹) topical sun-protective agents have only been available since the mid-1980s [2]. Sunscreens were initially developed to protect against UVB radiation, as the available compounds were UVB absorbers. This increased UVB protection of up to SPF, 60⫹ in the 1990s has, however, prompted concern that the consumer may have a false sense of security using such high SPF products and may prolong exposure time [3]. In the 1990s, compounds with UVA-absorbing ability became first available [8], but because the UVA protection is typically weaker than the UVB portion of a sunscreen protection spectrum, there has been growing concern that there may be a proportionally greater UVA exposure, resulting in increased risks to UVA-inducible damage.

Definition and Clinical Relevance of the Skin Protection Factor of Suncare Products

The biological activity and efficacy of a suncare product, as represented by the SPF, is evaluated by its ability to protect human skin from erythema and edema. It is measured by determination of the dose which is required to induce a just perceptible redness (MED ⫽ minimal erythema dose) on untreated and on sunscreen-treated skin. The SPF is defined as the ratio of the dose of UV radiation required to produce a minimal erythematic response 24 h after exposure

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on protected skin after application of 2 mg/cm2 of a sunscreen product to the dose needed to produce the same degree of erythema in unprotected skin (SPF ⫽ MED of sunscreen-treated skin/MED of unprotected skin). The SPF is therefore a useful assessment of primarily UVB (290–320 nm) filters. However, the SPF test does not adequately assess the complete photoprotective profile of sunscreens, specifically against long-wavelength UVA1 (340–400 nm). Currently, the SPF scale specified in a sunscreen product applies solely to UVB protection [5]. Because UVA is far less erythematogenic (by a factor of 1,000) than UVB, using erythema as the endpoint of testing becomes problematic, as the length of time required for volunteers to remain immobile during testing is too long to be practical. For labeling UVA, there exists no worldwide consensus [9]. Protocols have used immediate pigment darkening, delayed tanning and erythema with and without photosensitizer as in vivo methods. An in vitro method measures the absorption of UV radiation by sunscreen material and establishes the critical wavelength, the wavelength below which 90% of a sunscreen’s UV absorbance occurs [8]. It has been found that patients or consumers normally apply much lower amounts of sunscreens than the amounts of 2 mg/cm2 used under laboratory conditions for determining the SPF rating of a specific sunscreen product. Debuys et al. [10] reported that consumers normally applied between 0.5 and 1 mg/cm2 of the sunscreen product, therefore when patients use an SPF 30⫹ sunscreen in real life, the UVB protection might be much lower than the indicated one. Additionally, as commercial SPF testing is only conducted on subjects of Fitzpatrick’s skin types I–III (table 1), and preferentially on those with skin types I and II, this could be an important cause of laboratory overestimation of sunscreen efficacy during outdoor activities in a genetically diverse population of sunscreen users. Therefore, factors such as the differences in skin color and MED between the subjects used for SPF testing and the general population, the spectral differences between sunlight and artificial UV, as well as the tendency of the public to apply only small amounts of sunscreen and to reapply it infrequently, mean that laboratory and sunlight SPFs may be markedly different. In conclusion, multiple factors, such as UV source, sunscreen application, skin color and erythemal susceptibility in volunteers, interact to produce substantially lower SPFs in natural sunlight than in the laboratory, and differing SPFs between laboratories [11]. However, apart from erythema, sunlight triggers many biological processes such as photoaging, immune suppression and mutation of skin cells. Therefore, it has recently been suggested that the SPF value may not be a sufficient gauge of the sunscreen’s ability to protect against the many harmful biological reactions induced by sunlight. For instance, UV-induced immune suppression can be caused by radiation below the erythemal dose [4]. Based on these reflections, an immune protection factor as a measure of the effectiveness of a sunscreen

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Table 1. Human skin types and their reactivity to sunlight (modified according to Fitzpatrick) Skin phototype

Skin color without exposure to sun

Sensitivity to UV radiation

Tanning history

I

White

Very sensitive

Always burns easily, shows no immediate pigment darkening reaction, never tans

II

White

Very sensitive

Always burns easily, trace immediate pigment darkening reaction, tans minimally and with difficulty

III

White

Sensitive

Burns minimally, immediate pigmentation darkening ⫹, tans gradually and uniformly (light brown)

IV

Light brown

Moderately sensitive

Burns minimally, immediate pigment darkening ⫹⫹

V

Brown

Minimally sensitive

Rarely burns, immediate pigment darkening ⫹⫹⫹, tans profusely (dark brown)

VI

Dark brown

Insensitive or least sensitive

Never burns, immediate pigment darkening reaction ⫹⫹⫹, deeply black, tans profusely

product to protect against UV-induced immune suppression and a mutation protection factor as an estimate of a sunscreen’s protective activity, as obtained by the measurement of p53 mutation in the skin of mice, were proposed [1].

Composition of Sunscreen Products

UV filters of commercially available products are divided into two main groups, chemical (organic) and physical filters (inorganic). The effectiveness of


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physical filters is based on reflectance and diffusion of UV radiation, whereas organic compounds protect the skin by absorption of UV radiation. The absorption spectrum for para-aminobenzoic acid esters, salicylates and cinnamates is within the UVB spectrum. Benzophenones absorb UVB and some UVA (approx. 360 nm, with a peak at 290 nm). Butylmethoxydibenzoylmethane (avobenzone or Parasol 1789) and Mexoryl SX, a benzylidine camphor derivate, are both UVA absorbers [8]. The inorganic sunscreens are titanium dioxide and zinc oxide. Titanium dioxide offers excellent UVA2 protection, but inadequate UVA1 coverage. Zinc oxide provides adequate UVA1 protection. The popularity of sunscreens containing titanium dioxide or zinc oxide may be limited by their opaque cosmetic appearance, although recent micronization techniques for these pigments have resulted in more cosmetically elegant preparations [5]. Physical block instead of chemical filters is favored as third-line protection for use in childhood, because it has been alleged that inorganic filters may be safer than organic ones. In contrast to the latter, physical filters neither cause adverse skin reactions due to their biological inertness nor are they supposed to penetrate into the skin [7]. Apart from active ingredients, the composition of the vehicle of a suncare product is a very important factor in determining its effectiveness. Substantivity, that means the ability of a product to maintain its effectiveness during use, particularly during water exposure, depends strongly on the formulation of the vehicle. Certain sunscreening compounds are photolabile when irradiated in isolation. However, when combined with other compounds, this photoinactivation may be prevented. Therefore, photostability is not predictable on the basis of the product’s constituent UV absorbers alone. Additionally, if the product is judged to be cosmetically unacceptable to consumers, it will remain on the shelf [8]. According to national and international guidelines, the first and second lines of protection of children against UV radiation are (a) to keep them out of the sun and (b) to cover them with protective clothes (WHO 1998). In the past years complete protection over the entire range of UVA and UVB was rarely possible with a single UV filter. Therefore, most sunscreens had used a combination of several filters to cover the entire UV spectrum [7]. Only for a short time have chemical filters absorbing the UVA spectrum or broad-spectrum filters (UVA/UVB filters such as Mexoryl) become available as well [4].

Application of Sunscreen Products

The optimum frequency for the reapplication of a sunscreen product during the day has not been established. It is generally recommended that

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sunscreen products be reapplied after exertion and sweating and after swimming. Furthermore sunscreen products should be applied 30 min before sun exposure.

Legislation

In the EU sunscreen products are regulated by cosmetic legislation (Directive 76/768/EC); in the USA and Canada sunscreen products are considered as medical products and therefore have to be approved by the Food and Drug Administration or the Canadian Ministry of Health as over-the-counter drugs. Medical products have to be proven for clinical efficacy, safety and quality, whereas cosmetics have only to be safe and they have to fulfil certain standards of quality. The list of EU-approved chemical filters and their maximal permissible concentration in commercial sunscreen products has been published in Annex VII of the European Cosmetic Directive. Directive 76/767/EC comprised 9 chemical filters for the short-wave UVB spectrum.

Biological Effects and Side Effects of Suncare Products

In the past years, the safety and usefulness of sunscreens had been controversially and critically discussed on the basis of the following objections: the use of a sunscreen may convey a misleading impression of security to the consumer, which may result in longer sun exposure and, therefore, greater skin damage [12] and, therefore, UV erythema should serve as a warning signal to discontinue sun exposure instead of being suppressed by sunscreen use [13]. Ingredients of sunscreen products may also cause irritative, allergic or even photoallergic reactions on the skin. Allergic and photoallergic reactions to active ingredients in sunscreens are fairly uncommon [14]. There had been concern that sunscreens suppress the vitamin D synthesis in the skin following UVB exposure. However, in a double-blind randomized-control trial comparing sunscreen users to people using a placebo, the mean levels of 25-hydroxyvitamin D were the same for each group. None of the sunscreen users had a vitamin deficiency [15]. Although the short-term efficacy of a sunscreen in the prevention of sunburn is undisputed, there is also some evidence that long-term use of sunscreens prevents the appearance of nonmelanotic skin cancer such as solar keratoses [16, 17] and squamous-cell carcinoma but not of basal-cell carcinoma [18]. The results of published epidemiological studies examining sunscreen use and melanoma are extremely controversial. A meta-analysis performed by Bastuji-Garin and Diepgen [9] in 2002 denied a causative association between


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sunscreen use and melanoma due to discordant results triggered by the low relative risks, the lack of a dose-effect relationship and the numerous biases, especially the uncertainty that the sunscreen preceded melanoma. A further meta-analysis of 11 case-control studies published by Huncharek and Kupelnick [19] in the same year also found no association between sunscreen use and the development of melanoma, concluding that the available data do not support a relationship between increased risk of melanoma and sunscreen use. On the other hand, the reduction of melanoma incidence and mortality rate in Australia, where 74% of the population regularly uses sunscreens, might be evidence for the beneficial effect of sunscreens on melanoma incidence in larger populations. This thesis is supported by the observation that the melanoma rate is also falling among Hawaiian whites, a group that has the highest use of sunscreens per person in the USA [2]. Some evidence for the preventive benefit of the daily application of sunscreens comes from two clinical trials of sunscreen application in relation to benign solar keratoses. A trial of daily sunscreen application for 7 months among 588 people with solar keratoses in Australia suggested that the incidence of further keratoses was decreased by the regular use of a sunscreen [16]. A prospective double-blind, controlled trial over a 2-year period on 53 volunteer patients of a US dermatology clinic, who were randomly assigned either to daily application of a sunscreen (study population) or to sunscreen base (controls), confirmed these findings of Thompson et al. [16]. Hereby, the rate of appearance of new precancerous skin lesions was less for the treatment group than for control subjects [17]. Green et al. [18] found that cutaneous squamous-cell carcinoma, but not basal-cell carcinoma seemed to be amenable to prevention through the routine use of sunscreens by adults for 4.5 years, especially in people with a history of skin cancer. In their community-based randomized trial with a 2 by 2 factorial design, 1,621 residents of southeast Queensland, Australia, were assigned to one of the four groups: daily application of an SPF 15⫹ sunscreen to the head, neck, arms and hands, and ␤-carotene supplementation (30 mg/day); sunscreen plus placebo tablets; ␤-carotene only, or placebo only. The endpoints after 4.5 years of followup were the incidence of basal-cell and squamous-cell carcinoma both in terms of people treated for newly diagnosed disease and in terms of numbers of tumors that occurred: 250 out of 1,383 participants with complete follow-up developed 758 new skin cancers over the study period of 4.5 years. In terms of the number of tumors, there was no effect on the incidence of basal-cell carcinoma by sunscreen use or by ␤-carotene but the incidence of squamous-cell carcinoma was significantly lower in the sunscreen group than in the no-daily-sunscreen group. In summary, there was no beneficial or harmful effect on the rates of either type of skin cancer due to ␤-carotene application.

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A randomized controlled trial demonstrated that the use of a broad-spectrum sunscreen decreased the number of nevi developing in white children [20]. Additional benefits of UVA filters include prevention of photodermatoses, such as polymorphic light eruption or subacute cutaneous lupus erythematosus, and possibly photoaging.

Avoidance of Photosensitizing Drugs

Intake of phototoxic drugs (whose action spectrum almost always involves the UVA range) and exposure to UV radiation cause erythema and edema or even vesiculobullous lesions on sun-exposed skin within hours in susceptible patients. In contrast, a photoallergic reaction is a delayed-type hypersensitivity response in which patients do not have clinical manifestations upon the first exposure to the photoallergic drugs. Sensitized individuals may develop pruritic eczematous eruptions. Photoinduced lichenoid drug eruption (e.g. thiazide) can develop long after the drug has first been started [5].

Protective Clothing

The most common site of regularly visible photoaging and nonmelanotic skin cancer is the head and neck; therefore, the regular use of hats had been recommended as preventive measurement [2]. Marks [21] noted that the regular wearing of a hat with a 10-cm brim could lower the lifetime skin cancer risk by 40%. However, clothing alone may not provide adequate protection. Typical summer shirt fabrics only offer an SPF of 6.5. Weave tightness is the most important factor in sun protection followed by the fabric type. Darker-colored fabrics provide greater photoprotection than do lighter-colored fabrics [5]. It is also important to note that fabrics are significantly less photoprotective when wet [22]. Several clothing lines offering maximized UV protection (SPF 30) are currently being marketed [5]. Tinasorb, a potential laundry additive, has been developed to provide existing fabrics with increased sun-protective activity [23].

Systemic Photoprotective Agents

Several antioxidants have been studied as photoprotective agents. Apart from the use of ␤-carotene for erythropoietic protoporphyria, the role of other compounds has yet to be confirmed [8].


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In the prevention of nonmelanotic skin cancer, ␤-carotene was not effective in a double-blind study done in Australia [18].

T4N5 Liposomes

T4N5 is a bacterial endonuclease able to specifically repair chronic photodamage in UV-damaged DNA. T4N5 has been purified and encapsulated within liposomes for use as a topical therapy. It has been studied in animal models and in humans. The liposomes are taken up by keratinocytes and increase the rate of removal of chronic photodamage in both mice and humans. In people with xeroderma pigmentosum, T4N5 has been shown to decrease the incidence of actinic keratoses and basal-cell carcinoma [24].

Other Topical Preparations

In 2003, Burke et al. [25] confirmed that topical vitamin E and topical L-selenomethionine plus oral vitamin E were effective in protecting against skin

cancer (animal model).

References 1

2 3 4 5 6 7 8 9 10 11 12

Toyoshima M, Hosoda K, Hanamura M, Okamato K, Kobayashi H, Negishi T: Alternative methods to evaluate the protective ability of sunscreen against photo-genotoxicity. J Photochem Photobiol B Biol 2004;73:59–66. Rigel DS: Photoprotection: a 21st century perspective. Br J Dermatol 2002;146(suppl 61):34–37. Cole C: Sunscreen protection in the ultraviolet A region: how to measure the effectiveness. Photodermatol Photoimmunol Photomed 2001;17:2–10. Mang R, Krutmann J: Sonnenschutz im Urlaub. Hautarzt 2003;54:498–505. Ting WW, Vest CD, Sontheimer R: Practical and experimental consideration of sun protection in dermatology. Int J Dermatol 2003;42:505–513. Nghiem DX, Kazimi N, Clysdesdale G, et al: Ultraviolet A radiation suppresses an established immune response: implications for sunscreen design. J Invest Dermatol 2001;117:1193–1199. Nohynek GJ, Schaefer H: Benefit and risk of organic ultraviolet filters. Regul Toxicol Pharmacol 2001;33:285–299. Rosen CF: Topical and systemic photoprotection. Dermatol Ther 2003;16:8–15. Bastuji-Garin S, Diepgen TL: Cutaneous malignant melanoma, sun exposure, and sunscreen use: epidemiological evidence. Br J Dermatol 2002;146(suppl 61):24–30. Debuys HV, Levy SB, Murray JC, et al: Modern approaches to photoprotection: dermatologic aspects. Cosmetics 2000;18:577–590. Damian DL, Halliday GM, Stc Barneston R: Sun protection factor measurement of sunscreens is dependent on minimal erythema dose. Br J Dermatol 1999;141:502–507. Autier P, Doré JF, Negrier S, Lienard D, Panizzon R, Lejeune FJ, Guggisberg D, Eggermont AMM: Sunscreen use and duration of sunxposure: a double-blind, randomized trial. J Natl Cancer Inst 1999;91:1304–1309.

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Beani JC: Le danger des photoprotecteurs externes. Concours Méd 1996;29:1804–1808. Foley P, Nixon R, Marks R, Frowen K, Thompson S: The frequency of reactions of sunscreens: results of a longitudinal population-based study on the regular use of sunscreens in Australia. Br J Dermatol 1993;128:512–518. Marks R, Folley PA, Jolly D, Knight KR, Harrison J, Thompson SC: The effect of regular sunscreen use on vitamin D levels in an Australian population: results of a randomized controlled trial. Arch Dermatol 1995;131:415–421. Thompson SC, Jolley D, Marks R: Reduction of solar keratoses by regular sunscreen use. N Engl J Med 1993;329:1147–1151. Naylor MF, Boyd A, Smith DW, Cameron GS, Hubbard D, Neldner KH: High sun protection factor sunscreens in the suppression of actinic neoplasia. Arch Dermatol 1995;131:170–175. Green A, Williams W, Neale R, Hart V, Leslie D, Parson P, Marks GC, Gaffney P, Battistutta D, Frost C, Lang C, Russell A: Daily sunscreen application and betacarotene supplementation in prevention of basal-cell and squamous-cell carcinomas of the skin: a randomised controlled trial. Lancet 1999;354:723–729. Huncharek M, Kupelnick B: Use of topical sunscreens and the risk of malignant melanoma: a meta-analysis of 9,067 patients from 11 case-control studies. Am J Public Health 2002;92: 1173–1177. Gallagher RP, Rivers JK, Lee TK, Badjik CD, McLean DI, Goldman AJ: Broad-spectrum sunscreen use and the development of new nevi in white children: a randomized controlled trial. JAMA 2000;283:2955–2960. Marks R: Photoprotection and prevention of melanoma. Eur J Dermatol 1999;9:406–412. Gambichler T, Hatch KL, Avermaete A, Altmeyer P, Hoffmann K: Influence of wetness on the ultraviolet protection factor of textiles: in vitro and in vivo measurements. Photodermatol Photoimmunol Photomed 2002;18:29–35. Wang SQ, Kopf AW, Marx J, Bogdan A, Polsky D, Bart RS: Reduction of ultraviolet transmission through cotton T-shirt fabrics with low ultraviolet protection by various laundering methods and dyeing: clinical implications. J Am Acad Dermatol 2001;44:767–747. Yarosh D, Klein J, O’Connor A, Hawk J, Rafal E, Wolf P: Effect of topically applied T4 endonuclease V in liposomes on skin cancer in xeroderma pigmentosum: a randomized study. Lancet 2001;357:926–929. Burke E, Clive JC, Combs GF, Nakamura R: Effects of topical L-selenomethionine with topical and oral vitamin E on pigmentation and skin cancer induced by ultraviolet irradiation in Skh:2 hairless mice. J Am Acad Dermatol 2003;49:458–472.

Priv.-Doz. Dr. Birgitta Kütting Institute and Outpatient Clinic of Occupational Social and Environmental Medicine University of Erlangen-Nuremberg, Schillerstrasse 25 ⫹ 29 DE–91054 Erlangen (Germany) Tel. ⫹49 09131 85 26118, Fax ⫹49 09131 85 22312 E-Mail [email protected]


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Protection from Physical Noxae N.Y. Schürera, H. Dickelb a

Department of Dermatology, Human Sciences, University of Osnabrück, Osnabrück, and bUnit of Allergology, Occupational and Environmental Dermatology, Department of Dermatology and Allergology, Ruhr University Bochum, Bochum, Germany

Abstract Protection from physical noxae must include multiple approaches; physical irritant contact dermatitis develops most likely when the cumulative exposure to several physical factors, such as climatic environmental conditions and friction, pressure or occlusion is given. The additive effect of these conditions, frequently found in modern working environments, not only provokes barrier disturbances, but also inflammatory reactions of the deeper layers of the skin. This review reflects on some examples of occupational physical irritant contact dermatitis (PICD) and the current understanding of its possible pathomechanism. On the one hand, the literature reveals epidemiological studies and case reports and on the other hand murine studies. The combination of both views may permit new insights into the pathogenic mechanisms of PICD and its prevention. Copyright © 2007 S. Karger AG, Basel

Physical Irritant Contact Dermatitis

Physical irritant contact dermatitis (PICD) is a common occupational dermatosis with multiple types and many mechanisms involved in its development [1]. The diagnosis is primarily based on a history of exposure to a known irritant and negative patch test results to exclude contact allergy. The basic concept of PICD is physical skin damage without preceding or concomitant chemical irritation and sensitization, respectively. Initial PICD is characterized by a local inflammatory reaction, i.e. erythema, scaling and induration. PICD is accompanied by barrier disruption, i.e. stratum corneum changes. However, in vitro excessive physical insults, such as irradiation with 3,000 rad of X-ray, heating at 90⬚C for 3 min, freezing at ⫺196⬚C for 60 s or repeated placement in an extremely dry or humid condition, do not cause any change in the stratum corneum functions [2]. Because the viable skin is more vulnerable to environmental

Radiation (X-rays, ultraviolet rays, visual rays, infrared rays, laser)

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PICD Physical irritant contact dermatitis

Foreign body (e.g. wood, silk, nylon, oils, paraffin, hairs, silicone, talcum)

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Friction (paper, fabrics; dusts: metal, wood, plastics, cement; prostheses)

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Fig. 1. Mechanisms and agents that separately, concomitantly or sequentially – but frequently – cause PICD on exposed skin.

conditions than the stratum corneum, most of the stratum corneum abnormalities develop after environmental insults have induced an underlying inflammation. Stratum corneum abnormalities in inflamed skin are detectable as changes in the content of chemical mediators: physical insults enhance only in vivo the ratio between the proinflammatory interleukin (IL) 1 and its receptor antagonist (IL-1ra). Therefore, barrier disruption is one of the major pathogenic mechanisms of PICD. However, occupational skin disease caused by physical irritants is still a relatively underresearched area [1]. Further, the external environment seldom involves exposures to one single physical irritant: it is often a cumulative exposure to one or more mechanical and climatic irritants, respectively, and other influences (irradiation) with synergistic and antagonistic effects (fig. 1) [3].

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Epidemiology

In Finland PICD was noted in 139 of 4,320 cases of occupational skin disease during a 7-year observation period [4]. However, the actual number is probably higher, because mechanical forces are accepted as natural occurrences by most employees and are not reported. Thirty-two percent of individuals presenting with PICD are atopic and 6% suffer from psoriasis [5]. PICD is aggravated occupationally in 84% of cases, in 6% related to hobbies and in 6% due to medical devices. Body sites most likely affected are the hands (35%), face (26%), limbs (15%) and fingers (7%) [6]. Of 29,000 patients, an incidence of 1.4% of PICD was noted [1]. The mean age of the patients in the physical irritant study group was 39 years, with a greater proportion of males (ratio M:F ⫽ 1.3:1.0). Focusing on occupations of individuals affected, it was shown that office workers were affected in 21%, factory and assembly workers in 8%, machine operators in 6% and tailors in 4% of cases [1]. The range of physical irritants was diverse: most common was friction (36%), followed by drying (33%) and heating (11%).

Climatic Conditions

Humidity Environmental humidity has been shown to contribute to the appearance of the outermost surface of the skin. Employing a mouse model, the effects of the humidity on the skin’s pathology have been studied [7]: a dry environment leads to a drastic decrease in amino acids, i.e. filaggrin generation, and consecutively to stratum corneum imbalance and skin surface dryness. A decreased amino acid content has been found in dry skin [5]. In dry compared to normal skin, the expression of the differentiation-related epidermal keratins K1 and K10 is decreased and that of the associated suprabasal keratins K5 and K14 is increased [8]. These findings allow the assumption of a hyperproliferative disorder. Further, a premature expression of involucrin was observed in dry skin. When the relative humidity is less than 50%, the water content of the stratum corneum remains below 10%. At a water content of less than 10% the stratum corneum dries out and becomes brittle. The combination of low humidity, high temperature and, frequently, rapid air movement dehydrates the outer stratum corneum. This leads to pruritus and, finally, to low-grade eczema [9]. Low ambient humidity causes dehydration of the stratum corneum and impairment of the epidermal barrier function, followed by increased irritability of the skin [10]. In atopic subjects subclinical xerosis may occur within hours of exposure [11].

