Master's Thesis

UNIVERSITY OF LJUBLJANA FACULTY OF PHARMACY

DAMIJANA GREGORIČ

MASTER’S THESIS

UNIFORM MASTER’S STUDY OF PHARMACY

Ljubljana, 2016 UNIVERSITY OF LJUBLJANA FACULTY OF PHARMACY

DAMIJANA GREGORIČ

ALERGIJSKI KONTAKTNI DERMATITIS TER DRUGE KOŽNE REAKCIJE, POVZROČENE OB STIKU Z RASTLINAMI

Allergic contact dermatitis and other skin reactions caused by plants

UNIFORM MASTER’S STUDY OF PHARMACY

Ljubljana, 2016 My master thesis was written during my Erasmus exchange from March 2015 to July 2015 at Faculty of Pharmacy, Universidad de Granada, under the mentorship of prof. dr. Paloma Cariñanos González from department of Botany. In Slovenia was my supervision prof. dr. Samo Kreft.

THANKS: I would sincerely like to thank my prof. dr. Paloma Cariñanos González, for all her patience and professional directions during my work. Also I would like to thank my mentor, prof. dr. Samo Kreft for final comments to finish this thesis. Zahvala gre tudi mojim staršem. Hvala za vašo potrpežljivost ter podporo pri pripravi na zagovor.

STATEMENT: I declare that I have done this master thesis independently under supervision of prof. dr. Samo Kreft and co-supervision of prof. dr, Paloma Cariñanos González.

Ljubljana, May 2016 Damijana Gregorič

President of the Thesis defence committee: prof. dr. Stanislav Gobec, mag. farm Member of the Thesis defence committee: doc. dr. Pegi Ahlin Grabnar, mag. farm

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TABLE OF CONTENTS

LIST OF TABLES ...... VI LIST OF APPENDIX...... VI ABSTRACT ...... VII KEYWORDS ...... VIII ABBREVIATIONS ...... VIII POVZETEK ...... IX KLJUČNE BESEDE ...... XI 1 INTRODUCTION ...... 1 1.1 DERMATITIS AND OTHER SKIN REACTIONS ...... 1 1.1.1 ALLERGIC CONTACT DERMATITIS ...... 1 1.1.2 IRRITANT CONTACT DERMATITIS ...... 3 1.1.3 CONTACT URTICARIA ...... 8 1.1.4 PHYTOPHOTODERMATITIS ...... 8 2 WORK PLAN ...... 10 3 MATERIALS AND METHODS ...... 11 4 RESULTS ...... 12 4.1 ALLERGENS AND CHEMICAL COMPOUNDS ...... 12 4.2 MOST ALLERGENIC PLANTS FAMILIES ...... 15 4.2.1 Asteraceae or Compositae Family ...... 15 4.2.2 Jubulaceae Family ...... 22 4.2.3 Liliaceae family ...... 22 4.2.4 Alstroemeriaceae Family ...... 23 4.2.5 Anacardiaceae Family ...... 24 4.2.6 Ginkgoaceae Family...... 27 4.2.7 Proteaceae Family ...... 27 4.2.8 Primulaceae family ...... 28 4.2.9 Rutaceae family ...... 29 4.2.10 Alliaceae family ...... 30 4.2.11 Cruciferae family (Brassicaceae) ...... 31 4.2.12 Capparaceae Family ...... 32 4.2.13 Araliaceae family ...... 32 4.2.14 Apiaceae family (Umbelliferae) ...... 33

4.2.15 Solanaceae family ...... 34 4.2.16 Lamiaceae family (Labiatae family) ...... 35 4.2.17 Moraceae family ...... 36 4.3 PATCH TESTING, MIXTURES ...... 37 4.4 DISCUSSION ...... 40 5 CONCLUSIONS ...... 44 6 REFERENCES ...... 45 7 APPENDIX ...... 48

LIST OF TABLES

Table I: Common plants causing chemical and mechanical irritant contact dermatitis (2,7) ...... 4 Table II: Some examples of plants known to cause phytophotodermatitis (9, 17) ...... 9 Table III: Constituents of two commercial Compositae mixes (29) ...... 37 Table IV: Distribution of positive reactions to the constituents of Compositae mix 6% pet. in 76 patients with positive reactions to the mix (29) ...... 38 Table V: Results of distribution of positive reactions to the constituents Compositae mix 5% pet. (29) ...... 38 Table VI: Allergens contained within the plant series (28) ...... 39

LIST OF PICTURES

Picture 1: Number of plant families and their usage ...... 41 Picture 2: Frequent plant families that cause ACD ...... 42 Picture 3: Number of plant families and allergens ...... 43

LIST OF APPENDIX

Appendix 1: Plants responsible for causing allergic contact dermatitis in South Africa (6) 48 Appendix 2: An alphabetical list of plants that can cause urticarial responses (8) ...... 50

ABSTRACT

Plants have been used since ancient times. Nowadays their popularity is increased, not only as a food or decorative plants but also as herbal medicines and natural cosmetic. Because of that, we are daily in touch with them and it is necessary to know, which are the most harmful plants and allergens and what reactions on the skin they can cause. Allergic contact dermatitis, irritant contact dermatitis, contact urticaria and phytophotodermatitis are the most typical cutaneous reactions among phytodermatitis.

Our main purpose was to make a general overview of plants that can cause allergic skin reactions. We wanted to estimate which plant families are the most allergenic, which occupation are the most exposed to them and which are the possible allergens. We started our research on databases (Scopus, PubMed). Firstly we were searching after the most allergenic plant families. After that we focused on specific plants and case reports.

According to the literature we can say that allergic contact dermatitis is mostly generated by Compositae, worldwide known plant family. Anacardiaceae are the next plant family in which we have found more case reports. These plants are found in South and North America, Asia and South Africa. Primulaceae family is also common cause of ACD. Its plants are popular ornamental plants. According to our review, the most reported allergens are from group SQL. This group is mostly found in Compositae family, in Liliaceae and Alstroemeriaceae family as tulipalin A and also in Jubulaceae and Lamiaceae. On the second place are phenols and its derivates found in Anacardiaceae, Ginkgoaceae and Proteaceae. The most ACD is caused after direct contact with the raw plants. Mostly mentioned plant families are Compositae, Jubulaceae, Alstroemeriaceae, Anacardiaceae, Proteaceae, Primulaceae, Araliaceae and Lamiaceae. On the next two places are different occupations working with plants (arborists, chefs, cooks). Mostly mentioned families are Liliaceae, Alstroemeriaceae, Anacardiaceae, Rutaceae, Alliaceae, Cruciferae and Apiaceae. ACD from herbal cosmetic is less common. More cases of ACD are from home made preparations as are tinctures, bandages and other remedies.

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KEYWORDS Allergic contact dermatitis, Compositae, patch tests, phytodermatitis

ABBREVIATIONS

Airborne contact dermatitis (ABCD) Allergic contact dermatitis (ACD) Chemical irritant contact dermatitis (CICD) Compositae mix (Comp mix) Compositae mix 6% in pet. (CM 6%) Compositae mix 5% in pet. (CM5%) Day 2 (D2) Day 3(D3) Day 4 (D4) Day 5 (D5) Day 7 (D7) Doubtful reaction (±) Weak reaction (+) Strong reaction (+ +) Extreme reaction (+ + +) Irritant contact dermatitis (ICD) Mechanical irritant contact dermatitis (MICD) Petrolatum (Pet.) Phytophotodermatitis (PPD) Sesquiterpene lactone mix (SQL mix) Sesquiterpene lactones (SQL)

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POVZETEK

Uporaba rastlin je med ljudmi prisotna že do nekdaj. Priprava hrane, čajev, lajšanje in zdravljenje različnih bolezni ter vedno večja uporaba v kozmetiki so pripomogli k večjemu zanimanju za raziskovanje rastlin, ki povzročajo različne reakcije na koži. Le te se lahko pokažejo kot iritantni in alergijski kontaktni dermatitis, kontaktna urtikarija ter fitofotodermatitis. Prevalenca iritantnega kontaktnega dermatitisa je največja, saj lahko prizadene vsakogar. Alergijski kontaktni dermatitis pa prevladuje pri alergijskih kožnih spremembah občutljivih posameznikov. Na iritantni kontaktni dermatitis, poleg ostrih listov, bodic in trnjev, ki povzročajo mehansko draženje, vplivajo tudi kemične snovi, kot so izotiocianati, diterpenski estri, protoanemonin, kalcijev oksalat ter alkaloidi. Fitofotodermatitis se pojavi ob izpostavitvi kože rastlinskim delom, ki vsebujejo furokumarine ter sončni svetlobi. Kontaktna urtikarija se lahko pojavi pri vsakem posamezniku. Znan vzrok izpuščajev so koprive iz družine Urticaceae.

Namen magistrske naloge je, da s pregledom različnih virov, najdenih v podatkovnih bazah PubMed ter Scopus, naredimo sistematičen pregled rastlin, ki povzročajo alergijski kontaktni dermatitis. Poleg samih rastlin nas bo zanimalo, kateri alergeni naj bi povzročali občutljivost. Poskušali bomo ugotoviti, katere skupine ljudi so najbolj izpostavljene tveganju ter kakšen način stika z rastlino je najbolj škodljiv.

Pri delu smo se najprej osredotočili na iskanje splošnih informacij o družinah rastlin, ki se v literaturi najpogosteje pojavljajo kot alergene. Ko smo dobili to informacijo, smo se usmerili na posamezne rastline. Zanimivo je, da za nekatere družine, ki naj bi vsebovale alergene, nismo našli nobenega posebej omenjenega predstavnika. Nekatere rastline pa so bolj raziskane. To se predstavnice družine Compositae/Asteraceae (nebinovke). Rastline same po sebi ne povzročajo večjih težav, vendar pa zaradi čedalje večje uporabe v domačih zdravilnih pripravkih ter prisotnosti v naravni kozmetiki naraščajo tudi alergije, ki prizadenejo predvsem občutljive posameznike.

Za lažje prepoznavanje alergij ter predvidevanje navzkrižnih reakcij med posameznimi rastlinami je potrebno poznati alergene. Glavne skupine, ki povzročajo alergijski kontaktni

IX dermatitis, so: α-metilen-γ-butirolaktoni, kinoni, derivati fenola, terpeni ter disulfidi, izotiocianati in derivati poliacetilena.

Pojavnost alergijskih reakcij je odvisna tudi od same koncentracije alergenov. Le ta v rastlini variira glede na letni čas ter geografsko lego. Nekatere rastline rastejo le na območjih iz katerih izvirajo, zato tudi dermatitis, ki ga povzročajo, ni znan povsod.

Dobljeni rezultati kažejo, da se družina Asteraceae/Compositae (nebinovke) v literaturi največ omenja kot povzročiteljica alergijskega kontaktnega dermatitisa. Predstavlja rastline, ki se uporabljajo v prehrani, kot zelišča, dekorativne rastline ter v kozmetiki. To pa je verjetno tudi razlog za vse večje zanimanje pri raziskavah ter tudi več alergijskih reakcij. Med večkrat omenjenimi in raziskanimi rastlinami iz te družine so arnika, navadni rman, beli vratič, kamilica, ognjič, navadni regrat. Skupina alergenov, ki prevladuje, so seskviterpenski laktoni. Razlike v strukturi med njimi so majhne, vendar pa lahko povzročijo navzkrižne reakcije. Sledijo ji rastline družine Anacardiaceae (rujevke), ki rastejo predvsem na tropskih in subtropskih območjih. Te so znane povzročiteljice alergijskega kontaktnega dermatitisa v državah Severne in Južne Amerike, v Evropi pa so manj poznane. Večinoma so to predstavnice rodov Toxicodendron in Lithraea. Prevladujoči alergeni so iz skupine derivatov fenola. Nekatere rastline so zanimive za raziskave, ker jih uporabljamo v okrasne namene. Ena izmed takih je družina Primulaceae (jegličevke) s prevladujočim alergenom priminom, ki spada v skupino benzokinonov.

