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PubMed1990

Reactions to thimerosal in hepatitis B vaccines.

Hypersensitivity to thimerosal in vaccines has been reported to induce persistent local reactions, urticarial and generalized exanthematic eruptions, and, in the case of the hepatitis B vaccine, urticaria with asthma. The authors describe two cases of extensive reactions, one in a patient who did not form antibodies to the principal vaccine antigen. Although not all thimerosal-sensitive patients develop adverse reactions to vaccines containing this material, there is a potential risk, and the reactions can be very long lasting.

Adult↗
PubMed2004

Impact of thimerosal-related changes in hepatitis B vaccine birth-dose recommendations on childhood vaccination coverage.

CONTEXT: In July 1999, the longstanding preference to begin hepatitis B vaccination of all US infants at birth was temporarily suspended because of concerns about exposure to mercury contained in the vaccine preservative thimerosal. The suspension was lifted in September 1999 when preservative-free hepatitis B vaccine became available. OBJECTIVE: To determine the effects of changes in recommendations regarding administration of a hepatitis B birth dose on vaccination coverage. DESIGN, SETTING, AND PARTICIPANTS: Cohort analysis of vaccination status of 41,589 US children born before, during, and after the recommendation to suspend the birth dose. MAIN OUTCOME MEASURES: Association between birth cohort and age at receipt of hepatitis B vaccine dose 1, and receipt by 19 months of age of all recommended vaccines. RESULTS: The proportion of US infants who received dose 1 of hepatitis B vaccine at birth declined from 47% among those born 7 to 12 months before the suspension to 11% among those born during the suspension. Birth-dose coverage remained significantly lower in the year after the suspension was lifted (23% in the first 6 months and 33% in months 7-12). Coverage with 3 doses of hepatitis B vaccine by 19 months of age declined from 88% among those born 7 to 12 months before the suspension to 81% among those born during the suspension and 85% among those born in the 6 months after the suspension, but returned to baseline levels for those born 7 to 12 months after the suspension was lifted. These reductions represent 750,000 fewer newborns vaccinated during 2000 compared with 1998, and an excess 182,000 children undervaccinated for hepatitis B at 19 months of age compared with 1998 coverage levels. Coverage with other recommended vaccinations did not decline over this time. CONCLUSIONS: Reductions in hepatitis B vaccine birth-dose coverage persisted after recommendations were made to resume previous newborn vaccination practices. Although the recommendation to complete the series by 19 months of age was never changed, infants born between July and December 1999 were less likely to have completed the series by 19 months, compared with infants born during the previous year. The lack of impact on other vaccinations suggests that public confidence in immunization remained strong.

Cohort Studies↗
PubMed1977

Quantitative high-pressure liquid chromatographic determination of thimerosal in pharmaceutical formulations.

A quantitative high-pressure liquid chromatographic method an anion-exchange resin column and an aqueous perchlorate solution as the mobile phase is employed for the determination of thimerosal in pharmaceutical formulations. With a liquid formulation containing large amounts of edetate disodium, calcium chloride is used for complexation to eliminate the interference from edetate disodium.

Chromatography, High Pressure Liquid↗
PubMed1978

Thimerosal determination by high-pressure liquid chromatography.

A sensitive and useful high-pressure liquid chromatographic method for the determination of intact thimerosal was developed. This method is extremely fast and reliable, and its inherent specificity makes it a breakthrough over other common wet chemical methods.

Chromatography, High Pressure Liquid↗
PubMed2003

The thiol reagent, thimerosal, irreversibly inhibits meiosis reinitiation in mouse oocyte when applied during a very early and narrow temporal window: a pharmacological analysis.

The effect of the sulfhydryl reagent, thimerosal (TMS) on meiosis resumption in germinal vesicle (GV)-stage denuded mouse oocytes was studied. It irreversibly inhibits both GV breakdown (GVBD) and the first polar body (pb1) extrusion in concentration- and time-dependent manners, the most striking result being the very early and narrow temporal window during which denuded primary oocytes released from their follicle are susceptible to a pulse of the drug. This inhibition is bypassed by dithiothreitol (DTT) with an efficiency declining with time, while thiosalicylic acid (TA), an analog of TMS devoid of the mercury atom, has no effect on meiosis reinitiation. These results strongly suggest that the inhibitory effect of TMS is a consequence of its sulfhydryl group oxidising activity. The molecular target(s) of this inhibitory oxidation should however be identified. In contrast to DTT, okadaic acid (OA), known to bypass the inhibitory effect of drugs interfering with protein kinase activities, only induces chromatin condensation and GVBD in TMS-pulsed oocytes with a delay of about 8 hr as compared to the control situation. This confirms that a very early thiol oxidation induced by TMS exerts a much more dramatic effect on resumption on meiosis than any pharmacological manipulation of protein kinase activities leading to activation of MPF.

