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To ensure the quality of immunobiologicals, it is required to quantify the thiomersal preservative present in a number of them. The authors have previously developed an analytical procedure for thiomersal quantification in non-adsorbed immunobiological medicinal products, which is based on cold vapor atomic absorption spectrometry (CV AAS). The aim of the study was to analyse the possibility of using the CV AAS procedure for thiomersal content determination in adsorbed immunobiologicals and evaluate the comparability of thiomersal quantification results obtained by colourimetry and CV AAS. Materials and methods: the study used the national reference standard of mercury ions content and the pharmacopoeial reference standard of thiomersal content in adsorbed medicinal products (PhRS 3.1.00427), as well as samples of immunobiologicals by different manufacturers: a DTP vaccine, anatoxins, hepatitis B and influenza vaccines, and combined vaccines. The study involved CV AAS and the colourimetric reaction between mercury and dithizone. Results: the specificity of the CV AAS procedure is demonstrated by the coefficient of variation (3.95%) and the coefficient of correlation between the test sample volume and thiomersal content (0.9956). The regression analysis and the Fisher’s test value of 0.16 indicate the absence of bias. The trueness of the method is satisfactory, as the percent recovery differs from the total spiked amount by less than 10%. For the sensitivity of the CV AAS procedure, its quantification and detection limits are 6.9×10-3 μg/ mL and 2.3×10-3 μg/ mL, respectively. The Fisher’s test value obtained in the comparability assessment of the results of thiomersal quantification by colourimetry and CV AAS (1.29) is lower than the conventional tabulated one (3.96). Conclusions: according to the study, it is possible to use the CV AAS procedure for thiomersal quantification in adsorbed immunobiologicals. The established detection limit allows evaluating residual amounts of thiomersal in in-process intermediates during the production of preservative-free immunobilogical dosage forms. The comparability assessment of the results of thiomersal quantification by colourimetry and CV AAS, carried out using oneway ANOVA and Fisher’s test, showed the possibility of using PhRS 3.1.00427 to control the consistency of operation when reproducing the CV AAS procedure.

Thiomersal is an organomercurial compound but, despite that, it is widely used in vaccines formulations to inactivate organisms and toxins and to prevent microbial growth during storage and use. In this work, thiomersal (along with traces of mercurial residues) was determined after photo-degradation (using UV and H2O2) to produce Hg2+ that was determined by flow injection analysis using luminescence probing with carbon quantum dots (prepared from citric acid and thiourea). Linear analytical response was observed in the concentration range of 25 to 900 µg L−1 and the method was efficiently applied to the determination of thiomersal in vaccines against hepatitis B and diphtheria-tetanus with recoveries ranging from 93 to 94%.

The paper demonstrates results of testing different modes of Avibacterium paragallinarum inactivation with formaldehyde and thiomersal. The bacterium destruction by 0.20% and 0.10% formaldehyde proceeds at the constant rate thus indicating exponential dependence of the microorganism inactivation processes. This fact allows for calculation of the inactivation rate constant that amounts to 2.94 ± 0.37 h-1 for 0.10% formaldehyde and 5.86 ± 0.72 h-1 for 0.20% formaldehyde. Inactivation using formaldehyde at final concentration of 0.10% at 37 °С and continuous stirring (60 rpm) produces 7.0 dm3 of bacterin at concentration of 9.5 ± 0.2 lg microbial cells (mc)/cm3 in 4.3 ± 0.1 h. Thiomersal demonstrated bactericidal action against Avibacterium paragallinarum at concentration of 0.04% (1:2500) or higher. Herewith, inactivation process is specified by linearity and the inactivation rate constant amounts to 7.92±1.12 h-1. Under thiomersal sublethal concentration of 0.2% (1:5000) the survival curve is of irregular shape. However, the process of the microorganism death is not exponential, and under continuous decrease, the inactivation rate is going to zero thus making impossible the calculation of the inactivation rate constant. Inactivation mode involving use of 0.04% thiomersal at 37 °С allows production of 7.0 dm3 of bacterin at 9.5 ± 0.2 lg mc/cm3 concentration in 5.8 ± 0.1 h. Right after production, the hemagglutination activity of the thiomersal inactivated antigen was higher as compared to formaldehyde inactivated antigen (Р 0.05). The antigen produced using formaldehyde maintains high hemagglutination activity during storage that is critical for high quality vaccine production.