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Exposure to changes in humidity induces increased keratinocyte proliferation and markers of inflammation: immunohistochemical studies revealed higher amounts of IL-1␣ (mRNA and protein levels) in the epidermis of hairless mice kept at low humidity than in a high-humidity environment. Low humidity amplifies the hyperproliferative and inflammatory response to barrier disruption, and IL-1␣ mediates the relationship between environmental humidity and epidermal pathology [12]. Furthermore, in normal murine epidermis, exposure to low humidity increases epidermal DNA synthesis. Barrier disruption is followed by amplification of DNA synthetic activity, resulting in marked epidermal hyperplasia [13]. Exposure to a dry environment for 2 days results in dermal mast cell hypertrophy, degranulation as well as histological evidence of inflammation. The skin surface conductance in the stratum corneum of hairless mice was significantly lower 3–7 days after transfer from a humid (⬎80% relative humidity) to a dry (⬍10% relative humidity) environment than that of the mice transferred from a normal environment (40–70% relative humidity) to a dry environment [7], a condition air stewardesses are frequently confronted with [14]. Changes in environmental humidity may contribute to the seasonal exacerbations of cutaneous disorders, such as atopic dermatitis and psoriasis, diseases that are characterized by a defective barrier, epidermal hyperplasia and inflammation. In a factory manufacturing soft contact lenses, the air must be kept dry to prevent the softening of the acrylic polymers during machining. The interaction of low humidity, high temperature, flowing air and mechanical microtrauma from polymer particles reached an epidemic amount of complaints in the winter months of 1981 in fair-skinned workers [9]. Dry irritated skin occurs frequently in occupational settings, where different types of irritants – physical, chemical and mechanical – separately, concomitantly or sequentially disturb the epidermal barrier. Further, humidity is an independent risk factor for irritant hand dermatitis [15]: the importance of several meteorological factors (day means of temperature, relative and absolute humidity) was assessed in 742 hairdressing apprentices. An increased prevalence of irritant skin changes was noted during particularly cold winter months with low temperature and low absolute humidity. During the winter seasons, dry skin is more frequent and enhanced, respectively. Decreased skin surface/stratum corneum lipids have been reported in winter xerosis of Caucasians [16]. Winter-dependent decreases in skin temperature may influence the overall biosynthesis capacity of the epidermis, leading to decreased lipid biosynthesis [17]. Depletion of ceramide/linoleate in winter may contribute to the formation of an intrinsically weaker stratum corneum with an increased susceptibility to xerosis followed by skin irritation. An elevation of esterified oleic acid and a decline in linoleic acid and long-chain


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saturated fatty acids were found in Caucasian women, leading to a greater fatty acid desaturation, making the skin’s outermost surface more vulnerable to lipid peroxidation [16]. However, a season-related change in transepidermal water loss (TEWL) was not described. The reduction in lipids may in turn reduce the water content of the stratum corneum, which may influence the activity of the stratum corneum proteases involved in desquamation and which will interfere with the generation of natural moisturizing factors (NMFs). In winter dry skin degradation of corneodesmosomes has been found to be abnormal compared to normal controls [6]: the amounts of corneodesmosin, desmoglein 1 and plakoglobin detected were significantly higher in winter dry skin compared with normal skin extracts. Furthermore, during the cold winter months, risk factors for the development of occupational irritant hand dermatitis are increased [15]. Further, when contact hypersensitivity to 2,4,6-trinitrochlorobenzene was elicited in mice [18], the reaction was greater under low-humidity conditions (about 10%) than in mice housed under high-humidity conditions (80%). The study reveals that the cutaneous immune reaction is also regulated by humidity. Thus, environmental factors influence the incidence of occupational hand eczema and must therefore be taken into account in that field of dermatology. Many studies have demonstrated that a low humidity leads to a dehydration of the stratum corneum, a decreased amino acid and altered epidermal lipid biosynthesis. Barrier disturbances may follow accompanied by IL-1␣ expression, inflammation and exacerbation of cutaneous disorders. Therefore, an adjusted work environment contributes essentially to increase the resistance of the epidermal barrier: ventilation, avoiding drafts, room temperature between 18 and 22⬚C and an average relative humidity of at least 50%. An occlusive, water-impermeable plastic membrane, petrolatum or a nonocclusive humectant, applied both to nonperturbed and perturbed skin, prevents epidermal hyperplasia and dermal mast cell hypertrophy and degranulation induced by exposure to low humidity. Skin physiological measurements conducted before moisturizer treatment showed rather high TEWL values suggestive of an impaired skin barrier during cold winter months [19]. During the treatment with a moisturizing cream, significantly higher conductance values and lower TEWL values were found, accompanied by a decreasing IL-1ra/IL-1␣ ratio. Daily application of a moisturizing cream is effective in improving mild subclinical inflammation that is induced on the skin by the winter environment. Water Occupations that involve wet work and prolonged contact with water diminish the resistance of the skin by dissolving water-binding substances, i.e. NMFs, of the stratum corneum. Several hours of wet work daily diminish the barrier function of the stratum corneum. In pigskin, water alone disrupts stratum

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corneum intercellular lamellar bilayers, leading to bilayer delamination and ‘roll-up’ in a water milieu, bilayer disruption and nearly complete dissociation of corneocytes after 24 h of water exposure. Corneosomes show progressive degradation with exposure time. Water exposure results in the formation of amorphous intercellular lipids. Similar disruption of intercellular lamellar bilayers occurs in human skin in vivo at ambient temperature [20]. Hydration induces large pools of water in the intercellular space of the stratum corneum. Numerous intercellular pools of water are present throughout the stratum corneum by 4 h of water exposure. Within these cisternae lipid structures are disrupted by lamellar delamination [21]. Intercellular lamellar bilayer disruption by water, i.e. wet work, would be expected to enhance permeability and susceptibility to irritants; accordingly, increased attention should be given to the potential dangers of prolonged water contact. According to the current literature the duration of wet work should not exceed 4 h per day. Hence, corneosome degradation parallels intercellular lamellar bilayer disruption, other components, such as glycolic acid, for which corneosomal degradation has also been demonstrated [22], should be avoided in topical agents. However, calcium appears to offer some protection [20]. Heat Heat can induce PICD. Workers suffer from facial dermatitis, and thermal burns may leave permanent scarring. Burns may occur at 44⬚C. Burns may cause hyper- or hypopigmentation and susceptibility to irritant contact dermatitis. Erythema ab igne, characterized by mottled, reticulate hyperemia, can result from chronic exposure to heat. Veien et al. [23] commented on the fact that all patients with car-heater-induced dermatitis of the lower legs were middleaged males, spending considerable time in a car, driving on average 45,000 km/ year. In the winter season, car heaters blow warm dry air onto the legs of the affected person. As males are less likely than women to use emollients on their legs, it can be concluded that a lack of rehydration predisposes the development of this kind of PICD. Lengthy and repeated exposure to heat may lead to changes in the aggregation condition of the stratum corneum components. Electron spin resonance measurements were employed for spin probes of intact stratum corneum and certain model lipids (ceramides and cholesterol oleate) over a wide temperature range (from ⫺25 to 65⬚C) [24]. In tissue samples phase transitions were observed at both physiological and supraphysiological temperatures. However, these transitions did not coincide with those observed in sphingolipids, suggesting that thermal phenomena observed in vivo reflect interactions of more than one lipid and nonlipid membrane components of the stratum corneum, respectively. Epidermal lamellar lipids, i.e. ceramides, show little structural


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change with supraphysiological temperatures from 37 to 40⬚C [25]. After an interval of up to 30 years or more, erythema ab igne may even proceed to skin cancer [26]. Warm dry air dehydrates the stratum corneum, followed by the abovementioned epidermal pathomechanisms. The consequent and protective use of emollients may interfere with the development of this kind of PICD. Further, repeated exposure to heat may lead to an alteration of the aggregation condition of the stratum corneum components and may be even followed by changes of the viable epidermal and dermal components. Therefore, the goal should be to minimize the exposure to heat. Special heat-resistant, i.e. leather and special textile, gloves (Kevlar®, www.kcl.de) and clothing may protect from brief exposure to heat and welding. Cold The interaction of surrounding temperatures, humidity and wind must be considered when studying the effect of coldness. Freezing is based on three stages: (1) vasoconstriction, (2) transient vasodilatation and (3) skin temperature approaching the ambient temperature. The risk of frostbite increases from 5 to 95% as the skin surface temperature falls from ⫺4.8 to ⫺7.8⬚C [27]. Exposure to very low temperatures has profound effects on skin barrier function and is a frequent cause of occupational skin disease, as it occurs, for example, in the fish-processing industry [28]. While workers manipulate frozen fish stored on ice, their hands are exposed to very low temperatures. However, individuals only complain of sores, when they warm their skin. Most likely their hands dry out, and an increased TEWL is measurable. Sequential exposure to cold and hot temperatures may indeed disturb the barrier. Office workers work in warm dry atmospheres and leave during the winter months into the cold outdoors. Vice versa in the summer they stay in a cold, dry air-conditioned workplace and leave into humid, hot outdoor weather [29]. Dry irritated skin occurs mainly in winter and only in more susceptible individuals, i.e. older ones [30] or those with intrinsic defects in the epidermal barrier, such as atopic subjects [31]. In case of prolonged exposure to cold, dry wind in winter, dry irritated skin occurs mainly in air-exposed areas such as the dorsa of the hands and the face. Of the hands, the palms and fingertips are mainly affected. Palmar lipids are scarce, making the palms more susceptible to agents that disturb lipid lamellar arrangements [32]. Exposure to very low temperatures has profound effects on the epidermal barrier function and is a frequent cause of PICD. Subsequently, protection from low temperatures by wearing protective clothing, gloves (www.kcl.de) and shoes is essential. Education of the employees may help also to initiate ergotherapy prior to vasoconstriction.

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Occlusion Prolonged use of occlusive protective measures, i.e. protective gloves or shoes, especially over irritated dry skin, may disturb barrier function and aggravate PICD. Under occlusion water accumulates in the stratum corneum, eventually inhibiting the feedback signals that control barrier repair [33]. Due to stratum corneum overhydration, the conversion of profilaggrin to filaggrin and NMFs does not occur at the upper stratum granulosum [34]. Furthermore, maceration of the stratum corneum may further provoke barrier perturbation. When the occlusive effect is removed only for a few hours, as it is common to do so in wet work occupations, NMFs will be formed only in the innermost stratum corneum layers, while the most external layers of the stratum corneum remain deficient in NMFs and therefore tend to further lose water [5]. The vicious circle remains. Unfortunately workers commonly use occlusive gloves as secondary prevention of hand eczema after they have already experienced skin symptoms. This phenomenon leads to further aggravation of the skin condition [35].

Mechanical Influences

Friction Mechanical traumas to the skin can affect all levels from the stratum corneum to subcutaneous tissue. Excessive friction can result in the formation of various dermatoses. Hyperkeratosis, lichenification and calluses may be induced. However, sudden friction may induce blisters. Under experimental settings, tape strippings have been employed to induce PICD and to collect the intercellular composition of ceramides, sterols and fatty acids, i.e. stratum corneum lipids that maintain the water barrier of the skin. Skin physiological studies have demonstrated that experimental tape stripping of human skin may lead to an increased TEWL, i.e. disruption of the epidermal barrier [36]. Therefore, this technique has also been employed to increase the percutaneous penetration of potential allergens [37, 38]. Penetration of allergens may be considerably enhanced in occupations dealing with mechanical traumatization of the skin surface. However, the release of IL-1␣ from the skin immediately after tape stripping is significantly higher in a low-humidity than in a high-humidity environment [12]. Hence, both low humidity and mechanical friction, i.e. tape stripping, may amplify the hyperproliferative response leading eventually to hyperkeratosis, lichenification and calluses. PICD may result from poorly fitting prostheses including callus formation, lichenification, erythema and acroangiodermatitis associated with suction socket prostheses. A total of 34% of 210 amputees experienced skin problems.


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Lesions resulting from the combination of heat, friction, pressure and humidity under occlusion are common [39]. Microtrauma includes friction, abrasion, pressure, stretching, compression and cuts. Dermatological problems restrict for example the normal use of a prosthetic limb. Both low humidity and mechanical friction may amplify the hyperproliferative responses. Mechanical irritation can be reduced by small changes in work routines combined with education of the workers. Encapsulation of the most irritating steps of a production process is one suggestion. Further, an average relative humidity of at least 50% plus the avoidance of mechanical friction may prevent the induction of epidermal hyperplasia. Paper and Fabrics Handling paper can lead to PICD causing friction and desiccation of the finger pulps. In many cases, handling paper does not allow the application of any topical agents. Hence, prevention and treatment of this type of PICD is particularly challenging. Dusts Airborne particles are important when working with metals, woods, plastics, cement and plaster. The mechanical friction from sanding-down these materials may cause a chronic dermatitis of the hands and the face. Abrading dusts produced by finishing work, combined with the frictional effect of clothes, mechanically provoke PICD appearing as erythema, papules and eczematous reactions. Many workers have also symptoms on their lower legs and ankles, probably caused by the dust on the floor driven up into the air by the workers’ steps. Granulomatous Reaction The penetration of insoluble, nondegradable and slowly released substances into the skin may initiate a foreign-body granulomatous reaction. Such substances include wood, silk, nylon, paraffin, silicone, talcum and starch powder, oils and human hair [40]. Interdigital pilonidal sinus or ‘barber’s hair sinus’ is a foreign-body granuloma [41]. The interdigital space is shown to be a locus minoris resistentiae. Another form of foreign-body granulomatous reaction may occur after dermal injections for augmentation: injectable silicone tends to harden, migrate and cause inflammation and skin necrosis. Therefore, the Food and Drug Administration banned its use for the treatment of wrinkles and facial defects already in 1991. Superficial granulomatous reactions may also develop in acrylate-containing fillers and subsequently their use should be discouraged. Microscopic examinations reveal macrophages and giant cells at the center of the lesion, lymphocytes, monocytes and occasionally epithelioid cells.

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Protection from the penetration of insoluble, nondegradable substances into the skin may prevent a foreign-body granulomatous reaction. Mechanical irritation can be reduced by changes in the work routines combined with the education of the employees. Cleanliness of both the workers and the plant is a key factor. Gloves protect against minor mechanical traumas. Leather and textile gloves protect against abrasions, friction, lacerations and cuts. Fiberglass Dermatitis Fiberglass is made from silicon dioxide including various metal ions and other elements. Chemically, it is amorphous, stable, inert and is classed as a silicate [42]. Fiberglass dermatitis is one of the most common work-related PICDs. It is well known that fiberglass can provoke intense itching. However, only glass fibers of a magnitude greater than 5 ␮m will cause mechanical irritation of the skin. Fiberglass dermatitis includes folliculitis and paronychia, burning of the eyes, sore throat and cough. However, the sensitivity between individuals varies. A study on 98 glass-wool workers was performed [43]. Three groups of individuals were determined: group A with persistent troublesome itching from the fibers, group B without itching and group C who had ‘hardened’ to the itching. Neither anamnesis nor intense diagnostic tests revealed differences of the three groups that correlated with the subjectively increased sensitivity to the fibers in group A. To prevent the onset of fiberglass dermatitis, personal hygiene together with high accuracy of protection at the production line are fundamental [42]. Protective clothing must always be worn during high-risk processing procedures. Clothing must be changed at the workplace and not at home to avoid contamination. Prevention of fiberglass dermatitis includes also humidification of materials and adequate ventilation of the working environment. Most probably barrier creams and ointments will not be useful in the prevention of fiberglass dermatitis, because fibers may more easily stick to the skin’s surface and therefore exacerbate itching.

Electromagnetic Radiation

Electromagnetic radiation may irritate the skin. The effects of short-wave ultraviolet irradiation present a good example of this type of irritation. Details on UV protection are presented in the chapter by Kütting and Drexler (pp. 87–97). Changes in small cutaneous vessels, particularly capillaries, represent the earliest damage induced in the skin by ionizing radiation in those individuals


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administering X-rays. Later the caliber of the vessels increases, accompanied by a reduced blood flow. In severer forms of skin damage, atrophy, teleangiectasia, keratoses and epitheliomas may develop. Of 819 subjects professionally exposed to ionizing radiation, 27% revealed light, 16% moderate, 18% severe and 12% very severe damage of the capillaries [44]. The adherence and migration of leukocytes through the endothelium of blood vessels is an important early event following ionizing irradiation. Intercellular adhesion molecule (ICAM) 1, vascular cell adhesion molecule 1 and CD31 are membrane proteins of endothelial cells, mediating this process when the vessels are exposed to inflammatory stimuli [45]. Ionizing irradiation induces the expression of ICAM-1 and CD31 mRNA in a dose-dependent manner. CD31 may have a function in radiation-induced leukocyte extravasation. Both ICAM-1 and CD31 may be one of the therapeutic targets for the amelioration of radiation-induced normal tissue damage. The epidermal permeability barrier function is impaired in patients who exhibit clinical signs of radiation dermatitis [46]. In a prospective cohort study of 15 women receiving local radiation therapy, the TEWL was measured. Skin changes caused by radiation dermatitis are associated with an increase in TEWL. The onset of TEWL increase precedes the onset of radiation dermatitis, and the maximal TEWL measurements precede the peak of skin changes. Preservation of the epidermal permeability barrier function by topical treatment may ameliorate radiation dermatitis [46]. Prevention and Protection

The prognosis for PICD reactions is generally poor, especially if the individual remains in the same working environment [1]. Therefore, PICD may be best resolved by preventing it. The aim should be to reduce all kinds of exposure to irritants. A single approach is not enough. Prevention and protection should include multiple approaches, including education of employers and employees, drawing their attention to potential hazards. If barrier disruption is indeed one of the primary pathogenic mechanisms of PICD, induction of barrier repair must be an important part in the prevention and protection of physical irritants. References 1 2

Morris-Jones R, Robertson SJ, et al: Dermatitis caused by physical irritants. Br J Dermatol 2002;147:270–275. Tagami H, Kobayashi H, et al: Environmental effects on the functions of the stratum corneum. J Invest Dermatol Symp Proc 2001;6:87–94.

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Malten KE: Thoughts on irritant contact dermatitis. Contact Dermatitis 1981;7:238–247. Kanerva L, Jolanki R, et al: Statistics on occupational dermatoses in Finland. Curr Probl Dermatol 1995;23:28–40. Rawlings AV, Scott IR, et al: Stratum corneum moisturization at the molecular level. J Invest Dermatol 1994;103:731–741. Simon M, Bernard D, et al: Persistence of both peripheral and nonperipheral corneodesmosomes in the upper stratum corneum of winter xerosis skin versus only peripheral in normal skin. J Invest Dermatol 2001;116:23–30. Katagiri C, Sato J, et al: Changes in environmental humidity affect the water-holding property of the stratum corneum and its free amino acid content, and the expression of filaggrin in the epidermis of hairless mice. J Dermatol Sci 2003;31:29–35. Engelke M, Jensen JM, et al: Effects of xerosis and ageing on epidermal proliferation and differentiation. Br J Dermatol 1997;137:219–225. Rycroft RJ: Low humidity and microtrauma. Am J Ind Med 1985;8:371–373. Agner T, Serup J: Seasonal variation of skin resistance to irritants. Br J Dermatol 1989;121: 323–328. Eberlein-Konig B, Schafer T, et al: Skin surface pH, stratum corneum hydration, transepidermal water loss and skin roughness related to atopic eczema and skin dryness in a population of primary school children. Acta Derm Venereol 2000;80:188–191. Ashida Y, Ogo M, et al: Epidermal interleukin-1 alpha generation is amplified at low humidity: implications for the pathogenesis of inflammatory dermatoses. Br J Dermatol 2001;144:238–243. Denda M, Sato J, et al: Low humidity stimulates epidermal DNA synthesis and amplifies the hyperproliferative response to barrier disruption: implication for seasonal exacerbations of inflammatory dermatoses. J Invest Dermatol 1998;111:873–878. Rycroft RJ, Smith WD: Low humidity occupational dermatoses. Contact Dermatitis 1980;6:488–492. Uter W, Gefeller O, et al: An epidemiological study of the influence of season (cold and dry air) on the occurrence of irritant skin changes of the hands. Br J Dermatol 1998;138:266–272. Rogers J, Harding C, et al: Stratum corneum lipids: the effect of ageing and the seasons. Arch Dermatol Res 1996;288:765–770. Akimoto K, Yoshikawa N, et al: Quantitative analysis of stratum corneum lipids in xerosis and asteatotic eczema. J Dermatol 1993;20:1–6. Hosoi J, Hariya T, et al: Regulation of the cutaneous allergic reaction by humidity. Contact Dermatitis 2000;42:81–84. Kikuchi K, Kobayashi H, et al: Improvement of mild inflammatory changes of the facial skin induced by winter environment with daily applications of a moisturizing cream: a half-side test of biophysical skin parameters, cytokine expression pattern and the formation of cornified envelope. Dermatology 2003;207:269–275. Warner RR, Boissy YL, et al: Water disrupts stratum corneum lipid lamellae: damage is similar to surfactants. J Invest Dermatol 1999;113:960–966. Warner RR, Stone KJ, et al: Hydration disrupts human stratum corneum ultrastructure. J Invest Dermatol 2003;120:275–284. Fartasch M, Teal J, et al: Mode of action of glycolic acid on human stratum corneum: ultrastructural and functional evaluation of the epidermal barrier. Arch Dermatol Res 1997;289:404–409. Veien NK, Hattel T, et al: Low-humidity dermatosis from car heaters. Contact Dermatitis 1997; 37:138. Rehfeld SJ, Plachy WZ, et al: Calorimetric and electron spin resonance examination of lipid phase transitions in human stratum corneum: molecular basis for normal cohesion and abnormal desquamation in recessive X-linked ichthyosis. J Invest Dermatol 1988;91:499–505. Forslind B: A domain mosaic model of the skin barrier. Acta Derm Venereol 1994;74:1–6. Kaplan RP: Cancer complicating chronic ulcerative and scarifying mucocutaneous disorders. Adv Dermatol 1987;2:19–46. Danielsson U: Windchill and the risk of tissue freezing. J Appl Physiol 1996;81:2666–2673. Halkier-Sorensen L, Menon GK, et al: Cutaneous barrier function after cold exposure in hairless mice: a model to demonstrate how cold interferes with barrier homeostasis among workers in the fish-processing industry. Br J Dermatol 1995;132:391–401.


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Rudikoff D: The effect of dryness on the skin. Clin Dermatol 1998;16:99–107. Ghadially R, Brown BE, et al: The aged epidermal permeability barrier: structural, functional, and lipid biochemical abnormalities in humans and a senescent murine model. J Clin Invest 1995;95: 2281–2290. Imokawa G, Abe A, et al: Decreased level of ceramides in stratum corneum of atopic dermatitis: an etiologic factor in atopic dry skin? J Invest Dermatol 1991;96:523–526. Schurer NY, Plewig G, et al: Stratum corneum lipid function. Dermatologica 1991;183:77–94. Elias PM, Feingold KR: Coordinate regulation of epidermal differentiation and barrier homeostasis. Skin Pharmacol Appl Skin Physiol 2001;14(suppl 1):28–34. Harris IR, Farrell AM, et al: Permeability barrier disruption coordinately regulates mRNA levels for key enzymes of cholesterol, fatty acid, and ceramide synthesis in the epidermis. J Invest Dermatol 1997;109:783–787. Halkier-Sorensen L, Thestrup-Pedersen K: The efficacy of a moisturizer (Locobase) among cleaners and kitchen assistants during everyday exposure to water and detergents. Contact Dermatitis 1993;29:266–271. Bashir SJ, Chew AL, et al: Physical and physiological effects of stratum corneum tape stripping. Skin Res Technol 1993;7:40–48. Spier HW, Sixt I: Untersuchungen über die Abhängigkeit des Ausfalles der EkzemLäppchenproben von der Hornschichtdicke: quantitativer Abriss-Epikutantest. Hautarzt 1955;6: 152–159. Dickel H, Bruckner TM, et al: The ‘strip’ patch test: results of a multicentre study towards a standardization. Arch Dermatol Res 2004;296:212–219. Lyon CC, Kulkarni J, et al: Skin disorders in amputees. J Am Acad Dermatol 2000;42:501–507. Jones DP: Accidental self inoculation with oil based veterinary vaccines. NZ Med J 1996;109: 363–365. Zerboni R, Moroni P, et al: Interdigital pilonidal sinus in barbers. Med Lav 1990;81:138–141. Sertoli A, Giorgini S, Farli M et al: Fiberglass dermatitis; in Kanerva L, Elsner P, Wahlberg JE, Maibach H (eds): Handbook of Occupational Dermatology. Berlin, Springer, 2003, pp 122–133. Bjornberg A, Lowhagen GB, et al: Skin reactivity in workers with and without itching from occupational exposure to glass fibres. Acta Derm Venereol 1979;59:49–53. Fuga GC, Cavallotti C, et al: Microcirculatory damage in subjects exposed to the risk of ionizing radiation; in Marks R, Plewig G (eds): The Environmental Threat to the Skin. London, Dunitz, 1992, pp 121–123. Quarmby S, Hunter RD, et al: Irradiation induced expression of CD31, ICAM-1 and VCAM-1 in human microvascular endothelial cells. Anticancer Res 2000;20:3375–3381. Schmuth M, Sztankay A, et al: Permeability barrier function of skin exposed to ionizing radiation. Arch Dermatol 2001;137:1019–1023.

N.Y. Schürer University of Osnabrück, Department of Dermatology, Human Sciences Sedanstrasse 115 DE–49090 Osnabrück (Germany) Tel. ⫹49 541 405 1827, Fax ⫹49 541 969 2445, E-Mail [email protected]

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Protection from Combination Exposure Peter Elsner Department of Dermatology and Allergology, University of Jena, Jena, Germany

Abstract In the workplace, repeated skin exposure to a combination of irritants either simultaneously or one after the other is frequent. Therefore, assessing the efficacy of skin protection products only against single irritants is far from the daily life situation. We studied the interaction of irritants in a tandem repeated irritation test (TRIT). Shortly, healthy volunteers are exposed repeatedly to different irritants, and the skin reactions are assessed by visual scoring, transepidermal water loss, chromametry and skin capacitance. Using this model, a potentiation of irritation could be shown for several combinations of irritants, such as sodium lauryl sulfate (SLS) and toluene, SLS and mechanical stress, and SLS and hot airflow. The TRIT has been successfully used to prove the efficacy of a protective cream against a tandem application of 0.5% SLS and undiluted toluene. This test has great potential for the evaluation of skin care products to prevent irritant contact dermatitis. Copyright © 2007 S. Karger AG, Basel

Irritant contact dermatitis in particular of the hands remains to be one of the most prevalent occupational diseases in the industrialized world resulting in morbidity to the individual and in high costs to the community.

