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Evidence for Thimerosal Risk - Page 2

Toxicol Appl Pharmacol. 2004 Jan 15;194(2):169-79.

Dose-response study of thimerosal-induced murine systemic autoimmunity.

Havarinasab S, Lambertsson L, Qvarnström J, Hultman P.

Molecular and Immunological Pathology (AIR), Department of Molecular and Clinical Medicine, Linköping University, SE-581 85 Linköping, Sweden.

Abstract

The organic compound ethylmercurithiosalicylate (thimerosal), which is primarily present in the tissues as ethylmercury, has caused illness and several deaths due to erroneous handling when used as a disinfectant or as a preservative in medical preparations. Lately, possible health effects of thimerosal in childhood vaccines have been much discussed. Thimerosal is a well-known sensitizing agent, although usually of no clinical relevance. In rare cases, thimerosal has caused systemic immune reactions including acrodynia. We have studied if thimerosal might induce the systemic autoimmune condition observed in genetically susceptible mice after exposure to inorganic mercury. A.SW mice were exposed to 1.25-40 mg thimerosal/l drinking water for 70 days. Antinucleolar antibodies, targeting the 34-kDa protein fibrillarin, developed in a dose-related pattern and first appeared after 10 days in the two highest dose groups. The lowest observed adverse effect level (LOAEL) for antifibrillarin antibodies was 2.5 mg thimerosal/l, corresponding to an absorbed dose of 147 microg Hg/kg bw and a concentration of 21 and 1.9 microg Hg/g in the kidney and lymph nodes, respectively. The same LOAEL was found for tissue immune-complex deposits. The total serum concentration of IgE, IgG1, and IgG2a showed a significant dose-related increase in thimerosal-treated mice, with a LOAEL of 5 mg thimerosal/l for IgG1 and IgE, and 20 mg thimerosal/l for IgG2a. The polyclonal B-cell activation showed a significant dose-response relationship with a LOAEL of 10 mg thimerosal/l. Therefore, thimerosal induces in genetically susceptible mice a systemic autoimmune syndrome very similar to that seen after treatment with inorganic mercury, although a higher absorbed dose of Hg is needed using thimerosal. The autoimmune syndrome induced by thimerosal is different from the weaker and more restricted autoimmune reaction observed after treatment with an equipotent dose of methylmercury.

PMID: 14736497 [PubMed - indexed for MEDLINE]

What is the significance of these finding re: the doses of thimerosal infants and children have received?

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Mol Psychiatry. 2004 Sep;9(9):833-45.

Neurotoxic effects of postnatal thimerosal are mouse strain dependent.

Hornig M, Chian D, Lipkin WI.

Jerome L and Dawn Greene Infectious Disease Laboratory, Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY 10032, USA. mady.hornig@columbia.edu

Abstract

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.

PMID: 15184908 [PubMed - indexed for MEDLINE]

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Toxicology. 2004 Jan 15;195(1):77-84.

Effect of thimerosal, a preservative in vaccines, on intracellular Ca2+ concentration of rat cerebellar neurons.

Ueha-Ishibashi T, Oyama Y, Nakao H, Umebayashi C, Nishizaki Y, Tatsuishi T, Iwase K, Murao K, Seo H.

Laboratory of Cellular Signaling, Faculty of Integrated Arts and Sciences, The University of Tokushima, Tokushima 770-8502, Japan.

Abstract

The effect of thimerosal, an organomercurial preservative in vaccines, on cerebellar neurons dissociated from 2-week-old rats was compared with those of methylmercury using a flow cytometer with appropriate fluorescent dyes. Thimerosal and methylmercury at concentrations ranging from 0.3 to 10 microM increased the intracellular concentration of Ca2+ ([Ca2+]i) in a concentration-dependent manner. The potency of 10 microM thimerosal to increase the [Ca2+]i was less than that of 10 microM methylmercury. Their effects on the [Ca2+]i were greatly attenuated, but not completely suppressed, under external Ca(2+)-free condition, suggesting a possibility that both agents increase membrane Ca2+ permeability and release Ca2+ from intracellular calcium stores. The effect of 10 microM thimerosal was not affected by simultaneous application of 30 microM L-cysteine whereas that of 10 microM methylmercury was significantly suppressed. The potency of thimerosal was similar to that of methylmercury in the presence of L-cysteine. Both agents at 1 microM or more similarly decreased the cellular content of glutathione in a concentration-dependent manner, suggesting an increase in oxidative stress. Results indicate that thimerosal exerts some cytotoxic actions on cerebellar granule neurons dissociated from 2-week-old rats and its potency is almost similar to that of methylmercury.

PMID: 14698570 [PubMed - indexed for MEDLINE]

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Int J Toxicol. 2004 Nov-Dec;23(6):369-76.

Neurodevelopmental disorders following thimerosal-containing childhood immunizations: a follow-up analysis.

Geier D, Geier MR.

MedCon, Inc., Maryland, USA.

Abstract

The authors previously published the first epidemiological study from the United States associating thimerosal from childhood vaccines with neurodevelopmental disorders (NDs) based upon assessment of the Vaccine Adverse Event Reporting System (VAERS). A number of years have gone by since their previous analysis of the VAERS. The present study was undertaken to determine whether the previously observed effect between thimerosal-containing childhood vaccines and NDs are still apparent in the VAERS as children have had a chance to further mature and potentially be diagnosed with additional NDs. In the present study, a cohort of children receiving thimerosal-containing diphtheria-tetanus-acellular pertussis (DTaP) vaccines in comparison to a cohort of children receiving thimerosal-free DTaP vaccines administered from 1997 through 2000 based upon an assessment of adverse events reported to the VAERS were evaluated. It was determined that there were significantly increased odds ratios (ORs) for autism (OR = 1.8, p < .05), mental retardation (OR = 2.6, p < .002), speech disorder (OR = 2.1, p < .02), personality disorders (OR = 2.6, p < .01), and thinking abnormality (OR = 8.2, p < .01) adverse events reported to the VAERS following thimerosal-containing DTaP vaccines in comparison to thimerosal-free DTaP vaccines. Potential confounders and reporting biases were found to be minimal in this assessment of the VAERS. It was observed, even though the media has reported a potential association between autism and thimerosal exposure, that the other NDs analyzed in this assessment of the VAERS had significantly higher ORs than autism following thimerosal-containing DTaP vaccines in comparison to thimerosal-free DTaP vaccines. The present study provides additional epidemiological evidence supporting previous epidemiological, clinical and experimental evidence that administration of thimerosal-containing vaccines in the United States resulted in a significant number of children developing NDs.

PMID: 15764492 [PubMed - indexed for MEDLINE]

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Med Sci Monit. 2004 Mar;10(3):PI33-9. Epub 2004 Mar 1.

A comparative evaluation of the effects of MMR immunization and mercury doses from thimerosal-containing childhood vaccines on the population prevalence of autism.

Geier DA, Geier MR.

President, MedCon, Inc, Silver Spring, MD, USA.

Comment in:

Abstract

BACKGROUND: The purpose of the study was to evaluate the effects of MMR immunization and mercury from thimerosal-containing childhood vaccines on the prevalence of autism.

