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PubMed2004

Neurotoxic effects of postnatal thimerosal are mouse strain dependent.

The developing brain is uniquely susceptible to the neurotoxic hazard posed by mercurials. Host differences in maturation, metabolism, nutrition, sex, and autoimmunity influence outcomes. How population-based variability affects the safety of the ethylmercury-containing vaccine preservative, thimerosal, is unknown. Reported increases in the prevalence of autism, a highly heritable neuropsychiatric condition, are intensifying public focus on environmental exposures such as thimerosal. Immune profiles and family history in autism are frequently consistent with autoimmunity. We hypothesized that autoimmune propensity influences outcomes in mice following thimerosal challenges that mimic routine childhood immunizations. Autoimmune disease-sensitive SJL/J mice showed growth delay; reduced locomotion; exaggerated response to novelty; and densely packed, hyperchromic hippocampal neurons with altered glutamate receptors and transporters. Strains resistant to autoimmunity, C57BL/6J and BALB/cJ, were not susceptible. These findings implicate genetic influences and provide a model for investigating thimerosal-related neurotoxicity.

Animals↗
PubMed1999

Thimerosal enhances agonist-specific differences between [Ca2+]i oscillations induced by phenylephrine and ATP in single rat hepatocytes.

Single rat hepatocytes, microinjected with the Ca(2+)-sensitive photoprotein aequorin, respond to agonists acting through the phosphoinositide signalling pathway by the generation of oscillations in cytosolic free Ca2+ concentration ([Ca2+]i). The duration of [Ca2+]i transients generated is characteristic of the stimulating agonist; the differences lie in the rate of fall of [Ca2+]i from its peak. We considered that differential sensitivity of the InsP3 receptor may underlie agonist specificity. The thiol reagent, thimerosal, is known to increase the sensitivity of the Ca2+ stores to InsP3 by increasing the affinity of the InsP3 receptor for InsP3 in rat hepatocytes. We show here that a low dose of thimerosal (1 microM), insufficient alone to elevate [Ca2+]i, potentiates [Ca2+]i oscillations induced by phenylephrine or ATP in single, aequorin-injected, rat hepatocytes. Moreover, thimerosal enhances both the frequency and amplitude of phenylephrine-induced oscillations, whereas, in contrast, ATP-induced oscillations undergo an increase in the duration of the falling phase of individual [Ca2+]i transients. Thimerosal, therefore, enhances, rather than eliminates, agonist-specific differences in the hepatocyte [Ca2+]i oscillator.

Adenosine Triphosphate↗
PubMedDate not supplied

An assessment of the impact of thimerosal on childhood neurodevelopmental disorders.

The prevalence of autism in the US has risen from 1 in approximately 2500 in the mid-1980s to 1 in approximately 300 children in the mid-1990s. The purpose of this study was to evaluate whether mercury from thimerosal in childhood vaccines contributed to neurodevelopmental disorders. Neurodevelopmental disorder dose-response curves for increasing mercury doses of thimerosal in childhood vaccines were determined based upon examination of the Vaccine Adverse Events Reporting System (VAERS) database and the 2001 US' Department of Education Report. The instantaneous dosage of mercury children received in comparison to the Food and Drug Administration (FDA)'s maximum permissible dose for the oral ingestion of methylmercury was also determined. The dose-response curves showed increases in odds ratios of neurodevelopmental disorders from both the VAERS and US Department of Education data closely linearly correlated with increasing doses of mercury from thimerosal-containing childhood vaccines and that for overall odds ratios statistical significance was achieved. Similar slopes and linear regression coefficients for autism odds ratios in VAERS and the US Department of Education data help to mutually validate each other. Controls employed in the VAERS and US Department of Education data showed minimal biases. The evidence presented here shows that the occurrence of neurodevelopmental disorders following thimerosal-containing childhood vaccines does not appear to be coincidental.

Autistic Disorder↗
PubMed1997

Complete activation of porcine oocytes induced by the sulfhydryl reagent, thimerosal.

