this is beyond the scope of this section, we acknowledge this form of hypersen- sitivity due to the severity of the poten- tial reactions and direct the reader to key sources.1,2 Focus Allergic contact dermatitis represents a ALLERGEN T helper cell Type 1 (Th1) dependent delayed-type (Type IV) hypersensitivity reaction. The instigating exogenous antigens are primarily small lipophilic chemicals (haptens) with a molecular weight less than 500 Da. Unlike other haptens, metal antigens do not covalently bind to carrier pro- teins; instead they complex with pro- teins similar to the binding of cobalt 1 and vitamin B12. On direct antigen exposure to the skin or mucosa, an immunologic cas- cade is initiated that includes cytokines, i.e. interleukin 2 (IL-2) and interferon gamma (IFN-γ), T cells and Langerhan cells. This complex interaction leads to the clinical picture of ACD, an impor- tant disease with high impact both in terms of patient morbidity and eco- nomics. The primary focus of this section is to highlight the educational component of allergic contact dermatitis.

CLINICAL ILLUSTRATION A woman presented to the University of Miami Contact Dermatitis Clinic Focus on T.R.U.E. Test Allergens #23: with a 6-year history of generalized pruritus and inflammation of her treated unsuccessfully with antihista- mines and topical corticosteroids. Of note, she also had a small with a papular reaction in the area of Thimerosal red pigmentation. She did not know the ink constituents. BY SHARON E. JACOB, M.D., AND RAN HUO, B.S. THE HISTORY OF THIMEROSAL Thimerosal, C9H9HgNaO2S, is a llergic contact dermatitis (ACD) is an important disease mercuric derivative of thiosalicyclic with high impact both in terms of patient morbidity and acid that goes by many names (see Table A economics. The contact dermatitides include allergic 1). It has been used as a disinfectant contact dermatitis, irritant contact dermatitis and contact (Merthiolate) and a preservative in urticaria. some vaccines, , tattoo inks, Irritant contact dermatitis, the most common form, accounts eye drops and contact lens solutions. for approximately 80% of environmental- and occupational- The FDA banned the sale of topical- based dermatoses. ly applied thimerosal antibiotics in the Contact urticaria (wheal and flare reaction) represents an IgE 1980s due to severe, even crippling, and mast cell-mediated immediate-type hypersensitivity reaction that can lead to adverse skin reactions in sensitive indi- anaphylaxis; the foremost example of this would be latex hypersensitivity.Although viduals. And, in July 1999, the U.S.

16 JANUARY 2006 SKIN & AGING TABLE 1 chosis. Because of the major neurologi- ported “Lewis and Clark latrines” COMMON SYNONYMS OF THIMEROSAL cal risk mercury poses to the unborn around the country have uncovered the fetus, pregnant women are cautioned to locations of their campsites.7 • Ethyl (2-mercaptobenzoato-S) limit the consumption of high mercu- Mercury is a bioaccumulative toxin mercury sodium salt ry-containing fish to just once a month. that is readily absorbed through the • Mercurochrome Cutaneous changes may include con- skin, respiratory and gastrointestinal sys- 8 • Mercurothiolate tact dermatitis, burning of the , grey tems. Methyl mercury in the environ- or blue-black discoloration, flush- ment works its way up the food chain in • Merfamin ing, erythroderma, purpura and gin- fish through bioaccumulation, reaching • Merthiolate givostomatitis.5 especially high levels in larger species • Mertorgan such as shark (0.99 parts per million, or MERCURY IN THE ENVIRONMENT ppm), swordfish (0.97 ppm), and tuna • Merzonin Mercury pollution in the environ- (0.38 ppm). • Sodium ethylmercurithiosalicylate ment has increased threefold since the FDA toxicologists recommend limit- • Thiomersal industrial revolution, with soil deposi- ing the consumption of shark and • Thiomersalan tion rates ranging from 5 to swordfish to 7 ounces (one serving) a 15 µg/m2/year.6 week, and the consumption of fresh • Thiomersalate The major sources of environmental tuna to 14 ounces a week (canned tuna • [(o-carboxyphenyl)thio] Ethylmercury sodium salt mercury are coal-fired power plants, has around half the methyl mercury metal smelting, gold production, and