MATERIAL/METHODS: Evaluations of the Biological Surveillance Summaries of the Centers for Disease Control and Prevention (CDC), the U.S. Department of Education datasets, and the CDC's yearly live birth estimates were undertaken

RESULTS: It was determined that there was a close correlation between mercury doses from thimerosal--containing childhood vaccines and the prevalence of autism from the late 1980s through the mid-1990s. In contrast, there was a potential correlation between the number of primary pediatric measles-containing vaccines administered and the prevalence of autism during the 1980s. In addition, it was found that there were statistically significant odds ratios for the development of autism following increasing doses of mercury from thimerosal-containing vaccines (birth cohorts: 1985 and 1990-1995) in comparison to a baseline measurement (birth cohort: 1984). The contribution of thimerosal from childhood vaccines (>50% effect) was greater than MMR vaccine on the prevalence of autism observed in this study.

CONCLUSIONS: The results of this study agree with a number of previously published studies. These studies have shown that there is biological plausibility and epidemiological evidence showing a direct relationship between increasing doses of mercury from thimerosal-containing vaccines and neurodevelopmental disorders, and measles-containing vaccines and serious neurological disorders. It is recommended that thimerosal be removed from all vaccines, and additional research be undertaken to produce a MMR vaccine with an improved safety profile.

PMID: 14976450 [PubMed - indexed for MEDLINE]

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Int J Immunopathol Pharmacol. 2003 Sep-Dec;16(3):189-99.

Infections, toxic chemicals and dietary peptides binding to lymphocyte receptors and tissue enzymes are major instigators of autoimmunity in autism.

Vojdani A, Pangborn JB, Vojdani E, Cooper EL.

Lab. Comparative Immunology, Dept. Neurobiology, UCLA Medical Center, Los Angeles, CA, USA. DrAri@msn.com

Abstract

Similar to many complex autoimmune diseases, genetic and environmental factors including diet, infection and xenobiotics play a critical role in the development of autism. In this study, we postulated that infectious agent antigens such as streptokinase, dietary peptides (gliadin and casein) and ethyl mercury (xenobiotic) bind to different lymphocyte receptors and tissue enzyme (DPP IV or CD26). We assessed this hypothesis first by measuring IgG, IgM and IgA antibodies against CD26, CD69, streptokinase (SK), gliadin and casein peptides and against ethyl mercury bound to human serum albumin in patients with autism. A significant percentage of children with autism developed anti-SK, anti-gliadin and casein peptides and anti-ethyl mercury antibodies, concomitant with the appearance of anti-CD26 and anti-CD69 autoantibodies. These antibodies are synthesized as a result of SK, gliadin, casein and ethyl mercury binding to CD26 and CD69, indicating that they are specific. Immune absorption demonstrated that only specific antigens, like CD26, were capable of significantly reducing serum anti-CD26 levels. However, for direct demonstration of SK, gliadin, casein and ethyl mercury to CD26 or CD69, microtiter wells were coated with CD26 or CD69 alone or in combination with SK, gliadin, casein or ethyl mercury and then reacted with enzyme labeled rabbit anti-CD26 or anti-CD69. Adding these molecules to CD26 or CD69 resulted in 28-86% inhibition of CD26 or CD69 binding to anti-CD26 or anti-CD69 antibodies. The highest % binding of these antigens or peptides to CD26 or CD69 was attributed to SK and the lowest to casein peptides. We, therefore, propose that bacterial antigens (SK), dietary peptides (gliadin, casein) and Thimerosal (ethyl mercury) in individuals with pre-disposing HLA molecules, bind to CD26 or CD69 and induce antibodies against these molecules. In conclusion, this study is apparently the first to demonstrate that dietary peptides, bacterial toxins and xenobiotics bind to lymphocyte receptors and/or tissue enzymes, resulting in autoimmune reaction in children with autism.

PMID: 14611720 [PubMed - indexed for MEDLINE]

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Anal Chem. 2003 Aug 15;75(16):4120-4.

Determination of methylmercury, ethylmercury, and inorganic mercury in mouse tissues, following administration of thimerosal, by species-specific isotope dilution GC-inductively coupled plasma-MS.

Qvarnström J, Lambertsson L, Havarinasab S, Hultman P, Frech W.

Analytical Chemistry, Department of Chemistry, Umeå University, S-901 87 Umeå, Sweden. johanna.qvarnstrom@chem.umu.se

Abstract

Isotopically enriched HgO standards were used to synthesize CH3(200)Hg+ and C2H5(199)Hg+ using Grignard reagents. These species were employed for isotope dilution GC-ICPMS to study uptake and biotransformation of ethylmercury in mice treated with thimerosal, (sodium ethylmercurithiosalicylate) 10 mg L(-1) in drinking water ad libitum for 1, 2.5, 6, or 14 days. Prior to analysis, samples were spiked with aqueous solutions of CH3(200)Hg+, C2H5(199)Hg+, and 201Hg2+ and then digested in 20% tetramethylammonium hydroxide and extracted at pH 9 with DDTC/toluene. Extracted mercury species were reacted with butylmagnesium chloride to form butylated derivatives. Absolute detection limits for CH3Hg+, C2H5Hg+, and Hg2+ were 0.4, 0.2, and 0.6 pg on the basis of 3sigma of five separate blanks. Up to 9% of the C2H5Hg+ was decomposed to Hg2+ during sample preparation, and it is therefore crucial to use a species-specific internal standard when determining ethylmercury. No demethylation, methylation, or ethylation during sample preparation was detected. The ethylmercury component of thimerosal was rapidly taken up in the organs of the mice (kidney, liver, and mesenterial lymph nodes), and concentrations of C2H5Hg+ as well as Hg2+ increased over the 14 days of thimerosal treatment. This shows that C2H5Hg+ in mice to a large degree is degraded to Hg2+. Increased concentrations of CH3Hg+ were also observed, which was found to be due to impurities in the thimerosal.

PMID: 14632125 [PubMed - indexed for MEDLINE]

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Pediatr Rehabil. 2003 Apr-Jun;6(2):97-102.

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

Geier DA, Geier MR.

The Genetic Centers of America, 14 Redgate Court, Silver Spring, MD 20905, USA.

Abstract

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.

PMID: 14534046 [PubMed - indexed for MEDLINE]

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Int J Toxicol. 2003 Jul-Aug;22(4):277-85.

Reduced levels of mercury in first baby haircuts of autistic children.

Holmes AS, Blaxill MF, Haley BE.

SafeMinds, Cambridge, Massachusetts, USA.

Abstract

Reported rates of autism have increased sharply in the United States and the United Kingdom. One possible factor underlying these increases is increased exposure to mercury through thimerosal-containing vaccines, but vaccine exposures need to be evaluated in the context of cumulative exposures during gestation and early infancy. Differential rates of postnatal mercury elimination may explain why similar gestational and infant exposures produce variable neurological effects. First baby haircut samples were obtained from 94 children diagnosed with autism using Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM IV) criteria and 45 age- and gender-matched controls. Information on diet, dental amalgam fillings, vaccine history, Rho D immunoglobulin administration, and autism symptom severity was collected through a maternal survey questionnaire and clinical observation. Hair mercury levels in the autistic group were 0.47 ppm versus 3.63 ppm in controls, a significant difference. The mothers in the autistic group had significantly higher levels of mercury exposure through Rho D immunoglobulin injections and amalgam fillings than control mothers. Within the autistic group, hair mercury levels varied significantly across mildly, moderately, and severely autistic children, with mean group levels of 0.79, 0.46, and 0.21 ppm, respectively. Hair mercury levels among controls were significantly correlated with the number of the mothers' amalgam fillings and their fish consumption as well as exposure to mercury through childhood vaccines, correlations that were absent in the autistic group. Hair excretion patterns among autistic infants were significantly reduced relative to control. These data cast doubt on the efficacy of traditional hair analysis as a measure of total mercury exposure in a subset of the population. In light of the biological plausibility of mercury's role in neurodevelopmental disorders, the present study provides further insight into one possible mechanism by which early mercury exposures could increase the risk of autism.

