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BackgroundDermatological services in Laos, South East Asia are limited to the capital and patch testing is currently not available, so no data exists regarding the common cutaneous allergens in this population.ObjectivesThe aim of this study was to document common allergens in medical students in Laos. Patients/Materials/MethodsOne hundred and fifty medical students were patch tested using TRUE Test® panels 1 to 3 (35 allergens). Readings were taken at Days 2 and 4.ResultsThirty-eight students (25.3%) had a positive reaction to at least one allergen, accounting for 52 reactions in total. The proportion of the students with positive patch test reading was significantly higher in the female [33/96 (34%)] than in the male [5/54 (9%)], pConclusionThis study represents the first documented patch test results in Lao medical students and in the adult Lao population. The results of this study will inform any future research into contact allergy in Laos and give an insight into the background level of contact sensitivity in this population.

This study evaluated Thimerosal-containing childhood vaccines and the risk of a diagnosis called disturbance of emotions specific to childhood and adolescence (ED). Thimerosal is an organic-mercury (Hg)-containing compound used in some vaccines.A hypothesis-testing prospective, longitudinal case-control study evaluated Hg exposure from Thimerosal in hepatitis B vaccines administered at specific times within the first 6 months of life and its association with medically diagnosed ED (313.xx) (n = 517) in children born between 1991-2000 in comparison to controls (n = 27 491) in the Vaccine Safety Datalink (VSD) database.Cases diagnosed with ED were significantly more likely than controls to have received increased Hg exposure within the first month of life (odds ratio (OR) = 1.3384), the first 2 months of life (OR = 1.3367) and the first 6 months of life (OR = 2.37). When the data were separated by gender, similar significant adverse effects were observed for males, but not females. On a per microgram Hg basis, cases diagnosed with ED were significantly more likely than controls to have received increased exposure within the first 6 months of life (OR = 1.025 per microgram Hg).The results show a significant relationship between Hg exposure from Thimerosal-containing childhood vaccines and the subsequent risk of an ED diagnosis.

Vaccinations have been shown repeatedly to be extremely safe with low incidence of complications. Given the rarity, these adverse events, they must be reported and examined cautiously. This case report illustrates the first case of an adult presenting with Wells syndrome that developed soon after vaccination with the thiomersal, a common preservative, containing influenza vaccine. Wells syndrome, also known as eosinophilic cellulitis, is an uncommon dermatologic condition of unknown etiology. Lesions in patients with Wells syndrome (eosinophilic cellulitis) progress over a few days to become large indurated plaques with associated edema and erythema. Although the etiology of Wells syndrome remains unknown, certain precipitants have been described in the literature, including but not limited to parasitic infections, contact dermatitis, Churg-Strauss disease and various medications. This article describes a possible sensitivity to thiomersal, as well as describes other cases that have reported a similar sensitivity secondary to receiving thiomersal-containing vaccines.

Cognitive health is an emerging public health concern for the aging American population. Mercury (Hg) is a toxic element that can cause nervous system damage. This hypothesis-testing study evaluated the relationship between blood ethyl-Hg levels and cognitive decline in an older adult and elderly American population. A total of 1,821,663 weighted-persons between 60–80 years old with detectable blood ethyl-Hg levels within the 2011–2012 National Health and Nutritional Examination Survey were examined. Those persons with blood ethyl-Hg levels greater than the median were deemed the higher ethyl-Hg exposure group and those with ethyl-Hg levels less than the median were deemed the lower ethyl-Hg exposure group. Three tests were utilized to measure cognitive function: 1) Consortium to Establish a Registry for Alzheimer’s Disease – Word List Learning (CERAD W-L) delayed recall test, 2) animal fluency test, and 3) Digit Symbol Substitution Test. Each cognitive test score was categorized as higher for those with scores greater than the median and lower for those with scores less than the median. Survey logistic regression modeling with covariates was used to analyze the data for the relationship between blood ethyl-Hg levels and cognitive function scores. Significantly increased risks for lower animal fluency test (odds ratio (OR) = 13.652, p = 0.0029) and CERAD W-L delayed recall test (OR = 6.401, p = 0.0433) scores were observed among the higher ethyl-Hg exposure group as compared to the lower ethyl-Hg exposure group. This study supports the hypothesis that increased ethyl-Hg exposure is associated with significant cognitive decline in older adult and elderly Americans.

Background Allergic contact dermatitis is a common diagnosis in eyelid dermatitis. Sensitization to metals is prevalent in eyelid dermatitis and colour cosmetic products are frequently suspected as the source of metal exposure. Objective To investigate the contact allergens for eyelid dermatitis and to assess metal contents in eye shadow products. Methods Data were collected in the department of dermatology of Ewha Womans University hospital from December 1998 to February 2014. A total of 983 patients were patch tested during the period and 67 patients had eyelid dermatitis among them. To examine metal elements in colour cosmetic products for eyes, randomly selected 10 eye shadows were analysed. Results Frequent allergens were metals, thiomersal and phenylenediamine in patients with eyelid dermatitis. The sensitization rates of individual allergens were not significantly different between patients with eyelid dermatitis and without eyelid dermatitis. All 10 eye shadow products contained more than 5 ppm of at least one element, nickel, cobalt or chromium. Conclusion Metals were top-rank allergens in patients with eyelid dermatitis as in the remaining patients patch tested. The eye shadow products contained significant amount of nickel, cobalt or chromium to elicit allergic reactions.

Background Allergic contact dermatitis (ACD) caused by topical ophthalmic medications is often overlooked. Objectives To study the demographic characteristics, lesion locations and associated medical conditions of the patients with ACD caused by ophthalmic drugs, and to identify the most common allergenic culprits, as well as trends in frequencies over the years. Methods From January 1990 until December 2016, 16 065 patients were investigated in our clinic; all patients with a positive patch test reaction to an eye medication or its ingredient(s) having caused ACD were assessed. For each allergen identified, the number of positive test results as compared with the total number of those in the total population, as well as trends across three periods, namely 1990 to 1998, 1999 to 2007, and 2008 to 2016, were studied. Results One hundred and eighteen patients (0.7%) presented with positive patch test reactions to ingredients of and/or topical ophthalmic medications. Aminoglycoside antibiotics, followed by corticosteroids, as pharmacologically active ingredients, as well as wool alcohols, thiomersal, and benzalkonium chloride, as excipients, were the most frequent culprits. Chloramphenicol showed a decreasing trend of positive reactions over time, whereas reactions to tobramycin increased. Conclusion ACD caused by eye medication is mainly attributable to active principles, but other excipient ingredients, beside the products "as is," should be tested as well.

The National Center for Education Statistics reported that between 1990–2005 the number of children receiving special education services (SES) rose significantly, and then, from 2004–2012, the number declined significantly. This coincided with the introduction of Thimerosal-containing hepatitis B vaccine in 1991, and the subsequent introduction of Thimerosal-reduced hepatitis B vaccine in the early 2000s. This study examined the potential relationship between infant exposure to mercury from three doses of Thimerosal-containing hepatitis B vaccine and the risk of boys being adversely affected (as measured by receipt of SES). This cross-sectional study examined 1192 boys (weighted n = 24,537,123) 7–8 years of age (born: 1994–2007) from the combined 2001–2014 National Health and Nutritional Examination Survey (NHANES). Survey logistic regression modeling revealed that an exposed population receiving three doses of infant Thimerosal-containing hepatitis B vaccine (weighted n = 11,186,579), in comparison to an unexposed population (weighted n = 704,254), were at an increased risk of receipt of SES. This association was robust (crude odds ratio = 10.143, p = 0.0232), even when considering covariates, such as race and socioeconomic status (adjusted odds ratio = 9.234, p = 0.0259). Survey frequency modeling revealed that receipt of SES for the population that was exposed to three doses of Thimerosal-containing hepatitis B vaccine in infancy (12.91%) was significantly higher than the unexposed population (1.44%) (prevalence ratio = 8.96, p = 0.006, prevalence attributable rate = 0.1147). Despite the limitation of this cross-sectional study not being able to ascribe a direct cause-and-effect relationship between exposure and outcome, it is estimated that an additional 1.2 million boys received SES with excess education costs of about United States (US) $180 billion associated with exposure to Thimerosal-containing hepatitis B vaccine. By contrast, exposure to Thimerosal-reduced hepatitis B vaccine was not associated with an increased risk of receiving SES. Therefore, routine childhood vaccination is important to reduce the morbidity and mortality of infectious diseases, but every effort should be made to eliminate Thimerosal from all vaccines.

