This blog is a way of sharing the information and resources that have helped me to recover my son Roo from an Autism Spectrum Disorder. What I have learned is to view our symptoms as the results of underlying biological cause, which can be identified and healed. I say "our symptoms" because I also have a neuro-immune disorder called Myalgic Encephalomyelitis.

And, of course, I am not a doctor (although I have been known to impersonate one while doing imaginative play with my son)- this is just our story and information that has been helpful or interesting to us. I hope it is helpful and interesting to you!

Thursday, July 26, 2012

Studies Showing the Toxicity of Mercury and Thimerosal

(This post is a work in progress and will be added to over time.)

The question of whether mercury in vaccines is a contributing factor in the etiology of autism and other neurodevelopmental disorders is probably one of the most debated topics of our time.  Few people who argue that Thimerosal can not be relevant are aware of the many peer-reviewed studies that demonstrate cause for concern.  Below are links to some of these studies.

Methodological Issues and Evidence of Malfeasance in Research Purporting to Show Thimerosal in Vaccines Is Safe
BioMed Research International Volume 2014 (2014), Article ID 247218, 8 pages
"There are over 165 studies that have focused on Thimerosal, an organic-mercury (Hg) based compound, used as a preservative in many childhood vaccines, and found it to be harmful. Of these, 16 were conducted to specifically examine the effects of Thimerosal on human infants or children with reported outcomes of death; acrodynia; poisoning; allergic reaction; malformations; auto-immune reaction; Well’s syndrome; developmental delay; and neurodevelopmental disorders, including tics, speech delay, language delay, attention deficit disorder, and autism. In contrast, the United States Centers for Disease Control and Prevention states that Thimerosal is safe and there is “no relationship between [T]himerosal[-]containing vaccines and autism rates in children.” This is puzzling because, in a study conducted directly by CDC epidemiologists, a 7.6-fold increased risk of autism from exposure to Thimerosal during infancy was found. The CDC’s current stance that Thimerosal is safe and that there is no relationship between Thimerosal and autism is based on six specific published epidemiological studies coauthored and sponsored by the CDC. The purpose of this review is to examine these six publications and analyze possible reasons why their published outcomes are so different from the results of investigations by multiple independent research groups over the past 75+ years."
Integrating Experimental (in vitro and in vivo) Neurotoxicity Studies of Low-Dose Thimerosal Relevant to Vaccines
Neurochem Res.  2011 Jun;36(6):927-38. Epub 2011 Feb 25.
"There is a need to interpret neurotoxic studies to help deal with uncertainties surrounding pregnant mothers, newborns and young children who must receive repeated doses of Thimerosal-containing vaccines (TCVs)...Information extracted from studies indicates that: (a) activity of low doses of Thimerosal against isolated human and animal brain cells was found in all studies and is consistent with Hg neurotoxicity; (b) the neurotoxic effect of ethylmercury has not been studied with co-occurring adjuvant-Al in TCVs; (c) animal studies have shown that exposure to Thimerosal-Hg can lead to accumulation of inorganic Hg in brain, and that (d) doses relevant to TCV exposure possess the potential to affect human neuro-development.  Thimerosal at concentrations relevant for infants' exposure (in vaccines) is toxic to cultured human-brain cells and to laboratory animals."

Increased risk of developmental neurologic impairment after high exposure to thimerosal-containing vaccine in first month of life. 
" We identified 286 children with degenerative and 3702 with developmental neurologic disorders, and 310 with renal disorders. The relative risk (RR) of developing a neurologic development disorder was 1.8 ( 95% confidence intervals [CI] ::: 1.1-2.8) when comparing the highest exposure group at 1 month of age (cumulative dose> 25 ug) to the unexposed group. Within this group we also found an elevated risk for the following disorders: autism (RR 7.6, 95% Cl = 1.8-31.5), non organic sleep disorders (RR 5.0, 95% Cl = 1.6-15.9}, and speech disorders (RR 2.1, 95% (1=1.1-4.0)."

An Assessment of the Impact of Thimerosal on Childhood Neurodevelopmental Disorders
Pediatr Rehabil. 2003 Apr-Jun;6(2):97-102.
"The evidence presented here shows that the occurrence of neurodevelopmental disorders following thimerosal-containing childhood vaccines does not appear to be coincidental."

Neurodevelopmental Disorders Following Thimerosal-Containing Childhood Immunizations:  A Follow-Up Analysis
International Journal of Toxicology November 2004 vol. 23 no. 6 369-376
"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."

Maternal transfer of mercury to the developing embryo/fetus: is there a safe level?
Toxicological & Environmental Chemistry Volume 94, Issue 8, 2012 pages 1610-1627
"Mercury (Hg) exposure is ubiquitous in modern society via vaccines, fish/crustacea, dental amalgam, food, water, and the atmosphere. This article examines Hg exposure in the context of primary exposure to pregnant women and secondary exposure experienced by their unborn babies. Babies in utero are particularly at risk of higher Hg exposure than adults (on a dose/weight basis through maternal Hg transfer via the placenta), and are more susceptible to adverse effects from mercury and its biologically active compounds. It is, therefore, critical that regulatory advisories around maximum safe Hg exposures account for pregnant women and secondary exposure that children in utero experience. This study focused on standardized embryonic and fetal Hg exposures via primary exposure to the pregnant mother of two common Hg sources (dietary fish and parenteral vaccines). Data demonstrated that Hg exposures, particularly during the first trimester of pregnancy, at well-established dose/weight ratios produced severe damage to humans including death. In light of research suggestive of a mercuric risk factor for childhood conditions such as tic disorders, cerebral palsy, and autism, it is essential that Hg advisories account for secondary prenatal human exposures."

Ancestry of Pink Disease (Infantile Acrodynia) Identified as a Risk Factor for Autism Spectrum Disorder
Journal of Toxicology and Environmental Health, Part A, vol 74:18  pp 1185-1194
"The results showed the prevalence rate of ASD among the grandchildren of pink disease survivors (1 in 25) to be significantly higher than the comparable general population prevalence rate (1 in 160). The results support the hypothesis that Hg sensitivity may be a heritable/genetic risk factor for ASD."