PMID: 12933322 [PubMed - indexed for MEDLINE]

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Exp Biol Med (Maywood). 2003 Jun;228(6):660-4.

Neurodevelopmental disorders after thimerosal-containing vaccines: a brief communication.

Geier MR, Geier DA.

The Genetic Centers of America, Silver Spring, Maryland 20905, USA. mgeier@erols.com

Comment in:

Abstract

We were initially highly skeptical that differences in the concentrations of thimerosal in vaccines would have any effect on the incidence rate of neurodevelopmental disorders after childhood immunization. This study presents the first epidemiologic evidence, based upon tens of millions of doses of vaccine administered in the United States, that associates increasing thimerosal from vaccines with neurodevelopmental disorders. Specifically, an analysis of the Vaccine Adverse Events Reporting System (VAERS) database showed statistical increases in the incidence rate of autism (relative risk [RR] = 6.0), mental retardation (RR = 6.1), and speech disorders (RR = 2.2) after thimerosal-containing diphtheria, tetanus, and acellular pertussis (DTaP) vaccines in comparison with thimerosal-free DTaP vaccines. The male/female ratio indicated that autism (17) and speech disorders (2.3) were reported more in males than females after thimerosal-containing DTaP vaccines, whereas mental retardation (1.2) was more evenly reported among male and female vaccine recipients. Controls were employed to determine if biases were present in the data, but none were found. It was determined that overall adverse reactions were reported in similar-aged populations after thimerosal-containing DTaP (2.4 +/- 3.2 years old) and thimerosal-free DTaP (2.1 +/- 2.8 years old) vaccinations. Acute control adverse reactions such as deaths (RR = 1.0), vasculitis (RR = 1.2), seizures (RR = 1.6), ED visits (RR = 1.4), total adverse reactions (RR = 1.4), and gastroenteritis (RR = 1.1) were reported similarly after thimerosal-containing and thimerosal-free DTaP vaccines. An association between neurodevelopmental disorders and thimerosal-containing DTaP vaccines was found, but additional studies should be conducted to confirm and extend this study.

PMID: 12773696 [PubMed - indexed for MEDLINE]Free Article

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Mutat Res. 2003 Jun 6;537(2):151-68.

Characterization of cytotoxic and genotoxic effects of different compounds in CHO K5 cells with the comet assay (single-cell gel electrophoresis assay).

Kiffe M, Christen P, Arni P.

Syngenta Crop Protection AG, CH-4002 Basel, Switzerland. michael.kiffe@pharma.novartis.com

Abstract

Different variants of the comet assay were used to study the genotoxic and cytotoxic properties of the following eight compounds: chloral hydrate, colchicine, hydroquinone, DL-menthol, mitomycin C, sodium iodoacetate, thimerosal and valinomycin. Colchicine, mitomycin C, sodium iodoacetate and thimerosal induced genotoxic effects. The other compounds were found to be inactive. The compounds were tested in the standard comet assay as well as in the all cell comet assay (recovery of floating cells after treatment), designed in our laboratory for adherently-growing cells. This latter procedure proved to be more adequate for the assessment of the cytotoxicity for some of the compounds tested (hydroquinone, DL-menthol, thimerosal, valinomycin). Colchicine was positive in the standard comet assay (3h treatment) and in the all cell comet assay (24h treatment). Sodium iodoacetate and thimerosal were positive in the standard and/or the all cell comet assay. Chloral hydrate, hydroquinone, sodium iodoacetate, mitomycin C and thimerosal were also tested in the modified comet assay using lysed cells. Mitomycin C and thimerosal showed effects in this assay, whereas sodium iodoacetate was inactive. This indicates that it does not induce direct DNA damage. Compounds that are known or suspected to form DNA-DNA cross-links or DNA-protein cross-links (chloral hydrate, hydroquinone, mitomycin C and thimerosal) were checked for their ability to reduce ethyl methanesulfonate (EMS)-induced DNA damage. This mode of action could be demonstrated for mitomycin C only.

PMID: 12787820 [PubMed - indexed for MEDLINE]

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Toxicol Sci. 2003 Aug;74(2):361-8. Epub 2003 May 28.

Thimerosal induces DNA breaks, caspase-3 activation, membrane damage, and cell death in cultured human neurons and fibroblasts.

Baskin DS, Ngo H, Didenko VV.

Department of Neurosurgery, Baylor College of Medicine, 6560 Fannin Suite 944, Houston, Texas 77030, USA. dbaskin@tmh.tmc.edu

Abstract

Thimerosal is an organic mercurial compound used as a preservative in biomedical preparations. Little is known about the reactions of human neuronal and skin cells to its micro- and nanomolar concentrations, which can occur after using thimerosal-containing products. A useful combination of fluorescent techniques for the assessment of thimerosal toxicity is introduced. Short-term thimerosal toxicity was investigated in cultured human cerebral cortical neurons and in normal human fibroblasts. Cells were incubated with 125-nM to 250-microM concentrations of thimerosal for 45 min to 24 h. A 4', 6-diamidino-2-phenylindole dihydrochloride (DAPI) dye exclusion test was used to identify nonviable cells and terminal transferase-based nick-end labeling (TUNEL) to label DNA damage. Detection of active caspase-3 was performed in live cell cultures using a cell-permeable fluorescent caspase inhibitor. The morphology of fluorescently labeled nuclei was analyzed. After 6 h of incubation, the thimerosal toxicity was observed at 2 microM based on the manual detection of the fluorescent attached cells and at a 1-microM level with the more sensitive GENios Plus Multi-Detection Microplate Reader with Enhanced Fluorescence. The lower limit did not change after 24 h of incubation. Cortical neurons demonstrated higher sensitivity to thimerosal compared to fibroblasts. The first sign of toxicity was an increase in membrane permeability to DAPI after 2 h of incubation with 250 microM thimerosal. A 6-h incubation resulted in failure to exclude DAPI, generation of DNA breaks, caspase-3 activation, and development of morphological signs of apoptosis. We demonstrate that thimerosal in micromolar concentrations rapidly induce membrane and DNA damage and initiate caspase-3-dependent apoptosis in human neurons and fibroblasts. We conclude that a proposed combination of fluorescent techniques can be useful in analyzing the toxicity of thimerosal.

PMID: 12773768 [PubMed - indexed for MEDLINE]PMCID: PMC1892749Free PMC Article

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Arch Toxicol. 2003 Jan;77(1):50-5. Epub 2002 Nov 6.

Thimerosal induces micronuclei in the cytochalasin B block micronucleus test with human lymphocytes.

Westphal GA, Asgari S, Schulz TG, Bünger J, Müller M, Hallier E.