Animals↗
PubMed1996

Phosphatidylserine synthesis in glioma C6 cells is inhibited by Ca2+ depletion from the endoplasmic reticulum: effects of 2,5-di-tert-butylhydroquinone and thimerosal.

The effects of 2,5-di-tert-butylhydroquinone (DBHQ) and thimerosal on phosphatidylserine synthesis by the base exchange reaction and on calcium mobilization in intact glioma C6 cells were compared with that of thapsigargin, a selective inhibitor of the endoplasmic reticulum Ca(2+)-ATPase. It has been found that all these agents inhibit phosphatidylserine synthesis by 70%, but their effectiveness are different. The data show that this inhibition is caused by Ca2+ depletion of the endoplasmic reticulum, indicating that phosphatidylserine synthesis requires high concentration of Ca2+ within this structure. On this basis and on literature data, a new model for the localization of the serine base exchange enzyme in the endoplasmic reticulum membrane is proposed.

Brain Neoplasms↗
PubMed1997

Quantification of urinary uric acid in the presence of thymol and thimerosal by high-performance liquid chromatography.

A high-performance liquid chromatographic method was developed as an alternative to automated enzymatic analysis of uric acid in human urine preserved with thymol and/or thimerosal. Uric acid (tR = 10 min) and creatinine (tR = 5 min) were separated and quantified during isocratic elution (0.025 M acetate buffer, pH 4.5) from a mu Bondapak C18 column. The uric-acid peak was identified chemically by incubating urine samples with uricase. The thymol/thimerosal peak appeared at 31 min during the washing step and did not interfere with the analysis. We validated the high-performance liquid chromatographic method for linearity, precision and accuracy, and the results were found to be excellent.

Chromatography, High Pressure Liquid↗
PubMed2003

Effect of taxol and okadaic acid on microtubule dynamics in thimerosal-arrested primary mouse oocytes: a confocal study.

A pulse of thimerosal (TMS), a sulfhydryl reagent, induces an instantaneous, complete and long-lasting microtubule interphasic network disassembly in mouse primary oocytes, correlated with the irreversible inhibition of meiosis reinitiation This inhibition is bypassed by dithiothreitol (DTT) while thiosalicylic acid, an analog of TMS, does induce neither microtubules depolymerisation nor inhibition of reinitiation and resumption of meiosis. This strongly suggests that the dramatic and pleiotropic inhibitory effect of TMS is specifically related to its sulfhydryl group oxidising activity of critical molecules among which tubulin. In contrast to DTT, okadaic acid (OA), known to bypass the inhibitory effect of drugs interfering with protein kinase activities, induces a late chromatin condensation and GVBD in TMS-pulsed oocytes as compared to the control situation, with no significant concomitant microtubule assembly. These cytological features are suggested to be indirectly induced by a late MAPK activation and confirm that a very early thiol oxidation induced by TMS exerts a much more dramatic effect on resumption of meiosis than any pharmacological manipulation of protein kinase activities leading to activation of MPF. Finally, taxol was shown to promote tubulin polymerisation even when microtubules were irreversibly disassembled by thiol oxidation but fails to restore the ability to undergo maturation.

Animals↗
PubMed1996

The inositol 1,4,5-trisphosphate-gated Ca2+ channel: effect of the protein thiol reagent thimerosal on channel activity.

