Skin problems related to Indonesian leather & shoe production and the use of footwear in Indonesia Febriana, Sri Awalia

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1 University of Groningen Skin problems related to Indonesian leather & shoe production and the use of footwear in Indonesia Febriana, Sri Awalia IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2015 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Febriana, S. A. (2015). Skin problems related to Indonesian leather & shoe production and the use of footwear in Indonesia [Groningen]: Rijksuniversiteit Groningen Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date:

2 Skin Problems related to Indonesian Leather & Shoe Production and the use of Footwear in Indonesia Sri Awalia Febriana

3 ISBN : (printed version) ISBN : (e-version) S.A. Febriana, Groningen, The Netherlands s.a.febriana@umcg.nl awalia_febriana@ugm.ac.id All right reserved. No part of this thesis may be reproduced, stored in a retrieval system or transmitted in any form by any means, without permission from the author. Financial support for the publication of this thesis was provided by the Directorate General of Higher Education (DIKTI) Ministry of Education, Republic of Indonesia. Printing of the thesis was financially supported by the Research Institute for Health Research (SHARE), Graduate School of Medical Science. Cover design Photograph Lay out Printing : Obos Pramutya, Den Haag, The Netherlands : Surahyo Sumarsono and Piet Tonder, Groningen, The Netherlands : Aris Winarna, Yogyakarta, Indonesia : GVO drukkers & vormgevers B.V., Ede. The Netherlands Cover story: Photographs in the cover are the traditional shoe workers in Manding Yogyakarta, Indonesia and Leather produced by Indonesian tannery where our projects took place. In the background, there is a Batik in English literally defective big knife, is a traditional batik pattern from Yogyakarta. It is visualized as many defective parang (big knife) with diagonally format Indonesian batik patterns and designs, which refers to the attitude of the human perspective on the environmental landscape and life, expressed in forms stellar. This design was created by Sultan Agung of Mataram ( ) after a meditation on the South coast of Java. That said, inspiration comes from the phenomenon of large waves that break up rock and ruin.

4 Skin Problems related to Indonesian Leather & Shoe Production and the use of Footwear in Indonesia PhD Thesis to obtain the degree of PhD at the University of Groningen on the authority of the Rector Magnificus Prof. E. Sterken and in accordance with decision by the College of Deans This thesis will be defended in public on Monday anuary at. hours by Sri Awalia Febriana born on ebruary in Yogyakarta, Indonesia

5 Promotor : Prof. dr. P.J. Coenraads Prof. dr. H. Soebono Copromotor : Dr. M.L.A. Schuttelaar Beoordelingscommissie : Prof. dr. M. Bruze Prof. dr. T. Rustemeyer Prof. dr. D. Koh

6 Dedicated to The health of workers in Indonesia and other Newly Industrialized Countries Mas Yayok, my husband, best friend and great companion Keisha and Katya, the loves of my life

7 Paranymphs : Laura Bijkersma-Pot Astri Ferdiana

8 Contents Chapter 1 Introduction 9 Chapter 2 Chapter 3 Chapter 4 Chapter 5 Chapter 6 Chapter 7 Chapter 8 Inventory of the chemicals and the exposure of the workers skin to these at two leather factories in Indonesia Occupational allergic contact dermatitis and patch test results of leather workers at two Indonesian tanneries Occupational contact allergy caused by benzidine in three tannery workers Occupational skin hazards and prevalence of occupational skin diseases in shoe manufacturing workers in Indonesia Occupational allergic contact dermatitis and patch test results in Indonesian shoe factory workers Contact allergy in Indonesian patients with foot eczema attributed to shoes Thin layer chromatography (TLC) and gaschromatography-mass spectrometry (GCMS) examination of footwear materials from patients with shoe dermatitis Chapter 9 General discussion and future perspective 152 Chapter 10 Summary 177 Appendices Acknowledgments 190 Publications 198 Curriculum Vitae 200

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10 CHAPTER 1 Introduction Sri Awalia Febriana Department of Dermatology & Venereology, Gadjah Mada University, Yogyakarta, Indonesia Department of Dermatology, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands.

11 Introduction 1 10 The leather manufacturing industry as a whole has become the backbone of Indonesian export. 1, 2 Between January and September of 2013 its total annual export of leather and leather products was worth 163,605,136 US dollars 3, 4 and 6,500 workers were employed in medium and large factories. 5 Indonesian tanneries have been producing leather not only for domestic use but also for Europe, the United States, Australia, and Asia. Indonesia's footwear industry in particular has a long history. In the 1940s footwear manufacture for the foreign market began with the opening of a Czech factory, and the late 1960s marked the beginning of production for the domestic market. Since then Indonesia's footwear industry has continued to grow, and in various industrial locations throughout the country a broad variety of products are currently being manufactured for the market both at home and abroad. 6 According to SATRA (Shoes and Allied Trades Research Association, UK) Indonesia, along with the other leading countries in shoe production, produced 75.2% of 12.5 billion pairs of shoes manufactured worldwide in In 2008 the Indonesian footwear industry alone was producing 131 million pairs of shoes a year. 6 From January to September 2013 Indonesian footwear export was worth million US dollars 3, 4 and in the medium and large shoe industry alone 202,189 workers were employed, as well as millions of workers in other related industries. 5 If we consider the huge production in the leather and shoe manufacturing sector in Indonesia, the number of workers employed, and the associated skin hazards described below, it is clear that the burden of occupational skin diseases in this sector must be high. The manufacture of leather and shoes causes prolonged exposure of factory workers to many potent chemical irritants and sensitizers. During leather manufacture, employees working on various stages of leather preparation (including pre-treatment with water and lime as well as the processes of pre-tanning, tanning and finishing) come into contact with chemicals designed to alter the structure of animal hides. 2, 8-13 The workers are exposed to numerous materials such as leather, rubber, dyes, preservatives, and shoe adhesives (neoprene, epoxy resin and rubber glues) containing a broad spectrum of allergens Because of their exposure to these environmental hazards, together with very limited use of personal protective equipment (PPE), leather- and shoe-factory workers are prone to occupation-related skin problems.

12 Occupational skin diseases are those arising during occupational activity. These diseases, currently increasing in prevalence, are of great socioeconomic importance. Not only do they have major consequences for the affected patients and their families, but the annual cost to health insurance companies is equal to or even greater than that of other chronic inflammatory skin diseases like psoriasis and eczema. 15 In the USA the average annual cost per claim of Occupational Skin Disease was $3,552 and the average disability time 23.9 days. 16 In Germany, the annual cost to health insurance companies for each case of occupational hand eczema is about Epidemiological studies of occupational skin diseases (OSD) among leather factory workers in Europe were reported some decades ago in Sweden 18, and in 1996 an epidemiological study was made of occupational contact dermatitis (OCD) in Italian shoe factory workers. 14 The fact that no recent reports on this subject have been made may be the result of the more current outsourcing of leather and shoe manufacturing to Newly Industrialized Countries (NICs). Low labour costs, easy supply of raw materials, and a tradition of making shoes have been reasons for moving leather and shoe manufacturing industries to NICs. Another important issue is many industries in developed countries search for the countries t t o ta u at o o o a a o ut o a ot. 19 As a result, these countries are being burdened with the effects of hazardous industrial production processes. These conditions, in which workers are protected neither by their national regulatory frameworks nor provisions for a safe environment, places them under the tremendous hardship of work-related morbidity and mortality. 20 The problem of occupational diseases among tannery workers in Newly Industrialized Countries has been discussed in a few studies made in Argentina, India and Korea. 8-10, 21, 22 Studies related specifically to the shoe industry have been done in India, Thailand, and Poland. However, few of the published studies have focused on the kind of exposure, the potential sources of chemical and physical hazards, and the actual prevalence of occupational skin diseases in workers in these industries. Although in a quite different situation, patients who get shoe dermatitis because of conditions inside the shoe like occlusion and sweat have an exposure similar to that of shoe manufacturing workers For many hours every day, shoe consumers enclose their feet with materials like leather, plastic, rubber, cloth and shoe adhesive, all containing hundreds of chemicals. 28, 29 Different chemicals, combined with a hot and humid environment within the shoes, provide the perfect situation for the development of allergic contact dermatitis. 30 Additional factors like heat,

13 1 12 pressure and friction, together with standing and movement, can increase the development of skin sensitivity. 28 Evidence showed that there is an impressive change in the allergens producing contact dermatitis of the feet Unfortunately there are to date very few studies on shoe dermatitis and patterns of sensitivity to chemicals in footwear. Occupational Contact Dermatitis What is Occupational Contact Dermatitis and the burden of this kind of disease? Occupational skin disease is a pathological condition of the skin for which occupational exposure can be shown to be a major causal or contributory factor. 34 Occupational contact dermatitis ranks among the top three workrelated diseases; in all instances the diagnosis is allergic or irritant contact dermatitis or a combination of both. It is a reaction characterised by inflammation as a result of contact of the skin with substances found in the workplace In the pathogenesis of contact dermatitis, irritants and allergens are interwoven and endogenous and environmental factors are often involved as well. 36, 38 Occupational contact dermatitis constitutes over 90 95% of the wider spectrum of occupational skin diseases 36, not including chemical leukoderma, oil acne or chloracne, neoplasma, infections and infestation. 39 Occupational contact dermatitis is a common reaction of the skin due to contact with a number of chemical agents; it is a significant public health issue and considered to be the main cause of occupational dermatitis. Significant numbers of individuals are exposed every day to a variety of products which may provoke the development of OCD. This affliction, characterised by extreme itching, leads to many restrictions in daily life as well as loss of sleep and potential loss of income due to absenteeism and costs of treatment. Moreover, new products with new chemical components are constantly being launched into the market, exposing both workers and consumers to their possible ill effects. These facts point to the need for expertise in risk assessment as well as continual and adequate surveillance and diagnosis of individual patients Epidemiology of occupational contact dermatitis The average incidence of registered OCD in some countries lies between 0.5 and 1.9 cases per 1000 full-time workers per year 42 and is regarded as one of the leading causes of occupational morbidity and absenteeism. 44 The ascertained prevalence of occupational contact dermatitis may vary depending on differences in case definition. This definition can further vary

14 according to whether it is based on employer reporting, employee selfreporting, skin patch test results, workers compensation claims, or clinical diagnosis. 36, Some countries require mandatory notification of potential cases of OCD; this yields a high reporting rate but increases the possibility that non workrelated dermatitis may be included. Such reporting methods, however, do typically employ a consistent system of assessment. In all of three countries (Denmark, Finland and Germany) having compulsory national registration the incidence of reported cases was similar, with rates of five to eight cases per 10,000 workers per year There was a tendency for incidence to decrease with time: 10.7 per 10,000 workers in as compared with 4.9 per 10,000 workers in The Danish Register of Occupational Diseases reported an incidence of eight cases per 10,000 workers per year. 52 By contrast, the incidence rates registered by self reporting are variable The Netherlands reported considerably higher rates (15 per 10,000) 53 than did the UK (1.3 per 10,000) 54 or Australia (2.2 per 10,000) 55. The highest rates of occupational skin diseases were reported in population studies that relied on self-reporting Pathomechanism of contact dermatitis Contact dermatitis is a common inflammatory disorder of the skin induced by repeated exposure to irritants (irritant contact dermatitis) or allergens (allergic contact dermatitis). Even though it is clinically possible to differentiate between these diseases, they have significant similarities of clinical manifestation, histological and imunohistopathology features and molecular patterns. In both ACD and ICD the cascade of inflammation produced by epidermal and dermal cell activity appears to be similar and related. 56 Considering the strong similarity between both types of contact dermatitis, the important question arises: how to differentiate between skin irritation and skin allergy? The important difference is in the pathophysiological mechanism, involving allergen specific T-cells in the development of allergic contact dermatitis. Both types of contact dermatitis involve cell immunity, but ICD follows the activation of innate immunity whereas ACD is the result of the activation of acquired immunity and the induction of specific pro-inflamatory T-cell effectors. 56 The pathophysiology of contact sensitization consists of a sensitization phase and an elicitation phase. The sensitization phase begins with the person's first contact with the allergen and continues until he is sensitized and competent to generate a positive ACD reaction; this phase takes 4 days

15 to several weeks. The elicitation phase begins upon elicitation and continues until the clinical manifestation of ACD, which is fully developed in 1-4 days Clinical features and symptoms of occupational contact dermatitis Contact dermatitis can be acute, chronic or intermediate and there are no completely specific clinical features and symptoms for ACD or ICD. Acute dermatitis usually presents as papules, and occasionally as vesicles or bullae. 57 A histological characteristic of acute eczematous reactions is spongiosis of the epidermis, which leads to the formation of vesicles and bullae which can appear in both allergic and irritant contact dermatitis. 58 By continual contact with suspected substances chronic contact dermatitis may develop, with clinical characteristics like pruritus, lichenification, erythema, scaling, fissures and excoriation. 57 A nice example of the distinction between ACD and ICD can be made on the is placed onto the skin and occluded, erythema and slight infiltration occur, strictly limited to the patch test area. However, with substances capable of provoking an allergic reaction there is a markedly pruritic, infiltrated, popular or vesicular reaction that extends beyond the borders of the occlusion chamber. This happens when the amount of substance needed to elicit an allergic reaction is less than the amount necessary to elicit an irritant reaction. Recruitment of particularly sensitized cells and the release of non-specific cytokines facilitate an allergenic response outside the area of direct contact. 57 In occupational contact dermatitis, slow improvement seems to occur after a patient spends several consecutive days away from the workplace; symptoms fade during long vacation periods and recur promptly upon resumption of work. 35, 42, 59 Pruritus is the hallmark symptom of occupational contact dermatitis, but is marked by great variety in onset and intensity. An atopic dermatitis background can make pruritus worse, affecting the daily life of patients with irritant contact dermatitis. Milder symptoms like stinging sensations can appear, but these are not general symptoms of the irritancy. 60 Detailed description of symptoms can be helpful in differentiating between contact dermatitis and other dermatoses. 57

16 Diagnosis of occupational contact dermatitis Establishment of the diagnosis of occupational contact dermatitis is quite complicated since there are no specific clinical and histopathological characteristics. 37 Diagnosis of OCD involves two fundamental steps: 1) recognizing the existence of an occupational exposure and 2) assessing whether that exposure represents a cause or substantial aggravating factor in the patient s dermatitis. Usually, OCD improves when the patient is off work for more than a week and intensifies when work is resumed. To reach an accurate diagnosis, the dermatologist relies on comprehensive history taking, thorough skin examination and skin testing. A workplace visit is also included to gain important information in the investigation of suspected occupational dermatitis To arrive at an accurate diagnosis of OCD it is vital that the physicians involved have an adequate level of knowledge and skill as well as experience in this field. Moreover, it is important and often difficult to be able to confirm the relationship between OCD and a patient's exposure. Screening of the complete study population by one or more trained dermatologists using standardized criteria is the most reliable and therefore preferred method. 36 Mathias proposed 7 criteria for establishing occupational causation and aggravation of contact dermatitis 62 : 1) Is the clinical appearance consistent with contact dermatitis? 2) Are there workplace exposures to potential cutaneous irritants or allergens? 3) Is the anatomic distribution of dermatitis consistent with the form of cutaneous exposure in relation to the job task? 4) Is the temporal relationship between exposure and onset consistent with contact dermatitis? 5) Are non-occupational exposures likely as causes? 6) Does avoiding exposure lead to improvement of the dermatitis? and 7) do patch test or provocation tests implicate a specific workplace exposure? 63 The validity of these criteria was assessed by Ingber and Merims. 64 From a different angle, Rycroft et al (1996) stated that the clinical assessment of dermatitis in the workplace is based on four considerations: dermatitis and not atopic, seborrhoeic, discoid, stasis, or unclassified eczema; 3) Is it irritant contact dermatitis or allergic dermatitis and As mentioned by Mathias under point 3, the anatomical distribution and the type of skin lesion must be consistent with the nature of exposure. Nicholson calls attention to several more points, namely whether personal

17 1 16 protective equipment was used by workers (and used in a recommended manner), workers' behaviour, and the physical form of the hazardous substances. 43, 61 In relation to the latter, for example, contact dermatitis due to solid particles shows skin lesions with well-defined borders on the areas of exposure. Contact dermatitis caused by gases, fumes and vapours affects mainly exposed areas such as the face and eyelids, whereas dust or airborne substances can cause contact dermatitis in areas both exposed and underneath the clothing. Contact dermatitis due to liquid substances predominantly affects the dorsal aspect of the hands and fingers, finger webs and forearms. These facts illustrate that the clinical appearance of OCD can be intricate, and to diagnose it requires a systematic and thorough approach. 61 A comprehensive clinical history, skin examination and appropriate patch testing are essential for differentiating between Irritant Contact Dermatitis (ICD) and Allergic Contact Dermatitis (ACD). 35, 65 In spite of negative patch test results, for example, OICD may nonetheless be indicated if there is a temporal relationship with exposure to the irritant at work. 43 Moreover, OICD is generally confined to the area in contact with the irritant, whereas OACD may present a more widespread rash. In general, both OICD and OACD improve when the patient is off work for more than a week and intensify when the patient returns to work. However, when exposure is discontinued OACD improves more slowly than OICD and recurs more quickly, within a few days after returning to work. Cumulative irritant contact dermatitis, on the other hand, usually recurs gradually within days or weeks when exposure is resumed and is clinically indistinguishable from ACD. We must be extremely careful in our interpretation of all of the above facts because of the presence of so many confounding factors. 18, 61 There are 9 points to be considered in the assessment of occupational allergic contact dermatitis (OACD), as follows: 1) history of occupational exposure; 2) amount of time between occupational exposure and the actual onset of dermatitis; 3) patterns of the dermatitis consistent with occupational exposure; 4) positive patch test with appropriate vehicle and concentration; 5) repetition of patch test when excited skin syndrome is suspected; 6) positive Repeat Open Application Test (ROAT) to determine clinical relevance; 7) application, where needed, of serial dilutions of the tested chemical; 8) review of control for non-irritating concentrations and performance of a special (not commonly used) test for allergens; 9) clearing of dermatitis when allergen is removed or exposure is significantly decreased. 61, 66 The criteria for occupational allergic contact dermatitis based on the Danish study are: 1) positive patch test reaction to a

18 substance present at the workplace; 2) skin contact with the substance on the relevant skin area; 3) sufficient exposure intensity and duration to explain the dermatitis. 67, 68 Workplace survey and inspection Survey and inspection of the workplace are crucial 69 ; identification of hazards in the worker s environment is an essential step in diagnostic procedure 61 and should be carried out with several aims in mind: 1) to assess the risks in the workplace that could cause health damage; 2) to review previous risk assessments and controls that have been introduced and ensure that this is still being done properly; 3) to investigate further aspects of the environment where a person has suffered from occupational skin disease Two things are essential in workplace surveys and inspection: 1) the working process must be observed while actually in process, and 2) the observer must have enough time to observe the plant thoroughly. 37, 62, 69 Detailed information that must be acquired during the working process includes: 1) organization of the factory; 2) demographic data (number of workers and shift patterns); 3) technical notes on the working process (how the work is carried out; potential irritants and sensitizers to which workers are exposed and their degree and extent of skin contact); 4) preventive measures (broad impression of working conditions, protective installations and protective personal measures); 5) workers' skin complaints and clinical assessment; 6) epidemiological evaluation to estimate the frequency of occupational dermatoses; 7) etiological evaluation; and 8) summary of findings and recommendations for future investigation. 37, 62, 70 Sources of information on exposure to contact allergens All chemicals, whether or not they are responsible for ICD or ACD, could be regarded as irritants when present in concentrations high enough to induce irritation. Allergens are chemicals which behave as haptens. Some studies have shown that thorough investigation of exposure to contact allergens is beneficial for the prevention, treatment, and prognosis of patients with allergic contact dermatitis Exposure information can be acquired from different sources such as: 1) publications; 2) product labelling and declarations; 3) material safety data sheets (MSDS); 4) inquiries to manufacturers or suppliers; 5) chemical analysis and product databases; and 6) Online data bases and sources of information. 68, 74-76

19 1 18 Considering point 2 above, one of the best sources of information about the contents of chemical products (including the presence of contact allergens) should be product labelling and declarations, but unfortunately not all manufacturers confirm to the requirements for inclusion of all contents when labelling their products. Information about compounds added to materials is sometimes not stated in the declaration. 73 According to European regulations on the classification, labelling and packaging of substances and mixtures (Regulation EC No 1272/2008), for example, sensitizers are substances which after an initial exposure may provoke an allergic skin reaction (skin sensitizer); those have code R43- may cause redness and inflammation of the skin, but generally heal within a short period of time, have code R38. This code should be mentioned on labels, but is often omitted. A further complication is that consumers and physicians need to have sufficient knowledge to read and understand chemical names. Material safety data sheets (MSDS) explain the hazards of all chemicals produced, distributed, or used in a workplace. They also provide safe procedures for handling or working with the substances and include information such as physical data, toxicity, health effects, first aid, reactivity, storage, disposal, protective equipment, and spill-handling procedures. MSDS formats can vary from source to source between countries, depending on national requirements. 73, 75 When a dermatologist is trying to determine whether a particular product or substance may be the cause of a particular case of occupational skin disease he will look first at the MSDS. 77 However, according to an Australian study, sensitizers are frequently omitted from the MSDS and clinicians are often unsuccessful in obtaining crucial information from manufacturers; as a result the MSDS is inadequate for the protection and diagnosis of workers with suspected OCD. 78 significant intrinsic skin irritation and sensitisation hazards. The MSDS users have three options while using MSDS: take the information at first value, ignore the information, or treat the information as a stimulus to undertake more detailed investigation followed by an analysis of the 77 Another way to acquire useful information about ingredients in chemical products is to make inquiries to manufacturers or suppliers. However, although some manufacturers are willing to provide prompt and detailed information on specific products, this is a time consuming and not always successful approach, as a supplier may not even have access to detailed information.

20 To stay abreast of the rapid changes in chemical exposure in the workplace and the development of personal protective equipment, web-based sources of information are becoming increasingly important. There are many recommended websites, including those of national institutes (e.g for occupational health and safety and health insurance); ministries of employment; societies of contact dermatitis, task forces, national research centres; and corporations in many European countries such as Germany, Great Britain, the Netherlands, Denmark and other Scandinavian countries, as well as Austria and the United States. These sites provide reliable data in terms of authenticity and accuracy, they are easy to access and they offer comprehensive information. This information includes facts about hazardous substances, a database of protective gloves for various kinds of exposure, a platform on skin protection, health and welfare service information on occupational skin diseases and their prevention, information about safe handling of hazardous substances, information on MSDS, a platform to raise awareness, patient information on skin testing, and the database of occupational allergens Patch test examination It is important to identify any offending allergen in order to remove it from the worker's environment; this can play a significant role in the worker's recovery and help to prevent new cases of disease. 43 The most essential tool for the study of allergic contact dermatitis is patch test examination. When one is diagnosing occupational allergic contact dermatitis it is necessary to identify a broad series of allergens including baseline series, series of specific occupational allergens, and materials to which patients are exposed in the workplace. 61 This is made possible by patch testing. In the diagnosis of allergic contact dermatitis, two steps are essential: 1) to demonstrate the connection of a contact allergy to one or several allergens, and 2) to demonstrate the clinical relevance of the reaction. In the first step, we have to assess the morphology of the reaction and decide whether the response represents a true- or a false-positive allergic reaction. If there is an indication of contact sensitivity to a defined allergen, we still have to demonstrate its relevance in the clinical situation. 79 To assess the clinical relevance of a positive patch test reaction, we need to know whether the responsible allergen is the primary cause or only an aggravating factor of the patient s dermatitis. An allergen is clinically relevant if we can establish that exposure has taken place and that the patient s dermatitis can be partially or totally linked to the exposure. 61, 80

21 1 20 In searching for offending allergens in the preparation of patch testing for patients we can use information from a variety of sources. Besides that obtained from patient interviews, we can obtain information from textbooks, journals, material safety data sheets (MSDS), workplace visits, and the MEDLINE Resources Guide. 73, 75 Misclassification can easily occur when it is (erroneously) assumed that the mere absence of a positive patch test reaction implies a diagnosis of ICD. A positive patch test reaction has to be assessed for its relevance. Occupational skin problems in the leather industry As stated above, leather factory workers are exposed every day for long periods of time to potentially sensitizing chemicals. 11, 12 They come into contact with irritant and allergenic products and extreme environmental conditions which make them more susceptible to developing occupational skin problems. Diseases of the skin were found to be caused by toxic, irritant or sensitizing chemical substances including acid burns due to sulphuric acid, chrome ulcers caused by trivalent chromium, and contact dermatitis caused by exposure to lime solution, chromate, solvents or dyes. 10 Some compounds (benzene-based dyes and formaldehyde) which are used in the tanning process are considered to be carcinogenic to humans. 8 Although there is a high risk in the leather industries, occupational skin diseases are rarely reported. Those reports which are available include five cross sectional studies published in India, Argentina and Korea. 8-10, 21, 22 Shukla, Ory and Rastogi conducted a study in Indian tanneries. Rastogi et al (2008) reported that 9% of male workers drawn randomly from 10 tanneries in India had skin rash and papules along with complaints of itching. 8 Shukla et al (1991) carried out a comprehensive occupational study in 20 tanneries in an Indian urban slum area. They did a walkthrough survey in the workplace to quantify occupational and safety hazards and Personal Protective Equipment (PPE) practices. 10 Ory reported that 23% of 418 labourers in Indian tanneries had dermatitis. 9 In addition, in Brazil, a study of 110 male tannery workers revealed that 40% of them had occupational skin lesions. 21 Although skin diseases were indeed noted in all of the studies above, the research was focused primarily on occupational health problems in general and not specifically on the prevalence of occupational skin diseases. However, Lee et al did conduct a study in a leather tannery which focused on occupational dermatoses (1991). Besides contact dermatitis, workers were found to have other occupational related skin diseases like calluses, paronychia, burns, physical traumas, vitiligo and oil acne. 22

22 The reported point prevalence of occupational skin disease among tannery workers in Newly Industrialized Countries is between 2.6 and 26.4%. 8-10, 21 The wide range of point prevalence figures between countries is probably caused by differences in the definition of cases, as well as differences in working conditions, periods of screening and data collecting. Occupational skin diseases in shoe manufacturing industry 1 21 Footwear is defined as any garment or piece of clothing worn over the feet for protection. Historically, footwear throughout the world has varied according to climate, environment, terrain and available raw materials. They also varied due to the influence of technology, fashion, and the development of local cultures; these are in turn also influenced by other cultures 6 Shoe manufacturing has been delocalized from developed countries to Newly Industrialized Countries, including Indonesia, for several reasons like cheap labour, availability of materials, and ecological issues. 7 A great variety of materials are used in the production of shoes. Shoe uppers can be made from leather, rubber, or synthetic materials such as polyurethane and neoprene foam. 12, 13, 29 Outer and inner soles are made of rubber, polyurethane, polyvinylchloride or a combination of ethyl vinyl acetate and rubber polymers. Many kinds of adhesives like urethane, neoprene, hot melt, and natural rubber are used for different parts of the shoes, and to retain the shoe's shape, heel- and toe-stiffeners or counters are added. 13, 81 In shoe factories the various parts of the shoes are prepared and assembled. During the preparation process workers are cutting and edging shoe uppers, soles, insoles, quarters and linings. Workers are also priming, washing, gluing and sewing to assemble the various parts of the shoes. During the last steps in the finishing and packing department, workers are cleaning the shoes, trimming, adding waterproofing agents and packing the shoes for shipping As is true of the leather industry, the shoe manufacturing industry also exposes workers to many potential physical and chemical hazards. A number of epidemiological studies show a significant relationship between physical and chemical exposure during footwear manufacturing and adverse health effects, especially occupational skin diseases. 82, 83 The irritant activity of adhesives and solvents used in the production cycle and the sensitizing activity of allergens contained in adhesive, leather, rubber and dyes are well known. 12, 14, 29, 82 According to an epidemiological study in 5 Italian shoe factories between 1992 and 1994, 14.6% workers suffered

23 from occupational contact dermatitis; 6% had hyperkeratosis of the fingertips and 3.2% had pruritus sine materia Epidemiological studies on occupational health problems have been published on shoe manufacturing workers in Newly Industrialized Countries like India, Thailand and Portugal. 82, 83 However, the presence of occupational skin disease was mentioned only in the case of one shoe manufacturing worker in Thailand (13.6%). 83 As described in the first paragraph of this chapter, shoe manufacturing in Indonesia is an industrial sector that is increasing in response to a growing demand. The industry is labour intensive and concentrated in the small village industry for in-country production and in large scale units for export products. Indonesia is the largest footwear exporter after China and Vietnam. 84 Despite the significant number of workers in shoe manufacturing in Indonesia, there is still no published study on the actual risk and prevalence of occupational skin diseases in this industry. Shoe dermatitis Prior to 1940 shoe dermatitis was considered a dermatologic curiosity. We refer here to allergic contact dermatitis of the feet with a prevalence range from % of all cases presenting in a patch test clinic , 85, 86 In daily practice, patients are sometimes sceptical about their physicians' diagnosis that shoes may be responsible for their eczema. 87 Conversely, many patients attribute their foot eczema to a contact allergy to their shoes. Feet have specific anatomical features with the highest concentration of eccrine sweat glands in the plantar area, and in combination with the wearing of shoes this can increase maceration and enhance the absorption of chemicals; this creates an environment which favours the development of allergic contact dermatitis. 31, 88 Daily for many hours or intermittently for months or years and often under extreme conditions of temperature, humidity, barometric pressure and physical disturbances. 28, 89 We enclose our feet with leather, plastic, rubber, cloth and adhesives containing hundreds of chemicals. Skin contact with these chemicals, in combination with accumulation of sweat, produces hydration of the stratum corneum, and the heat, pressure, and friction accompanying movement and standing promote the development of sensitivity. 27, 28 Epidemiology of shoe dermatitis According to statistics available from patch test clinics, the prevalence of allergies due to shoe materials ranges from % , 85, 86 Epstein (1969) 90 documented 43 cases of shoe dermatitis over a period of 5 years;

24 Angelini (1980) 23 reported 108 positive cases over 4,5 years and Bajaj (1991) observed 1 case of shoe dermatitis every 2 weeks in the Dermatology Outpatient Clinic in Allahabad, India. 24 A review of admissions to the dermatology section of the Veterans Administration Hospital in the Bronx, New York for the five year period , revealed that approximately 1.9% of 2,243 admissions were due to dermatitis venenata caused by shoes The highest prevalences of shoe dermatitis have been recorded in warm climates. 30, 85, 86 According to a study of India 92 and Pakistan 30, 86, in tropical countries high temperatures and humidity combined with the large number of chemicals involved in shoe manufacturing, as well as the uncommon use of socks during summer and the rainy season, make shoe dermatitis a frequent phenomenon. There was, however, no correlation between the length of time that shoes were worn and the appearance of the dermatitis. 91 A predominance of shoe dermatitis among females was reported in studies in Belgium by Nardelli et al (female: male ratio (7:3)) 93, in India (6:4) 85, and in Pakistan (8:2) 30 but these differ from other studies which show equal incidences of shoe dermatitis in both genders. 25 In fact, a male predominance was reported in Spanish children with shoe dermatitis (male: female, ratio 8:2) 32 and in a Kansas study (7:3). 94 The differences in prevalence of shoe dermatitis in many publications appear to be due to differences in the study population or the design of the study: whether it was a case-control, cross sectional or follow-up study, or one using case ascertainment. 48 Many publications measure the prevalence of shoe dermatitis based on the number of cases with a positive patch test taken from all patients tested in a large clinic. 94, 95 Clinical features The clinical characteristic of shoe contact dermatitis is a rash limited to the dorsa of the foot. 90 The eruption tends to be bilateral and symmetrical, and its pattern can correspond with the shoe design. Redness may occur in the affected skin, which may vesiculate or remain dry and scaly. Secondary infection results in swelling, tenderness and pus formation. 28, 87, 90 There are two clinical patterns of shoe dermatitis: 1) hyperkeratotic lesions, usually caused by hypersensitivity to rubber soles, and 2) erythematous and/or scaly lesions on the dorsum of the feet, usually caused by sensitivity to chrome used in leather tanning and resins used in adhesive and synthetic leather. Most patients have dermatitis of the ante dorsal portion of the foot. The dermatitis usually starts on the dorsal

25 1 24 surface of the big toe as mild erythema with scaling, gradually became vesiculated, and at the same time showed a tendency to involve the back of the adjoining toe. In some cases the dermatitis remains localized to these areas; in others there is gradual involvement of the distal half of the dorsum of the foot; in still other cases the interdigital webs were also involved, spreading in a few cases to the plantar surface. The dermatitis either remains unilateral or involved the dorsal surface of the other foot in a similar fashion. In some cases the involvement of the second foot is almost simultaneous but in others it occurred after weeks and even months. When the involvement becomes extensive, the clinical picture is that of an intensely erythematous, exudative process covering the entire anterior half of one or both feet, usually only the dorsal surfaces but sometimes extending to the soles. The involved areas are macerated, denuded, oedematous, and secondarily infected. 91 Secondary infection results in swelling, tenderness and pus formation. In developing countries, the feet are the dirtiest parts of the body and understandably the dermatitis of the feet is often infected. 96 Occasionally the hands are also affected as a result of handling the shoes. 28 The design of the footwear determines to a large extent the appearance of the shoe dermatitis. Sandals may cause an eruption at one or more of the spaces between the toes and especially under straps over the instep and around the ankles. In patients with stocking dermatitis the skin lesions follow the figure of the stocking, involving the fossae poplitea and inner thigh in patients allergic to long stockings. 28 Employing only clinical criteria in diagnosis can be misleading since only two thirds of the patients had clinical characteristics of shoe contact dermatitis. A major diagnostic problem encountered in clinical practice is impetiginisation of the lesions, which often made dermatitis spread beyond the area of contact. Two other important factors that make the clinical features of shoe dermatitis atypical are previous medication and infection. Before consultation, the dermatitis is often treated with herbal concoctions, assorted medications and irritant soaps. Secondary sensitization to medicaments is not uncommon and often spreads the rash and produces atypical patterns. 96 Shoe dermatitis caused by rubber materials can have many kinds of skin lesions: amine antioxidants, especially IPPD, can cause acute and severe eczema; dermatitis caused by accelerators tends to be more subacute than chronic eczema and can also present as hyperkeratosis, purpura achromias and urticaria. 97 Leucoderma or achromia can be caused by the dispigmentary action of phenolic compounds sometimes used in footwear manufacture, such as the rubber antioxidant monobenzyl ether of

26 hydroquinone; it can also be caused by 4-tert-buthylphenol formaldehyde resin (PTBFR) used in neoprene rubber and synthetic leather. 27 There is also a purpuric eczematous type due to toxic capillaritis caused by sensitization to IPPD, an amine used as an antioxidant in black rubber manufacture. 27 Shoe dermatitis due to the mercaptobenzothiazole allergen can mimic palmo plantar psoriasis or pustular psoriasis. 98 Diagnosis and differential diagnosis 1 25 An accurate diagnosis of shoe dermatitis depends on history, clinical features, positive patch test reactions to shoe allergens and shoe materials, and the patient s ability to wear proper substitute shoes without dermatitis. 27, 99 A positive reaction to one or more of the known allergens in shoes is sufficient evidence for making a diagnosis of shoe dermatitis, unless the history and physical findings suggest otherwise. 28 The irritant/allergen can be dispersed by sweat, with the result that the original eruptions are submerged in a diffuse rash that can mimic any form of dermatitis. 87 Shoe dermatitis is often incorrectly diagnosed as a fungus infection, atopic eczema and sometimes plantar psoriasis, lichen planus and pustulosis plantaris, juvenile plantar dermatitis, and keratoderma plantaris should be considered. 27, 90 In contrast to a fungal infection, shoe dermatitis tends to be symmetrical, spares the webs of the toes and does not cause crumbling of the nails. Negative results after testing scraps of skin with potassium hydroxide and failure to respond to appropriate fungal infection treatment may well be the point at which shoes are first suspected. 87 In children with atopic dermatitis, the skin lesion could resemble subacute or chronic shoe dermatitis, and friction with the shoes could trigger an atopic condition. 28 Correct diagnosis of contact dermatitis can be achieved with thorough knowledge of the clinical features of skin reactions and various contactants. 57 A patient's medical history is also important when making a diagnosis of contact dermatitis. The family history of contact dermatitis seems to be less important than environmental factors, although heredity was found to be significant among twins with nickel contact allergy. 100 An established history of previous allergic contact dermatitis could indicate unintentional contact with the same haptens if there were an eruption of contact dermatitis episodes. 57 In the case of acute onset of shoe dermatitis it is useful to take a cautious history of a patient's exposure to contactants during the days previous to the skin eruptions. The sudden aggravation of chronic dermatitis or its recurrence over short intervals can help to establish its cause or aggravating factors.