Mercury (Hg) is a strong toxicant affecting mainly the central nervous, renal, cardiovascular and immune systems. Thiomersal (TM) is still in use in medical practice as a topical antiseptic and as a preservative in multiple dose vaccines, routinely given to young children in some developing countries, while other forms of mercury such as methylmercury represent an environmental and food hazard. The aim of the present study was to determine the effects of thiomersal (TM) and its breakdown product ethylmercury (EtHg) on the thioredoxin system and NADP(+)-dependent dehydrogenases of the pentose phosphate pathway. Results show that TM and EtHg inhibited the thioredoxin system enzymes in purified suspensions, being EtHg comparable to methylmercury (MeHg). Also, treatment of neuroblastoma and liver cells with TM or EtHg decreased cell viability (GI50: 1.5 to 20μM) and caused a significant (p0.05) decrease in the overall activities of thioredoxin (Trx) and thioredoxin reductase (TrxR) in a concentration- and time-dependent manner in cell lysates. Compared to control, the activities of Trx and TrxR in neuroblastoma cells after EtHg incubation were reduced up to 60% and 80% respectively, whereas in hepatoma cells the reduction was almost 100%. In addition, the activities of glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase were also significantly inhibited by all mercurials, with inhibition intensity of Hg(2+)MeHg≈EtHgTM (p0.05). Cell incubation with sodium selenite alleviated the inhibitory effects on TrxR and glucose-6-phosphate dehydrogenase. Thus, the molecular mechanism of toxicity of TM and especially of its metabolite EtHg encompasses the blockage of the electrons from NADPH via the thioredoxin system.

BACKGROUND To evaluate the safety and immunogenicity of the thiomersal-free (TF) and thiomersal-containing (TC) formulations of Hepavax-Gene in healthy Vietnamese neonates. METHODS A single-blind, randomized, controlled study in Ho Chi Minh City, Vietnam. Healthy infants, born after a normal gestational period (37-42 weeks) to hepatitis B surface antigen-negative mothers, participated in the study. Subjects were randomly allocated in a 1:1 ratio to receive either Hepavax-Gene TC or Hepavax-Gene TF using a standard 0-1-6-month administration schedule. Postvaccination blood samples were taken at months 1, 6 and 7. Parents/legal guardians recorded solicited local and systemic adverse events up to 4 weeks after each vaccination. RESULTS Very high proportions of subjects were seroprotected. Seroprotection rates at 1, 6 and 7 months were all above 95% using a 10 IU/L cutoff, and were mostly above 90% using a 100 IU/L cutoff. Seroprotection rates between the 2 formulations were equivalent within a 5% margin for either cutoff titer both after 6 and 7 months. There were no significant differences in the number of adverse events reported between the 2 formulations. Safety results were in line with previous reports for Hepavax-Gene. Both formulations of Hepavax-Gene were well tolerated. There were no local adverse events reported in the TF group. No serious adverse events were reported during the study. CONCLUSIONS The thiomersal-free formulation of Hepavax-Gene was noninferior to the thiomersal-containing formulation of Hepavax-Gene in terms of immunogenicity. There was evidence that the thiomersal-free vaccine was associated with fewer local adverse events.

Background Thimerosal is an organic-mercury (Hg)-containing compound (49.55% Hg by weight) historically added to many multi-dose vials of vaccine as a preservative and still added to some vaccines today. Concerns about the toxic effects from Thimerosal-containing childhood vaccines and the risk of an atypical autism diagnosis were evaluated in this study. Methods A hypothesis-testing, prospective longitudinal, case-control study assessed exposure to Hg from Thimerosal-containing hepatitis B vaccines (TM-HepB) among cases diagnosed with atypical autism (n = 164) and controls (n = 15,216). Automated medical records for subjects born from 1991 to 2000 and continuously enrolled in the Vaccine Safety Datalink (VSD) database were examined. Results Cases diagnosed with atypical autism were statistically significantly more likely to have received greater overall and dose-dependent exposures to Hg from TM-HepB vaccines administered within the first month of life, first two months of life, and first six months of life than the controls. Similar phenomena were observed when cases and controls were separated by gender. Conclusions Routine childhood vaccination is an important public health tool to reduce infectious diseases. The present study provides important epidemiological evidence significantly associating increasing Hg exposure from Thimerosal-containing childhood vaccines and the subsequent risk of atypical autism diagnosis, and suggests that Thimerosal should be eliminated from vaccines.

A novel flow-injection chemiluminescence method was developed for the selective determination of human immunoglobulin G (IgG) in the presence of thiomersal by changing the flow rates of peristaltic pump. The study was based on the independence and additivity of the CL signals of human IgG and thiomersal in the galangin–potassium permanganate–polyphosphoric acid system. In meantime, two equations relating to the concentrations of mixing solutions of human IgG and thiomersal vs the CL intensity were established and solved, on the basis of which the content of thiomersal included in samples was simultaneously determined too. The enhanced CL intensity was in proportion to concerntrations in the range 8.0 × 10−7 to 8.0 × 10−5 g/mL for human IgG and 1.0 × 10−7 to 2.0 × 10−6 g/mL for thiomersal with the detection limits of 5.0 × 10−7 g/mL for human IgG and 6.0 × 10−8 g/mL for thiomersal, respectively. The relative standard deviation for 1.0 × 10−5 g/mL human IgG was 0.8% and for 2.0 × 10−7 g/mL thiomersal it was 2.0% (n = 10). The proposed method was applied to determine three synthetic samples with recoveries of 91.5–109.5%. In addition, the possible chemiluminescence mechanisms are discussed as well. Copyright © 2010 John Wiley & Sons, Ltd.

International audience; Few studies show the reluctance of the people to get vaccinated against A (H1N1) influenza for fear of side effects of squalene (MF59, AS03, AF03) and thimerosal. The aim of this paper is to assess the safety in using these adjuvants and preservative reviewing data of clinical trials relative to wich formulation includes these compounds. In the current state of knowledge, these vaccines have proved to be effective even though they more frequently give local adverse events than non-adjuvanted influenza vaccines. Systemic side effects are generally not serious. In the studies, adjuvanted vaccines do not increase neither the risk of Guillain Barre syndrome nor auto-immune diseases. There is no convincing evidence that exposure to thimerosal in vaccines had any deletorious effect on physiological outcome.

HgCl2 is a known environmental neurotoxin, but is also used as preservative in vaccines as thimerosal containing ethyl mercury covalently linked to thiosalicylate. We recently reported that mercury chloride (HgCl2) can stimulate human mast cells to release vascular endothelial growth factor (VEGF), which is also vasoactive and pro-inflammatory. Here we show that thimerosal induces significant VEGF release from human leukemic cultured LAD2 mast cells (at 1 μM 326±12 pg/106 cells and 335.5±12 pg/106 cells at 10 μM) compared to control cells (242±21 pg/106 cells, n=5, p2 at 10 μM (448±14 pg/106 cells) (n=3, p2 (10 μM) inhibited VEGF release by 100%, while sodium salicylate or ibuprofen had no effect. Pretreatment for 10 min with the flavonoid luteolin (0.1 mM) before HgCI2 or thimerosal completely blocked their effect. Luteolin and methyl thiosalicylate may be useful in preventing mercury-induced toxicity.