The analysis of national and foreign normative documents regulating modern requirements for preservative quality assessment has been performed. The need for elaboration of modern requirements for quality assessment and standardization of preservatives used in the production of immunobiological preparation in accordance with the good manufacturing and laboratory practice (GMP and GLP) has been justified. The conducted analysis has shown that the most common preservatives in immunobiological preparations are thiomersal, phenol and formaldehyde. The requirements for these preservatives have been elaborated and systematized. International and national assay methods and requirements for thiomersal, phenol, formaldehyde, have been characterized. The results of the studies have been used in elaboration of general chapters related to the assay of thiomersal, phenol and formaldehyde in immunobiological preparations. The projects of general chapters have been approved the minutes of the Board of the Ministry of Health of the Russian Federation on the State Pharmacopoeia and proposed for inclusion in the State Pharmacopoeia of the Russian Federation XIII edition. The constant increase in the range of immunobiological preparations shows the need for further research of preservatives as a part of their content, as well as for studying their properties, mechanism of action and combinations with other preservatives.

This report allowed the detection of three substances using a carbon paste decorated with MoO2 (MoO/CPE). Tartrazine (TZ), sunset yellow (SY) and thiomersal (TMS) were analyzed for adsorptive voltammetry. The electrode was characterized by scanning electron microscopy, energy dispersive spectroscopy and cyclic voltammetry. TZ, SY and TMS were observed at 1.07, 0.80 and 0.95 V respectively. The detection limits (3*σ/m) for TZ, SY and TMS were 0.04, 0.06 and 0.10 μmol/L, respectively. The new analytical method was applied using pharmaceutical samples. [ABSTRACT FROM AUTHOR]

Thiomersal (TM) is an excellent preservative that is used in a wide variety of products, like pharmaceuticals, cosmetics, and vaccines, etc. Its usage has been in decline because of safety concerns. Since vaccine production is on the rise, its use may increase further in low-income and developing countries, as a cost-effective vaccine preservative. Further, Thiomersal is still being used as an essential component in various pharmaceutical preparations. In this light, the present study addresses its mechanism of toxicity in zebrafish and unveils a novel strategy for lessening its negative effects by conjugating cysteine to it, while retaining its antibacterial efficacy. We show that the mitochondrial membrane potential is destabilised by TM, leading to the induction of apoptosis. Interestingly, TM-cysteine conjugate (at a ratio of 1:1) showed no toxicity in zebrafish, whereas TM alone was highly toxic. Importantly, assaying for the bactericidal activity, tested using Escherichia coli (E. coli) and Methicillin-resistant Staphylococcus aureus (MRSA), revealed that the conjugate retains the antibacterial activity, demonstrating that the TM-cysteine conjugate is a safer alternative to TM as a vaccine preservative, and in all the other products that still use TM. [Display omitted] • TM causes apoptosis by interacting with intracellular proteins and mitochondria. • Equimolar mixture of cystine and TM stops TM-mediated toxicity. • Cysteine forms a stable conjugate with TM. • Conjugated form of TM still possesses a decent bactericidal efficacy. • Cysteine combination is the safer alternative to nullify the TM-mediated toxicity. [ABSTRACT FROM AUTHOR]

Epidemiological evidence suggests a link between mercury (Hg) exposure from Thimerosal-containing vaccines and specific delays in development. A hypothesis-testing longitudinal cohort study (n = 49,835) using medical records in the Vaccine Safety Datalink (VSD) was undertaken to evaluate the relationship between exposure to Hg from Thimerosal-containing hepatitis B vaccines (T-HBVs) administered at specific intervals in the first 6 months of life and specific delays in development [International Classification of Disease, 9th revision (ICD-9): 315.xx] among children born between 1991 and 1994 and continuously enrolled from birth for at least 5.81 years. Infants receiving increased Hg doses from T-HBVs administered within the first month, the first 2 months, and the first 6 months of life were significantly more likely to be diagnosed with specific delays in development than infants receiving no Hg doses from T-HBVs. During the decade in which T-HBVs were routinely recommended and administered to US infants (1991–2001), an estimated 0.5–1 million additional US children were diagnosed with specific delays in development as a consequence of 25 μg or 37.5 μg organic Hg from T-HBVs administered within the first 6 months of life. The resulting lifetime costs to the United States may exceed $1 trillion.