content of fresh tuna). Other animals that may accumulate mercury include sea birds (that feed on mercury contam- Department of Health mandated the inated fish). reduction of thimerosal in routine pedi- The U.S. Environmental Protection atric vaccines. Agency (EPA) limit for mercury con- In 2004, California and Iowa passed THE LEWIS AND CLARK tent in tap water is 2 parts per billion bans of mercury in all vaccinations, and (ppb), while the limit for cosmetics is 65 seven other states have similar legisla- PIONEERS WERE ppm (21CFR700.13).The average daily tion in progress.3 KNOWN TO INGEST mercury exposure from tap water and The main concern with thimerosal air in the general population is a thou- involves its metabolite — ethyl mercu- “THUNDERCLAPPERS” sand-fold less than that from seafood ry.Hat makers, or “hatters” in the 1800s intake.9 were notorious for suffering from (PILLS NEARLY No correlations have been published dementias due to the mercury nitrate 60% CONCENTRATED regarding mercury content in tap water used in felt processing. This mercury- and allergic contact dermatitis. associated dementia in felt workers was MERCURY) FOR the inspiration for the Mad Hatter in HOTLY DEBATED LINK Lewis Carroll’s Alice in Wonderland and GASTROINTESTINAL Just how similar the effects of ethyl the origin of the phrase “mad as a hat- AILMENTS. mercury (from thimerosal) and methyl ter”. The Mad Hatter’s disease, also mercury are on the human body is the known as erythrism, includes a constel- subject of much debate, with research lation of dementia, stomatitis, muscle suggesting that ethyl mercury stays in spasm, tremor and skin rashes.4 the body for a shorter period of time The ethyl mercury from thimerosal is and is generally less harmful. chemically similar to methyl mercury, the disposal (storing in landfills, inciner- Research is underway at the National which is 5 to 20 times as toxic as inor- ating) of mercury containing products Institutes of Health to determine the ganic mercury in its effects on the such as batteries, fluorescent bulbs and safety guidelines for thimerosal in the human central nervous and endocrine thermometers. hotly debated questionable link systems. Of historical interest, the persistence between thimerosal and the develop- Acute or chronic exposure to organ- of mercury in the soil allowed archeol- ment of childhood neurological prob- ic and inorganic mercury can result in ogists studying the Lewis and Clark lems, such as autism.10-13 renal, neurologic and dermal toxicity. expedition insight into the trail route. While most patients do not experi- Neurologic and psychiatric sequelae During their travels, the Lewis and ence an immediate allergic reaction to include tremor, muscle weakness, Clark pioneers were known to ingest thimerosal-containing intramuscular peripheral neuropathy, metallic taste, “Thunderclappers” (pills nearly 60% vaccines, the potential remains for hypersalivation, memory loss, ery- concentrated mercury) for gastrointesti- delayed hypersensitivity and toxic sys- thrism, depression, anxiety and psy- nal ailments. Traces of mercury in pur- temic effects.

JANUARY 2006 SKIN & AGING 17 TABLE 2 gens are often used in combination PRODUCTS CONTAINING THIMEROSAL/MERCURY with one another in products and co- sensitization occurs.16 ANTIBIOTICS FOR THE EYE Cortisporin Ophthalmic Suspension; Thimerosal-sensitive patients can Neosporin Ophthalmic Solution either be allergic to the mercuric moi- ety (most common) or the thiosalicylic CONTACT LENS SOLUTION Bausch & Lomb Sterile Preserved Saline Solution, Allergan acid moiety (these patients are advised Hydrocare, Advanced Medical Optics LC-65, Ocufen to avoid piroxicam, which also contains this moiety).17,18 TOPICAL MEDICATIONS, Mercurochrome (banned in the United States, Cinnabar (mercuric sulfide) used in ANTI-FUNGALS, ANTISEPTIC SPRAYS but used in other countries as antiseptic), red tattoo inks can lead to allergic reac- Merchromine tions and scarring.Tsuruta et al. report- ed a case of a 40-year-old Japanese man HORMONE INJECTIONS Testaqua, Testamone with a red tattoo who developed a NASAL PREPARATIONS Nasal Moist AF; Neo-Synephrine Pediatric Formula, Mild whole-body rash after eating 250 g of raw swordfish and