Several cases of skin sensitization have been reported following the application of thimerosal, which is composed of ethyl mercury and thiosalicylic acid (TSA). However, few in vitro studies have been carried out on human dendritic cells (DCs) which play an essential role in the initiation of allergic contact dermatitis. The aim of the present study was to identify the effect of thimerosal and other mercury compounds on human DCs. To address this purpose, DCs derived from monocytes (mono-DCs) were used. Data show that thimerosal and mercury derivatives induced DC activation, as monitored by CD86 and HLA-DR overexpression associated with the secretion of tumor necrosis factor α and interleukin 8, similarly to lipopolysaccharide and the sensitizers, 1-chloro-2,4-dinitrobenzene (DNCB) and nickel sulfate, which were used as positive controls. In contrast, TSA, the non-mercury part of thimerosal, as well as dichloronitrobenzene, a DNCB negative control, and the irritant, sodium dodecyl sulfate, had no effect. Moreover, oxidative stress, monitored by ROS induction and depolarization of the mitochondrial membrane potential, was induced by thimerosal and mercury compounds, as well as DNCB, in comparison with hydrogen peroxide, used as a positive control. The role of thiol oxidation in the initiation of mono-DC activation was confirmed by a pre-treatment with N -acetyl- l -cysteine which strongly decreased chemical-induced CD86 overexpression. These data are in agreement with several clinical observations of the high relevance of thimerosal in patch-test reactions and prove that human mono-DCs are useful in vitro tools for determining the allergenic potency of chemicals.

Objective Few prospective studies of inactivated split virion influenza vaccine have been conducted in infants and children. Our objective was to evaluate the safety, reactogenicity and immunogenicity of a thimerosal-free inactivated influenza vaccine (Fluvax®; CSL Limited, Parkville, Australia) in children aged 6 months to

Background Periocular contact dermatitis may appear as contact conjunctivitis, contact allergic and/or irritative eyelid and periorbital dermatitis, or a combination of these symptoms. The clinical symptoms may be induced by several environmental and therapeutic contact allergens. Objectives The aim of the present study was to map the eliciting contact allergens in 401 patients with periocular dermatitis (PD) by patch testing with environmental and ophthalmic contact allergens. Methods Following the methodics of international requirements, 401 patients were tested with contact allergens of the standard environmental series, 133 of 401 patients with the Brial ophthalmic basic and supplementary series as well. Results Contact hypersensitivity was detected in 34.4% of the patients. Highest prevalence was seen in cases of PD without other symptoms (51.18%), in patients of PD associated with ophthalmic complaints (OC; 30.4%), and PD associated with atopic dermatitis (AD; 27.9%). In the subgroup of PD associated with seborrhoea (S) and rosacea (R), contact hypersensitivity was confirmed in 17.6%. Most frequent sensitisers were nickel sulphate (in 8.9% of the tested 401 patients), fragrance mix I (4.5%), balsam of Peru (4.0%), paraphenylendiamine (PPD) (3.7%), and thiomersal (3.5%). By testing ophthalmic allergens, contact hypersensitivity was observed in nine patients (6.7% of the tested 133 patients). The most common confirmed ophthalmic allergens were cocamidopropyl betaine, idoxuridine, phenylephrine hydrochloride, Na chromoglycinate, and papaine. Limitations Patients with symptoms of PD were tested from 1996 to 2006. Conclusions The occurence of contact hypersensitivity in PD patients was in present study 34.4%. A relatively high occurence was seen in cases of PD without other symptoms, in PD + OC and in PD + AD patients. The predominance of environmental contact allergens was remarkable: most frequent sensitizers were nickel sulphate, fragrance mix I, balsam of Peru, thiomersal, and PPD. The prevalence of contact hypersensitivity to ophthalmic allergens did not exceed l.5%. Conflicts of interest None declared

Background Atopic dermatitis (AD) is a clinically well-defined, chronic-intermittant, genetically predisposed skin disease. The increasing number of adult cases observed in the last years has turned the attention to ascertaining factors eliciting skin symptoms. Studies have revealed numerous environmental components (e.g. contact and aeroallergens) that may play an important role in sustaining the symptoms. The aim of the study was to search for contact allergens and aeroallergens triggering the skin disease in adult AD patients. Methods Patients over 18 years from our Atopy Outpatient Department were included in the study. Diagnosis of AD was based on the clinical criteria of Hanifin and Rajka. The distribution of skin symptoms was characteristic for adult AD: hands, shoulders, neck, flexures, face and eyelids. The extremities and the trunk were less involved. The potentially provoking contact and aeroallergens were examined in symptom and drug-free period with atopy patch and epicutaneous tests (APT, ET), which were supplemented by in vitro allergy and Prick tests. The relevance of sensibilization was evaluated by the comparison of in vivo and in vitro test results, medical history and skin symptoms. Results A total number of 34 cases of adult AD (23 women and 11 men) were studied. Four of them were classified into the intrinsic group (IG; 12%), and 30 were classified into the extrinsic group (EG; 88%). The incidence of contact sensitization to environmental allergens was remarkable: 13 of the EG, 1 of the IG (14 of 34, 41%). In the IG, a late thiomersal positivity was detected without clinical relevance. In the EG, epicutaneous standard series late positivity was seen in 13 patients, in four of them with multiple sensitivity. The allergens causing positivity were nickel (6 of 13), thiomersal (3 of 13), mercury-amidochlorate (3 of 13), mercury-chloride (2 of 13), iodine chlorhyrdoxyquin (1 of 13), lanalcolum (1 of 13) and fragrance mix (1 of 13). Among the detected allergens, the following were relevant: lanalcolum (1 of 13: cosmetics), fragrance mix (1 of 13: cosmetics), nickel (1 of 13: metal objects), thiomersal (1 of 13: eyedrops). No immediate response was seen with APT. Relevant late positivity was shown with APT test in one patient in the IG (1 of 4) to Dermatophagoides pteronyssinus. We observed late positivity in 18 patients in the EG (18 of 30). Among the detected allergens, the following were clinically relevant: D. pteronyssinus and/or Dermatophagoides farinae (15 of 18), cat epithel (4 of 18), timothy pollen (1 of 18) and dog epithel (1 of 18). Furthermore, we examined the relevance of APT, specific immunoglobulin E (IgE) tests and Prick tests. We observed multiplex positivity by specific IgE tests, APT and Prick tests in 14 patients in EG. Sensitization to D. pteronyssinus and/or D. farinae (11 of 14) cat epithel (4 of 14), dog epithel (1 of 14) and timothy pollen (1 of 14) proved to be clinically relevant with the atopic skin symptoms and medical history. Conclusion The proportion of contact sensitization to environmental allergens in the 34 adult atopic patients was remarkable (14 of 34, 41%). Out of the verified contact allergens, nickel, fragrance mix, thiomersal and lanalcolum proved to be relevant. House dust mite and cat epithel proved to be the most common relevant aeroallergens. D. pteronyssinus and D. farinae sensibilization was high, particularly in patients with severe skin symptoms on the face, eyelids and hands. Pollens should be considered in patients with seasonal relapse of AD. Sensitization to animal epithel was usually indicated by the flare-up of skin symptoms upon contact with animals. The relevance of the eliciting effects of sensitization could easily be supported in most cases by the medical history and the distribution of skin symptoms. In some adult AD patients with long-lasting AD, the relevance of triggering factors is hard to determine.

The etiopathogenesis of perioral dermatitis (PD) is still unknown and, consequently, medical treatment is difficult, not precisely defined, and often unsatisfactory. On the basis of a peculiar case that appeared soon after multiple dental fillings with a mercury-containing amalgam, we proposed that neurogenic inflammation could play a role in the pathogenesis of PD. According to the new findings provided by clinical and basic research, neurogenic inflammation has a relevant part in the pathogenesis of many cutaneous diseases. We report a similar case of PD, taking into account, more specifically, the possible involvement of the cholinergic system. Also in this case, PD seems to be mainly related to the mercury contained in dental fillings and/or its organic compounds formed by oral/gut bacteria. We examined the possible role of these substances as causes of PD, providing new information on the possible cross-talk between neuroimmunodermatology and potential triggers of PD.