Med alergeni prevladujejo seskviterpenski laktoni, ki jih, poleg družine Compositae (nebinovke), najdemo tudi v družinah Lamiaceae (ustnatnice), Jubulaceae (jetrenjaki), Liliaceae (lilijevke) ter Alstroemeriaceae (narcisovke). Sledijo jim derivati fenola, ki so pogosti v družinah Anacardiaceae (rujevke), Ginkgoaceae (ginkovke) ter Proteaceae (protejevke). Splošno velja, da so najranljivejši tisti, ki so pogosto ter dalj časa v stiku z rastlinami. Največ poročanj o kožnih reakcijah je po neposrednem stiku z rastlinami ter pri delavcih, zaposlenih v vrtnarski, cvetličarski ter prehrambni industriji. Poročanj o alergijah na kozmetiko je bilo najmanj. To je verjetno zato, ker te rastline ne vsebujejo visokih

X koncentracij alergenov. Vendar pa čedalje večja uporaba naravne kozmetike, in s tem tudi povečan stik z alergeni, povzroča alergije pri bolj občutljivih posameznikih.

Ko je pri pacientu sum na alergijo zaradi določene rastline, se na njem opravi testiranje. To poteka tako, da se pacienta najprej povpraša po morebitnih potovanjih, vrtnarjenju ali kakršnem koli stiku z rastlinami, saj se na ta način lahko predvidi, katera rastlina bi lahko bila vzrok, ter če je reakcija posledica prvega stika, daljše izpostavljenosti ali pa navzkrižnih reakcij. Nato se naredijo testi z obliži, ki vsebujejo zmes seskviterpenskih laktonov; alantolaktone, kostunolide in dehidrokustuslaktone. Ker pa le ta zmes ne zazna vseh primerov, se za testiranje uporabljajo tudi pripravki izvlečkov rastlin iz družine Compositae (arnike, rmana, navadnega ter belega vratiča in nemške kamilice). Če je sum na alergijo iz določene rastline, se dodatno lahko testira tudi neposredno z rastlinskimi deli.

KLJUČNE BESEDE alergijski kontaktni dermatitis, nebinovke, test z obliži, fitodermatitis

1 INTRODUCTION

1.1 DERMATITIS AND OTHER SKIN REACTIONS

During increasing use of herbal medicines also increases the interest in the scientific field of research (1). Phytodermatitis (plant dermatitis) is a skin reaction caused after contact with plants or plant parts (9). Two main groups of contact dermatitis may be recognized: • irritant contact dermatitis (ICD) • allergic contact dermatitis (ACD) (3)

Other two cutaneous reactions seen after exposure to plant or their products are also: • contact urticaria • phytophotodermatitis (PPD) (2)

Airborne contact dermatitis (ABCD) can be classified as ACD or ICD. It is induced by particles, suspended in the air. But the term airborne is not always used in the literature, so the prevalence of ABCD is difficult to determine. In the USA, the prevalence of all forms of ABCD was estimated to be 13.6 per 1000 persons over a 1 year period between 1999 and 2006 (32).

1.1.1 ALLERGIC CONTACT DERMATITIS

ACD is one of the most common inflammatory skin diseases (3). It is classified as a type IV (delayed) hypersensitivity response (32). It occurs 24-48 hours after the contact with the allergen, and settles down in 4-10 days after last contact with it. The condition worsen with each subsequent exposure (2).

Prevalence rate of ACD in the Western world has been estimated as 15-20% and its occurrence increases with age. Incidence of ACD caused by plants is unknown. Reason for this is a lack of an appropriate purified allergens and difficulty to identify the species (3).

ACD begins at areas of contact but may spread outward (2). It is shown as edema, erythema and vesiculation. Sites of the body that are unprotected: face, V of neck, hands, forearms, upper part of the chest and wrists, are mostly affected with airborne dermatitis. Also areas on the face, where the skin is more thin (the upper eyelids) and the allergens can penetrate more easily, can be effected (4). The upper eyelids are affected because airborne materials easily deposit when the eye is closed and when the eye is opened; the material is trapped (32). ACD affect mostly middle-aged people and is equally distributed among both sexes. (4). The most relevant chemical allergens that cause plant ACD can be classified in 5 major families: α-methylene-γ-butyrolactones, phenol derivatives, quinones, terpenes, and other different structures (isothiocyanates, disulfides and polyacetylenic derivates). Knowing the specific allergens can help us to predict cross-reactivity among various species and families (5). Study, made in South Africa in the Eastern Cape Province, which is recognised for its rich biodiversity in plant species, was carried out among regional people, Xhosas, who are daily in touch with plants (gardeners, agriculture, medicinal plants collectors, farmers, florists, etc.). The participants were interviewed from April to June 2014. The questions in the interview were about local plants which can cause allergies. Among 161 people, 62 (39%) were men and 99 (61%) were women, with the mean age of 35.1 ± 14.2 years (6). According to this research, 24 plant species belonging to 11 families were presented as harmful plants of ACD. This families were Asteraceae (7 species), Solanaceae (3 species), Anacardiaceae (3 species) and Rutaceae (3 species). 67% of them have been used as a food and this is probably the cause of higher average risk of ACD among workers in the food industries (6). Results of this study are presented in Appendix 1. A retrospective study in the Allergy Contact Unity in Spain was performed to examine the overall incidence of ACD to plants. In a 7-year period, between January 1998 and December 2004, 2248 patients were tested. In all cases clinical interview and patch test with the standard series of the Spanish Research Group in Contact Dermatitis (GEIDC) were performed. Included allergens were sesquiterpene lactons (SQL) mix 0.1% and other allergens as primin. Readings were made on day 2 (D2) and day 4 (D4) (3). 3% of them had positive patch tests. The most common allergen in this study was diallyl disulfide (47 cases; 2.09% of all patients). Common clinical pattern was chronic hand eczema (49 patients; 71%) followed by uncovered parts of the face, forearms and hands

(14%). Predominantly involved were women at the average age of 50 years, working as housewives, cooks, restaurant employees and agricultural workers (3). SQL mix involved 11 cases (0.49% of all patients). Here were male in the predominance with the mean age of 49 years who worked as farmers and workers in countryside. On a third place of positive tests results were Compositae extracts in 8 patients or 0.36% of all examined patients. Clinical pattern mostly involved the face and upper extremities. To primin 4 patients (0.18%) were sensitized. All of them were female hobby gardeners with the mean age of 53 years. These patients had lesions on hand and forearm. 0.13% of patients, all females with the mean age of 42 years with chronic eczematous lesions of fingertips, were positive to tulipalin A. They were all working in floral shops (3).

1.1.2 IRRITANT CONTACT DERMATITIS

80% of all contact dermatitis reactions belong to ICD and anyone exposed to an irritant can be affected (7). Reactions appears within minutes to hours and last hours to days. They are shown as pruritus, erythema, edema, vesicles, rash with itchiness and pain. Normally they are limited to the areas of contact (2, 7).

ICD is a non-allergic inflammatory response (32). It can be mechanical or chemical. Physical characteristics (torns, spines, hairy appendages, sharp-edged leaves) induce MICD (mechanical irritant contact dermatitis) and they can also be infected with bacteria as are Clostridium tetani and Staphylococcus aureus or fungi Sporothrix schenckii. Chemical irritants as are calcium oxalate, protoanemonin, isothiocyanates, diterpene esters, bromelain, alkaloids, capsaicin and ranunculin are basic groups that cause CICD (chemical irritant contact dermatitis). They are found in organelles as are bulbs, steam, leaves or are suspended in a latex sap (2, 17).

In the table I are presented plants that can cause CICD and MICD.

Table I: Common plants causing chemical and mechanical irritant contact dermatitis (2,7)

Family Common name, Irritant Genus/Species Agavaceae Agave; Agave spp Calcium oxalate, saponins Alliaceae Garlic; Allium sativum Thiocyanates Chive; Allium Thiocyanates schoenoprasum Onion; Allium cepa Thiocyanates Amaryllidaceae Daffodil; Narcissus spp Calcium oxalate, alkaloids Apocynaceae Catharanthus roceus Alkaloid Araceae Dumb cane; Dieffenbachia Calcium oxalate, saponins spp Alocasia macrorrhizos Calcium oxalate Philodendron; Philodendron Calcium oxalate spp Colocasia esculenta Calcium oxalate Dieffenbachia maculata Calcium oxalate/saponin Asparagaceae Albuca setose Jacq. Not determined Asteraceae Daisy; Aster spp Calcium oxalate Asteraceae Bristles (MICD) Bidens pilosa Asteraceae Hairs (MICD) Arctotheca calendula Brassicaceae Black mustard; Brassica Thiocyanates nigra Radish; Raphanus sativus Thiocyanates Wasabi; Wasabia japonica Thiocyanates Horseradish; Armoracia Thiocyanates rusticana Brassica oleracea Isothiocyanates

Bromeliaceae Pineapple; Ananas comosus Bromealin, calcium oxalate Cactaceae Old man cactus; Calcium oxalate Cephalocereus senilis Opuntia aurantiaca Spines (MIDC) Capparaceae Caper; Capparis spinosa Thiocyanates Caricaceae Carica papaya Isothiocyanates Cucurbitaceae Cucurbita pepo Hairs (MICD) Cucumis africanus Hairs (MICD) Euphorbiaceae Spurge family; Many genera Diterpene esters (some with thiocyanates) Croton; Croton spp Diterpene esters Manchineel tree; Diterpene esters Hippomane mancinella Poinsettia; Euphorbia Diterpene esters pulcherrima Spotted spurge, petty Diterpene esters spurge, snow-on-the- mountain; Euphorbia spp Pencilbush; Euphorbia Diterpene esters tricualli Euphorbia ingens Diterpenes Euphorbia virosa Isothiocyanates Castor bean plant; Ricinus Diterpene esters, ricin communis Candelabra cactus; Diterpene esters Euphorbia lacteal Synadenium cupulare Diterpenes Fabaceae Acacia karroo Thorns (MICD) Caesalpinia decapetala Hairs (MICD) Gunneraceae Gunnera perpensa Hairs (MICD) Hyacinthaceae Hyacinth; Hyacinthus spp Calcium oxalate Juglandaceae Walnut tree; Juglans spp Juglone Moraceae Ficus natalensis Proteolytic enzyme

Salicaceae Osier, willow; Salix Salicylic acid viminalis Capsicum anuum Alkaloid Liliaceae Tulip; Tulipa spp Calcium oxalate, tulipalin A (allergen) Papaveraceae Argemone ochroleuca Spinose apical process (MICD) Poaceae Zea mays Hairs (MICD) Ranunculaceae Buttercup family; (many Protoanemonin genera) Buttercup; Ranunculus spp Protoanemonin Christmas rose, hellebore; Protoanemonin Helleborus niger Prairie crocus; Pulsatilla spp Protoanemonin Clematis, old man’s beard; Protoanemonin Clematis vitalba Ceratocephalus; Protoanemonin Ceratocephalus falcatus Rosaceae Rosa rubiginosa Prickles (MICD) Rubiaceae Canthium inerme Thorns (MICD) Rutaceae Citrus limon Terpene Citrus reticulata Terpene Citrus sinensis Terpene Clausena anisata Alkaloid Salvadoraceae Azima tetracantha Thorns (MICD) Solanaceae Chili pepper; Capsicum spp Capsaicin Tobacco; Nicotiana Nicotine tabacum Datura stramonium Prickles (MICD) Urticaceae Laportea grossa Stinging hairs (MICD) Laportea peduncularis Stinging hairs (MICD) Laportea alatipes Stinging hairs (MICD) Thymelaeaceae Winter daphne, February Daphnane (diterpene ester)

daphne; Daphne spp Xanthorrhoeaceae Gasteria oblique Spinose apical process (MICD) Aloe ferox Spinose apical process (MICD) Zingiberaceae Zingiber officinale Phenol

With other study made in South Africa wanted to record the plants capable of causing ICD. From April to June 2014, they interviewed 161 regional people who are daily in touch with plants (gardeners, cooks, farmer and agricultural workers, herbalists, etc.). The mean age of informants was 35.1±14.2 years (39% males and 61% female). 24 families (44 plant species) were reported as irritant. 23 species caused MICD mostly caused by Fabaceae and Rutaceae, 20 species CICD mostly by Euphorbiaceae and 6 species mechanico-chemical ICD mostly by Urticaceae (7). Results of the study are shown in Appendix 2. According to literature, 9 sorts of chemical compounds accountable for ICD were identified. Diterpenes are mostly distributed in Euphorbia spp., disulphides in Allim spp., terpenes in Citrus spp. and isothiocyanates in Brassica spp. (7).