A Case Series of Children with Apparent Mercury Toxic Encephalopathies Manifesting with Clinical Symptoms of Regressive Autistic Disorders
 2007 May 15;70(10):837-51
"There was a significant dose-response relationship between the severity of the regressive ASDs observed and the total mercury dose children received from Thimerosal-containing vaccines/Rho (D)-immune globulin preparations. Based upon differential diagnoses, 8 of 9 patients examined were exposed to significant mercury from Thimerosal-containing biologic/vaccine preparations during their fetal/infant developmental periods, and subsequently, between 12 and 24 mo of age, these previously normally developing children suffered mercury toxic encephalopathies that manifested with clinical symptoms consistent with regressive ASDs. Evidence for mercury intoxication should be considered in the differential diagnosis as contributing to some regressive ASDs."

B-lymphocytes from a population of children with autism spectrum disorder and their unaffected siblings exhibit hypersensitivity to thimerosal
.J Toxicol. 2013;2013:801517. doi: 10.1155/2013/801517. Epub 2013 Jun 9.
"The role of thimerosal containing vaccines in the development of autism spectrum disorder (ASD) has been an area of intense debate, as has the presence of mercury dental amalgams and fish ingestion by pregnant mothers. We studied the effects of thimerosal on cell proliferation and mitochondrial function from B-lymphocytes taken from individuals with autism, their nonautistic twins, and their nontwin siblings. Eleven families were examined and compared to matched controls. B-cells were grown with increasing levels of thimerosal, and various assays (LDH, XTT, DCFH, etc.) were performed to examine the effects on cellular proliferation and mitochondrial function. A subpopulation of eight individuals (4 ASD, 2 twins, and 2 siblings) from four of the families showed thimerosal hypersensitivity, whereas none of the control individuals displayed this response. The thimerosal concentration required to inhibit cell proliferation in these individuals was only 40% of controls. Cells hypersensitive to thimerosal also had higher levels of oxidative stress markers, protein carbonyls, and oxidant generation. This suggests certain individuals with a mild mitochondrial defect may be highly susceptible to mitochondrial specific toxins like the vaccine preservative thimerosal."

Comparison of Blood and Brain Mercury Levels in Infant Monkeys Exposed to Methylmercury or Vaccines Containing Thimerosal
Environmental Health Perspectives, Aug 2005.
The primary finding of this study is that ethyl mercury (in thimerosal) is not processed or excreted by the body the same way that methyl mercury is (the form found in fish), and that therefore the use of methyl mercury biochemistry to approximate the effects of ethyl mercury are not founded and are misleading.  Further, ethyl mercury is converted to inorganic mercury and accumulates in the brain more and stays there longer.

"Recent publications have proposed a direct link between the use of thimerosal-containing vaccines and the significant rise in the number of children being diagnosed with autism, a serious and prevalent developmental disorder (for review, see IOM 2001). Results from an initial IOM review of the safety of vaccines found that there was not sufficient evidence to render an opinion on the relationship between ethylmercury exposure and developmental disorders in children (IOM 2001). The IOM review did, however, note the possibility of such a relationship and recommended further studies be conducted. A recently published second review (IOM 2004) appears to have abandoned the earlier recommendation as well as backed away from the American Academy of Pediatrics goal. This approach is difficult to understand, given our current limited knowledge of the toxicokinetics and developmental neurotoxicity of thimerosal, a compound that has been (and will continue to be) injected in millions of newborns and infants."

Blood Levels of Mercury Are Related to Diagnosis of Autism: A Reanalysis of an Important Data Set
Journal of Child Neurology, Vol. 22, No. 11, 1308-1311 (2007)
"The question of what is leading to the apparent increase in autism is of great importance. Like the link between aspirin and heart attack, even a small effect can have major health implications. If there is any link between autism and mercury, it is absolutely crucial that the first reports of the question are not falsely stating that no link occurs. We have reanalyzed the data set originally reported by Ip et al. in 2004 and have found that the original p value was in error and that a significant relation does exist between the blood levels of mercury and diagnosis of an autism spectrum disorder. Moreover, the hair sample analysis results offer some support for the idea that persons with autism may be less efficient and more variable at eliminating mercury from the blood."

Reduced levels of mercury in first baby haircuts of autistic children.
Int J Toxicol. 2003 Jul-Aug;22(4):277-85.
"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."

Mercury induces inflammatory mediator release from human mast cells
Journal of Neuroinflammation 2010, 7:20
"Mercury is known to be neurotoxic, but its effects on the immune system are less well known. Mast cells are involved in allergic reactions, but also in innate and acquired immunity, as well as in inflammation. Many patients with Autism Spectrum Disorders (ASD) have "allergic" symptoms; moreover, the prevalence of ASD in patients with mastocytosis, characterized by numerous hyperactive mast cells in most tissues, is 10-fold higher than the general population suggesting mast cell involvement. We, therefore, investigated the effect of mercuric chloride (HgCl2) on human mast cell activation... HgCl2 stimulates VEGF and IL-6 release from human mast cells. This phenomenon could disrupt the blood-brain-barrier and permit brain inflammation. As a result, the findings of the present study provide a biological mechanism for how low levels of mercury may contribute to ASD pathogenesis."

Neurotoxic effects of postnatal thimerosal are mouse strain dependent
Molecular Psychiatry (2004) 9, 833–845
"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."