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. [ABSTRACT FROM AUTHOR]

Abstract A carbon-paste modified electrode decorated with La 2 O 3 (LaO x /CPE) is reported for the first time for the voltammetric determination of thiomersal (THM) content. The LaO x /CPE surface was characterized using cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS) and scanning electron microscopy (SEM). The presence of La 2 O 3 on the surface of the carbon paste reduces the charge transfer resistance and improves the sensitivity toward the oxidation of THM, with an oxidation current increase of almost 60% and allows its determination by square-wave stripping voltammetry (SWSV). The detection limit (3σ/b) was 0.09 μmol L−1 and the relative standard deviation was 2.5% (n = 7) with three different electrodes. Furthermore, the new sensor was applied in the detection of THM in vaccines and pharmaceutical dosages. Graphical abstract Unlabelled Image Highlights • New application for lanthanum oxide • A new selective, sensitive and stable sensor to detect thimerosal in biological and pharmaceutical samples • Easy to manufacture and reproducible • The samples do not need prior treatment before being analyzed. [ABSTRACT FROM AUTHOR]

Abstract This study investigates the binding of ethylmercury (EtHg+) released from the preservative thiomersal by hydrolysis to proteins in influenza vaccines via ultrafiltration and subsequent total reflection x-ray fluorescence (TXRF) analysis as well as size exclusion chromatography (SEC) hyphenated to inductively coupled plasma-mass spectrometry (ICP-MS). Binding of EtHg+ to the protein fraction was shown by means of ultrafiltration and TXRF in a qualitative matter. SEC/ICP-MS was applied to gain more information about the molecular weight of the bound protein and quantitative information. First experiments showed the necessity of a rinsing step during elution with a thiol-containing compound to prevent unspecific binding or mercury species to the chromatographic system. Adduct formation of EtHg+ and a high-molecular compound could be observed for different concentrations of EtHg+ applied. The mercury-containing fraction was larger than 133 kDa, indicating binding to hemagglutinin, which is the active ingredient in influenza vaccines. The applied SEC/ICP-MS method allowed for external calibration with EtHg+ and a binding of 141 μg L−1 Hg was shown for a vaccine solution that was incubated with EtHg+ (25 mg L−1 Hg). [ABSTRACT FROM AUTHOR]

Investigators postulated that early-life exposure to organic mercury (Hg) significantly increases the risk of childhood neurodevelopmental disorders (NDs). The Vaccine Adverse Event Reporting System database was utilized to conduct a hypothesis testing case-control study by evaluating 3486 total adverse event reports reported following Haemophilus influenza type b (Hib) vaccination. Exposed subjects received a Thimerosal-containing formulation (HIBTITER™, Wyeth-Lederle), while unexposed subjects received a Thimerosal-free formulation (PEDVAXHIB™, Merck). Subjects were included if they received either of these two Hib vaccine formulations between 1995 and 1999. Cases were defined as adverse event reports with a reported outcome of autism, developmental delay, psychomotor delay, or NDs in general. Cases with reported outcomes of febrile convulsions, pyrexia, or injection site pain, all of which have no biologically plausible relation to Hg exposure, were also examined. Controls were defined as adverse event reports without any mention of the specific case outcome examined. Cases of reported autism (odds ratio (OR) = 2.75, p < 0.02), developmental delay (OR = 5.39, p < 0.01), psychomotor disorder (OR = 2.38, p < 0.03), and neurodevelopmental disorder in general (OR = 2.70, p < 0.001) were each significantly more likely than their respective controls to receive Thimerosal-containing Hib vaccine than Thimerosal-free Hib vaccine. Significant effects for neurodevelopmental disorder in general were observed for males (OR = 2.52, p < 0.005), but not females when separated by gender. For the outcomes that had no biologically plausible relation to Hg exposure, the cases were no more likely than their respective controls to receive Thimerosal-containing Hib vaccine than Thimerosal-free Hib vaccine. This study provides suggestive evidence of an association between Thimerosal and neurodevelopmental outcomes and provides support for carrying out additional well-designed studies examining the association between Thimerosal-containing vaccines and a wide range of neurodevelopmental outcomes. [ABSTRACT FROM AUTHOR]