27 Anatomical features of shoes/construction of the shoes 1 26 It is to be expected that the precise chemicals causing shoe dermatitis will vary depending on differences in countries, times and manufacturing techniques employed. 29, 32 Having detailed information on shoe construction and the substances involved in the manufacturing process is important for diagnosing and treating shoe allergy. 29 Ordinary shoes when cut lengthwise are seen to consist basically of two parts, upper and lower. The upper shoe consists of all parts above the sole which cover the upper and front parts of the foot. Shoe uppers include the vamp (front part of the shoe), the quarters (the side and back parts of the shoe) and shoe linings. Shoe uppers can be made from leather, synthetic leather, cotton and cotton fabrics. For many years shoes were made from chrome tanned leather, and later vegetable and synthetic leather were used for certain purposes. 28 Shoe counters were usually made of leather, but in women's shoes they were often made of polyethylene and fibreboards. Most shoes have linings to improve comfort and extend the lifespan of the shoes. Shoe lining is placed on the side part of the shoe around the vamp and quarter and may consist of leather, synthetic leather and/or fabrics. 28 Linings are usually impregnated with a fungicide to prevent mildew. The toe box is an important part of the shoe that protects the toes. 91 It was formerly made of leather or nitrocellulose resin but is currently composed more and more of plastic materials extruded between cotton fabrics. 28, 101 The lower part of the shoe or shoe sole consists of an inner sole, midsole and outer sole. The inner sole is usually made of leather and attached to the midsole with rubber adhesives. The midsole is made of a layer of fabric glued onto a mixture of ground cork and rubber or a rubber sheet. The inner sole covers the joint between the upper and the sole and attaches the upper to the lower components. The majorities of insole boards are made from cellulose and are treated with additives to prevent bacterial growth. The outer sole is the part of the sole that is exposed directly to the ground; it can be made of various types of materials like plastic, rubber, leather and wood. Some shoes are manufactured using two or more materials with different densities to provide softer and more flexible midsoles for comfort on the inside and durability on the outside. Heels and toe counters and durable shoes made from fibreboard and leather coating can contain rubber additives like mercaptobenzothiazole and thiurams. 101 Chemical substances causing shoe dermatitis Financial setbacks in the shoe industry in 1919 triggered the efforts of shoe manufacturers to find cheaper materials. Many kinds of bonded, laminated,

28 coated and impregnated fabrics and papers were introduced. Modern footwear has become a labyrinth of thousands of chemicals. 89 In a textbook published by Duhring in 1877, socks and shoe linings were considered to be the cause of foot dermatitis, and it was not until 1930, when patch testing began to be widely used by dermatologists, that shoes were found to be a cause of dermatitis. 28 In the early 1930s shoe dermatitis was caused mainly by shoe dye. By the late 1930s reports of dermatitis caused by shoe leather began to be common, and the blame fell on various substances involved in the tanning, finishing and dyeing of leather. In the 1940s many cases of shoe dermatitis were reported and attributed to various resins, fillers, plastics and rubber adhesives which were replacing dyes and leathers as sources of contact dermatitis. Gaul and Underwood investigated 160 cases of dermatitis arising from footwear. They patch tested all of these patients with various materials from their footwear, showing clearly the shift from leather and dye to other adhesive materials in shoes as sources of contact dermatitis. 89 Blank and Miller (1952), in their report of cases of contact foot dermatitis, emphasized the relevance of rubber adhesives in women s shoes Allergens causing sensitization in shoe dermatitis patients can be found in leather, rubber components, dyes, nickel, leather preservatives and shoe adhesives. 27 Chromium compounds have been found to be the predominant allergens in India 24, 85, 92, 103, 104 and European countries like Italy 23, Belgium 93, and the UK 105, and also, according to a multi-centre study, in Germany, Austria and Switzerland. 31 Rubber chemicals were found to be more important in Australia 25 and Pakistan 86, and also in North America, according to a study made by the North American Contact Dermatitis Group. 106 In a prospective study conducted in Lahore, Pakistan shoe adhesives were found to contain the most common allergens. 30 Rubber and rubber chemicals. Rubber and rubber allergens have in various publications been reported to be common sensitizers, varying greatly depending on the manufacturer and country of origin. Some rubber products contain multiple sensitizing agents to which patients may be allergic. 97 The most common rubber allergens are mercaptobenzothiazole 94, 107, 108, followed by thiurams, carbamate and PPDA derivatives. 29 Rubber allergens are also found in athletic shoes and canvas sneakers. Ethyl butyl thiourea was detected within inner soles of athletic sport shoes and identified as a causative allergen in 10 patients with severe shoe dermatitis. Ethyl butyl thiourea is a chemical accelerator in some neoprene (polychlorprene) rubber products. 109 This inner sole material is similar to that used in skin divers' wetsuits, which have also occasionally been

29 associated with contact allergic reactions. 109 In addition to thiourea, styrenated phenol has also been identified in athletic shoes. 110, In a series of case studies of 4 Canadian patients with shoe contact dermatitis attributed to canvas sneakers, all of them reacted to a thiuram mix as well as to pieces of their suspected shoes. Thiurams in the rubber parts of the shoes were first suspected to be causative. The website of the shoe manufacturer mentioned that the shoe was made from unvulcanized rubber soles attached to canvas fabrics. Chemical analyses did not confirm this and the soles did not contain thiurams and thiocarbamates. This discrepancy could have been explained by the presence of 2- benzothiazolyl-n, and n-diethylthiocarbamysulfide (BT-DEC), which have structures similar to those of thiurams and MBT, but these substances could also not be found during chemical analysis of the shoes. 112 Phenylenediamine derivates such as N-iso propyl-n-phenylphenyleneddiamine (IPPD), N-phenyl-n-cyclohexyl-p-phenylenediamine (CPPD), and N-dipheniyl p-phenylenediamine (DPPD) are the most important rubber antioxidants with respect to their sensitization capacity. These phenylenediamine derivatives are found in almost all black coloured rubber. 97 Rubber boots made of black or dark coloured rubber worn by Japanese farmers were proved to contain IPPD, causing shoe dermatitis in this population of workers. Para-phenylenediamine (PPD) is a widely used precursor in many processes. 113, 114 Sensitization to PPD in a 10-year period was diagnosed in 4% of patients tested. Most cases of contact allergy to PPD occur from contact with hair dye. 115 In the case of positive reactions to PPD in shoe dermatitis patients, it is possible that the PPD cross reacts with certain rubber additives; therefore PPD allergy could simply suggest rubber rather than dye sensitivity. In Iran, some soles of Maleki shoes were made from rubber tyres. A man with rubber dermatitis on his foot soles had a positive patch test reaction to PPD and it was thought that this could be due to his maleki shoes. Another highly sensitizing rubber antioxidant is monobenzyletherhydroquinone, which usually causes contact leukoderma. 116 In a case of rubber boot dermatitis, which affects the dorsum and the soles and spreads up the legs to the top edge of the boot, the skin lesions were erythematous with vesicles and sometimes with blisters and intense itchiness. The responsible allergens were rubber vulcanizing accelerators from mercapto and thiuram groups. 27

30 Leather. For many years shoe uppers were made only from chrome tanned leather, but recently many are re-tanned with vegetable or synthetic tanning agents to achieve special qualities. The first case of dermatitis of the feet caused by sensitization to leather shoes was reported by Bloch. 117 The most common exposure to chromium has been found in leather tannery workers. Leather chemists have shown that perspiration can chrome salts generally migrate by capillary action toward the outer surface of the leather. Chemical analysis of chrome-tanned upper leather which has been exposed to heavy perspiration shows a definitely lower percentage of chrome oxide than in identical shoes which have not been exposed. 99 During leather tanning processes with chrome, several chrome or hide proteins form a cross linking complex which is influenced by temperature, ph and concentration. Other masking agents which can be present are vegetable tanning agents. All of these conditions make the saturation of chrome on the leather surface variable. 118 Some chromium compounds have been known to be used as dyes for leather and synthetic leather Chromium has been found to be a main cause of dermatitis of the feet in India 92 as well as in Italy in the case of 165 Italian patients suspected of having shoe allergy over a 4.5 year periode. 23 Chromate was also revealed to be the most important allergen in the foot dermatitis of Spanish children. This could be due either to a lack of appropriate legislation governing the use of chromium in the leather tanning process, or to the use of sandals without socks at an early age. 32 On the other hand, an English study showed that of 64 patients with a leather allergy, only 9 reacted to potassium dichromate, and the point was made that in England vegetable tanned leather was the most common cause of the dermatitis. 119 Moreover, another study of British shoe dermatitis patients concluded that vegetable tanned leather is not always safer than chrome tanned leather after a number of patients showed a reaction to East Indian vegetable tanning agents. 87 Finally, sensitivity to potassium dichromate, considered to be an important allergen according to studies in dermatology clinics in Barcelona between 1972 and 1979, was found to decrease from 27.5% to 9% over a 14 year period. 27 Furthermore, there was also possible exposure to allergens from newly tanned leather such as formaldehyde, glutaraldehyde, azo dyes and substances used in leather finishing. 120 Formaldehyde is another important leather allergen used as a leather tanning agent along with chromium. 30 In Portugal one case of leather shoe dermatitis was reported, caused by colophonium which was most likely used as a leather additive or in the finishing process. 121

31 1 30 Plastic and synthetic leather. Plastic and synthetic leather materials are used as cheaper alternatives for leather materials. The appearance of artificial leather is so deceptive that even experienced people working in the factory have difficulty in differentiating between artificial and real leather in shoe linings. Substances found in plastic and synthetic leather are precursors such as polyvinyl chloride and polyurethane resin. The other allergens is dodecyl mercaptan an additive used in the plastic industry to arrest the polymerization process. The plastic parts of many of our shoes contain this additive. 122 Catalysts, hardeners and plasticizers such as triethylenediamine, 4,4 - diaminodiphenylmethane, or dibutyl tin, used in the production of polyurethanes, have not been reported as a problem in the shoe industry. This could be due to underreporting of these substances as causes of shoe dermatitis; therefore we must keep in mind all of these substances when dealing with unclear cases of shoe allergy. 120 Furthermore, nickel and cobalt in green plastic shoes have also been reported in some cases to be causes of shoe allergy. 29 Adhesives. Diverse parts of shoes are attached together with urethane, neoprene, natural rubber, and many other shoe adhesives. Shoe adhesive was first used in 1910 primarily to prevent shoes from squeaking. 89 A few years later white spirit or mineral spirits came to be used as solvents for shoe adhesives and polishes. Important allergens in shoe adhesives are: neoprene adhesives (p-tertbuthylphenol formaldehyde resin, dodecyl mercaptan, and other additives); urethane adhesives which contain additives such as isocyanates, epoxy resins, or phenol formaldehyde resins; polyurethane-based adhesives which contain triethylenediamine and diphenylmethane diisocyanate; epoxyresin based adhesives (phenyl glycidyl ether); and preservative (formaldehyde and colophony). 12, 27 P-tertiary-buthylphenol formaldehyde resin (PTBP F-R) is the most important allergen in shoe adhesives. 14, 29, 120, 120, 123 It is a resin made from PTBP and formaldehyde and added to certain neoprene based adhesives because of its instant tackifying capacity. PTBP F-R is used mainly in adhesives for leather products in watch and shoes and in do-it-yourself adhesives. The first cases of contact dermatitis due to PTBP F-R were reported by Malten (1958) in shoemakers in the Netherlands. 124 Later, among patients with shoe dermatitis admitted to the dermatology outpatient clinic in Barcelona, Spain there was increasing sensitivity to paratertiary buthylphenol formaldehyde resin, from 2% in 1979 to 16% in 1982 and 27% in In Ethiopia, PTBP-F-R was reported to be the

32 most common cause of contact allergy in all patients patch tested in dermatology clinics over a one year period. The widespread use of resin in leather glues and plastic shoes is suspected to be the cause of this condition. 125 A higher rate of positive patch test reactions to PTBP in females and the prevalence of foot dermatitis in a Nigerian study has been linked to frequent use of open shoes fastened with glue containing PTBP F- R, which easily leaches out onto the skin. 125 However, it is interesting that according to a study by Holden and Gawkrodger (2005), PTBP-F-R and other plastic and adhesive chemicals previously thought to be important turned out to be less significant. 105 Another allergen to consider is colophony, a tackifier present in neoprene adhesives,and usually used to glue shoe insoles and shoe linings Many additives such as isocyanates, epoxy resins, acrylics, or phenol formaldehyde resins are also present in shoe adhesives. 29 Dodecyl mercaptan and polyurethane are two resins found to be important shoe allergens in a Spanish study made around the 1970s. Researchers observed 45 typical shoe dermatitis cases with negative responses to standard shoe allergens. They visited several shoe factories to obtain 64 pure substances actually used in the Spanish shoe industry. Patch tests were carried out with all of these substances and there were 2 possible contact allergens were found, namely dodecyl mercaptan and polyurethane resin that had never been mentioned previously. They found that the plastic part of the patients' shoes contained dodecyl mercaptan, an additive used in the plastic industry to arrest the polymerization process. Also dodecyl mercaptan was usually added to neoprene, widely used as a shoe adhesive. 122 Shoe dye. Shoe dermatitis due to shoe dye is rarely encountered, except an allergy to re-dyed leather or shoes made of fabric. 121, 126 Hundreds of dyes are used in the leather tannery and the exact combination of dyes used remains a secret, but Bismarck brown, p-aminobenzene, and p- phenylenediamine (PPD) have been recommended for patch testing. It is important to take into account that several antioxidants can cross-react with PPD, and sensitization to this agent does not necessarily signify contact sensitivity to dye. 28 PPD itself is not actually used as a shoe colouring, but it often cross reacts with dyes used in shoes. The addition of PPD proved helpful in alerting us to certain possibilities. 99 It is also useful to consider metal salts such as nickel and cobalt, which are sometimes used as dyes or pigments in green plastic shoes for medical personnel. 127

33 1 32 Preservatives. Chloroacetamide is sometimes used between two consecutive processes in leather preparation as a preservative against mould in the leather. These chemicals should disappear during the washing process. 128 However, Jelen et al. reported shoe dermatitis caused by chloracetamide based on clinical features, history, and the confession of leather manufacturers that they had used this chemical in the leather manufacturing process. 128 In another case, that of a 34 year old female with allergy to wooden shoes, the patient was tested with pieces of her shoe materials. A strong positive reaction to the insole material appeared after 2 days. The manufacturer confirmed that the insole was made of wood pulp to which thiram was added as protection against fungi and other microorganisms. 101 Cloth linings and other parts of the shoe may contain anti mildew agents such as phenylmercuric compounds and phenolic-type germicidal agents including phenylphenols, salicylanilides and formaldehyde. 28 Patch test in shoe dermatitis patients Diagnosis of shoe dermatitis is challenging, as even the final assemblers never know all the ingredients of materials used in shoe production; nevertheless, detailed history taking and specific clinical findings can be helpful. 12, 29 A patient's working history together with activities and hobbies outside work should be comprehensively assessed. 29, 94 Positive patch test reactions using the screening tray are the most objective evidence and provide the most important diagnostic criteria for shoe dermatitis. 93 Identification of the allergens causing a shoe allergy can be done with patch testing during disease free intervals. 25, 94 Patch testing for shoe allergy is performed using chemicals from the European Baseline Series but also with other shoe chemicals present in an expanded shoe series, as well as with pieces taken from suspected shoes. 29 When the clinical picture strongly suggests shoe dermatitis but the patient does not react to any of the mat necessary to patch test with actual materials from the suspected shoe. 29, 30, 119 Without this last test the source of the allergens could be missed. The causative chemicals are thus identified by a thorough and systematic approach. However, patch testing reactions to a suspected shoe material may be negative even when patients have been correctly tested with their suspected shoes; this can happen because patch testing cannot exactly duplicate friction, sweating and other conditions occurring when shoes are worn. 90 To achieve the most accurate possible results from patch testing

34 with shoe materials requires the following steps: 1) sample shoe materials should be thin pieces of at least 1.5 square centimetres and less than 2 mm thick, moistened with saline; 2) occlusive test covering should be applied for 48 hours; 3) patch test materials should be removed at least 30 minutes before reading, and 4) delayed test readings should be performed after 48 and 72 hours. 90, 93 Shoe materials should be obtained from the parts corresponding to the areas of dermatitis by cutting the shoes or scraping the materials off with sharp blades if necessary. 90 Scrapings should be taken from the box toe, inner sole and heels in quantities sufficient to cover patches which have previously been moistened with warm water. 28 Contamination of shoe materials with an allergen to which the patient is sensitive may, however, result in false positive results in diagnosis. 90 When the suspected shoes have been worn for a certain time, each layer becomes impregnated with various chemicals from other layers, and thus a positive patch test reaction to a given section from the shoes does not necessarily mean that the allergens were originally present at that site Sometimes we find negative reactions to the patient s own shoes but positive reactions to the chemicals used in shoe manufacturing. Such indirect evidence of shoe dermatitis should be evaluated by focusing on the clinical features. 90 As mentioned above, patch testing cannot exactly duplicate friction, sweating and other conditions present when the shoes are worn. As a consequence, patch test results may still be negative even though a patient has been correctly tested with his suspected shoes. 90 Rationale, objectives and outline of the thesis Rationale As the overview above makes clear, although leather and shoe industries have existed for several decades in Indonesia and more than thousands of workers were involved in the medium and large Indonesian leather and shoe industry in the year 2013, occupational skin diseases in these factory workers have not been fully studied. An investigation into the hazardous chemicals and physical agents involved in this industry, and the related occupational skin diseases is thus highly relevant. Also, shoe dermatitis, a troublesome disease among leather and shoe consumers; needs further elucidation, as do the important allergens that have been unravelled as causes of these diseases. The rationale of the studies in this thesis is presented below: High cost of labour, workplace safety and environmental issues have forced leather and shoe companies in developed countries to outsource their work into newly industrialized countries including Indonesia.

35 The Indonesian leather and shoe industry is an industrial sector with growing demands, exporting product worth thousands of millions of US dollars to many countries worldwide and employing thousands of workers in medium and large scale industry Indonesian leather and shoe manufacturing workers are exposed daily to potentially hazardous chemical irritants and sensitizers which may provoke the development of occupational contact dermatitis; this in turn affects one s daily activities, causes sleep disturbances, and leads to potential loss of income due to absenteeism and expensive treatments. Only few truly and well design epidemiological studies on the actual risk and prevalence of occupational skin disease have been published, and there are few publications on the inventory of potential chemical hazards exposing the workers in leather and shoe industries. Shoes are made of a broad variety of materials such as leather, plastic, synthetic leathers, and rubber. Shoe designs and materials change rapidly, and detailed information as to the substances used in making the shoes is lacking. Shoe dermatitis is a common problem affecting leather and shoe consumers, one which still presents diagnostic and therapeutic challenges. An ideal approach for treating and diagnosing shoe dermatitis, including identifying causative allergens, requires a thorough knowledge and detailed information about shoe construction and the chemical allergens present in shoes and shoe processing. Skin oriented research in leather and shoe manufacturing processes can provide knowledge not only in the managing of occupational skin problems in the leather and shoe industry but also in the management of shoe dermatitis patients worldwide. Objectives and outline of the thesis The above mentioned rationale is the basis of the objectives of the studies in this thesis: 1) to investigate the nature of exposure and the occurrence of occupational skin diseases among workers in leather and shoe manufacturing circumstances in Indonesia as one of the NICs and 2) to investigate shoe dermatitis patients as consumers of leather and shoe industries and to identify the responsible allergens by focusing on the following topics: Chapter 2. Inventory of chemicals and skin exposure in two leather processing factories in Indonesia. We observed the working process and

36 made an inventory and risk assessment of all chemicals that used in the tannery. The chemicals were classified as potential sensitizers/irritants and qualitative assessments were made as to the level of exposure of the chemicals. Workers were examined and interviewed using the NOSQ- 2002/LONG questionnaire to determine the prevalence of occupational skin diseases. Chapter 3. Occupational allergic contact dermatitis and patch test results of leather workers at two Indonesian tanneries. Having been interviewed using the NOSQ-2002/LONG questionnaire, all workers in a production process were examined by dermatologist. Workers with a current or history of occupational skin diseases, and a sub-sample of healthy workers, were patch tested using the European baseline series, shoe series and additional allergens from the workplace Chapter 4. Occupational contact allergy caused by benzidine in three tannery workers. In the context of our ongoing study in leather factory, we noted that a few workers had a positive reaction to benzidine, which was used for many years as a dye but was banned in several countries in the 80s due to its carcinogenic effect. Chapter 5. Occupational skin hazards and prevalence of occupational skin diseases in shoe manufacturing workers in Indonesia. This is a cross sectional study on the workers with an observation of the working process and an inventory and risk assessment of exposure to the physical condition and potentially sensitizing/irritating chemicals. We made a qualitative assessment of these physical and chemicals hazards and their resulting effects on the skin. Workers were examined by dermatologists and interviewed using NOSQ-2002/LONG to determine the prevalence of occupational skin diseases. Chapter 6. Occupational allergic contact dermatitis and patch test results in an Indonesian shoe factory. This chapter focuses on the prevalence of occupational allergic contact dermatitis and the patch test results. All workers in the production process were examined and patch tested by dermatologists, simultaneously with the NOSQ-2002/LONG guided interview. Patch testing was done using the European baseline series, shoe series and additional allergens from the workplace. Chapter 7. Shoe dermatitis patients in the dermatology clinic of the Sardjito University Hospital, Yogyakarta, Indonesia. In this chapter we describe the shoe contact dermatitis patients at our dermatology department and identified responsible allergens. Patch testing was done using the European baseline series, the shoe series, and additional

37 allergens based on the earlier studies of the leather and the shoe factory studies, and patients own shoe materials and extracts of these materials. Chapter 8. Thin layer chromatography examination of shoe extracts 1 36 In the above mentioned study in shoe dermatitis patients, we performed a patch test with thin layer chromatographs in 2 patients who reacted to materials from patient 1, but who failed to demonstrate a positive reaction to standard shoe aller ens. as-chromatography mass-spectrometry examination was performed to identify the allergens in their own shoes. References 1. Centre for Leather, ed. Academic background on national eco label criteria on leather of shoe upper, garment, glove and upholstery. Indonesia: Japan International Cooperation Agency (JICA) and Ministry of Environment (MOE) Republic of Indonesia; Centre for Leather, ed. Progress report: The study for eco label on leather and shoes product criteria. Indonesia: Japan International Cooperation Agency (JICA) and Ministry of Enviroment, Republic of Indonesia; Kusumastuti R, Sulihwangi K, eds. Foreign trade statistical bulletin. Jakarta, Indonesia: Statistics Indonesia; Biro Pusat Statistik; Available from: last accessed May 25, Kemenperindag; Available from: bs_indikator.php?indikator=3. last accessed May, 25, Trade Research and Development Agency (TREDA). Handbook of commodity profile : Indonesian footwear step to the world. 1 s t ed. Jakarta, Indonesia: Trade Research and Development Agency, Ministry of Trade, Republic of Indonesia; Anonim Available from: Global-Footwear-Industry. Last accessed 21 April Rastogi SK, Pandey A, Tripathi S. Occupational health risks among the workers employed in leather tanneries at kanpur. Indian J Dermatol Venereol Leprol 2008; 12:

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45 108. Roberts JL, Hanifin JM. Athletic shoe dermatitis. contact allergy to ethyl butyl thiourea. JAMA 1979; 241: Malten KE, Seutter E. Allergenic degradation products of para-tertiary butylphenolformaldehyde plastic. Contact Dermatitis 1985; 12: Kaniwa MA, Isama K, Nakamura A, et al. Identification of causative chemicals of allergic contact dermatitis using a combination of patch testing in patients and chemical analysis. application to cases from rubber footwear. Contact Dermatitis 1994; 30: Munk R, Sasseville D, Siegel PD, Law BF, Moreau L. Thiurams in shoe contact dermatitis -- a case series. Contact Dermatitis 2013; 68: Corbett JF MJ. Hair coloring. Cutis 1973; 12: McFadden JP, White IR, Frosch PJ. Allergy to hair dye. Br Med J 2007; 334: Patel S, Basketter DA, Jefferies D. Patch test frequency yo p-phenylenediamine: Follow up over the last 6 years. Contact Dermatitis 2007; 56: Oliver EA, Schwartz RA, Warren LH. Occupational leucoderma: Preliminary report. J Am Med Assoc 1939; 113: Bloch B. The role of idiosyncrasy and allergy in dermatology. Arch Derm Syphilol 1929; 19: Thorsten TC. Practical leather technology. 2 nd ed. Malabar, Florida: Robert E. Krieger Publishing Co; Calnan CD, Sarkany I. Studies in contact dermatitis. IX. Shoe dermatitis. Trans St John s Hosp Dermatol Soc 1959; 43: Geier J, Lessmann H. Shoe manufacturers and repairers. In: Kanerva's Occupational Dermatology, 2nd, Rustemeyer T, Elsner P, John SM, Maibach HI, eds. Springer-Verlag, Heidelberg New York Dordrecht London, 2012: Strauss RM, Wilkinson SM. Shoe dermatitis due to colophonium used as leather tanning or finishing agent in Portuguese shoes. Contact Dermatitis 2002; 47: Grimalt F, Romaguera C. New resin allergens in shoe contact dermatitis. Contact Dermatitis 1975; 1: Foussereau J, Cavelier C, Selig D. Occupational eczema from para-tertiary-butylphenol formaldehyde resins: A review of the sensitizing resins. Contact Dermatitis 1976; 2:

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47 1 46

48 CHAPTER 2 Inventory of the chemicals and the exposure of the workers skin to these at two leather factories in Indonesia Sri Awalia Febriana 1,2, Frank Jungbauer 2, Hardyanto Soebono 1, Pieter-Jan Coenraads 2 1 Department of Dermatology & Venereology, Gadjah Mada University, Yogyakarta, Indonesia; 2 Department of Dermatology, University Medical Centre Groningen / University of Groningen, Groningen, the Netherlands. Int Arch Occup Environ Health 2012; 85:

49 Abstract 2 48 Purpose Tannery workers are exposed to hazardous chemicals. Tannery work is outsourced to newly industrialized countries (NICs) where attention into occupational health hazards is limited. In this study, we investigated the skin exposure to hazardous chemicals in tannery workers and determined the prevalence of occupational skin diseases (OSDs) at tanneries in a NIC. Methods A cross-sectional study on the observation of the working process and an inventory and risk assessment of the chemicals used. Classification of chemicals as potential sensitizers/irritants and a qualitative assessment of exposure to these chemicals. Workers were examined and interviewed using NOSQ-2002/LONG. Results The risk of OSDs at the investigated tanneries was mainly related to the exposure of the workers skin to chemicals in hot and humid environmental conditions. In 472 workers; 12% reported a current OSD and 9% reported a history of OSD. In 10% of all cases, an OSD was confirmed by a dermatologist and 7.4% had an Occupational Contact Dermatitis (OCD). We observed that personal protective equipment (PPE) used was mainly because of skin problems in the past and not as a primary protection against OSD. Conclusion We observed a high frequency and prolonged exposure to many skin hazardous factors in tannery work although PPE was relatively easily available and which was generally used as a secondary preventative measure. The observed point-prevalence in this study was at the same level as that reported for other high risk OSDs in Western countries and other tanneries in NICs. However, the observed point-prevalence in this study was lower than that reported in India and Korea. The results of our study and those of other studies at tanneries from other NICs were probably influenced by Healthy Worker Survivor Effect (HWSE). Keywords Occupational skin diseases, Tannery workers, Skin exposure.

50 Introduction Chemicals used in leather manufacturing are intended to chemically alter the structure of the animal hides and may have the same effect on the human skin. These chemicals are potential irritants and sensitizers in workers who are frequently exposed to these for prolonged periods of time. 1, 2 Occupational skin diseases in the leather industry are rarely reported despite their potential high risk. In a study from among male workers in Sweden, it was reported that 12% of those suspected of occupational dermatitis and sensitized to chromium were tannery workers. 3 Recent reports on properly conducted occupational dermatological surveys in this industry are virtually absent. This situation may be the result of outsourcing leather manufacturing to newly industrialized countries (NIC: a country once designated as less developed, but which has undergone recent, rapid industrialization) where attention into occupational health hazards is limited. Trade and financial changes because of globalization have been associated with an increasing outsourcing and subcontracting of hazardous work from developed to developing countries. The burden of diseases from occupational hazards associated with globalization is difficult to determine. Occupational illness is less likely to be detected in developing countries partly as a result of inadequate occupational health services 4. Developing countries generally have fewer adequately effective occupational health programs and fewer adequately developed and enforced laws and regulations than those in the developed countries 5. This may be a reason why tannery work is not reported in statistics on occupational dermatoses in high-risk occupations 6. Another reason for the absence of occupational skin disease data in tanneries may be the extensive automation implemented in this industry as long as it remained in developed countries. 1 By outsourcing leather manufacturing, the occupational health risks that come along with it are also outsourced. Indonesia is one of the newly industrialized countries (NICs) with 586 leather factories operating in 2003 that produced leather for the European market. These factories use a combination of traditional and modern technologies. 7 Although tanning industry has been present in Indonesia for several decades, there are no statistics on occupational skin diseases among tannery workers in Indonesia. A careful investigation of representative workplaces and examination of the workers is imperative to establish the actual risk of occupational skin diseases in leather manufacturing industry The purpose of this study was to investigate the nature of exposure and the occurrence of occupational skin diseases in workers in leather

51 manufacturing industry in a NIC. An inventory of the chemicals to which the workers and the potential consumers may be exposed was compiled. Materials and Methods 2 50 A survey to obtain information on the working process and the skin exposure followed by a cross-sectional study to assess the prevalence of occupational skin diseases was conducted between March and December 2009 at two tanneries (one in Magelang, Central Java and one in Sidoarjo Industrial Area, East Java, Indonesia). We did not undertake random sampling because of the paucity of occupational health information in this industry. In order to get an overview of the working conditions in Indonesian tanneries, we selected one tannery that represented a highly mechanized and one that represented a medium mechanized plant according to the list provided by the Indonesian Centre for Leather. 7 All employees engaged in the production process and exposed to potentially hazardous chemicals were included in the study. A summary of the research flow is shown in Figure 1.

52 Observation of the workplace and identification of the chemicals All exposed workers interviewed guided with (NOSQ-2002) (n = 472) 2 51 Workers currently having skin problem related to occupation (n = 57) Workers with history of skin diseases related to occupation (n=42) Workers without skin diseases (n = 373) Skin examination by dermatologist (n = 57) Skin examination by dermatologist (n = 42) Skin examination by dermatologist (n = 373) Occupational Skin Diseases (n = 49) Non Occupational Skin Diseases (n = 8) Occupational Contact Dermatitis (n=35) Non Occupational Contact Dermatitis (n = 14) Figure 1. Research flow

53 Observation of the workplace 2 52 Preceding the cross-sectional study of skin symptoms and signs, the different work stations of the factories were observed with regard to the nature of skin exposures to occupational hazards according to guidelines by Rycroft. 8 Workplace observation was done by an occupational dermatologist. This included: 1. Observing and making a detailed report on the working process in the factories. At each working stage, we interviewed responsible personnel and recorded the number of workers involved, job tasks, the duration and the frequency of exposure, and indoor microclimates with a potential risk of causing occupational dermatoses. 2. Observing system of work, handling procedures, Personal Protective Equipment (PPE), and skin care products. 3. Surveying the chemicals warehouse, chemicals being used in workplace and interviewing the workers and their supervisors. Chemical product lists and Material Safety Data Sheets (MSDS) were collected from the tannery and from the manufacturers of the chemicals. Information was collected from the researchers and the database at the Centre for Leather, Rubber and Plastic Agency for Research and Development, Ministry of Industry and Trade, Republic of Indonesia. 4. Listing of chemicals (including the CAS numbers of all ingredients), the workers are exposed to during the working process. The potential risk of all chemicals as a skin irritant or a skin sensitizer was assessed using the MSDS, the National Institute for Occupational Safety and Health Institute (NIOSH) website 9, reference books 10, and a search using PubMed. Questionnaire study and physical examination A trained interviewer interviewed each exposed employee. All subjects gave their informed consent prior to their inclusion in the study. The interviewers were anthropologists and medical students who were trained

54 in interviewing skills by an occupational dermatologist. The interviews were guided by using the Nordic Occupational Skin Questionnaire 2002 long version (NOSQ-2002/LONG). Since the level of education and the reading skills of the workers were limited, the interviewers explained the questions in the questionnaire without giving a personal interpretation of the response. In accordance with the NOSQ procedures, the questionnaire was translated, adapted and modified for the specific circumstances in tanneries in Indonesia following the Guideline from Nordic Occupational Skin Questionnaire Group. 11 Adaptations were made on the question regarding location of the eczema (question D2), the specification of the workstation (question G1), and the list of chemicals the workers were exposed to (question G10). Since the interpretation of the English term skin problem 2 53 Besides the questionnaire, the skin of all included workers was examined by two dermatologists and a dermatologist with additional training in contact and occupational dermatitis to determine the prevalence of occupational skin diseases. This assessment was put forward as a series decisions: 1) classify as dermatitis and not psoriasis, tinea, or scabies; 2) classify as contact dermatitis and not atopic, seborrhoeic, discoid, stasis or unclassified; 3) define the probable (occupation related) causes. 12 Results Working process and list of chemicals that the workers were exposed to The leather processing itself involves three steps: 1) Preparation of hides (curing, soaking and hair removal liming) and pre-tanning stage (bating and pickling) in a special shed (called beam house) 2) Tanning stage (tanning, sammying and shaving) 3) Post-tanning or finishing stage (drying, fat liquoring and finishing). The working process and the relevant chemicals that the workers were exposed are shown in Figure 2. List of chemicals and the effect of each chemical on the skin are presented in Table 1

55 Hide Preparation and Pretanning Preservation Soaking NaCl, Pesticide (metam sodium) Insecticide (amino compound) Water (H2O) Microbiocide ( sodium dimethyl dithiocarbamate), Lipase enzyme, Protease enzyme Fleshing mechanically 2 54 Liming and unwatering NaHCO3,NaHS, Sodium Sulphide, Ca(OH)2, metam sodium, soda ash, caustic soda Fleshing dan splitting mechanically Batting Benzaldehydeglycol, acetid acid, Lipase Enzyme Pickling Formic acid, sulphuric acid, sodium formate, sodium chloride, acetic acid, urea Pickle Tanning Tanning Cr2O3, Cr2(OH)2(SO4)2.Na2SO4.x H2O Mercaptobenzothiazole, metam sodium Sammying & shaving mechanically wetblue Retanning (basic dye) Light fast resin, glutaraldehyde, polyethyl acrylate, anionic resin Finishing Fat liquoring Setting out, vacuum, stacking, milling mechanically Spray Laquers, ethyl glycol, polyurethane binder Finishing Figure 2. Flowchart of working process 1. Preparation of the hides and pre-tanning at the beam house The aim of the beam house process is to put the hides into a proper chemical and physical condition for the subsequent removal of unwanted substances in the finished leather. In a curing process, the hides are treated with sodium chloride and metam sodium. The salted hides are soaked to restore their natural humidity using a micro-biocide and enzymes. Hair removal/liming are done to remove the epidermis, hair and skin

56 appendices. Hides are put in drums filled with lime, metam sodium as pesticide, and sodium sulphide to achieve the alkaline condition, which destroys the epidermal keratin. Hair and skin appendices are also removed manually with fleshing knives and a rotating knives cylinder. In pre-tanning section hides are undergo de-liming, bating and pickling. Deliming is done to remove excessive lime using hydrogen peroxide and carbon dioxide. Bating is the next step to remove excess hair using a protease enzyme and to remove natural fat (degreasing) using a lipase enzyme. Finally, the hide is transferred into an acid condition (pickling) using formic acid, sulphuric acid, sodium formate, sodium chloride and sodium metabisulfite. The skin of the worker is exposed to sodium chloride, sodium formate and sodium metabisulfite in this step. Sodium chloride may dehydrate the worker s skin. Sodium metabisulfite is a skin sensitizer Sodium chloride, sodium sulphide, soda ash, caustic soda, acetic acid, formic acid and sulphuric acid have an irritant effect on the skin. 9, 10 Metam sodium is a skin irritant 16 and contact sensitizer Table 1. List of the chemicals and their effect on the skin Chemicals used Sensitizer / irritant Preparation of the hides in the beam house - Preservation - Soaking - Green fleshing - Liming and watering - Fleshing - Splitting Sodium chloride Metam sodium (fungicide) Octyl-isothiazolin (fungicide) Cl-Me-Isothiazoline Water Lipase enzyme Protease enzyme Metam sodium (fungicide) - Sodium sulphide (Na2S) Sodium hydrosulphide (NaHS) Lime Ca(OH) 2 Soda ash (CH2Na2O4) Caustic soda (NaOH) - - Irritant Irritant and Sensitizer Sensitizer Sensitizer Irritant - - Irritant and Sensitizer - Irritant Irritant Irritant Irritant Irritant - -

57 Chemicals used Sensitizer / irritant 2 56 Pre- tanning section - Deliming - Bating - Pickling Tanning section - Tanning Hydrogen peroxide (H2O2) Carbon dioxide (CO2) Benzaldehyde glycol Acetic acid Lipase enzyme Formic acid Sulphuric acid Sodium formate Sodium chloride Sodium metabisulfite Potassium dichromate Mercaptobenzothiazole Metam sodium Acetic acid (CH3COOH) Aluminium sulphate Phenosulfonic acid formaldehyde Polyethyl acrylate Glycine Chlorbenzene Oxalic acid Vegetable tanning (mimosa extract) Urea formaldehyde Glutaraldehyde Sensitizer, irritant Irritant Sensitizer Irritant - Irritant Irritant Sensitizer Irritant Sensitizer Sensitizer Sensitizer Sensitizer Irritant Irritant Sensitizer Sensitizer Sensitizer Sensitizer Sensitizer and irritant Sensitizer Sensitizer Sensitizer - Sammying - Shaving Finishing - Fat liquoring - Dyeing - Finishing Vegetable oil (free phenol compound) Disperse orange 3 Acid yellow 36 Phenylenediamine Hydrogen peroxide Epoxy resin (adhesive) Polyethylacrylate Formaldehyde Colophony (surface coating) Benzidine - Sensitizer Sensitizer Sensitizer Sensitizer Sensitizer Sensitizer Sensitizer Sensitizer Sensitizer

58 2. Tanning stage Tanning is the chemical process to convert the hides into tanned leather by stabilizing the collagen structure, protecting the leather from enzymatic degradation, enhancing the strength and increasing its resistance to heat, hydrolysis and microbial degradation. Trivalent chromium sulphate is the most widely used tanning agent to form cross-linking collagen. Although our factories also performed vegetable tanning (using a mimosa wattle extract), they normally used potassium dichromate and phenosulfonic acid formaldehyde, together with mercaptobenzothiazole and metam sodium as a biocide. Sodium bicarbonate is added to stabilize the collagen. Reducing the water content (sammying) and shaving of the pickled hides are done mechanically Chromate allergy is frequently observed in tannery workers. 6, 18, 19 Contact allergy to flower and leaf extract of the mimosa tree 20 and urea formaldehyde resin has also been reported Finishing stage In a post-tanning process, semi-finished leather undergoes dyeing, fat liquoring and coating to create elasticity, softness, impermeability and brightness of the tanned leather. Fat liquoring is used to soften the fibres of the hides and to increase water resistance using sulphonated oil. The coloured and fat-liquored leather is treated in a setting-out machine to make them smoother and then placed in a vacuum dryer to dehydrate the leather. After the drying process, the skin fibres have bonded to each other causing the hardening of the leather. Therefore, staking is done to soften the leather using a heavily vibrating metal pin. Leather is then stretched and pulled on a metal frame (toggling) and undergoes a trimming process to remove the unwanted parts of the hide. The last step in the finishing stage is the application of a protective and decorative coating. A waterbased dye containing an anionic azo-dye is applied, which binds to the cationic surface of the leather and is completed with formic and acetic acid. Polyethylene acrylate, polyurethane, nitrocellulose and biocide are added if needed. In this stage, workers are exposed to different sensitizers such as azo-dyes, acrylates, formaldehyde and glutaraldehyde. 18, 22-24

59 Work safety standards and the use of Personal Protective Equipment (PPE) Occupational dermatoses risk in tanneries is mainly related to the frequent and the prolonged exposure of the workers skin to chemical substances, to hot and humid environmental conditions and to machinery equipment. Workers are exposed to hazardous chemicals through skin absorption, inhalation, and ingestion. Workers at the beam house and tanning area are exposed to chemicals during the whole process including cleaning and disposing the chemical wastes. During the process, chemicals emit fumes, mist, vapours or dust thus exposing the workers to airborne chemical pollutants. Personal protective equipments required by the workers in this area are gloves, apron, safety boots, goggles and respirator. Respirators were not available. Almost all the workers wore a thin plastic apron that did not cover all the parts of the body that were exposed to chemicals. They also wore plastic boots that covered the lower legs and the feet. Some workers, when holding a hide or pickled hide used synthetic rubber gloves that covered their hands and lower arms. Some workers worked with bare hands and used a long metal tong. In the finishing process, workers were exposed to chemical splashes, dust and mist, leather dust, paint spray and organic vapours. Some workers in the shaving and buffing area used cotton and leather gloves. Synthetic rubber gloves with inner cotton gloves were used by workers in the spraying and dyeing area. Workers who handled vacuum dryers, staking, spraying, sorting and measuring wore dust masks. The majority of the workers practiced basic behavioural principles in personal protection such as refraining from eating, chewing, drinking and smoking in work areas. They washed the exposed skin areas thoroughly after handling chemicals. Moisturizers and hand creams were not available. Bathroom and dressing room were available at the observed tanneries. A description of the exposure to skin hazardous working circumstances is presented in Table 2. Despite this observation, we also noticed some reluctance against the use of PPE in this population. Especially the workers without skin problems were somewhat reluctant to use PPE, whereas workers with an OSD were more inclined to use PPE.