Effect of Repeated Exposure to Single Irritants and Proof of Efficacy of Skin Protection Products

Extensive research has been performed regarding the effect of irritants on the skin and the efficacy of skin protection products. Based on the repeated irritation test proposed by Frosch and Kurte [1] with cumulative irritation over a 2-week period by standard irritants such as sodium lauryl sulfate (SLS), sodium hydroxide, lactic acid and toluene (TOL), we proposed a modification to improve the safety of the test persons [2]. A multicentre study was subsequently

designed to standardize a test procedure for the evaluation of skin-protective products. In this irritation study, a repeated short-time occlusive irritation test was evaluated in 2 phases (12-day and 5-day protocol) in 4 and 6 skilled centres, respectively. Using 2 irritants (SLS and TOL, each applied twice daily for 30 min) and 3 different cream bases with different hydrophilicity, the evaluation showed that significant results could already be achieved with the 5-day protocol. Furthermore, the ranking of the vehicles regarding reduction of the irritant reaction was consistent in all centres [3].

Interaction of Irritants

However, this approach was limited, since only the cumulative effect of single irritants was tested. In contrast, in many professions the contact with hazardous substances can be very complex and manifold. For instance, workers in the metal industry are repetitively exposed to water-based metal working fluids, neat oils, detergents and organic solvents. The interaction between irritant chemicals at the workplace may have significant practical consequences. We therefore studied the effects of an interaction of irritants in a systematic way. Using the non-invasive bioengineering methods of measurements of transepidermal water loss (TEWL) and skin colour reflectance, we quantified the irritant effects of single and tandem applications of various irritants in vivo. For this purpose, a ‘tandem repeated irritation test’ (TRIT) was designed. Shortly, in this test either 1 irritant is applied twice daily or 2 irritants are applied once daily each to healthy skin of human volunteers for 4 days. Cumulative irritant dermatitis is quantitatively assessed on day 5.

Solvents

Repeated applications of [4] SLS, an anionic detergent, and TOL, a model solvent, induced an irritant reaction, as indicated by an increase in TEWL and skin redness. In contrast to SLS alone, the application of TOL alone induced only a moderate increase in TEWL, confirming previous results. Concurrent application of SLS/TOL and TOL/SLS induced significantly stronger reactions than those caused by a twice daily application of each irritant on its own. Our results demonstrate that a mixed application of an anionic detergent and an organic solvent has an additive effect on skin irritation. It is suggested that pretreatment with SLS causes an increased susceptibility to TOL irritation and vice versa. Thus, the necessity for special precautions against skin absorption of TOL when handling detergents such as SLS is emphasized.

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Disinfectants

n-Propanol is the active ingredient in many disinfectants [5]. Thus, it is of particular interest regarding occupational skin irritation in healthcare workers. Tandem application of SLS and n-propanol did not enhance cumulative skin irritation. Hand dermatitis in healthcare workers seems to be more related to hand washing than to disinfection.

Fruit Acids

Twice daily application of either citric or malic acid alone did not induce a significant irritant reaction. Combined exposure to one of the fruit acids [6, 7] and SLS caused marked barrier disturbance, but the latter irritant effect was smaller than that obtained by a combined exposure to SLS and water. Thus, the combined exposure to the above-mentioned fruit acids and SLS did not enhance cumulative skin irritation. In a second study, we assessed the irritant effects and barrier disruption properties of ascorbic acid, acetic acid (ACA) and sodium hydroxide (NaOH), again in combination with SLS. Repeated application of ascorbic acid and ACA caused a moderate increase in TEWL and erythema. The sequential application of ascorbic acid or ACA and SLS enhanced these effects. NaOH induced a strong reaction when applied both occlusively and non-occlusively as well as in combination with SLS, with an early onset of the inflammatory signs, leading to discontinuation of the application on the third day in most of the test fields. Notably, the irritant effect of NaOH was not as marked when applied sequentially with SLS.

Biogenic Amines

Regarding the irritative and barrier-disrupting properties of the biogenic amines [8] ammonium hydroxide, dimethylamine and trimethylamine in single and combined application with SLS, all 3 tested biogenic amines induced a barrier disruption and a pH increase paralleled with a 1-day-delayed onset of inflammatory signs. These effects were further enhanced and accelerated by a sequential application of SLS together with the biogenic amines, and inflammation occurred earlier than with the single compounds. ACA in contrast did only show mild barrier disruption and no significant inflammatory signs. Our system allowed a ranking of the different compounds in their irritative potential in the tandem irritation with SLS: SLS ⬎ NaOH ⬎ trimethylamine ⬎ ACA ⬎ ammonium hydroxide ⬎ dimethylamine. The results are suggestive that in the

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food-processing industry the simultaneous contact with biogenic amines and harmful detergents like SLS should be minimized. Mechanical Irritation

In this study, we found the following rank of irritancy [9]: occlusion with SLS and mechanical irritation ⬎ occlusion with SLS ⬎ occlusion with water and mechanical irritation ⬎ mechanical irritation and occlusion with water ⬎ occlusion with a glove and mechanical irritation ⬎ mechanical irritation ⬎ occlusion with water. Barrier disruption caused by occlusion or mechanical irritation was enhanced by the tandem application. The choice of irritant under occlusion, time of occlusion and order of tandem application all affected the degree of barrier disruption. Thus, physical irritants (friction, abrasive grains, occlusion) and detergents such as SLS represent a significant irritation risk and should be minimized, especially when acting together. Cold

Cold [10] alone caused no significant irritant skin reaction compared with untreated control. Exposure to SLS alone and SLS together with cold twice daily induced a clear irritant reaction and barrier disturbance. Reactions did not differ whether SLS was applied before or after cold. Furthermore, ‘tandem application’ of cold and SLS diminished the barrier disruption and irritant reaction compared with SLS alone. Warm Airflow

Airflow [11] alone did not lead to a significant increase in TEWL values. Sequential treatment with airflow and SLS led to an impairment of barrier function and irritation stronger than that produced by SLS alone. Two different airflow temperatures led to different skin temperatures but had no influence on permeability barrier function. Pilot Testing of a Skin Protection Product in the Tandem Repeated Irritation Test

As the model seemed to have potential for testing protective creams (PCs), the sequential application of 2 irritants in the TRIT was investigated in a study

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to evaluate the benefit of a commercially available PC compared to nonpretreated control sites [12]. Twenty healthy non-preselected Caucasian volunteers without any skin diseases were included. Informed consent was obtained from all participants, and the study passed the local ethical committee. Subjects were allowed to bathe as usual but were instructed to avoid any direct application of detergents, moisturizers or emollients on their forearms during the 5 days of investigation. As test product, a PC with a claim to protect both against hydrophilic and against lipophilic irritants was used (Stokoderm®, Stockhausen, now Degussa, Krefeld, Germany). The application area was the clinically normal skin of the medial volar forearms. The placement of test fields and arms (6 chambers on the right and left forearms) was randomized. Three test fields were treated with 0.05 ml of PC rubbed onto a skin area 2 cm in diameter with a gloved finger. The other test fields served as untreated controls. After 10 min pretreatment, the irritants were applied on all 6 premarked test sites on the forearms for 30 min under occlusion (Finn chambers, 12 mm in diameter, filling volume 0.05 ml; Epitest Ltd., Hyrlä, Finland). The volunteers were tested with 0.5% aqueous SLS (Sigma, St. Louis, Mo., USA) or undiluted TOL (E. Merck, Darmstadt, Germany). After removal of the patches, the skin was cleaned with a dry paper tissue. A second exposure with 0.5% aqueous SLS or undiluted TOL was performed on the same day after 3 h. Thus, 3 treatment combinations were investigated, resulting in a repeated irritation due to SLS/SLS, TOL/TOL, and SLS/TOL and the pre-irritation application of Stokoderm on the respective test areas. Since in our previous study the exact chronological order of the irritants was shown not to have any effect on the degree of irritation [4], the combination TOL/SLS was not included in the present study. Using this scheme of application, the volunteers were treated from day 1 to day 4 (in each case at the same time of day). All visual scoring (VS) and bioengineering measurements to compare the intensity of reactions were performed daily before starting treatments (day 1–4) and on day 5 by the same observer under controlled environmental conditions. All measurements were carried out in an air-conditioned room (room temperature 20–22⬚C, relative humidity between 34 and 46%) after 30 min for equilibration. The clinical score graded for erythema, scaling and fissuring was recorded according to Frosch and Kligman [13]. TEWL (expressed in grams per square meter per hour) was measured using an evaporation meter (Tewameter TM 210, Courage & Khazaka, Cologne, Germany). Instrumental colour measurements were taken with a Minolta Chromameter (CR-200, Minolta, Osaka, Japan). The colour coordinates were expressed in the L*a*b* 3-dimensional colorimetric system. The a* value is the component of separation between red (positive value) and green (negative value) as a sensitive measure for quantifying erythema.


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30 SLS/SLS Stokoderm/SLS/SLS

**

⌬TEWL (g/m2h)

25

*

20

15

* 10

5

0 2

3

4

5

Days

Fig. 1. ⌬TEWL (mean ⫾ SEM, n ⫽ 20) after sequential application of SLS/SLS. On days 3, 4 and 5, the protective effect of Stokoderm on the irritation was statistically significant (* p ⬍ 0.05, ** p ⬍ 0.01). From Wigger-Alberti et al. [12].

Electrical capacitance, indicating the hydration level of the skin, was measured by a Corneometer CM 825 (Courage & Khazaka). Statistical analysis was conducted with SPSS/PC⫹ (Version 10.0, SPSS, Chicago, Ill., USA). Data of VS are presented as means ⫾ SEM. TEWL, skin colour a* and skin hydration (differences between baseline values and after irritation) were determined. Differences between means were checked for significance using the Wilcoxon test for paired data for the erythema score, the comparison of TEWL, skin capacitance and skin colour. The chosen level of significance was p ⱕ 0.05. The results of the study are presented in figures 1–3 as means ⫾ SEM. Repeated application of SLS 0.5% twice daily induced an irritant reaction indicated by a moderate increase in the VS, a more pronounced increase in the TEWL values, a decrease in skin hydration and an increase in the a* values that confirmed the VS. There was a highly significant difference (p ⱕ 0.01) between SLS-treated sites and those that were pretreated with Stokoderm on day 5 for the VS, TEWL (fig. 1) and chromametry. In contrast to SLS/SLS, the application of TOL/TOL provided only a moderate increase in the TEWL over the study period that was slightly suppressed by Stokoderm (fig. 2). A moderate benefit of the test product against TOL was

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5.0 TOL/TOL

Stokoderm/TOL/TOL

4.5 4.0 ⌬TEWL (g/m²h)

3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 2

3

4

5

Days

Fig. 2. ⌬TEWL (mean ⫾ SEM, n ⫽ 20) after sequential application of TOL/TOL. The protective effect of Stokoderm on the irritation was not statistically significant. From Wigger-Alberti et al. [12].

45 40

SLS/TOL Stokoderm/TOL/SLS

**

⌬TEWL (g/m2h)

35 30

*

25 20 15 10 5 0 2

3

4

5

Days

Fig. 3. ⌬TEWL (mean ⫾ SEM, n ⫽ 20) after sequential application of SLS/TOL. On days 4 and 5, the protective effect of Stokoderm on the irritation was statistically significant (* p ⬍ 0.05). From Wigger-Alberti et al. [12].


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also confirmed by the measurement of skin capacitance and the chromametry while the VS showed contrary results. Monitoring of the instrumental measurements and the VS following sequential application of SLS/TOL showed that the induced reactions were significantly stronger than those caused by twice daily application of the single irritants SLS or TOL. Additionally, pretreatment with Stokoderm suppressed the irritant reaction presented by all measurements. The TEWL and the VS indicated a significant benefit of the product tested (fig. 3). Our results showed that the TRIT seems to have great potential in differentiating the efficacy of PCs in a relevant experimental setting that is quite close to a workplace situation where detergents and organic solvents are the major irritants used not exclusively, but concurrently.

Research Needs Regarding Protection from Combined Irritants

So far, the reported study has been the only one that assessed the efficacy of a skin protection product in a TRIT. Since combination exposures are the rule, not the exception in the workplace, further work in this area is dearly needed before skin protection products can be proposed in combination exposure situations. Especially the combined exposure to detergents on one side and solvents, mechanical stress and hot air on the other side seems to potentiate epidermal barrier damage and is therefore suggested for the study of protection products to be used in such workplaces. Finally, this model must be validated by field studies under actual usage conditions.

References 1 2 3

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5

6

Frosch PJ, Kurte A: Efficacy of skin barrier creams. IV. The repetitive irritation test (RIT) with a set of 4 standard irritants. Contact Dermatitis 1994;31:161–168. Schluter-Wigger W, Elsner P: Efficacy of 4 commercially available protective creams in the repetitive irritation test (RIT). Contact Dermatitis 1996;34:278–283. Schnetz E, Diepgen TL, Elsner P, Frosch PJ, Klotz AJ, Kresken J, Kuss O, Merk H, Schwanitz HJ, Wigger-Alberti W, Fartasch M: Multicentre study for the development of an in vivo model to evaluate the influence of topical formulations on irritation. Contact Dermatitis 2000;42:336–343. Wigger-Alberti W, Krebs A, Elsner P: Experimental irritant contact dermatitis due to cumulative epicutaneous exposure to sodium lauryl sulphate and toluene: single and concurrent application. Br J Dermatol 2000;143:551–556. Kappes UP, Goritz N, Wigger-Alberti W, Heinemann C, Elsner P: Tandem application of sodium lauryl sulfate and n-propanol does not lead to enhancement of cumulative skin irritation. Acta Derm Venereol 2001;81:403–405. Fluhr JW, Bankova L, Fuchs S, Kelterer D, Schliemann-Willers S, Norgauer J, Kleesz P, Grieshaber R, Elsner P: Fruit acids and sodium hydroxide in the food industry and their combined

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8

9

10

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12

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effect with sodium lauryl sulphate: controlled in vivo tandem irritation study. Br J Dermatol 2004;151:1039–1048. Schliemann-Willers S, Fuchs S, Kleesz P, Grieshaber R, Elsner P: Fruit acids do not enhance sodium lauryl sulphate-induced cumulative irritant contact dermatitis in vivo. Acta Derm Venereol 2005;85:206–210. Fluhr JW, Kelterer D, Fuchs S, Kaatz M, Grieshaber R, Kleesz P, Elsner P: Additive impairment of the barrier function and irritation by biogenic amines and sodium lauryl sulphate: a controlled in vivo tandem irritation study. Skin Pharmacol Physiol 2005;18:88–97. Fluhr JW, Akengin A, Bornkessel A, Fuchs S, Praessler J, Norgauer J, Grieshaber R, Kleesz P, Elsner P: Additive impairment of the barrier function by mechanical irritation, occlusion and sodium lauryl sulphate in vivo. Br J Dermatol 2005;153:125–131. Fluhr JW, Bornkessel A, Akengin A, Fuchs S, Norgauer J, Kleesz P, Grieshaber R, Elsner P: Sequential application of cold and sodium lauryl sulphate decreases irritation and barrier disruption in vivo in humans. Br J Dermatol 2005;152:702–708. Fluhr JW, Praessler J, Akengin A, Fuchs SM, Kleesz P, Grieshaber R, Elsner P: Air flow at different temperatures increases sodium lauryl sulphate-induced barrier disruption and irritation in vivo. Br J Dermatol 2005;152:1228–1234. Wigger-Alberti W, Spoo J, Schliemann-Willers S, Klotz A, Elsner P: The tandem repeated irritation test: a new method to assess prevention of irritant combination damage to the skin. Acta Derm Venereol 2002;82:94–97. Frosch PJ, Kligman AM: The soap chamber test: a new method for assessing the irritancy of soaps. J Am Acad Dermatol 1979;1:35–41.

Peter Elsner, MD Department of Dermatology, Friedrich Schiller University Erfurter Strasse 35 DE–07740 Jena (Germany) Tel. ⫹49 3541 937418, Fax ⫹49 3541 937350, E-Mail [email protected]


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Practical Applications of Skin Protection Schliemann S, Elsner P (eds): Skin Protection. Curr Probl Dermatol. Basel, Karger, 2007, vol 34, pp 120–132

Skin Protection in the Healthcare Setting Vera Mahler Department of Dermatology, University Hospital Erlangen of the Friedrich Alexander University, Erlangen, Germany

Abstract Professions of the healthcare setting are at high risk for occupational skin diseases. Irritant and allergic contact dermatitis of the hands frequently occurs, whereas contact urticaria and hospital-acquired infections are less common. Wet work and irritant exposure are frequent due to hand hygiene which is indispensable with regard to prevention of crossinfections. In the healthcare setting, protection gloves are frequently used alternating with protection creams. Since the use of occlusive protection gloves has adversary effects on the skin barrier, use times have to be limited. Furthermore, a 3-step concept consisting of skin protection before work, cleaning and skin care after work is one of the generally recommended measures to prevent occupational contact dermatitis. Recently, educational programmes for skin protection as measure of primary, secondary and tertiary prevention of occupational skin diseases have been effectively introduced in the healthcare setting. The effectiveness of skin care programmes is based on 3 factors: the effectiveness of the products used, the frequency of the application and, finally, the effectiveness of the education (reduction of exposure to skin-damaging substances). For the identification of contact allergens in healthcare workers with hand dermatitis, supplementary work-specific series as well as substances used at work should be patch-tested in addition to the standard series. Copyright © 2007 S. Karger AG, Basel

With a yearly incidence of 7.3 occupational skin diseases/100,000 healthcare workers, professions of the healthcare setting belong to the high-risk occupations in Germany [1]. This chapter will focus on skin protection in the healthcare setting with regard to hazardous exposures to which physicians, nursing staff and technical support staff are subjected to. In this field, irritant and allergic contact dermatitis is frequent, whereas contact urticaria and hospital-acquired infections are less frequent causes for occupational skin disease. In a survey for occupation-related skin diseases in northern Bavaria [1] in the healthcare setting, the hands were affected in 95%. Most frequently, not

Allergic contact dermatitis

Irritant contact dermatitis 51%

54%

46% Atopic skin diathesis

Fig. 1. Pathogenetic factors contributing to occupational dermatitis in the healthcare setting. The frequencies (in percent) are demonstrated in which the respective factor could be identified to be relevant in healthcare workers with occupational skin disease (n ⫽ 482).

only a single cause, but several pathogenetic factors (irritant and allergic contact dermatitis and atopic skin diathesis) contribute to the manifestation of occupational skin disease in this field (fig. 1). Early identification of individuals at risk and prevention by feasible protection measures are mandatory.

Protection against Infectious Agents

In the healthcare setting, disinfection and hand hygiene are indispensable with regard to prevention of cross-infections. Easy access to hand hygiene and skin protection appears necessary for a satisfactory hand hygiene behaviour. Alcohol-based hand rubs may be superior to traditional hand washing as they require less time, act faster, irritate the hands less often and have recently been shown to significantly contribute to a sustained improvement in compliance associated with decreased infection rates [2, 3]. At equal concentrations, npropanol is the most effective alcohol of those commonly used, and ethanol the least [2]. In particular, it is important to recall that: (1) alcohol-based formulations for hand disinfection (whether isopropyl, ethyl or n-propanol, at 60–90% v/v) are less irritant on the skin than any antiseptic or non-antiseptic detergents; (2) alcohols with the addition of appropriate emollients are at least as well tolerated and efficacious as detergents; (3) emollients for healthcare workers’ hand skin are recommended and may even be protective against cross-infection by keeping the resident skin flora intact, and (4) hand lotions help to protect the skin and may reduce microbial shedding [2, 4–6].

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According to national regulations – e.g. approved code of practice (TRGS) 525 (hazardous materials in the healthcare setting) in Germany [7] – certain general aspects and protective measures have to be followed when using disinfectants. Prior to disinfection, its indication has to be recalled. Unnecessary skin and mucosal contact with disinfectants has to be avoided. Hand disinfection, skin and mucosal disinfection, surface disinfection and disinfection of instruments have to be distinguished that require different chemical classes [8]. The choice of disinfectant has to be adapted to the anticipated spectrum of pathogens (viruses, bacteria, fungi, protozoa) [9] (table 1). Preferentially, by the use of automated dosing devices, concentrates have to be diluted accurately to the recommended use concentration with water not warmer than room temperature. When handling concentrates, protection gloves and goggles need to be worn. Mixing of different (incompatible) products has to be avoided. Due to the explosive nature of alcohols, hand disinfection with alcohols in proximity to open fire is not permissible. For surface disinfection alcohols may only be used when rapid disinfection is necessary and no alternative is available. When handling aldehyde-containing disinfectants, skin and mucosal contact, inhalation of their vapour and evaporating pools have to be avoided.

Protection against Irritants

Wet work and irritant exposure (table 2) in the healthcare setting are frequent due to hand hygiene which is indispensable with regard to prevention of cross-infections. Alcohol-based hand rubs may be superior to traditional hand washing and irritate the hands less often [2, 3]. Besides easy access to hand hygiene, skin protection has been introduced as a necessary prerequisite for a satisfactory hand hygiene behaviour [2]. In the healthcare setting, frequently protection gloves are used alternating with protection creams. Even when optimized, the latter never achieve the same level of protection as protection gloves do [10]. Which glove material should be used for which purpose is briefly summarized in table 3 [11]. The technical rule for hazardous substances (approved code of practice TRGS 220) describes the required contents of the safety data sheet in Germany. An essential change of the 2002 draft is the objective to facilitate the selection of suitable gloves for the users. Beyond the European directive 2001/58/EG, the TRGS includes the wearing time of gloves while working with chemicals [12]. In a recent study on the permeability of surgical gloves to 7 chemicals commonly used in hospitals, the gloves did not exhibit permeation of potassium

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Table 1. Characteristics of disinfectants by chemical composition (modified from Robert-Koch-Institut [8] and Thalmann [9]) Skin Protection in the Healthcare Setting

Classes

Spectrum of activity

Comments

Alcohols

B, T, F, cV

No effect following evaporation; sensitive to organic substances; synergistic effects with iodine, chlorhexidine and quaternaries

Aldehydes

B, T, F, S, cV, uV

Readily volatile, relatively unstable; may preserve impurities on instruments (unsuccessful disinfection outcome); formaldehyde causes respiratory problems in low concentrations and is suspected of being carcinogenic, glutaraldehyde fumes irritate eyes and airways; poor protein load tolerance

Amines

B, T, F, cV, uV

No compatibility with aldehydes, and therefore no aldehyde products should be used before or after treatment

Chlorine compounds (hypochlorites)

B, cV, uV

Good disinfectants on clean surfaces, quickly inactivated by dirt; more active in warm water than in cold water, irritating to skin, corrosive to metal

Hydrogen peroxide; peroxyacetic acid

B, T, F, cV, uV

Less corrosive than iodine and chlorine compounds; reaction with chlorine-cleaving substances and bisulphite, with toxic gases and fumes being formed; when diluting, transfer acid to water, not vice versa; do not use together with other cleaning agents; cleaning agents that contain hypochlorite release toxic gases that may harm the airways; exothermic reaction with lyes; risk of decomposition with impurities of any kind, particularly heavy metals

Iodine compounds

B, T, F, S, cV, uV

Iodine compounds are available as iodophors, which are combinations of elemental iodine and a substance that makes the iodine soluble in water; insensitive to blood and organic substances; active against hepatitis B viruses; absorption and systemic toxicity possible under certain conditions; incompatible with mercury compounds, metals and quaternaries; can stain clothing and porous surfaces

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Table 1. (continued) Mahler

Classes

Spectrum of activity

Comments

Phenol derivatives

B, T

Coal tar derivatives, turn milky in water, strong odour; toxic; stable, not very sensitive to organic substances; ineffective on hepatitis B virus; phenols must not come into contact with strong oxidizing agents such as peracetic acid; phenols modify rubber and synthetic materials

Quaternaries

B

Odourless, colourless, non-irritating, deodorizing; sensitive to organic substances, soaps, hard water; inactive against certain Gram-negative bacteria; cationic substances such as quaternaries are precipitated out by anionic derivatives (soaps and other detergents) and thus lose their effectiveness

Sodium hydroxide

B, T, F, cV, uV

Ammonia forms on contact with ammonium compounds

B ⫽ Bactericidal; cV ⫽ coated viruses; F ⫽ fungicidal; S ⫽ sporicidal; T ⫽ tuberculocidal; uV ⫽ uncoated viruses.

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Table 2. Frequent irritants in the healthcare setting Water Detergents/soap Antiseptics Alcohols Occlusion (glove-associated) Ethylene oxide Plaster of Paris Miscellaneous medications

Table 3. Recommended glove materials in the hospital setting (according to the AWMF Working Group for Hygiene in Hospital Practice [11])

Orthopaedic surgery General surgery Specific patient care (e.g. change of dressings) General patient care Cleaning Disinfection Handling of chemotherapeutic agents

Natural rubber latex

Nitrile

double gloving x x

latex allergy latex allergy latex allergy x

Polyvinyl chloride

Polyethylene

x

x x

x x

hydroxide (45%), sodium hypochlorite (13%) or hydrogen peroxide (30%), glutaraldehyde (2%) or chlorhexidine digluconate (4%) in the commercial disinfectant solutions studied. Slight permeation of peracetic acid (0.35%) and acetic acid (4%) from a disinfectant agent was observed through single-layered natural rubber materials. Clear evidence of formaldehyde permeation was detected through single-layered natural rubber gloves (breakthrough times were 17–67 min) [13]. The gloves in this study which offered most protection from chemical permeation were the chloroprene gloves and the thick double-layered natural rubber gloves. For 70% isopropyl alcohol, breakthrough times through surgical gloves when tested according to standard methods could be demonstrated from 4.8 to 38 min (ASTM F739) versus 4.6–122 min (EN 374) for different sorts of latex gloves and ⬎240 min (EN 374) versus 103 min (ASTM) for chloroprene rubber [14].