Attention-deficit/hyperactivity disorder (ADHD) is characterized by a marked pattern of inattention and/or hyperactivity-impulsivity that is inconsistent with developmental level and interferes with normal functioning in at least two settings. This study evaluated the hypothesis that infant Thimerosal-containing hepatitis B vaccine (T-HepB) exposure would increase the risk of an ADHD diagnosis. This cross-sectional study examined 4393 persons between 13 and 19 years of age from the combined 1999–2004 National Health and Nutritional Examination Survey (NHANES) by analyzing demographic, immunization, socioeconomic, and health-related variables using the SAS system. Three doses of T-HepB exposure in comparison to no exposure significantly increased the risk of an ADHD diagnosis using logistic regression (adjusted odds ratio = 1.980), linear regression (adjusted beta-coefficient = 0.04747), Spearman’s rank (Rho = 0.04807), and 2 × 2 contingency table (rate ratio = 1.8353) statistical modeling even when considering other covariates such as gender, race, and socioeconomic status. Current health status outcomes selected on an a priori basis to not be biologically plausibly linked to T-HepB exposure showed no relationship with T-HepB. The observed study results are biologically plausible and supported by numerous previous epidemiological studies, but because the NHANES data is collected on a cross-sectional basis, it is not possible to ascribe a direct cause-effect relationship between exposure to T-HepB and an ADHD diagnosis. During the decade from 1991 to 2001 that infants were routinely exposed to T-HepB in the United States (US), an estimated 1.3-2.5 million children were diagnosed with ADHD with excess lifetime costs estimated at US $350-$660 billion as a consequence of T-HepB. Although Thimerosal use in the HepB in the US has been discontinued, Thimerosal remains in the HepB in developing countries. Routine vaccination is an important public health tool to prevent infectious diseases, but every effort should be made to eliminate Thimerosal exposure. [ABSTRACT FROM AUTHOR]

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Thiomersal is employed as preservative in vaccines, cosmetic and pharmaceutical products due to its capacity to inhibit bacterial growth. Thiomersal contains 49.55% of mercury in its composition and its highly toxic ethylmercury degradation product has been linked to neurological disorders. The photo-degradation of thiomersal has been achieved by visible light using graphene quantum dots as catalysts. The generated mercury cold vapor (using adjusted experimental conditions) was detected by multipath atomic absorption spectrometry allowing the quantification of thiomersal at values as low as 20 ng L − 1 even in complex samples as aqueous effluents of pharmaceutical industry and urine. A kinetic study (pseudo-first order with k = 0.11 min − 1 ) and insights on the photo-degradation process are presented. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: 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. Methods: 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. Results: 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). Conclusions: The results show a significant relationship between Hg exposure from Thimerosal-containing childhood vaccines and the subsequent risk of an ED diagnosis. [ABSTRACT FROM PUBLISHER]

Background: Transport of methylmercury (MeHg) across the blood-brain barrier towards the brain side is well discussed in literature, while ethylmercury (EtHg) and inorganic mercury are not adequately characterized regarding their entry into the brain. Studies investigating a possible efflux out of the brain are not described to our knowledge. Methods: This study compares, for the first time, effects of organic methylmercury chloride (MeHgCl), EtHg-containing thiomersal and inorganic Hg chloride (HgCl2) on as well as their transfer across a primary porcine in vitro model of the blood-brain barrier. Results: With respect to the barrier integrity, the barrier model exhibited a much higher sensitivity towards HgCl2 following basolateral incubation (brain-facing side) as compared to apical application (blood-facing side). These HgCl2 induced effects on the barrier integrity after brain side incubation are comparable to that of the organic species, although MeHgCl and thiomersal exerted much higher cytotoxic effects in the barrier building cells. Hg transfer rates following exposure to organic species in both directions argue for diffusion as transfer mechanism. Inorganic Hg application surprisingly resulted in a Hg transfer out of the brain-facing compartment. Conclusions: In case of MeHgCl and thiomersal incubation, mercury crossed the barrier in both directions, with a slight accumulation in the basolateral, brain-facing compartment, after simultaneous incubation in both compartments. For HgCl2, our data provide first evidence that the blood-brain barrier transfers mercury out of the brain. [ABSTRACT FROM AUTHOR]