60 Table 2. Description of exposure to skin hazardous working circumstances. Area of operation Preparation and Pretanning (beam house) Tanning area Finishing Potential hazards present Direct and airborne exposure to acids/alkalis in chemical dusts and mists Pesticides Bacteria Direct and airborne exposure to acids/alkalis in chemical dusts and mists Injuries Chemical splashes Chemical dust and mist Leather dust Paint spray Organic vapour High humidity PPE required Gloves Safety boots Respirator Goggles Gloves Apron Safety boots Goggles Respirator Gloves Apron Safety boots Goggles Respirator Availability of PPE in the factory Gloves Apron Safety boots Cotton masks Gloves Apron Safety boots Cotton masks Gloves Apron Cotton masks Observation in workers practices Glove, apron cotton masks only used by < 50% of the workers Safety boots used by all workers Gloves, apron, safety boots used by 50% of the workers Cotton masks only used by < 30% of the workers Gloves and cotton masks only used by workers at dyeing section Aprons used by almost all workers 2 59 Questionnaire study and physical examination Four hundreds and seventy-two workers (112 females and 360 males) were enrolled into the study. Demographic characteristics of the workers are shown in Table 3. The prevalence of current occupational skin problems, based on the NOSQ, was 12% (it was reported by 57 workers - 13 from beam house and pre-tanning, 18 from tanning and 26 from finishing process). Forty-two workers had a history of OSD (18 workers from the beam house and pre-tanning, 10 from tanning and 14 from finishing process) and 373 worker had no skin problems. The prevalence rate of current OSD based on the dermatological examination of the skin in this population was 10% (Table 4). The dermatological diagnoses of occupational related skin diseases are shown in Table 5. From all OSDs, occupational contact dermatitis had the highest prevalence in this study (7.4%).

61 We observed that 59% of the workers with a past or present skin complaint and 49% of the healthy workers used gloves. Gloves were generally made of synthetic rubber (49%) and fabric materials (36%). Other workers used polyvinyl chloride, cotton and leather gloves (Table 6) Table 3. Demographic characteristics of the workers Characteristics Preparation of beam house & pre-tanning Tanning Finishing Age (years) 38.8 (10.3) 36.6 (9.8) 34.8 (9.8) Sex Man 101 (21.4) 105 (22.2) 154 (32.6) Woman 10 (2.1) 28 (5.9) 74 (15.7) Mean working in months (SD) 73.0 (78.2) 72.7 (80.2) 56.5 (65.1) History of childhood eczema 6 (29) 6 (29) 9 (43) Hand eczema in the last 12 months 21 (18.9) 17 (12.8) 26 (11.4) Working hours per week 45.9 (9.9) 46.9 (9.4) 47.2 (7.3) Table 4. Result of the questionnaire and physical examination Workers without skin problem (NOSQ-2002) Preparation & pretanning (n = 111) Tanning ( n = 133) Finishing (n = 228) Total (n = 472) 72% (80) 79% (105) 82% (188) 79% (373) Workers currently reported skin problem related to occupation 12% (13) 14% (18) 11% (26) 12% (57) (NOSQ-2002) Workers with history of skin disease related to occupation 16% (18) 8% (10) 6% (14) 9% (42) (12 months) (NOSQ-2002) Workers with current occupational related skin disease (according dermatological examination) 10% (11) 13% (17) 8% (19) 10% (47)

62 Table 5. Prevalence of Occupation Related Skin Disease Job Beamhouse & pretanning Number of workers Occupational Contact Dermatitis Pruritus Miliaria and folliculitis Dermatophyte Infection and Intertrigo Tanning Finishing Total (7.4%) 5 (1%) 5 (1%) 4 (0.8%) Table 6. Use of glove in the tanneries Past or present skin complaint No skin complaint Glove use 58 (59%) 181 (49%) No glove use 41 (41%) 192 (51%) Total number of workers Discussion In our study we were able to confirm the statement by Kolomaznik et al that tannery workers have a high risk of exposure to metal salts (mainly chromates) at their workplace. 2 Chemicals used in tanneries alter the structure of animal hide and therefore may have a damaging effect on the function and the structure to the worker s skin. We did not find large differences between the results of our cross-sectional survey on OSD with a high-risk for OSD in Western countries However, in the observed tanneries many typical hazardous situations were seen. In a spray-painting section, we saw workers without proper PPE working in small rooms with poor ventilation had a higher exposure to hazardous chemical vapours. Awareness of occupational health risk appeared to be low. Basic PPEs were available, but were mainly used as a secondary prevention measure. In many cases, small changes based on awareness of the health risk could decrease the risk of OSD dramatically. Activities of mixing the chemicals and painting the leather in open-air ventilated workplaces would considerably reduce the exposure to hazardous chemicals.

63 2 62 Similar to that reported in another study 29, we also observed the situation that gloves were mainly used to protect the already damaged skin. Lowering the prevalence of OSD could be achieved with substitution of hazardous substances, installation of the effective exhaust system, educational programme for workers and an effective use of PPE before skin problems arise. From the questionnaire study, from the 472 workers, we noted 57 workers with a current skin complaint (a prevalence of 12%), whereas 47 (10%) of them had current occupation-related skin diseases diagnosed by a dermatologist with occupational contact dermatitis reported in 35 (7.4%) workers. These results are in line with other NOSQ-2002 validation surveys. 21, 27, 30, 31 We found five published cross-sectional studies on tannery workers in three other newly industrialized countries: India, Argentina and Korea. Our results are higher than the prevalence reported from Buenos Aires 32 and 2 Indian tanneries A survey conducted in Buenos Aires, reported in short communication, 440 of the 1,100 male tannery workers had occupational skin lesions. 32 Rastogi et al (2008) reported 9% of the 197 male workers drawn randomly from 10 tanneries in India had skin rash and papules along with complaints of itching. A comprehensive occupational study was reported by Shukla et al (1991) who selected 497 workers with stratified random sampling from 20 tanneries in an urban slum in India. They reported 13 (2.6%) workers had contact dermatitis and made quantification of the workplace hazards and PPE practices. The point-prevalence in our study was lower than the reported pointprevalence of the 23% in a cross-sectional survey among 485 tannery workers in India 35 and 26% in Korean tannery workers. 36 Lee et al (1991) performed a dermatological examination in 310 tannery workers with a prevalence of contact dermatitis of 26.4%. They also reported other occupational related skin diseases like callus, paronychia, burn, physical trauma, vitiligo, joint deformity and oil acne. The wide range of reported prevalence figures for OSD among tannery workers in newly industrialized countries (between 2.6 and 26.4%) is probably caused by the differences in the definition of cases, period of

64 screening and data collecting Differences in the working conditions may also cause the wide range of reported point-prevalence. Similar to that in other cross-sectional studies on occupational diseases, our results may be affected by a Healthy Worker Survivor Effect (HSWE). Workers who experience health problems are more likely to leave highexposure jobs, either by ending employment or being transferred. This may lead to the biased conclusion that the high-exposure occupation is safe In this study, we were able to produce a detailed scheme of the working process with a focus on the risk of OSD in each step in tannery work. The difficulty in obtaining a random sample from tanneries in a NIC as the object of our study limits the interpretation of our data. Another limitation of our study is that we only have the qualitative data on the level of skin exposure to potentially hazardous chemicals. A quantitative assessment of exposure is necessary. In contrast to these limitations, we realize that this is one of the few studies on occupational skin disease risk in a NIC. More research into the effect of the occupational health risk of exporting such activities from Western countries to NIC is needed. Conclusion We observed a high frequency and a prolonged exposure to many skin hazardous factors in tannery work with a relatively easy availability of PPE, which was mostly used as a secondary prevention measure in a NIC. In this study, a point-prevalence of OSD was at the same level as that reported in other high-risk OSD in Western countries and some other tanneries in NICs. However, the observed point-prevalence in this study was lower than that reported in tanneries in India and Korea. The results of our study, as well as the results from other studies in this area are probably substantially influenced by HWSE. Conflict of interest statement: the authors declare that they have no conflict of interest. References 1. Geier J, Lessmann H. Leather and shoes. In: Kanerva's Occupational Dermatology, 2nd, Rustemeyer T, Elsner P, John SM, Maibach HI, eds. Springer-Verlag, Heidelberg New York Dordrecht London, 2012:

65 2. Kolomaznik K, Adamek M, Andel I, Uhlirova M. Leather waste--potential threat to human health, and a new technology of its treatment. J Hazard Mater 2008; 160: Fregert S. Occupational contact dermatitis in a 10-year material. Contact Dermatitis 1975; I: London L, Kisting S. Ethical concerns in international occupational health and safety. Occup Med 2002; 17: Levy BS. Global occupational health issues: Working in partnership to prevent illness and injury. AAOHN J 1996; 44: Athavale P, Shum KW, Chen Y, et al. Occupational dermatitis related to chromium and cobalt: Experience of dermatologists (EPIDERM) and occupational physicians (OPRA) in the U.K. over an 11-year period ( ). Br J Dermatol 2007; 157: Centre for Leather, ed. Academic background on national ecolabel criteria on leather of shoe upper, garment, glove and upholstery. Indonesia: Japan International Cooperation Agency (JICA) and Ministry of Enviroment (MOE) Republic of Indonesia; Rycroft RJG. Plant survey and inspection. In: Handbook of occupational dermatology, Kanerva L, ed. Springer-Verlag, Berlin, Heidelberg, 2004: Anonim [Internet]; Available from: de Groot A, ed. Patch testing : Test concentration and vehicles for 4350 chemicals. 3rd ed. The Netherlands: Acdegroot publishing; Nordic occupational skin questionnairre-nosq Nordic questionnaire for surveying work-related skin diseases on hands and forearms and relevant exposures. [Internet]. Denmark: Nordic Council of Ministers, Copenhagen Available from: Rycroft RJ. Clinical assessment in the workplace: Dermatitis. Occup Med (Lond) 1996; 46: Kaaman AC, Boman A, Wrangsjo K, Matura M. Contact allergy to sodium metabisulfite: An occupational problem. Contact Dermatitis 2010; 63: Madan V, Walker SL, Beck MH. Sodium metabisulfite allergy is common but is it relevant? Contact Dermatitis 2007; 57: Sasseville D, El-Helou T. Occupational allergic contact dermatitis from sodium metabisulfite. Contact Dermatitis 2009; 61:

66 16. Koo D, Goldman L, Baron R. Irritant dermatitis among workers cleaning up a pesticide spill: California Am J Ind Med 1995; 27: Pruett SB, Myers LP, Keil DE. Toxicology of metam sodium. J Toxicol Environ Health B Crit Rev 2001; 4: 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: Hansen MB, Rydin S, Menne T, Duus Johansen J. Quantitative aspects of contact allergy to chromium and exposure to chrome-tanned leather. Contact Dermatitis 2002; 47: Guin JD, Dwyer G, Sterba K. Clothing dye dermatitis masquerading as (coexisting) mimosa allergy. Contact Dermatitis 1999; 40: Sommer S, Wilkinson SM, Dodman B. Contact dermatitis due to urea-formaldehyde resin in shin-pads. Contact Dermatitis 1999; 40: Ancona A, Serviere L, Trejo A, Monroy F. Dermatitis from an azo-dye in industrial leather protective shoes. Contact Dermatitis 1982; 8: Goon AT, Bruze M, Zimerson E, Goh CL, Soo-Quee Koh D, Isaksson M. Screening for acrylate/methacrylate allergy in the baseline series: Our experience in Sweden and Singapore. Contact Dermatitis 2008: 59: Mancuso G, Reggiani M, Berdondini RM. Occupational dermatitis in shoemakers. Contact Dermatitis 1996; 34: Gruvberger B, Isaksson M, Frick M, Ponten A, Bruze M. Occupational dermatoses in a metalworking plant. Contact Dermatitis 2003; 48: Flyvholm MA, Mygind K, Sell L, Jensen A, Jepsen KF. A randomised controlled intervention study on prevention of work related skin problems among gut cleaners in swine slaughterhouses. Occup Environ Med 2005; 62: Attwa E, el-laithy N. Contact dermatitis in car repair workers. J Eur Acad Dermatol Venereol 2009; 23: Skudlik C, Dulon M, Wendeler D, John SM, Nienhaus A. Hand eczema in geriatric nurses in germany--prevalence and risk factors. Contact Dermatitis 2009; 60: Mellstrom GA, Boman A. Protective gloves. In: Condensed handbook of occupational dermatology,, Kanerva L, Elsner P, Wahlberg JE, Maibach HI eds. Springer-Verlag, Heidelberg, Berlin, 2004:

67 30. de Joode BW, Vermeulen R, Heederik D, van Ginkel K, Kromhout H. Evaluation of 2 selfadministered questionnaires to ascertain dermatitis among metal workers and its relation with exposure to metalworking fluids. Contact Dermatitis 2007; 56: Carstensen O, Rasmussen K, Ponten A, Gruvberger B, Isaksson M, Bruze M. The validity of a questionnaire-based epidemiological study of occupational dermatosis. Contact Dermatitis 2006; 55: Kvitko E. Occupational contact dermatitis in the tanning industry. Contact Dermatitis 2001; 45: Rastogi SK, Pandey A, Tripathi S. Occupational health risks among the workers employed in leather tanneries at Kanpur. Indian J Dermatol Venereol Leprol 2008; 12: Shukla A, Kumar S, Ory FG. Occupational health and the environment in an urban slum in india. Soc Sci Med 1991; 33: Ory FG, Rahman FU, Katagade V, Shukla A, Burdorf A. Respiratory disorders, skin complaints, and low-back trouble among tannery workers in Kanpur, India. Am Ind Hyg Assoc J 1997; 58: Lee JY, Kim YH, Kim HO, Kim CW. Occupational dermatoses in tannery workers. The Kor J of Occup Med 1991; 3: Siebert U, Rothenbacher D, Daniel U, Brenner H. Demonstration of the healthy worker survivor effect in a cohort of workers in the construction industry. Occup Environ Med 2001; 58:

68 CHAPTER 3 Occupational allergic contact dermatitis and patch test results of leather workers at two Indonesian tanneries Sri Awalia Febriana 1,2, Frank Jungbauer 2, Hardyanto Soebono 1, Pieter-Jan Coenraads 2 1 Department of Dermatology & Venereology, Gadjah Mada University, Yogyakarta, Indonesia; 2 Department of Dermatology, University Medical Centre Groningen / University of Groningen, Groningen, the Netherlands. Contact Dermatitis 2012; 67(5):

69 Abstract Background Tannery workers run a considerable risk of developing occupational contact dermatitis (OCD). Occupational skin diseases in tannery workers in newly industrialized countries have been reported, but neither the prevalence of occupational allergic contact dermatitis (OACD) nor the skin sensitizing agents were specifically examined in those studies Objectives To assess the prevalence of occupational allergic contact dermatitis at Indonesian tanneries, identify the causative allergens and propose a tannery work series of patch test allergens. Patients/Methods A cross-sectional study in all workers at two Indonesian tanneries for assessing the prevalence of occupational contact dermatitis via a questionnaire-based interview and skin examination. Workers with occupational contact dermatitis were patch tested to identify the causative allergens. Results Occupational contact dermatitis was suspected in 77 (16%) of the 472 workers. Thirteen (3%) of these 472 workers were confirmed to have occupational allergic contact dermatitis. Potassium dichromate (9.2%), n,n-diphenylguanidine (5.3%), benzidine (3.9%) and sodium metabisulfite (2.6%) were found to be the occupationally relevant sensitizers. Conclusions The sensitization pattern showed some differences with the data in studies reported from other newly industrial countries. We of these allergens may also be considered for patch testing in patients with (leather) shoe dermatitis. Keywords Occupational contact dermatitis; tannery workers; patch test; occupational allergic contact dermatitis.

70 Introduction Tanning is the process of converting animal hides into leather, a product that does not easily decompose. Tanning is used since 7,000 BC and is considered as a noxious and smelly trade and had to be confined to the outskirts of town amongst the poor areas. Chemicals used in leather manufacturing are intended to alter the structure of the animal hide and may have the same effect on the workers skin. Many of these chemicals are considered as potential sensitizers. Tannery workers, who are frequently exposed to these chemicals for prolonged periods, run a considerable risk of developing an occupational allergic contact dermatitis. 1, Occupational skin diseases in the leather industry have rarely been reported over the last decades despite their potential high risk. This lack of reporting may have been caused by the highly increased outsourcing of leather manufacturing to newly industrialized countries which do not have a comprehensive occupational disease registry and properly conducted occupational dermatological surveys as those in industrialized Western countries. 3 The relocation of hazardous industries to developing countries is driven by economic considerations: high unemployment, a cheaper labour force, lack of regulation and poor enforcement of any existing regulations making certain countries highly profitable for business ventures. 3, 4 Since the1980s many western countries prohibited the use of certain chemicals for tanning 5 and led companies to outsource tannery work to the newly industrial countries. Occupational allergic contact dermatitis in tannery workers was often encountered in Western countries decades ago prior to the introduction of the strict regulations on occupational exposure. 2, 6 Recently published data on occupational skin diseases in tannery workers were reported from newly industrial countries like India and Argentina, but the actual prevalence of occupational allergic contact dermatitis and the skin sensitization to tannery allergens were not investigated. 7-9 Outsourcing tannery work to newly industrial countries may influence the risk of developing occupational allergic contact dermatitis in workers in this industry. In a previous report, we presented a detailed overview on the exposure to the putative source of occupational irritant and sensitizing agents at tanneries and described the prevalence of occupational skin diseases in workers. 10 The purpose of this study is to 1) assess the prevalence of occupational allergic contact dermatitis in a population of tannery workers in a newly

71 industrialized country, 2) identify the causative allergens and 3) propose a tannery works series of patch test allergens. Materials and Methods 3 70 We conducted a cross-sectional study to assess the prevalence of occupational allergic contact dermatitis at two tanneries in Java, Indonesia between March and December These tanneries represent a high and a medium mechanized plant according to the list provided by the Indonesian Centre for Leather. 10 All employees engaged in the production process and thus exposed to potentially hazardous chemicals were included in the study. Structured interviews The interviews were conducted using the Indonesian translation of The Nordic Occupational Skin Questionnaire (NOSQ-2002/LONG). The questionnaire was translated, adapted and modified for specific circumstances at the tanneries following the Guideline from Nordic Occupational Skin Questionnaire Group Interviews were carried out to obtain information on the location and morphological aspect of the skin diseases and the exposure to relevant allergens in the workplace. Dermatological examination and patch testing The skin of all workers was examined by a team of dermatologists supervised by a dermatologist with additional training in contact and occupational dermatitis within a period of 5 weeks. Patch tests were done in 63 out of 77 tannery workers with current and history of occupational contact dermatitis and 108 tannery workers without skin disease as controls. We used allergens from the European standard series, shoe series (Chemotechnique Diagnostics, AB, Sweden) and additional allergens specific for tannery work. These additional allergens were identified on the basis of the previously reported inventory of potential allergens and exposure assessment at these tanneries. 10 We used the analytical grade chemicals for non-allergen manufacturer substances. We prepared sodium metabisulfite allergen in our laboratory using petrolatum as a vehicle to formulate a more stabile solution. A list of specific allergens to which the tannery workers were exposed to and used for the patch testing is shown in Table 1. The patch test procedures were done on the upper back of the workers using Finn (Epitest Ltd., Helsinki, Finland) mounted on an

72 acrylate-base adhesive tape (Scanpor Alpharma AS, Norway). The applied patch tests were reinforced with extra tape stuck at the margin and covering the chamber area: a procedure recommended in hot climates to avoid detachment of the strips. 14 After 48 hours occlusion, we removed the Finn-chambers and read the patch test result on days 2, 4 and 7 as recommended by the International Contact Dermatitis Research Group (ICDRG). 14, 15 Diagnostic criteria of occupational allergic contact dermatitis Diagnostic criteria for occupational allergic contact dermatitis (OACD) in this study were based on the information from three sources: workplace observation, questionnaire and dermatological examination including patch test results The diagnosis of occupational allergic contact dermatitis was established in cases meeting the following criteria: 11, 16, Confirmed as a case of occupation-related contact dermatitis 2. Exposure to the relevant occupational allergens 3. Confirmed type 4 sensitization to the relevant occupational allergens 4. Exposure confirmed as a cause or as an important aggravating factor in the development of the skin diseases. To confirm a case of occupational relevant contact dermatitis we used a combination of structured questionnaire-based interview and skin examination by dermatologists.

73 472 workers underwent interviewed guided with Indonesian translation of NOSQ-2002 and dermatological examination Patients fulfilling criteria for shoe dermatitis (n=64) 3 72 Workplace observation 8 workers with nonoccupational skin disease (non-osd) 91 workers with occupational skin disease (OSD) 14 workers with OSD non- 77 workers with occupational contact dermatitis (OCD) Patch tested 63 patch tested 14 not patch tested 13 workers with current occupational allergic contact dermatitis (OACD) Figure 1. Flowchart of the 472 workers Results Characteristics of the studied workers All the 472 workers (112 females and 360 males) employed in the production process at the two tanneries were included in the study. Their mean age was 36 years, with a mean duration of employment of 6 years and mean working hours per week of 47 hours. Twenty one workers (4%) had a history of childhood eczema, 96 workers (20%) had a history of

74 atopic respiratory diseases and 101 workers (22%) had atopic skin diathesis according to Diepgen s criteria. Development of specific tannery patch test series Based on the previously reported workplace observations and the list of allergens that were identified at these tanneries 18 a literature search was done to define a proper vehicle and adequate concentration of patch test allergens, which were commercially not available (Table 1) Dermatological examination and patch test results An occupational contact dermatitis was suspected in 77 (16%) of the 472 workers. Patch tests were done in 63 of these workers; 13 (3%) had a positive patch test to one or more of the tannery allergens and diagnosed having occupational allergic contact dermatitis (Figure 1). Location of skin lesions in workers with occupational contact dermatitis The location of the skin lesions in the 77 workers with occupational contact dermatitis is shown in Table 2. The hands and the wrist/forearms were the areas that generally affected by the occupation-related skin disease. In this population, we found more than half of workers with an involvement of the face/neck, the lower extremities and the trunk. Sensitization A list of the relevant allergens to which sensitizations were seen is presented in Table 3. We found sensitization to 15 allergens that were relevant in tannery work. The most frequent sensitizers observed were potassium dichromate (7 workers), n-n-diphenylguanidine (4 workers), benzidine (3 workers) and sodium metabisulfite (2 workers).

75 Table 1. Sensitizers to which the tannery workers were exposed Work area and process Chemicals used and identified as sensitizer Concentrati on and vehiculum CAS number 3 74 Preparation of the hides in the beam house Preservation Sodium n-methyl dithiocarbamate** (Supelco) 2-n-Octyl-4-isothiazolin-3-one* Cl+Me-Isothiazolinone* 0.03% pet 0.1% pet 0.02% aq Soaking Green fleshing Liming and watering Fleshing Splitting Sodium n-methyl dithiocarbamate** (Supelco) % pet Pre- tanning section De-liming Hydrogen peroxide**(sigma- Aldrich) 3% aq Bating 2-(2-bromoethyl) benzaldehyde** (Aldrich) 2% pet Pickling Sodium formate** (Sigma Aldrich) Sodium metabisulfite** (Sigma Aldrich) 2.0 % gly 1.0 % pet Tanning section Tanning Potassium dichromate* 2-Mercaptobenzothiazole* Sodium n-methyl dithiocarbamate**(supelco) Formaldehyde* Polyethyl acrylate** (Aldrich) Glycine** (Sigma) Chlorobenzene** (Sigma Aldrich) Oxalic acid** (Sigma Aldrich) Glutaraldehyde* Sodium n-methyl dithiocarbamate**(supelco) 2-(thiocyanomethylthio) benzothiazole** 0.5% pet 2.0% pet 0.03 % pet 1.0 % aq 5.0 % pet 2.0 % aq 5.0% olive oil 0.1% aq 0.2% pet 2.0% pet 0.2% pet Sammying Shaving Finishing Fat liquoring - - -

76 Dyeing Work area and process Chemicals used and identified as sensitizer Disperse orange 3* (CI 11005) Acid yellow 36* (CI 13065) N- Isopropyl-N-phenyl 4- phenylenediamine* Hydrogen peroxide** Benzidine** (Sigma) Concentrati on and vehiculum 1.0% pet 1.0% pet 0.1% pet 3.0% aq 1.0% pet CAS number Finishing Epoxy resin (adhesive)* Polyethylacrylate** (Aldrich) Formaldehyde* Colophony (surface coating)* 4-tert-buthylphenol formaldehyde resin* 1.0% pet 5.0% pet 1.0% aq 20.0% pet 1.0% pet * present in standard shoe series of Chemotechnique Diagnostics Sweden ** additional allergens for tannery work 3 75 Table 2. Location of the skin complaint in workers with current and past Occupational Contact Dermatitis Location of the skin lesion Number of workers * Hand wrist/forearm 68 Face / neck 5 Lower extremities 24 Trunk 52 *can be more than one area involved in a worker.

77 Table 3. Sensitization in workers with Occupational Allergic Contact Dermatitis (OACD) 3 76 Allergen Number of workers with positive patch test Source of exposure (n= 76) (%) a Potassium dichromate 7 (9.2%) tanning N,N-diphenylguanidine 4 (5.3%) synthetic rubber gloves 4-tert-Butylphenol formaldehyde surface coating and 1 (1.3%) resin varnishing 4-phenylenediamine base 1 (1.3%) intermediate in dyeing and finishing Colophony 1(1.3%) surface coating (finishing stage) Formaldehyde 1 (1.3%) tanning 2-mercaptobenzothiazole 1 (1.3%) tanning Epoxy resin 1 (1.3%) finishing Cl-Me-Isothiazolinone 1 (1.3%) preparation of the hides 2-n-octyl-4-isothiazolin-3-one 1 (1.3%) preparation of the hides Benzidine (1% pet) 3 (3.9%) finishing/dyeing Sodium metabisulfite 2 (2.6%) pickling sodium formate (2% glycerol) 1 (1.3%) pickling Chlorobenzene (5% olive oil) 1 (1.3%) tanning Oxalic acid 1 (1.3%) tanning n = number of workers with current and history of occupational contact dermatitis being patch tested Discussion A prevalence of 16% for occupational contact dermatitis in this group of exposed workers at the two Indonesian tanneries is lower than the prevalence of contact dermatitis in Korean tanneries (26.4%) 20, but higher compared with 2.6% in a study at the Indian tanneries. 21 The differences between these studies were explained in another publication. 18 The prevalence of occupational contact dermatitis in our population is similar to those reported for the wet-work exposure in Western populations The prevalence of occupational allergic contact dermatitis might be higher since we were not able to patch test all workers with occupational contact

78 dermatitis: 14 of the workers were not patch tested due to different reasons such as reluctance to be patch tested, moved to another factory and did not turn up for the examination. Workers in newly industrial countries where there is job uncertainty and lack of social security may be reluctant to be diagnosed with occupational allergic contact dermatitis. Nevertheless, we consider a prevalence of occupational skin disease (OSD) (21%), occupational contact dermatitis (OCD) (16.3%) and occupational allergic contact dermatitis (OACD) (3%) in this population of tannery workers to be high. These occupational diseases could probably be prevented with adequate and easily implemented measures In many cross-sectional studies on occupational diseases, the results may be affected by a healthy worker survivor effect. Workers who experience occupational health problems are more likely to leave high-exposure jobs, either by ending employment or being transferred to another department. 25 Observations and in-depth interviews with workers and management support this. The hands and the wrist/forearms were the most common areas (68%) involved in this study. However, in this study occupational contact dermatitis also affected other part of the body like the trunk, the lower extremities, and the face/neck in more than 50% of the workers. A possible explanation for these typical disease locations is the use of inappropriate personal protective equipment: working without a shirt, wear shorts and using wet and contaminated aprons or boots. 18 From the 63 workers who were patch tested, we found sensitizations to 15 allergens in 13 different workers. Determining the occupational relevance of sensitization is essential for the diagnosis of occupational allergic contact dermatitis. Potassium dichromate (9.2%), n,n-diphenylguanidine (5.3%), benzidine (3.9%) and sodium metabisulfite (2.6%) were found to be occupationally relevant sensitizers at these tanneries. The results of our study showed some differences with reported data from an outpatient clinic-based study in a Western country and epidemiological studies in other newly industrialized countries. Data from a compilation of patch test results were reported in Germany and Sweden. 2 Over the years , 12% of the Swedish male workers with chromate allergy were engaged in tannery work. 6 Studies at outpatients clinics in Germany

79 3 78 showed that the causative allergens for occupational allergic contact dermatitis in tannery workers were dichromate (3.2%), formaldehyde (1.3%), leather dyes (1.3%), and tanning agents (0.3%). 26 This study was performed before most of the tannery work was outsourced to newly industrialized countries. Sensitizations were assessed in Korean and Argentinean tannery workers. In a study of 310 Korean tannery workers, 10 out of 22 workers who underwent patch testing had a positive patch test to carba-mix, ammoniated mercury, gold sodium thiosulphate, formaldehyde, potassium dichromate, nickel sulphate, and mercaptobenzothiazole. 20 In Argentina, 187 workers had a positive patch test to potassium dichromate, mercaptobenzothiazole and hexachlorophene. 8 It is interesting to note that we found sensitizations to sodium metabisulfite (2.6%), benzidine (3.9%) and diphenylguanidine (5.3%). The prevalence of positive patch test to sodium metabisulfite in some occupational dermatologic clinics are between 3.4% 27 and 4.1% 28 of which occupational relevance only found in 1.9% 27 and 0.9% 28 patients. Occupational relevance exposures were found in bakers, caterer, rubber manufacturing plant, and textile dryer Leather industry is one of the occupational sources of sodium metabisulfite which is used as an acidifying agent in the tanning process. 30 In this study there were 2 workers had a relevance exposure to sodium metabisulfite. We noted that one of the tanneries used benzidine-based dyes and we found that 3.9% workers were sensitized to benzidine. Reports on benzidine sensitization are scarce: one was published three decades ago in a study of 4,600 patients who were patch tested in Spain between Grimalt et al (1981) performed histological studies of patch test reactions to confirm the allergic nature of the reactions. 32 Benzidine-based dyes were banned in 1978 in many countries because of their carcinogenic effect. 5, 33 This situation explained why there are no recent reports on benzidine sensitization. Nevertheless, the continued demand by the textile and leather industry for benzidine-based dye opened marketing opportunity in newly industrialized countries with less concern for workers and environmental safety. 5 The detection of ongoing exposure and sensitization to benzidine in these tanneries can be seen as a sign that outsourced tannery work need better enforcement of existing regulation.