Thimerosal-Derived Ethyl-mercury is a Mitochondrial Toxin in Human Astrocytes: Possible Role of Fenton Chemistry in the Oxidation and Breakage of mtDNA
J Toxicl 2012; 2012:373678
"We find that ethylmercury not only inhibits mitochondrial respiration leading to a drop in the steady state membrane potential, but concurrent with these phenomena are increases the formation of superoxide, hydrogen peroxide and Fenton/Haber-Weiss generated hydroxyl radical. These oxidants increase the levels of cellular aldehyde/ketones. Additionally, we find a five-fold increase in the levels of oxidant damaged mitochondrial DNA bases and increases in the levels of mtDNA nicks and blunt ended breaks. Highly damaged mitochondria are characterized by having very low membrane potentials, increased superoxide/hydrogen peroxide production, extensively damaged mtDNA and proteins. These mitochondria appear to have undergone a permeability transition, an observation supported by the five fold increase in Caspase-3 activity observed after Thimerosal treatment."

Thimerosal Exposure and the Role of Sulfation Chemistry and Thiol Availability in Autism
Int J Environ Res Public Health.  Aug 2013; 10(8):3771-3800
"Several recent studies suggest that children diagnosed with an ASD have abnormal sulfation chemistry, limited thiol availability, and decreased glutathione (GSH) reserve capacity, resulting in a compromised oxidation/reduction (redox) and detoxification capacity. Research indicates that the availability of thiols, particularly GSH, can influence the effects of thimerosal (TM) and other mercury (Hg) compounds. TM is an organomercurial compound (49.55% Hg by weight) that has been, and continues to be, used as a preservative in many childhood vaccines, particularly in developing countries. Thiol-modulating mechanisms affecting the cytotoxicity of TM have been identified. Importantly, the emergence of ASD symptoms post-6 months of age temporally follows the administration of many childhood vaccines. The purpose of the present critical review is provide mechanistic insight regarding how limited thiol availability, abnormal sulfation chemistry, and decreased GSH reserve capacity in children with an ASD could make them more susceptible to the toxic effects of TM routinely administered as part of mandated childhood immunization schedules."

Inhibition of the human thioredoxin system. A molecular mechanism of mercury toxicity
.J Biol Chem. 2008 May 2;283(18):11913-23. doi: 10.1074/jbc.M710133200. Epub 2008 Mar 4.
"Mercury toxicity mediated by different forms of mercury is a major health problem; however, the molecular mechanisms underlying toxicity remain elusive. We analyzed the effects of mercuric chloride (HgCl(2)) and monomethylmercury (MeHg) on the proteins of the mammalian thioredoxin system, thioredoxin reductase (TrxR) and thioredoxin (Trx), and of the glutaredoxin system, glutathione reductase (GR) and glutaredoxin (Grx). Overall, mercury inhibition was selective toward the thioredoxin system. In particular, the remarkable potency of the mercury compounds to bind to the selenol-thiol in the active site of TrxR should be a major molecular mechanism of mercury toxicity."

A Two-Phase Study Evaluating the Relationship Between Thimerosal-Containing Vaccine Administration and the Risk for an Autism Spectrum Disorder Diagnosis in the United States
Geier et al. Translational Neurodegeneration 2013,2:25
"Routine childhood vaccination is an important public health tool to reduce the morbidity and mortality associated with infectious diseases, but the present study provides new epidemiological evidence supporting an association between increasing organic-Hg exposure from Thimerosal-containing childhood vaccines and the subsequent risk of an ASD diagnosis."

Lasting neuropathological changes in rat brain after intermittent neonatal administration of thimerosal
Folia Neuropathol.  2010;48(4):258-69
"Thimerosal, an organomercurial added as a preservative to some vaccines, is a suspected iatrogenic factor, possibly contributing to paediatric neurodevelopmental disorders including autism... Numerous neuropathological changes were observed in young adult rats which were treated postnatally with thimerosal. They included: ischaemic degeneration of neurons and "dark" neurons in the prefrontal and temporal cortex, the hippocampus and the cerebellum, pathological changes of the blood vessels in the temporal cortex, diminished synaptophysin reaction in the hippocampus, atrophy of astroglia in the hippocampus and cerebellum, and positive caspase-3 reaction in Bergmann astroglia. These findings document neurotoxic effects of thimerosal, at doses equivalent to those used in infant vaccines or higher, in developing rat brain, suggesting likely involvement of this mercurial in neurodevelopmental disorders."

Environmental Mercury Release, Special Education Rates, and Autism Disorder: an ecological study of Texas
Health & Place, 2006
"There was a significant increase in the rates of special education students (controlling for district size) and autism rates associated with increases in environmentally released mercury. On average, for each 1,000 lb of environmentally released mercury, there was a 43% increase in the rate of special education services and a 61% increase in the rate of autism. The association between environmentally released mercury and special education rates were fully mediated by increased autism rates. This ecological study suggests the need for further research regarding the association between environmentally released mercury and developmental disorders such as autism. These results have implications for policy planning and cost analysis."

Autism Spectrum Disorders in Relation to Distribution of Hazardous Air Pollutants in the SF Bay Area
Environmental Health Perspectives – Vol. 114 No. 9, September, 2006
"The adjusted odds ratios (AORs) were elevated by 50% in the top quartile of chlorinated solvents and heavy metals [95% confidence intervals (CIs), 1.1–2.1], but not for aromatic solvents. Adjusting for these three groups simultaneously led to decreased risks for the solvents and increased risk for metals (AORs for metals: fourth quartile = 1.7; 95% CI, 1.0–3.0; third quartile = 1.95; 95% CI, 1.2–3.1). The individual compounds that contributed most to these associations included mercury, cadmium, nickel, trichloroethylene, and vinyl chloride."