Department of Occupational Health, Georg-August-University Göttingen, Waldweg 37, 37073 Göttingen, Germany. gwestph@gwdg.de

Abstract

Thimerosal is a widely used preservative in health care products, especially in vaccines. Due to possible adverse health effects, investigations on its metabolism and toxicity are urgently needed. An in vivo study on chronic toxicity of thimerosal in rats was inconclusive and reports on genotoxic effects in various in vitro systems were contradictory. Therefore, we reinvestigated thimerosal in the cytochalasin B block micronucleus test. Glutathione S-transferases were proposed to be involved in the detoxification of thimerosal or its decomposition products. Since the outcome of genotoxicity studies can be dependent on the metabolic competence of the cells used, we were additionally interested whether polymorphisms of glutathione S-transferases (GSTM1, GSTT1, or GSTP1) may influence the results of the micronucleus test with primary human lymphocytes. Blood samples of six healthy donors of different glutathione S-transferase genotypes were included in the study. At least two independent experiments were performed for each blood donor. Significant induction of micronuclei was seen at concentrations between 0.05-0.5 micro g/ml in 14 out of 16 experiments. Thus, genotoxic effects were seen even at concentrations which can occur at the injection site. Toxicity and toxicity-related elevation of micronuclei was seen at and above 0.6 micro g/ml thimerosal. Marked individual and intraindividual variations in the in vitro response to thimerosal among the different blood donors occurred. However, there was no association observed with any of the glutathione S-transferase polymorphism investigated. In conclusion, thimerosal is genotoxic in the cytochalasin B block micronucleus test with human lymphocytes. These data raise some concern on the widespread use of thimerosal.

PMID: 12491041 [PubMed - indexed for MEDLINE]
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T h e U C I U n d e r g r a d u a t e R e s e a r c h J o u r n a l (2003)


Thimerosal Induces Programmed Cell Death of Neuronal Cells via

Changes in the Mitochondrial Environment

Brown L

Abstract

Thimerosal, a preservative and anti-microbial agent used in vaccines, ophthalmic solutions, and cosmetics, is a mercury-containing compound that has raised public concern due to its potentially harmful effects. While past studies have implicated mercurial compounds in apoptosis, or programmed cell death, in human T-cells and cells of the central nervous system, no studies have examined the specific effect of thimerosal on neuronal cells, despite evidence that mercurial compounds readily cross the bloodbrain barrier. This study examines whether thimerosal induces apoptosis in neuronal cells, and, if so, via which mechanism. To this end, neuronal cells were incubated in the absence and presence of thimerosal at various concentrations for various exposure times and then examined for cell viability, specific morphological changes associated with apoptosis, and changes in the mitochondrial environment. Thimerosal decreased neuronal cell viability in time- and dose-dependent trials, with 90% viability at 2 hr, decreasing to 60% viability at 24 hr (1 μM); at 5 μM thimerosal, viability decreased below 20% at 24 and 48 hr. Thimerosal caused depolarization of the mitochondrial membrane and enhanced superoxide generation. At 5 μM thimerosal, cytochrome c was released from mitochondria to the cytosol in 30% of cells at 1 hr and 85% of cells at 3

hr. Apoptosis-Inducing Factor was released in 40% and 90% of cells at 30 min and 1 hr, respectively. The results suggest that thimerosal causes apoptosis via the mitochondrial pathway and warrant continued efforts to find a replacement compound.

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Exp Biol Med (Maywood). 2003 Oct;228(9):991-2; discussion 993-4.

Questions about thimerosal remain.

Mann JR.

University of South Carolina School of Medicine, Columbia, South Carolina 29203, USA. joshua.mann@palmettohealth.org

From the article: “All these issues aside, the authors’ findings are interesting and potentially very important, as they do give some support to what the authors note is generally a skeptically-viewed theory about the possible connection between thimerosal-containing vaccines and neurodevelopmental disorders. Perhaps future research can build on their work. In the meantime, it seems prudent for clinicians to use thimerosal-free vaccines when possible.

Comment on:

PMID: 14530505 [PubMed - indexed for MEDLINE]Free Article http://ebm.rsmjournals.com/cgi/content/full/228/9/991

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Genes Immun. 2002 Aug;3(5):270-8.

Biochemical and molecular basis of thimerosal-induced apoptosis in T cells: a major role of mitochondrial pathway.

Makani S, Gollapudi S, Yel L, Chiplunkar S, Gupta S.

Cellular and Molecular Immunology Laboratories, Division of Basic and Clinical Immunology, University of California, Irvine 92697, USA.

Abstract

The major source of thimerosal (ethyl mercury thiosalicylate) exposure is childhood vaccines. It is believed that the children are exposed to significant accumulative dosage of thimerosal during the first 2 years of life via immunization. Because of health-related concerns for exposure to mercury, we examined the effects of thimerosal on the biochemical and molecular steps of mitochondrial pathway of apoptosis in Jurkat T cells. Thimerosal and not thiosalcylic acid (non-mercury component of thimerosal), in a concentration-dependent manner, induced apoptosis in T cells as determined by TUNEL and propidium iodide assays, suggesting a role of mercury in T cell apoptosis. Apoptosis was associated with depolarization of mitochondrial membrane, release of cytochrome c and apoptosis inducing factor (AIF) from the mitochondria, and activation of caspase-9 and caspase-3, but not of caspase-8. In addition, thimerosal in a concentration-dependent manner inhibited the expression of XIAP, cIAP-1 but did not influence cIAP-2 expression. Furthermore, thimerosal enhanced intracellular reactive oxygen species and reduced intracellular glutathione (GSH). Finally, exogenous glutathione protected T cells from thimerosal-induced apoptosis by upregulation of XIAP and cIAP1 and by inhibiting activation of both caspase-9 and caspase-3. These data suggest that thimerosal induces apoptosis in T cells via mitochondrial pathway by inducing oxidative stress and depletion of GSH.

PMID: 12140745 [PubMed - indexed for MEDLINE]Free Article

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Altern Med Rev. 2002 Aug;7(4):292-316.

Autism, an extreme challenge to integrative medicine. Part: 1: The knowledge base.

Kidd PM.

Abstract

Autism, archetype of the autistic spectrum disorders (ASD), is a neurodevelopmental disorder characterized by socially aloof behavior and impairment of language and social interaction. Its prevalence has surged in recent years. Advanced functional brain imaging has confirmed pervasive neurologic involvement. Parent involvement in autism management has accelerated understanding and treatment. Often accompanied by epilepsy, cognitive deficits, or other neurologic impairment, autism manifests in the first three years of life and persists into adulthood. Its etiopathology is poorly defined but likely multifactorial with heritability playing a major role. Prenatal toxic exposures (teratogens) are consistent with autism spectrum symptomatology. Frequent vaccinations with live virus and toxic mercurial content (thimerosal) are a plausible etiologic factor. Autistic children frequently have abnormalities of sulfoxidation and sulfation that compromise liver detoxification, which may contribute to the high body burden of xenobiotics frequently found. Frequent copper-zinc imbalance implies metallothionein impairment that could compound the negative impact of sulfur metabolism impairments on detoxification and on intestinal lining integrity. Intestinal hyperpermeability manifests in autistic children as dysbiosis, food intolerances, and exorphin (opioid) intoxication, most frequently from casein and gluten. Immune system abnormalities encompass derangement of antibody production, skewing of T cell subsets, aberrant cytokine profiles, and other impairments consistent with chronic inflammation and autoimmunity. Coagulation abnormalities have been reported. Part 2 of this review will attempt to consolidate progress in integrative management of autism, aimed at improving independence and lifespan for people with the disorder.