80 In this population 5.3% of the workers with skin complaints were sensitized to n,n-diphenylguanidine and 4% (4 workers out of 108) in the group of workers without skin problems. Interpretation of n,ndiphenylguanidine patch test results remains difficult since results of the Information Network of Departments of Dermatology (IVDK) indicate that most of the positive reactions to diphenylguanidine are probably irritant reactions. 34 The assessment of patch test result was based on the visual inspection by a trained dermatologist. Skin reactions to diphenylguanidine can be irritant reactions; therefore we cannot completely exclude the possibility of irritant reactions. The source of exposure to n,n-diphenylguanidine to tannery workers in this study was probably synthetic rubber gloves In our study, we were able to make a careful identification of the possible sensitizers to which tannery workers were exposed. We assembled a allergens, for example sodium n-methyl dithiocarbamate, sodium formate, sodium metabisulfite and benzidine may also be considered for patch tests in patients with (leather) shoe dermatitis as an addition to the commonly used shoe series. In this study, we did not undertake random sampling in choosing the tanneries. The paucity of occupational health information in this industry made random sampling impossible. In order to get an overview of the working conditions at the Indonesian tanneries, we chose one tannery that represented two different types according to the list provided by the Indonesian Centre for Leather. 10 Further study with a larger population and random sampling is needed to clearly establish the occupational health risk in such outsourced industries. References 1. Kolomaznik K, Adamek M, Andel I, Uhlirova M. Leather waste--potential threat to human health, and a new technology of its treatment. J Hazard Mater 2008; 160: Geier J, Lessmann H. Leather and shoes. In: Kanerva's Occupational Dermatology, 2nd, Rustemeyer T, Elsner P, John SM, Maibach HI, eds. Springer-Verlag, Heidelberg New York Dordrecht London, 2012:

81 3. London L, Kisting S. Ethical concerns in International Occupational Health and Safety. Occup Med 2002; 17: Levy BS. Global occupational health issues: Working in partnership to prevent illness and injury. AAOHN J 1996; Dapson RW. Benzidine-based dyes: Effects of industrial practices, regulations, and world trade on the biological stains market. Biotech Histochem 2009; 84: Fregert S. Occupational contact dermatitis in a 10-year material. Contact Dermatitis 1975; I: Ory FG, Rahman FU, Katagade V, Shukla A, Burdorf A. Respiratory disorders, skin complaints, and low-back trouble among tannery workers in Kanpur, India. Am Ind Hyg Assoc J 1997; 58: Kvitko E. Occupational contact dermatitis in the tanning industry. Contact Dermatitis 2001; 45: Rastogi SK, Pandey A, Tripathi S. Occupational health risks among the workers employed in leather tanneries at Kanpur. Indian J Dermatol Venereol Leprol 2008; 12: Centre for Leather, ed. Academic background on national ecolabel criteria on leather of shoe upper, garment, glove and upholstery. Indonesia: Japan International Cooperation Agency (JICA) and Ministry of Enviroment (MOE) Republic of Indonesia; Ale IS, Maibach HA. Diagnostic approach in allergic and irritant contact dermatitis. Expert Rev Clin Immunol 2010; 6: Nordic occupational skin questionnaire NOSQ Nordic questionnaire for surveying work-related skin diseases on hands and forearms and relevant exposures. [Internet] Denmark: Nordic Council of Ministers, Copenhagen Available from: Susitaival P, Flyvholm MA, Meding B, et al. Nordic occupational skin questionnaire (NOSQ- 2002): A new tool for surveying occupational skin diseases and exposure. Contact Dermatitis 2003; 49: Lachapelle, JM. and Maibach, HI. Patch testing methodology. In: Patch testing and Prick Testing A Practical guide Official Publication of the ICDRG, 2 nd. Lachapelle JM. and Maibach, HI, eds. Springer-Verlag, Berlin Heidelberg, 2009: Lachapelle JM. and Maibach, HI. Clinical relevance of patch test reactions. In: Patch testing and Prick testing, 2 nd. Lachapelle J.M. and Maibach, HI, ed. Springer-Verlag, Berlin Heidelberg, 2009:

82 16. Nicholson PJ, Llewellyn D, English JS, Guidelines Development Group. Evidence-based guidelines for the prevention, identification and management of occupational contact dermatitis and urticaria. Contact Dermatitis 2010; 63: Ale S.I. and Maibach, H.I. Operational definition of occupational allergic contact dermatitis. In: Handbook of occupational dermatology. Kanerva L ed. Springer,Heidelberg, Germany, 2004: Febriana SA, Jungbauer F, Soebono H, Coenraads PJ. Inventory of the chemicals and the exposure of the workers' skin to these at two leather factories in Indonesia. Int Arch Occup Environ Health 2012; 85: de Groot A, ed. Patch testing : Test concentration and vehicles for 4350 chemicals. 3rd edition ed.the Netherlands: Acdegroot publishing; Lee JY, Kim YH, Kim HO, Kim CW. Occupational dermatoses in tannery workers. The Kor J of Occup Med 1991; 3: Shukla A, Kumar S, Ory FG. Occupational health and the environment in an urban slum in india. Soc Sci Med 1991; 33: Gruvberger B, Isaksson M, Frick M, Ponten A, Bruze M. Occupational dermatoses in a metalworking plant. Contact Dermatitis 2003; 48: Attwa E, el-laithy N. Contact dermatitis in car repair workers. J Eur Acad Dermatol Venereol 2009; 23: Skudlik C, Dulon M, Wendeler D, John SM, Nienhaus A. Hand eczema in geriatric nurses in germany--prevalence and risk factors. Contact Dermatitis 2009; 60: Siebert U, Rothenbacher D, Daniel U, Brenner H. Demonstration of the healthy worker survivor effect in a cohort of workers in the construction industry. Occup Environ Med 2001; 58: Wagner G, Wezel G. Nature and incidence of occupational skin damaging agents in schleswig-holstein. results of statistical analysis of expert opinions on occupational dermatoses at the kiel university dermatological clinic in Berufsdermatosen 1966; 14: Kaaman AC, Boman A, Wrangsjo K, Matura M. Contact allergy to sodium metabisulfite: An occupational problem. Contact Dermatitis 2010; 63: Sasseville D, El-Helou T. Occupational allergic contact dermatitis from sodium metabisulfite. Contact Dermatitis 2009; 61:

83 29. Madan V, Walker SL, Beck MH. Sodium metabisulfite allergy is common but is it relevant? Contact Dermatitis 2007; 57: Windholz M, Rahway N.J., eds. The Merck index. 10th ed. Merck and Co., Inc.; Romaguera C, Grimalt F. Statistical and comparative study of 4600 patients tested in Barcelona ( ). Contact Dermatitis 1980; 6: Grimalt F, Romaguera C. Cutaneous sensitivity to benzidine. Derm Beruf Umwelt 1981; 29(4): Request for assistance in health hazard alert-- benzidine-, o-tolidine-, and o-dianisidinebased dyes [Internet] Available from: Geier J, Lessmann H, Uter W, Schnuch A, Information Network of Departments of Dermatology (IVDK). Occupational rubber glove allergy: Results of the Information Network of Departments of Dermatology (IVDK), Contact Dermatitis 2003; 48:

84 CHAPTER 4 Occupational contact allergy caused by benzidine in three tannery workers Sri Awalia Febriana 1,2, Frank Jungbauer 2, Hardyanto Soebono 1, Pieter-Jan Coenraads 2 1 Department of Dermatology & Venereology, Gadjah Mada University, Yogyakarta, Indonesia; 2 Department of Dermatology, University Medical Centre Groningen / University of Groningen, Groningen, the Netherlands. Contact Dermatitis 2012; 66(6):

85 Key words: benzidine; contact dermatitis; allergic contact dermatitis; tannery workers 4 84 In the context of an on-going study at two leather tanneries in Indonesia 1 we patch tested all of 184 workers with the European baseline series, shoe series and a number of additional allergens including benzidine (1% pet). The selection of additional allergens was based on an inventory of the chemicals used at these factories. 1 Patch tests were read on days 2, 4 and 7 as recommended by the ICDRG. 2 A positive reaction to benzidine was observed in 3 workers. Case 1: A 38-year-old female tannery worker had occupational contact dermatitis on her wrists, forearms and palms. She had worked for 19 months at the finishing department of the tannery and was involved in measuring and packing the leather after a protective and decorative coating had been applied. No signs of atopic constitution were found. Patch testing showed positive reactions to myroxylon pereirae (+), fragrance mix I (+), fragrance mix II (+) and benzidine (+). The inventory of the chemicals at this tannery showed that they still used a benzidine-based dye. No other allergens were present at her work station. Case 2: A 46-year-old female tannery worker had occupation related dermatitis on her hands, wrists and forearms. The dermatitis appeared after she started to work at the tannery. Her dermatitis worsened after she had been exposed to chemicals at the tannery and to detergents when she washed her hands. She had worked at this tannery for almost 5 years. She had no other part-time job besides her main work. Her main duty was preparing chemicals for the tanning process. She always wore synthetic rubber gloves when working with the chemicals. She had a history of atopic dermatitis. Patch testing showed positive reactions to hydroquinone monobenzylether (+), primin (+) and benzidine (+). Based on our observational study at this tannery there was no exposure to hydroquinone monobenzylether and primin and we could not find any benzidine-based dyes.

86 Case 3: A 41-year-s old male tannery worker had a history tannery work-related dermatitis on his hands, wrists and forearms. The dermatitis appeared when he had started to work at the tannery. It worsened when he was exposed to chemicals at his work place and healed when he had a few days leave. He had worked at this tannery for 18 years. He had no other parttime job besides his main work at the tannery. He had a history of atopic dermatitis. On skin examination, there were no prominent skin lesions and we only noted that he had a dry skin. Patch testing showed positive reactions to N, N-diphenylguanidine (+) and benzidine (+). Based on the observational study at this tannery, there was no exposure to N, N- diphenylguanidine, benzidine or any benzidine-based dyes Discussion Benzidine and its derivatives have been used to manufacture dyes during many years in the past. 3 Sensitization to benzidine as one of the standard allergens was reported three decades ago in 5% of 4,600 patients patch tested in a 5-year periode between in Spain. 4, 5 In 1978, several countries banned the manufacture of dyes from benzidine because of its potential carcinogenic effect 3 therefore there are no recent reports on benzidine sensitization. Although substitutes of benzidine-based dye were plentiful, continued demands from the textile and the leather industries for the original dyes made from benzidine and its related compounds have persisted in newly developing industrial countries. 3 In case 1, there was a relevant current exposure to benzidine based dye during her work in the finishing process. In case 2 and 3 we found sensitization to benzidine without any current relevant exposure to benzidine in the workplace. The possibility of past exposure to benzidine based-dyes in these 2 workers can not be excluded. In conclusion, this report shows the possible exposure to benzidine-based dying in tanneries in newly developing countries.

87 References 1. Febriana SA, Jungbauer F, Soebono H, Coenraads PJ. Inventory of the chemicals and the exposure of the workers' skin to these at two leather factories in Indonesia. Int Arch Occup Environ Health 2012; 85: Lachapelle, J.M. and Maibach, H.I. Patch testing methodology. In: Patch testing and Prick Testing A Practical guide Official Publication of the ICDRG, 2nd, Lachapelle J.M. and Maibach, H.I. ed. Springer-Verlag, Berlin Heidelberg, 2009: Dapson RW. Benzidine-based dyes: Effects of industrial practices, regulations, and world trade on the biological stains market. Biotech Histochem 2009: 84: Grimalt F, Romaguera C. Cutaneous sensitivity to benzidine. Derm Beruf Umwelt 1981; 29: Romaguera C, Grimalt F. Statistical and comparative study of 4600 patients tested in barcelona ( ). Contact Dermatitis 1980; 6:

88 CHAPTER 5 Occupational skin hazards and prevalence of occupational skin diseases in shoe manufacturing workers in Indonesia Sri Awalia Febriana 1,2, Hardyanto Soebono 1, Pieter-Jan Coenraads 2 1 Department of Dermatology & Venereology, Gadjah Mada University, Yogyakarta, Indonesia; 2 Department of Dermatology, University Medical Centre Groningen / University of Groningen, Groningen, the Netherlands. Int Arch Occup Environ Health 2014; 87:

89 Abstract Purpose Shoe manufacturing workers are exposed daily to an extensive range of potential physical and chemical occupational hazards. Shoe manufacturing in Indonesia is one of the industrial sectors that has shown sustained growth amongst the newly industrialized countries (NICs). In this study, we investigated the possible potential exposure of the workers to physical and occupational hazards and determined the prevalence of occupational skin diseases at a shoe manufacturing factory in Indonesia Methods A cross-sectional study on the observation of the working process and an inventory and risk assessment of exposure to the chemicals used. Classification of chemicals as potential sensitizers/irritants and qualitative assessments of these chemicals were done. Workers were examined and interviewed using the Nordic Occupational Skin Questionnaire- 2002/LONG. Results The risk of Occupational skin diseases (OSD) at the shoe factory o potential physical and chemical hazards in hot and humid environmental conditions. From a total of 514 workers, 8.5% reported current OSD and 4.8% reported a history of OSD. Occupational skin diseases were diagnosed in 29% of the workers by dermatologists and 7.6% had an occupational contact dermatitis (OCD). Of the 39 workers with contact dermatitis, 33 consented to being patch tested, 14(3%) workers showed a positive results and considered as having an occupational allergic contact dermatitis (OACD) and 25(4.9%) had an occupational irritant contact dermatitis (OICD). Conclusion We observed a repeated and prolonged exposure of the workers to numerous physical and chemical skin hazards at this factory. Keywords shoe manufacturing; occupational skin diseases; skin exposure

90 Introduction Workers in the shoe manufacturing industry exposed daily to an extensive range of potential occupational hazards (physical or chemical). In shoe production, there are many possible occupational exposures to a broad spectrum of allergens contained in many adhesives, preservatives, acrylic resins, leather, rubber, dyes and many kind of glues (neoprene, epoxy resin and rubber glues). Adhesives and solvents used in production process may also be potential irritants. 1, 2 Occupational skin disease in shoe manufacturing workers has been rarely reported. A study over the years at 5 shoe manufacturers in Italy showed a prevalence of occupational contact dermatitis of 14.6%; hyperkeratosis of fingertips 6% and pruritus sine materia 3.2%. 3 Low labour costs, easy supply of leather and a tradition of shoe making allowed shoe manufacturing industries to move to newly industrialized countries. 4 Shoe manufacturing in Indonesia is one of the industrial sectors that have shown sustained growth. The industry is labour intensive and concentrated in the small cottage industry for the in-country production and in large scale units for export products. Indonesia is the largest footwear exporter after China and Vietnam 5 and accounted for about 75.2% of a global production of 12.5 billion pairs of shoe in In 2009, the Indonesian footwear export amounted to $ 1.7 billion 7 with approximately 115,000 workers and has been a major supplier for well-known brands of shoes with the biggest market being Europe for many years. 6 Despite the significant number of workers in shoe manufacturing industry in Indonesia, there is still no published study on the actual risk and the prevalence of occupational skin diseases in shoe manufacturing industry in Indonesia The objective of this study was to investigate the possible source of potential chemical and physical hazards to which the workers were exposed to at a shoe factory and to determine the prevalence of occupational skin diseases in workers involved in shoe manufacturing industry in Indonesia as one of the NICs.

91 Materials and Methods Subjects 5 90 A survey to obtain information on the working process and the skin exposure followed by a cross-sectional study to assess the prevalence of occupational skin diseases was conducted between January-March 2010 at a shoe factory in Sidoarjo Industrial Area, East Java, Indonesia. This shoe factory was chosen for the following reasons: it had more than 500 workers, used modern equipment and exported its products to leading brands in Europe, United States and other Asian countries. According to the footwear and leather industry competitiveness report, the shoe manufacturing process and the machinery used in the export quality shoe factories are more or less the same. 8 All 514 employees engaged in the production process and exposed to potential physical and chemical hazards were included in the study. A flow chart of the workers that were investigated is shown in Fig.1. Figure 1. Flowchart of interviews and skin examinations

92 Observation of the workplace Preceding the cross-sectional study of skin symptoms and signs, the different workplaces were observed with regard to the nature of skin exposures to occupational hazards. Observation was done by an occupational dermatologist when the shoe production was running during a whole day. This included: 1. Observing the working area to get an overview of the floor space, ceiling height, lighting, circulation and ventilation and the indoor microclimate inside the factory. 2. Observing and making detailed report on the working cycle, job tasks, the duration and the frequency of different chemical and physical exposures at each working stage, handling procedures and preventive measures used by the workers Making a list of the materials and chemicals the workers were exposed to in the factory. All chemical exposure data were doublechecked with the researchers and the database at the Centre for Leather, Rubber and Plastic Agency for Research and Development, Ministry of Industry and Trade, Republic of Indonesia and Indonesia Footwear Service Centre (IFSC). 4. Obtaining information on the content of contact allergens/ sensitizers (including the CAS number of all ingredients) in chemicals the workers were exposed to through product labelling and declaration. The potential risk of all chemicals as a skin irritant /sensitizer was assessed using the Material Safety Data Sheets (MSDS). If the MSDS or product declaration was not available, we contacted the manufacturer or the supplier. We also used on-line databases from the National Institute for Occupational Safety and Health Institute (NIOSH) website 9, PubMed and a reference book Listing of potential sensitizers in the raw materials the workers were exposed to in the factory based on previous studies.

93 Questionnaire study and physical examination 5 92 All subjects provided informed consent prior to their inclusion in the study. All exposed employees were interviewed by trained interviewers guided by using the Indonesian translation of The Nordic Occupational Skin Questionnaire 2002 long version (NOSQ-2002/LONG) following the guideline from Nordic Occupational Skin Questionnaire Group. 11 The validity and the relevance of this questionnaire in the epidemiology of occupational skin diseases were reported in the publication from the Nordic Occupational Skin Questionnaire Group. 12 The interviewers were medical students and anthropologists who were all trained in interviewing skills by an occupational dermatologist. Since the level of education and the reading skills of the workers were limited, the interviewers read all the questions in the questionnaire and filled in the answers without giving a personal interpretation of the response. In accordance with the NOSQ procedures, the questionnaire was translated, adapted and modified for the specific circumstances in shoe manufacturing in Indonesia following the guideline from the Nordic Occupational Skin Questionnaire Group. 11 Adaptations were made on the question regarding the location of the eczema (question D2), the specification of the workstation (question G1) and the list of chemicals the workers were exposed to (question G10). Since In line with the interview process, all workers were examined by two dermatologists and a dermatologist with additional training in contact and occupational dermatology to determine the prevalence of occupational skin diseases. Skin examinations by a derma the knowledge of the responses to the questionnaire) as a reference standard in order to evaluate the accuracy of our results. In half of the workers, patch testing was done with allergens from the European baseline series, the shoe series (Chemotechnique Diagnostics, Vellinge, Sweden) and additional allergens specific for shoe factory work. Patch test results were read on days 2,4,7 as recommended by the International Contact Dermatitis Research Group (ICDRG). 13 Detailed results of the patch-testing will be reported in a separate paper.

94 Statistical analyses were performed using chi-square test to compare the differences between interview-based prevalence and examination-based prevalence and to compare the prevalence of OSD between departments based on the interview and examination. All analyses were performed using commercially available software (SPSS, version 20). Results Working process and chemicals that the workers were exposed to The shoe making itself involves five steps: 1. Preparation (raw material warehouse, design, pattern making and cutting); 2. Preparing /upper sole (sewing preparation, sewing/stitching, folding and gluing); 3. Assembling (lasting, heating, buffing, outsole attaching, pressing, cooling, and last removing); 4. Finishing and 5. Packing. The exposure of the skin to a potential skin hazards in the factory are shown in Table 1. The relevant in was exposed to are shown in Table 2a and 2b. The chemicals were mostly irritants, but several sensitizers were also encountered Table 1. Potentially hazardous skin exposures in shoe factory workers Potential skin hazards Working process Physical Chemical Skin effects 1. Preparation Raw material ware house Design and pattern making Cutting - Skin cuts and skin friction from the knives and blades - Repetitive friction - Airborne exposure to the leather, polyurethane and rubber dust - Skin sensitization from the sensitizers potentially present in materials used (leather, polyurethane and rubber) - Localized itching on uncovered skin caused by dust - Hyperkeratosis and callus from friction - Cuts and lacerations

95 Potential skin hazards Working process Physical Chemical Skin effects 2. Preparing/upper sole Sewing preparation (skiving, embossing, embroidery, perforating, folding) Sewing/stitching Folding Glueing - Piercing injury from punch presses and sewing machines. - Repetitive friction - Skin exposure from spilling adhesives and solvent ingredients such as methyl ethyl ketone, acetone, ethyl acetate, cyclohexane and butyl acetate - Airborne exposure to dust from leather, polyurethane and rubber - Cuts and laceration - Hyperkeratosis and callus from friction - Irritant contact dermatitis to solvents, adhesives, and varnishes. - Allergic contact dermatitis to sensitizers potentially present in the materials used (leather, rubber, polyurethane and neoprene) 5 94 Lasting Heating Buffing Outsole attaching Pressing Cooling Last removing Accessories assembling 4. Finishing - Heat exposure from oven and press machines that heat and form shoe parts, stockfit machines used to assemble parts, heaters used to singe and remove stray fibres. - High ambient temperature (mean 34 o C) and high ambient humidity (mean 80%) - Heat exposure from cementspraying operations. - Repetitive vibrations from machinery parts - Exposure to a variety of solvents and organic chemicals such as methyl ethyl ketone, acetone, ethyl acetate, cyclohexane and butyl acetate. - Exposure to nickel sulphate - Airborne exposure to solvent and adhesive vapours - Hyperkeratosis and callus from friction - Miliaria. - Irritant contact dermatitis to solvents, adhesives and varnishes. - Allergic contact dermatitis to sensitizers potentially present in materials used (leather, rubber, polyurethane and neoprene) and accessories (nickel). Checking whether the shoe is clean and without excess adhesive. - Repetitive friction - Exposure to waterproof agents (acetone and methyl ethyl ketone) - Irritant contact dermatitis caused by waterproof agents - Localized itching in uncovered skin caused by dust. 5. Packing - Repetitive friction - - Hyperkeratosis and callus from friction

96 Tables 2a. Materials used in shoe making and their potential sensitizers Raw material exposing all workers irrespective of work station Finished leather* Sensitizers Preservatives/biocide - 2-N-octyl-4-isothiazolin-3-one - Cl + Me-Isothiazolinone - Metam sodium - Sodium diethyldithiocarbamate - 2- Thiocyanomethyl benzothiazole Tanning agents - Potassium dichromate - 2-Mercaptobenzothiazole - Formaldehyde - Glycine - Chlorbenzene - Glutaraldehyde Dyeing process - Disperse orange 3 (CI 11005) - Acid yellow 36 (CI 13065) - N-isopropyl-n-phenyl 4-phenylenediamine - 4-Aminoazobenzene - Benzidine 5 95 Rubber Polyurethane Neoprene *Described in details in Febriana et al (2011) Finishing process - Epoxy resin - Polyethylacrylate - Colophony - N-Isopropyl-N-phenyl-4-phenylenediamine - Hydroquinone monobenzylether - Thiuram mix - 4-Phenylenediamine base - Mercaptobenzothiazole - Mercapto mix - Carba mix - 1,3 Diphenylguanidine - Sodium diethyldithiocarbamate - Colophony - Toluene diisocyanate - Dodecyl mercaptan - Diphenyl methane-4, 4-diisocyanate - Dodecyl mercaptan - Diphenylthiourea - Diethylthiourea - Dibuthylthiourea - p-tert-butylphenol-formaldehyde resin

97 Table 2b. Chemicals used in shoe making and their potential sensitizers/irritants Work process Chemicals exposing the workers skin (based on workplace observation) Sensitizers/ Irritants 1. Preparation Raw material warehouse Design and pattern making Cutting 2. Preparing/upper sole - - Sewing preparation (skiving, embossing, embroidery, perforate, folding) Printing paints Cyclohexanone resin Methyl ethyl ketone (MEK) Methyl isobutyl ketone (MIBK) Irritant Irritant Irritant 5 96 Sewing/stitching Folding Gluing Solvents Toluene (methylbenzene) Cyclohexane (hexahydroxybenzene) Irritant Irritant 3. Assembling Lasting Heating Buffing Outsole attaching Pressing Cooling Last removing Accessories assembly Solvents Acetone (2-propane) Methyl Ethyl Ketone (MEK) Toluene (methylbenzene) Adhesive hardener Polyisocyanate Ethyl acetate (acetic acid ethyl ester) Neoprene based adhesive p-tert-butylphenol formaldehyde resin Dodecyl mercaptan Polyurethane based adhesive Triethylenediamine Diphenylmethane diisocyanate (MDI) Epoxyresin based adhesive Epoxyresin Phenyl glycidyl ether Ethylenediamine dihydrochloride Other glue and adhesive components Colophony Formaldehyde 2-Mercaptobenzothiazole Primer for sponge ethyl vinyl acetate Acetone (2-propane) Tetrahydrofuran Primer for leather and sole Methyl Ethyl Ketone (MEK) Toluene (methylbenzene) Irritant Irritant Irritant Irritant Irritant Sensitizer Sensitizer Sensitizer Sensitizer Sensitizer Sensitizer Sensitizer Sensitizer Sensitizer Sensitizer Irritant Irritant Irritant Irritant

98 Work process Chemicals exposing the workers skin (based on workplace observation) DMF (N,N-dimethyl formamide) Cyclohexanone (cyclohexyl ketone) Primer for sole Methyl Ethyl Ketone (MEK) Toluene (methylbenzene) Cyclohexane (hexahydroxybenzene) Primer for oily leather Methyl Ethyl Ketone (MEK) Ethyl acetate (acetic acid ethyl ester) Primer for leather Cyclohexane (hexahydroxybenzene) Primer for rubber Acetone (2-propane) Cleaning agent Methyl Ethyl Ketone (MEK) Sensitizers/ Irritants Irritant Irritant Irritant Irritant Irritant Irritant Irritant Irritant Irritant Irritant Solvent Dichloromethane Propylene oxide Shoe accessories Nickel sulphate Irritant Irritant Sensitizer Finishing and trimming Waterproof agent Acetone (2-propanone) Methyl Ethyl Ketone (MEK) Ethyl acetate (acetic acid ethyl ester) Cleaning agent Methyl Ethyl Ketone (MEK) Irritant Irritant Irritant Irritant 5. Packing - 1. Preparation Preparation department was divided into 3 sections: 1) raw material warehouse, 2) design and pattern making and 3) clicking and cutting. In the raw material warehouse workers loaded and unloaded, sorted and prepared shoe materials like leather, synthetic leather, outer soles, lining materials and shoe accessories. The upper shoe is made in the clicking and cutting department. After pattern drawing and desired pattern selection, the workers cut out various patterns of upper shoes using loose-knife tools, clicking machine or in sole moulding presses to obtain all the components of a shoe. They handled all of these materials with their bare hand and never used gloves.

99 2. Preparing (upper sole) In the preparing (upper sole) department, all the shoe components are sewn together by highly skilled workers to produce completed upper shoe. Before sewing, skiving, embossing, embroidery, perforation, and folding of the shoe materials was done. In early stage, the pieces were sewn together on the flat machine. In the later stages, the sewing surface of the machine was elevated on a post to enable to three-dimensional sewing of the upper shoe. At this stage, the eyelets were inserted in order to accommodate the laces of the finished shoe In the shoe manufacturing industry, there were several steps in the process of binding surfaces in many kinds of shoe components. In order to ensure the good adhesive bonding, the surfaces were conditioned with priming, washing and roughening process. In this step workers were exposed to liquid adhesives, but they never wore gloves. After the surfaces were adhered, the upper and the bottom stock were sewed and the outsole, insole and heel were glued to the upper portion of the bottom shoe and assembled. In the lasting and making department, the completed upper shoe was moulded into a shape of a foot using a plastic shape simulating a foot, which is called a last. First, an insole was temporarily attached onto the shoe bottom. The upper shoe was then stretched and moulded into the insole. After the procedure was completed, the shoe last was obtained. The next stage was sewing the welt (a strip of leather or plastic) onto the shoe. The excess material was trimmed followed by stitching the sole onto the welt. 3. Assembling In assembling department, workers covered the edge of the upper shoe with latex. They put the upper shoe inside the oven. Workers glued the inner shoe layer onto the shoe upper. Shoe upper, which was already covered with latex, was then attached to insole paper board. The upper side of the shoe was covered with primer, dried and then the outer and the upper sole were put in the oven. The next step was applying the adhesives, drying and putting in the oven. In the out sole assembling department, outer soles and upper soles were attached manually and then bonded by the pressing machine. The last step

100 was to put the shoes into the cooling room. In this department workers were exposed to liquid glue and vapours. They used a face mask while working but never used gloves. 4. Finishing In the finishing department, workers put the waterproof agent and cleaned with methyl ethyl ketone and inspected whether the shoes were clean and had no excess adhesive. The bottom of the sole was lightly buffed, stained and polished. Workers were exposed to liquid cleaner and waterproof agent. They did not wear gloves or face masks while working. 5. Packing In this department, the shoes were packed in a shoebox for shipment. The workers worked with bare hands and did not wear face masks. All of the operations described above were carried out manually, usually without any protective measures. Face masks were the only protective measure that was worn by the workers in the assembling department Questionnaire study and physical examination A total of 514 workers (497 females and 17 males) were enrolled into our study. Their age and the duration of the exposure of their skin to various chemicals are shown in Table 3. The overall prevalence of the current OSD reported by workers was 8.5% (it was reported by 44 workers; 7(14%) from warehouse, shoe-design, and cutting, 23 (7.4%) from upper-sole preparation and sewing, 10(7.9%) from assembling, 3(18.8%) from finishing and 1(7.7%) from packing. Twenty five (4.8%) workers reported a history of OSD; 1(2%) from warehouse, shoe-design and cutting, 14(4.5%) workers from upper sole, preparation and sewing, 9(7.1%) workers from assembling and 1(6.3%) worker from finishing). Out of the 514 workers, 445 (86%) reported no skin problems (Table 4a). The dermatological diagnoses of occupational related skin diseases are shown in Table 4b. The prevalences of OSD based on self reported symptoms and dermatological examination are not statistically significantly different between the departments. The prevalence rate of OSD based on dermatological examination (29%) was significantly higher (p<0.05)

101 compared to the prevalence of self reported symptoms (8.5%). The overall prevalence of occupational contact dermatitis (OCD) was 7.6%; in general, most cases (5.2%) had mild disease. Most of the workers with OCD work in the upper-sole and assembling department. In the assembling department, we found some cases of facial dermatitis that was caused by exposure to vapours from solvents and adhesives From 39 workers with contact dermatitis, 33 consented to being patch tested with the European baseline series, the shoe series and additional allergens specific for shoe factory work. Of these, 14(3%) had a relevant patch test reaction and were diagnosed as having an occupational allergic contact dermatitis (OACD). Occupational irritant contact dermatitis (OICD) were diagnosed in 25(4.9%) workers. In addition, callus/hyperkeratosis was a common condition (9.7%) especially in the upper sole sewing department and the assembling department where there is repetitive friction of the workers skin with shoe materials, sewing tools and machinery parts. The prevalence of pruritus sine materia was 8.2% and frequently found in all departments except finishing. Table 3. Demographic and occupational characteristics of the 514 workers Characteristics Mean age in years (SD) Mean working time in months (SD) Mean working hours/week (SD) Warehouse, shoe design, and cutting Upper-sole preparation and sewing Assembling Finishing Packing Total 33 (5) 32 (5) 32 (5) 32 (6) 32 (5) 32 (5) 118 (63) 94 (65) 100 (66) 86 (61) 62 (83) 97 (66) 51 (10) 47 (7) 49 (9) 48 (7) 49 (13) 48 (8) Table 4a. Results from the interview based NOSQ-2002 in 514 workers * Workers without skin diseases Workers with a current skin disease related to occupation (NOSQ- 2002) ** Warehouse, shoe design, and cutting Upper-sole, preparation, and sewing Assembling Finishing Packing Total 42 (84%) 272 (88%) 107 (85%) 12 (75%) 12 (92%) 7 (14%) 23 (7.4%) 10 (7.9%) 3 (18.8%) 1 (7.7%) 445 (86%) 44 (8.5%)

102 Workers with history of skin disease related to occupation (12 months) (NOSQ-2002) Total number of workers Warehouse, shoe design, and cutting Upper-sole, preparation, and sewing Assembling Finishing Packing Total 1 (2%) 14 (4.5%) 9 (7.1%) 1 (6.3%) - 25 (4.8%) * Significant difference between interview-based prevalence and examination-based prevalence ** No statistically significant differences in OSD prevalence between departments Table 4b. Results from dermatological examination in 514 workers* Workers with current occupation-related skin disease (assessed by dermatologist)*** Occupational contact dermatitis of which occupational allergic contact dermatitis Callus/hyperkeratosis Pruritus sine materia Skin cut/ laceration Miliaria Warehouse, shoe design, and cutting 21 (42%) 3 (6%) 1 (2%) 9 (18%) 5 (10%) 3 (6%) - Upper-sole, preparation, and sewing 81 (26%) 21 (5.4%) 9 (2%) 23 (7.4%) 27 (8.7%) 6 (1.9%) 1 (0.3%) Assembling Finishing Packing Total 42 (33%) 12 (9.5%) 3 (4%) 17 (13.5%) 8 (6.3%) 4 (3.2%) 1 (0.8%) 5 (31%) 2 (12.5%) 1 (6.3%) - 2 (12.5%) (15%) 1 (7.7%) - 2 (15.4%) (29%) 39 (7.6%) 14 (3%) 50 (9.7%) 42 (8.2%) 13 (2.5%) 2 (0.4%) * Significant difference between interview-based prevalence and examination-based prevalence *** No statistically difference in OSD prevalence based on the examination between departments Discussion Our results confirm that workers in the shoe manufacturing industry are exposed to many potential chemicals and physical skin hazards. The highest exposure occurred in those who performed gluing and cleaning tasks. The factory has a continuous work process, without physical separation of the workplaces. Therefore, all workers were exposed to solvent vapours. Moreover, in the preparing/upper sole and assembling department, there were direct skin exposures to a wide variety of solvents and organic chemicals. The high prevalence of occupational contact

103 dermatitis (9.5%) in the assembling department may have been caused by heat exposure from heat generating machines leading to a high ambient temperature (38-40 o C) and humidity (80%). We observed that the workers were generally exposed to the same chemicals as described in other similar studies 14-16, although in addition we found skin exposure to methyl ethyl ketone, acetone, ethyl acetate, cyclohexane and butyl acetate From the questionnaire study fewer workers reported a current skin complaint (44 workers, 8.5%), whereas 151 (29%) had current occupationrelated skin diseases diagnosed by dermatological examination. A s ste atic re ie of st dies s o ed t at agree ent et een or ers self-reports of or related diseases it t e reference standard of expert opinion was mainly low to moderate: the prevalence estimated by symptom-based questionnaires was higher than the prevalence estimated by reference standards, except for hand eczema and respiratory disorders. 17 We found published cross-sectional studies on shoe manufacturing workers at shoe factories in other NICs such as India, Thailand and Portugal Among the studies in the NICs, the prevalence of occupational skin diseases (13.6%) was only mentioned in Thailand. 14 Another survey at an Italian shoe factory reported that the prevalence of occupational skin diseases was 24.7%. 3 Our study indicates a higher pre alence. e ide range of reported pre alence fig res et een 13.6% and 29%) can probably be explained by the differences in the definition of cases, period of screening and data collecting. Differences in the working conditions may also cause the wide range of reported point prevalence. If we look at the number of workers employed in the shoe manufacturing sector in Indonesia, we can see that the burden of occupational skin diseases in workers in shoe manufacturing is high. Our observational study on tannery workers in the same area 18 showed that in tanneries, or ers ere e posed to ore inds of c e icals and et or co pared to s oe factor or ers. erefore t e occ pational contact dermatitis cases in the shoe factory were milder compared to the tanneries. The prevalence of callus/hyperkeratosis (9.7%) and pruritus sine materia (8.2%) in the shoe factory was higher compare to the workers in the tannery (1%) and probably caused by more intense repetitive friction and airborne exposure to dust from leather, polyurethane and rubber. Shoe factory workers were also exposed to heat more extensively than tannery workers especially in the assembly area where there is heatgenerating machinery. Personal protective equipments in both factories were not properly applied and mostly used as a secondary prevention measure. In this study, we were able to produce a detailed scheme of the working process with a focus on the risk of occupational skin diseases in each step

104 in shoe manufacturing. The difficulty in obtaining a random sample from shoe factories in Indonesia as the object of our study limits the interpretation of our data. Another limitation of our study is that we only have the qualitative data on the level of skin exposure to potential physical and chemical hazards. In contrast to these limitations, we realize that this is one of the few studies on occupational skin disease risk in a newly industrializing country. More research into the effect of the occupational health risk of exporting such activities from Western countries to these countries is imperative. Conclusion We observed a high frequency of exposure to potential chemical and physical skin hazards in shoe manufacturing workers in Indonesia. We noted that the prevalence of occupational skin diseases in workers in shoe manufacturing industry in Indonesia was higher than that reported in other NICs. Conflict of interest The authors declare that they have no conflict of interest References 1. Geier J, Lessmann H. Leather and Shoes. In: Kanerva's Occupational Dermatology, 2nd, Rustemeyer T, Elsner P, John SM, Maibach HI, eds. Springer-Verlag, Heidelberg New York Dordrecht London, 2012: Taylor JS, Erkek E, Podmore P. Shoes. In: Contact Dermatitis, 4th, Frosch PJ, Menne T, Lepoittevin JP, eds. Springer, Berlin, Heidelberg, 2005: Mancuso G, Reggiani M, Berdondini RM. Occupational dermatitis in shoemakers. Contact Dermatitis 1996; 34: Anonim [Internet]; Available from: Last accessed 11 March Indonesia accelerates in the footwear race [Internet]; Available from: Last accessed 11 March United nations commodity trade statistics database [Internet]; Available from: Last accessed 11 March Shoe makers expect hefty increase in exports this year [Internet] Jakarta; Available from: Last accessed 11 March 2011.

105 8. Wiryodiningrat S. Pengetahuan bahan pembuatan sepatu/ alas kaki. 1st ed. Citra Media, Yogyakarta, Indonesia, Anonim [Internet]; Available from: Last accessed 11 Macrh de Groot A, ed. Patch testing: Test concentration and vehicles for 4350 chemicals. 3rd edition ed. The Netherlands: Acdegroot publishing; Nordic occupational skin questionnairre-nosq Nordic questionnaire for surveying work-related skin diseases on hands and forearms and relevant exposures. [Internet]. Denmark: Nordic Council of Ministers, Copenhagen Available from: Susitaival P, Flyvholm MA, Meding B, et al. Nordic occupational skin questionnaire (NOSQ- 2002): A new tool for surveying occupational skin diseases and exposure. Contact Dermatitis 2003; 49: Lachapelle JM and Maibach, HI. Clinical relevance of patch test reactions. In: Patch testing and Prick testing, 2nd, Lachapelle J.M. and Maibach, H.I. ed. Springer-Verlag, Berlin Heidelberg, 2009: Todd L, Puangthongthub ST, Mottus K, Mihlan G, Wing S. Health survey of workers exposed to mixed solvent and ergonomic hazards in footwear and equipment factory workers in Thailand. Ann Occup Hyg 2008; 52: Tiwari RR. Child labour in footwear industry: Possible occupational health hazards. Indian J Occup and Environ Med 2005; 9: Mayan O, Pires A, Neves P, Capela F. Shoe manufacturing and solvent exposure in Northern Portugal. Appl Occup Environ Hyg 1999; 14: Lenderink AF, Zoer I, van der Molen HF, Spreeuwers D, Frings-Dresen MH, van Dijk FJ. Review on the validity of self-report to assess work-related diseases. Int Arch Occup Environ Health 2012; 85: Febriana SA, Jungbauer F, Soebono H, Coenraads PJ. Inventory of the chemicals and the exposure of the workers' skin to these at two leather factories in Indonesia. Int Arch Occup Environ Health 2012; 85:

106 CHAPTER 6 Occupational allergic contact dermatitis and patch test results in Indonesian shoe factory workers Sri Awalia Febriana 1,2, Hardyanto Soebono 1, Pieter-Jan Coenraads 2, Marie-Louise A Schuttelaar 2 1 Department of Dermatology & Venereology, Gadjah Mada University, Yogyakarta, Indonesia; 2 Department of Dermatology, University Medical Centre Groningen / University of Groningen, Groningen, the Netherlands. Submitted to Occupational Medicine

107 Abstract Background Shoe manufacturing workers are exposed daily to an extensive range of potential chemical skin hazards. Shoe manufacturing has in recent years been outsourced to Newly Industrialized Countries, where only limited attention has been paid to occupational health hazards. There has been little study of workers to determine the prevalence of occupational allergic contact dermatitis and the responsible allergens. Aims To evaluate the prevalence of allergic contact dermatitis in a population of shoe factory workers in a Newly Industrialized Countries and to identify the responsible allergens. To assess the frequency and relevance this study Methods A prospective cross-sectional study was done in a shoe factory in Java, Indonesia. All 514 workers were interviewed using an Indonesian translation of the Nordic Occupational Skin Questionnaire (NOSQ- 2002/LONG) and underwent skin examinations. Patch tests were done on 78 healthy workers 33 workers with OCD to identify the causative testing. Results Occupational contact dermatitis was suspected in 8% workers while 3% were diagnosed with and occupationally relevant contact allergy to 16 allergens. The most frequent sensitizers were shoe adhesives, followed by rubber and leather. Conclusions Our study showed a high prevalence of occupational allergic contact dermatitis in shoe factory workers in Indonesia. Like other studies we found adhesives and rubber allergens to be the most common sensitizers. But our study showed differences in the frequency and variation of sensitizing allergens. Key words Occupational dermatitis, shoe factory workers, patch test, allergic contact dermatitis.