According to South African study, 6 classes of mechanical structures were noted for plant- induced MICD. The most frequent were thorns, hairs, plants with sharp-edged leaves or prickles. They include plants such as Acacia karoo, Citrus spp., Aloe ferox, Agave americana, Rosa rubiginosa. They all induce wounds and pains. Irritation of the skin, itches and rashes can be produced by Gunnera perpensa, Cucurbita pepo, Zea mays and Cucumis africanus. The Urticaceae was the main family, reported for causing mechanico- chemical ICD. Plants in that survey are mostly used as food or ornamental plants (7).

1.1.3 CONTACT URTICARIA

Contact urticaria appears in minutes to about one hour after normal or eczematous skin has been in contact with certain agents. Rashes usually dissapears within 24 hours (2). Reactions of affected skin have been shown as an erythema and edema reactions with localised swelling, redness, tingling, itching, burning sensation (8). Contact urticaria may be localized (quite common symptom from plants) and generalized (rare symptom caused only by strong allergens). Most often occurs on the hands and lips and also on the other organs (8). Anyone is able to get contact urticaria (37).

The mechanism of urticarial rash can be classified into two groups:

. Non-immunological contact urticaria is toxin mediated reaction and occurs without prior exposure to an allergen. It develops in seconds and clear within minutes to hours. Typically causes mild localised reactions shown as erythema, edema with pruritus and urticaria (37). . Immunological (allergic) contact urticaria occurs after prior exposure to an allergen mostly in people who are susceptible to allergy (37). Patients with immunological contact urticaria can also experiences runny nose, nausea, lip swelling (2, 8).

One of a common cause of contact urticaria are nettles (Urticaceae). Furthermore birch, apple, potato, carrot, parsnip, celery, parsley, cinnamon and mustard can cause urticarial symptoms. (8) According to the article from Department of Dermatology, University of Oulu and book Botanical Dermatology has been done an alphabetical list of plants that can cause urticarial responses (8). They are shown in Appendix 2.

1.1.4 PHYTOPHOTODERMATITIS

Phytophotodermatitis (PPD) is a reaction due to direct contact with plant parts (which mostly contain psoralens) and also oral ingestion of them, followed by exposure to sunlight (9, 17). During the spring and summer months, when ultraviolet levels are the highest and furocoumarins are in the highest concentration in the plant, PPD occurs most commonly.

Furocoumarins consist of psoralens, angelicin, bergaptol and xanthotal (9). PPD is not immunologically mediated so it affects anyone without prior sensitisation (9, 13). Eruption normally starts one day after exposure and has peak at 48-72 hours later and can get worse with humidity or perspiration (9). On exposed skin appear erythema, irregular patches and burning sensation. After healing, the lesions are replaces by pigmented macules which fade in a few weeks to months (13). Most common plant families that cause PPD are Apiaceae, Rutaceae, Moraceae and Fabaceae (9). In the table II are presented some plants that cause PPD.

Table II: Some examples of plants known to cause phytophotodermatitis (9, 17)

Family Spacies Common Names Apiaceae Ammi majus Bishop's weed, large bullwort Apium graveolens Celery Heracleum sphondylium Cow parsnip Heracleum mantegazzianum Gigant hogwed Pastinaca sativa Parsnip Foeniculum vulgare Fennel Petroselinum crispum Parsley Fabaceae Psoralea corylifolia Babchi, scurf pea Moracea Ficus carica Fig Rutaceae Citrus bergamia Bergamot Citrus maxima Pomelo Dictamnus albus Gas plant Citrus limon lemon

2 WORK PLAN

The main purpose of this thesis is to find plants and plant families that can cause ACD. We want to estimate which occupations are the most exposed to plant allergens and which allergens mostly cause skin allergies.

Our work will start with researching articles on data bases. We will focus mostly on ACD and also on contact urticaria, ICD and PPD. Firstly we will present each condition and their main differences. Then we will make a general review of allergens, chemical irritants and plant families. To get more specific information about plants, we will focus on case reports. This will give us general information about harmful plants and allergens.

Because we do not have all documented case reports or the right patch test methods to identify the right allergen, this list of plants cannot be concluded.

3 MATERIALS AND METHODS

Articles were found on data bases like Scopus, Medline and PubMed. I did not use any filters; I included all years of publishing, articles, case reports and book chapters. I used only articles in English.

My first articles were found under key words as are ''plants AND allergic dermatitis'' (with 6548 results on Medline and 1869 on Scopus), ''plants AND irritant dermatits'' (2194 results on Medline and 400 on Scopus), ''plant AND contact urticaria'' (332 documented results on Scopus). For more specific research I had to use limitations, so I typed names of different plant families and specific plants. I was mostly searching on Scopus and I used words as are '' allergic contact dermatitis AND Compositae'' (277 results), ''allergic contact dermatitis AND Alliaceae'' (2 results), ''allergic contact dermatitis AND poison ivy'' (120 results). I have also found useful articles if I typed ''tulip fingers'' (21 results) when I was looking for articles about tulips and dermatitis.

Some plants are well documented and had more results like Chamaemelum nobile or Arnica montana. On the other hand there are only limited numbers of studies for several others. More specific key words for research showed fewer results. For example ''Hedera helix AND contact dermatitis'' (15 on Scopus) or ''Graviella robusta AND dermatitis'' with just 5 results. I hardly found information about plants that are not commonly used around the world and are domestic in particular places. For some plants with potential allergens I have not found reported cases or exist only limited number of documentation ( ''celeriac AND contact dermatitis'' with 2 results on Scopus).

4 RESULTS

4.1 ALLERGENS AND CHEMICAL COMPOUNDS

α-Methylene-γ-Butyrolactones

The α-methylene-γ-butyrolactones are mostly the sesquiterpene type (15-carbon-atom molecule) with α-methylene group attached the γ-lactone ring. Upon the SQL structure, they are classified into 6 groups. They are the main allergens in the Compositae, Jubulaceae, Magnoliaceae, Winteraceae, and Lauraceae. As more simple structures (tulipalin A), they are also found in the Liliaceae and Alstroemeriaceae (5).

Phenol and Derivates

They are a group of mono- or dihydroxybenzene derivatives (catechol, phenol, resorcinol, and salicylic acid) with a long alkyl or alkenyl carbon side chain (cardanol, grevillol, and ginkgolic acid). They are mainly found in Anarcardiaceae, Ginkgoaceae, Proteaceae (5). Urushiol is a mixture of catechols with alk(en)yl side chains at position 3 (3- pentadecylcatechol) and is the main allergen in the toxicodendron genus (3, 5).

Quinones

They are a group of (poly)cyclic compounds and present oxidized structures of ortho- or para- diphenol. At high concentrations, allergens as are benzoquinones or naphthoquinones cause irritation in Primulaceae (5). The major allergen of Primulaceae that cause dermatitis is a primin (2-methoxy-6-n- pentyl-p-benzoquinone). Other possible allergens that can caused sensitization are primetin (a flavone), and miconidin (2-methoxy-6-pentyl-1,4-dihydroxybenzene) which is its biosynthetic precursor (16). Primin has been found on the surface of the leaves, stems, flowers and microscopic glandular hairs (16).

Terpenes

The terpenes are produced by different plants, mostly conifers and are one of the important components of the essential oils (5). The terpenes consist of multiple isoprene (C5H8) units. By the number of isoprene units, they are sorted in hemiterpenes (1 unit), monoterpenes (2 isoprene units like are limonene, pinene and 3-carene), sesquiterpenes, diterpenes etc. (5). Geraniol, citral and the hydroperoxide derivates of d-limonene are the irritant terpenes in the essential oils of Citrus peel (Rutaceae). Oxidation products of limonene (limonene-1,2- oxide) are also known as sensitizers (7). Turpentine A is a mixture of various terpenoid compounds. It can auto oxidize into hydroperoxides, which turnout ketones and aldehydes (5). Terpenes are short of the electrophilic properties which are crucial to bind covalently to proteins in skin and caused sensitization. With chemical reaction they turn to haptens from prehaptens (5).

Diterpene esters

The most irritant diterpene esters are phorbol, dephnane and diterpene and are most commonly associated with Euphorbiaceae. Almost all plant members of this family produce irritant latex which contains diterpene esters (2). A combination of 13-diestres, phorbol 12, ingenol esters and euphorcinol has irritant effect in Euphorbia tirucalli. Latex with proteolytic enzyme (ficin) that causes irritation it is found in Ficus carica (7).

Alkaloids

The alkaloids are diverse chemical group with many bioactive compounds as ephedrine, morphine and quinolones. An alkaloid from Solanaceae family is capsaicin (8-methyl-N- vanillyl-6-nonenamide). In humans binds to vanilloid receptors and stimulates sensation of heat. Dose-related cutaneous burning, pain, erythema and irritation are most common to those who handle with chilli peppers (cooks, food vendors, housewives, etc.). Nicotine is an alkaloid from Nicotiana tabacum (tobacco plant). Is an antagonist to nicotinic receptors in the nervous system (7).

Disulfides

As the main low molecular weight allergens, allicin, diallyl disulfide and allyl propyl disulfide have been described. They are found in Alliaceae. Diallyl disulfide is the most common cause of ACD. Hyperkeratotic eczema appears when the bulb is cut of (5).

Isocyanates and Isothiocyanates (mustard oils)

Isocyanates are classified by the number of nitrogen-carbon-oxygen groups, a highly reactive, low molecular weight compound (5). Mono-isothiocyanates, firstly isolated from Cruciferae family (also called mustard family), appear in variety of other plants. They are generated upon plant injury (5, 7). Precursos of isothiocyanates, the glucosides (glucosinolates), are found in all parts of the plants. Upon damage of the plant the enzyme myrosinase is released and catalyze the oil- generating reaction to produce isothiocyanate (2).

Polyacetylenic Derivates

The polyacetylenic derivates consist of carbon-carbon triple bond or alkynyl functional group. They are mostly found in Araliaceae and Apiaceae and some other plant families. They contain aliphatic falcarinol type C17-polyacetylenic derivates (5).

Calcium oxalate

Calcium oxalate is a water-insoluble salt. The anatomically sharp needle-like crystals (raphides) can harm the skin and cause the mechanical irritancy. That way the penetration of other chemicals is enhanced and can cause chemical irritancy (7). The most cited example of calcium oxalate induced CICD is Dieffenbachia spp. Bulbs usually contain a high concentration of calcium oxalate. Dermatitis, known as bulb dermatitis is known among persons who cut the flowers (tulips, daffodils, hyacinths) as are florists, gardeners and bulb planters. The most affected are hands, fingertips and forearms (2).

4.2 MOST ALLERGENIC PLANTS FAMILIES

Plants (from trees, bushes, grasses, ferns to mosses and green algae) are part of the kingdom of Plantae, which contains more than 300000 species. According to ''Botanical Dermatology'' by Mitchell and Rook, there are at least 10.000 species (248 families), which can provoce ICD, ACD or several other reactions. Pharmacologically-active substances in the plants can diverse depending on the climate and geography (5, 11). Some plants grow only in areas in which they originated and that is why plant dermatitis vary from region to region (17).

With an observational study in Eastern Turkey they wanted to add new data to the literature about plants that cause skin dermatitis. Between 2005 and 2013, they evaluated 30 patients (22 women and 8 men) with the mean age 48.3 years with diagnosed plant dermatitis. 14 (46.7%) of them were diagnosed with PPD (phytophotodermatitis). Among them, Chenopodium album (Chenopodiaceae) caused reaction in 12 (85.7%) cases. The other 2 patients were sensitizded by Plantago lanceolata (Plantaginaceae). ICD was diagnosed in 14 (46.7%) cases and ACD in 2 (6.6%). Among 14 patients with ICD, Ranunculus kotschy (Ranunculaceae) caused reaction in 11 cases. Other plants were Malva neglecta, Mandragora autumnalis, Eryngium billardieri, and Onopordum acanthium. They belong to the Malvaceae, Solanaceae and Asteraceae families. ACD was caused by E. billardieri. Dermatitis was localized mostly on face and hands (14 patients; 46.6%) and upper extremities (2 patients; 6.6%). Professions that were most occupied with dermatitis were housewifes (70%) and farmers (23.3%) (17). In the USA, ABCD is usually caused by the Compositae and the Anacardiaceae family (32).

4.2.1 Asteraceae or Compositae Family

Among the flowering plants, the Asteraceae is the second largest family in the world (5). This family consists of a differetn edible plants (lettuce, chicory, salsify, sunflower, artichoke, etc.), decorative flowers (chrysanthemums, gerbera, calendula, dendranthema, dahlias, and heleniums), medicinal herbs (arnica, chamomile, feverfew, etc.) and many others known as weeds. The growing interest of herbal use in culinary, cosmetic and as medicinal products may result in increasing number of Compositae sensitizations (4, 10).