Thimerosal (200 microM) triggered Ca2+ oscillations in 56 of 56 mature porcine oocytes. The Ca2+ oscillations were blocked by the sulfhydryl-reducing agent dithiothreitol (DTT), thus supporting the hypothesis that thimerosal acts by oxidizing critical sulfhydryl groups on intracellular Ca2+-release proteins. Thimerosal treatment alone arrested the oocytes in metaphase, probably by oxidizing tubulin sulfhydryl groups and thus destroying the spindle. However, a 10-min exposure to 200 microM thimerosal followed by a 30-min incubation in 8 mM DTT induced complete activation, as 73.8% of the oocytes formed pronuclei. The second polar body was visible in 73.3% (55 of 75) of the activated oocytes. Combined thimerosal/DTT treatment of the oocytes also induced cortical granule exocytosis, as revealed by confocal microscopy, and the subsequent hardening of the zona pellucida. After activation, some oocytes were incubated in vitro, or in vivo in a ligated porcine oviduct, for 6 days. When cultured in vitro, 42.0% (37 of 88) of the oocytes developed to the compact morula or blastocyst stage; the average number of inner cell mass (ICM) and trophectoderm (TE) nuclei in the blastocysts was 8.6 +/- 0.7 and 20.1 +/- 1.3, respectively. Culture in a ligated oviduct resulted in 42.9% development to the compact morula or blastocyst stage, with the blastocysts having a mean number of 12.5 +/- 1.0 ICM and 63.6 +/- 9.2 TE nuclei.

Animals↗
PubMed1983

Reactions induced by the concurrent use of thimerosal and tetracycline.

We examined the reaction to thimerosal which occurred when patients were prescribed tetracyclines simultaneously. Nine patients were identified who had been using a 0.004% thimerosal-containing contact lens solution for over 6 months. All had developed varying degrees of ocular reaction (red eye, irritation, blepharitis) apparently as a result of taking tetracyclines concurrently. The reaction disappeared upon discontinuance of either the thimerosal or the tetracyclines. The hypothesis that the reaction was due to an interaction between thimerosal and tetracyclines was confirmed in rabbits.

Animals↗
PubMed1987

In vivo effects of thimerosal on the rabbit corneal endothelium: an ultrastructural study.

To assess ultrastructural alterations to the corneal endothelium, eye drops containing vehicle alone or vehicle plus 0.004% thimerosal with or without 0.1% disodium ethylenediaminetetraacetate (Na2EDTA) were administered hourly over a 2-day period to rabbit corneas in vivo. Twenty of the corneas received a 5-mm keratectomy that removed epithelium and superficial stroma and 10 corneas were left intact. The vehicle alone had no effect on the endothelium of normal corneas. Thimerosal drops with or without Na2EDTA caused some clarification of the cytoplasm and dilatation of the endoplasmic reticulum of endothelial cells. The mitochondria had dilated cristae and membrane condensations. After keratectomy and vehicle only drops, the central endothelium showed a marked increase in microvilli and mitochondrial changes. Addition of either thimerosal or thimerosal plus Na2EDTA resulted in a slight decrease in membrane activity but an increase in intracellular edema and dilatation and damage to organelles. The peripheral areas were less affected than the center. Although the endothelium was stressed, most changes were considered reversible.

Animals↗
PubMed1991

Cross-reactivity between sensitivity to thimerosal and photosensitivity to piroxicam in guinea pigs.

Piroxicam (PXM) is a nonsteroidal anti-inflammatory drug which may induce a photosensitive eruption shortly after administration. We examined whether animals sensitized to thimerosal developed a photosensitivity to PXM. Male Hartley strain guinea pigs were sensitized to thimerosal, thiosalicylate and PXM separately. The open patch test was used to evaluate sensitization to each drug and cross-reactions between the drugs. Animals sensitized to thimerosal exhibited positive patch test reactions to thiosalicylate and positive photopatch test reactions to PXM. Both those sensitized to thiosalicylate and to PXM showed positive patch test reactions to PXM. This study demonstrated that thimerosal induces cross-sensitivity to PXM in vivo and that the common active component among these compounds may be thiosalicylate.

Animals↗
PubMed2003

The nitric oxide- and prostaglandin-independent component of the renal vasodilator effect of thimerosal is mediated by epoxyeicosatrienoic acids.