The solubilized partially purified Ins(1,4,5)P3-sensitive Ca2+ channel from rat cerebellum has been reconstituted into planar lipid bilayer membranes by the 'tip-dip' method [Ehrlich (1992) Methods Enzymol. 207, 463-471] allowing low noise current records. Single-channel events have been recorded. In the presence of 10 microM Ins(1,4,5)P3, 50 microM ATP, and 0.2 microM Ca2+ the Ins(1,4,5)P3 receptor channel opens to a conductance level of 53 pS. In the presence of 100 microM thimerosal (TMS), a sulphydryl-oxidizing agent, three subconductance levels (60 pS, 80 pS and 120 pS) were observed. More than one population of mean open times was found, both in the absence and presence of TMS, although TMS affected the length of the open time by decreasing the short opening significantly from 4.05 ms to 2.78 ms and increasing the longer open time from 27.8 ms to 94.8 ms. The results indicate that TMS enhances Ins(1,4,5)P3-induced Ca2+ release by both altering the open times of the channel significantly and causing a shift to higher subconductance levels.

Adenosine Triphosphate↗
PubMed2004

Hepatitis B vaccine coverage among infants born to women without prenatal screening for hepatitis B virus infection: effects of the Joint Statement on Thimerosal in Vaccines.

BACKGROUND: As a result of controversy about mercury exposures from vaccines containing thimerosal, the American Academy of Pediatrics and the US Public Health Service recommended in July 1999 that the first dose of hepatitis B vaccine be deferred until 2 to 6 months of age, but only for infants born to hepatitis B surface antigen (HBsAg)-negative women. We investigated the effect of these recommendation changes on the management of Oregon infants born to women whose HBsAg status was "unknown." METHODS: Infants were identified by reviewing electronic birth certificate data from 34 Oregon hospitals during (1)April through June 1999 [before recommendation changes (T1)], (2) August through October 1999 [after recommendations changes (T2)] and (3) April through June 2000 [when resumption of pre-1999 practices were recommended (T3)]. We verified maternal HBsAg screening and newborn hepatitis B vaccination by chart review. RESULTS: We identified 147 infants born to women who were not screened for HBsAg. During T1, 27% of infants born to mothers of unknown HBsAg status were vaccinated within 12 h of birth, and 80% were vaccinated before hospital discharge. This decreased to 2 and 4%, respectively, during T2 and continued to remain lower during T3. CONCLUSION: Hepatitis B vaccine coverage for infants born to unscreened women declined significantly after the July 1999 announcement and remained significantly lower 10 to 12 months later. When changes are made in established vaccination practices, policy makers should ensure that such changes are not misinterpreted, resulting in failure to immunize appropriate groups.

Cohort Studies↗
PubMed1992

Photosensitivity to piroxicam is induced by sensitization to thimerosal and thiosalicylate.

Piroxicam (PXM), a nonsteroidal anti-inflammatory drug, has been well known to often induce photosensitive eruptions within a few days after its administration. It has been reported that this photosensitivity correlates well with a positive patch-test reaction to thimerosal (TMS) and also to thiosalicylate (TOS), which is an active hapten of TMS. But it has not yet been concluded whether this correlation is caused by a cross-reaction among the drugs or not. In our experiments, animals contact-sensitized with TMS or TOS developed positive photopatch-test reactions to PXM, and those photocontact-sensitized with PXM had positive patch-test reactions to TMS and TOS. Photosensitive reactions were also induced by UVA irradiation (photo test) performed 90 min after perioral administration of PXM in the animals contact-sensitized with TMS or TOS. Analysis of the UVA-treated PXM by nuclear magnetic resonance spectrography and thin-layer chromatography revealed that the high dose of UVA induced photodecomposition of PXM, and generated several other chemicals different from PXM. But the PXM treated with the high dose of UVA could not induce positive patch-test reactions in many of the animals contact-sensitized with TMS or TOS. The cross-reacting hapten generated from PXM by UVA treatment may not be stable in the absence of carrier proteins. These results taken together indicate that the PXM photosensitivity in man is induced by contact-sensitization with TMS, as shown in our animal model, and then is photoallergic in nature. But the identity of the cross-reacting substance remains unknown.

Animals↗
PubMed2006

Assessment of metallothionein and antibodies to metallothionein in normal and autistic children having exposure to vaccine-derived thimerosal.

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.

Autistic Disorder↗
PubMed1994

All these positive tests to thimerosal.

By and large, positive patch tests with thimerosal lack clinical relevance and should cause concern neither to the dermatologist nor to the patient. The substance should be retained in standard test series for scientific purposes, but on clinical grounds its inclusion does not seem to be indicated. Nevertheless, the phenomenon is intriguing in its own right.