Among 250 known contact-sensitizing plant families in Europe, more than 200 of them belong to the Compositae family (11). SQL are the predominant allergens in this family and are presented in fresh plants, particles from dried plants and in pollen. The skin can be affected by direct contact or by air (13). More than 1350 SQLs are discovered and almost 50% of them have the allergenic potential. Their concentration varies seasonally and geographically. Among them there is no dominant allergen for patch testing. That is why it is essential to include different plants from Compositae family for screening – to maximize the shared allergenic SQL. Even small differences in molecular structure of SQLs, can cause cross-reactions. This make diagnosis easy to overlook, be false positive (due to irritant reactions) or false negative (due to low content of allergens) if the patient is not examined with the appropriate plants/allergens (4, 5). SQL covers the flowers, leaves, stems and pollens and that can produce an allergic reaction after exposure. Patients who have allergy to various plants from Compositae family are possibly sensitized to the SQL (32). At least 15 species have been assumed of sensitization of Compositae dermatitis. These include arnica, German and Roman chamomile, marigold and elecampane (10). In study among Xhosas, Asteraceae represents the highest number of species. Mexican marigold (Tagetes minuta) and Sweet chamomile (Chamemelum nobile) had the most reports for ACD. Also some others medicinal plants, vegetables, and weeds were mentioned. (6).

Elecampane (Inula helenium)

Since Greek and Roman times, elecampane is one among the oldest curative herbs. The root and leaves are mostly used medicinally to treat cough and respiratory ailments but also as a vermicide and gastrointestinal tonic. Some recommendations of usability of elecampane extracts are to treat skin diseases as are eczema and acne although it can cause contact sensitization (11). 23 different SQL have been identified (at least 17 SQL in the above ground and 6 in the root). The strongest sensitizing contact allergens are alantolactone and isoalantolactone. Reports of sensitization are rare even if there is high sensitizational potencial. Cross reactions are possible with burmarigold, sunflowers and chrysanthemums (11).

Arnica (Arnica montana)

Arnica has been used since the 16th century. Extracts from different plant parts (the flower head to roots) have anti-inflammatory and wound-healing effects. Arnica ethanol-based tincture is mainly used for external application for bruises, muscle strains, hematomas, rheumatism, venous circulatory disorders, etc. and also for sanitary products, cosmetics, massage oils. Because of so widespread uses, allergy to arnica is relatively common (11). Potential contact allergens in arnica are helenalin, xanthalongin, carabron and also other SQL. Sensitization can be caused by plant itself, isolated SQL or commercially-available drug substance. Majority of sensitizations is found among people who improperly dilute the arnica tincture or topical remedies to treat injuries and also plant growers. Cross reactions can occur with other plants of Compositae family (yarrow, tansy, chrysanthemum, feverfew, sunflowers) or plants that contain SQL (11).

Marigold (Calendula officinalis)

Marigold has been used to cure wounds and skin diseases for centuries and nowadays is also popular as component in herbal cosmetics. The sensitizing substance may be a SQL or the lactone loliolide. Capability of plant extract to cause skin reaction is weak and incidence is low (11).

Arnica montana and Caledula officinalis

In the study from Austria they wanted to find out the frequency of delayed-type hypersensitivity to arnica and marigold. A total of 443 individuals (311 women and 132 men), with average age 40.4 years were examined between July and November 2000. They were patch tested with the European standard series: Compositae mix (Comp mix), ether extracts of arnica (0.5%) and marigold (10%) and propolis. 249 of them were also tested with SQL mix. Patients were interviewed about the use of these plants, reasons for and areas of application, possible adverse effects, free time activities and previous atopies (18). 5 patients (1.13%) with mean age 56.3 years and with chronic hand or face dermatitis, reacted positive to arnica. 2 patients were hobby-gardeners and 3 of them used arnica as a

17 topical remedy. 9 subjects (2.03%) with the mean age of 51.9 years, were sensitized to marigold. 2 had dermatitis of the hand and arms, 2 on legs, 3 on face and 1 patient on face and arms. After testing with the Comp. mix, 18 cases (4.06%) had positive reaction. Among them were 3 of 5 arnica responsive patients and 4 of the 9 marigold susceptible ones. 1 person reacted to the SQL mix (this patient was also positive to arnica) (18). For arnica and marigold is limited data on the current prevalence of delayed–type hypersensitivity reactions. Arnica is recognised as a potent contact sensitizer and marigold with rare allergenic properties (18).

German chamomile (Chamomilla recutita)

True chamomile is widely used around the world. Its effect has been proven as an anti- inflammatory, spasmolytic, wound-healing and sedative. It is found in different herbal cosmetic such as ointments, tinctures, medicinal soaps and cure for cough and flu, acne lotions, chamomile tea and also in sanitary items (11). From a dermatological point, the content of SQLs is very important. True chamomile contains either no or only small amounts of the SQL anthecotulide. It has very low incidence of contact sensitization and is caused by contamination with other species, usually dog chamomile (11). Other possible allergens can be coumarins (herniarin; 7- methoxycoumarin) or flavonoids (10). The active constituents are SQL as are α-bisabolol, the blue chamazulene, farnesene, polyenes and several flavonoids (10). The content of the drug differ between countries. Larger amounts of the strongly allergenic SQL anthecotulide (levels of 0.003 - 0.01 %) are detected in Chamomile imported from Argentina and Chile. Contamination with the morphologically alike dog fennel (Anthemis cotula), which has up to 7.3% anthecotulide, is also possible. Chamomile of European origin has lower content of anthecutolide (10, 11). Although the allergic potential of the German chamomile is low, European studies have presented a high prevalence of positive patch-test (ranging 57% - 64%) to ether extracts in persons with known Compositae contact allergy (19). From June 1991 and December 2009 a total 36 patients with recognized or assumed Compositae allergy were examined. They were patch tested with herniarin 1% petroletrum.

1 tasted positive (2.78%) and 3 had doubtful positive reactions. Among other 32 tested persons, 30 (94%) had positive test results to ether extracts of German chamomile (19).

In study in Germany checked 200 non-selected patients with 11 products and extracts of German chamomile. 21 (10.5%) persons had positive test results to chamomile preparations. Among them, 3 persons reacted positive on chamomile extract and 1 was due to prior respons to a chamomile ointment (10).

Roman chamomile (Chamaemelum nobile)

Like German chamomile, the drug has anti-inflammatory and spasmolytic characteristic and is used for the same intentions. Among various SQLs, the most important is nobilin, also contains flavonoids, the allergic α-pinen, limonene, and bisabolol (11). 2 cases of contact – allergic nipple reactions in breastfeeding women have been noted after using Kamillosan® ointment sold in England. This ointment in UK version consists of extracts and oil of Roman chamomile instead of German chamomile. Both of them had an extreme (+ + +) reaction to chamomile oil 0.1% pet. and negative response to other components (10).

Dandelion (Taraxacum officinale)

Since the middle ages, dandelion is indicated for chronic eczema, liver diseases, warts, gallbladder disease, and gall stones. Also it is used for cooking and in natural cosmetics. Dandelions is weakly allergenic and require high and prolonged exposure (11). The predominant SQL allergen is taraxinic acid-1’-O-β-D-glucopyranoside (10). After use of herbal cosmetic containing dandelion, there is no report of allergy. However, 2 examples of contact allergy have been presented. One after using milky plant juice to cure warts and other had been directly exposed to dandelion for several years because of feeding pets (10, 11).

Feverfew (Tanacetum parthenium)

Feverfew was used to treat fever, headache and has documented effect in migraine prevention. It is also used in stomach ache and gynaecological conditions. A feverfew extract is one of the components of the Compositae mix (11). Its allergen is SQL parthenolide (10). Sensitization is caused after touching the feverfew or cross reaction with chrysanthemum (Dendranthema) (11).

Yarrow (Achillea millefolium)

Products with yarrow have been used externally and internally because of its wound- healing effect. It has also been used for indigestion and liver disease because of its spasmolytic effect. Extracts are used as a ''biological additive'' in natural cosmetics (11). The most important SQL allergen is α-peroxyachifolide, an endoperoxide. Cross reactions are possible in patients with Compositae allergies. It is recommended that they do not use products with yarrow (candies, cosmetic, shampoos) (11).

Purple coneflower (Echinacea purpurea)

Echinacea purpurea is herb with immunostimulatory and wound-healing properties which has also been proven with experiments. Orally ingested purple cornflower is used to treat upper respiratory tract infections and externally for genital candidiasis. Side effects are rare but after oral ingestion some immediate reactions are possible. Contact dermatitis is more frequent in persons with known sensitivity to Compositae (11).

French marigold (Tagetes patula)

The French marigold is an ornamental plant. It contains phototoxic and allergenic α- terthienyl. Until now, only 1 case of sensitivity to French marigold has been mentioned in an aroma therapist (11).

Tea tree (Melaleuca alternifolia)

Because of its antiseptic, bactericidal, fungicidal, and wound healing properties, tea tree oil is used for cure of open wounds, different inflammatory skin problems, acne, psoriasis, fungal infections, sinus infections and other disorders. It contains high levels of 1, 8- cineole and low concentrations of terpinene-4-ol (11). Different test methods show that sensitization potential is week but this is probably due to too low concentrations and insufficiently methods. Sensitization has been regularly reported and is due to d-limonene, α-terpinene, aromadendrene, terpinene-4-ol, p-cymene and α-phellandrene. Exposure to light, possibly caused by longer storage and constant opening of bottles, heat, and oxygen causes peroxides, hydroperoxides, and also endoperoxides which are stronger sensitizers than the original substance. This is due to increased incidence of sensitization since 1990s (11).

Great burdock (Arctium lappa)

Infusions and plasters of leaves and root are used as a medicinal plant because of its antiseptic, diuretic and anti–inflammatory effects to treat psoriasis and acne. Patients with alopecia and dry seborrhea use the root oil as hair-growth stimulator. An allergen is SQL arctiopicrin (11). One example of dermatitis was described after long use of the root oil. 3 cases of ACD were reported after application of burdock plasters. In all of them elicited + + + reactions. In 20 controls the results were negative (10).

Cineraria hybrid

A 58-year-old female gardener had eczematous-oedematous dermatitis on the hands and forearms. A questionnaire revealed that she was handling a Cineraria hybrid. Her reactions with Italian standard SIDAPA series, Compositae mix and leaf were negative. Test with the flower showed a strong (+ +) reaction on day 2 (D2) and day 4 (D4). Patch tests with flowers were negative in the control group (34).

4.2.2 Jubulaceae Family

This family comprise 4 genera: Frullania, Jubula, Steerea and Neohattoria. Plants are more typical in tropical and subtropical areas but now can also be found all over the world (5). The most important allergen that causes ACD is frullanolide from α-methylene-γ- butyrolactone structural group. Other allergens from this group described as sensitizers are oxyfrullanolide, cis-b-cycloscotunolide, and eremofrullanolide. Uncovered areas of skin (face and the V of the neck) are typically injured after direct contact with trees or by airborne contact (5).

4.2.3 Liliaceae family

The most important genus of the Liliaceae is the tulip genus with 109 species (5). Tulip bulbs consist of glucosides as are tuliposides A and B with weak allergic potential. They hydrolysed into tulipalin A and B. Tulipalin A seems to be the predominant sensitizer. Tulipalin B also causes sensitization in guinea pigs. Higher concentrations of tuliposide A are found in flowers, leaves and stems but sensitivity can be developed by any part of the plant (5). Tulip fingers are the most frequent presentation of allergic and irritant hand dermatitis presented by painful, subungual, periungual erythematosquamous lesions. The most exposed professionals are workers who are handling with the bulb: bulb growers or bulb collectors and packers (5).

Asparagus (Asparagus officinalis)

27 patients diagnosed of asparagus allergy was patch tested with extracts of asparagus, garlic, onion and commercial contact allergen of garlic; diallyldisulphide. Also 10 healthy controls were tested. After 48 and 96 hr the results were evaluated. All 10 controls had negative test results. 10 subjects had positive reaction to asparagus but negative to garlic, onion and diallyldisulphide (20).