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However, the use of occlusive protection gloves itself has adversary effects on the stratum corneum barrier properties [15] so that use times have to be limited to the necessary [16]. For many years, a 3-step programme of occupational skin protection – consisting of skin protection (so-called barrier creams) before work, cleaning and skin care after work – has been introduced into practice. While protective creams are supposed to prevent skin damage due to irritant contact, skin cleansing should mildly remove aggressive substances from the skin, whereas postexposure skin care is intended to enhance epidermal barrier regeneration. This 3-step concept is strongly propagated and is one of the generally recommended measures to prevent occupational contact dermatitis [17]. In Germany, according to the approved code of practice TRGS 531 (wet work) [18], for occupations with ⬎2 h of exposure to wet work or occlusive conditions by protection gloves, employers have to provide a 3-step programme of occupational skin protection. In spite of intensive measurements for skin care and protection in Germany, the number of recorded occupational skin diseases according to BK 5101 did not decline over the past years (data of HVBG: general German employee liability insurance association) [17]. A recent study on skin protection and secondary prevention in healthcare workers revealed that prior to the reported intervention only 35% of participants had been using the provided skin care and protection products regularly [19]. Under model conditions for irritant contact dermatitis (repetitive irritation testing with sodium lauryl sulphate), it could recently be shown that the highest benefit was achieved if all 3 protective measures were combined. Thus, the efficacy of the integrated skin protection was confirmed; however, the use of a barrier cream appeared to be the most important part [20]. When critically questioned by criteria of evidence-based medicine, it was found that for an evidence-based recommendation of skin protection, further clinical studies were needed, especially under daily working conditions evaluating the contribution of each single element of skin care programmes (products, frequency of application and education programme) [17]. In a randomized double-blind study with hospital nurses [21], Excipial Protect was compared with its vehicle. Fifty hospital nurses with mild signs of compromised skin on their hands, such as roughness or slight erythema, were included. Half of the test population received the commercial product, whereas the other half received the vehicle for a month. The effects of both types of preparation were studied weekly by clinical examination and instrumental assessment of bioengineering parameters. Results showed no significant differences between barrier cream and vehicle. Even the vehicle alone was capable of positively influencing the skin status. Critical points of this study are the small study population, the lack of a control group without any cream application, the

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Table 4. Evidence-based recommendations for employees in wet-work occupations according to Held et al. [23] Wash your hands in lukewarm water; rinse and dry your hands thoroughly after washing Use protective gloves when starting wet-work tasks Protective gloves should be used when necessary but for as short a time as possible Protective gloves should be intact, and clean and dry inside When using protective gloves for more than 10 min, wear a cotton glove underneath Do not wear finger rings at work Do not use disinfectant agents unless they are recommended for special hygienic reasons Apply moisturizers on your hands during the working day or after work; select a moisturizer which is lipid rich and free from fragrance and with preservatives having the lowest allergen potential The moisturizer must be applied all over the hands inclusive webs, fingertips and dorsal aspects Take care also when you do domestic work (use protective gloves when doing dishwashing and cleaning) and when the weather is cold with low humidity (use insulating gloves)

short observation time and inclusion of subjects with already impaired skin conditions (roughness or slight erythema). Therefore the study qualifies for evaluating the therapeutic rather than the preventive properties of skin protection [17]. In a double-blind randomized trial [22], an oil-containing lotion was compared with a novel barrier cream in 54 healthcare workers with severe hand irritation, over a 4-week period. Subjects in both groups experienced marked improvement. Due to the inclusion criteria (impaired skin condition), this trial is qualified to prove therapeutic effects of skin protection creams. However, it has to be kept in mind that barrier creams are intended for the use on intact skin as part of the primary prevention and that they cannot substitute a proper dermatological treatment in manifest hand eczema [16]. In an intervention study in student auxiliary nurses (n ⫽ 61 in the intervention group and n ⫽ 46 in the control group), as part of the intervention an evidence-based skin care programme (table 4) was introduced, using knowledge from epidemiological and clinical experimental studies about proper glove use, correct hand washing, use of hand disinfectants and moisturizers [23]. After a 10-week period of initial practical training, 48% of the intervention group versus 58% of the control group had aggravation of skin problems. Frequency of use of hand disinfectant agents was significantly associated with aggravation of skin problems. Over the past 10 years, primary, secondary and tertiary prevention of occupational skin disorders has been shown to be successful in hairdressers,


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documented with appropriate statistical methods [24, 25]. Based on these promising results of educational aspects in skin care management in this highrisk profession, recently, in cooperation with the Accident Prevention and Insurance Association for Healthcare Workers (Berufsgenossenschaft für Gesundheitsdienst und Wohlfahrtspflege, BGW), disease prevention courses have been extended for secondary prevention of occupational skin disease in the healthcare professions [19]. In a recent intervention study for secondary prevention of hand dermatitis in geriatric nurses (n ⫽ 102 in the intervention group and n ⫽ 107 in the control group), 89% of the intervention group and 90% of the control group complained of occupational skin disease upon entry. The intervention group received repeated education and training in skin protection measures over a period of 6 months including a 3-step skin care programme, whereas the participants of the control group were seeing a dermatologist on demand. Upon study completion 6 months after the first encounter, 59% of participants of the intervention group were free of occupational skin disease. Questionnaires 3 months after study completion revealed skin lesions in 53% of the intervention group and 82% of the control group (p ⬍ 0.01) demonstrating that the education programme was superior in terms of health maintenance and employment [26]. The effectiveness of a skin care programme is based on 3 factors: first, the effectiveness of the products used; second, the frequency and elaborateness of the application of skin care products, and, finally, the effectiveness of the education (reduction of exposure to skin-damaging substances) [17]. No general agreement exists on how often workers should be advised to apply moisturizers on their hands, if they should use moisturizers at the workplace or after work or whether a 3-step skin care programme (including skin protection before work, cleansing and skin care after work) is superior.

Protection against Contact Allergens

Type IV sensitizations are frequently found in healthcare workers although most of the sensitizations are occupationally irrelevant. In a group of healthcare workers (n ⫽ 62) diagnosed as having occupational allergic dermatitis, 62.9% (n ⫽ 39) showed positive patch test reactions to the GIRDA standard series [27]. As clinically relevant allergens (number of patients in parentheses) nickel sulphate (26), cobalt chloride (6), thimerosal (4), methyl(chloro)isothiazolinone (3), p-phenylenediamine (3), fragrance mix (2), potassium dichromate (2), 4, 4-diaminodiphenylmethane (2), Myroxylon pereirae resin (1), isopropylphenylp-phenylenediamine (2), neomycin sulphate (2), formaldehyde (1), mercuric chloride (1), lanolin alcohol (1) and mercapto mix (1) were found.

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6%

Nickel (II) sulphate

39% 16%

12%

Own substances

16%

Cobalt (II) chloride 2% Glutaraldehyde Thiuram mix

12% 4%

Fragrance mix

Formaldehyde

4% 3%

PPD 2% 0

13% 12%

8%

Thimerosal 2%

MCI/MI

15%

13%

7% 7% Sensitization

Occupationally relevant

6% 10

20

30

40

%

Fig. 2. Frequency and occupational relevance of type IV allergies in healthcare workers with occupational skin disease (n ⫽ 482). Own substances: disinfectants, skin cleansers, skin care products, gloves. MCI ⫽ Methylchloroisothiazolinone; MI ⫽ methylisothiazolinone; PPD ⫽ p-phenylenediamine.

In our data for healthcare workers (n ⫽ 482) from the register of occupational skin diseases of Northern Bavaria, we could elucidate the frequency of type IV sensitizations found by patch testing and their occupational relevance as shown in figure 2 [28]. Further sensitizations (frequency and occupational relevance in parentheses) in the examined group of healthcare workers were found for M. pereirae resin (5%/1%), potassium dichromate (5%/1%), colophony (4%/1%), phenylmercuric borate (4%/1%), benzalkonium chloride (4%/25%), benzoyl peroxide (3%/1%), palladium chloride (3%/1%), tetramethylthiuram disulphide (2%/2%), zinc dimethyldithiocarbamate (2%/2%) and mercuric chloride (2%/1%). Although type IV allergies are frequently involved in the pathogenesis of occupational skin disease (fig. 1) in healthcare workers, an allergic contact dermatitis as the one and only cause of hand eczema is rather rare. Recently, contact dermatitis of the hands exclusively due to type IV allergy was found to be present in 14% of participants of a secondary prevention programme in healthcare workers [19]. As the standard series detect a relatively low proportion of occupational allergic contact dermatitis, it is not adequate to recognize an occupational allergic contact dermatitis [27]. Certain supplementary series specific for the work environment (e.g. according to the recommendations for patch testing for the


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healthcare setting [29] and geriatric nursing [30]) as well as substances used at work should also to be tested. An important factor in the development of contact allergy seems to be the degree of exposure, in terms of concentration and duration [27]. Skin care products are ineffective in the protection against contact allergens with regard to the induction as well as elicitation phase [16]. Avoidance measures have to be regarded including substitution of hazardous agents as well as personal protective gear. However, also gloves as part of the personal protective gear for hand dermatitis may induce allergies. In healthcare workers with glove-related symptoms (n ⫽ 295), irritant contact dermatitis was diagnosed in 85.1%, allergic contact dermatitis to rubber chemicals in 10.5% and contact urticaria due to latex allergy in 6.8% [31].

Protection against Protein Allergens

Most type I sensitizations found in healthcare workers are not occupationally relevant [19, 28]: 35% of participants in a disease prevention programme for healthcare workers had a diagnosed type I allergy to seasonal allergens, 9.6% to natural rubber latex [19]. Due to an increased use of medical gloves for single use made from natural rubber latex during the last decade of the last century, a constant increase in the incidence of type I allergies could be observed in healthcare workers. Annual incidence rates of latex sensitization of as much as 3.8/10,000 healthcare workers were found [28]. In Germany, this increase stopped when in December 1997 powdered latex gloves were explicitly banned by law [approved code of practice TRGS 540 (sensitizing substances)] as sensitizing substance from the work environment [28, 32]. Latex allergens bound to powder particles constitute occupational inhalative allergens that are easily propagated by air and may cause airway sensitization by inhalation [33]. Currently, most latex products are produced with a low content of latex proteins, e.g. the amount of leachable protein has been limited to ⬍30 ␮g/g glove (recommendation by the Accident Prevention and Insurance Association for Health Care Workers) in Germany. However, recently, foreign protein (e.g. casein) has been found in finished latex products [34, 35]. The substitution of genuine latex proteins by foreign proteins for improvement of material properties is largely unknown since it is unlabelled and may lead to a shift and novel increase in sensitization profiles elicited by the finished products. In a recent study, we could demonstrate a similar allergenicity and capacity to de novo sensitization of these proteins when compared to latex proteins in an animal model [35]. Thus, complete labelling constitutes a prerequisite for allergy prevention.

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References 1 2 3 4 5

6 7 8

9

10

11 12

13 14

15 16 17

18 19

20

21

Dickel H, Kuss O, Blesius CR, Schmidt A, Diepgen TL: Occupational skin diseases in Northern Bavaria between 1990 and 1999: a population-based study. Br J Dermatol 2001;145:453–462. Pittet D: Compliance with hand disinfection and its impact on hospital-acquired infections. J Hosp Infect 2001;48(suppl A):S40–S46. Kramer A, Jünger M, Kampf G: Hygienic and dermatologic aspects of hand disinfection and prophylactic skin antisepsis. Hautarzt 2005;56:743–751. Larson E: Skin hygiene and infection prevention: more of the same or different approaches? Clin Infect Dis 1999;29:1287–1294. Boyce JM, Kelliher S, Vallande N: Skin irritation and dryness associated with two hand hygiene regimens: soap and water hand washing versus hand antisepsis with an alcoholic hand gel. Infect Control Hosp Epidemiol 2000;21:442–448. Maki DG: The use of antiseptics for hand washing by medical personnel. J Chemother 1989;1: 3–11. Technische Regeln für Gefahrstoffe (TRGS) 525: Umgang mit Gefahrstoffen in Einrichtungen zur humanmedizinischen Versorgung. BArbBl 1998;5:99–105. Robert-Koch-Institut: Veröffentlichung des Robert-Koch-Institutes zu Desinfektion und Sterilisation. 2005. http://www.rki.de/cln_011/nn_527010/sid_531B4D6FF23900CD7AC0887 77941DD86/DE/ Content/Infekt/Krankenhaushygiene/Desinfektionsmittel/Desinf__RKIPublikationen.html__ nnn ⫽ true. Thalmann P: Practical information on disinfectants: standards, properties, search aid. State Laboratory of the cantons Basel City and Berne. 2001. http://www.kantonslabor-bs.ch/files/e_ praxis_ desinfektion.pdf. Korinth G, Geh S, Schaller KH, Drexler H: In vitro evaluation of the efficacy of skin barrier creams and protective gloves on percutaneous absorption of industrial solvents. Int Arch Occup Environ Health 2003;76:382–386. AWMF Working Group for Hygiene in Hospital Practice: Hygiene in Klinik und Praxis, ed 3. Wiesbaden, mhp-Verlag, 2004, p 191. Marschner B, Zuther F: Technical rule for hazardous substances (TRGS) 220: do revised material data sheets support the selection of adequate protective gloves? Derm Beruf Umwelt 2004:2: 47–53. Mäkelä EA, Vainiotalo S, Peltonen K: The permeability of surgical gloves to seven chemicals commonly used in hospitals. Ann Occup Hyg 2003;47:313–323. Mäkelä EA, Vainiotalo S, Peltonen K: Permeation of 70% isopropyl alcohol through surgical gloves: comparison of the standard methods ASTM F739 and EN 374. Ann Occup Hyg 2003;47: 305–312. Graves C, Edward C, Marks R: The effects of protective occlusive gloves on stratum corneum barrier properties. Contact Dermatitis 1995;33:183–187. Schliemann-Willers S, Elsner P: Occupational skin protection. J Dtsch Dermatol Ges 2005;3: 120–133. Kütting B, Drexler H: Effectiveness of skin protection creams as a preventive measure in occupational dermatitis: a critical update according to criteria of evidence-based medicine. Int Arch Occup Environ Health 2003;76:253–259. Technische Regeln für Gefahrstoffe (TRGS) 531: Gefährdung der Haut durch Arbeiten im feuchten Milieu (Feuchtarbeit). BArbBl 1996;9:65–67. Weisshaar E, Radulescu M, Bock M, Albrecht U, Zimmermann E, Diepgen TL: Skin protection and skin disease prevention courses for secondary prevention in health care workers: first results after two years of implementation. J Dtsch Dermatol Ges 2005;3:33–38. Berndt U, Gabard B, Schliemann-Willers S, Wigger-Alberti W, Zitterbart D, Elsner P: Integrated skin protection from workplace irritants: a new model for efficacy assessment. Exog Dermatol 2002;1:45–48. Berndt U, Wigger-Alberti W, Gabard B, Elsner P: Efficacy of a barrier cream and its vehicle as protective measures against irritant contact dermatitis. Contact Dermatitis 2000;42:77–80.


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McCormick RD, Buchman TL, Maki DG: Double-blind, randomized trial of scheduled use of a novel barrier cream and an oil-containing lotion for protecting the hands of health care workers. Am J Infect Control 2000;28:302–310. Held E, Wolf C, Gyntelberg F, Agner T: Prevention of work-related skin problems in student auxiliary nurses: an intervention study. Contact Dermatitis 2001;44:297–303. Schürer NY, Schwanitz HJ: Prevention and regeneration of barrier disturbances in occupational dermatology. J Dtsch Dermatol Ges 2004;2:895–904. Schwanitz HJ, Riehl U, Schlesinger T, Bock M, Skudlik C, Wulfhorst B: Skin care management: educational aspects. Int Arch Occup Environ Health 2003;76:374–381. Schürer NY, Klippel U, Schwanitz HJ: Secondary individual prevention of hand dermatitis in geriatric nurses. Int Arch Occup Environ Health 2005;78:149–157. Nettis E, Marcandrea M, Colanardi MC, Paradiso MT, Ferrannini A, Tursi A: Results of standard series patch testing in patients with occupational allergic contact dermatitis. Allergy 2003;58: 1304–1307. Mahler V, Bruckner T, Schmidt A, Diepgen TL: Occupational contact dermatitis in health care workers. Contact Dermatitis 2004;50:158–159. Koch P, Brehler R, Eck E, Geier J, Hillen U, Peters KP, Rakoski J, Rothe A, Schnuch A, Szliska C, Uter W: Berufsspezifische Epikutantestung für Angehörige der Heil- und Pflegeberufe. Dermatol Beruf Umwelt 2002;50:155–162. Proske S, Brehler R, Dickel H, Eck E, Geier J, Hillen U, Koch P, Peters KP, Rakoski J, Rothe A, Schnuch A, Szliska C, Uter W: Berufsspezifische Epikutantestung in der Altenpflege. Dermatol Beruf Umwelt 2005;53:50–53. Nettis E, Assennato G, Ferrannini A, Tursi A: Type I allergy to natural rubber latex and type IV allergy to rubber chemicals in health care workers with glove-related skin symptoms. Clin Exp Allergy 2002;32:441–447. Technische Regeln für Gefahrstoffe (TRGS) 540: Sensibilisierende Stoffe. BArbBl 2000;2:73–78. Baur X, Chen Z, Liebers V: Exposure-response relationships of occupational inhalative allergens. Clin Exp Allergy 1998;28:537–544. Ylitalo L, Mäkinen-Kiljunen S, Turjanmaa K, Palosuo T, Reunala T: Cow’s milk casein, a hidden allergen in natural rubber latex gloves. J Allergy Clin Immunol 1999;104:177–180. Busch M, Schroeder C, Baron J, Mahler V: Novel glove-derived proteins induce allergen-specific IgE in a mouse model. Arch Dermatol Res 2005;296:398.

Vera Mahler, MD Department of Dermatology, University Hospital Erlangen Friedrich Alexander University, Hartmannstrasse 14 DE–91052 Erlangen (Germany) Tel. ⫹49 9131 8533164, Fax ⫹49 9131 8533854, E-Mail [email protected]

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Skin Protection for Hairdressers Christoph Skudlik, Swen Malte John Department of Dermatology, Environmental Medicine, Health Theory, University of Osnabrück, Osnabrück, Germany

Abstract The application of protective creams in the hairdressing trade forms part of a complex concept for the prevention of occupational skin disorders. To date, no comparative controlled intervention studies have been carried out using different skin-protective creams. Previously published skin protection plans concerning barrier creams for the hairdressing trade are fairly general or rudimentary, reflecting our still limited knowledge on the subject. Bioengineering studies have even demonstrated a paradoxical effect of a certain skin-protective foam designed for hairdressers. Regarding other barrier creams, a certain protective effect could however be shown in studies concerning exposure to wetness and detergents. Pre-exposition skin protection seems to be of particular relevance. Thus, in principle, the regular application of adequate skin protection creams can be recommended in the hairdressing trade, although the protective effect should not be overvalued. Copyright © 2007 S. Karger AG, Basel

Those employed in the hairdressing trade are at a particularly high risk of contracting occupational skin disease, in particular occupational hand eczema. The reasons for this include exposure to considerable irritative influences typical of the trade, such as repeated or continual wetness in combination with detergents and other irritative agents, as well as exposure to allergens typical of the trade with a high sensitization risk (such as ammonium persulphate, p-phenylenediamine, p-toluylenediamine, glycerylthioglycolate) [1, 2]. Moreover, with regard to another risk factor specific to the trade, there are indications that, in the course of occupational activity in the field of hairdressing, hyperhidrosis of the hands can develop or become more pronounced [3–5]. Among other things, this considerably limits the comfort of wearing occlusive protective gloves, which in turn can increase irritation. Due to the considerable medical and socio-economic relevance of ‘hairdressers’ eczema’, effective prevention strategies have been developed in Germany

paradigmatically for other wet-work professions in the context of a hierarchical prevention concept (primary–secondary–tertiary prevention). In the meantime, this concept has been scientifically evaluated and implemented throughout the country [1, 6]. In the course of implementing these measures, a special ordinance was issued in Germany (the so-called Technical Rule 530), which regulates the application of suitable personal protective equipment. Moreover, the ordinance made it possible to take relevant allergens such as glycerylthioglycolate largely off the market and led to the establishment of health-educational skin protection seminars and in-patient rehabilitation programmes [1, 5, 6]. The skin protection plans and operating instructions issued for the whole of the Federal Republic of Germany by the responsible disablement insurance company, the Berufsgenossenschaft für Gesundheitsdienst und Wohlfahrtspflege (Accident Insurance Fund for Health and Welfare Services), which follow these scientifically based preventive measures, are directed primarily, with regard to preventive measures, at the consistent use of glove protection, e.g. made of vinyl or nitrile (see also www.bgw-online.de). In the above-mentioned instructions, it is merely pointed out that, before starting work, people in the hairdressing trade should apply an (unspecified) skin protection cream to their hands; the necessity of using a skin protection cream (without simultaneous glove protection) is only mentioned for activities involved in styling (i.e. contact with hairsprays and hair lacquers, hairdryer foams, hairdryer lotions, hair gels, setting lotions, wax, hair cream and styling cream). Details with regard to required glove protection are accordingly very clear in legal regulatory matters. However, this is in stark contrast to the rudimentary details given with regard to matters such as creams and skin protection creams (TRGS 530, as of January 2003). Comparable strategies for the prevention of hairdresser eczema have also been developed in the Netherlands, as well as in other countries. In operating instructions published accordingly, hairdressers are advised, among other things, to use a ‘water-resistant skin cream’ before starting work and several times throughout the working day, and also to use a skin care cream in the evening [2, 7]. No further specifications are given, however, regarding these creams. Several years ago, advertisements invited members of the hairdressing trade, among others, to use a skin-protective foam that was described as an ‘invisible’ or ‘liquid glove’. However, these attributes proved to be misleading since it could be pointed out that this skin-protective foam, based on stearin acid, was counterproductive. This was particularly so in the alkaline range, due to the formation of stearates, which lead to more pronounced skin irritations [8]. In a comparative study of 2 barrier creams (a skin protection cream containing beeswax launched by the hair cosmetics industry and a skin protection foam), both products tested for their protective abilities against hair shampoos

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demonstrated a reduction of irritation, whereby the skin protection preparation containing beeswax was significantly superior to the skin protection foam after an application period of 2 weeks [9]. The favourable effect of locally given adstringents containing tannic acid was observed in skin protection experiments conducted on hairdressers, among other things with regard to hyperhidrosis of the palms, which frequently occurs in this trade [10]. In some hairdresser establishments, CO2-enriched water is used to treat the hair and scalp; some users reported that such water led to positive effects on existing irritative skin changes of the hands: 76% of 102 hairdressers questioned for a study indicated that regular application of CO2-enriched water has a significant positive effect on irritative hand eczemas. Experimentally it could be pointed out that appropriate treatment with CO2-enriched water has a positive effect on epidermal lipid synthesis and on the repair of the epidermal barrier [11, 12]. In a double-blind crossover study on the effectiveness of a skin protection cream among hairdresser trainees, the protective effect of a skin protection cream containing 5% aluminium chlorohydrate was compared to its vehicle. In addition to a clinical assessment, bioengineering tests and subjective assessments on the part of the hairdresser trainees were carried out. Altogether, only very low, statistically insignificant differences between the protection cream and its vehicle were revealed. Furthermore, it could be shown that the cosmetic properties of the preparations with regard to their compliance among hairdresser trainees appear to be equally as important as their real protective effect [13]. Even if no significant differences were established between the active agent and the vehicle, it was concluded that the occurrence of aluminium chlorohydrate in the active cream has a positive effect, due to its stabilizing properties, since preservatives are not necessary. Furthermore, the observed slight dryness occurring after application of the cream containing aluminium chlorohydrate was judged to be beneficial in cases in which an increased hyperhidrosis of the palms could be problematic. In the course of a 4-week application observation, the effectiveness, skin compatibility and user acceptance of 2 skin protection creams (one containing aluminium chlorohydrate and the other containing beeswax, among other things) were established among a group of 25 hairdresser trainees each, all of whom had an irritative hand eczema. An improvement of the existing skin changes was proven clinically and using bioengineering methods in both study groups. In the comparison of the clinical assessment, which was judged as clearly positive in both groups, there were no clear differences with regard to the effects the 2 tested skin protection creams had on dryness, erythema and scaling of the skin. In the comparison of the bioengineering parameters, significant differences between the 2 trainee groups could be shown, particularly

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after a 4-week application, whereby the preparation containing aluminium chlorohydrate proved to be somewhat superior. Altogether, it could be shown that the tested barrier creams are suitable for the prevention of cumulative subtoxic hand eczemas in the hairdressing trade with regard to user acceptance, compatibility and effectiveness [14]. An intervention study with 73 hairdresser trainees was carried out with the aim of reducing the occurrence of hand eczema among hairdresser trainees. In this study, skin-protective products, including barrier creams developed by the hair cosmetic industry, were made available to the participants. The effects of the measures were compared with the results of an unmonitored control group. It could be shown that, towards the end of the first year of training, around 90% of the participants within the intervention group used cream on their hands more than 4 times a day, as opposed to only 60% in the control group. Altogether, it could be shown that the intervention measures led to a significant decline in skin changes. In this respect, the meaning of barrier creams does not have to be quantified, even if it can be pointed out that the combination of different preventive measures probably led to the positive results in the intervention collective [15]. No standardized recommendations were given with regard to barrier creams for hairdressers in the context of health-educational training sessions at our clinic (secondary and tertiary prevention). Individual recommendations concerning barrier creams were oriented towards galenicals, individual risk factors and, following the appropriate practical testing of various different available creams in simulated workplace models, the acceptance of those involved, since this is decisive for the compliance and general application of barrier creams. We recommend the use of the barrier creams before starting work and at the end of breaks. We frequently recommend a fragrance- and preservativefree barrier cream containing aluminium chlorohydrate (Excipial Protect®), which demonstrates a relatively high acceptance among our patients because ‘it rubs in quickly’. In the case of increased hyperhidrosis of the palms under occlusive protective gloves, we also prescribe a gel containing 20–30% aluminium hexahydrate to be applied to the insides of the hands in the evening (sometimes in combination with a iontophoresis of the hands). Furthermore, we frequently prescribe adstringents containing tannic acid, which are available in different galenicals for different skin types. For treatment at the end of the working day we prescribe various different, individually selected skin care and repair creams, e.g. containing urea. Due to the special skin-related risk factors in the hairdressing trade, it is important not to raise too many expectations on the part of hairdressers with regard to the use of barrier creams, to ensure that their protective effect against potent hairdresser allergens and, in particular, the considerable exposure to wetness and irritants is not overvalued. The application of barrier creams merely

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represents a supplementary measure in the context of complex prevention concepts for hairdressers. Adequate workplace-related and technical skin-protective measures (particularly with regard to the frequency of wet work, the avoidance of relevant allergens etc.) and the consistent use of adequate protective gloves remain the focus of such concepts.