Studies suggest a relationship between exposure to endocrine disrupters, such as mercury (Hg), and premature puberty. Hg exposure from Thimerosal-containing hepatitis B vaccine, administered at specific intervals within the first six months of life, and the child’s long-term risk of being diagnosed with premature puberty (ICD-9 code: 259.1), was retrospectively examined, using a hypothesis-testing, longitudinal case-control design on prospectively collected data, in the Vaccine Safety Datalink (VSD). Cases diagnosed with premature puberty were significantly more likely to have received increased exposure to Hg from hepatitis B vaccines preserved with Thimerosal given in the first month after birth (odds ratio (OR) = 1.803), first two months after birth (OR = 1.768), and first six months after birth (OR = 2.0955), compared to control subjects. When the data were separated by gender, the effects remained among females but not males. Female cases, as compared to female controls, were significantly more likely in a dose-dependent manner to have received a greater exposure to Hg from hepatitis B vaccines preserved with Thimerosal, given in the first six months after birth (OR = 1.0281 per µg Hg). The results of this study show a dose-dependent association between increasing organic Hg exposure from Thimerosal-containing hepatitis B vaccines administered within the first six months of life and the long-term risk of the child being diagnosed with premature puberty.

Merthiolate (Thiomersal) is known to be used as antimicrobial agent in inactivated vaccines without affecting vaccine potency. The present work investigated the effect of thiomersal contents in ND, AI and IBD inactivated vaccines on liver and kidney functions of vaccinated birds. The histopathological effect and the withdrawal time of such mercurial product from vaccinated chicken muscles were also investigated. Results revealed that residual thiomersal contents in ND, AI and IBD were 0.03; 0.02 and 0.03mg/ml respectively. Liver and kidney function parameters showed significant increases in serum activities of alanine aminotransferase (ALT) and serum aspartate aminotransferase (AST) up to the 4th week post vaccination. Serum urea was significantly decreased on the 3rd week in vaccinated birds compared to control ones. Significant increase in serum creatinine in vaccinated chickens was recorded on the 5th week post vaccination. Liver and kidney functions’ parameters remain high allover the experimental period (8 weeks). The histopathological examination of liver specimens revealed degeneration of hepatic cells and congestion of the central vein with inflammatory cell infiltration and congestion of blood vessels as well as coagulative necrosis. The spleen of vaccinated chickens showed depletion of lymphocytes while lungs showed thickening of the alveolar. Mercury contents in muscle were 0.72, 0.52; 0.046 and 0.00 mg/kg on the 1st, 2nd, 3rd and 4th week post last vaccination that considered safe to the consumer. It is recommended that vaccinated poultry with inactivated vaccines containing thiomersal should not be slaughtered before at least 4 weeks and it is preferable to use combined inactivated vaccines to reduce the thiomersal contents as possible.

Epidemiological evidence suggests a link between mercury (Hg) exposure from Thimerosal-containing vaccines and specific delays in development. A hypothesis-testing longitudinal cohort study ( n = 49,835) using medical records in the Vaccine Safety Datalink (VSD) was undertaken to evaluate the relationship between exposure to Hg from Thimerosal-containing hepatitis B vaccines (T-HBVs) administered at specific intervals in the first 6 months of life and specific delays in development [International Classification of Disease, 9th revision (ICD-9): 315.xx] among children born between 1991 and 1994 and continuously enrolled from birth for at least 5.81 years. Infants receiving increased Hg doses from T-HBVs administered within the first month, the first 2 months, and the first 6 months of life were significantly more likely to be diagnosed with specific delays in development than infants receiving no Hg doses from T-HBVs. During the decade in which T-HBVs were routinely recommended and administered to US infants (1991–2001), an estimated 0.5–1 million additional US children were diagnosed with specific delays in development as a consequence of 25 μg or 37.5 μg organic Hg from T-HBVs administered within the first 6 months of life. The resulting lifetime costs to the United States may exceed $1 trillion. [ABSTRACT FROM AUTHOR]