108 Introduction daily exposure of workers to an extensive range of potential skin hazards. Shoes are made from leather, wood, rubber, fabrics, or plastics coming from many parts of the world. The workers as final assemblers may not be aware of chemicals that have been used to prepare each part of the shoe. 1, 2 Shoe manufacturing involves hundreds of operations most of which are done manually without sufficient personal protective equipment. 3 As mentioned above, shoe manufacture involves a vast range of chemicals, many potentially sensitizing. 2 In spite of frequent high exposure of workers to these potential sensitizers, the prevalence of occupational allergic contact dermatitis and patch test results from workers have rarely been reported. The most recent cross-sectional study of shoe manufacturers was carried out by Mancuso et al (1996) in Italy during They reported a 6.5% prevalence of OACD in 246 shoe factory workers. Indonesia is a newly industrialized country (NIC) and classified as the biggest shoe producing countries in the world together with China and Vietnam. One third of the Indonesian shoe production is being exported to the EU market, including Northern and Eastern Europe. In a previous publication 5 we presented a detailed overview of the exposure to putative sources of occupational irritants and sensitizing agents in the Indonesian shoe manufacturing industry and described the prevalence of occupational skin diseases among the workers. However, at that time detailed results of patch testing of shoe factory workers had not yet been reported. The aims of this paper are thus: 1) to describe the prevalence of OACD in a population of shoe factory workers in a NIC; and 2) to identify the responsible allergens and clinical relevance of positive patch test reactions Methods For this purpose we performed a cross-sectional study in a shoe factory in Java, Indonesia. This factory was chosen for the following reasons: it had

109 more than 500 workers, used high quality technological equipment and exported branded shoes to Europe, the United States and other Asian countries. This study was approved by the medical ethic and research committee of the Faculty of Medicine Gadjah Mada University. All subjects provided informed consent prior to their inclusion in the study. Workers in the factory were divided into five different groups based on their specific activities and the types of materials and chemicals they were exposed to. These 5 groups were as follows: 1) preparation (raw material warehouse, design, pattern making, and cutting); 2) preparing-upper sole (sewing preparation, sewing/stitching, folding and gluing); 3) assembling (lasting, heating, buffing, outsole attaching, pressing, cooling, and removing); 4) finishing and 5) packing. All workers engaged in the production process and thus exposed to potentially hazardous chemicals were included in the study. All 514 workers were interviewed using a structured questionnaire and all underwent dermatological examination Structure interviews were carried out to obtain information as to the locations and morphological aspects of the skin diseases themselves as well as information regarding exposure to relevant allergens at the workplace. Interviews were conducted using the Indonesian translation of the Nordic Occupational Skin Questionnaire (NOSQ-2002/LONG). The questionnaire was translated, adapted and modified for specific circumstances at the shoe factory following the Guideline of the Nordic Occupational Skin Questionnaire Group. 6 All workers were examined within a period of 3 months by a member of a team of dermatologists supervised by a dermatologist with additional training in contact and occupational dermatitis. Patch tests were done on 33 of 39 shoe factory workers diagnosed with current occupational contact dermatitis (OCD); 78 workers without skin disease were also patch tested. We used allergens from the European baseline series, the shoe series (Chemotechnique Diagnostics, Vellinge, Sweden) and additional allergens specific to shoe factory work. These additional allergens were identified based on a previously reported inventory of potential allergens and exposure assessment at this shoe factory. 5 Some of the additional allergens were provided by Chemotechnique Diagnostics, Vellinge, Sweden. Allergens not commercially available were prepared in our laboratory; we used analytical-grade

110 chemicals for these substances. The specific allergens to which shoe factory workers were exposed to and which were used for the patch testing are listed in Table 1. Patch test procedures were performed on the upper backs of the workers, using Finn (Epitest Ltd., Helsinki, Finland) mounted on an acrylate-base adhesive tape (Scanpor Alpharma AS, Norgesplaster Facility, Norway). The applied patch tests were reinforced with extra tape stuck at the margin and covering the chamber area, a procedure recommended in hot climates to avoid detachment of the strips. 7 After 48 hours occlusion we removed the Finn-chambers and read the patch test results on days 2, 4 and 7 according to International Contact Dermatitis Research Group guidelines. 8 A positive patch test reaction to a substance in workers with OCD was judged clinically relevant if the worker had been exposed to the substance and there was a relationship between this exposure and the worker's skin lesions. In healthy workers we assessed a positive patch test reaction as relevant if the worker had been exposed to the substance. Table 1 Raw materials and sensitizing components to which workers were exposed and patch tested Material to which workers are exposed Leather Adhesive Allergens used for patch testing Concentration and vehiculum CAS number Preservatives/biocides 2-n-octyl-4-isothiazolin-3-one a 0.1% pet Cl +Me-isothiazolinone a 0.02% aqua Metam sodium b 0.03% pet Sodium diethyldithiocarbamate c 2% pet thiocyanomethyl benzothiazole c 0.2% pet Tanning agents Potassium dichromate a 0.5% pet mercaptobenzothiazole a 2.0% pet Formaldehyde a 1.0% aqua Polyethyl acrylate b 5.0% pet Glycine b 2.0% aqua Chlorbenzene b 5.0% olive oil Glutaraldehyde a 0.2% pet Finishing process Epoxy resin a 1.0% pet Polyethyl acrylate b 5.0% pet Methyldibromoglutaronitrile a 0.5% pet Colophony a 20.0% pet Dodecylmercaptan a 0.1% pet

111 6 110 Material to which workers are exposed Allergens used for patch testing Concentration and vehiculum CAS number 4-tert-Buthylphenol formaldehyde resin a 1.0% pet Rubber N-isopropyl-n-phenyl 4-0.1% pet phenylenediamine a Hydroquinone monobenzylether a 1.0% pet Sodium diethyldithiocarbamate c 2% pet N,N- diphenylguanidine a 1.0% pet mercaptobenzothiazole a 2.0% pet Polyurethane Toluene diisocyanate c 0,1% pet Diphenylmethane-4,4-diisocyanate c 2.0% pet Neoprene rubber Diphenylthiourea a 1.0% pet Diethylthiourea a 1.0% pet Dibuthylthiourea a 1.0% pet N-isopropyl-n-phenyl 4- phenylenediamine a 0.1% pet Epoxy resin Epoxy resin a 1.0% pet Phenyl glycidyl ether c 0.25% pet Ethylenediaminedihydrochloride c 1.0% pet Diaminodiphenylmethane c 0.5% pet Dyes Disperse orange 3 a (CI 11005) 1.0% pet Acid yellow 36 a (CI 13065) 1.0% pet Phenylenediamine base a 1.0% pet Aminoazobenzene a (dye) 0.25% pet Shoe accessories Nickel sulfate a 5.0% pet a allergen from European baseline series and shoe series (Chemotechnique Diagnostics ) b in-house preparation (chemicals were obtained from Sigma-Aldrich) c other allergen from Chemotechnique Diagnostics The diagnostic criteria for OACD in this study were based on information from three sources: workplace observation, questionnaire and dermatological examination including patch test results. Methods used in workplace observation have been detailed elsewhere. 5 A diagnosis of OACD was established in cases which met all of the following criteria: Diagnosed as OACD by a dermatologist with additional training in contact and occupational dermatitis 2. Exposure to relevant occupational allergens

112 3. Confirmed type 4 sensitization to the relevant occupational allergens 4. Exposure confirmed by a dermatologist with additional training in contact and occupational dermatitis as cause or important aggravating factor in the development of the OACD. Results Characteristics of workers All 514 workers (497 females and 17 males) employed in production at this shoe factory were included in the study. Their mean age was 32 (range: 19-47) years, their mean duration of employment 8 years, and mean working hours 48 hours per week. Fifty-two workers (10%) had a history of childhood eczema, 63 (12%) had a history of atopic respiratory diseases and 77 (15 %) had atopic skin diathesis according to Diepgen s criteria. Occupational contact dermatitis was suspected in 39 (7.6%) workers. Patch tests were done in 33 out of 39 workers with OCD as well as in 78 healthy workers. Of the 33 workers with OCD, 14 (42.42%) and of the 78 healthy workers, 6 (7.7%) showed relevant sensitization to one or more shoe factory work allergens (Figure 1). A total of 14 (2.7%) of 514 workers showed positive patch test reactions to one or more allergens which were relevant to the shoe factory work were diagnosed as having OACD. Of the 14 workers with OCD, OACD was found in 1 (2%) worker in the preparation (warehouse, shoe design, cutting); 9 (2%) in the preparing upper sole (sewing, folding, gluing); 3 (4%) in the assembling; and 1 (6.3%) in the finishing department (Table 2) The list of positive patch test reactions which were relevant to shoe factory work is presented in table 3. In 14 workers with OACD we identified relevant positive reactions to 16 allergens: 5 workers with 1 positive reaction and 9 workers with more than 1 positive reaction (Table 4). The most frequent sensitizers were shoe adhesives (n=9), followed by allergens present in rubber (n=8), leather/leather and synthetic leather finishing process (n=5), dyes (n=2), and shoe accessories (n=2). In the 78 healthy

113 workers we found positive patch test reactions relevant to their shoe factory work in 6 workers (Table 3) Figure 1 Flowchart of interviews, skin examinations and patch testing Figure 2. Workers in preparing department

114 Figure 3. Workers in assembling department Table 2 Occupational contact dermatitis and occupational allergic contact dermatitis in 514 shoe factory workers Working section Warehouse, shoe design, and cutting Upper-sole, preparation and sewing Number of workers Occupational contact dermatitis n(%) Occupational allergic contact dermatitis n(%) 50 3 (6) 1 (2) (5) 9 (2) Assembling (10) 3 (4) Finishing 16 2 (13) 1 (6) Packing 13 1 (8) - Total (8) 14 (3)

115 Table 3. Positive patch test reactions relevant with respect to shoe factory work in workers with occupational allergic contact dermatitis and in healthy workers Material to which workers are exposed Leather Allergens which was relevant for causing occupational allergic contact dermatitis Workers with occupational contact dermatitis N=33 n(%) Healthy workers N=79 n (%) Preservatives/biocides Cl +Me-isothiazolinone a 1 (3) - Tanning agents Potassium dichromate a 1 (3) - Formaldehyde a 1 (3) - Glutaraldehyde a 1 (3) - Leather and synthetic leather Rubber materials Adhesive Finishing process Polyethyl acrylate b 1 (3) - N-isopropyl-n-phenyl 4-phenylenediamine a 1 (3) - 4-Phenylenediamine base a 2 (6) 1(1) N,N- diphenylguanidine a 2 (6) - Dibuthylthiourea a 3 (9) Dyes Shoe accessories 4-tert-Buthylphenol formaldehyde resin (PTBP-F resin) a 2 (6) - Methyldibromoglutaronitrile 3 (9) 1(1) Dodecylmercaptan a 2 (6) 1(1) Epoxy resin a 1 (3) - Colophony a 1 (3) 1(1) 4-Aminoazobenzene a 2 (6) 3 (4) Nickel sulfate a 2 (6) - * in some workers more than one allergen was relevant for causing occupational allergic contact Dermatitis Table 4 Workers (all female)with occupational allergic contact dermatitis Age Working section Preparation Causes/aggravator of the skin symptoms Sensitization Description material 30 Cutting Leather Glutaraldehyde Formaldehyde Leather tanning agent Leather tanning

116 Age Working section Causes/aggravator of the skin symptoms Scissor and handle of mechanical cutting machine Sensitization Nickel sulphate Description material agent Scissor and cutting machine Preparing/ upper sole 29 Sewing Rubber insoles N-Isopropyl-N-phenyl- 4- phenylenediamine Dibuthylthiourea 35 Sewing Shoe adhesive 4 Aminoazobenzene 4-tert-Buthylphenol formaldehyde resin Rubber antioxidant, anti degradant Rubber accelerator and antidegradant Cross sensitization to n- isopropyl-n- phenyl-4- phenylenediamine Neoprene based adhesive Rubber insoles 4-Phenylenediamine base 1,3-diphenylguanidine Rubber antioxidant Rubber accelerator Sewing Rubber adhesive Rubber insoles Colophony 1,3-diphenylguanidine Rubber adhesive and tackifier in inner sole Rubber accelerator 30 Sewing Leather Oil paint Cl-Me-Isothiazolinone Potassium dichromate 4-Aminoazobenzene Biocide in leather processing Leather tanning agent Shoe adhesive 4-tert-Buthylphenol formaldehyde resin Polyurethane dye Neoprene based adhesive 32 Sewing preparation Shoe adhesive Dodecylmercaptan Neoprene based adhesives

117 Age Working section Causes/aggravator of the skin symptoms Sensitization Description material 41 Sewing Shoe adhesive Methyldibromoglutaron itrile Preservatives in shoe adhesive 41 Sewing Shoe adhesive Dodecyl mercaptan Neoprene adhesives 40 Sewing Rubber insoles Shoe adhesive Dibuthylthiourea Methyldibromoglutaron itrile Rubber accelerator and antidegradant Preservatives in shoe adhesive 39 Sewing preparation Rubber sole 4-Phenylenediamine base Rubber antioxidant Assembling 38 Shoe adhesive Methyldibromoglutaron itrile Preservatives in shoe adhesive Synthetic leather (polyurethane) Polyethyl acrylate Used in polyurethane finishing process 36 Adhesive Latex used for covering inside part of shoe upper Epoxy resin Dibuthylthiourea Preservatives in shoe adhesive Rubber accelerator and antidegradant 29 Shoe buckles and inlets Oil paint Nickel sulphate 4 Aminoazobenzene Shoe buckles/shoe inlets made from nickel polyurethane dye Finishing 49 Rubber sole 4-Phenylenediamine base rubber antioxidant

118 Discussion Our results showed that work-related skin problems in such factory are common: OCD was suspected in 8% of the workers, while 3% were diagnosed with an occupationally relevant contact allergy. The most frequent sensitizers were shoe adhesives, followed by rubber and leather. ing and we evaluated positive patch test results precise for clinical relevance. The fact that our study was done in one shoe factory may be considered as a limitation. However according to the Indonesian Footwear Services (IFSC), the factory chosen for our study is representative of a group of well-equipped shoe manufacturing facilities in Indonesia and likely to be similar to the situation described in other NICs. Therefore, our results are representative for other factories in Indonesia and other NICs which make export-quality shoes for the market in Europe, Asia and USA. The prevalence of occupational allergic contact dermatitis found in our study is difficult to compare with a previous study of Intalian shoe manufacturing workers (6.5%) because of difference in case ascertainment and study population. 4 The other epidemiological study of the shoe manufacturing industry has not mentioned the prevalence of occupational allergic contact dermatitis Our study showed that the majority of cases of OACD were in the preparing upper sole (Figure 2) and assembling department (Figure 3.) This could be caused by profound contact with shoe adhesives and materials like rubber and leather. The workers handled these adhesives with their bare hands without any personal protective equipment such as gloves. This could explain why occupational contact dermatitis was found mostly on the hands (n=13), wrists and forearms (n=17), which were in direct contact with chemicals or shoe materials. The majority of workers involved in cutting, preparing upper sole and assembling used cotton aprons to prevent the spilling of adhesives onto the clothing or skin, but there were still 14 workers with skin lesions on their trunks. The contact dermatitis on the face and neck in the 7 workers could have been caused by exposure to airborne dust from rubber, leather, or polyurethane in the preparing upper sole department; it could also have been caused by solvents in adhesives,

119 varnishes, primers and cleaning and waterproofing agents, as well as by exposure to heat from ovens and press machines in the assembling department. 5 The relevance of sensitization to the occupational allergens was determined on the basis of results of previous observations made in the same factory 5 ; this relevance has also been reported elsewhere. 2, 4 The sensitization patterns showed both similarities and differences with the data in previous studies. 4,12 The similarity between the studies was that allergens from shoe adhesives, especially 4-tert-buthylphenolformaldehyde resin, were found to be the most common sensitizers. A difference is that besides p-tert-buthylphenilformaldehyde, we found relevant sensitizations to dodecyl mercaptan, epoxy resin and colophony, which were present in shoe adhesives, but we found no sensitization to diphenylmethan diisocyanate as in the study by Mancuso (1996) Examining the role of shoe adhesives: relevant sensitization was observed mostly in people working in the preparing upper-sole department. Workers were directly exposed to liquid adhesives over a long period and they never wore gloves as a personal protective equipment. Sensitization to allergens in neoprene adhesives was seen for 4-tert-buthylphenolformaldehyde resin and for dodecylmercaptan. 4-terbuthylphenolformaldehyde resin is more commonly found as a sensitizer in neoprene adhesive than is dodecyl mercaptan. 4,12 PTBP-F-R is a main tackifier 11 and dodecyl mercaptan is used to stop polymerization in the neoprene adhesives for shoe-linings and insoles. 2 Sensitization to colophony was seen in 1 worker with occupational allergic contact dermatitis who worked in the preparing upper soles and had direct contact with rubber adhesive when gluing outsoles and insoles to the upper portion of the shoe. Colophony was used as a tackifier in the natural rubber adhesives used for attaching soles and layers below the insole. 13,14 One worker with occupational allergic contact dermatitis who worked in the assembling department had a positive patch test reaction to epoxy resin. Epoxy resin may be used as an additive for urethane adhesives. 2 In the Mancuso study, workers with occupational allergic contact dermatitis had relevant sensitization to epoxy resin present in adhesives used for gluing the toe caps and quarters. 4 Three workers with occupational allergic contact dermatitis who suspected shoe dermatitis to be an aggravator of the skin symptoms and two healthy

120 workers had a positive reaction to methyldibromoglutaronitrile. Although it has never been reported that shoe adhesives contain methyldibromoglutaronitrile, it is possible that the shoe factory used a water-based glue containing this chemical. Methyldibromoglutaronitrile was first used as an industrial biocide in various products, including adhesives, but recently this allergen has rarely been reported as present in adhesives, whereas was quite commonly found in skin care products in Europe. 15,16 There was a case report involving a baby food processing worker found to have occupational allergic contact dermatitis due to a glue paste containing this biocide, used for fastening commercial labels to jars of baby foods. 17 Examining the role of chemicals present in rubber used in shoe production, dibuthylthiourea was the most common relevant sensitizer (3 workers). This finding differed from that of other studies, where mercaptobenzothiazole was found to be the most common rubber allergen causing sensitization in the shoe factory workers. 4,15 Dibuthylthiourea is used as a rubber accelerator and antidegradant in chloroprene and neoprene rubber processing. Other rubber allergens which showed relevant positive patch test reactions in this factory were n,n diphenylguanidine (2 workers), 4-phenylenediamine base (2 workers), and n-isopropyl-n-phenyl 4-phenylenediamine (1 worker). All workers were exposed directly to rubber soles but sensitization was seen only in workers in the sewing department, who were exposed over longer periods as compared with other departments Another difference between other studies and our current one is patch test result with leather allergens. Sensitization to leather used for making shoe uppers was found in 2 workers. It is interesting that 1 worker was sensitized not only to potassium dichromate but also to formaldehyde and glutaraldehyde as tanning agents. In the study by Mancuso et al (1996), potassium dichromate was the only tanning agent which showed relevant sensitization in shoe factory workers. 4 Examining the role of dyes it is interesting that workers with occupational allergic contact dermatitis in the preparing upper sole department and assembling department and 2 healthy workers had positive reactions to 4- aminoazobenzene. This is an intermediate product in the production of diazo dyes; relevant sensitization was found in a pigment colorant used for

121 leather shoe materials 15 and for oil paints. Sensitisation to 4- aminoazobenzene could be caused by exposure to oil paints used in stencil paint for making shoe patterns. Sensitization to leather dye is rarely encountered 8 due to the strong adhesion of dye to leather. 4 There was also a possible cross-sensitization between n-isopropyl-n-phenyl-4 phenylenediamine and 4-aminoazobenzene in a worker with OACD who worked in the sewing department. In this study we were able to perform a careful identification of possible allergens to which shoe factory workers are exposed. We assembled a study provide beneficial information in treating patients with shoe dermatitis and for policy makers in developing programme to prevent occupational contact dermatitis in shoe manufacturing workers. Acknowledgement: We thank to the department of Research and Development, Ministry of Industry and Trade, Republic of Indonesia and Mr.Ferry representative from Indonesia Footwear Service Centre (IFSC) for their assistance References 1. Goossens A, Cattaert N, Nemery B, Boey L, De Graef E. Occupational allergic contact dermatitis caused by rhodium solutions. Contact Dermatitis 2011; 64: Geier J, Lessmann H. Leather and shoes. In: Kanerva's Occupational Dermatology, 2nd, Rustemeyer T, Elsner P, John SM, Maibach HI, eds. Springer-Verlag, Heidelberg New York Dordrecht London, 2012: Mayan O, Pires A, Neves P, Capela F. Shoe manufacturing and solvent exposure in Northern Portugal. Appl Occup Environ Hyg 1999; 14: Mancuso G, Reggiani M, Berdondini RM. Occupational dermatitis in shoemakers. Contact Dermatitis 1996; Febriana SA, Soebono H, Coenraads PJ. Occupational skin hazards and prevalence of occupational skin diseases in shoe manufacturing workers in Indonesia. Int Arch Occup Environ Health 2014; 87:

122 6. Susitaival P, Flyvholm MA, Meding B, et al. Nordic Occupational Skin Questionnaire (NOSQ-2002): A new tool for surveying occupational skin diseases and exposure. Contact Dermatitis 2003; 49: Lachapelle JM and Maibach HI Patch testing methodology. In: Patch testing and Prick Testing A Practical Guide Official Publication of the ICDRG, 2nd, Lachapelle JM and Maibach HI, eds. Springer-Verlag, Berlin Heidelberg, 2009: Wahlberg JE, Lindberg M. Patch testing. In: Contact Dermatitis, 4th, Frosch PJ, Menne T, Lepoittevin JP, eds. Springer, Berlin, Heidelberg, 2005: Ale IS, Maibach HA. Diagnostic approach in allergic and irritant contact dermatitis. Expert Rev Clin Immunol 2010; 6: Ale S.I. and Maibach, H.I. Operational definition of occupational allergic contact dermatitis. In: Handbook of Occupational Dermatology, Kanerva L, ed. Springer, Heidelberg, Germany, 2004: Nicholson PJ, Llewellyn D, English JS, Guidelines Development Group. Evidence-based guidelines for the prevention, identification and management of occupational contact dermatitis and urticaria. Contact Dermatitis 2010; 63: Guedes RV, Leite IB, Baptista AM. Contact allergy to shoe components in professionals and non-professionals of the shoe industry. Dermatitis 2013; 24: Saha M, Srinivas CR, Shenoy SD, Balachandran C, Acharya S. Footwear dermatitis. Contact Dermatitis 1993; 28: Grimalt F, Romaguera C. New resin allergens in shoe contact dermatitis. Contact Dermatitis 1975; 1: Aakhus AE, Warshaw EM. Allergy to methyldibromoglutaronitrile/phenoxyethanol (Euxyl k 400): Regulatory issues, epidemiology, clinical characteristics, and management. Dermatitis 2011; 22: Bordel-Gomez MT, Miranda-Romero A. Contact sensitization to Euxyl K-400. Actas Dermosifiliogr 2009; 100: Mathias CG. Contact dermatitis to a new biocide (Tektamer 38) used in a paste glue formulation. Contact Dermatitis 1983; 9: 418.

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124 CHAPTER 7 Contact allergy in Indonesian patients with foot eczema attributed to shoes Sri Awalia Febriana 1,2, Hardyanto Soebono 1, Pieter-Jan Coenraads 2, Marie-Louise A Schuttelaar 2 1 Department of Dermatology & Venereology, Gadjah Mada University, Yogyakarta, Indonesia; 2 Department of Dermatology, University Medical Centre Groningen / University of Groningen, Groningen, the Netherlands. Accepted for publication in Journal of European Academy Dermatology and Venereology

125 Abstract Background Shoe dermatitis is a form of contact dermatitis resulting from exposure to shoes. Allergens and types of shoes responsible may vary, depending on manufacturing techniques, climatic conditions and indigenous traditions. This study focuses primarily on as yet unexplored shoe dermatitis cases in Indonesia. Objectives To determine the prevalence of shoe dermatitis in the Dermatology outpatient clinic, Sardjito University Hospital, Yogyakarta, Indonesia over a period of 3 years and to identify the responsible allergens. Methods All patients meeting screening criteria for possible shoe contact dermatitis were patch tested with the European Baseline Series, shoe series, and additional series based on earlier studies of Indonesian leather and shoe manufacturers; some were also patch tested with their own shoe materials and shoe extracts. Results Sixty-four (7.1%) of 903 patients were diagnosed with shoe dermatitis. Twenty-five (52.1%) of 48 patch tested patients showed positive reactions to one or more allergens related to footwear. Sixteen patients were patch tested with their own shoe materials; 11 showed positive reactions. The most frequent relevant sensitizers were rubber allergens followed by preservatives, shoe adhesives and leather materials Conclusion Shoe dermatitis is common in Indonesia. Using three series we identified responsible allergens and patterns of sensitization in Indonesian shoe dermatitis patients. Keywords allergic contact dermatitis, contact allergy, patch test, shoes, foot

126 Introduction Shoe dermatitis is a form of allergic or irritant contact dermatitis resulting from exposure to shoes. 1 A patient is diagnosed with allergic shoe dermatitis or shoe allergy based on his history, the presence of skin lesions, and positive patch test reactions to one or more allergens in shoes; another indication is the absence of dermatitis when the patient wears proper substitute shoes. 2 Data on the prevalence of allergic shoe dermatitis are available from patch test clinics and various proportions of positive patch tests to allergens in shoes were reported. 1, 3-6 The highest prevalence has been recorded in warm climates 1, 5, 6 where heat, humidity and conditions inside the shoe like friction, sweating, pressure and occlusion in conjunction with various chemicals in shoe materials contribute to the prevalence of shoe dermatitis. 1, 6-8 Recently, leather, rubber and adhesives are reported to be the most common sources of shoe allergens. 1, 5, 9-11 However the chemicals causing shoe dermatitis may vary depending on manufacturing techniques. 9, 12 The types of shoes responsible will also differ depending on climatic conditions, socio economic factors and indigenous traditions. 5, 7, 9, 10 Our current study focuses primarily on shoe dermatitis in Indonesia, where several of the above mentioned factors contribute to its prevalence. Materials and methods Patients Over 3-years (January 2008-December 2010), we studied 903 patients with foot skin disorders who came to the Dermatology outpatient clinic, of the University hospital in Yogyakarta, Indonesia Patients fulfilling screening criteria for possible shoe dermatitis were eligible for further examination Screening criteria for shoe dermatitis The screening criteria for shoe dermatitis were: 1) presence of eczema on the area in contact with suspected footwear; 2) bilateral, symmetrical eruption, corresponding to the design of the shoes such as the contact site

127 of the shoe tips, uppers and sides, soles, heels, and sandal straps, and 3) no evidence of fungal infection or of other skin diseases. 9, Patch test examination After providing informed consent, patients meeting screening criteria were patch tested with the European Baseline Series and Shoe Series and 12 additional allergens, based on a literature review and our own earlier studies in Indonesian leather and shoe factories Test preparations were supplied by Chemotechniques Diagnostics, Vellinge, Sweden and by the laboratory of the Dermatology Department, Faculty of Medicine, Gadjah Mada University, Indonesia A number of patients consented to patch tests with their own shoe aterials hese were cut into parts s uare c wide and thick and; were moistened with saline before being applied. 12, 14 Patients with negative patch test reactions to shoe allergens but with positive patch test reactions to their own shoe materials were patch tested with an extract from their suspected shoes. The shoe materials were separated into layers, then each cut into a 0.5 x 0.5 cm piece and moistened with saline. An alcohol extract was made from different parts (i.e. rubber, leather/imitation leather and cloth) of the suspected shoes by adding 80 ml ethanol to 8 gr shoe materials. The material and ethanol were put into an ultrasonic bath for 2 hours and centrifuged for 5 minutes at 500 r.p.m. The supernatant was concentrated using a Buchi vacuum evaporator. Shoe extracts were prepared at the Organic Chemistry Laboratory, Faculty of Mathematics and Natural Sciences, Gadjah Mada University, Indonesia. Patch test materials were applied to the patient s upper back using Finn chambers (Epitest Ltd., Helsinki, Finland) mounted on acrylate-based adhesive tape (Scanpor Alpharma AS, Norgesplaster Facility, Norway). The patches were reinforced with extra tape at the edges and over the chamber area. After 48 hours occlusion we removed the Finn-chambers and read on days 2, 3 and 4 as recommended by the ICDRG. 18 The clinical relevance of positive patch test reactions to the shoe allergens was determined according to the following criteria: the probable presence of the allergen in the footwear; a clear relation between exposure to the

128 allergen and the location of skin lesions; and improvement of skin lesions after elimination of exposure. In patients tested with their own shoe material, the clinical relevance to positively tested allergens from the series was strengthened by a positive patch test with their shoe Figure 1. Research flow of patients with eczematous skin lesions on their feet 7 127

129 Figure 2. Patient with hypopigmented lesions who had a contact allergy to hydroquinone monobenzylether. Results Characteristics of patients Of the 903 patients (445 males and 458 females) visiting the Dermatology Clinic at Sardjito University Hospital for foot disorders, 64 (7.1%) were suspected of shoe dermatitis (Fig. 1). A total of 213 (23.6%) were diagnosed with other forms of eczematous dermatitis; the rest showed other foot skin disorders (Table 1). Of the 64 patients suspected with shoe dermatitis 44 (68.8%) were females and 20 (31.3%) males. The main complaint was pruritus, 58 patients (85.3%); only a minority had a history of atopy (Table 2). The dorsum of the foot was the most frequent location (47.6%) and rubber slippers/sandals the most suspected footwear (50.7%) (Table 3). Patch test results Forty-eight patients were patch tested with the European Baseline Series, shoe series and additional series. For various reasons patch tests were not performed in 16 patients: some thought they had already identified the footwear that had triggered the allergy; the rest could not be tracked down by telephone or by use of their registered addresses.

130 A total of 32 (66.7%) patients showed one or more positive patch test reactions and 25 (52.1%) patients had clinically relevant reactions, based on the probable presence of the allergen in the footwear and the relationship between the lesions and exposure to the allergens (Table 4). The most frequent positively tested shoe allergen was 2- mercaptobenzothiazole (13 patients) The most frequent relevant sensitizers were allergens from rubber materials, followed by preservatives, shoe adhesives and leather materials. Sixteen patients were patch tested with their own shoe materials: 11 showed positive reactions, 5 showed irritant or doubtful reactions. Of these 11 patients with positive reactions to their own shoe materials, 9 also had positive reactions to allergens from the three series described above, and 2 did not. These 2 were subsequently patch tested with an extract from their own shoe materials: one showed a positive reactions to the shoe extract and one did not (Fig. 1). Twelve patients with relevant positive patch tests to substances from three series could not be tested with their own shoe material for several reasons: five patients showed severe eczematous skin lesions in the area of contact with rubber footwear. In these patients we did not pacth test with pieces of rubber materials since patients were not motivated because they had noted that it was very likely that rubber footwear was the cause of their shoe dermatitis. Moreover we expected a strong positive patch test when we would test with own shoe material. Seven patients with positive reactions to rubber allergens experiencing eczema in the area of contact with their rubber footwear were found to have no more lesions when they stopped wearing the footwear. We asked them to use their rubber footwear again, and their skin lesions re-appeared. They were unwilling to have further patch testing with their own shoe materials Table 5 includes 16 patients who were patch tested with their own shoe materials. In a separate column, we recorded the allergens related to the positively tested shoe material or rubber footwear.