Proximity to Point Sources of Environmental Mercury Release as a Predictor of Autism Prevalence
Health and Place, 2008
"The objective of this study was to determine if proximity to sources of mercury pollution in 1998 were related to autism prevalence in 2002. Autism count data from the Texas Educational Agency and environmental mercury release data from the Environmental Protection Agency were used. We found that for every 1000 pounds of industrial release, there was a corresponding 2.6% increase in autism rates (p<.05) and a 3.7% increase associated with power plant emissions(P<.05). Distances to these sources were independent predictors after adjustment for relevant covariates. For every 10 miles from industrial or power plant sources, there was an associated decreased autism Incident Risk of 2.0% and 1.4%, respectively (p<.05). While design limitations preclude interpretation of individual risk, further investigations of environmental risks to child development issues are warranted."
Mitochondrial Dysfunction, Impaired Oxidative-Reduction Activity, Degeneration and Death in Human Neuronal and Fetal Cells Induced by Low-Level Exposure to Thimerosal and Other Metal Compounds
Toxicological and Environmental Chemistry, vol 91 issue 4, 2009
"Of particular recent concern, routine administering of Thimerosal-containing biologics/childhood vaccines have become significant sources of Hg exposure for some fetuses/infants...Thimerosal-induced cellular damage as evidenced by concentration- and time-dependent mitochondrial damage, reduced oxidative–reduction activity, cellular degeneration, and cell death in the in vitro human neuronal and fetal model systems studied. Thimerosal at low nanomolar (nM) concentrations induced significant cellular toxicity in human neuronal and fetal cells. Thimerosal-induced cytoxicity is similar to that observed in AD pathophysiologic studies. Thimerosal was found to be significantly more toxic than the other metal compounds examined. Future studies need to be conducted to evaluate additional mechanisms underlying Thimerosal-induced cellular damage and assess potential co-exposures to other compounds that may increase or decrease Thimerosal-mediated toxicity."

Mitochondrial Mediated Thimerosal-Induced Apoptosis in a Human Neuroblastoma Cell Line (SK-N-SH)
NeuroToxicology, vol.26 iss. 3, June 2005, pages 407-416
"Mercurials have been reported to cause apoptosis in cultured neurons; however, the signaling pathways resulting in cell death have not been well characterized. Therefore, the objective of this study was to identify the mode of cell death in an in vitro model of thimerosal-induced neurotoxicity... In cells treated for 24 h with thimerosal, fluorescence microscopy indicated cells undergoing both apoptosis and oncosis/necrosis... Taken together these findings suggest deleterious effects on the cytoarchitecture by thimerosal and initiation of mitochondrial-mediated apoptosis."

Neonatal Administration of Thimerosal Causes Persistent Changes in Mu Opioid Receptors in the Rat Brain
Neurochem Res. 2010 November; 35(11): 1840–1847. 
"Thimerosal added to some pediatric vaccines is suspected in pathogenesis of several neurodevelopmental disorders. Our previous study showed that thimerosal administered to suckling rats causes persistent, endogenous opioid-mediated hypoalgesia...Thimerosal administration caused dose-dependent statistically significant increase in MOR densities in the periaqueductal gray and caudate putamen, but decrease in the dentate gyrus, where it was accompanied by the presence of degenerating neurons and loss of synaptic vesicle marker (synaptophysin). These data document that exposure to thimerosal during early postnatal life produces lasting alterations in the densities of brain opioid receptors along with other neuropathological changes, which may disturb brain development."

Persistent Behavioral Impairments and Alterations of Brain Dopamine System After Early Postnatal Administration of Thimerosal in Rats
Behav Brain Res. 2011 Sep 30;223(1):107-18. Epub 2011 Apr 28.
"The neurotoxic organomercurial thimerosal (THIM), used for decades as vaccine preservative, is a suspected factor in the pathogenesis of some neurodevelopmental disorders. Previously we showed that neonatal administration of THIM at doses equivalent to those used in infant vaccines or higher, causes lasting alterations in the brain opioid system in rats...Males were more sensitive than females to some neurodisruptive/neurotoxic actions of THIM. These data document that early postnatal THIM administration causes lasting neurobehavioral impairments and neurochemical alterations in the brain, dependent on dose and sex. If similar changes occur in THIM/mercurial-exposed children, they could contribute to neurodevelopmental disorders."

Maternal Thimerosal Exposure Results in Aberrant Cerebellar Oxidative Stress, Thyroid Hormone Metabolism, and Motor Behavior in Rat Pups; sex- and strain-dependent effects.
Cerebellum.  2012 Jun;11(2):575-86.
"Methylmercury (Met-Hg) and ethylmercury (Et-Hg) are powerful toxicants with a range of harmful neurological effects in humans and animals....Our data thus demonstrate a negative neurodevelopmental impact of perinatal TM (thimerosal) exposure which appears to be both strain- and sex-dependent."

This study found that thimerosal was associated with a significant increase in cerebellar oxidative stress, in reduced motor learning, in reduced levels of thyroid hormone, and an alteration of gene expression due to the lower level of the thyroid hormone T3 in the cerebellum. 

Immunosuppressive and autoimmune effects of thimerosal in mice
Toxicol Appl Pharmacol. 2005 Apr 15;204(2):109-21
"In conclusion, the organic mercury compound thimerosal (EtHg) has initial immunosuppressive effects similar to those of MeHg. However, in contrast to MeHg, thimerosal treatment leads in genetically susceptible mice to a second phase with strong immunostimulation and autoimmunity, which is T-cell dependent, H-2 linked and may at least partly be due to the inorganic mercury derived from the metabolism of ethyl mercury."

Administration of Thimerosal to Infant Rats Increases Overflow of Glutamate and Aspartate in the Prefrontal Cortex:
Neurochem Res. 2012 February; 37(2): 436–447. 
"Thimerosal, a mercury-containing vaccine preservative, is a suspected factor in the etiology of neurodevelopmental disorders. We previously showed that its administration to infant rats causes behavioral, neurochemical and neuropathological abnormalities similar to those present in autism...Since excessive accumulation of extracellular glutamate is linked with excitotoxicity, our data imply that neonatal exposure to thimerosal-containing vaccines might induce excitotoxic brain injuries, leading to neurodevelopmental disorders."