El Poder Legislativo chileno propone una ley que elimine el timerosal como preservante de las vacunas parenterales del Programa Nacional de Inmunizaciones, proyecto que el Poder Ejecutivo se ha propuesto vetar. El mundo científico informa mayoritariamente que la sospecha de neurotoxicidad atribuida al timerosal es infundada. Pese a ello, las autoridades médicas han oscilado entre sostener que la precaución sugiere apoyar la ley y en otros momentos han manifestando que es más precautorio mantener los programas de vacunación actualmente vigentes. Estas contradicciones y oposiciones ilustran que materias que conciernen a la ciudadanía, requieren una reflexión bioética acabada sobre las políticas públicas sanitarias. Han quedado claro las deficiencias de la deliberación política y la falta de participación social en decisiones que, dado el grado de incertidumbre involucrada en temas como inmunización, requieren no sólo la inclusión de la ciudadanía sino el respeto de la autonomía individual para aceptar o rechazar la inclusión en los programas de vacunación propuestos por las políticas sanitarias. La participación ciudadana en nuestro país se ve severamente limitada por la falta de instrumentos sociales como el plebiscito, el ombudsman y, especialmente, la desidia en crear la Comisión Nacional de Bioética exigida por la Ley 20.120 de 2006, una de cuyas funciones más importantes es mediar deliberativamente entre legos, expertos y políticos en la generación de políticas sanitarias legitimadas por la participación ciudadana.

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 (HgCl 2 ) 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 HgCl 2 . In contrast to HgCl 2 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. [ABSTRACT FROM AUTHOR]

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 (GI 50 : 1.5 to 20 μM) and caused a significant (p < 0.05) 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 ≈ EtHg > TM (p < 0.05). 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. [ABSTRACT FROM AUTHOR]

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. A hypothesis testing case-control study evaluated automated medical records in the Vaccine Safety Datalink (VSD) for organic Hg exposure from Thimerosal in Haemophilus influenzae type b (Hib)-containing vaccines administered at specific times within the first 15 months of life among subjects diagnosed with pervasive developmental disorder (PDD) ( n = 534) in comparison to controls. The generally accepted biologically non-plausible linkage between Thimerosal exposure and subsequent diagnosis of febrile seizure ( n = 5886) was examined as a control outcome. Cases diagnosed with PDD received significantly more organic Hg within the first 6 months of life (odds ratio (OR) = 1.97, p < 0.001) and first 15 months of life (OR = 3.94, p < 0.0001) than controls, whereas cases diagnosed with febrile seizure were no more likely than controls to have received increased organic Hg. On a per microgram of organic Hg basis, cases diagnosed with a PDD in comparison to controls were at significantly greater odds (OR = 1.0197, p < 0.0001) of receiving increasing organic Hg exposure within the first 15 months of life, whereas cases diagnosed febrile seizure were no more likely than controls (OR = 0.999, p > 0.20) to have received increasing organic Hg exposure within the first 15 months of life. Routine childhood vaccination is an important public health tool to reduce the morbidity and mortality associated with infectious diseases, but the present study provides new epidemiological evidence of a significant relationship between increasing organic Hg exposure from Thimerosal-containing vaccines and the subsequent risk of PDD diagnosis in males and females. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effects of different concentrations of thiomersal on apoptosis and autophagy regulation of human leukemia cell lines U937, CEM-C1 and BALL-1., Methods: The inhibitory effect of thiomersal on the proliferation of U937, CEM-C1 and BALL-1 cells was detected by CCK-8 assay. Annexin V-FITC/PI double staining flow cytometry was used to detect the apoptosis rate. Western blot was used to detect the effects of thiomersal on autophagy signaling pathway and the expression of PI3K, Akt, mTOR, p-mTOR, caspase-3 and LC3-II proteins., Results: Within 24 and 48 hours, thiomersal inhibited the proliferation of U937, CEM-C1 and BALL-1 cell lines in a time and dose-dependent manner (r 24 h =0.295, r 24 h =0.452, r 24 h =0.103; r 48 h =0.821, r 48 h =0.665, r 48 h =0.821), but no significant time and dose-dependent effect was observed at 72 hours. After 48 hours treatment of thiomersal, the apoptosis rate of U937, CEM-C1 and BALL-1 cells increased in a dose-dependent manner ( r =0.819, r =0.763, r =0.835). After 48 hours treatment of thiomersal, the expression levels of PI3K, Akt, mTOR and p-mTOR protein in U937, CEM-C1 and BALL-1 cells decreased in a concentration-dependent manner, the R value of U937 cells was -0.975, -0.899, -0.925 and -0.915, respectively, that of CEM-C1 cells was -0.960, -0.920, -0.861 and -0.927, and that of BALL-1 cells was -0.939, -0.911, -0.896 and -0.926,. which suggested that thiomersal-induced apoptosis of U937, CEM-C1 and BALL-1 cells might be due to the inhibition of PI3K/Akt/mTOR pathway. Thiomersal promoted the apoptosis of U937, CEM-C1 and BALL-1 cells via caspase-3 pathway, and the expressions of caspase-3 and LC3-II were up-regulated in a dose-dependent manner ( r =0.976, r =0.914; r =0.976, r =0.986; r =0.961, r =0.974)., Conclusions: Thiomersal can inhibit the proliferation and promote the apoptosis of U937, CEM-C1 and BALL-1 cells. A certain concentration of thiomersal can down-regulate the expression of PI3K/Akt/mTOR pathway related proteins PI3K, Akt, mTOR and p-mTOR in U937, CEM-C1 and BALL-1 cells, and activate autophagy and apoptosis by down-regulation of PI3K/Akt/mTOR pathway.