Epoxyeicosatrienoic acids (EETs) are cytochrome P450-derived metabolites of arachidonic acid that elicit vasodilation via activation of K(+) channels. They have been implicated as endothelium-derived hyperpolarizing factors (EDHFs), mediating the effect of some endothelium-dependent vasodilator agents such as bradykinin in some vascular tissues. We reasoned that an agent that increases the availability of free arachidonic acid should also elicit cytochrome P450-dependent vasodilation that is associated with increased release of EETs and attenuated by agents that inhibit the synthesis or action of EETs. Thus, we used thimerosal as an inhibitor of reacylation of arachidonic acid and determined the contribution of prostaglandins, nitric oxide, and EETs to the vasodilator effect in the isolated, perfused, preconstricted kidney of the rat. Thimerosal elicited vasodilator responses that were unaffected by inhibition of cyclooxygenase with indomethacin but were reduced by the further inhibition of nitric oxide synthesis. The vasodilator activity that remained after inhibition of cyclooxygenase and nitric oxide synthase was reduced by inhibition of K(+) channels with tetraethylammonium and was associated with increased release of EETs measured by gas chromatography-mass spectroscopy following hydrolysis to the corresponding diols. Inhibition of cytochrome P450 with miconazole or epoxygenase with N-methylsulfonyl-6-(2-propargyloxyphenyl)hexamide reduced the nitric oxide- and prostaglandin-independent vasodilator effect of thimerosal and attenuated the increase in the release of EETs. We conclude that thimerosal causes vasodilation of the isolated perfused kidney via nitric oxide-dependent and -independent mechanisms. The nitric oxide-independent component of the response involves activation of K(+) channels and is likely mediated by EETs, possibly acting as EDHFs.

8,11,14-Eicosatrienoic Acid↗
PubMed1993

Fertilisation and thimerosal stimulate similar calcium spiking patterns in mouse oocytes but by separate mechanisms.

Exposure of freshly ovulated mouse oocytes to a fertilising spermatozoon, thimerosal, Sr2+ or acetylcholine induced similar Ca2+ spiking responses. We propose that each of the four agents reduces the threshold for Ca2+ release from internal stores, but by different mechanisms. All agents except thimerosal stimulated oocyte activation, but thimerosal caused dissassembly of the meiotic spindle and thus prevented progress into interphase. Dithiothreitol (DTT) completely blocked and reversed the spiking responses induced by thimerosal, but facilitated and accelerated those induced by spermatozoa, Sr2+ and acetylcholine. The stimulatory effect of DTT was not simply a consequence of progress into interphase, but was attributable, at least in part, to an enhancement of divalent cation entry, as measured by Mn2+ quench analysis of fura-2 in both fertilised and unfertilised oocytes. Possible mechanisms by which DTT might achieve its effects are discussed.

Animals↗
PubMed2004

Thimerosal exposure in infants and developmental disorders: a prospective cohort study in the United kingdom does not support a causal association.

OBJECTIVE: There is an established link between exposure to mercury and impaired childhood cognitive development and early motor skills. Thimerosal (also known as thiomersal), a preservative used in a number of children's vaccines, contains ethylmercury (an organic compound of mercury), and there has been concern that this exposure to mercury may be of some detriment to young children. The aim of this research was to test in a large United Kingdom population-based cohort whether there is any evidence to justify such concerns. METHODS: We used population data from a longitudinal study on childhood health and development. The study has been monitoring >14,000 children who are from the geographic area formerly known as Avon, United Kingdom, and were delivered in 1991-1992. The age at which doses of thimerosal-containing vaccines were administered was recorded, and measures of mercury exposure by 3, 4, and 6 months of age were calculated and compared with a number of measures of childhood cognitive and behavioral development covering the period from 6 to 91 months of age. RESULTS: Contrary to expectation, it was common for the unadjusted results to suggest a beneficial effect of thimerosal exposure. For example, exposure at 3 months was inversely associated with hyperactivity and conduct problems at 47 months; motor development at 6 months and at 30 months; difficulties with sounds at 81 months; and speech therapy, special needs, and "statementing" at 91 months. After adjustment for birth weight, gestation, gender, maternal education, parity, housing tenure, maternal smoking, breastfeeding, and ethnic origins, we found 1 result of 69 to be in the direction hypothesized-poor prosocial behavior at 47 months was associated with exposure by 3 months of age (odds ratio: 1.12; 95% confidence interval: 1.01-1.23) compared with 8 results that still supported a beneficial effect. CONCLUSIONS: We could find no convincing evidence that early exposure to thimerosal had any deleterious effect on neurologic or psychological outcome.