Methylmercury increases glutamate extracellular levels in frontal cortex of awake rats.
Neurotoxicol Teratol. 2002 Nov-Dec;24(6):767-71.
"A current hypothesis about methylmercury (MeHg) neurotoxicity proposes that neuronal damage is due to excitotoxicity following glutamate uptake alterations in the astrocyte. By sampling from a microdialysis probe implanted in the frontal cortex of adult Wistar rats, we measured the effects of acute exposure to either 10 or 100 microM MeHg through the microdialysis probe, on glutamate extracellular levels in 15 awake animals. After baseline measurements, the perfusion of MeHg during 90 min induced immediate and significant elevations in extracellular glutamate at 10 microM (9.8-fold, P<.001) and at 100 microM (2.4-fold, P=.001). This in vivo demonstration of increments of extracellular glutamate supports the hypothesis that dysfunction of glutamate neurotransmission plays a key role in MeHg-induced neural damage."

Transcriptomic analyses of neurotoxic effects in mouse brain after intermittent neonatal administration of thimerosal.
Toxicol Sci. 2014 Jun;139(2):452-65.
"Thimerosal-treated mice exhibited neural development delay, social interaction deficiency, and inclination of depression. Apparent neuropathological changes were also observed in adult mice neonatally treated with thimerosal. High-throughput RNA sequencing of autistic-behaved mice brains revealed the alternation of a number of canonical pathways involving neuronal development, neuronal synaptic function, and the dysregulation of endocrine system. Intriguingly, the elevation of anterior pituitary secreting hormones occurred exclusively in male but not in female thimerosal-treated mice, demonstrating for the first time the gender bias of thimerosal-mercury toxicity with regard to endocrine system. Our results indicate that higher dose of neonatal thimerosal-mercury (20× higher than that used in human) is capable of inducing long-lasting substantial dysregulation of neurodevelopment, synaptic function, and endocrine system, which could be the causal involvements of autistic-like behavior in mice."

Prenatal Exposure to Organomercury, Thimerosal, Persistently Impairs the Serotonergic and Dopaminergic Systems in the Rat Brain:  Implications for association with developmental disorders
Brain Dev. 2012 May 31.
"Here, we investigated whether prenatal thimerosal exposure causes persistent impairment after birth. Analysis on postnatal day 50 showed significant increase in hippocampal serotonin following thimerosal administration on embryonic day 9. Furthermore, not only serotonin, striatal dopamine was significantly increased. These results indicate that embryonic exposure to thimerosal produces lasting impairment of brain monoaminergic system, and thus every effort should be made to avoid the use of thimerosal."

Uncoupling of ATP-mediated Calcium Signaling and Dysregulated IL-6 Secretion in Dendritic Cells by Nanomolar Thimerosal
Environmental Health Perspectives, July 2006
"Immune dysregulation triggered by organic mercury can include suppression, stimulation, loss of tolerance, and generation of auto-antibodies. Therefore, the pattern of immunotoxicity induced by organic mercury is likely to depend not only on the chemical form, timing, and dose to which an individual is exposed but also on susceptibility factors that are poorly understood at present. Thus, significant attention is currently focused on identifying which types of immune cells and biomolecules are critical targets of low-level organic mercury and their functional consequences on overall immune status."

Comments on this research from Science Daily include 

"The study provides the first evidence that dendritic cells show unprecedented sensitivity to thimerosal, resulting in fundamental changes in the immune system's ability to respond to external factors. "

"When thimerosal, at a concentration as low as 20 parts per billion, alters the fidelity of normal calcium signals, dendritic cells show abnormal secretion of IL-6 cytokine -- a potent chemical signal that initiates inflammatory responses. Higher concentrations -- 200 parts per billion -- causes programmed death of dendritic cells, preventing them from maturing and doing their primary job of activating T-cells. Without proper feedback to guide its response, a normal dendritic cell can quickly become "a rogue, producing misinformation that could activate aberrant and harmful immune responses," Pessah explained. "Even one rogue dendritic cell can activate many inappropriate immune responses."

"Thimerosal is a cheap and effective mercury-based preservative. Its potential effects on embryonic neuron development led to its removal from many pediatric vaccines. However, it is still used in influenza, diphtheria and tetanus vaccines, blood products and many over-the-counter pharmaceuticals. The concentrations of thimerosal used by the UC Davis researchers were comparable to those attained in childhood vaccinations containing the preservative."

"Researchers and parents have previously proposed links between childhood vaccines and autism, a neurodevelopmental disorder that affects language skills and social interactions. The UC Davis study indicates that in addition to being a direct neurotoxicant, thimerosal may also be an immunotoxicant, leaving the immune system vulnerable to microbes and other external influences."

Activation of Methionine Synthase by Insulin-like Growth Factor-1 and Dopamine: a Target for Neurodevelopmental Toxins and Thimerosal
Molecular Psychiatry, July 2004.
"The ethylmercury-containing preservative thimerosal inhibited both IGF-1- and dopamine-stimulated methylation with an IC(50) of 1 nM and eliminated MS activity. Our findings outline a novel growth factor signaling pathway that regulates MS activity and thereby modulates methylation reactions, including DNA methylation. The potent inhibition of this pathway by ethanol, lead, mercury, aluminum and thimerosal suggests that it may be an important target of neurodevelopmental toxins."

Thimerosal Neurotoxicity is Associated with Glutathione Depletion: Protection with Glutathione Precursors
Neurotoxicology, Jan 2005.
"Thimerosol is an antiseptic containing 49.5% ethyl mercury that has been used for years as a preservative in many infant vaccines and in flu vaccines. Environmental methyl mercury has been shown to be highly neurotoxic, especially to the developing brain. Because mercury has a high affinity for thiol (sulfhydryl (-SH)) groups, the thiol-containing antioxidant, glutathione (GSH), provides the major intracellular defense against mercury-induced neurotoxicity. Cultured neuroblastoma cells were found to have lower levels of GSH and increased sensitivity to thimerosol toxicity compared to glioblastoma cells that have higher basal levels of intracellular GSH. Thimerosal-induced cytotoxicity was associated with depletion of intracellular GSH in both cell lines. Pretreatment with 100 microM glutathione ethyl ester or N-acetylcysteine (NAC), but not methionine, resulted in a significant increase in intracellular GSH in both cell types. Further, pretreatment of the cells with glutathione ethyl ester or NAC prevented cytotoxicity with exposure to 15 microM Thimerosal. Although Thimerosal has been recently removed from most children's vaccines, it is still present in flu vaccines given to pregnant women, the elderly, and to children in developing countries. The potential protective effect of GSH or NAC against mercury toxicity warrants further research as possible adjunct therapy to individuals still receiving Thimerosal-containing vaccinations."

