T he thin-layer rapid use epicutaneous (T.R.U.E) Test of23 common allergens is a valuable, first-line screeningtool used by many dermatologists. Although the test

focuses on common allergens, frequent questions have arisenfrom colleagues and patients as to where a specific allergen isderived or what products patients should avoid. With this inmind, this column was developed to provide educational infor-mation about the T.R.U.E.Test allergens.

A rich, interesting history accompanies each of the 23 aller-gens, and understanding these historic perspectives can help to

better educate patients. Each columnwill also highlight appropriate productsthat patients should avoid when theyare allergic to a specific allergen.

CONTACT DERMATIDESAllergic contact dermatitis is an

important disease with high impact onpatient morbidity and economics.

ACD represents a T-helper cell Type 1(Th1) dependent delayed-type (TypeIV) hypersensitivity reaction. The insti-gating exogenous antigens are primarilysmall lipophilic chemicals (haptens) witha molecular weight less than 500 Da.1

On direct antigen exposure to theskin or mucosa, an immunologic cascadeis initiated that includes cytokines, i.e.,interleukin 2 (IL-2) and interferongamma (IFN-gamma), T cells andLangerhan cells. This complex interac-tion leads to the clinical picture of ACD.

The contact dermatides includeallergic contact dermatitis, irritant con-tact dermatitis and contact urticaria.

Irritant contact dermatitis, the mostcommon form, accounts for approxi-mately 80% of environmental-occupa-tional based dermatoses.

Contact urticaria (wheal and flarereaction) represents an IgE and mastcell-mediated immediate-type hyper-sensitivity reaction that can lead to ana-phylaxis, the foremost example of thiswould be latex protein hypersensitivity.

While this is beyond the scope of thissection, we acknowledge this form ofhypersensitivity due to the severity ofthe potential reactions and direct thereader to key sources.1,2

The primary focus of this section isto highlight the educational compo-nent of allergic contact dermatitis.

CLINICAL ILLUSTRATIONWe report a case of a professional

painter with an avid outdoor basketballhobby. He presented to the ContactDermatitis Clinic at the University ofMiami with severe hand dermatitis,which he attributed to his latex paintproducts. He related that despite wear-ing protective rubber gloves, his handdermatitis had continued to worsen.Allergen-specific IgE antibody test(RAST) for latex demonstrated a nor-mal IgE level.

26 OCTOBER 2005 SKIN & AGING

Focus on T.R.U.E. Test Allergen #15:

CarbamatesBY SHARON E. JACOB, M.D., AND

L. MAGALY VILLAFRADEZ-DIAZ, M.D.

ALLERGENFocus

This expert provides an enlightening, practical look at common allergensso that you can better educate your patients about the basis for theirallergy and what products they need to avoid.

Sharon E. Jacob, M.D

THE HISTORY OF RUBBER ANDCARBAMATES

On Columbus’s second voyage toHaiti in 1493, he observed natives play-ing with high bouncing balls, a note-worthy discovery that improved theenjoyment of ball games. He learnedthat the natives made these balls fromprocured tree sap which was then curedover the smoke of palm nuts.3 Rubbertrees, especially Hevea brasiliensis, pro-duce a milky fluid from the lactiferouscells: the latex.The natural rubber latex(NRL) has a high composition of poly-cis-isoprene, an organic polymer thatconfers strength and elasticity.4 It alsocontains a variety of proteins, such ashevamine, hevein and rubber elonga-tion factor among the more than 10Hevea brasiliensis allergens known toinitiate type I (IgE-mediated) whealand flare (hives) and anaphylactic reac-tions.5

Early Mesoamerican cultures(Mayans) found that rubber sap mixedwith morning glory vine juice wouldbecome more durable with increasedelasticity.6 The natives of the Amazonvalley made shoes of this gum called“caoutchouc,” and Spanish soldiers hadspread their cloaks with it to water-proof them.

Caoutchouc was derived from theIndian word “cahuchu” meaning“weeping wood”. It is the root of thecommonly used Spanish word for rub-ber, “Caucho”.3

The modern world is highly depend-ent on rubber and rubberized products.Indonesia, Malaysia,Thailand and SouthAmerica are the current-day main sup-pliers of freshly harvested latex.

To enable mass transport to world-wide factories, the harvested latex istreated with ammonia preservatives toprevent autocoagulation and bacterialcontamination.4,6

At the factories, the long polymerchains are broken by mastication(applying mechanical forces to the rub-ber with rollers or rotating blades) toallow for further organic chemicalcompounding with antioxidants, accel-erators and vulcanizing additives.7

The accelerators, such as carbachemicals (zinc-dithiocarbamates anddiphenylguanidine) are added to speed

the cross-linking of the natural rubberlatex particles for proper alignment inproducing a heat-stable, elastic, strong,and durable product, also known asvulcanization.