A randomized double-blind trial was performed to determine the frequency of positive reactions to the Montenegro antigen (leishmanin) preserved in thimerosal (Merthiolate™) 1:10,000 or phenol 0.4%. The respective products were tested separately in 400 young healthy individuals from a non-endemic area for Leishmania ses. Each volunteer received one of the following reagents: merthiolated antigen, phenolated antigen, merthiolated saline, or phenolated saline. The frequency of positive responses to each reagent after the first application was as follows: 0% (phenolated saline), 9.2% (merthiolated saline), 34.6% (antigen in phenolated saline), and 41.1% (antigen in merthiolated saline). After 1 week, volunteers who had tested positive for merthiolated or phenolated antigen were retested with the respective preservative, while negatives were retested with the preservative they had not received during the first test. In all, 331 volunteers who received merthiolated saline during the study, of whom 41 (12.4%) tested positive. Meanwhile, 326 volunteers who received phenolated saline, 4 (1.2%) tested positive. Positive reactions in each group were similar in relation to gross appearance skin reactions. Considering the high frequency of hypersensitivity to thimerosal in the study population, it is recommended that this compound should be replaced as a preservative of the leishmanin antigen. Almost 30% of positive reactions to Montenegro antigen in what is considered a non-endemic region was surprising and will be the object of future studies.

Organic mercury (Hg) species exert their toxicity primarily in the central nervous system. The food relevant Hg species methylmercury (MeHg) has been frequently studied regarding its neurotoxic effects in vitro and in vivo. Neurotoxicity of thiomersal, which is used as a preservative in medical preparations, is to date less characterised. Due to dealkylation of organic Hg or oxidation of elemental Hg, inorganic Hg is present in the brain albeit these species are not able to readily cross the blood brain barrier. This study compared for the first time toxic effects of organic MeHg chloride (MeHgCl) and thiomersal as well as inorganic mercury chloride (HgCl2) in differentiated human neurons (LUHMES) and human astrocytes (CCF-STTG1). The three Hg species differ in their degree and mechanism of toxicity in those two types of brain cells. Generally, neurons are more susceptible to Hg species induced cytotoxicity as compared to astrocytes. This might be due to the massive cellular mercury uptake in the differentiated neurons. The organic compounds exerted stronger cytotoxic effects as compared to inorganic HgCl2. In contrast to HgCl2 exposure, organic Hg compounds seem to induce the apoptotic cascade in neurons following low-level exposure. No indicators for apoptosis were identified for both inorganic and organic mercury species in astrocytes. Our studies clearly demonstrate species-specific toxic mechanisms. A mixed exposure towards all Hg species in the brain can be assumed. Thus, prospectively coexposure studies as well as cocultures of neurons and astrocytes could provide additional information in the investigation of Hg induced neurotoxicity. published

Introduction Thimerosal (or Thiomersal) is a trade name for an organomercurial compound (sodium ethyl-mercury (Hg) thiosalicylate) that is 49.55% Hg by weight, which rapidly decomposes in aqueous saline solutions into ethyl-Hg hydroxide and ethyl-Hg chloride. Developed in 1927, it has been and is still being used as a preservative in some cosmetics, topical pharmaceuticals, and biological drug products, including vaccines. Concerns have been voiced about its use because it is toxic to human cells. Although it is banned in several countries, it continues to be added to some vaccines in the United States and many vaccines in the developing world. Discussion This critical review focuses on the clinical, epidemiological, and biochemical studies of adverse effects from Thimerosal in developing humans. This review will include research that examines fetal, infant, and childhood death; birth defects; neurodevelopmental testing deficits in children; and neurodevelopmental disorders (attention deficit/hyperactivity disorder, autism spectrum disorder, tic disorder, and specific developmental delays). The review will also look at the research that examined the outcomes of acute accidental ethyl-Hg poisoning in humans. The studies that examine the underlying biochemical insights into the neuronal cellular damage will also be explored. Conclusion The culmination of the research that examines the effects of Thimerosal in humans indicates that it is a poison at minute levels with a plethora of deleterious consequences, even at the levels currently administered in vaccines.

A thiomersal-free (TF) formulation of the recombinant hepatitis B vaccine Hepavax-Gene ® has been developed. This study compared immunogenicity and safety of Hepavax-Gene ® , Hepavax-Gene ® TF and Engerix-B ® (containing trace amounts of thiomersal) in a large healthy adult population ( N = 770) using two vaccination schedules: the priming 0–1–2 months or the standard 0–1–6 month schedule. Hepavax-Gene ® TF was non-inferior to Hepavax-Gene ® and Engerix-B ® with respect to seroprotection rates (≥10 IU/L) 1 month after the third vaccination using the 0–1–6 month schedule, with 99.1% for both Hepavax-Gene ® formulations and 100% for Engerix-B ® of subjects’ seroprotected in each group. The seroprotection rate after the 0–1–2 schedule was 89.6% for Hepavax-Gene ® TF, lower than for Hepavax-Gene ® (94.2%) but comparable to Engerix-B ® (86.4%). Furthermore, Hepavax-Gene ® TF was as well tolerated as the comparator vaccines.

Allergic autoimmune reaction after exposure to heavy metals such as mercury may play a causal role in autism, a developmental disorder of the central nervous system. As metallothionein (MT) is the primary metal-detoxifying protein in the body, we conducted a study of the MT protein and antibodies to metallothionein (anti-MT) in normal and autistic children whose exposure to mercury was only from thimerosal-containing vaccines. Laboratory analysis by immunoassays revealed that the serum level of MT did not significantly differ between normal and autistic children. Furthermore, autistic children harboured normal levels of anti-MT, including antibodies to isoform MT-I (anti-MT-I) and MT-II (anti-MT-II), without any significant difference between normal and autistic children. Our findings indicate that because autistic children have a normal profile of MT and anti-MT, the mercury-induced autoimmunity to MT may not be implicated in the pathogenesis of autism.

In this study 27 full scale production batches of influenza sub-unit vaccine were evaluated on their stability. The batches varied with respect to the strains they contained and regarding the presence of the preservative thiomersal in the solution. The stability study showed that haemagglutinin content was the most sensitive parameter. An increase in the storage temperature strongly increased the degradation rate of haemagglutinin. The degradation rate of the haemagglutinin differed for the different strains tested. However, statistical evaluation of the data obtained for the most sensitive strain tested showed that even exposure during a 2 week period of the vaccine to room temperature would not adversely affect the shelf life claim of the influenza subunit vaccine of 1 year in the refrigerator. Moreover, this study showed that the presence of thiomersal in the solution has no effect on the stability of the vaccine. (c) 2005 Elsevier Ltd. All rights reserved.

Without a preservative, such as thiomersal (known as thimerosal in the US), multi-dose liquid presentations of vaccine are vulnerable to bacteriological contamination that can result in death or serious illness of the recipient. Concerns about levels of mercury exposure from thiomersal-containing vaccines were first raised in the US during 1999 in the context of Hepatitis B vaccine for newborns. Since then, a large body of evidence from animal and epidemiological studies has accumulated on the safety of thiomersal. Ironically, these data have become largely irrelevant in wealthy countries, where mono-dose, thiomersal-free vaccines have been introduced as a precautionary measure in almost all childhood vaccines, in part related to residual public scepticism. In poor countries, multi-dose vials remain important for vaccine delivery. There is a real danger that this controversy may result in the loss to the world of thiomersal as a preservative, simply from popular pressure. In reality, it would be impossible to cease overnight using thiomersal and maintain the supply of vital vaccines. This paper reviews and summarises the data available from published studies on mercury toxicity, and thiomersal in vaccines in particular, that overwhelmingly indicate continued use of thiomersal is safe in those countries where it is most needed.