Increases in the number of reactive glia in the visual cortex of Macaca fascicularis following subclinical long-term methyl mercury exposure.
Toxicology and Applied Pharmacology, 1994
"The number of neurons, astrocytes, reactive glia, oligodendrocytes, endothelia, and pericytes in the cortex of the calcarine sulcus of adult female Macaca fascicularis following long-term subclinical exposure to methyl mercury (MeHg) and mercuric chloride (inorganic mercury; IHg) has been estimated by use of the optical volume fractionator stereology technique. Four groups of monkeys were exposed to MeHg (50 micrograms Hg/kg body wt/day) by mouth for 6, 12, 18, and 12 months followed by 6 months without exposure (clearance group). A fifth group of monkeys was administered IHg (as HgCl2; 200 micrograms Hg/kg body wt/day) by constant rate intravenous infusion via an indwelling catheter for 3 months. Reactive glia showed a significant increase in number for every treatment group, increasing 72% in the 6-month, 152% in the 12-month, and 120% in the 18-month MeHg exposed groups, and the number of reactive glia in the clearance group remained elevated (89%). The IHg exposed group showed a 165% increase in the number of reactive glia. The IHg exposed group and the clearance group had low levels of MeHg present within the tissue; however, the level of IHg was elevated in both groups. These results suggest that the IHg may be responsible for the increase in reactive glia."

Neurodevelopmental disorders, maternal Rh-negativity, and Rho(D) immune globulins: a multicenter assessment
Neuro Endocrinol Lett.  2008 Apr;29(2):272-80
"Many formulations of Thimerosal (49.55% mercury by weight)-containing Rho(D) immune globulins (TCRs) were routinely administered to Rh-negative mothers in the US prior to 2002...  It was hypothesized: (1) if prenatal Rho(D)-immune globulin preparation exposure was a risk factor for neurodevelopmental disorders (NDs) then more children with NDs would have Rh-negative mothers compared to controls; and (2) if Thimerosal in the Rho(D)-immune globulin preparations was the ingredient associated with NDs, following the removal of Thimerosal from all manufactured Rho(D)-immune globulin preparations from 2002 in the US the frequency of maternal Rh-negativity among children with NDs should be similar to control populations...  There were significant and comparable increases in maternal Rh-negativity among children with NDs...  Children with NDs born post-2001 had a maternal Rh-negativity frequency (13.6%) similar to controls."

Autism: a novel form of mercury poisoning
Medical Hypotheses vol 56 (4), pp 462-471, april 2001
"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."

Attention-Deficit Hyperactivity Disorder and Blood Mercury Level: a case-control study in Chinese children
Neuropediatrics, August 2006 - P.R. Kong [Department of Pediatrics and Adolescent Medicine, The University of Hong Kong].
"There was significant difference in blood mercury levels between cases and controls (geometric mean 18.2 nmol/L [95 % CI 15.4 - 21.5 nmol/L] vs. 11.6 nmol/L [95 % CI 9.9 - 13.7 nmol/L], p < 0.001), which persists after adjustment for age, gender and parental occupational status (p < 0.001). The geometric mean blood mercury level was also significantly higher in children with inattentive (19.4 nmol/L, 95 % CI 13.3 - 28.5 nmol/L) and combined (18.0 nmol/L, 95 % CI 14.9 - 21.8 nmol/L) subtypes of ADHD. Blood mercury levels were above 29 nmol/L in 17 (26.9 %) cases and 6 (10.2 %) controls. Children with blood mercury level above 29 nmol/L had 9.69 times (95 % CI 2.57 - 36.5) higher risk of having ADHD after adjustment for confounding variables."

Thimerosal induces TH2 responses via influencing cytokine secretion by human dendritic cells

Journal of Leukocyte Biology, February 2007 vol. 81 no. 2 474-482
"Thimerosal is an organic mercury compound that is used as a preservative in vaccines and pharmaceutical products. Recent studies have shown a TH2-skewing effect of mercury, although the underlying mechanisms have not been identified... Thimerosal exposure of DC led to the depletion of intracellular glutathione (GSH), and addition of exogenous GSH to DC abolished the TH2-promoting effect of thimerosal-treated DC, restoring secretion of TNF-α, IL-6, and IL-12p70 by DC and IFN-γ secretion by T cells. These data suggest that modulation of TH2 responses by mercury and thimerosal, in particular, is through depletion of GSH in DC."Environ Health Perspect Jul 2006;114(7):A429
"Thimerosal, an ethylmercury-based compound used for decades as a vaccine preservative, has previously been linked to neurotoxic effects. New research reveals that it may also affect the immune system by altering how dendritic cells respond to biochemical signals. Dendritic cells are influential primary actors in the immune system’s response to infectious invasion of the body. Once activated, a single dendritic cell can direct hundreds of T cells against an infectious agent. This ability, however, depends on the dendritic cell responding appropriately to signals. Exposure to thimerosal at concentrations as low as 20 ppb altered the time course of these responses,.. Exposure to thimerosal at concentrations above 200 ppb caused immature dendritic cells to die. The continuing use of thimerosal in some vaccines and other products warrants further investigation of possible immunotoxic effects of this compound and its constituent ethylmercury. The researchers also note that the human RyR1 gene is highly polymorphic, an observation that raises several questions about the role of RyR1 in the immune system’s genetic vulnerability to mercury."