alfonsino.19 In this Formula, Regular Strength, and Extra Strength Nasal Spray case the mercuric tattoo pigments EAR PREPARATIONS Coly-mycin S Otic; Cortisporin Otic Suspension; caused the initial sensitization to mer- Pediotic Suspension cury in the patient, producing a delayed hypersensitivity reaction. COSMETICS, BLEACHING CREAMS L’Oreal Miracle Wear Mascara, Stagelight Mascara, Miss Key Subsequent exposure of the patient to Whitening Cream, Crema Santa, Dermaline Cream, Crema de mercury-containing products either Belleza (all banned in the United States, but still being sold)21 through ingestion/inhalation/injection (mercury vapor, mercury-laden fish, VACCINES Engerix-B, FluShield and Fluzone, Hep-B-Gammagee, HyperHEP, vaccines, toxoids, amalgam dental HyperTET Tetanus and diphtheria toxoids, Menactra, Menomune, fillings) or direct contact (mercury- Recombivax HB containing creams, contact lens solution) precipitated the allergic contact Cinnabar (mercuric sulfide) dermatitis. While the ink compositions that are used in and permanent makeup are subject to FDA regulation, this has THIMEROSAL USE IN PRODUCTS The increased incidence in cooks and not been enforced. Importantly, no ink In addition to vaccines and healthcare workers is related to the is approved for injection into the skin, antitoxins, thimerosal is also used as increased prevalence of vaccinations which is what entails the actual practice a preservative in cosmetics, such as associated with these professions. of tattooing.20 Further compounding makeup removers, eye , In addition, people allergic to the difficulty in regulation is that man- mascaras and bleaching creams14 thimerosal are more likely to be allergic ufacturers of inks and pigments are not (see Table 2). to neomycin, bacitracin and tixocortol required to reveal the contents, since It is found in soap-free , pivalate, due to the fact that these aller- the information is proprietary.Inks vary nose/eye/eardrops, topical medications, anti-fungals, antiseptic sprays, contact lens solutions, hormonal injections and TABLE 3 tattoo inks.8 QUESTIONS TO ELICIT MERCURY EXPOSURE RISK Tosti et al. reported patients who had follicular allergic contact conjunctivitis DOES/DID THE PATIENT: induced by thimerosal-containing eye • work in the chemistry industry or a laboratory? drops.15 • have mercury fillings (dental amalgam) or work in a dentist’s office? WHO IS AFFECTED? Demographically,thimerosal is • have a mercury thermometer at home or any recent accidents involving mercury thermometers? more commonly found among women, • wear contacts (contact lens solution)? healthcare workers and cooks. The increased incidence of thimeros- • have any meals containing swordfish/alfonsino/fresh tuna/shark associated with the breakout? al allergy in women may be explained • use any cosmetic products containing thimerosal/mercury? by the presence of the compound in certain eye cosmetics. • recently have a vaccination or tetanus shot?

18 JANUARY 2006 SKIN & AGING 6. United States Environmental Protection Agency. by manufacturer, even among like- too art, and the potential for system- Mercury Study Report to Congress. EPA-452/R- colored pigments. atized contact dermatitis in individuals 97-005. December 1997. With the recent growth in popularity with red tattoos. I 7.“Doctor” Lewis’Thunderclappers. Smithsonian of tattoos, the FDA is taking a closer took Magazine. June 2004. at related safety questions regarding Dr. Jacob is the Director of the Contact adverse reactions to tattoo colors.21 Dermatitis Clinic at the University of 8. National Poisons Information Service Centre (United Kingdom) – Entry: Mercury. Miami. She’s also an Assistant Clinical TESTING FOR THIMEROSAL SENSITIVITY Professor in the Department of Dermatology 9. U.S. Food and Drug Administration. Mercury In Patch testing for thimerosal allergy and Cutaneous Surgery. Fish: Cause For Concern? FDA Consumer maga- zine. September 1994. can be accomplished with the thin-layer rapid-use epicutaneous (T.R.U.E.) test Ran Huo is a second-year medical student 10. Hviid A, Stellfeld M,Wohlfahrt J, Melbye M. Association between thimerosal-containing vaccine (site #23). at the University of Miami. and autism. JAMA. 2003 Oct 1;290(13):1763-6. The T.R.U.E. test is the commercial- ly available, globally used, allergen 11.Waly M, Olteanu H, Banerjee R, Choi SW, Mason JB, Parker BS, Sukumar S, Shim S, Sharma screening system. While it is A, Benzecry JM, Power-Charnitsky VA, widely used, the discrepancy in allergen Deth RC.Activation of methionine synthase prevalence and uncertain relevance has by insulin-like growth factor-1 and dopamine: led to scrutiny of its utility. The a target for neurodevelopmental toxins and T.R.U.E test contains 23 allergens and thimerosal. Mol Psychiatry. 