PMID: 12197782 [PubMed - indexed for MEDLINE]Free Article

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Med Hypotheses. 2001 Apr;56(4):462-71.

Autism: a novel form of mercury poisoning.

Bernard S, Enayati A, Redwood L, Roger H, Binstock T.

ARC Research, Cranford, New Jersey 07901, USA.

Abstract

Autism is a syndrome characterized by impairments in social relatedness and communication, repetitive behaviors, abnormal movements, and sensory dysfunction. Recent epidemiological studies suggest that autism may affect 1 in 150 US children. Exposure to mercury can cause immune, sensory, neurological, motor, and behavioral dysfunctions similar to traits defining or associated with autism, and the similarities extend to neuroanatomy, neurotransmitters, and biochemistry. Thimerosal, a preservative added to many vaccines, has become a major source of mercury in children who, within their first two years, may have received a quantity of mercury that exceeds safety guidelines. A review of medical literature and US government data suggests that: (i) many cases of idiopathic autism are induced by early mercury exposure from thimerosal; (ii) this type of autism represents an unrecognized mercurial syndrome; and (iii) genetic and non-genetic factors establish a predisposition whereby thimerosal's adverse effects occur only in some children.

Copyright 2001 Harcourt Publishers Ltd.

PMID: 11339848 [PubMed - indexed for MEDLINE]

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Drugs. 2001;61(5):565-72.

Vaccines without thiomersal: why so necessary, why so long coming?

van't Veen AJ.

Department of Dermatology and Venereology, Erasmus University Hospital Rotterdam-Dijkzigt, Rotterdam, The Netherlands.

Abstract

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

PMID: 11368282 [PubMed - indexed for MEDLINE]


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Neurotoxicology. 2001 Oct;22(5):691-7.

Predicted mercury concentrations in hair from infant immunizations: cause for concern.

Redwood L, Bernard S, Brown D.

Coalition for Safe Minds, Cranford, NJ 07016, USA. tlredwood@mindspring.com

Abstract

Mercury (Hg) is considered one of the worlds most toxic metals. Current thinking suggests that exposure to mercury occurs primarily from seafood contamination and rare catastrophic events. Recently, another common source of exposure has been identified. Thimerosal (TMS), a preservative found in many infant vaccines, contains 49.6% ethyl mercury (EtHg) by weight and typically contributes 25 microg of EtHg per dose of infant vaccine. As part of an ongoing review, the Food and Drug Administration (FDA) announced in 1999 that infants who received multiple TMS-preserved vaccines may have been exposed to cumulative Hg in excess of Federal safety guidelines. According to the centers for disease control (CDC) recommended immunization schedule, infants may have been exposed to 12.5 microg Hg at birth, 62.5 microg EtHg at 2 months, 50 microg EtHg at 4 months, 62.5 microg EtHg at 6 months, and 50 microg EtHg at approximately 18 months, for a total of 237.5 microg EtHg during the first 18 months of life, if all TMS-containing vaccines were administered. Neurobehavioral alterations, especially to the more susceptible fetus and infant, are known to occur after relatively low dose exposures to organic mercury compounds. In effort, to further elucidate the levels of ethyl mercury resulting from exposure to vaccinal TMS, we estimated hair Hg concentrations expected to result from the recommended CDC schedule utilizing a one compartment pharmacokinetic model. This model was developed to predict hair concentrations from acute exposure to methymercury (MeHg) in fish. Modeled hair Hg concentrations in infants exposed to vaccinal TMS are in excess of the Environmental Protection Agency (EPA) safety guidelines of 1 ppm for up to 365 days, with several peak concentrations within this period. More sensitive individuals and those with additional sources of exposure would have higher Hg concentrations. Given that exposure to low levels of mercury during critical stages of development has been associated with neurological disorders in children, including ADD, learning difficulties, and speech delays, the predicted hair Hg concentration resulting from childhood immunizations is cause for concern. Based on these findings, the impact which vaccinal mercury has had on the health of American children warrants further investigation.

PMID: 11770890 [PubMed - indexed for MEDLINE]

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Int Arch Allergy Immunol. 1994 Jul;104(3):296-301.

Thimerosal induces toxic reaction in non-sensitized animals.

Uchida T, Naito S, Kato H, Hatano I, Harashima A, Terada Y, Ohkawa T, Chino F, Eto K.

Department of Safety Research on Biologics, National Institute of Health, Tokyo, Japan.

Comment in:

Abstract

The effects of injection of thimerosal solution on nonsensitized animals was investigated. Intrafootpad injection of thimerosal solution in nonsensitized mice resulted in a swelling response which peaked 1 h after injection and lasted for more than 24 h. Histopathological examination showed that there were severe edema and infiltration of polymorphonuclear neutrophils at the site of injection. An increased vascular permeability was observed after cutaneous injection of thimerosal solution on the back of nonsensitized rats. Since mercuric chloride and methyl mercury induced severer reactions, and thiosalicylic acid had no effect, mercury contained in thimerosal would have caused the reactions observed in this study. These results suggest that part of these hypersensitivity reactions against thimerosal observed among patients were possibly induced by the toxic effect of thimerosal. Therefore, thimerosal contained as a preservative in vaccine may augment the side-effects of the vaccination.

PMID: 7518269 [PubMed - indexed for MEDLINE]

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Mutat Res. 1993 May;287(1):57-70.

C-mitosis and numerical chromosome aberration analyses in human lymphocytes: 10 known or suspected spindle poisons.

Sbrana I, Di Sibio A, Lomi A, Scarcelli V.

Dipartimento di Scienze dell'Ambiente e del Territorio, Università di Pisa, Italy.

Abstract

As a part of a coordinated EEC project to validate suitable assays for chemically induced genomic mutations, numerical chromosomal aberrations and spindle effects were studied in human lymphocyte cultures exposed to cadmium chloride, chloral hydrate, colchicine, diazepam, econazole, hydroquinone, pyrimethamine, thiabendazole, thimerosal and vinblastine. Chromosome number analysis was carried out after treatment for 48 and 72 h; spindle effects, i.e., increases in the mitotic indices and c-mitoses, were analyzed in cultures treated 5 h before fixation. Dose-related numerical chromosomal aberrations are induced by colchicine and vinblastine, the only chemicals that also induce c-mitotic effects in a wide range of doses. Hyperdiploidy is induced by chloral hydrate, cadmium chloride and thimerosal without dose-effect relationship; chloral hydrate and thimerosal affect spindle functions while only a weak spindle effect is produced by cadmium chloride. Tetraploid and/or endoreduplicated cells are induced without dose-effect relationship by hydroquinone, thiabendazole and thimerosal, all of them able to produce c-mitotic effects. Diazepam and econazole induce only hypodiploidy; pyrimethamine does not induce numerical chromosomal aberrations.

PMID: 7683385 [PubMed - indexed for MEDLINE]

C-mitosis is abnormal mitosis.

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Mutat Res. 1993 May;287(1):47-56.

Induction of mitotic aneuploidy using Chinese hamster primary embryonic cells. Test results of 10 chemicals.

Natarajan AT, Duivenvoorden WC, Meijers M, Zwanenburg TS.

MGC Department of Radiation Genetics and Chemical Mutagenesis, State University of Leiden, The Netherlands.