Mercury and autism: accelerating evidence?
Neuro Endocrinol Lett. 2005 Oct;26(5):439-46.
"Recently, it was found that autistic children had a higher mercury exposure during pregnancy due to maternal dental amalgam and thimerosal-containing immunoglobulin shots. It was hypothesized that children with autism have a decreased detoxification capacity due to genetic polymorphism. In vitro, mercury and thimerosal in levels found several days after vaccination inhibit methionine synthetase (MS) by 50%. Normal function of MS is crucial in biochemical steps necessary for brain development, attention and production of glutathione, an important antioxidative and detoxifying agent. Repetitive doses of thimerosal leads to neurobehavioral deteriorations in autoimmune susceptible mice, increased oxidative stress and decreased intracellular levels of glutathione in vitro. Subsequently, autistic children have significantly decreased level of reduced glutathione. Promising treatments of autism involve detoxification of mercury, and supplementation of deficient metabolites."

This study provides another piece in the puzzle.  It was done because "(a) recent report shows a correlation of the historical use of thimerosal in therapeutic immunizations with the subsequent development of autism; however, this association remains controversial. Autism occurs approximately four times more frequently in males compared to females; thus, studies of thimerosal toxicity should take into consideration gender-selective effects."  The results of this small study show "the first report of gender-selective toxicity of thimerosal and indicate that any future studies of thimerosal toxicity should take into consideration gender-specific differences."  For those who don't know, autism occurs in boys about 4 to 5 times more often than it does in girls.

Management Guidelines for Medicinals Containing Thimerosal
South Dakota Department of Environment & Natural Resources
Waste Management Program/Hazardous Waste Section
"Containing about 50 percent mercury, thimerosal has been valued as an anti-bacterial agent or as a preservative in vaccine vials that hold a number of doses. Because of the presence of mercury, unusable products containing thimerosal might be regulated as hazardous waste under state and federal waste management requirements."

"State and federal hazardous waste regulations establish that any waste containing 0.2 milligrams per liter (mg/L) or more of mercury, as determined using the EPA-mandated Toxicity Characteristic Leaching Procedure (TCLP), requires management as hazardous waste."

"In the case of vaccines manufactured using thimerosal, the amount of thimerosal per dose is included on manufacturer package inserts specific to each product. Testing thimerosal-containing products using the TCLP test provides the specific level of mercury within a specific product. In June 2010, SDDENR contracted a thirdparty laboratory to analyze the level of mercury in two brands of multi-dose H1N1 vaccines preserved with 0.01 percent thimerosal to obtain general information relative to vaccines containing thimerosal. Based upon calculations (50 ppm mercury/5 mL vial) and test results (40 ppm and 43 ppm/5 mL vial), the department determined the level of mercury in multidose thimerosal-containing vaccines tested exceed the 0.2 ppm TCLP standard for mercury. With the information provided by the manufacturer and results from the TCLP analyses, unused multidose vials containing thimerosal that are destined for disposal need to be managed as a hazardous waste. Consequently, unless a manufacturer or generator has information or a TCLP analysis performed on a vaccine that documents otherwise, unwanted vaccines containing thimerosal should be managed as hazardous waste that exhibits the characteristic of mercury toxicity."

"In addition to the multidose vaccines containing thimerosal discussed above, some companies offer a 0.5 mg/L single dose, pre-filled syringe vaccine. Some of these products are labeled “preservative- or thimerosal-free”. Preservative-free products may contain trace amounts (less than or equal to 1 microgram/0.5 mL dose) because thimerosal was used during the manufacturing process. The term preservative- or thimerosal-free can be utilized if the manufacturer further purified the product, leaving only trace amounts (less than or equal to 1 microgram/0.5 mL) per dose. Even at this level, calculations indicate mercury would exceed the TCLP standard; therefore these vaccines, if deemed unusable, should be managed as hazardous waste as well."

Exposure to methyl mercury results in serum autoantibodies to neurotypic and gliotypic proteins
"Environmental exposure to methyl mercury (MeHg) continues to pose a threat to humans, making early detection of neurotoxic effects a pressing concern... GFAP levels as a marker of neurotoxicity were determined in the cortex, hippocampus and cerebellum. Exposure to 32ppm MeHg resulted in decreased (p < 0.05) levels in the cortex at 14 days. Both levels of MeHg resulted in increased GFAP in the cerebellum at 14 days. This study suggests that assay of autoantibodies against nervous system proteins may provide a means of assessing the early neurotoxic effects of environmental MeHg exposure."

Does inorganic mercury play a role in Alzheimer's disease? A systematic review and an integrated molecular mechanism
J Alzheimers Dis. 2010;22(2):357-74. doi: 10.3233/JAD-2010-100705.
"Mercury is one of the most toxic substances known to humans. It has been introduced into the human environment and has also been widely used in medicine. Since circumstantial evidence exists that the pathology of Alzheimer's disease (AD) might be in part caused or exacerbated by inorganic mercury, we conducted a systematic review using a comprehensive search strategy... Thirty-two studies, out of 40 testing memory in individuals exposed to inorganic mercury, found significant memory deficits. Some autopsy studies found increased mercury levels in brain tissues of AD patients... In vitro models showed that inorganic mercury reproduces all pathological changes seen in AD, and in animal models inorganic mercury produced changes that are similar to those seen in AD. Its high affinity for selenium and selenoproteins suggests that inorganic mercury may promote neurodegenerative disorders via disruption of redox regulation. Inorganic mercury may play a role as a co-factor in the development of AD. It may also increase the pathological influence of other metals. Our mechanistic model describes potential causal pathways. As the single most effective public health primary preventive measure, industrial, and medical usage of mercury should be eliminated as soon as possible."