The compounded rubber is thensheeted, extruded into the desired shapesand molded.7 Finally, once the vulcan-ized rubber is dried and rinsed, it is dry-

lubricated with cornstarch or talc pow-ders to bind residual latex proteins.4,8

Charles Goodyear first made theobservation that rubber mixed withsulphur produced an elastic and weath-erproof compound, when these ingre-dients were accidentally dropped onto ahot stove. Ultimately, he patented theprocess for vulcanized rubber in1844.3,7 The process was subsequentlyrefined, and by the 1920s the role ofaccelerators was defined. The sulphuratoms, within the dithiocarbamates,were determined to participate in thecross-linking of the natural rubber latexmolecules in the vulcanized endprod-uct with definitive improvement of thefinal physical properties of the rubber.

The carbamate acceleration chemi-cals are present in almost every rubberproduct, in addition to medicinal andagricultural uses. (See Table 1.)4,8

Ironically, this highly used chemical wasonce a royalty restricted product.Carbamates were originally extractedfrom the Guinean Gulf calabar bean(Physostigma venenosum) grown near themouth of the Old Calabar River.

OCTOBER 2005 SKIN & AGING 27

This patient is suffering from a contact dermatitis to carbamates.

EARLY MESOAMERICAN

CULTURES (MAYANS)

HAD DISCOVERED

THAT RUBBER SAP MIXED

WITH MORNING GLORY

VINE JUICE WOULD

BECOME MORE DURABLE

WITH INCREASED

ELASTICITY.

This exotic West African plant, calledDoomsday Plant by the natives, was origi-nally an “ordeal poison”. People suspectedof committing a crime were obligated toswallow an infusion of the seeds.

According to the native ordeal test,depending on the cholinomimeticeffect produced on the accused, a ver-dict was given. A guilty verdict wasplaced if the imbiber passed away, des-ignating them to a life of servitude.Theaccused were found innocent and liber-ated, if the seed was vomited.9 To con-secrate this royal crime judgment, thenative king ordered massive destructionof community crops of the ordeal seed.

This monopolization of the calabarbean plant barred early attempts atbotanical classification.9 The classifica-tion of the calabar seed, however, final-ly became possible when a British mis-sioner in Africa sent dark brown kid-ney-shaped seeds back to Edinburgh,for identification. Of medical historicalnote, these (Physostigma venenosum)seeds also became the source of a valu-able alkaloid, Physostigmine (aka eser-

ine). In 1863, Dr.Argyll Robertson firstdescribed the ophthalmologic mioticeffect of this alkaloid, which is still isuse today for treating glaucoma.9

On another note, carbamates areimportant agricultural fungicides andare an occupational hazard for pesticidehandlers, field workers and gardeners.10

Carbamates, as reversible inhibitors ofacetylcholinesterases, are among themost popular pesticides for home use,both indoors and for lawns and gardens.

Carbaryl is the best-known and mostapplied carbamate pesticide. Commer-cially, the fungicide Maneb (a dithio-carbamate) is used in the Midwest toprevent ginseng weed from producingpotato blight11 and related compoundssuch as Oxamyl, among others, are usedby tobacco growers in North Carolina.Contact dermatitis to carbamate fungi-cides is well known.4,8,10-12

An important note regarding theallergenicity of carbamate compoundswas the discovery that these compoundscan become greater antigens whenexposed to common household bleach.

In 1975, Jordan and Bourlas12 report-ed the bleached rubber syndrome bywhich exposure of underwear elastic tohypochlorite (bleach) caused newchemical byproducts. For example, therubber accelerator zinc dibenzyldithio-carbamate (ZDC) became N,N-diben-zylcarbamyl chloride when exposed tohypochlorite. This change in configu-ration proved to make a potent aller-gen that undoubtedly caused allergicdermatitis in the exposed subjects.

TESTING FOR CARBAMATE SENSITIVITYPatch testing for Carbamate allergy

can be accomplished with the T.R.U.E.test [site # 15].The T.R.U.E test recog-nizes only 23 of the more than 3,700possible allergens that can cause allergiccontact dermatitis. Therefore, it needsto be known that this test is a merescreening tool that could be used bygeneral dermatologists everywhere.

Unfortunately, we are faced withimportant workforce economics. Thereare roughly 14,500 U.S. members of theAmerican Academy of Dermatol-ogyand many of these dermatologists serveremote locations. In contrast, theAllergic Contact Dermatitis Society(www.contactderm.org) has about 450members. This ratio translates to onecomprehensive patch tester to every 33dermatologists, if the distribution wasevenly cast, which it isn’t.

Thus, in geographic areas with limit-ed access, the T.R.U.E. test should berecognized and utilized as a basic andnecessary screening tool and its limita-tions understood as such.