References 1 2 3 4

5 6 7 8

9 10 11

12 13 14

15

Uter W, Wulfhorst B: BK-Nr. 5101/Friseure; in Schwanitz HJ, Szliska C (eds): Berufsdermatosen. München-Deisenhofen, Dustri-Verlag, 2001, vol 1, pp 6b.1–6b.12. Van der Walle HB: Hairdressers; in Kanerva L, Elsner P, Wahlberg JE, Maibach HI (eds): Handbook of Occupational Dermatology. Berlin, Springer, 2000, vol 1, pp 960–968. Borrelli S, Kraft JS: Hyperhidrosis manuum als isolierter Kaltwellschaden bei Friseurpersonal. Hautarzt 1955;6:540–541. Schlesinger T, Revermann K, Schwanitz HJ: Dermatosen bei Auszubildenden des Friseurhandwerks in Niedersachsen – Ein Vergleich zwischen 1989, 1994 und 1999. Dermatol Beruf Umwelt/Occup Environ Dermatol 2001;49:185–192. Skudlik C, Schwanitz HJ: Tertiäre Prävention von Berufsdermatosen/Tertiary prevention of occupational skin diseases. JDDG 2004;2:424–433. Schwanitz HJ, Riehl U, Schlesinger T, Bock M, Skudlik C, Wulfhorst B: Skin care management: educational aspects. Int Arch Occup Environ Health 2003;76:374–381. Van der Walle HB: Dermatitis in hairdressers. II. Management and prevention. Contact Dermatitis 1994;30:265–270. Frosch PJ, Schulze-Dirks A, Hoffmann M, Axthelm I: Efficacy of skin barrier creams. II. Ineffectiveness of a popular ‘skin protector’ against various irritants in the repetitive irritation test in the guinea pig. Contact Dermatitis 1993;29:74–77. Pilz B, Frosch PJ: Hautschutz für Friseure – die Wirksamkeit von zwei Hautschutzprodukten gegenüber Detergentien im repetitiven Irritationstest. Dermatosen 1994;42:199–202. Schöbel K: Gerbstoff; in Schwanitz HJ, Uter W, Wulfhorst B (eds): Neue Wege zur Prävention – Paradigma Friseurekzem. Osnabrück, Universitätsverlag Rasch, 1996. Bock M, Schwanitz HJ: Prävention irritativer Kontaktekzeme bei Friseuren durch topische Anwendung von CO2-imprägniertem Wasser – empirische und experimentelle Untersuchungen. Dermatosen 1999;47:53–57. Bock M, Schürer NY, Schwanitz HJ: Effects of CO2-enriched water on barrier recovery. Arch Dermatol Res 2004;296:163–168. Perrenoud D, Gallezot D, Van Melle G: The efficacy of a protective cream in a real-world apprentice hairdresser environment. Contact Dermatitis 2001;45:134–138. Bock M, Wulfhorst B, Gabard B, Schwanitz HJ: Effektivität von Hautschutzcremes zur Behandlung irritativer Kontaktekzeme bei Friseurauszubildenden. Dermatol Beruf Umwelt/ Occup Environ Dermatol 2001;49:73–76. Riehl U: Interventionsstudie zur Prävention von Hauterkrankungen bei Auszubildenden des Friseurhandwerks; in Schwanitz HJ (eds): Studien zur Prävention in Allergologie, Berufs- und Umweltdermatologie. Osnabrück, Universitätsverlag Rasch, 2001, vol 3.

Christoph Skudlik, MD Department of Dermatology, Environmental Medicine, Health Theory University of Osnabrück, Sedanstrasse 115 DE–49090 Osnabrück (Germany) Tel. ⫹49 541 969 2357, Fax ⫹49 541 969 2445, E-Mail [email protected]

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Skin Protection in the Food Industry A. Bauera, D. Kelterera, R. Bartschb, M. Stadelerc, P. Elsnera a

Department of Dermatology and Allergology, University Hospital, and bInstitute of Occupational, Social and Environmental Medicine, Friedrich Schiller University Jena, Jena, and cResearch Centre for Applied System Safety and Industrial Medicine, Erfurt, Germany

Abstract In food occupations, like in many other skin risk occupations, the regular use of personal protection equipment, i.e. of skin protection ointments and protective gloves, is recommended as well as regular skin care for the prevention of occupational hand dermatitis. We investigated the uptake and maintenance of different prevention strategies (instructions for skin protection and skin care, prevocational skin hardening with UV light) in food occupations and their efficacy in the primary prevention of vocationally caused hand dermatitis. We could show that the acceptance and regular use of skin protection and care measures could be significantly increased by theoretical and practical instructions in food industry trainees. The highest acceptance was seen with skin protection ointment (100%) and skin care (90%). Protective gloves (43.3%) were used to a lesser extent. The hand dermatitis point prevalence in the groups after 6 months was 13.3% (skin protection), 19.4% (UV hardening) and 29.1% (controls). These clinical trends were supported by statistically significant differences in the basal TEWL values. Adequate skin protection and regular skin care seem to be promising for the prevention of occupationally caused hand dermatitis. The experimental approach using UV hardening prevocationally did not fulfil the expectations. Copyright © 2007 S. Karger AG, Basel

Hand dermatitis is not only a problem in the general population. It has emerged to be the most common occupational disease in the working population in Germany in recent years [1]. In other industrialized countries the situation is comparable. Occupational skin diseases count for about 30% of all registered occupational diseases in most European countries and the USA in the last decade [2–5]. Irritant contact dermatitis (ICD) is the major problem. Malten [6] described ICD as a localized, superficial, exudative, non-immunological inflammation of the skin caused by the direct influence of one or more external factors. Dermatitis may be acute or chronic. In acute dermatitis the clinical

symptoms develop quickly after the exposure and at least initially resolve quickly after the causal factor has been removed. Chronic dermatitis is caused by a summation of subclinical exposures, i.e. dermatitis arises as a result of continued low-grade exposure to mild irritants such as soap, water and other irritative agents like disinfectants, food components, cutting oil etc. It is most prevalent in workers that have been exposed to high cumulative irritant damage [6]. The exposure time and the characteristics of the irritants involved determine the extent of the resulting irritative skin damage. Moreover, interindividual differences in susceptibility and regenerative capacities play a major role, indicating an individual threshold for irritation [7–12]. Hand dermatitis is no life-threatening disease and does not influence daily life to a large extent when the clinical manifestation is mild. However, severe cases are often accompanied by an uncertain prognosis and can have a huge impact on quality of life [2, 13–18]. Skoet et al. [19] reviewed the literature concerning the impact of dermatitis and especially hand dermatitis on the quality of life. All studies reviewed found that contact dermatitis is associated with impaired health-related quality of life. Interestingly, hand dermatitis appeared to be as equally impairing as generalized dermatitis [19]. Recently, many experimental and clinical studies have been performed in the field of occupational hand dermatitis. As main risk factors for the development of occupational hand dermatitis, high loads of wet work, exposure to irritants and atopic skin diathesis have been reported [20, 21]. Others and we have shown that hand dermatitis seems to start early during apprenticeship [22–25]. Therefore, preventive measures should be implemented early in the vocational training at the occupational schools and the companies to achieve optimal efficacy [26–28]. The principles and measures of technical-organizational hazard control and individual protective measures are well defined [29–31]. Barrier creams and gloves combined with adequate skin care are recommended widely as the most important means of personal protective equipment in professions with skin hazards. Various in vivo and in vitro methods are in place to investigate their efficacy [32–39]. Besides these established prevention strategies, a further possible method proposed to prevent ICD is skin hardening by ultraviolet (UV) radiation. Lehmann et al. [40] reported that UV radiation (1.5-fold the minimal erythema dose of UV, 3 times/week for 3 weeks) led to a significant thickening of the stratum corneum from 16.8 ⫾ 5.3 to 22.6 ⫾ 4.2 horny cell layers (p ⬍ 0.005). The UV-irradiated skin consecutively showed a higher resistance against experimental irritation with sodium lauryl sulphate, sodium hydroxide and dimethylsulphoxide [40]. Moreover changes in lipid synthesis, suppression of inflammation and immunoreactivity were reported after UV radiation [40–45]. Therefore, pre-occupational UV hardening of the back of the hands, the area

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where ICD occurs primarily, might be capable of increasing the resistance of the skin to occupational real-world conditions. The aim of this controlled intervention study in healthy baker apprentices was to evaluate the uptake and acceptance of preventive measures and the comparative efficacy of standard prevention techniques – barrier creams, moisturizers and gloves – versus skin hardening with UV light to prevent and alter the course of occupational hand dermatitis and skin barrier disruption in a skin risk profession. Moreover, both measures were compared to no intervention to generate evidence for or against a broader use of either concept. Methods The study started in September 2000 and was terminated in February 2001. Ninety-four healthy apprentices of the occupational school for food-processing trades, Gera, Germany, were included in this controlled intervention study after providing their and their parents’ written informed consent. The study was approved by the ethical committee of the Friedrich Schiller University of Jena. Fifty-eight apprentices were assigned to the UV hardening group (UV), and the remaining 49 apprentices were assigned to the skin prevention group (SP). At the beginning of the training and at 4 about monthly follow-ups (FUs), a dermatological examination of the hands, the transepidermal water loss (TEWL) measurement and a structured interview were performed. The probability of contamination between the intervention groups was low because of their different school timetables. The additional control group was historical and was recruited from a recent cohort study in baker apprentices in the same occupational school from 1996 to 1999 (initial examination, IE, n ⫽ 91 apprentices, FU after 6 months of training n ⫽ 79 apprentices). The interview covered different topics related to personal history and occupational exposure. Age and sex were documented. Personal history was directed towards former skin diseases, especially atopic dermatitis using the ‘Erlangen atopy score’ [46]. Respiratory atopy was documented as well. Occupational exposure was evaluated qualitatively and quantitatively. The apprentices were asked whether and for how long (⬍1 h; 1–4 h; ⬎4 h) they had to carry out exposure-specific tasks (cleaning of workplace and machines, cleaning of workroom and storage rooms, skin contact with wet dough, fruit handling, layer cake and chocolate preparation, oven work). Skin protection measures were documented, i.e. the use of gloves, protective creams and moisturizers. Additionally, hand washing frequency was monitored (⬍10; 10–20 times; ⬎20 times a day). Leisure time activities including wet work and contact with irritants like exposure to cleaning and dishwashing, baby care, car maintenance, house building or repair and gardening (never, daily, weekly, monthly) were documented. The dermatological examination of the hands was performed by dermatologists trained in allergy and occupational dermatology. Hand dermatitis was defined as mild when erythema and scaling appeared on the dorsal aspects and/or interdigital folds of the hands, as moderate when infiltration and papules were seen and the affected area was enlarged and as severe when the palms and back of the hands were involved and vesicles and fissures appeared. Decisions about differential diagnoses were made from the clinical picture, course of the disease, personal history and pre-existing allergy tests. No further allergy tests were performed.

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The SP group underwent a theoretical and practical skin protection training. The training lasted 60 min and comprised a standardized video lecture (15 min), a tutorial (15 min) and hands-on training (30 min) at the beginning of the apprenticeship and after 4 weeks of vocational training. The video lecture (Turimed, Wallisellen, Switzerland) provided general information about skin hazards in skin risk professions, about the structure and function of the skin, about common occupational skin diseases as well as skin protection, cleaning and care. The tutorial dealt with special information about skin hazards in the food-processing industry and means of prevention. In the following hands-on training, the correct application and use of gloves, skin care and barrier cream was practised intensively. Skin protection ointment (Excipial Protect®), skin care ointment (Lipoderm Lotio®) and protective gloves (DuoNit 901, Solo Ultra 999) were provided free of charge. The topics taught and trained were underpinned by written information material. The apprentices in the UV group were asked about their light sensitivity prior to the onset of the study. All apprentices were skin type II and III, no apprentice had pathological light sensitivity. The UV hardening was started with an initial dose as low as 0.01 J/cm2 (minimal erythema dose of UV: 0.108 J/cm2) and was increased by 20–30% at each application time point (5 days a week in the first 3 weeks of the training, cumulative dose: 2.1 ⫾ 0.3 J/cm2). A Dermalight vario 2 (Hönle, Germany; 285–400 nm, selective UV phototherapy radiation) was used as the UV source. TEWL was measured at the back of the dominant hand 3 cm proximal from the mediocarpophalangeal joint of the 3rd finger (Tewameter TM 210, Courage & Khazaka, Cologne, Germany). The volar forearm (8 cm distal from the elbow crease) was used as the control area. Three measurements were obtained per site, and mean values were calculated for each participant. The results were presented as overall mean values and SD for the measurement site at the back of the hand. The measurements were performed according to the Guidelines of the Standardization Group [47]. The measurement took place at the occupational school and therefore no air-conditioned environment was available. To reduce draught a top-open box was used. The probe was held with an insulated glove. Apprentices were advised not to use skin care products or barrier creams 12 h prior to the measurement. Descriptive statistics were performed on all data. Point prevalence of hand dermatitis was calculated for the interventions for each examination time. Differences in prevalence of hand dermatitis, in uptake of prevention measures, in demographic and atopic profile as well as in workload between the intervention groups and between the interventions and the control group were analysed by using the ␹2 test. TEWL mean values at the examination time points were compared using one-way ANOVA (multiple comparison procedure: Tukey’s test), the unpaired t test (intergroup differences) and the paired t test (intragroup differences). For multiple comparisons of the differences of TEWL values between the IE and each FU, Dunnett’s test was used to get an overall significance level of ⬍0.05 [48]. The specific test assumptions were checked and were valid for all tests performed in the analysis. The statistical analysis was done using the software package SPSS 10 for Windows.

Results

Characteristics of the Groups The demographic and atopy profiles of the groups were similar (table 1). At the IE, no significant differences were found between the SP and UV groups


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Table 1. Demographic profile and atopy in baker apprentices Attributes

Control group (n ⫽ 91)

Demographic profile Sex (female) Age, years Piercing Costume jewellery Allergy Atopy No skin atopy Skin atopy Rhinitis Asthma

UV group (n ⫽ 55)

SP group (n ⫽ 39)

p values

%

n

%

n

%

n

57 16.5 ⫾ 1.1 63.7 28.2

59 91 66 20

61.8 16.9 ⫾ 1.5 61.8 25.5

34 55 34 14

71.5 16.8 ⫾ 0.9 71.5 33.3

28 39 28 13

0.34 0.28 0.33 0.70

86.8 13.2 9.9 5.5

79 12 9 5

85.4 14.6 16.4 1.8

47 8 9 1

87.2 12.8 20.5 5.1

34 5 8 2

0.95 0.96 0.44 0.55

Table 2. Uptake (%) of SP and skin care measures in the groups at the examination times Measures

IE (n ⫽ 94, 100%)

1st FU (n ⫽ 83, 88%)

2nd FU (n ⫽ 77, 82%)

3rd FU (n ⫽ 68, 72%)

4th FU (n ⫽ 61, 65%)

UV SP

UV SP

UV SP

UV SP

UV SP

Barrier cream

0 2.7 p ⫽ 0.40

0 75 p ⬍ 0.0001

0 83.9 p ⬍ 0.0001

5 96.4 p ⬍ 0.0001

3.2 100 p ⬍ 0.0001

Protective gloves

14.5 7.7 p ⫽ 0.13

25.5 47.2 p ⫽ 0.005

17.4 32.3 p ⫽ 0.046

27.5 32.1 p ⫽ 0.17

32.3 43.3 p ⫽ 0.71

Skin care

61.7 67.6 p ⫽ 0.57

68.1 88.9 p ⫽ 0.025

73.9 87.1 p ⫽ 0.16

77.5 85.7 p ⫽ 0.39

83.9 90 p⫽0.71

concerning hand washing frequency, workload at work and at home. Moreover, no significant differences were found in protective glove, skin care and barrier cream use (table 2). The control group differed significantly from the SP and UV groups concerning pre-occupational hand washing frequency (p ⫽ 0.02, more often in SP and UV than controls), skin care (p ⫽ 0.044 SP and UV used skin care more regularly), leisure time chores (daily cleaning and dishwashing,


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p ⫽ 0.046, more frequent in controls) and size of company (p ⫽ 0.001, in the control group more apprentices worked in small-scale companies). During the FU period cleaning at work (p ⫽ 0.023) was found to be significantly different in the SP and UV groups at the 1st FU. The uptake of SP measures differed significantly between SP and UV groups (barrier creams p ⬍ 0.0001, gloves p ⫽ 0.046, skin care p ⫽ 0.025). For protective gloves and skin care, differences between the groups diminished during the course of training (table 2). After 6 months of training, significant differences between control group and SP and UV groups were found in company size (p ⬍ 0.0001). No significant differences were apparent for hand washing frequency or for other activities at work and at home. The figures concerning acceptance of SP measures in the control group were lower than in the SP and UV groups for glove use (10.1%, p ⬍ 0.0001) and skin care (46%, p ⫽ 0.02). Data for the level of barrier cream use were only available at the end of the training (6.3%). The level was comparable to that of the UV group. Acceptance and Uptake of Skin Protection Measures At the IE no significant differences were found in protective glove, skin care and barrier cream use in the SP and UV groups. Barrier cream use in the SP group was incorporated in the daily routine very well from the start (75%, 1st FU) and reached 100% at the end of the examination period. The differences between SP and UV groups were highly significant over the entire study period (p ⬍ 0.0001). There was a significant difference in glove use for the 1st FU (p ⫽ 0.005) and 2nd FU (p ⫽ 0.046) in the SP and UV groups but the level of acceptance was considerably lower than for barrier creams. Differences between the groups diminished in the course of the training. Acceptance levels in both groups were 43.3% (SP) and 32.2% (UV) after 6 months of training. The initial level of regular skin care was high in both groups. After the intervention the acceptance of skin care rose to 88.9% in the SP group (p ⫽ 0.025) compared to 68.1% in the UV group. Differences between the groups diminished in the course of the training. Take-up levels in both groups were 90% (SP) and 83.9% (UV) at the end of the trial period (table 2). After 6 months of training, the figures concerning acceptance of skin protection measures in the control group were lower than in the SP and UV groups for glove use (10.1%, p ⬍ 0.0001) and skin care (46%, p ⫽ 0.02). Data for the level of barrier cream use were only available at the end of the training (6.3%). The level was comparable to that of the UV group. Prevalence of Hand Dermatitis in the Course of Training The prevalence of hand dermatitis was consistently higher in the UV group compared to the SP group over the entire observation period. It rose continuously


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UV hardening

Prevalence of hand dermatitis (%)

30

SP

Controls 29.1

27.5

25 19.4

19.6 20

17.9

17

16.1

15 13.3

10 5.6 5 0 1st FU

2nd FU 3rd FU Examination time points

4th FU

Fig. 1. Prevalence of hand dermatitis at the examination time points in the intervention groups and the controls. The prevalence of hand dermatitis at the IE was 0% in both groups.

to 27.5% (UV) and 17.9% (SP) at the 3rd FU and dropped down to 19.4% (UV) and 13.3% (SP) at the 4th FU. Mean differences in hand dermatitis frequency between SP and UV were 11.5% (95% confidence interval, CI, ⫺2.7–25.6), 3.5% (95% CI ⫺14.1–21.0), 9.6% (95% CI ⫺10.8–30.1) and 6.1% (95% CI ⫺12.6–24.6) at the 1st, 2nd, 3rd and 4th FU, respectively. After 6 months of training 29.1% (n ⫽ 23) of the controls (n ⫽ 79) had developed hand dermatitis. The difference between SP and control groups was 15.8% (95% CI ⫺2.4–33.9). The difference between UV group and controls was 9.7% (95% CI ⫺8.5–28.1; fig. 1). ICD was by far the most common diagnosis at each examination time point. At the 4th FU, all affected apprentices (n ⫽ 10) had ICD. In 2 apprentices ICD was combined with atopic hand dermatitis. TEWL Measurements TEWL values were measured in 83 apprentices at the IE. At the FUs, 79, 78, 64 and 56 apprentices were examined. In the UV and SP groups, in all 209 and 151 measurements were performed. At the IE no significant differences were apparent neither between the SP and UV groups (p ⫽ 0.26) nor between SP, UV and control groups (p ⫽ 0.18) The TEWL measurements at the FUs were consistently higher in the UV group than in the SP group (fig. 1). After 6 months of training the control group showed the highest TEWL values (IE ⫽ 11.9 g/m2h, after 6 months ⫽ 16.8 g/m2h, p ⬍ 0.0001; fig. 2). Overall TEWL values rose significantly from the IE to the 1st FU (p ⫽ 0.015), 2nd FU


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30

UV hardening

SP

Controls

TEWL (g/m2h)

25 20 15 10 5 0 IE

1st FU 2nd FU 3rd FU Examination time points

4th FU

Fig. 2. TEWL values at the examination time points (intervention groups: differences between FU time p ⫽ 0.001, differences between groups p ⫽ 0.015; controls: differences between IE and 4th FU p ⬍ 0.0001).

Table 3. Differences (⌬) between the mean TEWL values (g/m2h) in the SP, UV and control groups at the different examination time points Test statistic and group

⌬IE TEWL (n ⫽ 83)

⌬1st FU TEWL (n ⫽ 79)

⌬2nd FU TEWL (n ⫽ 78)

⌬3rd FU TEWL (n ⫽ 64)

⌬4th FU TEWL (n ⫽ 56)

Unpaired t test UV vs. SP

–1.45 ⫾ 1.29 p ⫽ 0.26

3.44 ⫾ 1.27 p ⫽ 0.008

4.97 ⫾ 0.93 p ⬍ 0.0001

1.93 ⫾ 1.34 p ⫽ 0.15

2.18 ⫾ 1.81 p ⫽ 0.23

One-way ANOV A Control vs. UV ⫹ SP

p ⫽ 0.18

p ⫽ 0.48

–0.62 ⫾ 1.01 (p ⫽ 0.81) –2.08 ⫾ 1.12 (p ⫽ 0.15) –1.45 ⫾ 1.25 (p ⫽ 0.48)

–0.02 ⫾ 1.74 (p ⫽ 1) 2.16 ⫾ 1.84 (p ⫽ 0.47) 2.18 ⫾ 2.21 (p ⫽ 0.59)

Tukey Control vs. UV Control vs. SP UV vs. SP

One-way ANOVA was carried out with allowance for multiple comparisons (Tukey’s test).

(p ⫽ 0.001) and 3rd FU (p ⫽ 0.001), respectively. After allowance for multiple comparisons (Dunnett’s test), the difference between IE and 2nd (p ⫽ 0.01) and 3rd FU remained significant (p ⫽ 0.008). The difference between the IE and the 1st FU was no longer significant (p ⫽ 0.07; table 3).


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Discussion

The skin care and protection lecture and the hands-on teaching approach were tailor made for the typical exposition profiles in baker apprentices [21, 49, 50]. The main emphasis was laid on the regular, frequent and correct application of skin care and skin protection products and the comprehensive and correct use of protective gloves [35, 51]. To deepen the theoretical knowledge and the practical handling, the intervention was repeated after 4 weeks and the FU examinations served as maintenance surveillance and reinforcements. The intervention was based on a conventional primary prevention approach in health promotion representing the medical model rather than the social model of health. The approach mainly dealt with the individual apprentice and focused on reducing morbidity rather than changing social, economic or environmental determinants of occupational health [52]. The SP intervention was highly successful in long-term behaviour change (6 months) concerning barrier cream and skin care use. Glove use was accepted to a lesser extent. Held et al. [53] examined the influence of a comparable prevention concept in nursing. Those trainees in the intervention group, who had received theoretical and practical instruction about skin risks and about possible preventive measures, followed the instructions not to use hand disinfectants unnecessarily often to a large extent. No significant differences were seen with the use of protective gloves and skin care [53]. The overall acceptance and uptake of the actual SP concept for baker apprentices was good under the intensive artificial conditions of the intervention study. As to whether it will be working at a comparable level when integrated in a routine curriculum of occupational schools and delivered by teachers has to be investigated in a second step. Moreover, the teaching concept concerning glove use needs rethinking. Without any intervention a considerable proportion (approx. 30%) of baker apprentices developed hand dermatitis in the first months of the training [21]. Similar hand dermatitis prevalence profiles were previously reported in hairdressing and nursing apprentices [23, 25, 54]. The present study identified combined SP measures to be consistently superior to UV hardening in the reduction of hand dermatitis prevalence in baker apprentices in the first 6 months of training. Both interventions showed better outcomes compared to no intervention (control group). The trends in the clinical results were confirmed by statistically significant differences in TEWL values. There was an overall significant difference between the TEWL levels at the FUs (p ⫽ 0.001). Like hand dermatitis prevalence, TEWL values were consistently higher in the UV and control groups compared to the SP group (p ⫽ 0.015) during the entire course of the observation period, indicating a higher level of barrier disruption in the UV and control groups. Held et al.