Methylmercury alters glutamate transport in astrocytes
Neurochem Int. 2000 Aug-Sep;37(2-3):199-206.
"Neurotoxicology and Teratology 19, 417-428) suggest that fetal exposure at levels attained by mothers eating fish regularly during pregnancy are associated with neurological deficits in their offspring. Astrocytes play a key role in MeHg-induced excitotoxicity. (1) MeHg preferentially accumulates in astrocytes. (2) MeHg potently and specifically inhibits glutamate uptake in astrocytes. (3) Neuronal dysfunction is secondary to disturbances in astrocytes. (4) Co-application of nontoxic concentrations of MeHg and glutamate leads to the typical appearance of neuronal lesions associated with excitotoxic stimulation. (5) MeHg induces swelling of astrocytes. These observations are fully consistent with MeHg-induced dysregulation of excitatory amino acid homeostasis, and indicate that a glutamate-mediated excitotoxic mechanism is involved. This manuscript details the role of astrocytes in mediating MeHg-induced excitotoxicity, and elaborates on the protective role afforded by metallothioneins (MTs) in attenuating MeHg cytotoxicity."

Demethylation of methyl mercury in different brain sites of Macaca fascicularis monkeys during long-term subclinical methyl mercury exposure
Toxicol Appl Pharmacol. 1995 Oct;134(2):273-84.
"The concentration of I-Hg increased in all brain sites, but especially in the thalamus and pituitary, with the time of MeHg exposure. In most brain sites, I-Hg constituted about 9% of T-Hg at 6 and 12 months, and 12% of T-Hg at 18 months. In the pituitary, I-Hg increased from 20% of T-Hg at 6 months to 46% at 18 months. Elimination T 1/2 for I-Hg was extremely long, 230-540 days in most brain sites and considerably longer in the thalamus and pituitary. The concentration of I-Hg in the thalamus did not decrease during the clearance period (6 months), while I-Hg in the pituitary continued to increase in spite of no additional exposure. The MeHg exposed monkeys had several times higher I-Hg concentrations in the brain than monkeys exposed to HgCl2, indicating that I-Hg was formed by demethylation of MeHg in the brain, and not by brain uptake of I-Hg formed by demethylation elsewhere in the body. There were large variations in the relative concentration of I-Hg between individual monkeys, but not between brain sites (except thalamus and pituitary). Obese monkeys (5.0-6.1 kg body wt) exposed to MeHg had higher concentrations of both MeHg and I-Hg than normal weight monkeys in all brain sites, except in the pituitary."

Involvement of glutamate and reactive oxygen species in methylmercury neurotoxicity
Braz J Med Biol Res. 2007 Mar;40(3):285-91.
"We emphasize that oxidative stress plays a significant role in mediating MeHg-induced neurotoxic damage with active involvement of the mitochondria in this process. Furthermore, we provide a mechanistic overview on oxidative stress induced by MeHg that is triggered by a series of molecular events such as activation of various kinases, stress proteins and other immediate early genes culminating in cell damage."

Intermingled modulatory and neurotoxic effects of thimerosal and mercuric ions on electrophysiological responses to GABA and NMDA in hippocampal neurons.
 2010 Dec;61(6):753-8.
"The organomercurial, thimerosal, is at the center of medical controversy as a suspected factor contributing to neurodevelopmental disorders in children. Many neurotoxic effects of thimerosal have been described, but its interaction with principal excitatory and inhibitory neurotransmiter systems is not known. We examined, using electrophysiological recordings, thimerosal effects on GABA and NMDA-evoked currents in cultured hippocampal neurons...following exposure for 60-90 min to 1 or 10 μM thimerosal, there was a significant decrease in NMDA-induced currents (p<0 .05="" 60-90="" a="" after="" also="" and="" currents="" damaging="" exposure...="" gabaergic="" min="" neurons="" neurotoxic="" of="" p="" proportion="" significant="" span="" thimerosal="" was="">Mercuric chloride, at concentrations 1 μM and above, was even more toxic, killing a large proportion of cells after just a few minutes of exposure. Recordings from a few sturdy cells revealed that micromolar mercuric chloride markedly potentiated the GABAergic currents (p<0 .05="" act="" actions="" and="" are="" binding="" both="" but="" chloride="" complex="" currents="" decreasing="" effects="" electrophysiological="" enhancing="" gaba="" interactions="" interwoven="" involve="" ions="" likely="" macromolecules.="" mercurials="" mercuric="" modulatory="" most="" neurotoxic="" nmda-evoked="" nmda="" of="" on="" p="" rapidly="" receptors.="" receptors="" reduced="" reducing="" responses.="" responses="" results="" reveal="" slowly="" span="" the="" their="" these="" thimerosal="" to="" which="" while="" with="" works="">

Poisoning by Ethyl Mercury Toluene Sulphonanilide
Br J Ind Med. Oct 1961; 18(4): 303–308
"Poisoning by a fungicide used for seed-borne diseases of cereals, ethyl mercury p-toluene sulphonanilide (Granoson M, Dupont), is described. It affected a large number of farmers and their families who used the dressed seed in the preparation of home-made bread. Many systems were involved, including the kidneys, the gastro-intestinal tract, the skin, the heart, and the muscles, but involvement of the nervous system was the most constant with disturbance of speech, cerebellar ataxia, and spasticity. Mental abnormalities were occasionally observed. Many patients died. The changes in the electrocardiograms are described and illustrated. The importance of effective measures for prevention and the need for further studies of treatment are stressed."

Level of trace elements (copper, zinc, magnesium and selenium) and toxic elements (lead and mercury) in the hair and nail of children with autism
Biol Trace Elem Res. 2011 Aug;142(2):148-58
"The study showed a significant elevation (p < 0.001) in the levels of toxic metals Pb and Hg in both hair and nail samples of autistic children when compared to healthy control group. The elevation was much pronounced in LFA group subjects when compared among autistic groups MFA and HFA. The levels of trace elements Mg and Se were significantly decreased (p < 0.001) in autistic children when compared to control. The trace element Zn showed significant variation in both hair and nails of LFA group children when compared to control group and other study groups. The significant elevation in the concentration of Cu, Pb, and Hg and significant decrease in the concentration of Mg and Se observed in the hair and nail samples of autistic subjects could be well correlated with their degrees of severity."