Animals↗
PubMed2005

Being on the track of thimerosal. Review.

The common preservative thimerosal is one of the most important organic mercury compounds human populations are exposed to. It has toxic effect on several cell lines, and it also induces programmed cell death in in vitro experiments. Association is suggested between application of thimerosal-containing vaccines and the occurrence of neurodevelopmental disorders, like autism. While specific recommendations were made to eliminate thimerosal from vaccines, consistent evidence is still lacking for an association of exposure and disease. Unfortunately, it is very hard to study the molecular background of complex human diseases directly; however, investigations on more simple model organisms may lead to a better understanding of thimerosal as a possible disease inducing factor.

Animals↗
PubMed1999

Recommendations regarding the use of vaccines that contain thimerosal as a preservative.

On October 20, 1999, the Advisory Committee on Immunization Practices (ACIP) reviewed information about thimerosal in vaccines and received updates from CDC's National Immunization Program and several vaccine manufacturers on the current and anticipated availability of vaccines that do not contain thimerosal as a preservative. The review was prompted by a joint statement about thimerosal issued July 8, 1999, by the American Academy of Pediatrics (AAP) and the Public Health Service (PHS) (1) and a comparable statement released by the American Academy of Family Physicians (2). These statements followed a Congressionally mandated Food and Drug Administration (FDA) review of mercury in drugs and food, which included a reassessment of the use of thimerosal in vaccines.

Legislation, Drug↗
PubMed1991

Ocular hypersensitivity to thimerosal in rabbits.

Rabbits were immunized to thimerosal conjugates and challenged with specific antigen-sensitized contact lenses. The symptoms of acute ocular hypersensitivity observed included corneal edema, corneal infiltration and erosion, infiltration of the anterior chamber, iritis, conjunctival edema and hyperemia, and a significant increase in mucous production. Occasional evidence of corneal neovascularization and giant conjunctival papillae were seen. All these parameters were assessed on a five-point scale (0 to +4) and tabulated as an ocular index. The index of ocular hypersensitivity correlated with the titers of the serum antibodies to thimerosal. The major class of serum antibodies consisted of immunoglobulin (Ig) G, with IgA compromising approximately 5% of serum antibodies. During the ocular challenge, the total and IgG tear antibody titers increased as a result of increased vascular permeability. The tear IgA titers increased to a lesser extent than IgG. The influx of serum proteins directly into the tear film was confirmed by a protein-dye tracer technique. Histologic analysis showed that the ocular inflammatory response was accompanied by both polymorphonuclear and mononuclear cell infiltrates into the cornea and conjunctiva. In conclusion, thimerosal-immunized rabbits show an exquisite sensitivity to the minute quantities of thimerosal conjugates adsorbed to contact lenses. Both serum and tear antibodies correlate with the severity of the ocular inflammatory response. This model would appear to simulate an antibody-mediated immune complex or Arthus type of ocular hypersensitivity commonly seen to foreign antigens including preservatives.

Animals↗
PubMed1982

Factors affecting survival of Pseudomonas cepacia in decongestant nasal sprays containing thimerosal as preservative.

Strains of Pseudomonas cepacia, isolated from packages of nasal spray preserved with thimerosal, showed a high degree of resistance to the organomercurial, as compared to low and moderate resistance of standard laboratory strains or isolates from water. The product isolates were shown to degrade the thimerosal to metallic mercury which volatilized from the product or assay medium. The addition of organic nutrient was essential for survival of unadapted cells in the product. However, when cells were first grown in diluted product containing added nutrient and then inoculated into the full-strength product, survival and growth occurred even in the absence of added nutrient. The time required for growth to occur was inversely related to the amount of added nutrient. At low nutrient concentrations, approximately 99.9% of the inoculated cells were killed rapidly, but after a lag time of 7-12 days, the few survivors began to increase in numbers and eventually attained high cell concentrations. These findings should be useful in planning production and testing programs with thimerosal-preserved products.