4.2.4 Alstroemeriaceae Family

The main allergen is tulipalin A (α-methylene-γ-butyrolactone) and is found mostly in the stem and petals. Dermatitis most often shows as palm eczema in florists who are exposed to an injured plant when stripping off the leaves (5). In the study made in the Netherlands wanted to find the frequency of hand dermatitis among workers in the horticultural industry. They investigated how many workers of Alstroemeria cultivation has been sensitized by tulipalin. Investigation was a combination of a questionnaire-based cross-sectional study and a dermatologic examination. Questionnaires were made among all workers at these companies (employers and employees of 51 Alstroemeria companies in Holland). Workers who were rated positively for hand dermatitis upon questionnaire were also tested with tulipalin A to confirm sensitization. Upon questions and skin symptoms of the hands dermatitis they were divided in a groups as major dermatitis (with erythema, papules, vesicles, fissures), minor dermatitis (erythema, slight chapping of the skin and scaling), no hand dermatitis and other skin disorders. Further on, patch tests were done on the persons who were categorized as having major and minor dermatitis (12). Major hand dermatitis had been reported in 29.5% workers. Among workers with hand dermatitis, approximately 50% had been sensitized by tulipalin A (12).

Peruvian lily/ Inca lily (Alstroemeria cultivars)

A cut flower, Peruvian lily, originally from Chile and Peru, it is nowadays cultivated also in Europe and North America. Allergen is tulipalin A. ACD is caused among florists, workers in cut flower industry and after handling plant during gardening (35). 65-year-old woman developed dermatitis with erythema, peeling, scaling on the first three fingers of the right hand. She also described less severe symptoms on her left hand and some itching on the neck and face. The symptoms appeared when she started gardening and cutting flowers such as Alsotroemeria, and worsened in flowering season (35). She was tested with European standard series, plant series and also with stem portions of Alstroemeria, Lilium, Zantedeschia, garlic, and onion. Results showed + + + reaction to Alstroemeria and tulipalin A. Patch tests in healthy controls were negative (35).

4.2.5 Anacardiaceae Family

This is a family of flowering plants, which are native to tropical and subtropical areas, and some species can also be found in temperate regions. It includes about 650 species of trees, shrubs, and woody vines. Important and the most studied members of the family that can cause ACD are: poison ivy, poison oak, poison sumac (Toxicodendron genus), mango (Mangifera indica), lacquer tree (Toxicodendron vernicifluum), and cashew nut (Anacardium occidentale) (5). To the Toxicodendron genus allergic people can also evolve cross-reactions to other components, as are cashew nut oil, mango skin and the fruit of the Ginkgo biloba tree (32). In South America, ACD is frequently caused by species of Lithrea genus (Lithraea molleoides and L. brasiliensis) (3). In the South African study the main causes of phytodermatitis are mango fruit tree (M. indica) with 33 citations, cashew nut tree (Anacardium occidentale) and poison ivy (Smodingium argutum) (6). Poison oak, poison ivy and poison sumac are typical cause of allergic phytodermatitis in North America. (13). Urushiol can cause ACD after touching the plant and also through airborne contact with smoke particles when burning plants of the Toxicodendron genus (32). Urushiols are nonelectrophilic compounds. They are composed from two parts; the catechol ring and the alk(en)yl side chain. Both are important for these substances to be sensitizers and irritants. The length of the side chain and the number of double bounds affect the structure activity. Sensitization to the analogues with highest grades of unsaturation is more frequent (21). In Asia the most common cause of allergic phytodermatitis are lacquer tree, mangoes fruit tree and hardwood Gluta renghas (13).

Lithraea genus

Lithraea molleoides and Lithraea brasiliensis grow in Brazil, Argentina and Uruguay and are known as harmful. Dermatitis caused by Lithraea can occur in any season. Erhytema, edema and papules predominates on exposed areas of the skin but by contaminated fingers can be transferred on other areas. The eruption appears in 1 or 2 days after exposure and last 2 or 3 weeks (3).

Lithraea genus is frequent reason of ACD in South America. The allergenic substance is called urushiol (21). In study 17 volunteers with previous Lithraea dermatitis, 10 controls without any plant dermatitis and 4 North Americans who were highly positive to poison oak were examined. The goal of the study was to identify the allergic compounds of Lithraea molleoides and Lithraea brasiliensis and to investigate the cross-reactions with Toxicodendron allergens. Volunteers were tested with poison oak urushiol and purified Lithraea molleoides and Lithraea brasiliensis extracts and also had to answer the questions about previous contact with poison ivy or poison oak or other poisonous species of the genus Toxicodendron. They denied previous contact with these species. The second group of 4 highly Toxicodendron-sensitive subjects from North America was tested with the same substances and also denied previous contact with Lithraea (21). All 17 subjects with Lithraea dermatitis had positive reaction to poison oak urushiol and 13 of them also responded to (Lithraea molleoides) and/or (Lithraea brasiliensis) extracts. Minimal amount of allergen to cause positive reaction was lower for urushiol than for Lithraea extracts. Also the responses to urushiol were more intense. Maybe the reason is that the urusihol contain more unsaturated bonds. None of the control group without a history of Lithraea dermatitis reacted to urushiol or to Lithraea extracts even with the highest dose (in the control group test was repeated 3 months after). All 4 volunteers with sensitivity to Toxicodendron showed positive reaction to poison oak urushiol and to Lithraea extracts. In this group, urushiol made stronger responses and threshold was lower than for Lithraea extracts (21). The results shows that the alk(en)yl catechols with both 15 and 17 carbon atoms in the side chain can cause allergies. Also cross-reactivity between Lithraea extracts and urushiol can be due to chemically similar allergens (21).

Poison Ivy (Toxicodendron radicans), Oak, (Toxicodendron diversilobum, T. toxicarium) and Sumac (Toxicodendron striatum, T. vernix)

Poison ivy, poison oak and poison sumac are plants of Anacardiaceae, domestic to the United States, Canada, and northern Mexico (14).

Toxicodendron is the most allergenic genus of the Anacardiaceae. Although the toxicodendron dermatitis is unknown in Europe affects millions of North Americans (50%- 70% of the population seems to be sensitized) (3, 5). It includes poison ivy (Toxicodendron radicans), poison oak (Toxicodendron diversilobum, Toxicodendron toxicarium), and poison sumac (Toxicodendron striatum, T. vernix). In the resin of the plant are the sensitizers of Toxicodendron plants (5). Most exposed are outdoor occupations as agriculture, forestry and fire fighting (14). The high allergenic oleoresin is called urushiol and cause the ACD of Toxicodendron plants. It is found in the stems, roots, leaves (young leaves have higher levels of urushiol) and skin of the fruits which contain the most of urushiol. It is colourless or slightly yellow. When it is exposed to the air, it oxidizes, polymerize and turn black. (14). Contact dermatitis firstly appears after touching the oleoresin from damage and injured plant (5, 14). Leaves have the highest amount of urushiol during the fall but in winter the urushiol is reabsorbed into the plant and the fallen dry leaves are nonallergenic (14). Contact dermatitis normally occurs in 2 - 4 days but can also as late as 2 weeks after contact. Without treatment the dermatitis normally last 1-2 weeks but sometimes also up to 6 weeks (5, 14). Clinically it is present as intense pruritus and an erythematous reaction with multiple papules and vesiculo-bullous lesions mostly on the face, neck and genitalia (14).

Mango (Mangifera indica)

Mango is cultivated from Asia to Florida, Mexico and countries of Central America. Its allergens are heptadecenylresorcinol, heptadecadienylresorcinol and pentadecylresorcinol (5). It contains also other substances like cardol, limonene and β-pinene. They are found in the peel, stems and leaves. Fruit juice does not contain allergens so can be drunk by sensitized persons. ACD appears when the sap of the mango skin, leaf or bark of the tree comes in contact with skin (5, 6). When mango is eaten unpeeled, can cause facial and perioral dermatitis in sensitized individuals (13).

Cashew nut tree (Anacardium occidentale)

Cashew nut tree originate from Brazil and nowadays it has been cultivated also in other tropical countries. The fruit of the tree is cashew nut. In the middle of the double-layered outher shell is irritant and allergenic oil. ACT is mostly caused by direct contact with the oil and can also be induced by any part of the cashew tree (5). The most important allergens are anacardic acid (a combination of 2-carboxyl-3-alkyl phenols) and cardol (a combination of 5-alkyl resorcinols) (5). When nuts are properly roasted catechols are destroyed (13).

4.2.6 Ginkgoaceae Family

Ginkgo tree (Ginkgo biloba)

The ginkgo tree is one of the oldest tree species in the world and is the only representative of the Ginkgoaceae. It grows in temperate areas but originate from southeastern China. Contact dermatitis is due to fruit from female ginkgo tree (5). As the potential allergens have been identified the alkylphenols (anacardic or ginkgolic acids, cardols, and cardanols) (5). The most important allergen is ginkgolic acid. It is detected in the fruit and also in leaves. Allergic responses are result of contact with open fruit. Contact dermatitis appears mostly in East Asians, who eat the seed kernels and do not remove the pulp. Pruritic, edematous and erythematous plaques develop on the hands, face, arms, and everywhere the seed pulps are spread (5).

4.2.7 Proteaceae Family

The Proteaceae family consist of 1050 species. The most important genus is the genus Grevillea (5). The majority of genus Gravillea is native to Australia (15). Various Grevillea species and hybrids can cause ACD after touching the wild or cultivated tree. Bollous eruptions are similar to those caused by Toxicodendron sp. Eruptions are the most common among men who cut the trees. The allergens are 5-tridecylresorcinol (grevillol), 5-pentadecylresorcinol and 5-pentadecenylresorcinol and they differ between species (5).

Silver oak (Gravillea robusta)

Gravillea robusta, known as silver oak is an evergreen tree, originating in eastern Australia and is planted as ornamental and shade tree in many countries. After first record of contact dermatitis to Grevillea in 1847, many reports of ACD to different Gravilla species have been made. The allergens in G. robusta are 5- tridecylresorcinol (95% grevillol), 5-pentadecylresorcinol (5%) and 5- pentadecenylyresorcinol (2%). Two examples of contact dermatitis to G. robusta have been presented in New Zealand. Both were male, 32 and 38 years old arborists with symptoms as are itchy skin, oedema on forearms, neck and face. One of them was working with G. robusta for many years (repeated occurrence) but more severe reaction occurred after pruning branches of G. robusta. He was patch tested with pieces of wood and leaf. After 48h the results were negative, after 96h he had + reaction to wood. Other arborist had first allergy to Toxicodendron succedaneum and since then each contact with sawdust from G. robusta leaded to contact dermatitis. When he previously worked with G. robusta no reactions appeared. Patch testing to small quantities of G. robusta sawdust in Vaseline caused a weak (+) response at 48 h and 96 h (15).

The first example shows that plant contact dermatitis can be developed after longer exposure to an allergen and according to the second case; cross-reactions among various plant species can develop (T. succedaneum, G. robusta). This is why some occupations as arborists, gardeners and forestry workers should be more aware (15).

4.2.8 Primulaceae family

This family of flowering plants is divided in approximately 1000 species. Primula was exported from China to Europe but less in America. Species of Primula which can cause allergies are P. auricula, P. denticulata and P. vulgaris. An ACD occurs as a variety cutaneous reactions (erythematous papules, vesicles and bullae) with facial dermatitis, limb dermatitis and hand dermatitis (5).

Primula obconica

Primula obconica is an ornamental plant originally from China and is nowadays popular around the world in gardens or in flower boxes. Primin (2-methoxy-6-penthyl-1, 4 - benzoquinone) is the prime allergen (22). Since 2000 P. obconica cultivars, which has less primin, has been cultivated in Europe. The survey of primin sensitivity in Italy shows that the contact allergy to primin is still high in retired persons and household workers (22). Sensitization can occur by direct or indirect contact and is more common in females elder than 35 years. Results after testing with the European baseline series show 1.1% prevalence of sensitivity to primin (0.3% in men, 1.6% in women). To investigate a responsiveness to primin in north-eastern Italy was made a study from 1996 to 2012 in 23774 patients (16 056 or 67.5% of women and 7718 or 32.5% of men) with symptoms or suspected allergic dermatitis. After the standardized questionnaire the patch tests were done. The patches with primin 0.01% pet. were applied for 48 hr on the upper part of the back. The general prevalence of primin sensitization was 1.9% (2.6% in women and 0.5% in men). The mean age was similar for both; 43.0±17 years. The frequency of occupational dermatitis was higher; 7.7% (6.9% in women and 9.3% in men). Dermatitis most commonly occurs on the hand/forearm (31.0%) and face. The frequency of sensitization was high among household workers (5.16%), retired persons (4.37%), and workers in chemical industry (2.08%) (22).