146

[53, 55] reported similar results in their cohorts of auxiliary nurses and wet work employees. Despite experimental evidence that UVB-irradiated skin provided protection against various irritants, hand dermatitis prevalence was only reduced up to a limited amount in the UVB group [40, 42]. Lehmann et al. [40] had shown that a significant increase in the thickness of the stratum corneum had already appeared after 1 week of UVB radiation. Therefore, theoretically the apprentices should have developed a thicker stratum corneum with better protective capacities from the start. The prevalence figures did not support this theory, but compared to the controls, the UV group showed a slight statistically non-significant advantage in hand dermatitis prevalence. This raises two possibilities, firstly that this advantage, if genuine, was due to the radiation regimen administered or secondly and more likely to the improved skin care and protection regime in the UV group induced by the repeated interviews at the FUs or by accidental contamination between the groups. This theory is substantiated by the fact that in the UV group the use of skin care and protective gloves was significantly higher compared to the control group.

Conclusion

Primary prevention strategies which combine theoretical and practical education are able to induce short- and long-term behaviour changes. However, there is further research needed, in order to identify and standardize the most effective concepts. In future, evidence-based skin protection concepts will surely have a place in the primary prevention of occupationally caused hand dermatitis. The instructions can be easily introduced in the theoretical and practical parts of the vocational training. Recent studies show promising results, but there is still a high need for further intervention studies, in order to evaluate different approaches and to identify the most promising strategies. Pre-occupational UV hardening could not fulfil the expectations for the moment and therefore cannot be recommended for the primary prevention of occupational hand dermatitis.

References 1 2

Hauptverband der gewerblichen Berufsgenossenschaften: Geschäfts- und Rechnungsergebnisse der gewerblichen Berufsgenossenschaften 2001. Paderborn, Bonifatius, 2002. Diepgen TL, Coenraads PJ: The epidemiology of occupational contact dermatitis. Int Arch Occup Environ Health 1999;72:496–506.


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Burnett CA, Lushniak BD, McCarthy W, Kaufman J: Occupational dermatitis causing days away from work in US private industry. Am J Ind Med 1993;34:568–573. Karjalainen A, Aalto L, Jolanki R, Keskinen H, Savela A: Occupational Diseases in Finland 1996. Helsinki, Finnish Institute of Occupational Health, 1998, p 60. Cherry N, Meyer JD, Adisesh A, Brooke R, Owen-Smith V, Swales C, Beck MH: Surveillance of occupational skin disease: EPIDERM and OPRA. Br J Dermatol 2000;142:1128–1134. Malten KE: Thoughts on irritant contact dermatitis. Contact Dermatitis 1981;7:238–247. Tupker RA, Pinnagoda J, Coenraads PJ, Nater JP: The influence of the repeated exposure of surfactants on the human skin as determined by transepidermal water loss and visual scoring. Contact Dermatitis 1989;20:108–114. Tupker RA, Pinnagoda J, Coenraads PJ, Nater JP: Baseline transepidermal water loss (TEWL) as a prediction of susceptibility to sodium lauryl sulfate. Contact Dermatitis 1989;20: 265–269. Pinnagoda J, Tupker RA, Coenraads PJ, Nater JP: Prediction of susceptibility to an irritant response by transepidermal water loss. Contact Dermatitis 1989;20:341–346. Agner T: Basal transepidermal water loss, skin thickness, skin blood flow and skin colour in relation to sodium-lauryl-sulfate-induced irritation in normal skin. Contact Dermatitis 1991;25: 108–114. Fartasch M: Human barrier formation and reaction to irritation; in Elsner P, Maibach HI (eds): Irritant Dermatitis: New Clinical and Experimental Aspects. Curr Probl Dermatol. Basel, Karger, 1995, vol 23, pp 96–103. Rietschel RL: Mechanisms in irritant contact dermatitis. Clin Dermatol 1997;15:557–559. Jowett S, Ryan T: Skin disease and handicap: an analysis of the impact of skin conditions. Soc Sci Med 1985;20:425–429. Hogan DJ, Dannaker CJ, Maibach HI: The prognosis of contact dermatitis. J Am Acad Dermatol 1990;23:300–307. Meding B, Swanbeck G: Consequences of having hand eczema. Contact Dermatitis 1990;23:6–14. Rycroft RJG: Occupational contact dermatitis; in Rycroft RJG, Menne T, Frosch PJ, Benezra C (eds): Textbook of Contact Dermatitis. Berlin, Springer, 1995, pp 343–400. Goh CL: Prognosis of contact dermatitis following secondary preventive measures. Curr Probl Dermatol 1996;25:154–162. Goh CL: Prognosis of contact and occupational dermatitis. Clin Dermatol 1997;15:655–659. Skoet R, Zachariae R, Agner T: Contact dermatitis and quality of life: a structured review of the literature. Br J Dermatol 2003;149:452–456. Uter W, Pfahlberg A, Gefeller O, Schwanitz HJ: Hand dermatitis in a prospectively followed cohort of hairdressing apprentices: final results of the POSH study. Contact Dermatitis 1999;41: 280–286. Bauer A, Bartsch R, Hersmann C, Stadeler M, Kelterer D, Schneider W, Seidel A, Schiele R, Elsner P: Occupational hand dermatitis in food industry apprentices: results of a 3-year follow-up cohort-study. Int Arch Occup Environ Health 2001;74:437–442. Smit HA, Rijssen A, Vandenbroucke JP, Coenraads PJ: Susceptibility to and incidence of hand dermatitis in a cohort of apprentice hairdressers and nurses. Scand J Work Environ Health 1994;20:113–121. Bauer A, Seidel A, Bartsch R, Wollina U, Gebhardt M, Diepgen TL: Entwicklung von Hautproblemen bei Berufsanfängern in Hautrisikoberufen. Allergologie 1997;20:179–183. Bauer A, Bartsch R, Stadeler M, Schneider W, Grieshaber R, Wollina U, Gebhardt: Development of occupational skin diseases during vocational training in baker and confectioner apprentices: a follow-up study. Contact Dermatitis 1998;39:307–311. Uter W, Pfahlberg A, Gefeller O, Schwanitz HJ: Prevalence and incidence of hand dermatitis in hairdressing apprentices: results of the POSH study. Int Arch Occup Environ Health 1998;71: 487–492. Elsner P: Irritant dermatitis in the workplace. Dermatol Clin 1994;12:461–467. Wigger-Alberti W, Maraffio B, Wernli M, Elsner P: Training workers at risk for occupational contact dermatitis in the application of protective creams: efficacy of a fluorescence technique. Dermatology 1997;195:129–133.


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Kalimo K, Kautiainen H, Niskanen T, Niemi L: ‘Eczema school’ to improve compliance in an occupational dermatology clinic. Contact Dermatitis 1999;41:315–319. Mathias CG: Prevention of occupational contact dermatitis. J Am Acad Dermatol 1990;23:742–748. Halkier-Sorensen L, Thestrup-Pedersen K: The efficacy of a moisturizer (Locobase) among cleaners and kitchen assistants during everyday exposure to water and detergents. Contact Dermatitis 1993;29:266–271. Wigger-Alberti W, Elsner P: Preventive measures in contact dermatitis. Clin Dermatol 1997;15: 661–665. Boman A, Mellström GA: Percutaneous absorption of 3 organic solvents in the guinea pig: effect of barrier creams. Contact Dermatitis 1989;21:134–140. Frosch PJ, Kurte A: Efficacy of barrier creams. IV. The repetitive irritation test (RIT) with a set of 4 standard irritants. Contact Dermatitis 1993;31:161–168. Treffel P, Gabard B, Juch R: Evaluation of barrier creams: an in vitro technique on human skin. Acta Derm Venereol (Stockh) 1994;74:7–11. Mellström GA, Carlsson B: European standards on protective gloves; in Mellström GA, Wahlberg JE, Maibach HI (eds): Protective Gloves for Occupational Use. Boca Raton, CRC Press, 1994, pp 39–43. Henry NW: Protective gloves for occupational use – US rules, regulations, and standards; in Mellström GA, Wahlberg JE, Maibach HI (eds): Protective Gloves for Occupational Use. Boca Raton, CRC Press, 1994, pp 45–50. Gabard B, Treffel P, Charton-Picard F, Eloy R: Irritant reactions on hairless micropig skin: a model for testing barrier creams; in Elsner P, Maibach HI (eds): Irritant Dermatitis: New Clinical and Experimental Aspects. Curr Probl Dermatol. Basel, Karger, 1995, vol 23, pp 275–287. Zimmerli T: European standards on protective gloves; in Elsner P Lachapelle JM, Wahlberg JE, Maibach HI (eds): Prevention of Contact Dermatitis. Curr Probl Dermatol. Basel, Karger, 1996, vol 25, pp 177–181. Wahlberg JE, Boman AS: Prevention of contact dermatitis from solvents; in Elsner P, Lachapelle JM, Wahlberg JE, Maibach HI (eds): Prevention of Contact Dermatitis. Curr Probl Dermatol. Basel, Karger, 1996, vol 25, pp 57–66. Lehmann P, Melnik B, Hölzle E, Neumann N, Plewig G: Zur Wirkung von UV-A- und UV-BBestrahlung auf die Hautbarriere. Hautarzt 1992;43:344–351. O’Dell BL, Jessen RT, Becker LE, Jackson RT, Smith EB: Diminished immune response in sun damaged skin. Arch Dermatol 1980;116:559–561. Lehmann P, Helbig S, Hölzle E, Plewig G: Bestrahlung mit UV-A oder UV-B wirkt protektiv gegenüber Irritantien. Zentralbl Hautkr 1988;54:686–692. Lavker RM, Gerberick GF, Veres D, Irwin CJ, Kaidbey KH: Cumulative effects from repeated exposures to suberythemal doses of UVB and UVA in human skin. J Am Acad Dermatol 1995;32:53–62. Krutmann J, Hönigsmann H, Elmets CA, Bergstresser PR: Dermatological Phototherapy and Photodiagnostic Methods. Berlin, Springer, 1995. Krutmann J, Elmets CA: Photoimmunology. Oxford, Blackwell Science, 2001. Diepgen TL, Fartasch M, Hornstein OP: Kriterien zur Beurteilung der atopischen Hautdiathese. Occup Environ Dermatol 1991;39:79–83. Pinnagoda J, Tupker RA, Agner T, Serup J: Guidelines for transepidermal water loss (TEWL) measurement. Contact Dermatitis 1990;22:164–178. Altman DG: Practical Statistics for Medical Research. London, Chapman & Hall, 1991. Bauer A, Kelterer D, Bartsch R, Schlegel A, Pearson J, Stadeler M, Kleesz P, Grieshaber R, Schiele R, Elsner P, Williams H: Prevention of hand dermatitis in bakers’ apprentices: different efficacy of skin protection measures and UV hardening. Int Arch Occup Environ Health 2002;75:491–499. Bauer A, Kelterer D, Bartsch R, Pearson J, Stadeler M, Kleesz P, Elsner P, Williams H: Skin protection in bakers’ apprentices. Contact Dermatitis 2002;46:81–86. TRGS Technische Regeln für Gefahrstoffe 531: Gefährdung der Haut durch Arbeiten im feuchten Milieu (Feuchtarbeit). Bundesarbeitsblatt 1996;9:65. Jones L, Naidoo J: Theories and models in health promotion; in Kaatz J, Peberty A (eds): Promoting Health: Knowledge and Practice. London, McMillan, The Open University, 1997, pp 75–88.


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Held E, Wolff C, Gyntelberg F, Agner T: Prevention of work-related skin problems in student auxiliary nurses: an intervention study. Contact Dermatitis 2001;44:297–303. Majoie IML, von Blomberg BME, Bruynzeel DP: Development of hand eczema in junior hairdressers: an 8-year follow-up study. Contact Dermatitis 1996;34:243–247. Held E, Mygind K, Wolff C, Gyntelberg F, Agner T: Prevention of work related problems: an intervention study in wet work employees. Occup Environ Med 2002;59:556–561.

Andrea Bauer, MD Department of Dermatology and Allergology Friedrich Schiller University Jena, Erfurterstrasse 35 DE–07740 Jena (Germany) Tel. ⫹49 03641 937370, Fax ⫹49 03641 937343, E-Mail [email protected]


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Skin Protection in the Metal Industry Ulrich Funke Medical Department, Audi AG, Ingolstadt, Germany

Abstract In the metal industry, workplaces with a high skin risk used to be frequent. This has changed in recent years in big plants, where technological progress and automatization have eliminated many hazards. However, in many small and middle-sized companies without supervision by an occupational physician, high-risk workplaces may still prevail. Therefore skin protection plays an important role in this industry, with its focus on irritant exposures. From our own studies and campaigns, the following conclusions can be drawn: prework occupational examination and counselling of high-risk groups, especially workers with a history of hand eczema, are essential; skin protection plans have to be simple and should be communicated clearly; the use of skin protection seems to depend more on the endogenous skin risk factors of the individual than on the objective hazards at the workplace; the support of the management and the involvement of production teams are essential for the success of skin protection campaigns. Copyright © 2007 S. Karger AG, Basel

The metal industry as it is today is characterized by the increasing quality of products, accurately organized processes and generally well-designed workplaces. In all larger manufacturing plants in Germany, a well-established system of occupational medical care has been established, which reduces the risks from allergens by evaluation and selection of substances, available safety equipment and on-hand advice for a safe handling of (unavoidable) hazardous substances. Irritants generally have a significantly higher relevance than allergens in the metal industry regarding untoward effects on the skin [1, 2]. Actually, the main interest focuses on wet work and persons with susceptible skin like atopic individuals [3]. While personal skin protection and in particular use of barrier creams have a long tradition in the metal industry, new research results indicate that the use of inappropriate barrier creams might increase the dermal uptake of certain solvents [4]. However, direct skin contact with solvents is rare in the metal industry, and skin protection measures are implemented and conducted

by well-experienced occupational physicians, who avoid to cast any doubt on the dutiful concept of skin protection with barrier creams. In reality, only moderate skin exposures are present at the workplace, and most of the occurring hand eczema in the workers is caused by endogenous and other non-occupational factors. Under these circumstances, the use of barrier creams often substitutes for dermatological therapy.

Exposures at the Workplace

Measures of skin protection depend on the one hand on exposures at the workplace and on the other hand on individual skin ‘sensitivity’ and history of hand eczema in the past. Relevant allergens in the metal industry are e.g. epoxy resins, acrylics, polyurethane, polyester and phenol-formaldehyde resin systems, colophony and p-phenylenediamine [2]. Preservatives and biocides in metalworking fluids may generally be discussed as relevant allergens, whereas metals like chromate and nickel seem to be less important [5]. As barrier creams are sufficiently effective against sensitizaton and allergens, only by the design of workplace processes and the use of personal protective equipment, i.e. protective gloves, is it possible to prevent skin contact. Common irritants in the metal industry are water-based metalworking fluids, metal chips, different grinding dusts, glues, solvents, dirty work, wet work in general, including kitchen/canteen work, and long-term use of occlusive gloves. The risk of irritant dermatitis is more related to a combination of factors like personal skin susceptibility and duration of exposition than to any specific substance. Figure 1 provides an overview on the average duration of irritant exposures, such as wet work and soiling work, in different jobs in the metal industry [6]. The data are representative, since during the apprenticeship each relevant task to learn is specified carefully (procedure, tools, period) in Germany and during final examinations performance of all tasks is checked precisely.

Principles of Skin Protection Plans

In the comparatively big plants of the metal industry with different dermal exposures, it is reasonable to use differentiated skin protection plans. The barrier creams to be used prior and in-between different dermal exposures are precisely listed, as well as the necessary cleansing products and the afterwork emollients, providing both employees and management with sufficient medical advice on the products to use. Furthermore, this plan reduces the sometimes confusing variety of available barrier creams with often unproven efficacy,

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Soiling work (median) Wet work (median)

White-collar occupations n⫽ 174 Electronics eng.: prod. n ⫽ 220 Mechanics: construction n ⫽ 98 Mechanics: production n ⫽168 Tool mechanics: systems n⫽180 Automobile electricians n⫽120 Automobile mechanics n⫽265 Lathe operators n ⫽ 57 Model makers n ⫽34 Mechanics: systems n ⫽ 185 Paint-sprayers n ⫽ 54 Milling machine operators n⫽ 57 Tool mechanics (manual): n ⫽ 51 Cooks n ⫽ 13 0

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Fig. 1. Wet and soiling work in different apprenticeships.

makes the supply economical, avoids adverse effects of certain barrier creams on products (especially in paint shops) and of irritant cleansing agents (if not mandatory). Skin protection plans have to be as simple as possible. However, the old paradigm saying that the barrier cream must not be washed away by the medium (use oils in watery mediums and vice versa) is no longer operational. Qualified manufacturers of skin-protective preparations are characterized by the ability to provide suitable scientific results on the benefit of their products, which should take into account different exposures of the skin and differentiated mechanisms of action of barrier creams. Finally, the acceptance of barrier creams is of enormous relevance [7]. Daily experience has shown that in general barrier creams without any fragrance will not be accepted in the workforce. The risk of fragrance-associated allergy has to be balanced in relation to the benefit of the effective use of barrier creams. For example, if barrier creams are intended to be used in a primary preventive attempt, which means by workers with no experience of hand dermatitis or atopic eczema, a fatty preparation, which is hardly adsorbed and needs an intense effort to be massaged in, will have difficulty to achieve acceptance. Those workers will prefer creams with a comparatively large fraction of water and a relatively low component of effective substances. In contrast, workers with recurring hand eczema and recent experience of work-related hand eczema may prefer more fatty creams, because they feel themselves really protected. Then it is necessary to offer different types of barrier creams especially for the afterwork skin care.

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Provided that an appropriate plan of skin protection exists, the constant supply with barrier creams and easy access must be guaranteed. Dispenser systems only work in comparatively uniform exposure settings at the workplace, since the number of dispensers that can be placed reasonably at one washing place is limited. Anyway the responsibility for the regular check and refilling of the dispensers has to be well defined. Therefore, in many cases the use of tubes, associated with less logistic expenses, responsibility on the part of the worker and independence of a special washing place, seems to be preferable.

Practical Determinants of the Use of Barrier Creams

Even if a proper logistics of barrier creams is assured and workers are provided with adequate medical advice on dermal exposures at the workplace and skin protection (plan), one must not automatically expect that they will use barrier creams properly! Figure 2 shows that subjects with a very high risk of hand eczema on the one hand (⫽ group 1 in instructions for special periodical medical examinations for the prevention of occupational skin diseases [8] but only non-relevant dermal exposures at the workplace) are likely to use barrier creams more frequently compared to subjects with relevant exposures but no history of hand eczema (⫽ not included in groups 1–3 in the instructions).

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Workplace: Rubber gloves

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Fig. 3. Dermal exposures, use of barrier creams and hand eczema (HE): example.

Apparently, pre-existence of atopic eczema (e.g. manifestation in the flexures) without any history of hand dermatitis also triggers the attitude to use barrier creams on a more regular basis, more than dermal exposures combined with adequate advice do. For this reason, in all major epidemiological studies significant positive associations (i.e. in multivariate models) between hand eczema and frequency of use of barrier creams can be found, a phenomenon that might be misinterpreted at first thought. Psychological factors and patterns of individual behaviour have also to be considered. As with all behaviour-dependent preventive measures, the subjects’ use of barrier creams is associated with their general expectance of effectiveness of the measures for themselves. This expectance of self-effectiveness develops in childhood and is associated with the social class. Consequently, some behavioural patterns are developed almost completely at the age the subject will start his/her working life. This explains why we found that without intervention the frequency of use of barrier creams is rather constant (no, low or high) after apprenticeship and to some degree independent from dermal exposures at the workplace or the (additional) experience of hand eczema. Figure 3 gives an example of this typical behaviour (PACO II pilot study). Exposures at the workplace and even hand eczema did not change the rare use of barrier creams. Then the expectance of a private dermal exposure raised the frequency of use of barrier creams but was not successful in avoiding any more hand eczema.


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Individual Measures to Improve Skin Protection

A central component in a strategy to improve the skin protection behaviour at the workplace is to perform regular dermatologically focused medical examinations for all subjects at risk. With the new Regulation on Hazardous Substances (‘Gefahrstoffverordnung’) introduced in Germany in 2005, these special periodical medical examinations became mandatory for all workers with an exposure of at least 4 h of wet work at the workplace. The German Occupational Health Insurances have just revised their instructions for special periodical medical examinations for the prevention of occupational skin diseases [8]. All subjects with a relevant exposure to irritants at the workplace, e.g. with 2 h of wet work a day and more, unavoidable skin contact with potent sensitizers or in industries with elevated dermatological risks are supposed to be included in special periodical medical examinations. These contain identification of high-risk groups, advice for job selection or the choice of career according to the individual risk, early diagnosis of beginning occupational skin diseases, individual advice to minimize skin contact with irritants/allergens and instructions regarding the appropriate use of protection equipment and barrier creams. Risk groups for occupational skin diseases according to the abovementioned criteria are defined as follows (examples): • group 1 (very high risk): atopic eczema (severe) ⫹ hand eczema (longlasting or recurring), hand eczema (severe ⫹ chronical or recurring); • group 2 (high risk): atopic eczema (without hand eczema), dyshidrosis; • group 3 (moderate risk): wool intolerance, itch when sweating, xerosis. To minimize the requirement for exclusion from jobs with exposures to irritants, which remains relevant for group 1 (with a very high risk for occupational skin diseases), all other subjects were included in periodical examinations. Intervals of examinations were then adjusted for risk group and degree of exposure. Accordingly, subjects of group 2 with intense exposure to irritants like hairdressers are supposed to be examined every 3 months within the first year, and subjects without predisposing factors and only less intense exposure to irritants at the workplace may be seen by the doctor after 2 years again. Since implementation of barrier creams and postexposure skin care is based on the subject’s knowledge of dermal risks, the availability of adequate barrier creams and especially the subject’s individual history of preceding hand and/or atopic eczema, risk-group-related advice on skin protection is a quite effective tool and pedagogic concept to modify and improve attitudes towards appropriate skin protection. Even in subjects with no history of hand eczema, it is possible to predict their future risk with respect to the risk group and dermal exposures and thus to motivate them to use barrier creams. Therefore, above all

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in small and middle-sized companies that might not have realized a standardized and well-developed system of occupational safety and health comparable to big companies, the concept of regular periodical medical skin examinations is an effective tool of prevention.

Risk-Group-Related Measures in Production Teams

Special periodical medical examinations will trigger and enforce awareness and avoiding behaviour regarding the exposure to irritants and potential skin hazards as well as the proper use of protection equipment and barrier creams. However, for the continuous risk stabilization, an appropriate behaviour, individual awareness of risks as well as communication and behaviour patterns within the production teams are decisive [9]. To enforce risk awareness, the self-assessment of the hand eczema risk is a simple but effective tool. Within a skin protection campaign in a department manufacturing motor and chassis parts of the car industry, 4 questions concerning the self-assessment of hand eczema risk were answered by 2,102 workers with the following results: • hand eczema (history): 26.5%; • flexural eczema (history): 7.9%; • hay fever, allergic asthma or allergic conjunctivitis (history): 14.2%; • itch when sweating: 14.6%. In order to maintain risk-adjusted behaviour patterns, the communication within the production teams has to be influenced. Team leaders may play a central role in the prevention of occupational skin diseases, if they are instructed adequately. In the example given above, the leaders of 237 production teams were used as distributors for a brochure containing self-assessments of hand eczema risk, use of barrier creams at the workplace and at home, as well as some risk-group- and exposure-related advice for skin protection and medical care. Finally, a small competition was included. All team leaders were trained about the aims, objectives and the organization of the campaign. Then each team leader distributed the brochures in his production team. During regular team meetings, the questions were discussed and answered. The return of the questionnaire part of the brochure was again organized by the team leaders, and a return rate of 94% (2,102/2,236) could be achieved in this way. In the next step, the team leaders were responsible for the feedback of the campaign results to the workers. At the team meetings, the proportion of subjects with susceptible skin, the hazards at the workplace, adequate behaviour and skin care were discussed. A central issue in this discussion was that only 48.2% of the workers with and 30.9% of those without a history of hand eczema had used the freely available barrier creams twice a day and more (once a day and more:


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Fig. 4. Use of barrier creams and preventive measures.