Abstract

Using primary Chinese hamster embryonic cells, 10 known or suspected aneugens supplied as a part of the EC 4th Environmental Research and Development Programme were evaluated by the technique described by Dulout and Natarajan (1987). The chemicals included cadmium chloride, chloral hydrate, colchicine, diazepam, econazole, hydroquinone, pyrimethamine, thiabendazole, thimerosal and vincristine. All chemicals except pyrimethamine gave clearly positive effect at most of the doses tested. The ease with which the assay is performed and reproducible results that are obtained with the suspected compounds indicate that this in vitro test using primary embryonic fibroblasts is a promising one for routine screening.

PMID: 7683384 [PubMed - indexed for MEDLINE]

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Dermatol Clin. 1990 Jan;8(1):161-4.

Reactions to thimerosal in hepatitis B vaccines.

Rietschel RL, Adams RM.

Department of Dermatology, Ochsner Clinic, New Orleans, Louisiana.

Abstract

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.

PMID: 2137393 [PubMed - indexed for MEDLINE]

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Ann Dermatol Venereol. 1988;115(8):793-6.

[Multicenter survey related to the frequency of positive patch tests with mercury and thiomersal].

[Article in French]

Lachapelle JM, Chabeau G, Ducombs G, Lacroix M, Martin P, Reuter G, Marot L.

Unité de Dermatologie Professionnelle et de l'Environnement, Université Catholique de Louvain, Bruxelles, Belgium.

Abstract

A multicentric study concerning the frequency of positive allergic patch test reactions to mercury and to thiomersal has been conducted in France and in Belgium among 2,000 adult patients submitted to routine patch testing. 73 (3.6 p. 100) patients had a positive patch test to mercury and 47 (2.3 p. 100) to thiomersal, 22 (1.1 p. 100) reacted positively to both mercurials. These high figures are most probably in relation with a broad use of mercurials in both countries, as antiseptics as well as preservative agents in topical drugs. They lead to a careful use of mercurials, which have to be avoided when they can be advantageously replaced by other antiseptics or preservative agents. As far as cosmetics are concerned, the use of mercurials (chemical nature and concentration) is restricted by a Recommendation of the European Council.

PMID: 2974266 [PubMed - indexed for MEDLINE]


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Am J Optom Physiol Opt. 1988 Nov;65(11):867-73.

Toxic effects of ophthalmic preservatives on cultured rabbit corneal epithelium.

Simmons PA, Clough SR, Teagle RH, Jaanus SD.

Department of Basic and Visual Sciences, Southern California College of Optometry, Fullerton.

Abstract

We investigated the effects of the ophthalmic preservatives thimerosal and sorbic acid on the proliferation and survival of rabbit corneal epithelial cells in tissue culture. Normally, explants of corneal epithelium grow vigorously during the first 7 days in culture. With 0.004% thimerosal present in the culture medium, the normal proliferation of corneal cells is suppressed completely. When 0.1% sorbic acid is present, proliferation is delayed and the lifespan of the corneal cells is reduced. After a 1-h exposure to concentrations of thimerosal of 0.0005% or greater, virtually all corneal cells present in established cultures are killed. These results suggest that use of ophthalmic preparations containing these chemicals may affect the metabolic and proliferative capacity of the corneal epithelium adversely.

PMID: 3252733 [PubMed - indexed for MEDLINE]

But okay to inject?

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Contact Dermatitis. 1988 Apr;18(4):229-33.

Thiomersal allergy and vaccination reactions.

Cox NH, Forsyth A.

Department of Dermatology, Royal Victoria Infirmary, Newcastle-upon-Tyne, UK.

Abstract

Thiomersal is the preservative in all toxoid vaccines routinely administered to children in the UK, but exposure from other sources is uncommon. Delayed hypersensitivity to thiomersal was demonstrated in 1% of individuals attending the Contact Dermatitis Investigation Unit, and 50 of these patients with positive patch tests to thiomersal were studied. Cross-reaction with other mercurials occurred in 17 of 29 patients tested (59%). 31 of the patients replied to a questionnaire regarding vaccination reactions, and were compared with case-controls matched for age, sex, and site of dermatitis. 4 patients in each group reported reactions to vaccines which contained thiomersal, suggesting that thiomersal hypersensitivity was not associated with an increased risk of vaccination reactions. However, individual cases of severe reactions to thiomersal demonstrate a need for vaccines with an alternative preservative.

PMID: 3378430 [PubMed - indexed for MEDLINE]

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Presse Med. 1988 Apr 30;17(16):795-6.

[Allergy to mercurothiolate in an infant during heparinization of an intracaval catheter].

[Article in French]

Chastagner P, Morali A, Trechot JP, May I, Vidailhet M.

Service de Médecine infantile 3, CHRU de Brabois, Vandoevre.

Abstract

A 4-month old infant developed an immediate and proven systemic allergic reaction to mercurothiolate. The acute accident occurred while an intracaval catheter was being treated with a dry-frozen heparin which excipient contains mercurothiolate. This conservative agent is present in numerous pharmaceutical preparations for topical and systemic use.

PMID: 2968567 [PubMed - indexed for MEDLINE]

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Contact Dermatitis. 1988 May;18(5):268-73.

Thimerosal: a hidden allergen in ophthalmology.

Tosti A, Tosti G.

Department of Dermatology, University of Bologna, Italy.

Abstract

We report 36 patients with thimerosal-induced follicular allergic contact conjunctivitis. 18 patients had follicular conjunctivitis without eyelid involvement, while 5 patients had follicular conjunctivitis associated with an allergic contact dermatitis of the eyelids; all these patients had been using thimerosal-containing eye drops. A further 13 patients were soft contact lens wearers who became sensitized to their own thimerosal-containing lens solutions. All 36 patients showed a positive patch test reaction to thimerosal, while only 1 of them reacted to an ophthalmic solution. Thimerosal sensitization appears to be clinically relevant in ophthalmic patients.

PMID: 3416589 [PubMed - indexed for MEDLINE]

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Arch Toxicol. 1985 Sep;57(4):260-7.

The comparative toxicology of ethyl- and methylmercury.

Magos L, Brown AW, Sparrow S, Bailey E, Snowden RT, Skipp WR.

Abstract

Neurotoxicity and renotoxicity were compared in rats given by gastric gavage five daily doses of 8.0 mg Hg/kg methyl- or ethylmercuric chloride or 9.6 mg Hg/kg ethylmercuric chloride. Three or 10 days after the last treatment day rats treated with either 8.0 or 9.6 mg Hg/kg ethylmercury had higher total or organic mercury concentrations in blood and lower concentrations in kidneys and brain than methylmercury-treated rats. In each of these tissues the inorganic mercury concentration was higher after ethyl- than after methylmercury. Weight loss relative to the expected body weight and renal damage was higher in ethylmercury-treated rats than in rats given equimolar doses of methylmercury. These effects became more severe when the dose of ethylmercury was increased by 20%. Thus in renotoxicity the renal concentration of inorganic mercury seems to be more important than the concentration of organic or total mercury. In methylmercury-treated rats damage and inorganic mercury deposits were restricted to the P2 region of the proximal tubules, while in ethylmercury-treated rats the distribution of mercury and damage was more widespread. There was little difference in the neurotoxicities of methylmercury and ethylmercury when effects on the dorsal root ganglia or coordination disorders were compared. Based on both criteria, an equimolar dose of ethylmercury was less neurotoxic than methylmercury, but a 20% increase in the dose of ethylmercury was enough to raise the sum of coordination disorder scores slightly and ganglion damage significantly above those in methylmercury-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

PMID: 4091651 [PubMed - indexed for MEDLINE]

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Hautarzt. 1984 Apr;35(4):192-6.