Immunoadsorption is an adsorption technique for extracorporeal removal of circulating autoantibodies in autoimmune diseases. To prevent microbial growth during storage, the protein A columns are primed with thiomersal, which contains toxic ethyl mercury, which may be released during the procedure and potentially begin to accumulate and become toxic. To reduce the thiomersal-related mercury release during immunoadsorption treatment, we introduced a modified rinsing solution containing N-acetylcysteine, which is an avid mercury scavenger. Thirteen patients received 17 protein A immunoadsorption treatments and their venous blood samples were collected immediately before and after each session. The total blood mercury levels were measured by atomic absorption spectrometry, and the ethyl mercury levels by atomic fluorescence spectrometry. Following the manufacturer's recommendations, we used 600 mg of N-acetylcysteine to rinse the mercury from protein-loaded columns before each immunoadsorption treatment. After immunoadsorption, the ethyl mercury levels increased from 0.148 +/- 0.402 ng/g to 2.026 +/- 1.944 ng/g (P < 0.001), and the total blood mercury levels increased from 2.447 +/- 3.065 ng/g to 20.437 +/- 28.603 ng/g (P = 0.02). The post-treatment values of total blood mercury exceeded the upper safety level of 5 ng/g in all 17 immunoadsorption treatments, but no patient developed clinical signs of mercury toxicity. The results of our study showed an increase in total blood mercury and ethyl mercury levels during the immunoadsorption treatments, suggesting mercury release from thiomersal-primed columns despite the addition of N-acetylcysteine to the rinsing solution.

A number of affluent countries are moving to eliminate thiomersal (thimerosal), an ethylmercury preservative, from vaccines as a precautionary measure because of concerns about the potential adverse effects of mercury in infants. The WHO advocates continued use of thiomersal-containing vaccines in developing countries because of their effectiveness, safety, low cost, wide availability and logistical suitability in this setting. The guidelines for long-term mercury exposure should not be used for evaluating risk from intermittent single day exposures, such as immunisation using thiomersal-containing vaccines. Similar or higher mercury exposures likely occur from breast feeding and the health benefit of eliminating thiomersal from a vaccine, if any, is likely to be very small. On the other hand, the benefits accrued from the use of thiomersal-containing vaccines are considerably greater but vary substantially between affluent and developing regions of the world. Because of the contribution to overall mercury exposure from breast milk and diet in later life, the removal of thiomersal from vaccines would produce no more than a 50% reduction of mercury exposure in infancy and

Introduction Allergic contact dermatitis (ACD) is equally as likely in infancy as in adulthood, and represents 20% of all cases of dermatitis in children. Its true prevalence and incidence are, however, unknown. Materials and methods We have conducted a retrospective study over 10 years of a group of patients aged 15 years or less, with clinical suspicion of ACD. Patch tests were performed in accordance with the standards of the GEIDC. Results The study covered 96 patients with a mean age of 10.57 ± 0.67 years. The zones most frequently affected by eczemas were those of diffuse distribution (28% of patients) and of the hands (27%). We found at least one positive response in 52% of the cases. The most frequent allergens were thiomersal (21%), mercury (19%) and nickel (18%). We have found a statistically significant association between age of less than 15 years and positive response to thiomersal [P

Background. Immunoadsorption is increasingly used to treat antibody-mediated autoimmune diseases. To prevent microbial growth during storage, reusable protein A–Sepharose gel columns are primed with ethyl mercury thiosalicylate (thiomersal, 0.1% solution) and rinsed with phosphate buffer before use. In this study, we tested the hypothesis of systemic mercury exposure in protein A immunoadsorption. Methods. Whole blood mercury levels were measured by atomic absorption spectroscopy before and after protein A immunoadsorption (11 patients, 26 treatments), anti-IgG immunoadsorption (eight patients, 13 treatments) and LDL apheresis (DALI and Therasorb systems; nine patients, 14 treatments). Results. Patients treated with protein A immunoadsorption had significantly elevated baseline mercury levels compared with the other groups, which were not different from healthy controls. Following protein A immunoadsorption, mercury levels increased from 5.9±1.4mg/l (mean±SEM, normal

One month after the last dose (i.e. at month 7), geometric mean titres (GMTs) of antibodies directed against hepatitis A virus (anti-HAV) were generally greater in participants (aged 12-15 years) receiving combined two-dose (0 and 6 months) hepatitis A and B vaccine (AmBirix) compared with the three-dose (containing one half the dose of the two active components per dose, given at 0, 1 and 6 months; Twinrix Paediatric) schedule. Moreover, at month 7 all patients had seroconverted to anti-HAV. GMTs of antibodies directed against hepatitis B surface antigen greatly exceeded the threshold for seroprotection (>/=10 mIU/mL) 1 month after the last dose of vaccine. Seroprotection rates against hepatitis B virus (HBV) were similar 1 month after completion of either a two- (97.9%) or three-dose (100%) vaccination schedule. At 24 months' follow-up, all patients tested remained positive for anti-HAV, and 93.3% and 96.2% of those treated with the two- and three-dose schedules, respectively, remained above the threshold for seroprotection against HBV. Administering the second dose in the two-dose series at 12 months rather than at 6 months did not compromise the immune response to the combined vaccine in adolescents aged 12-15 years in a randomised, multicentre trial. Local adverse events reported in the 4 days following administration of combined two-dose hepatitis A and B vaccine include pain or soreness, redness and swelling; systemic symptoms included headache, fatigue, gastrointestinal events and fever.

A hypothesis testing case-control study evaluated concerns about the toxic effects of organic-mercury (Hg) exposure from thimerosal-containing (49.55% Hg by weight) vaccines on the risk of neurodevelopmental disorders (NDs). Automated medical records were examined to identify cases and controls enrolled from their date-of-birth (1991–2000) in the Vaccine Safety Datalink (VSD) project. ND cases were diagnosed with pervasive developmental disorder (PDD), specific developmental delay, tic disorder or hyperkinetic syndrome of childhood. In addition, putative non-thimerosal-related outcomes of febrile seizure, failure to thrive and cerebral degenerations were examined. The cumulative total dose of Hg exposure from thimerosal-containing hepatitis B vaccine (T-HBV) administered within the first six months of life was calculated. On a per microgram of organic-Hg basis, PDD (odds ratio (OR) = 1.054), specific developmental delay (OR = 1.035), tic disorder (OR = 1.034) and hyperkinetic syndrome of childhood (OR = 1.05) cases were significantly more likely than controls to receive increased organic-Hg exposure. By contrast, none of the non-thimerosal related outcomes were significantly more likely than the controls to have received increased organic-Hg exposure. Routine childhood vaccination may be an important public health tool to reduce infectious disease-associated morbidity/mortality, but the present study significantly associates organic-Hg exposure from T-HBV with an increased risk of an ND diagnosis.

The toxicologically most relevant mercury (Hg) species for human exposure is methylmercury (MeHg). Thiomersal is a common preservative used in some vaccine formulations. The aim of this study is to get further mechanistic insight into the yet not fully understood neurotoxic modes of action of organic Hg species. Mercury species investigated include MeHgCl and thiomersal. Additionally HgCl2 was studied, since in the brain mercuric Hg can be formed by dealkylation of the organic species. As a cellular system astrocytes were used. In vivo astrocytes provide the environment necessary for neuronal function. In the present study, cytotoxic effects of the respective mercuricals increased with rising alkylation level and correlated with their cellular bioavailability. Further experiments revealed for all species at subcytotoxic concentrations no induction of DNA strand breaks, whereas all species massively increased H2O2-induced DNA strand breaks. This co- genotoxic effect is likely due to a disturbance of the cellular DNA damage response. Thus, at nanomolar, sub-cytotoxic concentrations, all three mercury species strongly disturbed poly(ADP-ribosyl)ation, a signalling reaction induced by DNA strand breaks. Interestingly, the molecular mechanism behind this inhibition seems to be different for the species. Since chronic PARP-1 inhibition is also discussed to sacrifice neurogenesis and learning abilities, further experiments on neurons and in vivo studies could be helpful to clarify whether the inhibition of poly(ADP-ribosyl) ation contributes to organic Hg induced neurotoxicity.