131 Table 1. Characteristics of 903 patients with foot skin disorders. Condition Number of subjects Percentage Male Sex Female Shoe dermatitis Other forms of eczematous dermatitis Psoriasis Plantar keratoderma Bacterial infection Warts/Viral infection Fungal infection Corn and Calluses Ulcer Others Total Table 2. Characteristics of 64 patients screened with shoe dermatitis. Sex Number of patients (%) Male 20 (31.3) Female 44 (68.8) Occupation Housewife 11 (17.2) Office worker 17 (29.3) Students 11 (17.2) Farmers 2 (3.1) Unemployed 2 (3.1) Others 15 (23) No information 6 (9.4) Chief complaint * Pruritus 58 (85.2) Pain 7 (10.3) Others 3 (4.4) History of atopy Yes 19 (29.7) No 33 (51.6) No information 12 (18.8)

132 Number of patients (%) Age range (years) (3.1) (7.8) (20.3) (12.5) (25.0) (14.1) (9.4) (7.8) * Some patients had more than one chief complaint Table 3. Location of skin lesions and type of footwear suspected to be the cause of shoe dermatitis in 64 patients. Number of patients (%) Location of skin lesions* Dorsum feet 50 (47.6) Dorsal toes 24 (23.5) Plantar feet 17 (10.8) Plantar toes 3 (2.9) Lateral feet 3 (2.9) Heel 2 (1.9) Interdigital spaces 2 (1.9) Ankle feet 1 (0.98) Type of footwear ** Rubber slipper 31 (43.7) Imitation leather sandal 11 (15.5) Imitation leather shoes 10 (14.1) Leather sandals 5 (7.0) Rubber sandals 5 (7.0) Plastic sandals 4 (5.6) Sneakers 2 (2.8) Leather shoes 2 (2.8) Leather slipper 1 (1.4) * Some patients had more than one site of lesion involved. ** Some patients had contact dermatitis to more than one type of footwear 7 131

133 Table 4. Relevant results of patch testing in 48 patients screened with shoe dermatitis Allergens related to the shoe dermatitis (% vehicle) Number of patients with positive reactions to allergens relevant to shoe dermatitis Description Mercapto mix 13 Rubber accelerator 2-Mercaptobenzothiazole (2.0 pet) 11 Rubber accelerator 1,3-Diphenylguanidine (1.0 pet) 5 Rubber accelerator Methylchloroisothiazoline/ methylisothiazolinone (0.02 aq) Diphenylthiourea (1.0 pet) 3 4 Shoe preservatives Accelerator and activator for neoprene rubber 4,4 -Dithiodimorpholine (1.0 pet) 3 Rubber vulcanizer Formaldehyde (1.0 aq) 3 Leather tanning agent and used in finishing process Dodecyl mercaptan (0.1 pet) 3 Neoprene adhesives; polymerization inhibitor added to polyurethane resin Thiuram mix 2 Rubber accelerator Potassium dichromate (0.5 pet) 2 Leather tanning agent 2-Thiocyanomethyl-thiobenzothiazole Leather (biocide in leather 2 (0.2% pet) processing) Shoe adhesives (resin Colophony (20.0 pet) 2 extract in glue and finishing); tackifier in heel stiffener 4-tert-Buthylphenolformaldehyde resin (1.0 pet) 2 2-n-Octyl-4-isothiazolin-3-one (0.1 pet) 4-Aminoazobenzene (0.25 pet) 2 Resin used in shoe adhesive (mainly in shoe lining and shoe insoles glue) 2 Shoe preservatives Polyurethane dye in inner soles and shoe linings Nickel sulphate (5.0 pet) 2 Shoe buckles and eyelet N-Isopropyl-N-phenyl-pphenylenediamine (0.1 pet) 1 Rubber antioxidant Hydroquinone monobenzylether (1.0 pet) 1 Rubber antidegradant Epoxy resin (1.0 pet) 1 Shoe adhesives Glutaraldehyde (0.2 pet) 1 Leather tanning agent Disperse orange 3 (1.0 pet) 1 Dye * Some patients had more than one relevant allergen causing shoe dermatitis Additional allergens Shoe series

134 Table 5. Sixteen patients patch tested with own shoe materials. Gender (M/F)/ age (y) Skin location Suspected footwear/ shoe materials Patch test results own shoe materials Positive patch test reactions related to suspected footwear/ shoe materials M/79 Dorsum foot Side foot Leather sandals (shoe upper) Positive reaction to inner side of leather sandal straps F/71 Dorsum foot Leather sandals Positive reaction to upper side of sandal straps F/47 Plantar pedis Heels Side foot M/35 Plantar pedis Side foot (contact with shoe lining) F/19 Dorsum foot and toes F/22 Dorsum foot (sandal strap) Dorsal toes F/58 Dorsum foot Interdigital 1 Plantar foot Imitation leather shoes (polyurethane) Rubber insole Polyurethane shoe Rubber insole Glues with rubber component, in shoe lining Shoe adhesives in imitation leather shoes Rubber insole Leather sandal Rubber sandals Leather sandals Positive reaction to polyurethane shoes Positive reaction to lateral part of shoe upper Positive reaction to inner side of shoe upper Positive reaction to shoe upper, shoe straps and inner sole made from leather Positive reaction (++) to rubber inner sole and straps Positive reaction to inside of leather sandals F/68 Dorsum foot Leather sandals Positive reaction to outer and inner parts of leather shoe uppers M/34 Dorsum toes Plantar toes Shoe adhesive Rubber sandals Positive reaction to inner part of Formaldehyde Methylchloroisothiazoline / methylisothiazolinone 2-Thiocyanomethylthiobenzothiazole Formaldehyde 2-Thiocyanomethylthiobenzothiazole 4-tert- Butylphenolformaldehyde resin 4-Aminobenzene Diphenylthiourea Mercapto mix 4-Aminobenzene 1,3-Diphenylguanidine 4,4 -Dithiodimorpholine Colophony 1,3-Diphenylguanidine Mercapto mix Methylchloroisothiazoline/Methylisothiazolinone 4,4 -Dithiodimorpholine 2-Mercaptobenzothiazole Mercapto mix Potassium dichromate Methylchloroisothiazoline / methylisothiazolinone 2-n-Octyl-4-isothiazolin- 3-one Glutaraldehyde Potassium dichromate Formaldehyde Epoxy resin 1,3-Diphenylguanidine 7 133

135 Gender (M/F)/ age (y) Skin location Suspected footwear/ shoe materials Patch test results own shoe materials Positive patch test reactions related to suspected footwear/ shoe materials F/66 Dorsum foot Dorsum toes M/50 Dorsum toes Plantar pedis Imitation leather sandals Imitation leather sandals M/9 Plantar foot Plantar toes F/38 Side foot Heels F/31 Dorsum foot Plantar foot Dorsum toes Rubber insole in sneakers made of neoprene Imitation leather shoes Imitation leather shoes shoe and upper (toe cap) Positive reaction to inner part of sandal strap Positive reaction to inner part of sandal strap Doubtful reaction to inner sole Doubtful reaction to lateral area of polyurethane shoes Irritant reaction to inner sole of sport shoes Irritant reaction to inner side of polyurethane shoes Irritant reaction to inner and outer part of imitation leather shoes Negative patch tests Negative patch tests Disperse orange 3 Methylchloroisothiazoline / methylisothiazolinone Dodecyl mercaptan Diphenylthiourea M/20 Dorsum foot (sandal strap) Dorsum toes Plantar foot Leather shoes F/54 Dorsum foot Imitation leather sandal (polyurethane) 4-tert- Butylphenolformaldehyde resin Colophony Negative patch tests Discussion Patterns of shoe dermatitis have changed over the years, reflecting changes in fashion and shoe manufacturing technology as well as variations between countries. For the current study we accurately selected patients with shoe dermatitis from a group with skin disorders on their feet. We patch tested patients with an extensive, carefully selected range of allergens and critically assessed the relevance of the positively tested allergens to the exposure to the shoe material. This explains our high percentage (52.1%) of patients with clinically relevant positive patch test reactions. Our results approach a study by Angelini et al. (65.4%). 19 In this

136 Italian study shoe dermatitis patients were well characterized. However, positive reactions probably not all relevant for shoe dermatitis were included. They showed 49 positive reactions to p-phenylenediamine in 108 tested patients. All positive reactions to p-phenylenediamine were included in the reported prevalence of positive reactions, though probably not relevant to shoe allergy. Reported prevalences are difficult to compare due to differences in study design, types of allergens/shoe materials tested, and investigator s critical assessment of clinical relevance. Also, as high temperatures and humidity in tropical countries like Indonesia create an ideal environment for the development of shoe dermatitis, it is understandable that the highest prevalence of shoe dermatitis has been recorded in such locations. 7, 8, Shoe dermatitis may affect all parts of the foot but the most typical location is the dorsa of the foot and toes, sparing the interdigital spaces 5, 12, 14, 19, 23, 24 ; our study confirms the dorsum to be most frequently affected area (47.6%). This area, with its large surface area and thin stratum corneum, is especially vulnerable to shoe allergy. 9 Our patients most commonly wore slippers or sandals (89.1%). The majority of our patients with rubber allergy had skin lesions on the dorsum area in contact with the sandal/slipper strap. In Indonesia, sandal/slipper straps are ussually made of natural rubber latex, and insoles made from neoprene rubber covered with fabric. The female to male ratio in our study was 3:1. Female predominance was also reported in studies. 5,12,25 Current exposure of women to an increasing variety in footwear increases their risk of shoe allergy. Moreover, Indonesian housewives are more prone to irritant dermatitis of the feet because of regular exposure to water, household detergents and cleansing agents when doing housecleaning with bare feet in slippers. This condition can result in impaired epidermal function and eventually lead to greater penetration by shoe allergens. In our study most shoe contact dermatitis occurs between the ages of 21 and 50 years (57.8%), this agrees with earlier reports. 1,26 At these ages individuals are most active, likely to be regularly exposed to various allergens and thus more vulnerable to shoe allergy Our study found rubber, the most common material in Indonesian footwear, to be the most common cause of shoe dermatitis; the same was

137 reported in other countries. 9,13,19,24, Mercaptobenzothiazole and 1,3- diphenylguanidine caused the most frequent relevant sensitization in our patients; this corroborates results from other studies. 1,5,10,12,31 Other rubber allergens showing relevant sensitization in our study were 4,4'- dithiodimorpholine, N-isopropyl-N'-phenyl-p-phenylenediamine, and hydroquinone monobenzylether. According to a study by Shackelford and Belsito 9 the rubber vulcanizer 4,4'-dithiodimorpholine causes the most frequent relevant positive reactions in shoe dermatitis patients. Our study showed 3 patients with relevant sensitization to 4,4'-dithiodimorpholine, one of which was possibly a cross reaction with 1,3-diphenylguanidine. The majority of our patients with rubber allergy showed hyperkeratotic skin lesions associated typically with rubber. 9 Interestingly 5 patients with rubber allergy had an extensive bilateral dorsal eczematous reaction on their feet, and the feet of 4 were covered with crusts, possibly caused by secondary infections. Moreover, the dispigmentary action of a phenolic compound used in footwear manufacture is known to cause leucodermic lesions. 32 Our study included a patient with hypopigmented lesions who had a contact allergy to hydroquinone monobenzylether (Fig. 2) Our study showed 4 patients with skin lesions on the plantar area, which were sensitized to the rubber insole, and one patient sensitized to his shoe linings showed a relevant positive reaction to rubber allergens. This could be due to an adhesive-containing rubber component. Heel and toe counters exposed patients to a number of potential allergens containing rubber resin, such as mercaptobenzothiazole and thiuram. 30,33 This could explain why a patient with skin lesions of the heel showed sensitization to rubber allergens. Diphenylthiourea, another sensitizer, is present in various synthetic rubber and plastic products due to its use as a stabilizer in the manufacture of PVC and an accelerator in the production of neoprene. 34 Allergic contact dermatitis caused by diphenylthiourea was found in patients allergic to orthopedic braces and suits made from neoprene, but almost never to neoprene shoes Liipo et al. studied sensitization to thiourea derivatives among patients suspected with contact dermatitis, 5 showed sensitization to diphenylthiourea; one had foot dermatitis and was also sensitized to diaminodiphenylmethane. 39 Friis et al. noted contact allergy to neoprene shoes, but reported positive patch test reactions to diethylthiourea instead of to diphenylthiourea. 40

138 Interestingly, our study showed that relevant sensitization to leather allergens is probably caused by leather preservatives (methylchloroisothiazoline/ methylisothiazolinone; 2-n-octyl-4- isothiazoline-3-one and 2-thiocyanomethyl-thiobenzothiazole) rather than by leather tanning agents (formaldehyde, potassium dichromate and glutaraldehyde). Other studies, in other tropical countries like India and Pakistan 1,5,41, pointed chromium to be the allergen most responsible for causing leather shoe dermatitis 9,19,32 a finding contradictory to our study, in which positive relevant sensitization to potassium dichromate showed in only 2 patients. This could be the result of a newer fixation process in leather manufacture whereby chrome allergy manifests less frequently as shoe dermatitis. 9 According to Thyssen et al (2014), most leather footwear contained chromium which was extracted and examined with the X-ray fluorescence spectroscopy. 42 We patch tested the patient with 2- thiocyanomethyl-thiobenzothiazole from our additional series because this chemical is used as a leather preservative in the leather tanning process in Indonesia 16 and 2 patients were sensitized to this allergen. We would therefore consider this allergen when patch testing patients with suspected shoe allergy. We did not patch test with dimethylfumarate 43 because, based on our study in shoe factories 15 and our consultations with the Centre of Leather and Rubber as well as the Indonesian Footwear Association, this chemical was not used as a preservative in Indonesian footwear manufacturing. Although many parts of the shoe were sewn with nylon, polyester and linen thread, shoe adhesives are still used throughout. Adhesive allergens which caused sensitization in the current study were 4-tertbuthylphenolformaldehyde resin (2 patients) dodecyl mercaptan (2 patients), colophony (2 patients), and epoxy resin (1 patient). 4-tertbuthylphenolformaldehyde resin is used as a rubber latex or neoprene adhesive for gluing insoles and shoe linings and is occasionally present in heel and toe stiffeners as a tackifier. 1,31 Epoxy resin is present in some adhesives used for gluing the toecaps and quarters. 44 Patients sensitive to colophony and 4-tert-buthylphenolformaldehyde resin should wear shoes either without lining, or with leather lining or stitched lining without heel and toe support

139 Nickel sensitivity plays a minor role in shoe dermatitis. Fisher et al. nevertheless found several shoe dermatitis patients caused by metallic nickel sulphate found in shoe buckles, shoe eyelets or other shoe accessories. 2 In the current study 6 patients had nickel sensitivity; only 2 of these had a history of eczema related to shoe buckles. One patient with leather shoe dermatitis who sensitized to disperse orange. However, in this case it is not certain that the allergy was caused by the leather dye since the result of patch testing with suspected shoe material was in this case doubtful. According to the literature, primary dye dermatitis caused by leather shoes is rare. 2,45 This could be attributed to the firm fixation of dye in leather products. Allergies to shoe dye appear in patients who re-dyed their shoes 45, patients allergic to dye in fabric or plastic shoes 12 or patients allergic to stocking dye The limitation of this study is that not all patients agreed to be patch tested with the three series or their own shoe materials. Despite this limitation, we have many advantages not found in similar studies of shoe dermatitis patients. Our study is a prospective study, following patients with skin problems of the feet. Most other studies are retrospective, taking their data from past results in a patch test clinic. The number of allergens tested in our study (51 allergens) was also higher compare to similar studies 1,5,12,19 and we evaluated positive patch test results very precisely for clinical relevance. We also patch tested 16 patients with pieces of suspected shoe, a procedure followed only in one other study 12 in which patch testing with shoe extract was performed on 2 patients. Moreover we provided detailed descriptions of patients who agreed to be patch tested with their own shoe materials. Conclusion In this study we prospectively screened patients with shoe dermatitis, which were patch tested with a wide range of clearly identified allergens. We showed in a high percentage of positive patch test reactions in which we precisely described the relation to footwear. Positive patch test reactions to their own shoe materials/shoe extract tests supported our patch test results. The most frequent clinical relevant sensitizers were rubber allergens followed by preservatives, shoe adhesives and leather

140 materials. This correlates well with the preference of Indonesian people for shoes like rubber slipper or sandals. References 1. Rani Z, Hussain I, Haroon TS. Common allergens in shoe dermatitis: Our experience in Lahore, Pakistan. Int J Dermatol 2003; 42: Fisher AA. Some practical aspects of the diagnosis and management of shoe dermatitis. AMA Arch Derm 1959; 79: Landeck L, Uter W, John SM. Patch test characteristics of patients referred for suspected contact allergy of the feet-retrospective 10-year cross-sectional study of the IVDK data. Contact Dermatitis 2012; 66: Gamez L, Reig I, Marti N, Revert A, Jorda E. Allergic contact dermatitis to footwear in children. Actas Dermosifiliogr 2011; 102: Chowdhuri S, Ghosh S. Epidemio-allergological study in 155 cases of footwear dermatitis. Indian J Dermatol Venereol Leprol 2007; 73: Suhail M, Ejaz A, Jameel K. Value of patch testing with indigenous battery of allergens in shoe dermatitis. J Pakistan Ass of Dermatol 2009; 19: Olumide Y. Contact dermatitis in Nigeria (IV). Dermatitis of the feet. Contact Dermatitis 1987; 17: Bajaj AK, Gupta SC, Chatterjee AK, Singh KG. Shoe dermatitis in India: Further observations. Contact Dermatitis 1991; 24: Shackelford KE, Belsito DV. The etiology of allergic-appearing foot dermatitis: A 5-year retrospective study. J Am Acad Dermatol 2002; 47: Holden CR, Gawkrodger DJ. 10 years' experience of patch testing with a shoe series in 230 patients: Which allergens are important? Contact Dermatitis 2005; 53: Warshaw EM, Boralessa Ratnayake D, Maibach HI, et al. Positive patch-test reactions to iodopropynyl butylcarbamate: Retrospective analysis of North American Contact Dermatitis Group data, from 1998 to Dermatitis 2010; 21: Nardelli A, Taveirne M, Drieghe J, Carbonez A, Degreef H, Goossens A. The relation between the localization of foot dermatitis and the causative allergens in shoes: A 13-year retrospective study. Contact Dermatitis 2005; 53: Cronin E. Shoe dermatitis. Br J Dermatol 1966; 78: Epstein E. Shoe contact dermatitis. JAMA 1969; 209: Febriana SA, Jungbauer F, Soebono H, Coenraads PJ. Inventory of the chemicals and the exposure of the workers' skin to these at two leather factories in Indonesia. Int Arch Occup Environ Health 2012; 85:

141 Febriana SA, Jungbauer F, Soebono H, Coenraads PJ. Occupational allergic contact dermatitis and patch test results of leather workers at two Indonesian tanneries. Contact Dermatitis 2012; 67: Febriana SA, Soebono H, Coenraads PJ. Occupational skin hazards and prevalence of occupational skin diseases in shoe manufacturing workers in Indonesia. Int Arch Occup Environ Health 2014; 87: Lachapelle JM and Maibach HI. Patch testing methodology. In: Patch testing and Prick Testing A Practical guide Official Publication of the ICDRG, 2nd, Lachapelle JM. and Maibach HI, eds. Springer-Verlag, Berlin Heidelberg, 2009: Angelini G, Vena GA, Meneghini CL. Shoe contact dermatitis. Contact Dermatitis 1980; 6: Leppard BJ, Parhizgar B. Contact dermatitis to PPD rubber in maleki shoes. Contact Dermatitis 1977; 3: Lynch PJ, Rudolph AJ. Indian sandal strap dermatitis. JAMA 1969; 209: Sharma SC, Handa S, Sharma VK, Kaur S. Footwear dermatitis in Northern India. Contact Dermatitis 1991; 25: Onder M, Atahan AC, Bassoy B. Foot dermatitis from the shoes. Int J Dermatol 2004; 43: Freeman S. Shoe dermatitis. Contact Dermatitis 1997; 36: Lazzarini R, Duarte I, Marzagao C. Contact dermatitis of the feet: A study of 53 cases. Dermatitis 2004; 15: Saha M, Srinivas CR, Shenoy SD, Balachandran C, Acharya S. Footwear dermatitis. Contact Dermatitis 1993; 28: Weston JA, Hawkins K, Weston WL. Foot dermatitis in children. Pediatrics 1983; 72: Lynde CW, Warshawski L, Mitchell JC. Patch test results with a shoe wear screening tray in 119 patients, Contact Dermatitis 1982; 8: Matthys E, Zahir A, Ehrlich A. Shoe allergic contact dermatitis. Dermatitis 2014;25: Munk R, Sasseville D, Siegel PD, Law BF, Moreau L. Thiurams in shoe contact dermatitis -a case series. Contact Dermatitis. 2013; 68: Katugampola RP, Statham BN, English JS, et al. A multicentre review of the footwear allergens tested in the UK. Contact Dermatitis 2005; 53: Romaguera C. Shoe contact dermatitis. Int J Dermatol 1987; 26: Goossens A, Taylor JS. Shoes. In: Contact Dermatitis (Johansen JD, Frosch PJ, Lepoittevin JP, eds, 5th edn. Berlin, Heidelberg: Springer, 2011; Samuelsson K, Bergstrom MA, Jonsson CA, Westman G, Karlberg AT. Diphenylthiourea, a common rubber chemical, is bioactivated to potent skin sensitizers. Chem Res Toxicol 2011; 24:

142 35. Aplin CG, Bower C, Finucane K, Sansom JE. Contact allergy to IPPD and diphenylthiourea in an orthopaedic brace. Contact Dermatitis 2001; 45: Alcantara M, Martinez-Escribano J, Frias J, Garcia-Selles FJ. Allergic contact dermatitis due to diphenylthiourea in a neoprene slimming suit. Contact Dermatitis 2000; 43: Boehncke WH, Wessmann D, Zollner TM, Hensel O. Allergic contact dermatitis from diphenylthiourea in a wet suit. Contact Dermatitis 1997; 36: Villarreal Balza de Vallejo O. Contact dermatitis from diphenylthiourea in a knee brace. Contact Dermatitis 1997; 36: Liippo J, Ackermann L, Hasan T, Laukkanen A, Rantanen T, Lammintausta K. Sensitization to thiourea derivatives among Finnish patients with suspected contact dermatitis. Contact Dermatitis 2010; 63: Friis UF, Johansen JD, Krongaard T, Menne T. Quantitative assessment of diethylthiourea exposure in two cases of occupational allergic contact dermatitis. Contact Dermatitis 2011; 64: Saha M, Srinivas CR, Shenoy SD, Balachandran C, Acharya S. Footwear dermatitis. Contact Dermatitis 1993; 28: Thyssen JP, Strandesen M, Poulsen PB, Menne T, Johansen JD Chromium in leather footwear-risk assessment of chromium allergy and dermatitis. Contact Dermatitis 2014;66: Švecová D, Šimaljakova M, Doležalová A. Footwear contact dermatitis from dimethyl fumarate. Int J Dermatol 2013;52: Mancuso G, Reggiani M, Berdondini RM. Occupational dermatitis in shoemakers. Contact Dermatitis 1996; 34: Belsito DV. The diagnostic evaluation, treatment, and prevention of allergic contact dermatitis in the new millennium. J Allergy Clin Immunol 2000; 105:

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144 CHAPTER 8 Thin layer chromatography and gas chromatography-mass spectrometry (GCMS) examination of footwear materials from patients with shoe dermatitis Sri Awalia Febriana 1,2, Erik Zimerson 3, Cecilia Svedman 3, Winarto Haryadi 4, Pieter-Jan Coenraads 2, Marie-Louise Anna Schuttelaar 2 1 Department of Dermatology & Venereology, Gadjah Mada University, Yogyakarta, Indonesia; 2 Department of Dermatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; 3 Department of Occupational and Environmental Dermatology, SUS Malmö, University of Lund, Malmo, Sweden; 4 Department of Chemistry, Faculty of Mathematics and Natural Sciences, Gadjah Mada University, Yogyakarta, Indonesia Abridge version accepted for publication in Contact Dermatitis

145 Keywords: shoe dermatitis; thin layer chromatography (TLC); gas chromatography-mass spectrometry (GCMS); patch testing; shoe materials; 2(3H)-benzothiazolone; methyl dehydroabietate; 7-oxodehydroabietic acid methyl ester; colophony Introduction Shoe materials are known to be a common source of contact dermatitis, but the actual causative allergens are often unknown. Patch testing with allergens in a standard screening tray containing chemicals used in shoe manufacturing has been found to be insufficient. 1, 2 Negative reactions to those allergens do not necessarily exclude shoe dermatitis; 25-50% of reactions are due to allergens not present in the screening tray, often because modern shoes are manufactured from unknown not defined components provided by outside suppliers. 3 Therefore, when the clinical picture strongly suggests shoe dermatitis but the patient does not reacted to materials from the screening tray, one must extract and identify individual substances from the suspected shoes and patch test to possibly prove a contact allergy. Case 1. A 50-year-old male with shoe dermatitis had symmetrical eczematous skin lesions on the dorsum of both feet (Figure 1). After wearing imitation leather sandals for about 6 months his feet began to itch and skin lesions appeared. His lesions healed when he was not wearing the sandals. Upon re-exposure the itch and lesions recurred (Figure 1). The patient had no history of atopic manifestations but his grandfather had suffered from recurrent eczema Figure 1. Eczematous lesion on the dorsum of the feet of patient 1 (left). Upper part of the patient 1 s sandal which in direct contact with skin lesion (right).

146 Case 2 A 53-year-old female was diagnosed with shoe dermatitis on her dorsum and plantar surfaces of the feet (Figure 2). The dermatitis appeared every time she wore sandals made from imitation leather. Her lesions healed when she stopped wearing the sandals and reccured afrer re-exposure to the same sandals. When she had first started using the sandals, she felt itchiness and a mild burning sensation. The lesions worsened when her feet got wet. Upon performing a skin examination, we also found atypical clinical features of shoe dermatitis possibly due to herbal medication and antiseptic soap used to treat the current symptoms of shoe dermatitis. Figure 2. Skin lesion on the dorsum of the feet of patient 2 Patch testing Both patients were patch tested with allergens from the European Baseline Series, Shoe Series and additional series, based on our own earlier studies in Indonesian leather and shoe factories. 4 Test preparations were supplied by Chemotechniques Diagnostics, Vellinge, Sweden and by the laboratory

147 of the Dermatology Department, Faculty of Medicine, Gadjah Mada University, Indonesia. Patch test procedures were performed on patients upper backs using Finn chambers (Epitest Ltd., Helsinki, Finland) mounted on acrylate-based adhesive tape (Scanpor Alpharma AS, Norgesplaster Facility, Norway). The patches were removed after 48 hours and read on D2, D3 and D4 as recommended by the International Contact Dermatitis Research Group. Result were negative in both patients. Both patients were then patch tested with suspected shoe materials (imitation leather) taken from the upper parts of the sandals which were directly in contact with the corresponding areas of the skin lesions. Each patients was also patcch tested with the material of the other patient. These materials were cut into pieces 1 cm 2 and 2 mm thick and were moistened with saline before being applied. Both patients reacted to the inner part of the sandalas uppers of patient 1 (Table 1). Shoe materials from both patiens were examined. Extract of suspected materials of both patients were prepared at the Organic Chemistry Laboratory, Faculty of Mathematics and Natural Sciences, Gadjah Mada University, Indonesia by adding 80 ml ethanol to 8 gr shoe material, then extracted with an ultrasonic bath for 2 hours, and centrifuged for 5 minutes at 500 r.p.m. The supernatant was then concentrated using a 'Buchi' vacuum evaporator. 5 Both patients reacted to the shoe extract of patient 1 but not to the extract of patient 2. The extract of patient 1 was thus suspected of containing interesting allergens. We patch tested the extracts on 10 healthy volunteers as controls and showed negative reactions to both shoe extracts. The extract of patient 1 was thus suspected to contain possible interesting shoe allergens Thin layer chromatography (TLC) was performed in order to separate the components of the extracts of the shoe materials of patient 1 and to obtain a TLC strip for patch testing (TLC plastic roll, Silica Gel 60F 254, Merck KGaA, Darmstadt, Germany). The TLC was prepared at the Dept. of Occupational and Environmental Dermatology, Malmö, Sweden. The TLC strips were applied to the back using Scanpor tape. The position of the TLC strip and its spot were carefully marked. The TLC strip was removed after 48 hours and read on D2, D4 and D7 according to ICDRG criteria. 6 Both patients reacted to spots A and B on the TLC strip and patient 2 also reacted to spot C and spot D (Figure 3). Areas corresponding to the positive

148 reactions were scraped off the silica gel for each spot, respectively, from an exact copy of the tested TLC strip and extracting the gel with a minimal amount of ethyl acetate. The resulting solutions were analyzed by gas chromatography-mass spectrometry (GCMS). 7 It was found that positive TLC spots contained methyl dehydroabietate (Spot A), 7-oxodehydroabietic acid methyl ester (Spot B), and 2(3H)-benzothiazolone (Spot C) (Figure 3 and 4) The main substance in spot D was unidentifiable. Both patients were patch tested with 2(3H)-benzothiazolone 0.1% and 1.0% in petrolatum. Patient 1 showed a doubtful reaction and patient 2 was found positive to both concentrations (Figure 3) Figure 3. Patient 2 reacted to Spots A, B, C and D in TLC strip and to 2(3H)-benzothiazolone 0.1% and 1.0% pet

149 H N S O 2(3H)-Benzothiazolone CAS: MW Oxodehydroabietic acid methyl ester CAS MW 328 O O O Methyl dehydroabietate MW 314 O O Figure 3. Chemical structures, names, CAS numbers and molecular weights of confirmed and suspected allergens.

150 Discussion Commercially available patch test kits are helpful for testing patients, but the constantly growing number of substances in everyday modern products make such tests inadequate. To improve accuracy patch testing with the patient s own products is often reccomended. However, in a product an allergen may be present in a concentration so low that it gives a negative patch test result. One solution would be to get content information from the producer on the ingredients and then patch test these ingredients. We could also patch test directly with an extract of the product. 5 In an extract the chemical components of a product will be tested at a higher concentration, and therefore the patch test will be more sensitive and also compensate for repeated exposure to a product that is often needed to give allergic eczema. A positive reaction to an extract can be verified by patch testing controls. The patient can be advised to avoid the product and sometimes, as often the case with cosmetics, this is sufficient. With regard to some everyday objects, for example further investigation is often needed in order to establish the identity of the allergen and make it possible for the dermatologist give advice on how to avoid the allergen in the future. Patch testing with TLC strips of the positive extract is often helpful for identification of allergens. 6 The chemical substances in the extract are separated onto the TLC strip and this greatly facilitates chemical analysis. Identification the substances present in a positive TLC strip patch can often be done with GCMS (or a similar method). The 2 cases described here illustrate that neither purchased shoe series or extracts (extract patient 1) may be enough. The clinical symptoms of our patients led to a suspicion of contact dermatitis, but routine investigation indicated no contact allergens. Since both patients arrived simultaneously at the clinic the shoe materials of each were patch tested on both. Shoe material no.1 (from shoe patient 1) was positive in both patients whereas shoe material no. 2 (from shoe patient 2) was negative in both. Extracts and further TLC testing (with TLC from shoe extract no 1) gave similar results (Table 1)

151 Table 1: Test results from patch testing of patch test series, materials, extracts and thin layer chromatography strips (TLC strips) Test material Concentration Vehicle Patient 1 Patient 2 Shoe material pat 1 (upper) as is + + Shoe material pat 2 as is - - Shoe extract pat 1 ethanol + + Shoe extract pat 2 ethanol - - TLC spot A TLC strip (+) + TLC spot B TLC strip (+) + TLC spot C TLC strip - + TLC spot D TLC strip - + 2(3H)-Benzothiazolone 1.0% pet (+) + 2(3H)-Benzothiazolone 0.10% pet (+) + Triclosan 2.0% pet - - European standard (15 allergens) - - Shoes series (22 allergens) including colophony - - Additional allergens (12 allergens) - - Reactions: (+) = doubtful reaction + = non vesicular reaction, palpable erythema and slight infiltration Because the extracts were to be sent to an external laboratory and the clinical investigation was to occur in a geographically remote area, both extracts were actually analysed before patch testing (Table 2). Analysis indicated the presence of several possible allergens in the extracts. Based on these findings we patch tested 2(3H)-benzothiazolone and the preservative triclosan on both patients. Triclosan gave negative results for both but patient 2 reacted positively to 2(3H)-benzothiazolone whuc (according to GCMS) was present in the shoe extract of patient 1.

152 Table 2 Substances found in the analysis of shoe extracts. Patient Substances Patient 1 Cinnamic acid (CAS ) 2(3H)-Benzothiazolone (CAS ) Triclosan (CAS ) Colophony Diethylhexyl phthalate (CAS ) Diisobutyl phthalate (CAS ) 2,4-Di-tert-butylphenol (CAS ) 1-Dodecanol Patient 2 Cinnamic acid (CAS ) Diisobutyl phthalate (CAS ) Diethylhexyl phthalate (CAS ) Nonylphenol ethoxylates 1-Dodecanol 1-Chlordodecan Patch testing with the TLC strip showed that patient 2 reacted to four spots on the TLC (spots A, B, C and D). 2(3H)-Benzothiazolone was identified on spot C. In spots A and B, respectively, methyl dehydroabietate and 7- oxodehydroabietic acid methyl ester were found, both derivatives of colophony. The main component in spot D was unidentifiable and thus not patch tested. Also spot C contained some substances that could not be identified. Patient 1, whose shoe extract provided important information on patient 2, reacted only to the shoe extract and the shoe material. The TLC spot C with 2(3H)-benzothiazolone was negative, the patch testing with this allergen doubtful, as was the spot containing colophony derivatives (Spot A and B). What do we conclude from this? With regard to patient 1 we can only be certain that he had an allergic contact reaction to the extract and his shoe material (controls were patch tested). Patient 2, had no reaction to either his own shoe material or its extract, but he did react to shoe material extract patient 1 and the allergens found there. We have thus not been able to prove a contact allergy with regard to the shoe. This does, however, indirectly emphasize the need for an updated shoe series; allergens giving positive reactions may not be common but could very well be present in shoes. 2(3H)-Benzothiazolone is a rare allergen which we have not previously encountered. However, an Indian paper reported it as a common sensitizer used as a corrosion inhibitor

153 This substance could have been added to the product, or it could be a degradation product from the rubber chemical mercaptobenzothiazole or an oxidation product from benzothiazole. We previously discovered the latter substance as an antimicrobial agent used in bras (unpublished findings). Methyl dehydroabietate and 7-oxodehydroabietic acid methyl ester indicate the presence of colophony or modified colophony in shoe materials, probably as a component of glue. As colophony can be produced either from pines or other plants it may contain different allergens. The best approach is to patch test the colophony to which the patient was exposed, which in this case was not possible; the two detected colophony substances were not available at the time. At least with the inforamtion from the TLC patch testing patient 2 can be advised not wearing shoes possibly containing colophony derived glues. References 1. Lynde CW, Warshawski L, Mitchell JC. Patch test results with a shoewear screening tray in 119 patients, Contact Dermatitis 1982; 8: Angelini G, Vena GA, Meneghini CL. Shoe contact dermatitis. Contact Dermatitis 1980: 6(4): Romaguera C. Shoe contact dermatitis. Int J Dermatol 1987; 26: Febriana SA, Jungbauer F, Soebono H, Coenraads PJ. Inventory of the chemicals and the exposure of the workers'skin to these at two leather factories in Indonesia. Int. Arch Occup Environ Health 2012; 85: Bruze M. The use of ultrasonic bath extracts in the diagnosis of contact allergy and allergic contact dermatitis. In: Patch testing tips. Lachapelle JM, Bruze M, Elsner P, eds. Springer- Verlag, Berlin Heidelberg, 2014: Bruze M, Frick M, Persson L. Patch testing with thin-layer chromatograms. Contact Dermatitis 2003; 48: Svedman C, Zimerson E, Bruze M. Allergic contact dermatitis caused by benzanthrone in a pair of trousers. Contact Dermatitis 2014; 71: Mathur AK, Khanna SK. Dermal toxicity due to industrial chemicals. Skin Pharmacol Appl Skin Physiol 2002; 15:

154 CHAPTER 9 General Discussion and future perspective Sri Awalia Febriana Department of Dermatology & Venereology, Gadjah Mada University, Yogyakarta, Indonesia Department of Dermatology, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands.