72.0%/56.5%). Experience of hand eczema was the most important factor for the frequent use of barrier creams, but on the other hand there were 23.2% of workers with a history of hand eczema, who neither used barrier creams at the workplace nor at home. To analyse the success of this procedure and to give basic information for the management, evaluation processes are essential. A low or decreasing consultation frequency of the workers with the companies’ occupational physicians does not automatically indicate the success of such measurements, since there is a large number of unrecorded cases of hand eczema in a plant’s population. To intensify awareness will mean an increase in consultations. Therefore, the evaluation of the amount of distributed barrier creams at regular intervals is a more reliable tool regarding skin protection behaviour. As a result of the skin protection campaign and the following team meetings in autumn 1994, the consumption of barrier creams could be increased (fig. 4). One year later, however, the consumption of barrier creams decreased again. By the distribution of an additional brochure (content: general information about skin hazards and preventive measures) and a well-accepted (not fatty) additional barrier cream, it was possible to stabilize the individual skin protection on a significantly higher level than before the first skin care campaign. The monitoring of the consumption of barrier creams was also differentiated by subdepartments and shown to the management regularly. If a commitment to prevention of hand eczema is established in the management, the consumption of barrier creams is a wellaccepted tool in risk management. The preventive effects may result from the

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barrier creams themselves. On the other hand the use of barrier creams indicates that workers are aware of risks and will also avoid skin hazards by adequate behaviour.

Future Perspectives in Skin Protection

In contrast to many other occupational diseases, occupational skin diseases are not hidden. As they are visible for the subject and his environment with signs on the hands/forearms, the necessity, success, but also the failure of preventive measures will be obvious for all participants. Therefore, teaching the company management and the workers about existing dermatological risks at the workplace and their consequences is reasonable. It is also easy to convince both groups that there are good opportunities to reduce and sometimes avoid the risks, and that the use of barrier creams is one central issue in this context. But it is hard to ensure a continuous use of barrier creams in subjects without any experience of (hand) eczema. Therefore, in addition to the advice on individual risks of hand eczema by a physician, it is necessary to develop selfassessment systems for the risk of hand eczema by individual factors and exposures at the workplace. Such systems could be convenient also in small and middle-sized companies with high dermal exposures and no occupational physician available. In the bigger companies of the metal industry – mainly as an effect of technological development – dermal exposures are diminishing continuously. This is why the substantial majority of hand eczema seen by an occupational physician in the metal industry is not caused predominantly by workplace-related factors. In this context barrier creams are part of the prevention and sometimes even part of the therapy of non-occupational hand eczema.

References 1 2 3 4 5 6 7

de Boer EM, van Ketel WG, Bruynzeel DP: Dermatoses in metal workers. I. Irritant contact dermatitis. Contact Dermatitis 1989;20:212–218. Goh CL, Yuen R: A study of occupational skin disease in the metal industry (1986–1990). Ann Acad Med Singapore 1994;23:639–644. Berndt U, et al: Hand eczema in metalworker trainees – An analysis of risk factors. Contact Dermatitis 2000;43:327–332. Drexler H: Skin protection and percutaneous absorption of chemical hazards. Int Arch Occup Environ Health 2003;76:359–361. Geier J, et al: Patch test results with the metalworking fluid series of the German Contact Dermatitis Research Group (DKG). Contact Dermatitis 2004;51:118–130. Funke U, Fartasch M, Diepgen TL: Incidence of work-related hand eczema during apprenticeship: first results of a prospective cohort study in the car industry. Contact Dermatitis 2001;44:166–172. Bauer A, et al: Skin protection in bakers’ apprentices. Contact Dermatitis 2002;46:81–85.


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Berufsgenossenschaften, Hdg: Berufsgenossenschaftliche Grundsätze für arbeitsmedizinische Vorsorgeuntersuchungen: G 24 Hauterkrankungen (mit Ausnahme von Hautkrebs).: Stuttgart, Gentner, 2004. Funke U: Risikogruppenbezogene Prävention von Hautkrankheiten im Betrieb. Arbeitsmed Sozialmed Umweltmed 1995;30:257–264.

Ulrich Funke Gesundheitsschutz Audi AG Postfach 100 220 DE–85045 Ingolstadt (Germany) Tel. ⫹49 841 894783, Fax ⫹49 841 894801, E-Mail [email protected]

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Skin Protection Training The Route to Practical Applications

Ute Pohrt BGW Berlin, Germany

Abstract A skin protection cream can only provide effective protection at exposed workplaces if it is applied sufficiently and without gaps. This is sometimes difficult to achieve. Various studies have shown that success in the primary, secondary and tertiary prevention of occupational skin diseases is possible with intervention measures which include skin protection training. However, knowledge alone does not automatically lead to a change of attitudes, and this in turn may not automatically lead to a change of behaviour. The generation of health protection behaviour is in fact a very complex process. This complexity, together with the various intervention time points (primary, secondary or tertiary prevention) and the target groups should be taken into account when deciding the goals, contents and methods of skin protection training as well as the selection of the trainer. Typical goals, contents and methods are given for practical training which allow ‘learning with head, heart and hand’. Copyright © 2007 S. Karger AG, Basel

Recent studies have shown the effectiveness of skin protection programmes both in the primary, secondary and tertiary prevention of work-related skin problems [1–7]. These programmes were able to prevent the formation of occupational hand eczema or, in the case of existing diseases, to achieve effective improvements, and in almost all cases the affected individuals were able to continue work. The success of such a programme depends not only on choosing skin protection creams, cleansing agents and skin care products which are appropriate to the requirements of the individuals at their workplace and which are matched to one another. Success also depends on providing personnel with appropriate training about how to use these products properly [1, 3, 7, 8]. It is worrying that even in high-risk occupational groups the application of skin protection is not always part of the accepted standard procedures, and in

many cases there are shocking gaps in knowledge [1, 4, 7]. Rough and reddened skin is sometimes accepted in such vocational groups as an inevitable part of the work. Even people who have had to change their vocation because of work-related skin diseases said that they had never or only rarely used skin protection [9]. Arguments for not using skin protection include: I don’t need it • • It disturbs me during my work • It is too much trouble • It takes too long • I can’t stand it • I prefer to use my own cream [4] Even when effective skin protection preparations are used, there can often be considerable gaps in their application before exposure – in particular between the fingers and at the wrist [10]. This shows clearly that when it comes to the implementation of skin protection measures such as the application of barrier creams, in addition to knowledge, acceptance and opportunity also play important roles and should therefore be taken into consideration in training measures.

Legal Regulations

The basis for legislation on vocational protection in the member states of the European Union is article 137 (formerly 118a) of the Treaty of Nice, in which the signatory states undertake to work towards the ‘improvement in particular of the working environment to protect workers’ health and safety’. Directives are passed which establish minimum standards, which are then passed into law in the member states. Important directives in this context included the Council Directive 89/391/EEC (Measures to encourage improvements in the safety and health of workers at work) and the Directive 89/656/EEC (Use by workers of personal protective equipment). Article 12 of the first of these directives obliges employers to ensure that workers receive adequate safety and health training, in a form appropriate for their job or assignment. This training should be repeated if necessary at regular intervals during working hours. The Directive 89/656/EEC on the use by workers of personal protective equipment explicitly mentions barrier creams in the list of examples of applications. Article 4(8) of this directive specifies: ‘The employer shall arrange for training and shall, if appropriate, organize demonstrations in the wearing of personal protective equipment.’

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In the USA protective equipment is governed by the Occupational Safety and Health Act (OSHA) which specifies the duties of employers to care for the safety of employees. The general responsibility for occupational safety is extended to include the obligation to observe all the additional standards relating to occupational health and safety. The OSHA places strict demands on the employer but does not generally regulate the way the specific occupational safety measures should be put into practice. It is left to the employer to decide how to implement the requirements of the OSHA [11]. Personal protective equipment is addressed in specific standards for maritime, construction and general industries. Both in the ‘general industry’ standard and in the ‘maritime industry’ standard there are ‘Non-mandatory Guidelines for Hazard Assessment, Personal Protective Equipment (PPE) Selection, and PPE training program’. There we read: ‘…the general procedure for selection of protective equipment is to:... fit the user with the protective device and give instructions on care and use of the PPE. It is very important that users be made aware of all warning labels and limitations of their PPE.’

Theoretical Basis

Skin protection training courses are by their nature primarily intervention measures at the level of health-related behavioural prevention. In the sphere of primary prevention this would involve the training required under the legislation discussed above for employees whose skin was at risk, to be provided either at work or as lessons at vocational training colleges. The spheres of secondary and tertiary prevention primarily involve patient training in the sense of a ‘highrisk strategy’ aimed primarily at changing the behaviour of those who already have skin diseases. However, it would be wrong to assume that passing on knowledge automatically leads to a change in attitude, and that this again automatically brings about a change in behaviour – health-related behaviour is in fact much more complicated. It is not possible here to explain the processes involved in depth on the basis of behavioural psychology and health pedagogy. But even non-specialists can find it useful to consider certain approaches and models as an aid to understanding how some aspects of health-related behaviour originate, so as to be able to develop more efficient intervention and training measures. An approach, which is currently popular, is the ‘social-cognitive process model’ after Schwarzer [12], and according to this the following factors should be taken into account to understand health behaviour:

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Expected outcome Severity of symptoms Threat

Self-efficacy belief

Volational process Intention

Personal vulnerability

Plan of action

Subjective Situative barriers and resources e.g. social support

Monitoring actions Action

Objective

Fig. 1. The social-cognitive process model of health-related actions.

(1) expectations of the outcome – the conviction that a certain way of behaving can result in avoiding a health problem; (2) self-efficacy beliefs – confidence about being able to cope with a situation; this depends among other things on the abilities someone believes they have, their resources and their previous experience; external reinforcement can come from a boss, colleagues or from other patients, for example; (3) risk perception – the result of the subjective severity of the anticipated physical damage and the individual’s estimate of the resources available for resistance (severity and vulnerability); (4) situative barriers and resources – result from the perceived and real social desirability of the required behaviour. The interaction of these factors is shown in figure 1. Special importance is attached to the self-efficacy beliefs [12]. Both this and other models (e.g. the transtheoretical model of Prochaska et al. [13]) describe various stages of the change in behaviour which can be variously supported and which must be taken into consideration in effective intervention. Precontemplation is the stage at which there is no intention to change behaviour in the foreseeable future. Many individuals in this stage are unaware or not sufficiently aware of the problem, i.e. there is a failure to appreciate that the vocational activity can represent a threat for the skin with possible serious health consequences. ‘It isn’t that they can see the solution... they can’t see the problem.’ Precontemplators may sometimes use skin protection, but generally

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only because of pressure from others (e.g. their team leader). As soon as this pressure is removed, the desired behaviour stops, in our case the skin barrier is no longer applied. Contemplation is the stage in which people are aware that a problem exists but have not yet made a commitment to take action. People can remain stuck in the contemplation stage for long periods. Contemplation is knowing where you want to go but not being quite ready yet. Another important aspect of the contemplation stage is the weighing of the pros and cons of the problem. Serious consideration of problem resolution is the central element of contemplation. Preparation (or pre-action phase) is a stage that combines intention and behavioural criteria. This phase involves the planning and initiation of behaviour. Action is the stage in which individuals modify their behaviour so that this is visible for those around. However, it would be wrong to equate a (first) action with a change of behaviour. A consequence of this error can be that people overlook both the work still needed to prepare for action and the important efforts necessary to maintain the changes following action [13]. After the first action there is an intrapersonal evaluation. Successes and failures – depending on whether these have extrapersonal or personal causes – may support, impede or obstruct the stabilization of the desired behaviour [14]. Maintenance is thus not a static stage. It involves the continuation of change, not an absence [13].

Practical Implementation

It is important to take into account the complex origins of health-related behaviour as well as the various intervention points (primary, secondary or tertiary prevention) and also the target groups when determining the goals, contents and methods for skin protection training and also when selecting the trainer [15]. Goals It is important to formulate goals for the alteration of the behaviour which the training is to lead to. On the basis of the goals it is then possible to choose suitable course contents and methods and also to check whether the goals have been achieved. There are three types of goals: (1) cognitive goals – these are related to thinking, knowledge and problemsolving, as well as to experience and intellectual abilities;


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(2) affective goals – these refer to the changes in interests, the willingness to do or think something, and to the development of established attitudes; (3) psychomotor goals – these refer to manipulative and motor skills. However, in general these dimensions are not apparent to the trainees. The overriding goal of the skin protection training is to promote the ability of the workers to act to maintain a healthy skin or to stabilize a skin disease and restore the skin to health. This involves carrying out appropriate skin protection measures in the situations encountered at work. Depending on the target group and the timing of the intervention, a skin protection training course could include the following points: at the cognitive level, the course participants • know the structure and the functioning of the skin and the pathogenesis and possible consequences of occupational skin diseases; • know the legislation relating to skin protection; • know the specific threat factors for the skin at their place of work, the effects of these and possible protection against the threats; • know how skin creams work, their limitations and the correct way to apply them; • know who to contact if they have problems or questions, if they notice changes to their skin or find they cannot tolerate the skin barriers provided etc.; • learn to identify warning signs of skin diseases and know what steps to take (improving skin care, consulting a dermatologist etc.); at the affective level, the course participants • appreciate the importance of caring for a healthy skin; • feel responsible for keeping their skin healthy; • regard skin protection as a necessary and effective way of keeping their skin healthy; • regard skin protection measures as a regular part of their work; • are prepared to carry out the necessary skin protection measures over the long term; at the psychomotor level, the course participants • apply skin protection in the right way in a given situation; • choose the appropriate barrier cream; • apply the barrier cream at the right time; • use the barrier cream often enough; • apply the barrier cream all over the skin without leaving gaps (taking particular care between the fingers and near the wrist).

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Contents Until very recently, skin protection was not really recognized as a part of healthy behaviour, and though awareness has begun to increase regarding the protection against UV rays, it still does not form a part of general healthy behaviour. In contrast to topics such as non-smoking, physical exercise or healthy nutrition, it is not possible to assume that people already have basic knowledge. Therefore in a first training course it will be necessary to lay these foundations in order to create awareness for the problem. Basic contents of a course on skin protection could include [16]: • structure and function of the skin; the skin as the interface organ to the environment, the layers of the skin, the particular importance and structure of the epidermis, requirements for an intact barrier function; • occupational factors which can lead to skin damage, like irritants (water, alkalis, acids, detergents, cooling lubricants, cement etc.) or allergens (natural latex, chromates, isocyanates, formaldehyde etc.); • formation of a contact eczema; mechanism of the irritative contact eczema with early symptoms, mechanism of the allergic contact eczema, 2-phase eczema. On this basis, specific skin risks at the workplace can be identified, and protection strategies can be developed. Although we are concerned here with skin protection training, in each case an effective skin protection strategy should include the discussion of all preventive options in the following order: • technical measures (e.g. use of machines); • organizational measures (e.g. alternation of dry and wet work); • personal protection measures (use of gloves and skin protection products). The topic of ‘skin protection products’ can also have various aspects: • skin protection – skin cleaning – skin care; effects and limitations of skin protection products, selection and application of skin protection products, avoidance of skin contamination, careful hand cleansing and effective drying of hands as support for the regeneration; selection and application of skin care products; • implementation of the skin protection measures at work; legal and company regulations, skin protection measures as part of regular work processes, compatibility of skin protection and product protection (e.g. in the electronics industry or the foodstuffs industry), or of hygiene and skin protection (e.g. in the health service). For the skin protection training in the secondary and tertiary prevention of occupational skin diseases there are other important items: • skin protection as a basic component of skin disease management, avoidance of trigger factors, consideration of special sensitization;


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• • •

skin protection in private life; skin protection for housework and garden work, skin protection for certain hobbies; argumentation training for skin protection at work.

The final point reflects the fact that secondary and tertiary prevention training is not generally provided at the workplace with the team co-workers. That means that the participants may well find that their new skin protection behaviour meets with the scepticism and even rejection of their co-workers.

Methods and Examples The effectiveness and attractiveness of training courses often depends on the methods used. These should help the participants to work on the topic and to develop new attitudes and skills. Normally, skin protection training courses are attended by adults with a certain level of experience, but they are very often unaccustomed to learning situations. They will want to be accepted as individuals and treated with respect, and are more likely to enter into learning processes when they can play an active part in forming these and when they can raise their own questions and problems but can also contribute their experience. The chosen method should not only allow this but should also encourage it. Attractive methods can motivate the participants and get them to cooperate even when dealing with less exciting topics and problems. The combination of a variety of methods helps to avoid boredom and allows for the fact that different people have different preferences and different ways of learning. The selection of the methods to be used should take account of the goals, the contents to be taught, the group of participants and the training situation. Basically, many methods used in continuous education are suitable for skin protection courses – the important thing is that they provide opportunities for ‘learning with head, heart and hand’. The aspect of self-efficacy belief which is central for health behaviour can be improved by direct experience of one’s own self-efficacy, perhaps together with representational or symbolic experience (learning with models) [17]. An overview of all possible methods cannot be provided here, but a skin protection training course could include the following aspects: structure of the skin and the formation of eczema: • plastic skin model (e.g. from CEDIP, praxishop.ch or a simple model, see www.paedagogik.net/wochenthemen/Sinnesorgane/hautmodell. html); • overhead foils (see e.g. www.2haende.ch);

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Table 1. Examples of skin protection training in the health service Duration

Contents

Method/media

10 min

Welcome Introduction to the subject Contact eczema – repetition

Trainer introduction, impulse talk Overhead foils

10 min

Effects Pros and cons of barrier creams

Experiment (sugar lumps) Group discussions Flip charts

10 min

Application of barrier creams

Exercise with UV lamp Stepwise application of cream under the guidance of the trainer

10 min

Work rules

Group discussion on occupational hygiene and skin protection plan

10 min

Clarification of unresolved questions, conclusion

Card quiz

• comparison of the epidermis with a brick wall (the bricks correspond to horn cells, the cement to the intercellular substances; washing out the cement leads to the destruction of the wall); • videos or DVDs (e.g. from the Institution for Statutory Accident Insurance and Prevention in the Health and Welfare Services or from Bode-Chemie); effects/application of skin protection products: • demonstrations, e.g. an untreated sugar lump dissolves in water faster than one which has been coated with a skin protection product; the shell of an untreated egg in vinegar quickly begins to be attacked – but an egg protected by a barrier cream remains intact much longer; model dirt can be washed off much easier if skin protection cream has been applied etc.; • practical demonstration of the stages of application of a cream; • videos or DVDs (see above); • use of a fluorescent cream and a UV lamp (e.g. Dermalux) to identify gaps in the application [18]. A skin protection training course for a small group of nurses could look like the example given in table 1. This is a primary prevention measure, and the participants, who work together, all have at least basic medical knowledge about the skin and the formation of eczema. They have been trained in the use of protective gloves.


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Schwanitz HJ, Riehl U, Schlesinger T, Bock M, Skudlik C, Wulfhorst B: Skin care management: educational aspects. Int Arch Occup Environ Health 2003;76:374–381. Schürer NY: Secondary individual prevention in geriatric nurses. Am J Contact Dermat 2003;14: 112. Klippel U: Prävention berufsbedingter Dermatosen bei Beschäftigten in der Altenpflege: Studien zur Prävention in der Allergologie, Berufs- und Umweltdermatologie. Göttingen, V&R unipress, 2004. Diepgen TL, Schmidt A, Kresken J: Prävention berufsbedingter Handekzeme durch Hautschutzmassnahmen – Ergebnisse einer betrieblichen Interventionsstudie. Arbeitsmed Sozialmed Umweltmed 2004;39:307–314. Held E, Mygind C, Wolff C, Gyntelberg F, Agner T: Prevention of work related skin problems: an intervention study in wet work employees. Occup Environ Med 2002;59:556–561. Bauer A, Kelterer D, Bartsch R, Pearson J, Stadeler M, Kleesz P, Elsner P, Williams H: Skin protection in bakers’ apprentices. Contact Dermatitis 2002;46:81–85. Stadeler M, Kelterer D, Bauer A, Grosch J, Elsner P: Präventionsprojekt bei berufsbedingten Hauterkrankungen im Back-, Hotel- und Gaststättengewerbe. Allergologie 2003;26:403–412. Perrenoud D, Gogniat T, Olmstead W: Importance of education with appropriate material for the prevention of occupational dermatitis. Dermatol Beruf Umwelt 2001;49:88–90. Diepgen TL, Schmidt A, Fartasch M: Demographic and legal characteristics of occupational skin diseases. Allergologie 1994;17:84–89. Wigger-Alberti W, Paraffino B, Elsner P: Anwendung von Hautschutzpräparaten durch Patienten mit Berufsdermatosen: Notwendigkeit einer verbesserten Verhaltensprävention. Schweiz Med Wochenschr 1997;127:899–904. Debatin A: Das Arbeitssicherheitsrecht in den USA und Deutschland. Konstanz, Hartung-Gorre, 1997. Schwarzer R: Psychologie des Gesundheitsverhaltens. Göttingen, Hogrefe, 1992. Prochaska JO, Di Clemente CC, Norcross JC: In search of how people change. Am Psychol 1992;47:1102–1114. Knäuper B, Schwarzer R: Selbstwirksamkeitserwartungen in der Verhaltensschulung. Prax Klin Verhaltensmed Rehab 2000;51:5–10. Wulfhorst B, Schwanitz HJ: Gesundheitserziehung in Hautrisikoberufen. Allergologie 2003;26: 387–395. Wulfhorst B: Konzeption, Implementation und Evaluation einer gesundheitspädagogischen Massnahme: Studien zur Prävention in der Allergologie, Berufs- und Umweltdermatologie. Osnabrück, Rasch, 2001. Bandura A: Self-efficacy: toward a unifying theory of behavioural change. Psychol Rev 1977;84: 191–215. Wigger-Alberti W, Maraffino B, Wernli M, Elsner P: Training workers at risk for occupational contact dermatitis in the application of protective creams: efficacy of a fluorescence technique. Dermatology 1997;195:129–133.

Ute Pohrt, MD Berufsgenossenschaft Gesundheitsdienst und Wohlfahrtspflege Karlsruher Strasse 19–22 DE–10711 Berlin (Germany) Tel. ⫹49 30 89685 500, Fax ⫹49 30 89685 501, E-Mail [email protected]

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Limitations of Skin Protection Interaction of Gloves and Skin Protection Products

Sibylle Schliemann Department of Dermatology and Allergology, Friedrich Schiller University, Jena, Germany

Abstract Skin protection products and gloves are essential constituents of personal protective equipment at workplaces, which can be used in a complementary way, each offering particular benefits and disadvantages. In many workplace situations, both measures are being used either in an alternating or in a combined manner, typically in professions with exposures to mild irritants and a high wet-work load, such as hairdressers, healthcare workers or employees in the food-processing industry. Skin protection creams can be used to reduce unnecessarily long glove usage in order to reduce occlusion-related effects on the skin barrier. Whenever rotating machines are used, these products are the only option due to safety regulations. However, some particular requirements can be postulated for skin-protective products claimed especially to be used in combination with gloves. Reduction of glove-induced perspiration, of stratum corneum swelling, and postocclusive barrier impairment are intended attributes of such products, which have been already successfully implemented in some commercially available products. On the other hand it has to be proven that the ingredients do not interfere with the glove material, neither in the way of degrading the material, thus making it permeable for harmful substances, nor by enhancing the potential release of rubber allergens. Examples out of the literature are reviewed showing that skin products can exhibit unpredictable effects on the allergen release of rubber materials, if not thoroughly tested for this purpose beforehand. Some raw materials should be avoided in protection products, though they are of established value when used in afterwork emollients to accelerate barrier recovery. Usage of moisturizers, in contrast to special barrier products, at the workplace together or even under gloves is therefore judged critically, although selected products showed beneficial effects in particular experimental settings. Another future option is the implementation of ‘active gloves’ that are intended to gradually release ingredients that help to strengthen and preserve skin barrier integrity. Copyright © 2007 S. Karger AG, Basel

Both skin-protective products as well as protective gloves are essential components of personal protective equipment that shall be used in a complementary way

at the workplace whenever technical measures and re-organization of working processes are not sufficient for protection against potentially harmful substances. However, although in many workplaces skin-protective preparations and protective gloves are used alternately or even in a combined manner, only limited scientific studies have investigated the interaction of both measures. Ideally, efficacy-proven protection creams and protective gloves can complete one another effectively, e.g. by perspiration-reducing ingredients of a barrier cream worn under the glove [1]. However, potential untoward effects of combined usage have also to be considered. What Skin Protection Means

To be clear, the concept of integrated skin protection addressed in this article includes usage of pre-exposure skin protection creams, mild skin cleansers for decontamination of the skin and afterwork emollients in order to support barrier regeneration. But why not use only one product for protection as well as for barrier regeneration? The question whether protection creams and emollients really have to be differentiated from one another not only for didactic purposes has been raised many times in recent years in an attempt to simplify the idea of skin protection. However, it has to be stressed that protective creams and skin moisturizers have to be different regarding their constituents as well as their intended actions and therefore cannot be exchanged, although protection creams will exhibit also skin care efficacy to some extent [2]. While some ingredients are highly beneficial when used in afterwork emollients and moisturizers, such as urea, they are nowadays regarded as inappropriate for protection creams, due to their potential enhancement of skin penetration of irritants [3, 4]. Results of our own studies showed that the best protective efficacy can only be achieved by usage of all 3 constituents [5]. Therefore, this threefold concept is reflected by elaborately adapted skin protection plans at the workplace for good reasons. Fields of Combined Application

Application of skin protection cannot be regarded as equivalent to usage of protective gloves [6]. While gloves are indispensable in exposure settings with toxic or mutagenic materials, dangerous microbes, as well as when dealing with strong irritants, skin-protective products are primarily intended to diminish the barrier-impairing effects of repeated exposure to mild irritants and a high wetwork load in order to prevent irritant contact dermatitis of the cumulative type. In contrast to skin products, gloves can also offer more effective protection against allergens [7], provided that they are of appropriate material, which cannot be penetrated by the allergens addressed [8, 9]. Nevertheless, in many

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Harmful interaction

☺ Beneficial interaction Glove

Aggravation of allergen release? Material degradation

Reduction of allergen release (contact allergens, type I allergens)?