Cross Reactions↗
PubMed1998

Thimerosal positivities: the rôle of SH groups and divalent ions.

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.

Alkylmercury Compounds↗
PubMed1999

Thimerosal positivities: patch testing to methylmercury chloride in subjects sensitive to ethylmercury chloride.

The aim of this paper was to evaluate whether methylmercury chloride (MeHgCl) aq., when patch tested in a group of thimerosal-positive subjects reacting to ethylmercury chloride (EtHgCl), might be a reliable model for the better understanding of interactions between alkylmercury compounds and the skin. 19 out of 21 consecutive patients who previously had given positive patch-test reactions to both ethylmercury chloride 0.0165% eth.(EtHgCl, 0.615 mM) and MeHgCl 0.031% aq.(1.23 mM), and negative reactions to thiosalicylic acid 0.05% (3.24 mM) aq./eth. 50/50, were repatch tested to 8 microl of MeHgCl 0.031% aq. and to 8 microl of aq. solutions containing MeHgCl mixed with cysteine, glutathione, ZnSO4, MgSO4, MnSO4, ZnCl2, MgCl2 and MnCl2, respectively. The results showed that cysteine, glutathione and Zn(II) salts were able to abolish the positive reactions, demonstrating the rôle played by both thiol groups and Zn(II) itself. Patch tests concomitantly carried out in 16 out of 19 patients to 8 microl of aqueous MeHgCl and to 8 microl of aqueous solutions containing MeHgCl and MeHgCl mixed to fragment 56-61 of metallothionein I (MT I), MT I and MT II-Zn, respectively, revealed that all the MTs tested were able to reduce or to inhibit the reactions, demonstrating the effect of the thiol groups. Due to the close chemical similarities to EtHgCl and to its water solubility, MeHgCl seems to be a suitable model for evaluating the reactivity of alkylmercury compounds in the skin. We speculate that both EtHg- and MeHg-derivatives are xenobiotics with similar reactivity. However, the lack of clinical relevance of the reactions to both alkyl compounds lead us to conclude that, since environmental exposure does not seem to play a pivotal rôle, they probably have mostly to do with compounds included in in the standard series, and are elicited by reduced function of physiological SH chelators.

Adult↗
PubMed2006

Uncoupling of ATP-mediated calcium signaling and dysregulated interleukin-6 secretion in dendritic cells by nanomolar thimerosal.

Dendritic cells (DCs) , a rare cell type widely distributed in the soma, are potent antigen-presenting cells that initiate primary immune responses. DCs rely on intracellular redox state and calcium (Ca2+) signals for proper development and function, but the relationship between these two signaling systems is unclear. Thimerosal (THI) is a mercurial used to preserve vaccines and consumer products, and is used experimentally to induce Ca2+ release from microsomal stores. We tested adenosine triphosphate (ATP) -mediated Ca2+ responses of DCs transiently exposed to nanomolar THI. Transcriptional and immunocytochemical analyses show that murine myeloid immature DCs (IDCs) and mature DCs (MDCs) express inositol 1,4,5-trisphosphate receptor (IP3R) and ryanodine receptor (RyR) Ca2+ channels, known targets of THI. IDCs express the RyR1 isoform in a punctate distribution that is densest near plasma membranes and within dendritic processes, whereas IP3Rs are more generally distributed. RyR1 positively and negatively regulates purinergic signaling because ryanodine (Ry) blockade a) recruited 80% more ATP responders, b) shortened ATP-mediated Ca2+ transients > 2-fold, and c) produced a delayed and persistent rise (>/= 2-fold) in baseline Ca2+. THI (100 nM, 5 min) recruited more ATP responders, shortened the ATP-mediated Ca2+ transient (>/= 1.4-fold) , and produced a delayed rise (>/= 3-fold) in the Ca2+ baseline, mimicking Ry. THI and Ry, in combination, produced additive effects leading to uncoupling of IP3R and RyR1 signals. THI altered ATP-mediated interleukin-6 secretion, initially enhancing the rate of cytokine secretion but suppressing cytokine secretion overall in DCs.DCs are exquisitely sensitive to THI, with one mechanism involving the uncoupling of positive and negative regulation of Ca2+ signals contributed by RyR1.