Determination of thiomersal was made by the temporally selective photo-degradation, mediated by graphene quantum dots (GQDs) and TiO 2 nanoparticles (GQDs-TiO 2) composite, producing the Hg0 quantified by atomic absorption spectrometry (AAS) using a multipass detection cell. The UV photo-reactor was directly adapted to the mercury dedicated spectrometer with samples mixed, into quartz tube, to a solution (buffered at pH 4.0) containing formic acid (1% v /v) and the dispersed GQDs-TiO 2 (0.18 mg L−1). Hg0 temporal profile from thiomersal was detected after 16 min of UV exposure. Different kinetics of Hg0 releasing allowed speciation as the Hg0 from other mercurial species were produced at different times. Analytical linear range was from 15 ng L−1 (LOD) up to 1000 ng L−1. Temporal separation of Hg0 formation was confirmed by gas chromatography coupled to atomic fluorescence spectrometry, also indicating that thiomersal is firstly degraded to ethylmercury before turning into Hg2+ and then into Hg0. The method was applied in the determination of thiomersal in vaccines and residual levels of Hg2+ and ethylmercury were also detected. [Display omitted] • CV_AAS thiomersal quantification was made after photo-degradation with GQDs-TiO 2. • Temporal formation of Hg0 allowed selectivity towards other mercurial species. • Thiomersal was converted into Hg0 without use of further chemical reduction of Hg2+. • Mechanism of thiomersal photo-degradation was studied. • Thiomersal was determined in vaccines along with residual ethylmercury and Hg2+. [ABSTRACT FROM AUTHOR]

This study was performed to determine the effects of long-term freezing on milk composition and to evaluate the possible effects on analysis of four preservative substances ( Azidiol, Kathon CG, Na OH and Thiomersal) on the determination of milk cholesterol, progesterone and lactoferrin concentration. Collected milk was separated in aliquots, stored at 20 °C in 10mL plastic vials and analysed after 1, 6 and 12 months. It could be shown that the preservatives are not equally appropriate for all analysing methods used in this experiment. Preservatives and storage conditions for milk samples have to be carefully selected during the study design depending on the parameters to be measured. [ABSTRACT FROM AUTHOR]

Background: Within the first 3 years of life, the brain develops rapidly. Its development is characterized by critical developmental periods for speech, vision, hearing, language, balance, etc.; and alteration in any of the processes occurring in those critical periods can lead to specific delays in development. Aims: The present study evaluated the potential toxic effects of organic-mercury exposure from Thimerosal (49.55% mercury by weight) in childhood vaccines and its hypothesized possible relationship with specific delays in development. Materials and Methods: A hypothesis testing case-control study was undertaken to evaluate the relationship between exposure to Thimerosal-containing hepatitis B vaccines administered at specific intervals in the first 6 months among cases diagnosed with specific delays in development and controls born between 1991-2000, utilizing data in the Vaccine Safety Datalink database. Results: Cases were significantly more likely than controls to have received increased organic-mercury from Thimerosal-containing hepatitis B vaccine administered in the first, second, and sixth month of life. Conclusion: Though routine childhood vaccination may be an important public health tool to reduce the morbidity and mortality associated with infectious diseases, the present study supports an association between increasing organic-mercury exposure from Thimerosal-containing childhood vaccines and the subsequent risk of specific delays in development among males and females. [ABSTRACT FROM AUTHOR]