Background: Diisocyanates are widely used in industry, for example at hospitals as a constituent of Scotch Cast soft casts (3M, Glostrup, Denmark). They are a cause of occupational asthma and have been described as causing cutaneous problems both as irritants and as sensitizers. Objective: The sensitizing potential of diisocyanates has previously only sporadically been described, predominantly in case reports. Therefore, we conducted this study to investigate eventual work-related skin sensitization to diisocyanates in a regularly exposed population. Methods: The nursing staff of an orthopaedic outpatient clinic, consisting of 10 persons, were interviewed and subjected to patch testing using 5 types of diisocyanates and the TRUE Test (ECDRG Standard Series) to elucidate possible other type IV allergies with similar symptoms. Patch test results were evaluated according to the guidelines of the International Contact Dermatitis Group. Results: We found no relationship between exposure time and severity of symptoms. Symptoms were mild, consisting of redness, itching, or both, lasting about 30 minutes. There was no suggestion that they result in any chronic skin problems. One nurse presented a doubtful reaction towards diaminophenylmethane (MDA) and isophorene diisocyanate (IPDI). Nine persons had no reactions to the 5 diisocyanates used in the patch test. Positive reactions were seen to nickel (4/10), thiomersal (2/10), and perfume mix (1/10). Conclusion: Our observations suggest that diisocyanates are primarily irritants rather than sensitizers in the professional setting studied. The skin symptoms of irritation were all mild and temporary.

Background: Environmental, cultural, occupational, genetic, individual, and racial differences are important factors in the study of contact dermatitis. Some epidemiologic studies have compared overall sensitization rates among different racial groups, but similar data are lacking on individual allergens. Objective: Determine differences in sensitization rates between 2 racial groups in North America undergoing patch testing over a period of 4 years at the Cleveland Clinic Foundation (CCF), Ohio. Methods: Retrospective computer review of the standard screening tray results of 991 patients with an average age of 45.9 years consisting of 877 (88.5%) whites and 114 (11.5%) blacks. Results: Nickel sulfate and thiomersal (both 8.0%) and nickel sulfate and p -phenylenediamine (both 10.6%) were the 2 most common sensitizers among whites and blacks respectively. There was a statistically significant difference ( P = .00599) in the sensitization rate for p -phenylenediamine in blacks (10.6%) compared with whites (4.5%). There were also statistically significant differences in sensitization rates for p -phenylenediamine (21.2%; P = .00005) and imidazolidinyl urea in petrolatum (pet.) (9.1%; P = .04103) in black men compared with white men ( p -phenylenediamine [4.2%] and imidazolidinyl urea [2.6% pet.]). Conclusion: The differences in sensitization rates, especially for p -phenylenediamine, may reflect variations in allergen exposure among racial groups or interindividual variations in the N-acetylation (N-acetyltransferase 1 [NAT1] and 2 [NAT2]) capacities of human skin for p -phenylenediamine.

Background. On July 7, 1999, the American Academy of Pediatrics and the US Public Health Service issued a joint statement calling for removal of thimerosal, a mercury-containing preservative, from vaccines. This action was prompted in part by a risk assessment from the Food and Drug Administration that is presented here. Methods. The risk assessment consisted of hazard identification, dose-response assessment, exposure assessment, and risk characterization. The literature was reviewed to identify known toxicity of thimerosal, ethylmercury (a metabolite of thimerosal) and methylmercury (a similar organic mercury compound) and to determine the doses at which toxicity occurs. Maximal potential exposure to mercury from vaccines was calculated for children at 6 months old and 2 years, under the US childhood immunization schedule, and compared with the limits for mercury exposure developed by the Environmental Protection Agency (EPA), the Agency for Toxic Substance and Disease Registry, the Food and Drug Administration, and the World Health Organization. Results. Delayed-type hypersensitivity reactions from thimerosal exposure are well-recognized. Identified acute toxicity from inadvertent high-dose exposure to thimerosal includes neurotoxicity and nephrotoxicity. Limited data on toxicity from low-dose exposures to ethylmercury are available, but toxicity may be similar to that of methylmercury. Chronic, low-dose methylmercury exposure may cause subtle neurologic abnormalities. Depending on the immunization schedule, vaccine formulation, and infant weight, cumulative exposure of infants to mercury from thimerosal during the first 6 months of life may exceed EPA guidelines. Conclusion. Our review revealed no evidence of harm caused by doses of thimerosal in vaccines, except for local hypersensitivity reactions. However, some infants may be exposed to cumulative levels of mercury during the first 6 months of life that exceed EPA recommendations. Exposure of infants to mercury in vaccines can be reduced or eliminated by using products formulated without thimerosal as a preservative.

The inorganic mercurial thiomersal (merthiolate) has been used as an effective preservative in numerous medical and non-medical products since the early 1930s. Both the potential toxicity of thiomersal and sensitisation to thiomersal in relation to the application of thiomersal-containing vaccines and immunoglobulins, especially in children, have been debated in the literature. The very low thiomersal concentrations in pharmacological and biological products are relatively non-toxic, but probably not in utero and during the first 6 months of life. The developing brain of the fetus is most susceptible to thiomersal and, therefore, women of childbearing age, in particular, should not receive thiomersal-containing products. Definitive data of doses at which developmental effects occur are not available. Moreover, revelation of subtle effects of toxicity needs long term observation of children. The ethylmercury radical of the thiomersal molecule appears to be the prominent sensitiser. The prevalence of thiomersal hypersensitivity in mostly selected populations varies up to 18%, but higher figures have been reported. The overall exposure to thiomersal differs considerably between countries. In many cases a positive routine patch test to thiomersal should be considered an accidental finding without or, probably more accurately, with low clinical relevance. In practice, some preventive measures can be taken with respect to thiomersal hypersensitivity. However, with regard to the debate on primary sensitisation during childhood and renewed attention for a reduction of children's exposure to mercury from all sources, the use of thiomersal should preferably be eliminated or at least be reduced. In 1999 the manufacturers of vaccines and immunoglobulins in the US and Europe were approached with this in mind. The potential toxicity in children seems to be of much more concern to them than the hidden sensitising properties of thiomersal. In The Netherlands, unlike many other countries, the exposure to thiomersal from pharmaceutical sources has already been reduced. Replacement of thiomersal in all products should have a high priority in all countries.

Objective Thimerosal is an important preservative in vaccines and ophthalmologic preparations. The substance is known to be a type IV sensitizing agent. High sensitization rates were observed in contact-allergic patients and in health care workers who had been exposed to thimerosal-preserved vaccines. There is evidence for the involvement of the glutathione system in the metabolism of thimerosal or its decomposition products (organomercury alkyl compounds). Thus detoxification by polymorphically expressed glutathione S-transferases such as GSTT1 and GSTM1 might have a protective effect against sensitization by these substances. Methods To address this question, a case control study was conducted, including 91 Central European individuals with a positive patch-test reaction to thimerosal. This population was compared with 169 healthy controls and additionally with 114 individuals affected by an allergy against para-substituted aryl compounds. The latter population was included in order to test whether possible associations were due to substance-specific effects, or were a general feature connected with type IV immunological diseases. Homozygous deletions of GSTT1 and GSTM1 were determined by polymerase chain reaction. Results Glutathione S-transferase M1 deficiency was significantly more frequent among patients sensitized to thimerosal (65.9%, P = 0.013) compared with the healthy control group (49.1%) and the "para-compound" group (48%, P = 0.034). Glutathione S-transferase T1 deficiency in the thimerosal/mercury group (19.8%) was barely elevated versus healthy controls (16.0%) and the "para-compound" group (14.0%). The combined deletion (GSTT1-/GSTM1-) was markedly more frequent among thimerosal-sensitized patients than in healthy controls (17.6% vs. 6.5%, P = 0.0093) and in the "para-compound" group (17.6% vs. 6.1%, P =0.014), revealing a synergistic effect of these enzyme deficiencies (healthy controls vs. thimerosal GSTM1 negative individuals, OR = 2.0 [CI = 1.2-3.4], GSTT1-, OR = 1.2 [CI = 0.70-2.1], GSTM1/T1-, OR = 3.1 [CI = 1.4-6.5]). Conclusions Since the glutathione-dependent system was repeatedly shown to be involved in the metabolism of thimerosal decomposition products, the observed association may be of functional relevance.