Adenosine Triphosphate↗
PubMed2003

Impact of the thimerosal controversy on hepatitis B vaccine coverage of infants born to women of unknown hepatitis B surface antigen status in Michigan.

OBJECTIVE: Hepatitis B vaccine is recommended for all infants, and the series may be started during the delivery admission. For infants who are born either to women who are positive for hepatitis B surface antigen (HBsAg) or to women whose HBsAg status is unknown, vaccination should be started within 12 hours of birth to prevent perinatal and early childhood hepatitis B virus infection. Because of concerns about mercury exposures from vaccines that contain thimerosal, the United States Public Health Service (USPHS) and the American Academy of Pediatrics (AAP) recommended in July 1999 that the first dose of hepatitis B vaccine be deferred until 2-6 months of age but only for infants who are born to HBsAg-negative women. To assess the impact on birth-dose vaccine coverage for infants who are born to women with unknown HBsAg status, we measured coverage before and after July 1999. METHODS: A sample of Michigan infants who were born to women whose HBsAg status was either unknown or missing were identified by reviewing newborn screening cards for infants who were born during 1) March-April 1999 (before recommendation changes [T1]); 2) July 15-September 15, 1999 (immediately after recommendation changes [T2]); and 3) March-April 2000 (6 months after resumption of pre-1999 practices were recommended [T3]). We verified maternal HBsAg screening and newborn hepatitis B vaccination by reviewing infant and maternal hospital records. RESULTS: Of 1201 infants who were born to women whose HBsAg status was indicated as unknown or missing on the newborn screening card during the 3 time periods, 216 (18%) were born to women whose status was truly unknown at the time of delivery, as determined by medical record review. During T1, 53% of these 216 infants received hepatitis B vaccine before hospital discharge, compared with 7% of infants who were born during T2 and 57% of infants who were born during T3. During T1, 19% of these infants received hepatitis B vaccine within 12 hours of birth compared with 1% of infants who were born during T2 and 14% of infants who were born during T3. CONCLUSIONS: Hepatitis B vaccine birth-dose coverage for infants who were born to women whose HBsAg status was unknown at the time of delivery was already low in Michigan before the July 1999 USPHS/AAP Joint Statement but decreased significantly during the 2 months after the USPHS/AAP Joint Statement. Abrupt changes in established vaccination recommendations for lower risk children may lead to decreased coverage among higher risk children. Increases in hepatitis B vaccine coverage at birth are necessary to reduce the risk of perinatal infection for infants who are born to women with unknown HBsAg status.

Contraindications↗
PubMed2001

Impact of the 1999 AAP/USPHS joint statement on thimerosal in vaccines on infant hepatitis B vaccination practices.

On July 8,1999, the American Academy of Pediatrics (AAP) and the U.S. Public Health Service (PHS) jointly recommended reducing infant exposure to thimerosal, a commonly used vaccine preservative that contains mercury. Specific recommendations were made to postpone the first hepatitis B vaccine dose until 2-6 months of age for infants born to hepatitis B surface antigen (HBsAg)-negative (i.e., not hepatitis B virus [HBV]-infected) women. Infants born to HBsAg-positive (i.e., HBV-infected) women, or to women whose HBsAg status was unknown, were recommended to receive postexposure prophylaxis with the first dose of hepatitis B vaccine administered within 12 hours of birth. By mid-September 1999, when adequate supplies of preservative-free hepatitis B vaccine became available, PHS advocated a return to previous infant hepatitis B vaccination practices, including administering the first dose of hepatitis B vaccine to newborns in hospitals that had discontinued the practice. In 2000, preliminary assessments of the impact of these policy changes on routine hepatitis B vaccination practices were conducted by public health officials in Wisconsin, Oklahoma, Oregon, and Michigan. This report summarizes the results of these analyses, which indicate that many hospitals in Wisconsin have not reinstated policies to ensure routine administration of hepatitis B vaccine to newborns despite the availability of preservative-free hepatitis B vaccine, that the number of hepatitis B vaccine doses given to newborns in Oklahoma and Oregon has declined, and that an unvaccinated Michigan infant died from fulminant hepatitis B. Restoring routine newborn hepatitis B vaccination practices may require active advocacy by professional and government groups.

Hepatitis B↗