In the study made in UK researchers wanted to find out if the incidence of ACD decreased after usage of primin-free P. obconica. Analysis showed that the incidence falls from 0.785% to 0.429% in 2002 (16).

4.2.9 Rutaceae family

This family is distributed in tropical and temperate regions. Rutaceae includes 900 species. Mostly cause phototoxic reactions but ACD has also been described (5). Well known species are orange (Citrus sinensis), bergamot (Citrus aurantium), and lemon (Citrus Limon). Citrus are used as food, for aromatic oils, soaps, perfumes and cosmetic (7).

Citrus Genus

ACD to citrus fruits is not common. Hand dermatitis has been noted in persons who handled with food (6). Also irritation around the mouth after contact with essential oils from the peel has been observed (7). The possible sensitizers are geraniol, citral and the hydroperoxide derivative of d-limonene. According to a study from South Africa, ACD is caused with Citrus sinensis (19 citations) and Citrus Limon (18 citations) (6).

4.2.10 Alliaceae family

This family is widely distributed around the world, preferably in temperate and subtropical areas. Its members are known by garlic smell and soft, fleshy leaves. The most important genus in dermatology is genus Allium. The most recognisable vegetables are garlic (Allium sativum) and onion (Allium cepa) (5). Some older classifications place garlic and onion in the family Liliaceae (31). ACD to garlic is not new but to onion is less frequently noted. Cross-reactions are also possible among patients with ACD to onion or garlic (5).

Garlic (Allium sativum)

Garlic has been cultivated as folk remedy due to its antibacterial, spasmolytic, choleretic and anti-atherosclerotic effect. It is also used to improve food flavour (7). The main low- molecular weight compounds in garlic are allicin, diallyl disulfide and allyl propyl disulfide. Beside ACD, garlic can also cause ICD, cheilitis and pemphigus vulgaris-like eruption. ACD is caused with the allergen diallyl disulfide (23). All injured parts of garlic release irritant and allergic sap. Mostly hyperkeratotic eczema affects the tips of the fingers of the hand, known as finger-pulp dermatitis, while cutting of the bulb (5, 23). As an occupational hazard it is known among chefs, cooks and housewives (7). Contact allergy to diallyl disulfide was presented in a retrospective study (from January 2000 to December 2005) in a Spanish population. 1092 patients were patch tested (673 women and 419 men) with diallyl disulfide 1% in pet. Their mean age was 41.4± 16.5 years. 19 (1.7%) patients had positive reaction to diallyl disulfide (18 women and 1 man).

Allergy mostly appears on hands (15 patients). Occupational groups were mostly housewives, health care professionals and cooks (23). Also other studies in Spain found a similar prevalence of contact allergy to diallyl disulfide (2% in Santiago de Compostela) (23). The hypersensitivity shows with asymmetrical finger pulpitis mostly on first three fingers of non dominant hand (23, 5). Using garlic for medicinal purposes can cause lesions at different locations because of its sensitizing and irritating potential. Application of garlic as a topical remedy should be limited (5).

4.2.11 Cruciferae family (Brassicaceae)

The Cruciferae family consist of around 3200 species. Among them are some well known vegetables, as are cabbage (Brassica oleracea), radish (Raphanus sativus), cauliflower (B. oleracea), turnip (Brassica campestris), horse radish (Armoracia rusticana) and mustard (Brassica nigra). ACD is more commonly seen in food handlers and plant growers. Occupational contact dermatitis in patients sensitized to vegetables can be caused by cabbages and cabbage juice or an acute vesiculo-bullous dermatitis on palms by chopping a radish Raphanus sativus. ACD and hand eczema can be induced by Brassica nigra and Brassica oleracea (5). Because of the small series of patients and case reports, the literature on ACD from Cruciferae is limited. To estimate the prevalence of contact allergy to allyl isothiocyanate, the study of 259 Danish patients (73% female and 27% male) was done. Persons with assumed contact allergy were tested. This group represents chefs, sandwich-makers and housewives during the years 1994-2003. Patients were patch tested with allergens related to food products including allyl isothiocyanate 0.1% in petrolatum. Patches were applied for 2 days. The responses were observed on days 3, 4 and 7 (24). Positive reaction, seen as homogeneous infiltration and redness after testing to allyl isothiocyanate, was developed in 2 patients (0.8%). 196 patients (75.7%) had negative test. Other 43 patients (16.6%) had ± reaction, 15 patients (5.8%) had irritant reaction and 3 (1.0%) evolved a follicular reaction. Despite frequent contact with plants form Cruciferae family, sensitization and ACD occur in limited number of cases. The test concentration probably fails to reveal all patients with allergy (24).

4.2.12 Capparaceae Family

The Capparaceae comprises of 650 species of shrubs and small trees. Typical example of this family is caper bush (Capparis spinosa) (5). Contact dermatitis from C. spinosa appears on the exposed areas of the upper limbs as eczematous eruption (6). Caper bush led to an acute vesiculo-bullous ACD on woman’s arm after application of a wet compress of the leaves and fruits (5). Various species consist of thioglucosides. In the presence of water, they are enzymatically broken down to isothiocyanates, the most crucial allergens. These plants have high potential to cause ICD and low for ACD. (5).

4.2.13 Araliaceae family

This family mostly occur in tropical regions but some of the 700 species become widespread by gardening and as houseplants. The most recognisable plant in Europe, North Africa and Asia is common ivy (Hedera helix) (5). The most important allergens of this family, that can cause ICD and ACD, are falcarinol and didehydrofalcarinol. They are found in stalks, leaves, and roots. Sensitization can be caused by pruning and handling the plants or some other kind of contact. Hands, forearms, and also face and neck are the most frequently affected. Dermatitis generally begins with itching and erythema that in a couple of days lead to a vesicular eczema (5).

Common ivy (Hedera helix)

Common ivy is an evergreen plant that can caused ICD and ACD. At least 28 examples of contact dermatitis have been reported since 1987. The next study describes one case of ACD after airborne exposure to common ivy. A male gardener (21 years) whit no previous skin disease evolved dermatitis on his neck and extremities (legs, ankles, upper arms, hands) for 4 days. 2 days before out brake he had been handling with common ivy. He was patch tested with European baseline series, fragrance substance series and a small and a large leaf of common ivy. Patches were put on upper back for 2 days. Check-up was performed on day 2, 3 and 7. Positive reactions were detected to the both leaves. At 1-year follow-up he evolved previous symptoms and also rhinitis, conjunctivitis (30).

4.2.14 Apiaceae family (Umbelliferae)

This family of 2850 species grows generally in temperate parts of the world. Most of the members have high concentration of psoralenes and can produce phototoxic reactions. Decorative plants, weeds and also edible plants of this family have been able to cause ACD (5). Falcarinol has been shown as a potential contact allergen. Celeries (Apium graveolens), carrot (Daucus carota) and parsnip (Pastinaca sativa) can cause an allergenic reaction. ACD of Apiaceae is less frequently reported, possibly because of low concentration of falcarinol in edible plants (26). Untill now, some cases of ACD caused by Apiaceae root vegetables were reported. 21-year old female evolved hand eczema after peeling parsnips. Also she noted itching and burning sensation of oral mucosa. After ingestion of celeriac she felt ill. She had perioral dermatitis as a teenager and also some members of her family had symptoms of atopy. Patch testing showed strongly positive reaction to celeriac and parsnip but negative to carrot. Other example is about gardener from France. He developed celery dermatitis after scraped roots of celery. Other study is about 13 workers with occupational carrot dermatitis. 3 of them had also positive reaction to raw celeriac and other 3 to parsnip (26).

Centella asiatica (Hydrocotyle asiatica)

Centella asiatica is native to northern Australia and some regions of Asia. The fresh or dried leaves and stems have been used topically in many dermatological problems as are scars, slow-healing wounds and keloids (5). The possible allergens are triterpenoid saponins - madecassoside, asiatic acid and asiaticoside (25). A non-atopic, 42 year-old woman had serious eczema on her neck and upper chest, after using Madecassol® ointment. After one month, she had positive reaction to patch tests with ointment and C. asiatica extract (1% and 5% pet.). 20 controls had negative reaction after patch tests with C. asiatica extract 1% and 5% (25).

Carrot (Daucus carota vars)

Carrot is edible root vegetable mostly in orange and yellow colour but can also be found in purple, red or white. The main allergen is falcarinol and it is found in leaves and fruits. Typical clinical pattern of ACD involve hand, fingertips and also face. Employees working in canning factories are mostly affected (5). The first reports of carrot contact dermatitis are from 1932. 4 women developed hand eczema after handling carrots. Also 5 of 7 female cannery workers evolved symptoms after handling diced carrots for 2 - 4 days. All of them showed positive reaction to raw and blanched carrots after 24 hr. Among 205 controls, 32 (15.6%) tested positive after 3 days of application (26).

4.2.15 Solanaceae family

According to study in South Africa, pepper (Capsicum annuum) with 26 citations, potato (S. tuberosum) with 25 citations and tomato (Solanum lycoperiscum) with 14 citations, were associated to ACD. S. tuberosum caused urticaria, eczema, atopic dermatitis and itchy skin during direct contact with raw potato while peeling. Patatin is the allergen that can cause eczema. But it is sensitive to the heat and cooked potatoes do not cause allergic reactions (6).

Tomato (Solanum lycopersicum)

The tomato plant originates from the western areas of South America and since 1540 is one of the most important crops. ACD caused by the tomato plant, unripe or ripe fruit, is rarely reported but immediate-type reactions are well known. Heat-stable and heat-labile allergens may be responsible for allergy to tomato plant. Cinnamyl alcohol and conifery alcohol may be also playing a role in sensitization by tomato (27). The aim of the next survey is to find actual information on tomato contact dermatitis. For patch testing they prepared ether extract from tomato plant in 10% ethanol and since 2005 this extract has also been used for patch testing. 93 patients and 10 controls were examined with it between January 2005 and December 2011. Patches were applied on the back for two days and readings were performed on days 3, 4, 5 and 7. 8 (9%) tested positive, 3 of

34 the 10 controls had ± (doubtful) reactions and one of the control group had + (weak) reaction on day 3 (D3) and day 7 (D7) and was added in the positives (27).

4.2.16 Lamiaceae family (Labiatae family)

Rosemary (Rosmarinus officinalis) Rosemary is native to Mediterranean area. It has been used as a medicinal, aromatic, and cosmetic herb, spice, flavoring agent, and also as a preservative. Oraly it is used to relif of dyspepsia and mild spasmodic disorders and cutaneously to relief of muscular pain and also to stimulate hair growth (1). Many chemical compositions of R. officinalis can have medicinal effects. In the leaves we can find 1, 2-cineole, α-pinene, carnosol, limonene, thymol, rosmarinic acid and many others. Caffeic acid, rosmarinic acid, ursolic acid, carnosol and carnosic acid are the main active compounds of Rosmarinus officinalis (1). Contact dermatitis of Rosmarinus officinalis is not common but can be caused by raw material or rosemary extracts. In the article about contact dermatitis caused by Rosmarinus officinalis they represent 7 cases (1). 7 examples of allergy to rosemary products have been presented. 6 of the patients were 45- 62 years old and they have been using rosemary as preservative, rosemary leaf plaster to treat pain on knee, poultice to treat muscular pain, handling with fresh rosemary or using homemade alcoholic preparation containing a mixture of several plants of Labiatae family. One case was 23 years old women using cosmetic and a cleansing gel. They all had swelling, cutaneous eczematous and itchy dermatitis lesions on hand, forearm and face. They were patch tested with rosemary leafs and extracts and had positive reaction mostly on D2, D4 and D5 (1).