155 General Discussion This thesis is based on a series of studies into the nature of exposure and occurrence of occupational skin diseases (OSD), primarily occupational contact dermatitis (OCD), among workers in leather and shoe manufacturing in Indonesia as a newly industrialized country (NIC). We also studied shoe dermatitis among Indonesian consumers of leather and shoes and identified the responsible allergens. Based on workplace observations and references to relevant sources and institutions, in Chapters 2 and 5 we present an inventory of hazardous chemicals to which workers are exposed. We also deal with the prevalence of occupational skin diseases (OSD) and practices with regard to Personal Protective Equipment (PPE). In Chapters 3 and 6 we present relevant patch test results and expand on the prevalence of occupational allergic contact dermatitis (OACD) in leather and shoe factory workers. The resulting evidence and the identification of relevant series of allergens can be valuable for workers management of OSD. In Chapter 7, we present prospectively screened shoe dermatitis patients and their relevant clinical and patch test examination results. In Chapter 8 we discuss the chemical analysis of shoe materials using Thin Layer Chromatography (TLC) and Gas Chromatography-Mass Spectrometry (GCMS). This final chapter (Chapter 9) presents the main findings within the broader theoretical context outlined in Chapter 1, followed by a review of important strengths and limitations in the present study and an elucidation of possible implications for public health and future research. Indonesia as a representative NIC for the study Indonesia is one of the NICs, a group of nations which have undergone rapid economic growth and recently become prominent as an exporters of manufactured products. 1 Newly industrialized countries were chosen by businesses in developed countries seeking to set up overseas factories with cheap labour and resources, and lenient environmental regulations. This s tuat on llustrates w at s alle t e ollut on aven ot es s ef ne by Eskeland and Harrison (1997): The pollution haven hypothesis, is perhaps, best seen as a corollary to the theory of comparative advantages: as pollution control costs begin to matter for some industries in some countries, other countries should gain comparative advantages in those industries, if pollution control costs are lower there (for whatever reason)." Increased outsourcing and subcontracting of hazardous jobs from developed to

156 developing countries, especially NICs, includes outsourcing of related occupational health risks. Indonesia is widely known for its production of premium leather, including raw pickled leather, crust leather and wet blue leather, and was in 2011 ranked 14 th in worldwide leather export. 2 Indonesia is the world s third largest footwear producer 3, employing 202,189 workers in medium and large shoe factories, and in great demand by buyers in Europe and the USA. 4 As our study focuses on the medium and large industries, we chose two tanneries, each representative of types listed by the Indonesian Centre of Leather 5 : one highly mechanized and one medium mechanized tannery, both producing export quality products. In Chapter 5 we explain our choice of shoe factory based on the numbers of workers (more than 500), the use of advanced equipment and their export of products to leading shoe brands in Europe, the USA and other Asian countries. Inventory of chemicals to which workers in Indonesian leather and shoe industries are exposed Chemicals are indispensable in the manufacture of globally acceptable products. Nevertheless, workers, employers and authorities continue to struggle to control exposure to these chemicals in the workplace and to limit undesirable emissions into the environment. 6 The main pathways of (occupational) contact with hazardous substances are inhalation and contact with the skin. 7 Comprehensive knowledge of a patient s chemical environment can significantly improve the accuracy of a physician's evaluation of the clinical relevance of these substances. By visiting the workplace physicians can get a comprehensive picture of actual working conditions and grasp the clinical significance of many details. 8 It is impossible to get the whole picture when investigating a patient with contact dermatitis without visiting patients workplaces". 9 Measurement of skin exposure to certain chemicals can be intricate to interpret, as is identification of the exact nature of those chemicals. In Chapters 2 and 5 we discuss the findings of our workplace survey. First we visited the plant and observed the workers actually involved in their tasks. We noted how the work was done, how great their exposure to potential irritants and sensitizers and their degree of skin contact. We recorded the process with video recorder and camera. To get a detailed list of chemicals, we observed while workers prepared a chemical solution, noting in detail the product labels and declarations on containers. A visit to the chemical warehouse was the next step. We made an interview, observed the available chemicals and checked relevant data from MSDS. In shoe factory, we visited the finished materials warehouse to obtain 9 155

157 information about leather, rubber, synthetic materials and adhesives used and about their supplier. We contacted finished materials suppliers for particulars about product declaration and chemicals they used in the production process. The rubber supplier gave us data about vulcanizing agents, accelerators, antioxidants, and rubber dyes. Suppliers of synthetic materials and shoe adhesives shared information about some of the chemicals used. However, since suppliers did not provide exhaustive details about all chemicals used in the production process we gained further information from the Centre for Leather, Rubber and Plastic, the Ministry of Industry and Trade, Republic of Indonesia, and the Indonesian Foot wear Service Centre (IFSC). Both centres are responsible for research into leather and shoe production and resulting environmental pollution; they try to find alternative, environmentally friendly chemicals. The IFSC trains apprentices for shoe manufacture. The Centre for Leather and Rubber also runs the Indonesian Academy of Leather, educating future factory supervisors, leather researchers, as well as research and development personnel. The Centre for Leather and Rubber provided data on the Indonesian leather industry: classification of materials, work methods, and chemicals needed in leather processing. They also provided complete information on the characteristics and composition of all finished materials and adhesives used in shoe production. Prevention practices in Indonesian leather and shoe factories Occupational diseases can be prevented by elimination, substitution, engineering controls and safe work practices; they can also be avoided by the proper use of Personal Protective Equipment (PPE). 10, 11 Effective intervention to manage OCD as discussed in several published studies included the use of disposable towels rather than contaminated fabrics 12, the use of fabric softeners in work clothing, and the wearing of gloves and protective clothing. 13 Avoidance of relevant irritants and sensitizers also helped to alleviate dermatitis. Two studies showed, however, that avoidance of irritation by using PPE or changing one s job did not result in clinical improvement. 14, Chapters 2 and 5 describe in detail the presence of potential hazards also the availability and use of PPE in the leather and shoe factories. In the beam house and tanning area, for example, tannery workers were exposed directly to hazardous chemicals and airborne chemical pollutants during the whole working cycle (including cleaning and disposing of chemical waste). All required basic PPE equipment (except respirators) was available in the observed tanneries, but the utilization rate was only 30-50%; PPE was used mainly as a secondary preventive measure. This was similar to a situation discussed in another study, where gloves were used

158 mainly to protect already damaged skin. 16 In the finishing stages, workers were exposed to chemical splashes, dust and mist, leather dust, paint spray and organic vapours while working in small, poorly ventilated rooms without proper PPE. Used vinyl gloves were never replaced with new ones and some workers used oversized gloves. Moreover, as spills of water and hazardous chemicals onto gloves are likely to create dampness on the inside, intensive wearing of gloves can even increase the development of OICD. 12, 17 However, cotton gloves inside the occlusive rubber ones can prevent destruction of the skin barrier function caused by prolonged wearing of occlusive gloves. 13 Nonetheless, our interviews and observation of workers in leather and shoe factories revealed that workers found it unnecessary to use the required PPE in spite of safety information provided by factory management and physicians. Questionnaires and physical examinations used for workers in leather and shoe factories Unclear definitions of OSD and limited surveillance data, as well as differences in work situations and diagnostic criteria, make it difficult to determine the actual prevalence of occupational skin disease. 7 Moreover, current data are available only in voluntary or mandatory reporting schemes and compensation registries, or from specialized dermatology clinics Therefore for our study we used the active case ascertainment approach involving the use of questionnaires and/or clinical examinations. The number of cases obtained by questionnaires will be different from that by clinical examination. 21 Chapter 2 points out that current dermatitis cases clinically reported by dermatologists (10%) are fewer than those in the questionnaire based study (12%). These results parallel other NOSQ validation surveys One explanation for this is that workers filling in a questionnaire may confuse eczema with other diseases such as psoriasis or to underestimation of the prevalence of dermatitis. 24 Workers with health problems are likely to leave high exposure jobs, concluding their employment or being reassigned to another department. 26 Self-reported skin problems may be subject to bias and lead to either under- or over-estimation of the problem. Correlation of self-reported and clinically diagnosed skin diseases was attempted with a population of cement workers in Taiwan. In spite of good correlation between both diagnostic tools, some inaccuracies and under-reporting were noted. 27 Chapter 5 points out that dermatological examination (29%) resulted in a significantly higher prevalence (p<0.05) than did self-reporting of symptoms (8.5%). 28 Under-reporting of skin problems could be because 9 157

159 workers with callus/hyperkeratosis, pruritus sinae materia and skin cuts/lacerations were hesitant to admit that they had a skin disease related to their work. Some had learned to live with their skin problems and were afraid to lose their jobs because of health issues. Another factor is the limitations of factory workers' levels of education and reading skills and their lack of time and concentration to read and answer the questionnaires. All were therefore interviewed by trained interviewers using the Indonesian version of the Nordic Occupational Skin Questionnaire 2002 long version (NOSQ-2002/LONG) (See Chapters 2 and 5). However, as with self-reporting, some workers were not open about all of the skin problems caused by their working conditions. Our observational study of workers in tanneries (Chapter 2) showed that they were exposed to more wet activities and more varieties of chemicals than shoe factory workers. This can explain why OCD in the shoe factory was milder. However, intensive repetitive friction and airborne exposure to leather, polyurethane and rubber dust made the prevalence of callus/hyperkeratosis (9.7%) and pruritus sine materia (8.2%) higher in the shoe factory than in the tanneries (Chapter 5). Case ascertainment of occupational contact dermatitis in leather and shoe factories One can ascertain active cases of OCD in a large study population by intensive clinical examination of the whole study population, by selfadministered questionnaires or by combining both. Screening by trained dermatologists using standardized criteria is the most reliable and preferred method but is generally not feasible, especially in large populations. 21, 29 OCD is the most often reported OSD (70-90% of all reported OCD) in most developed countries Published data on occupational skin disease in many countries usually are obtained from occupational disease registries 36, medical records of patients visiting dermatology outpatient clinics, data from patch test clinics 37-39, and a few cross-sectional studies of occupational groups. 27, Population based studies provide the most accurate estimation of the incidence of occupational skin diseases To calculate the numbers of people in a population suffering with contact dermatitis one needs explicitly described diagnostic criteria, often lacking in many studies. 21 The difference between occupational and non occupational dermatitis must be clearly defined, as must the difference between OICD and OACD. 7 To diagnose OCD, the gold standard is clinical assessment by an occupational dermatologist using the above-emphasized clear criteria 44, 45, patch testing and, where indicated, serum IgE testing or

160 prick testing. 46 In Chapters 3 and 6 we base our criteria for diagnosis of OACD on information from workplace observation, questionnaires and dermatological examinations (including patch testing). Diagnosis was established in cases meeting the latter criteria and several criteria drawn from other publications. 7, 8, 47 OCD was suspected in 16.3% of tannery workers and 7.6% of shoe factory workers. OACD was diagnosed in 3% of tannery workers and 2.7% of shoe factory workers. We considered the prevalence of OCD and OACD among tannery and shoe manufacturing workers to be high. The prevalence of OACD might have been even higher if we could have patch tested all the workers who had OCD. Fourteen workers with OCD in the tanneries and 6 in the shoe factory were not patch tested: as mentioned above, many did not want to be diagnosed with a serious skin problem and they did not want to lose their jobs. Observations and in-depth interviews with workers and management showed that some workers with occupational skin diseases leave the factory or are tr sferre to ot er e rt e t t is is c e s t e e t -workers survivor effect. Patch tests in Indonesian leather and shoe factory workers: results and factors influencing clinical interpretation Studies of contact dermatitis are usually based on subjects recruited from patients visiting a clinic for suspected contact dermatitis. 21 Because we aimed to identify and analyse occupational groups at particular risk we included all workers directly exposed to hazardous chemicals. Instead of using data from patch test clinics where it could take years to collect enough cases, we visited factories and included all workers in the production process. We also avoided another major problem of patientbased studies in a clinic that prevalences found in a particular group of patients can be misinterpreted as prevalences for a whole population. 21 In Chapters 3 and 6 we discuss the patch test results of Indonesian leather and shoe factory workers. The patch tests were performed with allergens from the European Baseline Series, Shoe Series and a number of additional allergens. However, use of an additional series of allergens is needed to improve results and clinical interpretations, as studies have shown that patch tests using standard series are insufficient. 48 Based on our observations in tanneries (Chapter 2) and a shoe factory (Chapter 5) we compiled a list of chemicals encountered by workers. To identify additional allergens, we first had to assess whether the chemicals were sensitizing allergens; we used the Material Safety Data Sheet (MSDS), the online database from the NIOSH website 49 and references from Pubmed. We studied the literature to determine preferred vehicles and concentrations of additional allergens. 50 When the additional allergens were not available 9 159

161 from commercial patch test manufacturers we prepared them in our laboratory, using analytical-grade chemicals. Legal and financial consequences make it important to ensure the validity of diagnoses of occupational contact sensitization. To improve the reliability of the patch testing technique researchers worked continuously to compose series of tests, focusing on concentrations and vehicles of chemicals and on standardization of patch test reading 51 and interpretation of clinical relevance. 52 Patch tests can have a limited reproducibility as a standard diagnostic procedure, partly due to meteorological conditions and changes of season. One multicentre study showed an increase of irritation and doubtful reactions with dyes and biocides during cold and arid conditions, but not with adhesives, plastic and rubber. The authors thus had to consider the influence of weather conditions on the diagnostic value of the test. 53 We were patch testing subjects at work in a hot climate; because perspiration could loosen the patches they had to be reinforced with extra tape, making them uncomfortable to wear. Many workers refused to participate or withdrew from the study. Some subjects took off the patches before 48 hours occlusion or showered or scrubbed the patch test area. To get workers to agree to patch testing and follow proper procedures we had to convince them of the importance of the study. They were more enthusiastic once they realized its importance for other workers in the same industry and for leather and shoe consumers. Clear results from our study could lead to recommendations for factory management, government and stake holders and also for the chemical industry providing substances for leather and shoe manufacture. The most difficult and intricate part of the patch test procedure is assessing the clinical relevance of positive patch test reactions in the occupational setting, a task requiring skill, experience and curiosity. 52 Based on International Contact Dermatitis Research Group (ICDRG) criteria, we concluded that a positive patch test rea tion is rele ant i the aller en has een tra ed rrent rele an e re ers to the patient s present dermatitis ast rele an e re ers to a past lini al disease and is not dire tly related to current symptoms. 52, 54 During patch testing we found sensitization to 15 allergens relevant to tannery work and 16 allergens relevant to shoe factory work. Judgement as to the clinical relevance of those allergens was possible only after we were able to establish, first, an exposure and, second, whether the worker s dermatitis was partially or totally linked to the exposure For some allergens in finished materials (rubber, plastic or synthetic materials) we used the information from the material suppliers. There is, however, a possibility that the suppliers did not disclose complete

162 information about all chemicals used. We consulted the Centre for Leather and Rubber for additional information on additives and other chemicals used in the production of rubber and synthetic materials. In spite of our care in these matters, however, the possibility remains that some finished materials contained allergens which we were unable to detect. We will therefore need further chemical analysis to identify these allergens. In chapter 3, we identified possible sensitizers encountered by tannery such as sodium n- methyldithiocarbamate, sodium formate, sodium metabisulfite and benzidine could be considered for patch tests with patients with (leather) shoe dermatitis, but we needed further chemical analyses of leather materials to prove that these allergens affected shoe leather consumers. We discuss in detail the reported differences in patterns of sensitivity in our study and a similar study in Korea 55 and one in an Argentinean tannery. 56 Benzidine sensitization results were of particular interest here because sensitization to this allergen is not common and was last described in 1980 by a Spanish researcher 57 ; the substance has been banned in several countries due to its potential carcinogenic effect 58, 59, but as reported in Chapter 4 60 With respect to sodium metabisulfite, although relevant occupational exposure has been published about bakers, caterers, rubber manufacturers and workers with textile dyes 61-63, to our knowledge ours is the first published study to report cases of occupational sensitization to this substance among leather and shoe workers. In chapter 6 we determined relevant sensitization to occupational allergens in shoe factory workers. Allergens from shoe adhesives were found to be the most common sensitizers and were observed mostly in people working in the upper sole department. Beside 4-tert-butylphenol formaldehyde resin (PTBP-F-R) as a popular sensitizer, we found relevant sensitizations to dodecyl mercaptan, epoxy resin and diphenylmethan diisocyanate. Dibuthylthiourea was the most common relevant sensitizer in rubber production and workers in the sewing department were the most commonly sensitized because they were exposed over longer periods than workers in other departments. Sensitizations to leather tanning agents were seen not only to potassium dichromate but also to formaldehyde and glutaraldehyde. Shoe dermatitis: epidemiology and problems with diagnosis Shoe dermatitis is a common type of contact dermatitis and a major cause of recurrent plantar dermatitis, which in most cases remains undiagnosed, 9 161

163 misdiagnosed and diagnosed empirically without any information as to the contributory allergens. 64 Shoe dermatitis is a specific form of allergic or irritant contact dermatitis resulting from exposure. A comprehensive history and skin examinations are crucial for accurate diagnosis. Accurate diagnosis, appropriate treatment and patch testing to identify the causative agent can prevent further potentially debilitating episodes of shoe dermatitis. 65, 66 Chapter 7 presents a prospective study of patients coming over a 3 year period with foot skin problems to dermatology out-patient clinics. Of 903 patients with skin disorders of the feet, 64 (7.1%) were screened as having shoe dermatitis. Pruritus was the most common complaint (85.3%). Rubber slippers and sandals (50.7%) were the most suspected footwear, followed by imitation leather sandals and shoes (29.6%), leather sandals and slippers (11.2%), plastic sandals (5.6%) and sneakers (2.8%). In Indonesia, rubber slippers and sandals are the most common footwear. People always wear sandals at home, including for wet work, and more than half of the patients suspected rubber footwear as the cause of their shoe dermatitis. However, some patients refused to return to the polyclinic for patch testing; after their lesions were healed they saw no need to know the allergens causing their disease. Therefore, to get accurate data we visited patients at their homes to perform dermatology and patch test examinations. We cannot assume that all suspected eczema of the feet is shoe dermatitis; not all allergic contact reactions are eczematous in presentation. The most reliable clue to the allergic nature of the dermatitis is its cutaneous distribution. 67, 68 In a study by Shackelford, more than 7/20 of patients with eczema limited to the feet were diagnosed as having psoriasis. 69 If we base the differential diagnosis of shoe dermatitis on its cutaneous distribution, their findings suggest that one should just as often consider a diagnosis of psoriasis as one of shoe dermatitis. Shoe dermatitis is often diagnosed as another form of skin dermatoses such as eczema, psoriasis or dermatomycoses. 64 In our dermatology polyclinic we met shoe dermatitis patients first diagnosed with recurrent chronic eczema of the foot, dermatomycoses or keratoderma plantaris. However, after careful anamnesis, dermatological and patch test examinations we regarded these patients as having shoe dermatitis. Allergens causing shoe dermatitis Patients with intermittent or chronic foot dermatitis should be considered to have shoe dermatitis until proven otherwise. 65 The diagnosis of shoe dermatitis depends on the history, clinical picture, positive patch test reactions to shoe materials, and the patient s ability to wear proper substitute shoes without dermatitis. 70 Patch testing for shoe dermatitis is

164 performed with allergens from the baseline series, shoe allergens in an expanded shoe series, and samples from the patients suspected shoes. 65 Many studies assembled allergen series by separating the shoe s components and identifying all possible culprits Our study is prospective, following actual patients with skin problems of the feet; unlike retrospective studies which gather their data from patients patch test results in dermatology polyclinics. Our number of allergens patch tested (51 allergens) was higher than that reported in similar studies 64, and our analysis of their clinical relevance was meticulous. Our patch tests with shoe materials and shoe material extract were in line with an Italian study. 77 Rubber, the most common footwear materials used in Indonesia, was the most common sensitizer. In our study, patients were sensitized to many rubber allergens: allergens frequently reported (mercaptobenzothiazole and diphenylguanidine) and allergens that were rarely reported (4,4'-dithiomorpholine 1%, N-isopropyl-N'-phenyl-pphenylenediamine, and hydroquinone monobenzylether). Patch testing with leather allergens showed that a few patients were sensitized to TCMTB, a leather preservative in Indonesian leather manufacturing. 79 Adhesives causing sensitizations were 4-tert-buthylphenolformaldehyde resin, dodecyl mercaptan, colophony, and epoxy resin. The first two allergens are neoprene based adhesives which are frequently used in Indonesia. Patch test with suspected shoe materials Patch testing is an assay for establishing contact allergy which is crucial for a diagnosis of allergic contact dermatitis. A multicentre study showed that patch testing with the European Baseline Series only detected 37-73% responsible allergens in contact dermatitis patients. Meanwhile additional series showed positive reactions in 5-23% patients. 80 It has been found that 25-50% of reactions to materials in suspected shoes are due to allergens not present in the screening tray, often because modern shoes are manufactured from unknown components provided by outside suppliers. 81 Furthermore, industrial grade chemicals may not be in a pure form or may have been modified during the process of manufacture, undergoing degradation, oxidation or other chemical reactions. The modified chemicals may then cross-react with standard screening allergens and complicate the patch-test results. 82, 83 Moreover, reactions to test allergens in the shoe tray may be due to concomitant factors or broadening of the allergic base. Where the clinical picture strongly suggests shoe dermatitis and the patient does not react to any of the materials in the screening tray, it may be necessary to patch test with actual materials from the suspected shoe. 65, 72, 78, 84 It must be emphasized that a negative patch test reaction to the shoe 9 163

165 materials does not necessarily exonerate the shoe from being the cause of shoe dermatitis, since friction, maceration, and the leaching effect of sweat during actual use are not duplicated in a standard patch test. Even with a positive patch test with shoe materials observed in a shoe dermatitis patient, the relevance of the test is often uncertain because the actual allergen has not been extracted from the patient s shoes. Jung et al.(1988) found it necessary to use chromatographic separation to isolate and identify the causative allergens in a suspected shoe dermatitis case caused by a tennis shoe insole. 85 Patch testing with thin layer chromatograms can provide quick identification of a contact sensitizer present in a compound, as textiles or shoes, to which a subject has tested positively. 86 In Chapter 8 we reported two shoe dermatitis patients who showed no positive reaction to shoe allergens but did give positive reactions to an extract from the shoe materials. We had performed chemical analyses with Thin Layer Chromatography (TLC) and Gas Chromatography-Mass Spectrometry (GCMS) to find the substances causing the problems. Chemical analyses isolated the possible allergens and based on the patch test examinations with TLC-strips and GCMS analysis, 2(3H)- benzothiazolone, methyl dehydroabieatate and 7-oxodehydroabietic acid methyl ester were shown to be the allergens present in the shoe materials. 2(3H)-benzothiazolone is a new allergen rarely reported before. These substances could be a degradation product from the rubber chemicals. Methyl dehydroabieatate and 7-oxodehydroabietic acid methyl ester are colophony derivatives, probably present in colophony-derived glues in shoes. Strengths and limitations of the studies In Chapters 2 and 5 we were able to produce a detailed scheme of the factory processes, focusing on the risk of OSD in each stage of leather and shoe production. One limitation in our studies was that our choice of factories was not based on random sampling due to the paucity of occupational health information in these industries. In order to get overview of the working conditions in Indonesian leather and shoe factories, we chose representatives of medium and highly mechanized tanneries and an export quality shoe factory based on the data base of the Centre for Leather, Indonesian Foot Service Centre, and according to a leather and footwear competitiveness report Another limitation of our study was that we did not make a quantitative assessment of the level of skin exposure. Nevertheless, ours is one of the few studies which investigate the nature of exposure and occurrence of occupational skin disease in NICs. We were able to produce a detailed

166 scheme of the working process, focusing on the risk of OSD in each step of production. We describe potential hazards present in each working stage, the requirements for and availability of PPE, and workers practice of standard safety procedures in the workplace. The strength of our study is that we used the most reliable method to screen our complete study population: the application of standardized criteria by trained dermatologists. A common characteristic in most observational studies is the occurrence of non-responders among invited study participants. 21 In our study, all employees engaged in the production process took part in interviews and dermatological examinations. This high response rate enabled us to make generalisations about the workers in medium and highly equipped tanneries, and export quality shoe factories. In Chapters 3 and 6 we were able to perform careful identification of possible sensitizers to which tannery and shoe manufacturing workers and potential consumers were exposed. In the leather factory, to identify relevant sensitizers we directly observed workers as they prepared solutions; we were also able to see the details on product labels and declarations of the chemicals. A limitation in the shoe factory, however, was that we were not able to directly observe the production of finished materials such as rubber and synthetic materials (polyurethane and neoprene). To identify sensitizers in the finished materials we had to contact the suppliers for exact details about the composition of each material. Even though the suppliers were willing to provide us information about their products, not all suppliers fully disclosed the information needed as they often did not have access to complete information. We were able to obtain additional information from the database of the Centre for Rubber and Leather, but, because the composition of certain finished materials may have changed, we cannot be sure whether the finished materials contained other allergens. Another limitation was that 14 leather and 6 shoe factory workers with OCD refused to be patch tested or withdrew from the study due to discomfort from the patch test application. This could influence the results because if these workers agreed to be patch tested, the prevalence of OACD could be higher. In Chapter 7 we discuss our patch test examinations of shoe dermatitis patients. In comparison with other studies of shoe dermatitis patients, we did our patch test examinations using a well characterized group of patients and an extensive and carefully selected range of allergens. We also critically assessed the relevance of positive patch test reactions to the exposure to suspected shoe materials. Comparable studies in the literature are scarce; most authors reported only on subjects with positive patch tests. Percentages from our study approach results reported by Angelini et 9 165

167 al (65.4%) 76 : shoe dermatitis in this Italian study was well characterized. However, the authors admitted that some positive reactions included in the study were probably not relevant for shoe dermatitis. Reported prevalences are difficult to compare due to differences in study design, types of allergens/shoe materials patch-tested, and investigators assessment of the relevance of the positively tested allergens to the exposure to the shoe material. A limitation of our study is a possibility of selection bias, since the subjects we included were all patients who came to the dermatology clinic of a referral hospital in Indonesia. Patients who came to this hospital were mostly those with severe or recurrent skin problems. From 64 patients fulfilling the criteria for shoe dermatitis, 16 refused to be patch tested or lost to follow up. A study based only on patients visiting dermatology clinics cannot be used to directly estimate population-related prevalences, since we were less likely to include patients who are undiagnosed/misdiagnosed, patients who visited primary care/ family doctors and patients who did not return to follow up. 21 We reported in Chapter 7 that in some shoe dermatitis cases patch testing with allergens in a standard screening tray and expanded shoe series containing chemicals used in shoe manufacture has been found to be insufficient. In Chapter 7, we performed ultrasonic bath extract examination of suspected shoe materials to obtain solutions for patch testing. To establish allergic contact dermatitis to the shoe we patch tested with shoe materials extract and TLC strips. To demonstrate the presence of possible causative allergens in shoe materials we used GCMS. Analyses indicated the presence of allergens (2(3H)-benzothiazolone, methyl dehydroabieatate and 7-oxodehydroabietic acid methyl ester) which had not previously been encountered in the shoe material. This evidence indirectly emphasizes the need for an updated shoe series. Recommendations for future practice and research regarding occupational skin diseases in Indonesia Indonesia is a country with abundant natural resources and manpower, and has experienced rapid economic and industrial growth. However, excessive uses of resources, uncontrolled emissions and lenient environmental regulations have led to a number of negative effects, including occupational skin disease. On the basis of our studies we would therefore like to make some recommendations for future practice and research with regard to occupational skin diseases and shoe dermatitis patients in Indonesia:

168 Collaboration with the Ministry of Industry and Ministry of Manpower, Republic of Indonesia and Leather and Shoe Factories Since the start of our project in the leather and shoe industries we have collaborated with the Centre for Leather, Rubber and Plastic, Ministry of Industry and Trade, Republic of Indonesia and the Indonesian Foot wear Service Centre (IFSC). We have shared information about the latest developments in working processes and chemicals used in the leather and shoe industries. We have also shared the results of our research with the Directorate General of Labour Inspection within the Indonesian Ministry of Manpower, whose job it is to oversee working conditions and promote occupational safety and health. These institutions have agreed to more intensive future co-operation. Added to this, close cooperation between employers, workers, physicians and authorities can lead to better prevention and reduction the prevalence of Occupational Skin Diseases in Indonesia. The purpose is to have a better control of chemical exposure and hazards in the workplace. A strategy is needed to implement stronger preventive measures including elimination, substitution, engineering controls, and PPE. Where we provide information on hazardous agents, the Centre for Leather and Rubber can develop alternative chemicals to use in the production process. Manufacturers can implement engineering measures, one being to build exhaust ventilation systems in the spray-painting section to decrease exposure of solvent vapours to tannery workers. In shoe factory, regular monitoring of workers exposure to volatile organic compound and the arrangement of exhaust ventilation system is needed to decrease exposure to chemical solvent vapours and airborne dust from leather, rubber and synthetic materials. Part of dealing with hazardous materials is knowing exactly what those materials are. As explained earlier, we often encountered difficulties when trying to gather information from factory managers about chemicals or the compositions of finished materials. Since 1987, factories selling to international buyers have been required to have ISO 9001 certification. This includes Hazard Identification and Risk Assessment by the office of Occupational Safety and Health under the Ministry of Manpower. We recommend the factory to have a complete and up-to-date list of chemicals and compositions of finished materials used in factories; this will be useful not only for workers but also for the factory s management. However, even with these suggested improvements workers remain exposed to many potential hazards. Effective PPE is needed to reduce the risk. According to our observations workers had a very low awareness of 9 167

169 the value of using PPE. We therefore recommend more education to raise their awareness, for example by providing simple and practical advice via personal conversations and group discussions. Skin awareness campaigns carrie out in many e elope countries such as healthy s in wor organized by the European Initiative for the Prevention of Occupational in iseases an afe or in ustralia pro i e good examples. We also recommend strengthening the role of occupational physicians in OSD notification, hazard identification and risk measurement. Occupational physicians are required to regularly report occupational diseases in their workplaces and to assess possible risks. The Directorate General of Labour Inspection monitors physicians compliance with these obligations. However, in actual practice occupational physicians are more occupied with curative health care and rarely perform workplace observations. Among the reasons for this are lack of time and fear of creating problems with factory management. Our recommendation is to empower occupational physicians to be independent and professionally accountable for their own practice and not be influenced by the factory s interests. For the near future we recommend expanding our current collaboration with relevant agencies to develop more innovative activities. One activity would be to develop informative websites to keep workers, health care professionals, general practitioners, occupational physicians, manufacturers, policy makers, consumers and patients informed about the rapid changes in chemicals used in the workplace and the availability of new personal protective equipment. Physicians and other experts could be consulted to keep the website information up-to-date. Collaboration with Ministry of Health, Republic Indonesia; Indonesian Society of Dermatology and Venereology; and the Indonesian Occupational Skin Disease Work Group In collaboration with the Ministry of Health we must continue to educate general practitioners about primary health care for work-related diseases. Moreover, we need to better train occupational physicians in their assessment of skin exposure, helping them to find practical solutions for its management, including prevention and elimination. In this context we recommend more active cooperation between the Indonesian Society of Dermatology and Venereology and the Indonesian Occupational Skin Disease Work Group; the latter has an Occupational Skin Diseases programme which includes courses, workshops and work group discussions to keep general practitioners, occupational physicians and

170 dermatologists abreast of the newest findings on occupational skin diseases. Based on our own experience in leather and shoe factories, we recommend improved access to diagnostic and treatment services, in particular affordable patch test materials and series of allergens. In Indonesia, as insurance does not cover patch test fees the patients have to pay all the costs; because materials have to be imported from other countries these costs are high. The result is inadequate use of patch tests. To find a solution for this, our Department of Dermatology at Gadjah Mada University, Indonesia has begun with local production of patch test materials and standard allergens, but we need more research and standardization. In the future we hope to continue to provide additional allergens not commercially available. We recommend that the Indonesian Society of Dermatology and Venereology continue to lobby for new policies and regulations, including coverage of patch test examinations by Indonesian National Health Insurance. As emphasized in our study of shoe dermatitis patients, patch tests with baseline series and an expanded shoe series are not sufficient. TLC and GCMS analyses in collaboration with other centres in Indonesia and the Department of Occupational and Environmental Dermatology, University of Lund, Malmö, Sweden have proven beneficial in revealing the presence of suspected allergens. However, the constantly growing number of allergens in patients own materials and working environments underlines the importance of using these chemical analyses in collaboration with such centres. Based on findings in our studies in leather and shoe factory workers and shoe dermatitis patients we propose to update the shoe pat h test series of allergens for investigating patients with shoe dermatitis and propose a tanner work series o allergens or patch testing. Recommendations for future research - Surveillance studies are needed in low mechanized tanneries and small shoe factories. Such studies can be done in collaboration with Ministry of Health and Ministry of Manpower, Republic Indonesia, especially for data collection and notification of general practitioners and occupational physicians in the study area. - Intervention studies in the leather and shoe factories are needed to improve prevention. A prospective intervention study could, for example, evaluate the effect of skin awareness campaigns on leather and shoe factory workers. Such a study could be multidisciplinary, involving 9 169

171 for example a researcher from the Centre for Leather and Rubber to share his ideas about less hazardous manufacturing processes. - More attention should also be given to quantitative assessment of dermal exposure in leather and shoe factories. - Research is needed to eliminate well-known sensitizers in the leather and shoe industry, such as chromate and PTBF-resin, and to develop alternative chemicals which are safer and environmentally friendly. Ongoing study to develop mineral and vegetable tanning agents as alternative substances for chrome is being conducted by the Centre of Leather and Rubber. Related studies to develop alternative substances for shoe adhesives are needed. It is our hope that our studies will substantially advance diagnosis, treatment and prevention of skin diseases among leather and shoe factory workers and consumers in Indonesia, but also worldwide. References 1. Berlage L, Terweduwe D. The classification of countries by cluster and by factor analysis. World Development 1988; 16: Ministry of Industry Republic of Indonesia. Leather and leather product. 2011; 10: Biro Pusat Statistik; Available from: Last accessed May 25, Kemenperindag; Available from: indikator.php?indikator=3. Last accessed May 25, Centre for Leather, ed. Academic background on national ecolabel criteria on leather of shoe upper, garment, glove and upholstery. Indonesia: Japan International Cooperation Agency (JICA) and Ministry of Enviroment (MOE) Republic of Indonesia; International Labour Organization (ILO), ed. Recording and notification of occupational accident and diseases. Geneva, Switzerland: International Labour Organization; Nicholson PJ, Llewellyn D, English JS, Guidelines Development Group. Evidence-based guidelines for the prevention, identification and management of occupational contact dermatitis and urticaria. Contact Dermatitis 2010; 63:

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178 CHAPTER 10 Summary Sri Awalia Febriana Department of Dermatology & Venereology, Gadjah Mada University, Yogyakarta, Indonesia Department of Dermatology, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands.

179 Summary A series of studies into the skin exposure and the occurrence of occupational skin disese (OSD), primarily occupational contact dermatitis (OCD) among leather and shoe factory workers, and shoe dermatitis patients in Indonesian are described in this thesis. A general introduction on occupational contact dermatitis and shoe dermatitis are presented in Chapter 1. Although leather and shoe industries have existed in Indonesia for several decades and more than thousands of workers are employed in the medium and large factories, occupational skin diseases in these factories have not been fully studied. An investigation into the hazardous chemicals and physical agents encountered by workers in this industry, and the related occupational skin diseases is thus highly relevant. Also, shoe dermatitis, a troublesome disease among leather and shoe consumers, need further elucidation, as do the important allergens that have been unravelled as cause of these diseases. An introduction on the OCD in the leather and shoe factory workers and the shoe dermatitis described in this thesis is presented in the first chapter. Rationale, objectives and outline of the thesis are also described. In the study in Chapter 2, we did a cross-sectional study on the observation of the working process and an inventory and risk assessment of the chemical used. Classification of chemicals as potential sensitizers/irritants and qualitative assessment of exposure to these chemicals were presented. Workers were examined and interviewed using Nordic Occupational Skin Questionnaire (NOSQ-2002/LONG). The risk of OSDs at the investigated tanneries was mainly related to the exposure to 472 workers; 12% reported a current OSD and 9% reported a history of OSD. In 105 of all cases, an OSD was confirmed by dermatologist and 7.4% had an OCD. We observed that personal protective equipment (PPE) used was mainly because of skin problems in the past and not as a primary protection. We observed a high frequency and prolonged exposure to many skin hazardous factors in tannery work although PPE was relative easily available and which was generally used as a secondary preventive measure Occupational skin diseases in tannery workers have been reported, but neither the prevalence of occupational allergic contact dermatitis (OACD) nor the the skin sensitizing agents were specifically presented in those studies. In Chapter 3, we presented a cross-sectional study in all workers at two Indonesian tanneries for assessing the prevalence of occupational contact dermatitis via personal interview and skin examination. Workers with occupational contact dermatitis were patch tested to identify the causative allergens. Occupational allergic contact dermatitis was confirmed

180 in 3% workers. Chromate (9.2%), n,n-diphenylguanidine (5.3%), benzidine (3.9%) and sodium meltabisulfite (2.6%) were found to be the occupationaly relevant sensitizers. The sensitization pattern showed some differences with the data in studies reported from other Newly allergens may also be considered for patch testing. A number of these allergens may also be considered for patch testing in patients with (leather) shoe dermatitis. In the context of an ongoing study at two leather tanneries in Indonesia mentioned above, in Chapter 4 Indonesian tannery workers. Benzidine and its derivatives have been used to manufacture dyes during many years in the past but in 1978 several countries banned the manufacture of dyes from benzidine because of its potential carcinogenic effect. Indonesia is a NICS and classified as the biggest shoe producing countries in the world together with China and Vietnam. In Chapter 5 we performed a cross-sectional study on the observation of the working process and an inventory and risk assessment of exposure to the chemicals used. Classification of chemicals as potential sensitizers/irritants and qualitative assessments of these chemicals were done. Workers were examined and interviewed using the NOSQ-2002/LONG. From a total of 514 workers, 8.5% reported current OSD and 4.8% reported a history of OSD. Occupational skin diseases were diagnosed in 29% of the workers by dermatologists and 7.6% had an occupational contact dermatitis (OCD). Of the 39 workers with contact dermatitis, 33 consented to being patch tested, 14 (3%) workers showed positive results and considered as having an occupational allergic contact dermatitis (OACD) and 25(4.9%) had occupational irritant contact dermatitis (OICD). In a Chapter5 we presented a detailed overview of the exposure to putative sources of occupational irritants and sensitizing agents in the Indonesian shoe manufacturing industry and described the prevalence of occupational skin diseases among the workers. However, detailed results of patch testing of shoe factory workers had not yet been reported. In Chapter 6 we performed a cross sectional study in a shoe factory in Java, Indonesia. All 514 workers were interviewed using an Indonesian translation of the NOSQ-2002/LONG and underwent skin examinations. Patch test were done on 33 workers with OCD and 77 healthy workers to of allergens for patch testing. Occupational relevant contact allergy was diagnosed in 2.7% of the workers. We identified relevant positive reactions to 16 allergens. Like other studies, we found shoe adhesives and rubber allergens to be the most frequent sensitizers. But our study showed

181 differences in the frequency and variation of sensitizing allergens. Results of this study provide beneficial information in treating patients with shoe dermatitis and for policy makers in developing programme to prevent OCD in the shoe manufacturing workers. Shoe dermatitis is a form of contact dermatitis resulting from exposure to shoes. Allergens and types of shoes responsible may vary depending on manufacturing techniques, climate conditions and indigenous traditions. The highest prevalence has been reported in warm climates where heat, humidity and inside the shoe like friction, sweating, pressure and occlusion in conjuction with various chemicals in shoe materials contribute to the prevalence of shoe dermatitis. In Chapter 7 we performed a study focuses primarily on as yet unexplored shoe dermatitis cases in Indonesia. Our study was a prospective study, following actual patients with skin problem of the feet. All patients meeting screening criteria for possible shoe contact dermatitis were patch test with the European Baseline Series, shoe series and additional series based on our earlier studies described the previous chapter about the Indonesian shoe and leather manufacturers. Some patients were also patch tested with their own shoe materials and shoe extracts. We were able to show a high percentage (52 %) of positive patch test reactions and precisely describe their relation to footwear. Positive supported our results of patch testing with allergens. The most frequent relevant sensitizers were rubber allergens followed by preservatives, shoe adhesives and leather materials Patch testing with allergens in a standard screening tray containing chemicals used in shoe manufacturing has been found to be insufficient. Negative reactions to those allergens do not necessarily exclude shoe dermatitis; 25-50% of reactions to materials in suspected shoes are due to allergens not present in screening tray often because modern shoes are manufactured from unknown components provide by outside suppliers. In Chapter 8, we reported 2 shoe dermatitis patients who showed no positive reactions to shoe allergens but did give positive reactions to an extract from the shoe materials. We had performed chemical analyses with Thin Layer Chromatography (TLC) and Gas Chromatography-Mass Spectrometry (GCMS) to find substances causing the problems. Chemical analyses isolated the possible allergens and based on the patch test examinations with TLC-strips and GCMS analyses, 2(3H)-benzothiazolone, methyl dehydroabieatate and 7-oxodehydroabietic acid methyl ester were shown to be the allergens present in the shoe materials. 2(3H)-benzothiazolone is an allergen rarely reported before. These substances could be a degradation product from the rubber chemicals. Methyl dehydroabieatate

182 and 7-oxodehydroabietic acid methyl ester are colophony derivatives, probably present in colophony-derived glues in shoes. In the final chapter, the findings of this thesis are discussed in a broader context. Reccomendations to the Indonesian public and occupational health authorities are presented