2004 Apr;9(4):358-70 one negative control. At best, this test WITH THE RECENT 12. Geier DA, Geier MR.A two-phased is a minimum screening tool, as it population epidemiological study of the tests only 23 of the more than 3,700 safety of thimerosal-containing vaccines: a GROWTH IN POPULARITY follow-up analysis. Med Sci Monit. 2005 possible allergens that can cause allergic Apr;11(4):CR160-70 contact dermatitis. OF TATTOOS, 13. Madi A. Being on the track of thimerosal. Krob et al. recently demonstrated THE FDA HAS BEGUN Review. Acta Microbiol Immunol Hung. through meta-analytic techniques 2005;52(1):95-103 that nickel, thimerosal, cobalt, fragrance TAKING A CLOSER LOOK 14. 21. Engler DE. Mercury “bleaching” creams. and balsam of Peru are the most J Am Acad Dermatol 2005; June 52(6):1113-4. prevalent allergens detected by the AT RELATED SAFETY T.R.U.E. test.They noted that a signif- 15.Tosti A,Tosti G.Thimerosal: a hidden allergen QUESTIONS REGARDING in ophthalmology. Contact Dermatitis. 1988 icant number of relevant allergens, not May;18(5):268-73. present on the T.R.U.E. test, would ADVERSE REACTIONS 16. Suneja T, Belsito DV.Thimerosal in the potentially be missed by this screening detection of clinically relevant allergic contact 21 TO TATTOO COLORS. tool alone. reactions. J Am Acad Dermatol 2001;45:23-7. 17. Goncalo M, Figueiredo A, Goncalo S. THE VALUE OF THIS PATIENT CASE Hypersensitivity to thimerosal: the sensitizing moi- Our patient tested positive for ety. Contact Dermatitis. 1996 Mar;34(3):201-3. thimerosal.The patient deferred surgical 18. de la Cuadra J. [Cutaneous sensitivity to excision of her red tattoo. Thus, we mercury and its compounds]. Ann Dermatol treated the papular reaction in the tat- Venereol. 1993;120(1):37-42. too with topical corticosteroids and 19.Tsuruta D, Sowa J, Higashi N, Kobayashi H, implemented a strict avoidance regi- References: Ishii M.A red tattoo and a swordfish supper. men, including substitution of mercury- Lancet. 2004 Aug 21-27;364(9435):730. free personal products and a low mer- 1. Cohen DE, Kaufmann JM. Hypersensitivity reactions to products and devices in . 20. U.S. Food and Drug Administration.Tattoos cury diet. Notably,her edema and Facial Plast Surg Clin North Am 2003;11(2):253-65. and Permanent Makeup. Office of Cosmetics and pruritus dramatically improved. Colors Fact Sheet. July 1, 2004. 2.Valks R, Conde-Salazar L, Cuevas M.Allergic Once an allergen is identified, patient contact urticaria from natural rubber latex in 21. Krob HA, Fleischer AB Jr, D'Agostino R Jr, education on allergen avoidance is of healthcare and non-healthcare workers. Haverstock CL, Feldman S. Prevalence and rele- the utmost importance, as the mainstay Contact Dermatitis 2004; 50(4): 222-4. vance of contact dermatitis allergens: a meta-analy- of treatment for allergic contact der- sis of 15 years of published T.R.U.E. test data. J Am 3. Environmental Working Group.“EWG Report Acad Dermatol. 2004 September; 51(3):349-53. matitis is lowering the exposure dose to – Autism”. December 13, 2004. the allergen.The first step in avoidance 4. O'Carroll RE, Masterton G, Dougall N, Ebmeier is the knowledge of what not to use. KP, Goodwin GM.The neuropsychiatric sequelae This patient underscores the impor- of mercury poisoning.The Mad Hatter's disease tance of appropriate allergen patch test- revisited. Br J Psychiatry 1995; Jul;167(1):95-8. Disclosure: The authors have no conflict of ing, the need for education and regula- 5. Graeme KA, Pollack CV.Heavy metal toxicity, interest with any subject matter discussed in this tion of mercurial pigments used in tat- Part I: arsenic and mercury. J Emerg Med; 16:45-56. month’s column.

JANUARY 2006 SKIN & AGING 21