Protective cream Penetration enhancement (allergens/irritants)

Reduction of perspiration Reduction of glove-induced roughness/irritation Reduction of stratum corneum swelling (protein complexes)

Skin

Fig. 1. Schematic illustration of potential harmful and beneficial interactions of a combined use of protective creams together/under protective gloves on the skin barrier.

workplaces with multiple exposure patterns, skin-protective products and gloves are used alternately or even in a combined manner. Whenever rotating devices are used, skin-protective preparations are the only option due to work safety. Furthermore, long-term wearing of gloves can itself exhibit untoward effects such as impairment of the skin barrier function [10, 11] or rubber glove allergy [12, 13]. Therefore, usage of protective creams can help to reduce unnecessarily long glove application. Some typical professions using both gloves and skin-protective products include hairdressers, health professions, food professions, cleansing and metal work, which are all characterized by a high wet-work load. Figure 1 summarizes potential effects of interaction between gloves, protective creams and the skin barrier. Untoward Effects

Some ingredients of skin protection products, though principally hardly indispensable for stability and/or acceptance reasons, such as preservatives and fragrances, can induce contact sensitization [4, 14]. Therefore, fragrance ingredients should be used with caution and be limited to substances with a proven low sensitizing potential, in particular because these products will also be used

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on already impaired skin in many cases. Chemical ultraviolet filters are also potentially capable of inducing allergic as well as photo-allergic contact dermatitis in rare cases. As mentioned above, protective creams should be free of penetration-enhancing ingredients such as propylene glycol, urea and particular emulsifiers [3, 4]. Gloves themselves can contribute to skin irritation when used over long periods without intermission. Therefore, protection from skin damage caused by potential noxae has always to be balanced against untoward glove effects. It has been shown that glove powder accelerates skin roughness by using skin replicas and profilometry [15]. Singular glove occlusion with a duration of 4 and 8 h, respectively, was found to induce temporary increase of stratum corneum permeability as demonstrated by a nicotinate penetration test as well as significant elevation of transepidermal water loss, whereas repeated wearing of polyvinylchloride gloves on 2 days (2 ⫻ 6 h) caused prolonged barrier disturbance that persisted the following day, indicating a cumulative irritant effect [16]. Repetitive experimental usage of non-latex gloves for 6 h/day for 14 days on normal skin was able to induce elevated transepidermal water loss as the most sensitive bioengineering parameter of disturbed barrier integrity [11]. Apparently, glove occlusion is more likely to cause barrier impairment in the presence of coexposure to detergents. While gloves worn on 3 successive days for 6 h each did not cause significantly negative effects on the water barrier function, the combination with pre-exposure to sodium lauryl sulphate (SLS) induced a significant barrier disturbance [10]. In a recent experimental study, which compared barrier impairment caused by combined exposure to occlusion together with or without water or SLS and with or without mechanical irritation caused by skin friction, the ranking regarding irritancy was as follows: occlusion with SLS and mechanical irritation ⬎ occlusion with SLS ⬎ occlusion with water and mechanical irritation ⬎ mechanical irritation and occlusion with water ⬎ occlusion with a glove and mechanical irritation ⬎ mechanical irritation ⬎ occlusion with water [17]. The new technical rule for hazards induced by skin contact recently implemented in Germany (TRGS 401) stigmatizes the usage of gloves for more than 2 h/day, equivalent to wet work of the same duration, which is classified as a ‘medium skin hazard’. However, it is still under debate whether data are sufficient to equate wet work and wearing of occlusive gloves [18]. Resulting from the above-mentioned obstacles, which general requirements can be postulated for skin products to be used together and under gloves, respectively? The intended effects should include reduction of perspiration, reduction of stratum corneum swelling after occlusion and postocclusive barrier impairment. On the other hand, it has to be proven that the ingredients do not interfere with the glove material, neither in the way of degrading the material, thus making it permeable for harmful substances, nor by enhancing the potential

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release of rubber allergens. While some concepts for skin protection creams have already been successfully implemented, e.g. by using particular ingredients such as aluminium chlorohydrate or synthetic tanning agents in order to reduce perspiration and to diminish swelling by formation of protein complexes [19], there are also some results from the literature indicating that caution is warranted regarding uncritical enthusiasm for combined usage. Moisturizers are in general not qualified to be used under gloves, due to potential inappropriate ingredients, causing penetration enhancement or even sensitization under occlusion. These products, which are intended to elevate the stratum corneum hydration level by their composition, should be restricted for afterwork barrier regeneration. In an experimental study, Held and Jorgensen showed beneficial effects of a moisturizer applied on SLS-impaired skin under glove occlusion. In contrast to the exclusively SLS-impaired and occluded hands in their immersion test, the moisturizer was found to diminish the negative effect on the skin barrier function [20]. However, their results must not be generalized; moreover, the concept of using moisturizers under gloves has to be seen very critically for the above-mentioned reasons. The question whether protective creams capable of preventing allergen release from gloves can be created is complex and cannot be answered generally [21–23]. Depending on the different types of glove materials (natural latex vs. synthetic elastomers vs. plastic materials) as well as the fabrication process on the one hand and the constituents of the skin product and its circumstances of application on the other, different scenarios can result, as illustrated by two studies dealing with the same objective but coming to controversial results. While Allmers [22] showed a reduced rate of contact urticaria caused by latex from natural rubber latex gloves in a glove use test when applying a special protective cream beforehand, Baur et al. [21] experienced an increased positive response rate from 30 to 41% of subjects with specific IgE against latex in a use test with another commercially available protective cream. Moreover, they were able to demonstrate that the product even elicited contact urticaria in 5% of 109 test persons, who did not respond to a glove with a low latex allergen content [21]. These findings stress that ideally, standardized efficacy and interaction testing of skin-protective products especially intended to be used under gloves should be performed, which has not been routinely implemented yet, in parallel to in vivo efficacy testing of barrier creams, which is being recommended in interdisciplinary guidelines [1].

Future Developments

The concept of combined usage of gloves and skin products can theoretically also be realized by implementing ‘active gloves’, a tempting idea. Indeed,


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singular studies have already focused on this objective. In an attempt to reduce skin dryness, 29 assembly line workers used Aloe-vera-coated gloves in a contralateral comparison study. The coating was intended to gradually deliver A. vera gel to the cracked skin surface. The photo-evaluation of blinded dermatologists revealed clinically improved skin conditions on the hands treated with the active glove [24]. However, in principle the same provisos formulated against moisturizers also apply to the concept used here. It has to be taken into account that the study was only based on visual evaluations, in parallel to another investigation which was only based on 1-day application and selfassessment [25]. Another very recent study suggests a benefit from usage of gloves with an inside pH of 5.5 in order to maintain a tight control over the skin surface pH under and after occlusion, based on the concept that a more alkaline skin surface pH might contribute to irritation and dryness. Therefore, 20 healthy subjects wore the study glove in a 4-week setting for 8 h on 5 days/week compared to a control glove on the opposite hand. The study glove maintained a lower skin pH than the control glove and tended towards having less irritation in the clinical assessments. Observers stated increases in dryness and scaling in both hands after 4 weeks but significantly less dryness in the study hand at week 4. The pH 5.5 glove maintained lower skin pH levels than the control glove [26]. However, the effects observed regarding the pH differences at the end of the study period were minimal. Thus scepticism appears justified with respect to clinical relevance of these findings.

References 1

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3 4 5

6 7 8

Wigger-Alberti W, Diepgen TL, Elsner P, Korting HC, Kresken J, Schwanitz HJ: Beruflicher Hautschutz – Gemeinsame Leitlinie der Arbeitsgemeinschaft für Berufs- und Umweltdermatologie (ABD) in der Deutschen Dermatologischen Gesellschaft (DDG) und der Gesellschaft für Dermopharmazie (GD). Dermatol Beruf Umwelt 2003;51:D15–D21. Berndt U, Wigger-Alberti W, Gabard B, Elsner P: Efficacy of a barrier cream and its vehicle as protective measures against occupational irritant contact dermatitis. Contact Dermatitis 2000;42: 77–80. Drexler H: Skin protection and percutaneous absorption of chemical hazards. Int Arch Occup Environ Health 2003;76:359–361. Schliemann-Willers S, Elsner P: Occupational skin protection. J Dtsch Dermatol Ges 2005;3: 120–133, quiz 134–126. Berndt U, Gabard B, Schliemann-Willers S, Wigger-Alberti W, Zitterbart D, Elsner P: Integrated skin protection from workplace irritants: a new model for efficacy assessment. Exog Dermatol 2002;1:45–48. Mygind K, Sell L, Flyvholm MA, Jepsen KF: High-fat petrolatum-based moisturizers and prevention of work-related skin problems in wet-work occupations. Contact Dermatitis 2006;54:35–41. Schliemann S, Wigger-Alberti W, Elsner P: Prevention of allergy by protective skin creams: possibilities and limits. Schweiz Med Wochenschr 1999;129:996–1001. Andersson T, Bruze M, Gruvberger B, Bjorkner B: In vivo testing of the protection provided by non-latex gloves against a 2-hydroxyethyl methacrylate-containing acetone-based dentin-bonding product. Acta Derm Venereol 2000;80:435–437.

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9

10 11 12

13 14

15 16 17

18

19 20 21 22 23

24 25 26

Andreasson H, Boman A, Johnsson S, Karlsson S, Barregard L: On permeability of methyl methacrylate, 2-hydroxyethyl methacrylate and triethyleneglycol dimethacrylate through protective gloves in dentistry. Eur J Oral Sci 2003;111:529–535. Ramsing DW, Agner T: Effect of glove occlusion on human skin. I. Short-term experimental exposure. Contact Dermatitis 1996;34:1–5. Ramsing DW, Agner T: Effect of glove occlusion on human skin. II. Long-term experimental exposure. Contact Dermatitis 1996;34:258–262. Geier J, Lessmann H, Uter W, Schnuch A: Occupational rubber glove allergy: Results of the Information Network of Departments of Dermatology (IVDK), 1995–2001. Contact Dermatitis 2003;48:39–44. Knudsen BB, Hametner C, Seycek O, Heese A, Koch HU, Peters KP: Allergologically relevant rubber accelerators in single-use medical gloves. Contact Dermatitis 2000;43:9–15. Uter W, Schnuch A, Geier J, Pfahlberg A, Gefeller O: Association between occupation and contact allergy to the fragrance mix: a multifactorial analysis of national surveillance data. Occup Environ Med 2001;58:392–398. Brehler R, Voss W, Muller S: Glove powder affects skin roughness, one parameter of skin irritation. Contact Dermatitis 1998;39:227–230. Graves CJ, Edwards C, Marks R: The effects of protective occlusive gloves on stratum corneum barrier properties. Contact Dermatitis 1995;33:183–187. Fluhr JW, Akengin A, Bornkessel A, Fuchs S, Praessler J, Norgauer J, Grieshaber R, Kleesz P, Elsner P: Additive impairment of the barrier function by mechanical irritation, occlusion and sodium lauryl sulphate in vivo. Br J Dermatol 2005;153:125–131. Ochsmann E, Drexler H, Schaller KH, Korinth G: Wet work versus occlusive gloves – An attempted evidence-based evaluation of these two potential skin hazards. Dermatol Beruf Umwelt 2006;54:3–12. Perrenoud D, Gallezot D, van Melle G: The efficacy of a protective cream in a real-world apprentice hairdresser environment. Contact Dermatitis 2001;45:134–138. Held E, Jorgensen LL: The combined use of moisturizers and occlusive gloves: An experimental study. Am J Contact Dermat 1999;10:146–152. Baur X, Chen Z, Allmers H, Raulf-Heimsoth M: Results of wearing test with two different latex gloves with and without the use of skin-protection cream. Allergy 1998;53:441–444. Allmers H: Wearing test with 2 different types of latex gloves with and without the use of a skin protection cream. Contact Dermatitis 2001;44:30–33. Modak S, Gaonkar TA, Shintre M, Sampath L, Caraos L, Geraldo I: A topical cream containing a zinc gel (allergy guard) as a prophylactic against latex glove-related contact dermatitis. Dermatitis 2005;16:22–27. West DP, Zhu YF: Evaluation of Aloe vera gel gloves in the treatment of dry skin associated with occupational exposure. Am J Infect Control 2003;31:40–42. Davis DD, Harper RA: Using gloves coated with a dermal therapy formula to improve skin condition. AORN J 2005;81:157–162, 165–167. Mirza R, Maani N, Liu C, Kim J, Rehmus W: A randomized, controlled, double-blind study of the effect of wearing coated pH 5.5 latex gloves compared with standard powder-free latex gloves on skin pH, transepidermal water loss and skin irritation. Contact Dermatitis 2006;55:20–25.

Sibylle Schliemann, MD Department of Dermatology and Allergology Friedrich Schiller University, Erfurter Strasse 35 DE–07743 Jena (Germany) Tel. ⫹49 3641 937301, Fax ⫹49 3641 937425, E-Mail [email protected]


177

Author Index

Allef, P. 19

John, S.M. 133

Bartsch, R. 138 Bauer, A. 138 Brodsky, B. 76

Kelterer, D. 138 Klotz, A. 19 Kütting, B. 87

Dickel, H. 98 Drexler, H. 87

Mahler, V. 120 Maibach, H.I. 47 Miteva, M. 33

Eichler, J.-O. 19 Elsner, P. 1, 33, 111, 138 Fluhr, J.W. 33 Funke, U. 151

Skudlik, C. 133 Smith, E.W. 11 Stadeler, M. 138 Surber, C. 11 Thörner, B. 19 Veeger, M. 19 Weimans, S. 19 Wormser, U. 76

Pohrt, U. 161 Schalock, P.C. 58 Schliemann, S. 171 Schürer, N.Y. 98

Zhai, H. 47 Zhang, J. 11 Zug, K.A. 58 zur Mühlen, A. 19

178

Subject Index

Acrylic resin, glove protection 69, 70 Allergens glove penetration 60, 61, 68 healthcare worker protection 128–130 occupation-specific risks 60, 62 sex differences 61 skin protection approaches allergen elimination or replacement 63, 64 allergen identification 63 barrier creams 64–67 educational programs 72 gloves 68–71 hygiene 71, 72 overview 62 postexposure skin care 72, 73 protective clothing 71 types in occupational contact dermatitis 60 Baker, see Food industry Barrier cream, see also Protective cream allergen-specific protection 64–67 application 49 composition 49, 50 definition 35, 48 duration of action 49, 53 mechanism of action 49 metal workers education 156 use determinants 154, 155 moisturizer comparison 47 rationale 48, 49

Carcinogenicity, safety testing 44 ␤-Carotene, photoprotection studies 95, 96 Clothing, sun protection 95 Cobalt, protective creams 66, 67 Cold physical irritant contact dermatitis effects 104 tandem repeated irritant test 116 Contact dermatitis (CD), see also Physical irritant contact dermatitis allergens, see Allergens forms 47, 58 irritant reaction 48 Copper, protective creams 66, 67 Disinfectants spectrum of activity by type 122–124 tandem repeated irritant test 113 Electrical capacitance, tandem repeated irritant test 116, 118 Epoxy resin glove protection 69 protective creams 65, 66 Evidence-based medicine, skin protection 37, 126 Fiberglass, dermatitis 107 Food industry baker apprentice study of hand dermatitis prevention demographics of study groups 141–143 prevalence findings 143, 144, 146

179

Food industry (continued) baker apprentice study of hand dermatitis prevention (continued) skin protection measure acceptance and uptake 143 study design 140, 141 transepithelial water loss testing 144, 145 ultraviolet hardening effects 139, 140, 143, 146, 147 hand dermatitis epidemiology 138, 139 prevention 139, 140

allergen protection 128–130 infectious agent protection 121, 122 irritant types and protection 122, 125–128 occupational skin disease epidemiology 120, 121 protective creams 126, 127 Hydrofluoric acid (HF), povidone-iodine protection 83 Hypersensitivity safety testing 43 types 59

Galenicals historical perspective 11, 12 properties 13 prospects 16, 17 selection of vehicle 15, 16 vehicle effect 13–15 Genotoxicity, safety testing 43 Gloves allergen penetration 60, 61, 68 coated active gloves 175, 176 limitations 173–175 materials for hospital workers 122, 125 pH optimization 176 protection acrylic resins 69, 70 epoxy resins 69 glutaraldehyde 70 glyceryl monothioglycolate 71 nickel 69 protective cream interactions 171–176 Glutaraldehyde, glove protection 70 Glyceryl monothioglycolate, glove protection 71

Interleukin-1 (IL-1), release assay in skin model 24, 25 Iodine anti-inflammatory agent combination 83 povidone-iodine protection comparison 78 toxicant protection human studies 83, 84 mechanism of action 84 overview 78

Hairdressers carbon-dioxide-enriched water benefits 135 Germany regulations 133, 134 occupational skin disease prevention 136, 137 protective creams 134–136 sensitization risks 133 Hazard identification, safety testing 41 Healthcare workers

Subject Index

Lactate dehydrogenase (LDH), assay of cell viability in skin model 24 Melanoma, sunscreen prevention studies 93, 94 Metal workers barrier cream education 156 use determinants 154, 155 risk-group-related measures in production teams 157–159 risk stratification for occupational skin disease 156 skin exposures 151, 152 skin protection principles 152–154 prospects 159 Moisturizer barrier cream comparison 47 definition 49, 50 irritant contact dermatitis prevention 52, 53 skin effects 50–52 Mutagenicity, safety testing 43

180

Nickel glove protection 69 protective creams 65–67 Occupational skin disease (OSD), see also specific occupations allergens, see Allergens economic impact 3, 5, 58 incidence and prevalence 2, 59 prevention 6, 8, 9 prognosis 2, 3, 59 risk factors 5, 34, 35 skin protection training, see Training, skin protection Phototoxicity avoidance 95 safety testing 44 Physical irritant contact dermatitis (PICD) climate effects cold 104 heat 103, 104 humidity 100–102 water 102, 103 clinical features 98, 99 diagnosis 98 electromagnetic regulation 107, 108 epidemiology 100 etiology 99 mechanical influences fiberglass dermatitis 107 friction 105, 106 granulomatous reaction 106, 107 occlusion effects 105 prevention and protection 108 Potassium dichromate, protective creams 66, 67 Povidone-iodine anti-inflammatory agent combination 83, 84 iodine protection comparison 78 toxicant protection human studies 83, 84 hydrofluoric acid 83 overview 78 spectrum of activity 82, 83 sulfur mustard 79–81 tetraglycol formulation 79–81

Subject Index

Pre-work cream skin model testing advantages of three-dimensional human skin model 20, 21, 29, 30 controls 22 inflammatory response interleukin-1 release assay 24, 25 prostaglandin E2 secretion 25, 26 lactate dehydrogenase assay of cell viability 24 limitations of animal skin 20 lipid analysis 26–29 materials 21 multiple emulsion testing 22, 23 repetitive occlusive irritation test 21, 22 testing overview 20 Prostaglandin E2, secretion assay in skin model 25, 26 Protective cream (PC) cooling effect 36 definition 35 evidence-based medicine and skin protection 37 glove interactions 171–176 hairdressers 134–136 healthcare workers 126, 127 hydrating effect 36 limitations 173–175 safety testing 41–44 test systems 37–41 Risk allergen exposure by occupation 60, 62 metal workers risk-group-related measures in production teams 157–159 risk stratification for occupational skin disease 156 safety testing characterization 41 evaluation 41 Safety testing carcinogenicity 44 human data sources 44 irritation tests 42

181

Safety testing (continued) mutagenicity and genotoxicity 43 overview 41 photoirritation 42, 43 phototoxicity 44 preclinical toxicology 42 sensitization and photosensitization 43 subchronic toxicity 43 toxicokinetics 44 Skin care versus skin protection 35, 36 Skin-conditioning product, definition 35 Skin model, pre-work cream testing advantages of three-dimensional human skin model 20, 21, 29, 30 controls 22 inflammatory response interleukin-1 release assay 24, 25 prostaglandin E2 secretion 25, 26 lactate dehydrogenase assay of cell viability 24 limitations of animal skin 20 lipid analysis 26–29 materials 21 multiple emulsion testing 22, 23 repetitive occlusive irritation test 21, 22 Skin-protective cream, see Protective cream Skin regeneration product, definition 35 Stratum corneum (SC), function 33, 34 Sulfur mustard, povidone-iodine protection 79–81 Sun protection, T4N5 liposomes 96 Sunscreen application 92, 93 cancer prevention studies 93–95 composition 91, 92 historical perspective 89 regulatory aspects 93 skin phototypes 90, 91 SPF (sun protection factor) clinical relevance 90, 91 definition 89, 90 ultraviolet radiation spectrum bands 88, 89 vitamin D synthesis effects 93

Subject Index

Tandem repeated irritant test (TRIT) biogenic amines 113, 114 cold studies 116 disinfectants 113 fruit acids 113 irritant interactions 112 mechanical irritation 114 prospects 118 protective cream testing electrical capacitance 116, 118 technique 114, 115 transepithelial water loss 115, 116 rationale 111, 112 solvents 112 warm airflow studies 114 Training, skin protection implementation contents 166, 167 examples 168, 169 goals 165, 166 importance 161, 162 regulatory aspects 162, 163 theory action 165 contemplation 164, 165 precontemplation 164 preparation 165 ‘social-cognitive process model’ 163, 164 Transepithelial water loss (TEWL) baker apprentice study, of hand dermatitis prevention 144, 145 tandem repeated irritant test 115, 116 Ultraviolet radiation, see also Sunscreen hardening effects in hand dermatitis prevention 139, 140, 143, 146, 147 spectrum bands 88, 89 Urushiol, protective creams 64–66 Vehicles, see Galenicals Vitamin D, sunscreen effects on synthesis 93 Vitamin E, skin cancer prevention studies 96

182

Skin Protection: Practical Applications in the Occupational Setting (Current Problems in Dermatology Vol 34)

Biofunctional Textiles And the Skin (Current Problems in Dermatology)

Environmental Factors in Skin Disease (Current Problems in Dermatology Vol 35)

Telemedicine and Teledermatology (Current Problems in Dermatology Vol 32)

Management of Leg Ulcers (Current Problems in Dermatology Vol 27)

Safety Assessment of Cosmetics in Europe (Current Problems in Dermatology)

Oxidants and Antioxidants in Cutaneous Biology (Current Problems in Dermatology)

Ethnic Dermatology: Clinical Problems and Skin Pigmentation

Lyme Borreliosis: Biological and Clinical Aspects (Current Problems in Dermatology)

The Foot: Problems in Podiatry and Dermatology

Current Topics in Developmental Biology, Volume 34

Dermatology for Skin of Color

Practical Equine Dermatology

Practical Immunopathology of the Skin (Current Clinical Pathology)

Practical Occupational Medicine

Innovative Techniques in Skin Surgery (Basic and Clinical Dermatology)

Skin in the Game

Primary Care of Musculoskeletal Problems in the Outpatient Setting

Dermatology in Clinical Practice

Laser Dermatology: Pearls and Problems

Prescribing in Dermatology

Telemedicine in Dermatology

Antioxidants in food: practical applications

Antioxidants in Foods: Practical Applications

Antioxidants in food: practical applications

Antioxidants in Foods: Practical Applications

Photodynamic Therapy in Dermatology

Vitamin D in Dermatology

Topics in Current Chemistry (vol. 168)

Topics in Current Chemistry (vol 155)

Ichthyoses: Clinical, Biochemical, Pathogenic and Diagnostic Assessment (Current Problems in Dermatology)

Skin Protection: Practical Applications in the Occupational Setting (Current Problems in Dermatology Vol 34)

Biofunctional Textiles And the Skin (Current Problems in Dermatology)

Environmental Factors in Skin Disease (Current Problems in Dermatology Vol 35)

Telemedicine and Teledermatology (Current Problems in Dermatology Vol 32)

Management of Leg Ulcers (Current Problems in Dermatology Vol 27)

Safety Assessment of Cosmetics in Europe (Current Problems in Dermatology)

Oxidants and Antioxidants in Cutaneous Biology (Current Problems in Dermatology)

Ethnic Dermatology: Clinical Problems and Skin Pigmentation

Lyme Borreliosis: Biological and Clinical Aspects (Current Problems in Dermatology)

The Foot: Problems in Podiatry and Dermatology

Current Topics in Developmental Biology, Volume 34

Dermatology for Skin of Color

Practical Equine Dermatology

Practical Immunopathology of the Skin (Current Clinical Pathology)

Practical Occupational Medicine

Innovative Techniques in Skin Surgery (Basic and Clinical Dermatology)

Skin in the Game

Primary Care of Musculoskeletal Problems in the Outpatient Setting

Dermatology in Clinical Practice

Laser Dermatology: Pearls and Problems

Prescribing in Dermatology

Telemedicine in Dermatology

Antioxidants in food: practical applications

Antioxidants in Foods: Practical Applications

Antioxidants in food: practical applications

Antioxidants in Foods: Practical Applications

Photodynamic Therapy in Dermatology

Vitamin D in Dermatology

Topics in Current Chemistry (vol. 168)

Topics in Current Chemistry (vol 155)

Ichthyoses: Clinical, Biochemical, Pathogenic and Diagnostic Assessment (Current Problems in Dermatology)

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