Aerosols↗
PubMed1995

The effects of thimerosal, a sulfhydryl reagent, on phasic myometrial contractions.

Thimerosal inhibits calcium uptake and IP3-induced calcium release from IP3-sensitive endoplasmic reticulum; this study sought to evaluate the effects of thimerosal on agonist-stimulated phasic myometrial contractions. Thimerosal was found to significantly inhibit phasic contractions stimulated by oxytocin, aluminum fluoride, potassium chloride, ionomycin, and Bay K 8644. These observations provide support for the hypothesis that calcium uptake and IP3-induced calcium release are important events during agonist-stimulated phasic myometrial contractions.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1993

Reversible blockade of the calcium-activated nonselective cation channel in brown fat cells by the sulfhydryl reagents mercury and thimerosal.

We have used patch-clamp techniques to study the effect of the sulfhydryl group oxidizing agents mercury and thimerosal on calcium-activated nonselective cation channels from brown adipose tissue. 100 nmol/l mercury and 50 mumol/l thimerosal induced a complete block. Blockade could be reversed by reduction of the mercaptide by dithiotreitol (DTT). Mercury was found to be the most potent blocker (IC50-value 21 x 10(-9) mol/l), whereas thimerosal (IC50-value 1.5 x 10(-6) mol/l) was as effective as 3',5-dichlorodiphenylamine-2-carboxylic acid (DCDPC). The DCDPC effect, however, could not be reversed by DTT, indicating different blocking mechanisms. It is concluded that SH-groups are involved in gating of the calcium-activated nonselective channel.

Adipose Tissue, Brown↗
PubMedDate not supplied

Two further examples of IgG thimerosal-dependent antibodies and their serological characteristics.

Two further examples of IgG thimerosal-dependent antibodies have been found by routine immunohematological tests carried out in our laboratory. Both antibodies fixed the complement and had no apparent blood group specificity. Their reactivity was inhibited by adding thimerosal to the serum prior to the addition of red blood cells. If cross matching is performed accordingly, thimerosal-dependent antibodies should not any longer represent a blood bank problem.

ABO Blood-Group System↗
PubMed1985

Modified cation activation of the (Na+K)-ATPase following treatment with thimerosal.

Treatment of the Na,K-ATPase enzyme, isolated from canine renal outer medulla, with thimerosal (ethylmercurithiosalicylate) resulted in significant inhibition of the overall Na,K-ATPase with only slight, if any, inhibition of the Na-ATPase and ATP:ADP exchange activities. The K-stimulated PNPPase activity was stimulated [see G. R. Henderson and A. Askari (1977) Arch. Biochem. Biophys. 182, 221-226]. Examination of the Na dependence of the ATPase and ATP:ADP exchange activities revealed an Na-independent, ouabain-sensitive activity that was inhibited by Na in the range 0-10 mM. At greater than or equal to 10 mM concentration of Na the treated and modified enzymes showed similar activities. The apparent affinity of the modified enzyme for ATP in the presence of 100 mM Na was the same as that of the untreated enzyme (0.2-0.3 microM). In the absence of Na, the modified enzyme hydrolyzed ATP with a relatively low affinity (about 120 microM). The enhancement of p-nitrophenylphosphatase (PNPPase) activity measured in the presence of K ions was due to the appearance of K-independent, ouabain-sensitive PNPP activity. The modification was without major affect on the apparent affinity of the enzyme for K ions in the PNPPase activity. Treatment of the thimerosal-modified enzyme with dithiothreitol removed (or greatly reduced) the cation-independent, ouabain-sensitive activities and the Na,K-ATPase activity returned. Modification of a set of enzyme -SH groups in the Na,K-ATPase enzyme made it able to hydrolyze ATP in the absence of Na ions and PNPP in the absence of K ions. The -SH groups modified by thimerosal are evidently critical to the major dephosphoenzyme conformational changes but are not involved in the major transport conformational change between phosphoenzymes.

4-Nitrophenylphosphatase↗