[Reactions to vaccinations against tetanus and tick-borne encephalitis caused by merthiolate (thiomersal)].

[Article in German]

Lindemayr H, Drobil M, Ebner H.

Abstract

Thirty patients with suspected adverse reactions to tetanus- or tick-borne encephalitis-vaccines were subjected to allergy tests. In 8 of 30 patients epicutaneous and/or intracutaneous tests with merthiolate were positive. Testing anorganic mercury, formaldehyde, aluminium hydroxide, gentamycin and egg white (i.c. and RAST), no positive reactions were found. After vaccination - prior to testing - merthiolate - positive patients had suffered from local inflammatory reactions at the injection site, fever and lymphadenopathy (four patients), urticarial (three patients) or lichenoid exanthemas (one patient). Reviewing the literature it is suggested that alternatively merthiolate-free vaccines be provided for sensitized individuals.

PMID: 6724907 [PubMed - indexed for MEDLINE]

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Am J Optom Physiol Opt. 1983 Sep;60(9):759-61.

Reactions induced by the concurrent use of thimerosal and tetracycline.

Crook TG, Freeman JJ.

Abstract

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.

PMID: 6681469 [PubMed - indexed for MEDLINE]

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Transfusion. 1982 May-Jun;22(3):241-3.

Thimerosal dependent agglutination, a newly described blood bank problem.

Shulman IA, Hasz LA, Simpson RB.

Abstract

A number of ABO grouping, Rh typing, antibody screening, and antibody identification problems are associated with chemicals in blood bank reagents. We describe a newly discovered agglutination phenomenon due to a thimerosal (Merthiolate)-dependent agglutinin found in the serum of a normal blood donor. Thimerosal is used as a preservative in several low-ionic strength reagents. This agglutination phenomenon is detected only in test systems (low-ionic-strength, albumin, saline, ficin treated test cells) in which test cells are incubated in the presence of thimerosal. Agglutination does not occur in the absence of thimerosal. The thimerosal-dependent agglutinin behaves like an IgG IgG autoantibody. There is no evidence that the thimerosal-dependent agglutinin is responsible for increased red cell destruction.

PMID: 7090037 [PubMed - indexed for MEDLINE]

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Contact Dermatitis. 1980 Jun;6(4):241-5.

Merthiolate hypersensitivity and vaccination.

Förström L, Hannuksela M, Kousa M, Lehmuskallio E.

Abstract

Epicutaneous tests with 0.1% merthiolate in petrolatum showed hypersensitivity in 96 of 4647 eczema patients (2.0%) and in seven of 105 healthy recruits (7%). There was a marked preponderance of young age classes in the eczema group. Twelve of 41 merthiolate-positive patients tested reacted to mercury alone, three to thiosalicylic acid alone and one to both. The remaining 25 patients reacted to neither of the individual components although the merthiolate complex as a whole gave a positive test result. Forty-five of the merthiolate-positive patients were tested subcutaneously with 0.5 ml of a 0.01% merthiolate solution, i.e. a dose equal to that contained in one shot of tetanus toxoid, for example. Nine patients developed a local reaction at the site of the injection, and the area became eczematous in four cases. In one of the patients the eczema spread over the body, causing fever. Since merthiolate-sensitive patients also react to merthiolate administered intracutaneously, the vaccinator should avoid the use of a needle whose outer surface has been contaminated when the vaccine was aspirated from the bottle. However, even when this precautionary measure is taken, local reactions can be expected in such a high percentage of merthiolate-sensitive persons that merthiolate in vaccines should be replaced by another antibacterial agent.

PMID: 6447032 [PubMed - indexed for MEDLINE]

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J Neurol Neurosurg Psychiatry. 1980 Feb;43(2):143-9.

Accidental ethyl mercury poisoning with nervous system, skeletal muscle, and myocardium injury.

Cinca I, Dumitrescu I, Onaca P, Serbänescu A, Nestorescu B.

Abstract

Four case reports are presented of patients who ate the meat of a hog inadvertently fed seed treated with fungicides containing ethyl mercury chloride. The clinical, electrophysiological, and toxicological, and in two of the patients the pathological data, showed that this organic mercury compound has a very high toxicity not only for the brain, but also for the spinal motoneurones, peripheral nerves, skeletal muscles, and myocardium.

PMID: 7359151 [PubMed - indexed for MEDLINE]PMCID: PMC490489Free PMC Article

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Toxicology. 1979 Mar-Apr;12(3):325-33.

Problems associated with the use of merthiolate as a preservative in anti-lymphocytic globulin.

Heyworth MF, Truelove SC.

Abstract

The cytotoxic properties of 2 anti-lymphocytic globulin (ALG) preparations were investigated in vitro by measuring the release of 51Cr from labelled human peripheral blood mononuclear cells, tonsil lymphocytes and Chang cells, incubated with different concentrations of ALG. One of the ALG preparations showed non-selective cytotoxicity in the absence of complement. Evidence was obtained to suggest that this effect was due to merthiolate (sodium ethylmercurithiosalicylate) which had been added to the ALG as a preservative during manufacture. The mercury concentration in the ALG was found to be greater than that stated by the manufacturers. It is conceivable that the clinical use of such as ALG preparation might lead to mercury accumulation in the tissues, with resulting toxic effects. The whole question of the use of merthiolate in the preparation of sera for administration to human subjects needs to be reconsidered.

PMID: 494313 [PubMed - indexed for MEDLINE]

But okay to inject?

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Arch Dis Child. 1977 Dec;52(12):962-4.

Organ mercury levels in infants with omphaloceles treated with organic mercurial antiseptic.

Fagan DG, Pritchard JS, Clarkson TW, Greenwood MR.

Abstract

Samples of fresh and fixed tissues from infants with exomphalos treated by thiomersal application were analysed for mercury content. The results showed that thiomersal can induce blood and organ levels of organic mercury which are well in excess of the minimum toxic level in adults and fetuses. The analysis of fresh and fixed tissues must be carefully controlled against normal tissues in order to interpret mercury levels accurately.

PMID: 606172 [PubMed - indexed for MEDLINE]PMCID: PMC1545035Free PMC Article

This appears to mean that even topical application can result in toxic internal levels.

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Invest Ophthalmol Vis Sci. 1977 Apr;16(4):273-80.

Effect of the ophthalmic preservative thimerosal on rabbit and human corneal endothelium.

Van Horn DL, Edelhauser HF, Prodanovich G, Eiferman R, Pederson HF.