183 Samenvatting In deze thesis wordt een reeks van studies beschreven over de aard van blootstelling en het voorkomen van werkgerelateerde huidziekten (occupational skin disease, OSD) - voornamelijk werkgerelateerde contactdermatitis (occupational contact dermatitis, OCD) - onder zowel leer- en schoenfabriekwerkers als Indonesische leer- en schoeiselconsumenten met schoendermatitis. In Hoofdstuk 1 wordt een algemene introductie over werkgerelateerde contactdermatitis en schoendermatitis gegeven. Hoewel leer- en schoenfabrieken in Indonesië reeds meerdere decennia bestaan en er duizenden arbeiders in de middelgrote- en grote fabrieken werkzaam zijn, is het voorkomen van werkgerelateerde huidziekten in deze fabrieken nooit uitgebreid onderzocht. Het is dus uiterst relevant om de gevaarlijke chemische stoffen en fysische agentia die in deze fabrieken worden gebruikt te onderzoeken in relatie tot werkgerelateerde huidziekten. Tevens behoeft schoendermatitis, een hinderlijke aandoening onder gebruikers van leer en schoenen, verdere opheldering, evenals de belangrijke allergenen die verantwoordelijk worden gehouden voor deze ziekte. Er wordt een introductie gegeven over OCD in leer- en schoenfabriekwerkers en de schoen dermatitis welke beschreven wordt in deze thesis. De rationale, de doelstellingen en de opzet van de studies in deze thesis worden ook beschreven In Hoofdstuk 2 wordt een cross-sectionele studie beschreven van het werkproces en een werd er een inventarisatie en risico-evaluatie gepresenteerd van de gebruikte chemische stoffen. Zowel de classificatie van potentiële sensibiliserende stoffen/irriterende chemicaliën als een kwalitatieve analyse van blootstelling aan deze chemicaliën werden beschreven. Medewerkers werden onderzocht en geïnterviewd door (NOSQ- waren voornamelijk gerelateerd aan blootstelling van de huid van de medewerkers aan chemicaliën in warme en vochtige omgevingscondities. In een groep van 472 medewerkers rapporteerde 12% een actuele OSD en 9% rapporteerden een voorgeschiedenis van een OSD. In 105 van de gevallen kon een OSD door een dermatoloog worden bevestigd, waarvan 7.4% een OCD had. Wij constateerden dat de persoonlijke beschermingsmiddelen hoofdzakelijk werden gebruikt vanwege huidproblemen in het verleden en niet als primaire bescherming. We stelden vast dat er een hoog frequente en langdurige bloostelling was aan vele, voor de huid schadelijke factoren tijdens het werken in de leerlooierij, hoewel PPE relatief eenvoudig

184 beschikbaar was. Werkgerelateerde huidziekten in leerlooierijwerkers werden eerder gerapporteerd, maar zowel de prevalentie van allergic contact werden niet specifiek benoemd in de betreffende studies. In Hoofdstuk 3 beschreven we een cross-sectionele studie aangaande alle medewerkers van de twee Indonesische leerlooierijen. Op basis van een interview en huidonderzoek kon de prevalentie van werkgerelateerd contacteczeem worden vasgesteld. Medewerkers met werkgerelateerd contacteczeem allergenen te identificeren. Werkgerelateerd allergisch contacteczeem werd bevestigd in 3% van de medewerkers. Chromaat (9.2%), n,ndiphenylguanidine (5.3%), benzidine (3.9%) en Natriummetabisulfiet (2.6%) kwamen als de meest relevante werkgerelateerde sensibiliserende stoffen naar voren. Het sensibilisatiepatroon toonde enkele verschillen met samen van allergenen die ook kunnen worden overwogen voor patchtesten. Een aantal van deze allergenen kunnen ook overwogen worden het patchtesten van patiënten met (leer)schoendermatitis. Binnen de context van een lopend onderzoek in de twee bovengenoemde leerlooierijen in Indonesië, beschreven we in Hoofdstuk 4 in drie Indonesische leerlooierijmedewerkers. Benzidine en haar derivaten werden in het verleden gedurende vele jaren gebruikt, maar in 1987 hebben meerder landen de vervaardiging van kleurstoffen uit benzidine verboden vanwege het mogelijke carcinogene effect. Indonesië is een NIC en wordt geclassificeerd als een van de grootste schoenen producerend landen en samen met China en Vietnam. In Hoofdstuk 5 werd een cross-sectionele studie beschreven die werd verricht in een schoenfabriek in Java, Indonesie bestaande uit een observatie van het werkproces en een inventarisatie en risico-evaluatie van de blootstelling aan de gebruikte chemische stoffen. Er werd zowel een classificatie van potentiële sensibiliserende stoffen/irriterende chemicaliën als een kwalitatieve analyse van blootstelling aan deze chemicaliën uitgevoerd. Medewerkers werden onderzocht en geïnterviewd door middel van de NOSQ-2002/LONG. Van een totaal van 514 medewerkers, rapporteerde 8.5% actuele OSD en 4.8% rapporteerde een voorgeschiedenis van OSD. Werkgerelateerde huidziekten werden bij 29% van de medewerkers door een dermatoloog gediagnosticeerd en 7.6% hiervan had een werkgerelateerd allergisch contacteczeem. Van de 39 medewerkers met allergisch contacteczeem stemden 33 in met een

185 patchtest. Hiervan lieten 14 (3%) medewerkers positieve reacties zien en dit werd beschouwd als het hebben van een werkgerelateerd allergisch contacteczee (4.9%) medewerkers werkgerelateerd irritatief contacteczeem hadden

186 Ringkasan Disertasi ini menguraikan serangkaian penelitian tentang paparan bahan kimia terhadap pekerja dan munculnya penyakit kulit akibat kerja terutama dermatitis kontak akibat kerja diantara pekerja penyamak kulit danpabrik sepatu, serta alergi sepatu di Indonesia. Bab1 memerikan pendahuluan tentang penyakit kulit kontak akibat kerja serta alergi sepatu. Meskipun industri sepatu dan kulit di Indonesia telah berdiri sejak beberapa dekade yang lalu, dan lebih ribuan orang bekerja di pabrik skala menengah dan besar, penyakit kulit akibat kerja pada pekerja pabrik sepatu dan kulit belum pernah diteliti secara komprehensif. Oleh karena itu investigasi tentang bahan kimia dan agen fisik yang berbahaya yang dihadapi oleh para pekerja di industri ini, serta penyakit kulit akibat kerja di industri tersebut relevan untuk dikerjakan. Begitu pula dengan penyakit kulit yang timbul pada konsumen kulit dan sepatu perlu diteliti lebih lanjut, serta perlu ditemukan alergen penyebabnya. Pendahuluan tentang penyakit kulit akibat kerja pada pekerja penyamakan kulit dan sepatu digambarkan pada bab ini. Demikian pula rasionalisasi, tujuan serta garis besar tesis juga digambarkan pada bab ini. Pada Bab 2, dilaporkan penelitian observasional potong lintang tentang proses pekerjaan serta inventarisasi dan penilaian risiko terhadap bahan kimia yang digunakan. Klasifikasi bahan kimia sebagai agen sensitisasi/ iritasi yang potensial serta penilaian kualitatif terhadap paparan bahan kimia disajikan. Dilakukan pemeriksaan pada para pekerja dan dilakukan wawancara dengan menggunakan terjemahan Nordic Occupational Skin Questionnaire (NOSQ-2002/LONG). Demikian pula risiko terjadinya penyakit kulit akibat kerja pada penyamakan kulit terutama berhubungan dengan paparan pekerja terhadap bahan kimia pada kondisi lingkungan kerja yang panas dan lembab. Pada 472 pekerja; seratus lima orang (12%) dilaporkan menderita penyakit kulit akibat kerja dan 9% pekerja memiliki riwayat terkena penyakit kulit akibat kerja. Diagnosis penyakit kulit akibat kerja dikonfirmasi oleh spesialis kulit dan 7.4% diantaranya menderita dermatitis kontak akibat kerja. Kami mengobservasi bahwa peralatan perlindungan kerja digunakan terutama karena penyakit kulit yang diderita di masa lalu dan bukan merupakan proteksi primer. Kami mengamati tingginya frekuensi dan paparan yang lama para pekerja terhadap berbagai faktor yang berbahaya di penyamakan kulit walapun peralatan perlindungan kerja relatif mudah tersedia namun pada umumnya hanya digunakan sebagai pencegahan sekunder. Dermatoses akibat kerja pada penyamak kulit telah dilaporkan namun dermatitis kontak akibat kerja dan bahan sensitisasi belum disajikan secara spesifik. Pada Bab 3, disajikan penelitian potong lintang pada seluruh

187 pekerja di dua pabrik penyamakan kulit di Indonesia untuk menilai prevalensi penyakit kulit kontak akibat kerja melalui wawancara dan pemeriksaan kulit. Dilakukan juga uji tempel terhadap para pekerja dengan penyakit kulit kontak akibat kerja untuk mengidentifikasi alergen penyebab. Dermatitis kontak alergi ditemukan pada 3% pekerja. Ditemukan sensitizer okupasional yang relevan terdiri atas kromat (9.2%), n,n-difenilguanidin (5.3%), bensidin (3.9%) and sodium meltabisulfit (2.6%). Pola sensitisasi ini menunjukkan beberapa perbedaan dengan data yang dilaporkan di Negara industri baru lainnya. Dari penelitian ini kami dapat mengkompilasi alergen seri pekerja kulit yang bisa dipertimbangkan untuk pelaksanaan uji tempel. Sehubungan dengan penelitian diatas, pada Bab 4 dilaporkan paparan yang relevan saat ini serta kemungkinan paparan dimasa lalu terhadap benzidin pada 3 pekerja penyamakan kulit di Indonesia. Bensidin dan derivatnya telah digunakan untuk pembuatan bahan pewarna di pabrik sejak bertahun tahun lampau namun pada tahun 1978 bahan tersebut dilarang untuk digunakan pada beberapa negara karena efek karsinogeniknya. Indonesia adalah negara industri baru dan digolongkan sebagai negara penghasil sepatu terbesar di dunia bersama dengan Cina dan Vietnam. Pada Bab 5 dilakukan penelitian potong lintang yang mengobservasi proses pekerjaan dan inventarisasi serta penilaian risiko pada pekerja di pabrik sepatu. Selanjutnya dilakukan klasifikasi bahan kimia sebagai bahan sensitisasi/iritansi potensial. Dilaksanakan pemeriksaan pada para pekerja dan diwawancara menggunakan the NOSQ-2002/LONG. Dari keseluruhan 514 pekerja, 8,5% ditemukan adanya penyakit kulit akibat kerja dan 4,8% melaporkan riwayat penyakit kulit akibat kerja. Penyakit kulit akibat kerja didiagnosis pada 29% pekerja oleh spesialis kulit dan 7,6% diantaranya menderita dermatitis kontak akibat kerja. Dari 39 pekerja dengan dermatitis kontak 33 bersedia menjalani uji tempel dan 14 (3%) diantaranya didiagnosis menderita dermatitis kontak alergi akibat kerja dan 25 (4,9%) menderita dermatitis kontak iritan akibat kerja Pada Bab 6 dilakukan penelitian lanjutan tentang sumber iritasi dan sensitisasi okupasional di pabrik sepatu di Inonesia dan prevalensi penyakit kulit akibat kerja pada para pekerja. Dengan menggunakan desain potong lintang dilakukan penelitian potong lintang pada suatu pabrik sepatu di Jawa, Indonesia. Seluruh 514 pekerja dilakukan wawancara menggunakan NOSQ-2002/LONG dan pemeriksaan klinis. Dilakukan juga uji tempel pada 33 (2,7%) pekerja yang didiagnosis dermatitis kontak akibat kerja dan 77 pekerja sehat untuk mengidentifikasi allergen penyebab. Ditemukan hasil uji tempel positif yang relevan terhadap 16 alergen. Seperti hanya pada penelitian lain, ditemukan bahwa lem sepatu dan alergen pada karet merupakan alergen yang paling sering ditemui.

188 Namun ada beberapa perbedaan frekuensi dan variasi alergen. Penelitian ini memberikan informasi berharga dalam penanganan pasien dengan alergi sepatu dan untuk para pemegang kebijakan dalam mengembangkan program pemberantasan penyakit kulit akibat kerja pada pekerja pabrik sepatu. Alergi sepatu merupakan bentuk dermatitis kontak yang diakibatkan oleh paparan terhadap sepatu. Alergen dan tipe sepatu yang menyebabkan dermatosis bervariasi sesuai dengan teknik manufaktur, kondisi iklim dan tradisi masing masing negara. Prevalensi tertinggi dilaporakan pada daerah dengan iklim panas dimana panas dan kelembaban di dalam sepatu serta gesekan, berkeringan, tekanan dan oklusi bersama dengan berbagai macam bahan kimia memberikan kontribusi terhadap pervalensi alergi sepatu. Pada Bab 7 dilakukan penelitian terhadap material sepatu yang berkontribusi terhadap kejadian alergi sepatu di Indonesia. Seluruh pasien yang memenuhi kriteria diagnosis untuk alergi sepatu dilakukan pemeriksaan uji tempel dengan menggunakan European Baseline Series, shoe series dan additional series berdasarkan hasil penelitian sebelumnya yang dijelaskan pada bab tentang pekerja penyamakan kulit dan industri sepatu di Indonesia. Beberapa pasien dilakukan uji tempel menggunakan material dan ekstrak dari sepatu mereka. Didapatkan persentase yang cukup tinggi (52%) hasil reaksi uji tempel positif yang secara tepat berhubungan dengan sepatu yang mereka curigai. Hasil uji tempel positif terhadap material sepatu dari pasien maupun ekstrak sepatu mendukung hasil uji tempel dengan alergen. Bahan sensitisasi yang paling sering ditemukan adalah alergen karet diikuti dengan pengawet, perekat sepatu dan material kulit. Uji tempel menggunakan alergen standar yang mengandung bahan kimia yang digunakan pada proses produksi sepatu dipandang tidak mencukupi. Reaksi uji tempel negatif terhadap alergen tersebut tidak begitu saja menyingkirkan diagnosis alergi sepatu; 25-50% reaksi terhadap material sepatu yang dicurigai diakibatkan oleh alergen tidak bisa ditemukan pada alergen standar dikarenakan pembuatan sepatu modern menggunakan bahan dari supplier yang tidak diketahui kandungan bahan kimianya. Pada Bab 8, dilaporkan 2 pasien alergi sepatu yang menunjukkan reaksi negatif terhadap alergen sepatu namun menunjukkan rekasi positif terhadap ekstrak sepatu. Selanjutnya dilakukan pemeriksaan Thin Layer Chromatography (TLC) and Gas Chromatography-Mass Spectrometry (GCMS) untuk menemukan alergen penyebab. Analisis kimiawi untuk mengisolasi alergen yang dicurigai dan berdasarkan uji tempel menunjukkan bahwa 2(3H)-benzothiazolone, methyl dehydroabieatate and 7-oxodehydroabietic acid methyl ester ditemukan pada bahan sepatu. 2(3H)-benzothiazolone

189 merupakan alergen yang jarang dilaporkan sebelumnya. Methyl dehydroabieatate and 7-oxodehydroabietic acid methyl ester merupakan turunan kolofoni, yang kemungkinan ditemukan pada lem sepatu. Pada Bab terakhir, hasil penemuan pada disertasi ini didiskusikan dalam kontek yang lebih luas. Disampaikan juga rekomendasi bagi pemegang kebijakan publik dan kesehatan kerja di Indonesia

190 Appendices Sri Awalia Febriana Department of Dermatology & Venereology, Gadjah Mada University, Yogyakarta, Indonesia Department of Dermatology, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands.

191 Acknowledgements Studying abroad, far away from my country, to pursue my PhD degree in the Netherlands has been one of the most wonderful experiences in my life (also for my hubby and our girls) but it has also been like riding a roller coaster. I have had to maintain my endurance, energy, passion, and spirit for the whole 4 years. Alhamdulillah, thanks to Allah SWT that I have finally come to the end of this fruitful journey. First of all I would like to express my appreciation and sincere thanks to my supervisors Prof. Pieter-Jan Coenraads, Prof. Hardyanto Soebono and Dr. Marie-Louise Schuttelaar. Dear Pieter-Jan, From the first time we met in Singapore in 2007, I knew that I was very fortunate to know you and to be the student of a good-hearted professor. You welcomed me warmly and sincerely to your research group at the dermatology department at the UMCG. You are a great teacher and mentor. Thanks for all of your guidance, your knowledge and expertise, and for your patience to teach me, a dermatologist from a country very different from the Netherlands. From you I have learned how to be critical, diligent, detailed. You let me make my own choices and learn from my own mistakes to become a good researcher. You opened a door for me to enter the world of occupational and environmental dermatology and contact dermatitis. You gave me the opportunity to gain knowledge from a great expert. I could not have come to where I am now without all of your help and guidance. I wish you all the best, Pieter-Jan, and also for Hao and Yu-yien. 190 Dear Marie Louise, Thank you very much for your guidance in writing and finishing the manuscript. I really appreciate the way you have taught me. You showed me my strengths and weaknesses, you were always open to tell me honestly what you thought about my work. I enjoyed our time discussing our manuscript but also the chit-chat about our kids every Friday evening after your polyclinic session. We also had a great time when we travelled to my home town, Yogyakarta, Indonesia for the Asia Pacific Conference on Occupational Dermatology. At that time I got to know you more personally and feel comfortable with you as a person and a mentor. I wish you, Jaap, Elise, Reinoud and Frederique the best, and still look forward to hearing the interesting news of your family. Pieter-Jan and Marie Louise, thanks again for everything and I look forward to more collaboration with you in the future.

192 Prof. Hardyanto, Thank you for your support and guidance to me in good times and bad times when I was pursuing my PhD. I know that you always placed a lot of faith in me from the first time you asked me to join the academic staff of Dermatology, Gadjah Mada University and then went on to give me the opportunity to know Pieter-Jan as the promoter for my PhD. I hope I can live up to your expectations as a researcher and lecturer. You, Bu Endang, and your wonderful kids Dik Wulan, Bayu and Shinta are a family that we can count on. All the best to you all. I would like to thank the members of the reading committee, Prof. dr. M. Bruze, Prof. dr. T. Rustemeyer and Prof.dr. D. Koh, for reading and judging my manuscript. Prof. dr. J.W. Groothoof, Prof. dr. R.J. Scheper and Prof. dr. R.P. Zwiestra, thanks for being my opponents on my PhD Thesis Defence. Dear Magnuz, thank you for always inspiring me with your knowledge, your work and your ability in conducting research and managing such a great society of researchers in Contact Dermatitis and Occupational and Environmental Dermatology. Together with other members of the International Society of Contact Dermatitis: Prof. Goh Chee Leok, Prof. Kayoko Matsunaga, Dr. John McFadden, Prof. Hee Chul Eun, Prof Iris Ale; Prof.Hemangi Jerajani, Prof. Rosemary Nixon, Prof. Thomas Diepgen, and Prof MarléneIsaksson, I will never forget our fruitful and inspiring journey to Kasongan and Bantul for our field visit to batik and clay factory workers. You all showed us how to conduct a workplace visit. We learned a lot from your patience, your enthusiasm, your passion in this field. Hopefully I still can share and learn from your experience at future meetings/conferences, and in collaboration studies. I would like also like to thank Dr. C. Svedman and Dr. E. Zimerson. Thank you for sharing your knowledge and experience on contact dermatitis, especially in performing TLC and GC-MS examinations, and for cooperating on the manuscript on Indonesian shoe dermatitis patients. I have learned a lot, and enjoyed my very short visit to your laboratory in Malmo, Sweden. Hopefully I can continue collaboration with your wonderful groups in Malmo. To my paranymphs, Laura Bijkesma Poot and Astri Ferdiana, my appreciation for all of your support and help in preparing my PhD promotion. Laura, I was fortunate to meet you as a colleague in Dermatology at the UMCG. You offered me a warm and convenient ambience to work in so far away from my home country. 191

193 Astri, in your unique way you gave me a lot of support in finishing my dissertation. Thanks also for being a special sister for me. I will make an engraving for you in my success in finishing your dissertation. I would like to express my gratitude to Directorate for Higher Education, Ministry of Education, Republic Indonesia for granted me DIKTI- Schoolarship. My appreciation goes to the Indonesian Ambassador to the Netherlands, Ibu Retno Marsudi, and to the Indonesian Attaches for education Prof. Bambang Hari Wibisono and Pak Ramon Mahondas, also to the KBRI staff Bu Rina and Bu Vevi, for all of your support for me, my family and the Indonesian students in Groningen. Thank you for International School Groningen and Parent Support Groups (PSG) also Groningse School Vereniging (GSV) for providing the good education and pleasant environment for my daughters to learn. Thank you, Prof. Marcell Jonkman, for allowing me to be part of the dermatology family at UMCG. Hopefully our collaboration with Gadjah Mada University will continue in the future. Frank Jungbauer and Gerda Lensen, I will never forget your important roles as my tutor and mentor, especially in the early years when I started my PhD project. Frank, I still remember how you supported me when I was really depressed and wanted to quit. You and Corry were also like family for us, you showed me Groningen and invited us to dinner in your cosy house. Gerda, you mean a lot to me. You are a good colleague and a good friend. You showed me how to do proper fieldwork in occupational dermatology. Thanks for showing me the factory in Delfzijl and cooking me a dinner at home. Both of you, Frank and Gerda, played an important part in my PhD dissertation and in my mastering of the field of Occupational and Environmental Dermatology. 192 JoAnn, you are not only my proof-reader but also the one I can rely on to keep my spirits up. Your positive personality always made me feel confident, especially in the last moments before submitting my dissertation. Thanks to you and Hans for the dinner and movie time at your place. Anneke Hoekstra thank you very much for being so kind and for helping me with all of the secretariat stuff. Your help made me feel at ease and happy working in the department. Piet Tonder, thanks for your assistance in making my photograph more beautiful for the publication of my manuscript and dissertation book. Renate Kroese thank you for your kindness to do all of SHARE stuff for me. Joline, thank you for helping me with all kinds of documents and receipt for the reimbursement. Mathilde Pakelaer, thank you for your kindness assistance for everything related to

194 GSMS. Tim Zwagstra, thanks for everything, I promise to keep our friendship and collaboration more fruitful in the future. Thanks to Bu Cecil and Bu Sulistyah from the Centre for Leather and Rubber and the Ministry of Industry of the Republic of Indonesia, to Mas Ferry from IFSC, and to Widhy from UNISBA for all of your important help in providing me with data, information as well as support for my research project in the leather and shoe industries. Mb Diana, mb Dewi Ismimashitoh, mb Vetty, Sauma, Itrid, Arvie and Allyn, and also mb Novi and Anang Tri Yoga - thanks a lot for your support during my field work in Indonesia. I could not have finished my work without all of you. Jose, Nelleke, Anne Marie, and Jessica, Hilde, Kitty, thank you very much for being my lunch mates and sharing stories about everything and anything at our lunch sessions in the personnel restaurant of UMCG. Caroline and Tom, thank you for your hospitality, for routinely inviting us for dinner at your nice home. Thanks to the wonderful research people in Dermatology -- Angelique, Antoni, Kasja, Ena, Gerda, Iana, Janine, Jeroen, Joost, Wianda, Tanja, Laura De Sena, Nisha Chandran, Klaziena, Maarit, Frederica and also my friends in researchers room 2.075: Rixt, Marjoleine, Mariele, Hilde, Rakita, Raisa and Jonathan. Friends from the Derma Lab: Henry, Miranda and Duco. Thank you for the wonderful times we spent together, from the Friday morning meetings until our drink times, dinner nights, movie nights and music rehearsals for the Christmas dinner. It all made me feel at home. I am looking forward to your coming to Indonesia someday. My gurus in Dermatology and Venereology, Faculty of Medicine, Gadjah Mada University -- Dr. Sunardi, dr. Etnawati, Dr. Widodo, dr. Fadjar, dr. Sudirman, dr. Suyoto, dr. Satiti, dr. Agnes, dr. Wiwik, dr. Niken, dr. Iryani and also my colleagues Retno, Arif, Niken, Titut, Devi Flandi, Mira, Agnes, Yuda -- thank you for your support when I was away and could not help with all tasks. Prof. Rika, Prof. Teguh, Prof. Gufron, Prof. Harjo, Dr. Romi, Bu Titi, Bu Uut, Bu Ova, finally I have come to the end of my journey. Thank you very much for the full support of the Faculty of Medicine. I will going back home soon and look forward to working on the academic staff of Gadjah Mada University. Thanks to all of my teachers in SD Marsudirini, SMP Negri 5 and SMA 1 Teladan Yogyakarta. You were the ones who gave me a basic education. Thanks also to my lecturers at the Faculty of Medicine, Gadjah Mada University, Yogyakarta, Indonesia. You shaped my learning process, 193

195 building my character to what it is now. I will never forget all of your support and prayers. Being far away from our family in Indonesia and facing quite a huge challenge was really not easy for us. We have been very fortunate to have you as our family here in the etherlands. ou ha e een our arents - Mb Indah-Mas Yon (and Pandu Pandji Sisi); Mb Ari-Mas Herman; Tante Pantja- Oom Bas; Oom Rudie-Tante Sylvi, and Oom Mul-Tante Monique. There are not enough words to describe how thankful we are for all of your patience and sincere desire to see us happy. May Allah SWT always bless you and your families. I am blessed that I was surrounded by wonderful and special people. All have been my best friends, my shoulders to cry on, people I could rely on and discuss everything with. Carla Marchira, Poppy Ismalina, Christina Avanti, and Retno Danarti, finally I joined you in the fellowship of PhD moms. I was always able to rely on all of you at good and bad times during my PhD journey. We shared scientific talk, moms talk and women s talk. Thanks for being friends who know all about me and still love me. Gama Yogatama, thanks for your true friendship. Having a discussion with you, Mas Hengki Purwoto, Haryo Nindito, and Anies Baswedan, is always inspiring. Thanks for helping me to think logically and realistically, to see many aspects of life and think more deeply about problems. Mutia Delina, Laely Khoiriyah, Alva Nadia, Dewajani, thanks for always being there for me, even in the middle of the night, and for trying to find a good internet connection so you could hear all of my complaints via Skype or LINE., my hus and and my dau hters were ery fortunate to ha e ood family est friends. ina-vinny and Bang Zul; Poppy-Nico (and Astrid Amel); Mb Erna-Mas Hengki (and Ines Nanta); Carla-Mas Sonny (and Axa Alexa); Astri-Arqi and Bobby; Gama-Mena Raka Arya; Dito-Fatma Ansa; Azis Nurwahyudi; Fanny Lintong; Bulan-Bronsan (and Jenna Naomar); Desti- Iging and Daanish; Nita Kenzo; mb Iin-Mas Eddy (Kiani Reyhan); Mb Fitri- Mas Ucok; Ully-Dondy and Raffi; Mutia-Mas Rano (and Haikal Reyhan); Rina Agustina-Mas Is (Aya Titha); Ratna-Arvie (and Hassan Ibrahim); Pandji-Faizah and Hanna; Neily-Auliya and Almira; Donny-Nieke and Azkiya; Sista-Adhi (Arzade Belva); Tina-Taufik (Rayyan Maya); Mb Ciptasari and Nida and Kadek-Laksmi (and Fina Dita) thank you for the wonderful times that we spent together, including difficult times that made our friendship stronger. There are not enough words to describe how lucky we are to ha e you all as our family est friends. ay llah less you all. 194 I was also blessed to have you all while we were living in Groningen: Uwak As-Oom Menno; Mas Archie-Bu Marie; Tt Tatik-Oom Syaak; Pak Dakir-Bu

196 Soemini; Bude Nani-Oom Fred; Mb Dian Padma; Indres-Bayu and Cia; Tt Tini-Oom Fred; Bude Dicky; Tt Trix-Oom Henk; Bu Yayuk-Oom; Bude Olga- Oom; Mb Arini-Mas Ferry. May our friendship and family bonds last forever. Mb Arjanti Radyowijati, Tita, Nurul, Adit, Mira, Puri, Ari, Eneng, Wangsa, Yeni, Sita, Ismail-Agnes (and Lala-Malik); Puti-Arramel and Meysa; Muizz- Mb Sri and Nabiel; Wahono-Dini and Alletta; Wisnu-Yuli and Joshua; Guntur-Intan; Nila-Alex and Alena; Intan Taufik-Enci; Teguh-Tessa: you were my family, especially during my first stay here in Groningen (in 2009) Ahmad, Mora and Widyandana thanks for sharing our story while finishing PhD in the Netherlands. Bulan, Astri Rizkiya, Dayu Kirana, Renren, mb Titin, Mita and Meme, thanks for being our wonderful family and housemates on Ranonkelstraat 20 and Werumeus Bunningstraat, a home full of a nice memories. Astri and Aarqi, Amanda Sembel, Tiurma, Ida, Dwi Esti, you are also part of our Ranonkelstraat family. Your smiles, laughs, tears, screams always made us happy at home. We will never forget the cooking and chatting time before dinner. Also the movie times, karaoke times and games times full of laughter and screams. And of course the piano lessons. room which made me smile and forget the difficulties at work. Amirah, Doti, Putri, Panji, Astri Handayani, Yota, Didik, Aul, Nelly, Niar, Radit, Nia, Adhyat, and Ury, I wish you all the best with your PhD programmes. Keep me smiling and entertained with our chit-chat in the whatsaap group. Unyu- whatsaap group discussions about shopping, travelling and our med school GMU, my life would be boring. Success, and keep your spirits (shopping, trave Mas Ronny, Fean, Ella, and Mb Nur thank you for filling my life especially when my hubby and kids were far away. Family Rosel Didik (Najwa Nafi), Ferro-Aarkhan, Kuswanto-Fitri (Haidar-Piya), Rully-Intan; Icha-Krisna (Rayyan); Pak Tatang-Bu Rohmah (Aussie Barli Fia); mb Inung-Dawa; mb Suwatin-Disya Galih; Pak Asmoro-bu Rini (Adi Rifa Rifat); Susan-Bino and Anika; Yuni-Mas Hary and Adzakiya; Fajar-Monik and Runa my 195

197 appreciation and thanks for everything, for sharing moments and for helping us when we had to move to Indonesia, and also for preparing everything for my defence. The opportunity to share in the wonderful activities of PPI G (the Indonesian Student Association in Groningen) and DeGromiest (the Indonesian Muslim Association in Groningen) gave us many rich experiences. All of these activities made us more proud to be Indonesian. Amanda Sembel, Gina, Marisa, Muji, Yoshier, Esther, Rangga, Hadar, Martin, Ryan, Mas Eddy, Fikri, Zaki-Shella, Ria, Ilmi, Almas, Niken, Habib, Pamela, Icha Maisya and also many people mentioned above thanks for sharing all those activities with us. My Faculty of Medicine mates Mb Ita, Nafiah, Gusur, Tri Wibowo, Hamim, Anton, Abah Kardi, Ristan, Ardi, Tonny, Nanik, Lukas, Eas, Yuni, Moi, Rozaida, Enny, Umi and many other friends. My Dermatologist colleges Mb Retno, Esta, Mb Lisa, Ida, Melok, Haphap, Mb Nenny, Mb Betty, Mb Aning. My Teladan 88 group: Martin cs; Brittle 3i SMP 5 Yogyakarta Oki Mutia Dani Daly Nita Ira Gembong Titi cs; My SMP 5 study group: Ami Ratih, Mia, Adhi; SD Marsudirini group: Ines, Patrice, Ani, Fitri, Neni, Mima, Nana thank you for making my day. You always cheered me up in the morning and make me relaxed at night with your funny chit-chat. All the best to you all. My extended family, those who have always taken care of and prayed for me since I was a baby: Eyang kakung and Putri Suratiman Poerbohusodo; Pakde Bambang-tt Nik; Tt Tini-Om Tomo; Tt Gianti-Om Addy; Tt Wati; Tt Tiwi-Om Marwan; Tt Locky-Om Yono; Om Yoyok-Mb Wiwik. Dan sepupuku tercinta di Soe family. Eyang Kakung Putri Sastrowijoto; Pakde Bude Siti; Pakde Bude Sri; Pakde Bude Darsono; Pakde Bude Udoyo; Tt Mulyani- Om Wid; Om Raji-Tt Ninuk; Om Bambang; Om Siswanto-Mb Nur serta sepupuku keluarga besar Sastrowijoto. All of you have inspired me. I am happy that I was born into a great family of teachers and physicians, all of whom have helped me to reach my goal of teaching future physicians. All the best to you all. Bapak Ibu Kabul Sumarsono and Suprihatin, thank you very much for being my lovely parents in law. You have always offered a helping hand, taking care of Keisha and Katya while I was away to pursue my education. You never made demands on me and you have loved me the way I am. Agus-Evi and Poppy, Anang and Rara, thanks for being my wonderful brother and sister. 196 Lulu (Sri Morisonya Mauludianna), you are my sister and the best friend I ever had. You really love me unconditionally and always support me

198 whenever you can. Our personalities are very different but that makes our relationship colourful. You and Imam, Zachery and Shailend have made my PhD journey more wonderful. I love you all. Dito (Bambang Pediantoro), my only brother, you have grown to be much more wise than I am. Your passion for your work and family make me happy. I love you just the way you are. Yaya (Cahya Dewi Satria), thanks for being a nice daughter in law and helping Dito to take care of Papa Mama while I have been away; you are a good wife for Dito and a wonderful sister for me. Bu Lia also loves you, Mahes and Nadine. Papa and Mama, o are m ever th n m l elon r s m sho l ers to cry on, my role models, discussion friends, my everything. I know the most wonderful thing in my life is to be your daughter. I am sorry for making you sad during my bad times. I dedicate my PhD degree to both of you and I promise to keep my work ethic up to as high a standard as I can so I can fulfil your expectations as a lecturer, researcher and physician. Mas Yayok, my soul mate, you have always made me laugh, wiped my tears, hugged me tight, watched me succeed, seen me fail, cheered me on and kept me strong. You are a promise from God that I will have a friend forever. Thank you for being there for me and our beautiful daughters. Keisha and Katya, the loves of my life, my BFF (Best Friends Forever). You are the glaze on my donuts, the spring in my steps, the blue in my sky, the sweet in my dreams and the beat of my heart. Thank you for being my lovely daughters, sharing stories, doing window shopping and everything together. I will never regret giving both of you an opportunity to study abroad and experience the diversity of many cultures. These experiences have made you independent and well-behaved girls who still love your country and culture, Indonesia. Thanks to all others whom I have not been able to name here. 197

199 Publication Febriana SA, Jungbauer F, Soebono, H, Coenraads PJ. Inventory of the Chemicals and the Exposure of the Workers Skin to these at Two Leather Factories in Indonesia.Int Arch Occup Environ Health 2012; 85: Febriana SA, Jungbauer F, Soebono, H, Coenraads PJ. Occupational allergic contact dermatitis and patch test results of leather workers at two Indonesian tanneries.contact Dermatitis 2012; 67(5): Febriana SA, Jungbauer F, Soebono, H, Coenraads PJ. Occupational Contact Allergy caused by benzidine in three tannery workers. Contact Dermatitis 2012; 66(6): Febriana SA, Soebono H, Coenraads PJ.Occupational skin hazards and prevalence of occupational skin diseases in shoe manufacturing workers in Indonesia. Int Arch Occup Environ Health 2014; 87: Febriana SA, Soebono H, Coenraads PJ, Schuttelaar ML. Contact allergy in Indonesian patients with foot eczema attributed to shoe. Accepted for publication in Journal of European Academy Dermatology and Venereology Febriana SA, Zimerson E, Svedman C, Haryadi W, Soebono H, Coenraads PJ, Schuttelaar ML.Thin layer chromatography and gas chromatography-mass spectrometry (GCMS) examination of footwear materials from patients with shoe dermatitis. Accepted for publication in Contact Dermatitis. Febriana SA, Soebono H, Coenraads PJ, Schuttelaar ML. Occupational allergic contact dermatitis and patch test results in Indonesian shoe factory workers. Submitted to Occupational Medicine Abstracts (oral presentations and posters) Febriana SA, Jungbauer F, Soebono, H, Coenraads PJ. Inventory of chemicals used and worker s exposure in two Indonesian leather factories.contact Dermatitis Sept; 63: Febriana SA, Jungbauer F, Soebono, H, Coenraads PJ. Occupational skin exposure and occupational dermatoses in Indonesian shoe manufacturing. Contact Dermatitis Jun 1; 66:47

200 Febriana SA, Soebono H, Coenraads PJ, Schuttelaar ML.Contact allergy in Indonesian patients with foot eczema. Contact Dermatitis Jun 1; 70:

201 Curriculum Vitae 200 Sri Awalia Febriana was born in Yogyakarta, Indonesia on 5 February She graduated from senior high school in 1988 at SMA 1 Teladan Yogyakarta, Indonesia. She continued her study and completed medical degree at the Faculty of Medicine, Gadjah Mada University, Yogyakarta (1994). After her graduation, she served the Ministry of Health, Republic, Indonesia to work as a physician at Primary Health Centre in Tigaraksa, Tangerang, West-Java, Indonesia ( ). At the same time, she worked part-time as an occupational physician in the shoe factory in Balaraja Industrial Area, Tangerang, West-Java, Indonesia. In 1999 she had a chance to stay in Melbourne, Australia and work as a research assistant in the Royal Children Hospital. Back to Indonesia, she worked as a research assistant in Public Health Department, Faculty of Medicine, Gadjah Mada University, Yogyakarta until From , she continued her education in dual degree Master of Science in Clinical Epidemiology and Dermatology Residency Training Programme in Faculty of Medicine, Gadjah Mada University, Yogyakarta, Indonesia. Since 2005, she became an academic lecturer and researcher in Dermatology and Venereology Department, Faculty of Medicine, Gadjah Mada University, Yogyakarta, Indonesia. She also works as dermatologist in Sardjito University Hospital, Yogyakarta, Indonesia. Beside that, she was also actively involved in developing medical curriculum and writing modules for skills laboratory and block Adolescents at Faculty of Medicine, Gadjah Mada University, Yogyakarta, Indonesia. In November 2008, she decided to pursue his doctoral degree in the Netherlands and wrote a research proposal, which was granted a scholarship by the Directorate General of Higher Education, Ministry of Education, Republic of Indonesia. In September 2010, she officially started her PhD research in the Dermatology Department, University Medical Centre Groningen, University of Groningen, Groningen,