Sage (Salvia officinalis)

Sage, originally from Mediterranean region, is now cultivated throughout the world. Medicinally it is used to relieve skin injuries as are cuts and wounds and also in culinary. The strongest active constituents are essential oils. They are included in different pharmaceutical, cosmetic and hygienic preparations. Cross-reactivity reactions are possible among different plants in Lamiaceae family. Allergic reactions to Salvia officinalis have

35 infrequently been reported. Until now, there is only one report of ACD caused by S. officinalis, which has been proved by a positive patch test. Causative constituent is alantolactone (33). Case of contact allergy to Salvia extract from cosmetic (lip balm) has also been presentet. An 83-year-old woman had history of swelling, redness and tightness of the lips and surrounding skin. Patch testing showed positive reaction to her own lip balm at D2 and D4. She also developed positive reaction to the Salvia extract, S. officinalis in water and in pet. Tests were negative in 20 healthy controls (33)

4.2.17 Moraceae family

Fig tree (Ficus carica)

Fig tree, originally from western Asia and brought to the Mediterranean, is also cultivated in New Zealand as a fruit tree. Unripe fruit and the leaves contain the furocoumarins (lipid- soluble, penetrate the epidermis), psoralen, bergapten, coumarins, marmesin, 5'- dihydropsoralen and umbelliferone, 4' (9). Other Ficus spacies which may cause cross reactions are Cluster fig (F. racemosa), Weeping fig (F. benjamina) and Sycamore Fig (F. sycomorus) (9). Phytophotodermatitis from Ficus carica is poorly recognised and is more common to arborists, gardeners, forestry workers and orchardists (9). In Auckland 2 male arborists were working with injured limbs from fig tree. After 9 hours one arborist noted a burning on right arm and in the next 12 hours it became swollen, erythematous and sore. On the wrist, forearm and back of the hand appeared bullae within 24 hours after contact with tree. The second arborist treated his blistering skin with manuka honey. After that appeared swelling and formation of large bulge (9).

4.3 PATCH TESTING, MIXTURES

To determine contact allergy to plants, patch tests with a Compositae mix (Comp. mix) or Sesquiterpene lactone mix (SQL mix) and also patient history with information about occupational or recreational contact with plants (hobbies, trips) should be done. (11). Commercial tests for patch testing plants are limited and none of the mixes with Compositae plant extracts has been accepted for a European plant mix. Among European baseline series SQL mix is suggested screening agent for Compositae contact allergy (29). It can identify about 60% of SQL sensitization cases. The mixture contains 3 equimolar quantities of the 6 fundamental structural groups of SQL: dehydrocostuslactone costunolide and alantolactone. To detect more cases, an alternative preparation of the Comp. mix was prepared. It consists of a variety plant extracts (tansy, feverfew, yarrow, German chamomile and arnica) (5). In the study about patch tests and constituents of Comp. mix, they were comparing two Comp. mixes to decide which constituents were most suitable in identifying Compositae contact dermatitis. Study included Compositae-sensitive patients who were positive to Compositae mix 6% in pet. (CM6%) or/and Compositae mix 5% in pet. (CM 5%) and were tested with their relevant constituents. The tapes with plant extracts and allergens were applied for 2 days. Readings were done on D3, D4, D5 and D7 (29).

Table III: Constituents of two commercial Compositae mixes (29)

Compositae mix 6% pet. Compositae mix 5% pet. Feverfew extract 1% pet Parthenolide 0.1% pet. (Tanacetum parthenium) Tansy extract 1% pet. Tansy extract 1% pet. (Tanacetum vulgare) (Tanacetum vulgare) German chamomile extract 2.5% pet. Roman chamomile extract 2.4% pet. (Chamomilla recutita) (Chamaemelum nobile) Yarrow extract 1 % pet. Yarrow extract 1 % pet. (Achillea millefolium) (Achillea millefolium) Arnica extract 0.5% pet. Arnica extract 0.5% pet. (Arnica montana) (Arnica montana)

76 patients, 62 females and 14 males, who reacted positive to CM 6% were examined with its constituents. Among them, 12 patients reacted positive to all five component of the mix. They were tested between July 2000 and March 2004. The results of the study are shown in table IV.

Table IV: Distribution of positive reactions to the constituents of Compositae mix 6% pet. in 76 patients with positive reactions to the mix (29)

Allergen Total number of positive reactions Feverfew extract 1% pet 57 Tansy extract 1% pet. 54 German chamomile extract 2.5% pet. 53 Yarrow extract 1 % pet. 35 Arnica extract 0.5% pet. 20

Also 29 patients (24 females and 5 males) who had positive reaction to CM 5% were tested with its ingredients. Results are shown in the table V (29).

Table V: Results of distribution of positive reactions to the constituents Compositae mix 5% pet. (29)

Allergen Total number of positive reactions Parthenolide 0.1% pet. 26 Tansy extract 1% pet. 21 Roman chamomile 1% pet. 0 Yarrow extract 1 % pet. 10 Arnica extract 0.5% pet. 0

Among two mixtures; the CM 6% and the CM 5%, the 6% mixture recognises higher percentage of positive reactions (29).

Also V. Goulden and S. M. Wilkinson tasted 97 patients between October 1995 and February 1997, to establish value of testing to detect Compositae contact allergy with Compositae extracts and SQLs mix. The included patients were hobby gardeners with hand eczema or pattern dermatitis. They were tasted with patch test of SQL mix 0.1% pet,

Compositae extracts (plant series shown in table VI) and other appropriate allergens. Patches were put to the skin of the back for 2 days and the readings were done on D2 and D4 comparing to the scale of the International Contact Dermatitis Research Group (28).

Table VI: Allergens contained within the plant series (28)

Chamomilla romana (chamomile) 1% pet. (Arnica montana); arnica 0.5% pet. (Taraxacum officinale); dandelion 2.5% pet. (Achillea millefolium); yarrow 1% pet. (Chrysanthemum cinerariae) folium; 1% pet. pyrethrum (Tanacetum vulgare); tansy 1% pet. (Tanacetum parthenium); feverfew flower 1% pet. (Dahlia sp.) 1% pet. (Tagetes sp.); marigold 1% pet.

26 (13 men and 13 women with the average age of 63.5 years) of the 97 patients had allergic response to SQL mix or Compositae extracts. SQL mix and Compositae extracts caused positive reaction in 15 patients of 26. 11 patients had a negative result to SQL mix but showed positive reaction to Compositae extracts. No one had a positive result to SQL mix but negative to Compositae extracts. From Compositae extract, positive reaction to dandelion was the most frequent. It was seen in 8 of the 11 SQL mix-negative patients and in 9 from 15 SQL-positive patients. SQL-positive patients had also visible reaction to Compositae extracts as tansy, yarrow, dandelion and fewerfew. The SQL-negative patients had mostly hand eczema and among them, positive reaction to dandelion occur most frequently (28). According to this study, SQL mix did not recognise 38% of Compositae-susceptible patients. This is why it is essential to test SQL-negative patients with Compositae extracts (28). A study from Department of Dermatology in Australia also shows that SQL mix cannot detect all Compositae-sensitive patients. In a survey, patients with assumed Compositae allergy were examined with the SQL mix and respective Compositae oleoresins. SQL mix

39 detected 35% examples of Compositae allergic reactions. In conclusion, it is not sufficient as a screening test. To detect Compositae allergy it is important to include the SQL mix and assumed plants or extracts (4).

4.4 DISCUSSION

Because of an increase use of plants as herbal medicines, in natural cosmetic and occupations that are daily exposed to the plants, occurrence to plant induced ACD is increasing. Until now, different studies have been made. Studies have been done among specific professions, on smaller population and other on bigger. Also the time of observation was different; from few days to some months and even years. One studies focused on persons that already have diagnosed dermatitis, others on the healthy population. The mean age of persons included in investigations was similar and all of them had to answer on questions about previous contact with plants. This variable information make us hard to estimate, which plants are the most harmful and which occupations are the most vulnerable. Anyway, these studies and case reports can give us some general data about harmful plants and allergens and can help us to estimate which of them cause the most ACD. We found out that plants vary from region to region and the content of allergen can differ among species, climate and geography. On the picture 1 we can see that the most ACD is caused after direct contact with the raw plants. Mostly mentioned plant families are Compositae, Jubulaceae, Alstroemeriaceae, Anacardiaceae, Proteaceae, Primulaceae, Araliaceae and Lamiaceae. These families represent plants that are found all over the world and can be also used as food, ornamental plants and home remedies. On the next two places are different occupations working with plants as are agricultural workers, workers in Alstroemeria companies in Netherlands, workers in bulb industry (bulb growers), and food making industry as are chefs, cooks (allergy to diallyl disulfide in Spain) and sandwich makers. They are exposed to the harmful plants for longer period and to higher concentration of allergen. Mostly mentioned families are Liliaceae, Alstroemeriaceae, Anacardiaceae, Rutaceae, Alliaceae, Cruciferae and Apiaceae. In these groups ACD mostly appear on hand and fingers (tulip fingers known among bulb growers and Alstroemeria workers). ACD from herbal cosmetic is also possible probably because of increased usage of plants in cosmetic. These plants are mostly known as week sensitizers

40 and normally do not causes skin reactions except in sensitive individuals. Plants mostly used in cosmetic are from Compositae and Lamiaceae family. More common is ACD from home made preparations as are tinctures, bandages or other remedies. This represents plants form Compositae family and also Lamiaceae and Caparaceae.

10 9 8 7 6 5

of plant families 4

3 2 1 Number Number 0

Picture 1: Number of plant families and their usage

In general, the most represented family that causes ACD is the family of Asteraceae/Compositae (see picture 2). This is probably because this family presents the worldwide plant family, and, as mentioned before, its plants are used as food, in cosmetic, and as medicinal herbs. Skin sensitization is caused by SQL. But allergenicity of the plant is not determined just with allergen content but also with its amount and contamination with other plant species. That shows us an example of chamomile. The chamomile from Chile and Argentina has larger amount of SQL anthecotulide as the European one. Some plants, as dandelion, can cause allergy after prolonged exposure to the allergen (like treating warts with plant juice or for feeding pets). Also dermatitis caused by great burdock was caused after a long use of the root oil. Others, like elecampane, contain strongly sensitizing allergens as are alantolactone and isoalantolactone, but reports of sensitization are rare. This is because of low content of an allergen in the plant. Arnica is known as a potential sensitizer especially among people who improperly dilute arnica tincture. Some plants, like tea tree, are used for many skin conditions and their sensitization potential is

41 weak. Reactions are probably due to inappropriate storage, which causes more powerful sensitizers as are peroxides, hydroperoxides, and also endoperoxides.

Anacardiaceae are the next plant family in which we have found more case reports. These plants are also quite widespread. They are found in South and North America, Asia and also South Africa. Although around 60% of North Americans seem to be sensitized to Toxicodendron spacies, the toxicodendron dermatitis is unknown in Europe. This family mostly represent trees, scrubs and vines. They cause skin reaction after direct contact (cleaning damaged limbs and pruning branches), airborne contact and also through cross- reactions (sensitization to Lithraea and Toxicodendron species). Like in the other species, the most exposed are outdoor occupations. Papules, edema and erythema appear on exposed areas of the skin but by contaminated fingers can be transferred on other parts of the body. Primulaceae family is also common cause of ACD. Its plants (Primula oblonica) are popular ornamental plants among housewife and retired persons who are daily in touch with these plants.

14 12 10 8 6 4 2 Number of of Number plants reported 0 Liliaceae Alliaceae Apiaceae Rutaceae Moraceae Cruciferae Araliaceae Lamiaceae Jubulaceae Solanaceae Proteaceae Compositae Primulaceae Ginkgoaceae Capparaceae Anacardiaceae

Alstroemeriaceae Picture 2: Frequent plant families that cause ACD

According our review (see picture 3), the most reported allergens that cause ACD are from group SQL. This group is mostly found in Compositae family, in Liliaceae and Alstroemeriaceae family as tulipalin A and also in Jubulaceae and Lamiaceae. In general,

42 plants of these families are used in cosmetic, as medicinal remedies, ornamental plants and in industry. On the second place are phenols and its derivates found in Anacardiaceae, Ginkgoaceae and Proteaceae.

Number of plant families plant of Number 1

Picture 3: Number of plant families and allergens

ACD differ from country to country. Lifestyle of habitants and health care system is also important. People from different tribes in Africa are more connected with the nature and also more familiar to the plants they are using and know which of them are harmful. On the other hand, healthcare system there is not that well developed as in Europe. They have lack of medicinal personnel, and people, which may have ACD, are not identified. That could be a reason why it is harder to find specific case reports from there. Through research study in South Africa, the most representative families that can cause ACD are Asteraceae, Solanaceae, Anardiaceae and Rutaceae. Chemical ICD is mostly caused by Euphorbiaceae, mechanical ICD by Fabaceae and Rutaceae, and mechanico-chemical ICD by Urticaceae.