Abstract

Widespread use of the mercurial-containing preservative thimerosal as an antibacterial agent in ophthalmic drugs and solutions warranted an investigation into its possible cytotoxic effects on the functional and ultrastructural integrity of the corneal endothelium. No changes in corneal thickness were observed during 5 hours' perfusion of the endothelium of rabbit and human corneas with 0.0001 and 0.0005 percent thimerosal in glutathione bicarbonate Ringer's solution (GBR). Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) of the endothelium of the 0.0001 percent group revealed normal ultrastructure. SEM and TEM of the endothelium of corneas perfused with 0.0005 percent thimerosal for 5 hours revealed condensed mitochondria, cytoplasmic vacuoles, and cytoplasmic flaps at the apical end of the cellular junctions. Perfusion of higher concentrations (0.001 and 0.005 perecnt) of thimerosal in GBR resulted in increases in corneal thickness after 2 hours and irreversible ultrastructural damage to the endothelial cells by 5 hours. Corneas perfused with 0.01 and 0.1 percent thimerosal in GBR showed a rapid and immediate increase in corneal thickness and endothelial cell death and necrosis within 1 hour. It is postulated that the mercury in thimerosal becomes bound to the cell membrane protein sulfhydryl groups, causing an increase in cellular permeability; These results suggest that the prolonged exposure of the corneal endothelium to thimerosal in the accepted antimicrobial dosage of 0.005 to 0.001 percent may result in functional and structural damage to the endothelium.

PMID: 844986 [PubMed - indexed for MEDLINE]Free Article

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Poult Sci. 1976 Sep;55(5):1913-7.

Preliminary study of the effects of feeding ethyl mercury chloride on four breeds of chickens.

Al-Soudi KA, Al Fayadh HA, Al-Khazrje AK, Mehdi AW, Al-Jiboori A, Al Muraib S.

Abstract

Different breeds of chickens namely Single Comb White Leghorn (S.C.W.L.), New Hamsphire (N.H.), Iraqi (IRQ) and a cross (CRS.) S.C.W.L. X N.H. X IRQ. were housed in small pens (20 females and 2 males each) and given, in the diet, 40% wheat treatmed with ethyl mercury chloride, for 88 days. Throughout the whole experiment all birds remained active and showed no symptoms of toxicity. The Iraqi breed was significantly higher than the other breeds with respect to egg production. The results also indicated that mercury in egg white is almost three times as much as that in the yolk, although there was no significant difference between the breeds. The liver and kidney of the four breeds tended to accumulate the highest amount of mercury. Significant differences appeared between sexes according to liver and kidney. White Leghorn and local breeds behaved the same, but N.H. had the highest concentration of mercury in most tissues.

PMID: 792857 [PubMed - indexed for MEDLINE]

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Poult Sci. 1976 Mar;55(2):772-9.

Effects of feeding ethyl mercury chloride to chickens.

Al-Fayadh H, Mehdi AW, Al-Soudi K, Al-Khazraji AK, Al-Jiboori NA, Al-Muraib S.

Abstract

Four groups, 0, 5, 10 and 20%, of Single Comb White Leghorn chickens (30 males plus 30 females each) were fed a diet which contained either 0, 5, 10 or 20% ethyl mercury chloride dressed wheat for a period of 88 days. The wheat was dressed with the organic mercury compound at the rate of 500 gm. ethyl mercury chloride per metric ton of wheat. Therfore, the diets contained respectively 0, 25, 50 and 100 mg. organic mercury compound/kg. With average daily feed consumption of 101, 102, 101 and 98 gm. by the individual birds of the respective groups, the birds did not show any symptoms of disease during the course of the study. Egg production, egg quality and mortality of the treatment groups were comparable with those of the control group. The amount of residual mercury in egg white and yolk was determined at intervals. The residual mercury of egg white of the treatment groups was about three times as much as that of egg yolk, and made its significant appearance in the 20% group on the third day of the trial. The concentration was increasing with time in both white and yolk and was parallel to the concentration of the organic mercury in the diet. The liver followed by the kidney of both sexes accumulated the highest amounts of mercury. Tissues of female birds accumulated less mercury than tissues of male birds did probably due to the passage of some of the ingested mercury with the egg white and yolk. The results were discussed on the basis that the kind of mercury compound, daily intake and duration of treatment play major roles in the determination of induced effects.

PMID: 778821 [PubMed - indexed for MEDLINE]

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Toxicology. 1975;3(2):171-6.

Tissue concentrations of mercury after chronic dosing of squirrel monkeys with thiomersal.

Blair AMJN, Clark B, Clarke AJ, Wood P.

Abstract

Squirrel monkeys were dosed intranasally with saline or thiomersal (sodium ethylmercurithiosalicylate, 0.002 percent w/v) daily for six months. The total amounts of thiomersal given during the six months period were 418 mug (low dose group) and 2280 mug (high dose group). This was equivalent to 207 and 1125 mug mercury. The dose differential was achieved by more frequent administration to the high dose group. Mercury concentrations were significantly raised over control values in brain (high dose group only), liver, muscle and kidney, but not in blood. Concentrations were highest in the kidney, moderate in liver and lowest in brain and muscle. Much of the mercury was present in the inorganic form (37-91 percent). No evidence of toxicity due to thiomersal was seen in any animal. Nevertheless accumulation of mercury from chronic use of thiomersal-preserved medicines is viewed as a potential health hazard for man.

PMID: 804725 [PubMed - indexed for MEDLINE]

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Arch Ophthalmol. 1975 Jan;93(1):52-55.

Teratogenicities of ophthalmic drugs. II. Teratogenicities and tissue accumulation of thimerosal.

Gasset AR, Itoi M, Ishii Y, Ramer RM.

Abstract

Under the conditions of this study, systemically or topically applied thimerosal was found to have no teratogenic effect even when given in concentrations approaching the 50% lethal dose of these compounds. A comparison of topical and subcutaneous administration of thimerosal to rabbits shows that a substantial concentration of mercury was present in blood and tissues of the treated animals and their offspring. Thimerosal was found to cross the blood-brain and placenta barriers.

PMID: 1111489 [PubMed - indexed for MEDLINE]

Topical as well as subcutaneous…


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Contact Dermatitis. 1975 Aug;1(4):221-2.

Acute laryngeal obstruction presumed secondary to thiomersal (merthiolate) delayed hypersensitivity.

Maibach H.

Abstract

A patient treated his slight score-throat with a thiomersal first aid spray. The next day, because of continued discomfort, he repeated its use. Laryngeal obstruction followed within hours. Emergency tracheostomy produced prompt improvement. Patch testing revealed an extreme spreading reaction to thiomersal. It is our interpretation that the acute laryngeal obstruction was delayed hypersensitivity to this first aid spray.

PMID: 1235252 [PubMed - indexed for MEDLINE]

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Science. 1972 Jan 21;175(19):328-31.

Ethyl mercury p-toluene sulfonanilide: lethal and reproductive effects on pheasants.

Spann JW, Heath RG, Kreitzer JF, Locke LN.

Abstract

Ethyl mercury p-toluene sulfonanilide (active ingredient of Ceresan M) at a dietary concentration of 30 parts per million (12.5 parts of mercury per million) was lethal to adult ring-necked pheasants. Egg production and survival of third-week embryos were sharply reduced when breeders were maintained on feed containing 10 parts of this compound per million (4.2 parts of mercury per million).

PMID: 5008162 [PubMed - indexed for MEDLINE]




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Aneugen

Genetics. Any agent that affects cell division and the mitotic spindle apparatus resulting in the loss or gain of whole chromosomes, thereby inducing an aneuploidy.

Aneuploidie

Genetics. A genetically unbalanced condition in which a cell or an organism has a number of chromosomes that is not an exact multiple of the haploid number for that species. E.g., trisomy 21 is a form of aneuploidy.

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