An overview of the literature concerning the effects of thimerosal is presented. Because of its antibacterial effect, thimerosal is used for a variety of practical purposes such as antiseptic and preservative. In biomedical studies, thimerosal is used as a sulfhydryl reagent, and as a calcium-mobilizing agent. The ability of thimerosal to act as a sulfhydryl group is related to the presence of mercury. Relatively little study has been devoted to the mechanism of the reaction of thimerosal with the sulfhydryl group; the sulfhydryl reactive capacity is mostly concluded on the basis of inactivation of the effect by dithiothreitol (DTT). Thimerosal causes a release of calcium from intracellular stores in many cells types; this is followed by an influx of extracellular calcium. Both InsP3- and ryanodine-sensitive calcium stores may be affected. Studies with permeabilized cells or organelles show that the effect of thimerosal on calcium is dependent on the concentration: low concentrations of thimerosal stimulate calcium release, high concentrations are inhibitory. This dependence is not found in intact cells. Thimerosal may activate or inhibit a number of cell functions. These are often related to the ability to release calcium or with the sulfhydryl reactivity. In platelets, thimerosal causes aggregation, increase of arachidonic acid metabolism, and exocytotic release of serotonin. In neutrophils, thimerosal causes, besides an increase of cytosolic free calcium, an increase of formyl-methionyl-leucyl-phenylalanine (fMLP)-activated leukotriene release, and a modulation of chemotactic migration and exocytosis. At low concentrations, thimerosal induces chemotactic migration of neutrophils, in the absence of other chemoattractants. The effect is also observed with thiosalicylic acid, indicating that the stimulation of migration was due to the thiosalicylic acid moiety of the thimerosal molecule. At higher concentrations, thimerosal causes inhibition of fMLP-activated migration. Low concentrations of thimerosal, but not of thiosalicylic acid, induced exocytotic enzyme release from neutrophils. High concentrations of thimerosal inhibited fMLP-activated exocytosis. The results point to an involvement of calcium mobilization and calcium influx of activation, and reaction with sulfhydryl groups for inhibition.

Background No data exist on allergic contact dermatitis (ACD) in the United Arab Emirates (UAE). Aim Our aim was threefold: (i) to determine the incidence of ACD; (ii) to identify responsible allergens using the European Standard Series, TRUE TEST, and other substances; (iii) to tentatively explore population-specific reactions in Al Ain, UAE. Design This is a prospective, descriptive, hospital-based, study. Setting Tawam Hospital, Al Ain Medical District, UAE. Patients During the years 1989–1996, 373 patients (male : female = 2 : 3), presenting with cutaneous manifestations possibly related to contact allergy, were patch tested. Results 93.8% of patients presented with dermatitis affecting mostly the hands (45.1%), feet (21.4%), face (12.6%), and legs (4.6%). Two hundred and twenty-four patients (60%) (male : female = 1 : 2) tested positive for at least one substance. Nickel was the commonest sensitizer (15%) in both genders. “Fragrance mix” (8%), p-tertiary butylphenolformaldehyde (p-TBPF) resin (7.5%), thiomersal (7.5%), chromium (7.2%), cobalt (6.4%), ethylenediamine (6.4%), neomycin (5.1%), and parabens (5.1%) were prominent allergens. Glutardialdehyde, an additional substance tested together with the European Standard Series, scored significantly (4.8%). Variations from the results reported from other countries may be explained by the specific lifestyles and customs of the UAE population. Conclusions Substances contained in the TRUE TEST, plus glutardialdehyde, may be considered as the standard series for patch testing in the UAE population.

There is conflicting evidence regarding the reproducibility of patch testing. Discordant results have been reported in up to 44% of cases. The clinical relevance of these discordant patch tests has not been previously assessed. We studied 383 consecutive patients receiving simultaneous duplicate patch testing on opposite sides of the upper back with 10 allergens from the European standard series. Completely discordant patch tests-a negative test on one side with a positive test on the opposite side-were recorded in 30 (8%) patients. Two patients had discordant tests to two of the allergens; 28 had discordant reactions to one allergen. Completely discordant tests were recorded for nickel in 10 (3%) patients, balsam of Peru in two (0.5%), thiomersal in one (0.3%), cobalt in four (1%), paraphenylenediamine in three (0.8%), fragrance mix in two (0.5%), formaldehyde in four (1%), potassium dichromate in two (0.5%), lanolin in three (0.8%) and Kathon CG in one (0.3%). Of those patients with completely discordant patch tests, the allergen was deemed to be a true positive in 11 (3% of total) cases and of possible relevance in a further three. The allergen was felt to be relevant to the presenting complaint in seven (2% of total) patients.

Thimerosal as a preservative (in all but trace amounts) was removed from vaccines used in infants starting in the late 1990s, though the preservative-including inactivated influenza vaccine is still available for use in individualsor=6 months of age. We compared the proportion of injection site reactions, rash, and infections reported to the Vaccine Adverse Event Reporting System (VAERS) after preservative-free (PFV), preservative-including (PIV), and preservative unknown (PUV) vaccines in reports from 7/1/2004 to 1/4/2006. There were 145, 175, and 216 reports after vaccination with PFV, PIV, and PUV, respectively. The most frequently reported coding terms (fever, rash, and urticaria) were seen in similar proportions in the PFV, PIV, and PUV groups. No difference was detected in the proportion of injection site reactions (ISR), rash, or infections in the PIV, PFV, and PUV reports. Keeping in mind the inherent limitations of VAERS, including underreporting and potential reporting biases, we conclude that there were no substantial differences in the proportion of rash, ISR, and infection reports in the PIV, PFV and PUV reports in infants.

For a better understanding of the mechanistic details of the interactions of organomercury compounds inside the skin, 32 subjects who previously had given positive patch-test reactions to thimerosal (TH) and negative reactions to thiosalicylic acid, were divided into 2 groups. 16 subjects were repatch tested to ethylmercury chloride (EtHgCl) and to solutions containing EtHgCl mixed with L-cysteine and glutathione, respectively. The remaining 16 were repatch tested to EtHgCl and to solutions containing EtHgCl mixed with chlorides of Zn, Mg, and Mn, respectively. The results showed that whilst L-cysteine, glutathione and ZnCl2 were able to abolish or to reduce the positive reactions to EtHgCl, chlorides of Mg and Mn were unable to do so. Patch tests revealed that in causing positive reactions to TH, EtHg probably interacted with thiol groups and with Zn ions, as in biological systems when causing toxic effects. The limited number of TH reactions in the general population, the constant presence of concomitant positive reactions to EtHgCl and MeHgCl, and the lack of cross-reactivity with other organic or inorganic mercury compounds, lead us to speculate that reactions to TH are due to organomercury alkyl compounds, and that positive subjects have a constitutively reduced capability to metabolize organomercury compounds, rather than to reveal previous exposure.

Contact allergy to thimerosal (TH) has not been considered a marker for mercury allergy, since there is a low degree of cross-sensitivity to inorganic as well as to organic mercury salts. 40 subjects, who previously gave a positive patch test reaction only to thimerosal 0.1% pet. (Hermal), when simultaneously repatch-tested to solutions containing TH, mersalyl acid, p-amino-phenylmercuric acid, mercuric acetate and thiosalicylic acid, respectively, gave positive reactions only to TH. 36 out of 40 subjects were divided into 2 groups of 18 subjects and simultaneously repatch-tested to solutions containing TH, methylmercury chloride (MeHgCl), thiosalicylic acid, and, ethylmercury chloride (EtHgCl), respectively. EtHgCl was tested in the 1st group at 0.031% and in the 2nd group at 0.015%. The results showed that all subjects gave concomitant positive reactions to TH, EtHgCl and MeHgCl. EtHgCl 0.031% gave a higher number of reactions than EtHgCl 0.015%, underlining the rôle of the solvent in these reactions. Patch test results in 300 consecutive patients to a standard series, to which MeHgCl was added, showed that MeHgCl and TH were never able to give isolated positive reactions, and that the concomitant positive reactions occurred in only 3.6% of subjects. In conclusion, our data seem to suggest that the positive reactions to TH found in our patients were due to EtHgCl, and that the structural similarities with MeHgCl were so close that the skin reacted against each as if they were identical.