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Highlights: [•] Thiomersal was determined on line using FI-MW/UV-CVGAFS. [•] MW/UV allows a “green” on line oxidation of organic mercury to HgII. [•] Each measure requires less than 5min with a LOD of 3ngmL−1 (as mercury). [•] Hg concentration in commercial ophthalmic solutions ranges between 7.5 and 59.0μgmL−1. [Copyright &y& Elsevier]

A traditional infectious disease vaccine is a preparation of live attenuated, inactivated or killed pathogen that stimulates immunity. Vaccine immunologic adjuvants are compounds incorporated into vaccines to enhance immunogenicity. Adjuvants have recently been implicated in the new syndrome named ASIA autoimmune/inflammatory syndrome induced by adjuvants. The objective describes the frequencies of post-vaccination clinical syndrome induced by adjuvants. We performed a cross-sectional study; adverse event following immunization was defined as any untoward medical occurrence that follows immunization 54 days prior to the event. Data on vaccinations and other risk factors were obtained from daily epidemiologic surveillance. Descriptive statistics were done using means and standard deviation, and odds ratio adjusted for potential confounding variables was calculated with SPSS 17 software. Forty-three out of 120 patients with moderate or severe manifestations following immunization were hospitalized from 2008 to 2011. All patients fulfilled at least 2 major and 1 minor criteria suggested by Shoenfeld and Agmon-Levin for ASIA diagnosis. The most frequent clinical findings were pyrexia 68 %, arthralgias 47 %, cutaneous disorders 33 %, muscle weakness 16 % and myalgias 14 %. Three patients had diagnosis of Guillain-Barre syndrome, one patient had Adult-Still's disease 3 days after vaccination. A total of 76 % of the events occurred in the first 3 days post-vaccination. Two patients with previous autoimmune disease showed severe adverse reactions with the reactivation of their illness. Minor local reactions were present in 49 % of patients. Vaccines containing adjuvants may be associated with an increased risk of autoimmune/inflammatory adverse events following immunization. [ABSTRACT FROM AUTHOR]

Abstract: A new simple gas diffusion flow injection method has been developed for the determination of thiomersal in biological samples. The method is based on cold vapor generation of monoatomic mercury from thiomersal reaction with acidic stannous chloride solution (0.6%) acting as reducing agent. The evolved mercury partially diffuses through a Teflon membrane into an acidic permanganate (2.25×10−4 molL−1) acceptor stream, where it is oxidized and re-converted to Hg(II). The resulting decrease in acceptor stream absorbance is sensitively monitored at 528nm. Flow injection variable parameters such as reagents concentrations, injected volume, reactor length, temperature and flow rate were carefully investigated and optimized. The concentration–response relationship was linear over a concentration range of 1–30mgL−1 with a correlation coefficient greater than 0.99 and a good reproducibility (RSD<1.42%, n =6) at 10mgL−1. A detection limit of 0.07mgL−1 (S/N =3) and a sampling frequency of 5samplesh−1 were obtained. The method was successfully applied for the determination of thiomersal in different types of vaccines and gave results in close agreement with those found by previously established HPLC method with no significant interference from vaccines matrices. [Copyright &y& Elsevier]

Cytophagic histiocytic panniculitis (CHP) is a rare disease mostly caused by viral infections and/or lymphoproliferative diseases. We describe a case of CHP associated with H1N1 vaccine during the winter 2009-2010 vaccination campaign and discuss the cutaneous side effects of influenza vaccines. A 6-year-old child presented with inflammatory subcutaneous nodules, which had appeared 1 month after the first injection of H1N1 vaccine and 1 week after the second injection. There was no history of recent infection. The skin lesions spontaneously disappeared without scarring. In CHP the abnormal cytokine secretion from neoplastic or reactive T cells promotes monocyte-macrophage activation and haemophagocytosis. Vaccination is not a common cause of CHP, but it seems possible that, as in infectious diseases, reactive T cells to the vaccine antigen could trigger CHP. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]