We have found more information about plant allergies in Europe. Studies focus on different occupations, which have the most contact with plants; among Danish gardeners, in Northern Italy among housewife and florists who are handling Primula obconica,

Alstroemeria workers in Netherlands and others. The most vulnerable are also persons working in rural areas, agricultural workers, housewives, etc.

5 CONCLUSIONS

• Compositae/Asteraceae produces the most ACD. Also ACD from Anacardiaceae and Primulaceae is common.

• SQL are predominant allergens in Compositae plants. On the second place are phenol derivates.

• The lesions of ACD are mostly found on hand, finger tips, forearm, and can also be transferred on the face or other parts of the body.

• Papules, edema and erythema are the main signs of ACD.

• More vulnerable are persons who are daily in touch with the raw plants, as are agricultural workers, housewives, hobby gardeners, cooks, florists, etc.

• Some plants that cause ACD in America are unknown in Europe (Toxicodendron dermatitis).

• ACD appear after prolonged exposure to the plants or can be induced after cross- reaction with the plant with similar allergens.

• SQL mix cannot detect all Compositae positive patients.

• Beside SQL mix and Comp. mix, different parts of the plant (leaves, stems, flowers) can help to determine ACD.

6 REFERENCES

1. Miroddi M., Calapai G., Isola S., Minciullo P. L., Gangemi S.: Rosmarinus officinalis L. as cause of contact dermatitis. Allergol Immunopathol (madr). 2014; 42 (6): 616-619. 2. Modi G. M., Doherty C.B., Katta R., Orengo I. F.: Irritant Contact Dermatitis from Plants. American Contact Dermatitis Society 2009; 20 (2): 63-78. 3. Cabanillas M., Fernández-Redondo V., Toribio J.: Allergic contact dermatitis to plants in a Spanish dermatology department: a 7-year review. Contact Dermatitis 2006; 55: 84-91. 4. Gordon L. A.: Continuing medical education review: Compositae dermatitis. Australasian Journal of Dermatology 1999; 40: 123-130. 5. Rozas-Muñoz E., Lepoittevin J. P., Pujol R. M., Giménez-Arnau A.: Allergic Contact Dermatitis to Plants: Understanding the Chemistry will Help our Diagnostic Approach. Actas Dermosifiliográficas 2012; 103 (6): 456-477. 6. Otang W. M., Grierson D. S., Afolayan A. J.: A survey of plants responsible for causing allergic contact dermatitis in the Amathole Distric, Eastern Cape, South Africa. South African Journal of Botany 2015; 97: 32-39. 7. Wilfred M. Otang, Donald S. Grierson, Anthony J. Afolayan: A survey of plants responsible for causing irritant contact dermatitis in the Amathole district, Eastern Cape, South Africa. Journal of Ethnopharmacology 2014; 157: 274-284. 8. Lahti A.: Contact Urticaria to Plants, Clinics in Dermatology 1986; 4: 127-136. 9. Derraik J. G B, Rademaker M.: Phytophotodermatitis caused by contact with a fig tree (Ficus carica). The New Zealand Medical Journal 2007; 120: 1-5. 10. Paulsen E.: Contact sensitization from Compositae-containing herbal remedies and cosmetics. Contact Dermatitis 2002; 47: 189-198. 11. Aberer W.: Contact allergy and medicinal herbs. JDDG 2008; 6: 15-24. 12. F. van der Mai I. A., M. de Boer E., Bruynzeel D. P.: Contact dermatitis in Alstroemeria workers. Occup. Med. 1998; 48: 397- 404. 13. Goon A. J., Goh CL: Plant dermatitis: Asian perspective. Indian J Dermatol 2011; 56: 707-10. 14. Gladman A. C.: Toxicodendron Dermatitis: Poison Ivy, Oak, and Sumac. Wilderness and Environmental Medicine 2006; 17: 120-128.

15. Derraik J. GB, Rademaker M.: Allergic contact dermatitis from exposure to Gravillea robusta in New Zeland. Australasian Journal of Dermatology 2009; 50: 125-128. 16. Connolly M., Cune J.Mc., Dauncey E., Lovell C. R.: Primula oblonica – is contact allergy on the decline? Contact Dermatitis 2004; 51: 167-171. 17. Ozkol H. U., Calka O., Akdeniz N., Pinar S. M.: Phytodermatitis in Eastern Turkey: A Retrospective, Observational Study. American Contact Dermatitis Society 2014; 25: 140-146. 18. Reider N., Komericki P., Hausen B. M., Fritsch P., Aberer W.: The seamy side of natural medicines: contact sensitization to arnica (Arnica montana L.) and marigold (Calendula officinalis L.). Contact Dermatitis 2001; 45: 269-272. 19. Paulsen E., Otkjǣr A., Andersen K. E.: The coumarin herniarin as a sensitizer in German Chamomile [Chamomilla recututa (L.) Rauschert, Compositae]. Contact Dermatitis 2010; 62: 338-342. 20. Tabar A.I., Alvarez-Puebla M. J., Gomez B., Sanchez-Monge R., García B. E., Echechipia S., Olaguibel J. M. and Salcedo G.: Diversity of asparagus allergy: clinical and immunological features. Clin. Exp. Allergy 2004; 34: 131-136. 21. Alé S. I., Ferreira F., González G., Epstein W.: Allergic Contact Dermatitis Caused by Lithraea molleoides and Lithraea brasiliensis: Identification and Characterization of the Responsible Allergens. American Journal of Contact Dermatitis 1997; 8: 144-149. 22. Bongiorni L., Prodi A., Rui F., Belloni Fortina A., Corradin M. T., Larese Filon F.: Primin sensitization in north-eastern Italy: a temporal trend from 1996 to 2012. Contact Dermatitis 2015: 1-5. 23. Bordel-Gómez M. T., Miranda-Romero A.: Sensitivity to diallyl disulfide in a Spanish population. Contact Dermatitis 2008; 59: 125-126. 24. Lerbǣk A., Rastogi S. C., Menné T.: Allergic contact dermatitis from allyl isothiocyanate in a Danish cohort of 259 selected patients. Contact Dermatitis 2004; 51: 79-83. 25. Gomes J., Pereira T., Vilarinho C., Duarte M. L., Brito C.: Contact dermatitis due to Centella asiatica. Contact Dermatitis 2010; 62: 54-55.

26. Paulsen E., Petersen T. H., Fretté X. C., Andersen K. E., Christensen L. P.: Systemic allergic dermatitis caused by Apiaceae root vagetables. Contact Dermatitis 2013; 70: 98-103. 27. Paulsen E., Christensen L. P., Andersen K. E.: Tomato contact dermatitis. Contact Dermatitis 2012; 67: 321-327. 28. Goulden V., Wilkinson S. M.: Patch testing for Compositae allergy. British Journal of Dermatology 1998; 138: 1018-1021. 29. Paulsen E., Andersen K. E.: Patch testing with constituents of Compositae mixes. Contact Dermatitis 2012; 66: 241-246. 30. Breqnbak D., Menné T., Johansen JD.: Airborne contact dermatitis caused by common ivy (Hedera helix L. ssp. Helix). Contact Dermatitis 2015; 72: 243-244. 31. Electronic source: https://en.wikipedia.org/wiki/Allium (23.6. 2015) 32. Schloemer J. A., Zirwas M., Burkhart C. G.: Airborne contact dermatitis: common causes in the USA. International Journal of Dermatology 2015; 54: 271–274. 33. Mayer E., Gescheidt-Shoshany H., Weltfriend S.: Allergic contact dermatitis caused by Salvia officinalis extract. Contact Dermatitis; 64: 237–244. 34. Corazza M., Miscioscia R., Lauriola M. M., Poli Ferruccio, Virgili A.: Allergic contact dermatitis because of Cinereria hybrid in a keen gardener housewife. Contact Dermatits 2008; 58: 309-310. 35. Tavares B., Loureiro G., Pereira C., Chieira C.: Home gardening may be a risk factor for contact dermatitis to Alstroemeria. Allergol et Immunopathol 2006; 34 (2): 73-75. 36. http://dermnetnz.org/dermatitis/contact-allergy.html (dostopno 17. 10. 2015) 37. http://www.dermnetnz.org/reactions/contact-urticaria.html (dostopno 17. 10. 2015)

7 APPENDIX

Appendix 1: Plants responsible for causing allergic contact dermatitis in South Africa (6)

Family Allergen Scientific name Local name Amaryllidaceae Diallyl disulfide Allium sativum L. Garlic Anacardiaceae Heptadecyl catechols Smodingium argutum E. Anacardiaceae Urushiol Mangifera indica L. Mango Anacardiaceae Urushiol Anacardium occidentale L. Cashew nut tree Apiaceae Falcarinol Daucus carota L. Carrot Asteraceae SQL, lactucin, lactucopicrin Lactuca sativa L. Lettuce Asteraceae SQL Artemisia afra Asteraceae SQL Arctotheca calendula L. Asteraceae SQL Erigeron bonariensis L. Asthmaweed Asteraceae Thiophenes, hydroxytremetone, 5-(3-buten-

Tagetes minuta L. 1-ynyl)-2,2'-bithiophene, α-terthienyl Asteraceae SQL, taraxanic acid Taraxacum campylodes Asteraceae SQL, nobilin Chamaemelum nobile L. Sweet chamomile Brassicaceae Isothiocyanate Brassica oleracea L. Cabbage Brassicaceae Isothiocyanate Brassica oleracea L. Cauliflower Brassicaceae Falcarinol Apium graveolens L. Celery Capparaceae Phytosterol, 24-ethylcholestan-5-en-3-ol Capparis tomentosa Lam. Caricaceae Isothiocyanates Carica papaya Euphorbiaceae Prohevein Hevea brasilliensis Musaceae ND Musa paradisiaca L. Banana Rutaceae Geraniol, citral, D-limonene Citrus limon L. Lemon Rutaceae Geraniol, citral, D-limonene Citrus sinensis L. orange Solanaceae Patatin Solanum tuberosum L. Potato

Solanaceae Patatin Solanum lycopersicum L. Tomato

Appendix 2: An alphabetical list of plants that can cause urticarial responses (8)

Scientific Name Common Name Actinida chinensis Kiwi Algae Agave americana American aloe Allium cepa Onion Allium Sativum Garlic Allium schoenoprasum Chrives Apium graveolens Celery Betula verrucosa Birch Bertholletia excesla Brazil nut tree Blumea gariepina Brassica oleracea 'capitata' Cabbage Brassica oleracea 'botrytis' Cauliflower Carum carvi Caraway Cichorium endivia Endive Cinnamomum Cinnamon Cirsium Thistle Citrus limon Lemon Citrus paradisi Grapefruit Citrus sinensis Sweet orange Cnidoscolus stimulosus Bull nettle Coffea arabica Coffee Coriandrum sativum Coriander Cornus sanguinea Bloodtwig dogwood Cotoneaster dammeri

Cotoneaster microphylla Crataegus monogyna Singleseed hawthorn Chrysanthemum cinerariifolium Cucumis melo Melon Cucumis sativus Cucumber Dalbergia latifolia Indian rosewood Ductus carota Carrot Eucalyptus Gramineae Grass family Havea brasiliensis Rubber tree Humulus lupulus Hop Iris Lactuca sativa Lettuce Laportea Nettle Larix decidua Larch Lawsonia inermis Henna Lichens Linum usitatissimum Flaxseed Lycoperisicon lycopersicum Tomato Lyngbya majuscula Malus Apple Mangifera indica Mango Medicago sativa Alfalfa, lucerne Monstera deliciosa Ceriman Mucuna pruriens Buffalo bean Musa Banana Myroxylon balsamum Balsam of Peru Pastinaca sativa Parsnip Petroselinum sativum Parsley Prophocarpus tetragonolobus Winged bean Prunus persica Apricot Prunus domestica Plum Prunus persica Peach

Pyrus communis Pear Ricinus communis Castor oil plant Sarcostemna viminale Shorea Philippine red mahogany Sinapis Mustard Solanum tuberosum Potato Tectona grandis Teak Terminalia superba Limba tree Thuja plicata Western red cedar Trifolium pratense Red clover Triplochiton scleroxylon Obeche, abachi Triticum aestivum Wheat Tulipa Tulip Urera Urtica Nettle Verbesina encelioides Golden crownbeard Xanthium pungens Zea mays Corn, maize