The American Contact DermatitisSociety (ACDS) recognizes the needfor comprehensive patch testing andpatch test support for general derma-tologists and patients suffering fromallergic contact dermatitis.

The ACDS is actively engaged inmaintaining access to this important test-ing modality by training new providers(ACDS-Fujisawa mentorship program)and providing patient education materialsthrough the Contact Allergen Replace-ment Database (CARD).

THE VALUE OF THIS PATIENT CASEOur patient with allergy to carba-

mates underscores the importance of

28 OCTOBER 2005 SKIN & AGING

FREQUENT USESCondoms, cosmetic applicators, diaphragms, pacifiers, pillows and mattresses, rubberized toothbrush handles, shoe soles, tires, underwear.

MEDICAL EQUIPMENTBandages, blood pressure cuffs, dental dams, disposable gloves, intravenous ports, microscopeeyepieces, safety goggles, stethoscopes, surgical masks, syringe plungers, thiuram (anti-abusedrug), tourniquets.

LAWN AND GARDEN PRODUCTSCOMMERCIAL: Aldicarb, Mancozeb, Methomyl.HOUSEHOLD: Bendiocarb (Ficam), Propoxur (Baygon).

OFFICE SUPPLIESAdhesive tape, carpet backing, electrical cords, envelopes, erasers, glue, mouse pads, pen grips, rubber bands, stamps.

SPORTS SUPPLIESHandgrips, rubber balls, shoes, swimwear, swimming goggles and caps.

PRODUCTS CONTAINING CARBAMATESTABLE I

Taro (Lustra Ultra) Ad

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appropriate patch testing and subsequent patient educa-tion.The presence of carbamates/rubber in such a widevariety of products makes it an especially common, dif-ficult to avoid, contactant in daily activities. Rubberproducts can be tested for carbamate content by extrac-tion with a methylisobutylketone and cuprous acetatesolution (a positive reaction turns olive green).

To the greatest extent possible, we advised the patientto remove rubber products from his daily routine,including protective rubber gloves, rubberized tooth-brush, paint roller gripper and the basketball.With thesechanges, the patient dramatically improved, consistentwith the fact that the mainstay of treatment for allergiccontact dermatitis is avoidance. n

Dr. Jacob is the Director of the Contact Dermatitis Clinic atthe University of Miami. She’s also an Assistant ClinicalProfessor in the Department of Dermatology and CutaneousSurgery.

Dr.Villafradez-Diaz is a dermatologic surgery fellow at theUniversity of Miami.

References:

1. Belsito DV. Eczematous Dermatitis. In IM Freedberg et al., eds.,Fitzpatrick’s Dermatology in General Medicine, 5th Ed., (New York,McGraw-Hill. 1999: 1531-1532.

2.Valks R, Conde-Salazar L, Cuevas M. Allergic contact urticariafrom natural rubber latex in healthcare and non-healthcare workers.Contact Dermatitis. 2004; 50(4): 222-4.

3.Warshaw E. Latex allergy. Skinmed. Nov-Dec 2003; 2(6):359-66.

4.Thompson H.The early history of rubber available athttp://inventors.about.com/cs/inventorsalphabet/a/rubber_2.htm.

5. Behrman AJ, Howarth M, Louden M. Latex allergy. eMedicine.March 2005. Available at: http://www.emedicine.com/emerg/topic814.htm.

6.Wagner S, Brightener H. Hevea brasiliensis latex allergens:Current panel and clinical relevance. Int Arch Allergy Immunol 2005;136:90-97.

7. Ownby DR. A history of latex allergy. J Allergy Clin Immunol.2002; 110:s27-s32.

8.The International Rubber Research and Development Board(IRRDB). Available at: http://www.irrdb.com/IRRDB/NaturalRubber/History/History2.htm.

9. Ngan V. Rubber accelerator contact allergy. DermNet NZ.May 2005. Available at: http://dermnetnz.org/dermatitis/rubber-antioxidant-allergy.htlm.

10. Lloyd JU.Physostigma venenosum (Calabar) in The WesternDruggist. Chicago, O. 1897. Available at www.swsbm.com/ManualsOther/Physostigma-Lloyd.PDF

11. Cope WG, Avery RC, Storm JF et al. Pesticides and humanhealth. Available at Http://www.cals.ncsu.edu/toxicology/extension_pgm/pdfs/Growers1.pdf.

12. Rietschel RL, Fowler JF. Fisher’s Contact Dermatitis. LippincottWilliams & Wilkins 2001.

13. Jordan WP, Bourlas MC. Allergic contact dermatitis to underwearelastic. Chemically transformed by laundry bleach. Arch Derm. 1975;111:593-595.

Disclosure:The authors have no conflict of interest with any subject matter discussed in this month’s column.

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