Preservatives are biologically reactive substances, and their allergenic potential has been known for a long time. This study examined the role of different preservatives in a large number of patients with suspected allergic contact dermatitis. Patch test data and data from the patients' history were collected from the 24 departments participating in the Information Network of Departments of Dermatology from 1 January 1990 to 31 December 1994. Patch test data from 28,349 patients tested with preservatives of the standard series (SS), from 11,485 patients tested additionally with a preservative series (PS), and from 1787 patients tested with an industrial biocide tray (IB) were evaluated. Sensitization rates (standardized) of the SS preservatives were all > 1%, with thiomersal rating highest (5.3%), the parabens lowest (1.6%), and the remainder (chlormethylisothiazolinone/methylisothiazolinone, formaldehyde and methyldibromoglutaronitrile/phenoxyethanol (MDBGN/PE)) in the range of 2%. The most important allergens of the PS were, in women, alkylaminobenzoate (contained in milking fat) (2.5%), MDBGN/PE (2.2%), benzalkonium chloride (1.8%), chloracetamide (1.4%), diazolidinyl urea (1.3%), octylgallate (1.2%) and Bronopol (1.1%). In men rates differed only with regard to alkylaminobenzoate (0.9%). Patients tested with the IB series reacted most often to methylene-bis-thiocyanate (5%), but with a reaction index of -0.7, many reactions were most probably false positives. A further seven preservatives, mostly formaldehyde-releasers used in cutting fluids, gave sensitization rates of between 1% and 3%. Glutaraldehyde, not contained in the series but often tested additionally, showed a remarkable increase in sensitization during the study period. Health care personnel were frequently affected. Altogether, this study identified areas of concern within the different groups of preservatives. The overall impact of most of the preservatives on public health seems to be low, but for diagnostic reasons preservatives must be included in patch test series.

We describe eight patients suffering from Mercurochrome allergy. Patch and prick tests were carried out with the following organic and inorganic mercury compounds: thimerosal, Mercurochrome, phenylmercuric acetate, phenylmercuric nitrate, metallic mercury, and mercuric chloride, and with sodium fluorescein. Two patients had an anaphylactic reaction a few minutes after application of Mercurochrome. The prick tests with Mercurochrome were positive and they were negative with the other tested products. All patch tests were negative. In the other six patients, the clinical picture was local eczema, and the patch tests were all positive with Mercurochrome and the inorganic mercuric derivatives. Positive patch tests with thimerosal were found only in two patients, and only one had a positive patch test with salts of phenylmercury. In four patients, the prick test with Mercurochrome, negative in immediate reading, gave a late eczematous reaction.

The aim of this study was to determine the prevalence of Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis and Prevotella intermedia in a group of adolescents and investigate the association of these organisms with various clinical parameters. A total of 527, 11-13-year-old children, of whom 333 (63%) were white Caucasian, 187 (35%) Indo-Pakistani and 7 (1%) Afro-Caribbean, participated in the study. Subgingival plaque samples, collected from the mesio-buccal of both upper first permanent molars using sterile paper points, were stored in phosphate buffered saline with 0.01% thiomersal and analysed for the presence of A. actinomycetemcomitans, P. gingivalis and P. intermedia using ELISA. The mesio-buccal sites of both upper 1st permanent molars were also examined and the presence/absence of supragingival plaque, subgingival calculus, bleeding on probing and pocket depths greater than 3 mm were recorded. The % of white Caucasian children in whom the monoclonal antibody identified at least 1 site with A. actinomycetemcomitans, P. gingivalis and P. intermedia were 4%, 3% and 2%, respectively, and for Indo-Pakistanis were 3%, 17% and 2%. The difference for P. gingivalis was statistically significant (p0.001). The associations between the clinical parameters and the 3 organisms were considered separately for both upper first molar sites. The prevalence of P. gingivalis was higher for sites with subgingival calculus, pockets3 mm and bleeding on probing (p0.01).

Case Report: A 44-year-old man ingested 83 mgfkg Thiomersal. He developed gastritis, renal tubular failure, dermatitis, gingivitis, delirium, coma, polyneuropathy and respiratoryfailure. Treatment was symptomatic plus gastric lavage and the oral chelating agents dimercaptopropane sulfonate and dimercaptosuccinic acid. The patient recovered completely. Maximum mercury concentrations were blood 14 mg/L, serum 1.7 mg/L, urine 10.7 mg/L, and cerebrospinal fluid 0.025 mg/L. Mercury concentration in blood declined with two velocities: first with half-time 2.2 days, then with half-time 40.5 days. The decline of mercury concentration in blood, urinary mercury excretion, and renal mercury clearance were not substantially influenced by chelation therapy.

[Extract] Thiomersal (also known as thimerosal in the United States) is a bacteriostatic preservative used in vaccines and other biologic products since the 1930s for several specific reasons: as a broad bacteriostatic agent; as a preservative; and to inactivate specific moieties. Its concentration in most vaccines results in delivery of about 25 μg of thiomerosal in each dose administered. Importantly, thiomerosal is only 50% ethylmercury by weight. Many regulators, including the United States Code of Federal Regulations, require the addition of a preservative to multi-dose vaccine vials. Multi-dose vials have several advantages. They are cheaper than single dose formulations, and because more doses can be stored in a smaller space, they allow for decreased storage costs across the cold chain from production to final administration. These costs can be quite substantial for large immunization programs.

The ability of spherule-derived coccidioidin containing 0.4 % phenol and 0.0001 % thimerosal in buffered saline to induce delayed-type hypersensitivity (DTH) was evaluated in four separate studies. The skin test antigen was titrated in 20 adult volunteers with a recent history of pulmonary coccidioidomycosis using intradermal doses of 0.4, 0.8, and 1.6 μg of antigen, based on total dry weight. Based on these data, a dose of 1.27 μg was shown to elicit a mean ± SEM induration response of 23.5 ± 2.3 mm at 48 h, similar to the 23.6-mm response after 48 h of the U. S. Reference coccidioidin last tested approximately 13 years ago. The 1.27 μg dose in 0.1 mL of the spherule-derived antigen (Spherusol) was then examined in three separate groups of adult volunteers to determine the sensitivity and specificity of the product. Fifty-nine of 60 individuals living in a non-endemic area for coccidioidomycosis were skin test negative to Spherusol. Twelve subjects with a recent history of pulmonary histoplasmosis were skin test negative to Spherusol. Finally, 51 of 52 individuals with a recent diagnosis of acute pulmonary coccidioidomycosis were skin test positive to Spherusol. Within this group, prior therapy with fluconazole did not appear to reduce the reactivity to Spherusol. No serious adverse events were observed in the four studies. From these data, Spherusol was found to be safe and has an overall observed sensitivity and specificity of ≥ 98 % in detecting DTH in coccidioidomycosis.

Immunization with the hepatitis B virus (HBV) is effective and safe with an estimated incidence of adverse reactions, either local or systemic, of less than 0.1%. Cutaneous side effects are rare and include lichen planus (LP) and lichenoid reactions. We report the case of a 21-year-old female, in whom a persistent, papulonodular lesion developed at the site of the injection, 6 weeks after the second dose of the HBV. Histological examination revealed lichenoid and pseudolymphomatous features. In addition, sensitization to thiomersal, a vaccine constituent, was documented by patch testing. The association of LP with chronic liver disease is well established. Furthermore, less than 20 cases of lichen or lichenoid reactions, following HBV vaccination, have been reported. Although several arguments have been presented, it is still debated whether there is a causal association or the occurrence of LP following HBV vaccination is a simple coincidence. It has been speculated that a T-cell-mediated, graft-versus-host-like reaction, triggered by a sensitizing protein, is directed against keratinocytes expressing an epitope of hepatitis B surface antigen or a similar epitope. Our case may represent a localized lichenoid reaction to HBV vaccination, a local reactive hyperplasia or a persisting delayed hypersensitivity reaction to a vaccine constituent. This is the first case of a local lichenoid reaction at the injection site of the HBV vaccine, providing further documentation for a causal association linking the HBV vaccine with LP.