Mercury as a hapten: A review of the role of toxicant-induced brain autoantibodies in autism and possible treatment considerations.

BACKGROUND: Mercury has many direct and well-recognized neurotoxic effects. However, its immune effects causing secondary neurotoxicity are less well-recognized. Mercury exposure can induce immunologic changes in the brain indicative of autoimmune dysfunction, including the production of highly specific brain autoantibodies. Mercury, and in particular, Thimerosal, can combine with a larger carrier, such as an endogenous protein, thereby acting as a hapten, and this new molecule can then elicit the production of antibodies. METHODS: A comprehensive search using PubMed and Google Scholar for original studies and reviews related to autism, mercury, autoantibodies, autoimmune dysfunction, and haptens was undertaken. All articles providing relevant information from 1985 to date were examined. Twenty-three studies were identified showing autoantibodies in the brains of individuals diagnosed with autism and all were included and discussed in this review. RESULTS: Research shows mercury exposure can result in an autoimmune reaction that may be causal or contributory to autism, especially in children with a family history of autoimmunity. The autoimmune pathogenesis in autism is demonstrated by the presence of brain autoantibodies (neuroantibodies), which include autoantibodies to: (1) human neuronal progenitor cells; (2) myelin basic protein (MBP); (3) neuron-axon filament protein (NAFP); (4) brain endothelial cells; (5) serotonin receptors; (6) glial fibrillary acidic protein (GFAP); (7) brain derived neurotrophic factor (BDNF); (8) myelin associated glycoprotein (MAG); and (9) various brain proteins in the cerebellum, hypothalamus, prefrontal cortex, cingulate gyrus, caudate putamen, cerebral cortex and caudate nucleus. CONCLUSION: Recent evidence suggests a relationship between mercury exposure and brain autoantibodies in individuals diagnosed with autism. Moreover, brain autoantibody levels in autism are found to correlate with both autism severity and blood mercury levels. Treatments to reduce mercury levels and/or brain autoantibody formation should be considered in autism.

A ten year longitudinal examination of the incidence rate and age of childhood encephalopathy diagnoses in an autism spectrum disorder diagnosed cohort.

Autism spectrum disorder (ASD) is defined by persistent deficits in social communication/interaction and stereotypic behaviors with many diagnosed persons experiencing a developmental regression at >1 year­old. It was hypothesized that progressive childhood encephalopathy is an important etiological factor in ASD pathogenesis. This hypothesis­testing study examined the relationship between diagnosed childhood encephalopathy and ASD. The Independent Healthcare Research Database is composed of de­identified linked eligibility and claim healthcare records prospectively generated from the Florida Medicaid system. A cohort of 101,736 persons eligible for Florida Medicaid from 1990­2009 and continuously eligible with ≥10 outpatient office visits during the 120 month period following birth were examined using SAS software. There were 1,397 persons (7,223 person­years) in the ASD diagnosed cohort and 100,339 persons (980,786 person­years) in the undiagnosed cohort. The incidence rate of encephalopathy was examined using Cox proportional hazards ratio models. In the ASD cohort relative to the undiagnosed cohort, a significantly increased incidence rate of diagnosed encephalopathy was observed in the unadjusted and adjusted models. The risk for an encephalopathy diagnosed at >1 year­old was greater than for an encephalopathy diagnosed at <1 year­old. This study provides important new evidence supporting the hypothesis that a significant number of children with an eventual ASD diagnosis experience a progressive childhood en cephalopathy diagnosed at >1 year­old.

Examining the evidence that ethylmercury crosses the blood-brain barrier.

Scientific research can provide us with factual, repeatable, measurable, and determinable results. As such, scientific research can provide information that can be used in the decision-making process in the care of patients and in public policy. Although it has been suggested that ethylmercury (C2H5Hg+)-containing compounds do not cross the blood-brain barrier (BBB), this review examines the literature that addresses the question as to whether ethylmercury-containing compounds cross the BBB. The review will begin with cellular studies that provide evidence for the passive and active transport of mercury species across the BBB. Then, animal and clinical studies will be presented that specifically examine whether mercury accumulates in the brain after exposure to ethylmercury-containing compounds or Thimerosal (an ethylmercury-containing compound used as a preservative in vaccines and other drugs that metabolizes or degrades to ethylmercury-containing compounds and thiosalicylate). The results indicate that ethylmercury-containing compounds are actively transported across membranes by the L (leucine-preferring)-amino acid transport (LAT) system, the same as methylmercury-containing compounds. Further, 22 studies from 1971 to 2019 show that exposure to ethylmercury-containing compounds (intravenously, intraperitoneally, topically, subcutaneously, intramuscularly, or intranasally administered) results in accumulation of mercury in the brain. In total, these studies indicate that ethylmercury-containing compounds and Thimerosal readily cross the BBB, convert, for the most part, to highly toxic inorganic mercury-containing compounds, which significantly and persistently bind to tissues in the brain, even in the absence of concurrent detectable blood mercury levels.

A Cross-Sectional Study of Blood Ethylmercury Levels and Cognitive Decline Among Older Adults and the Elderly in the United States.

Cognitive health is an emerging public health concern for the aging American population. Mercury (Hg) is a toxic element that can cause nervous system damage. This hypothesis-testing study evaluated the relationship between blood ethyl-Hg levels and cognitive decline in an older adult and elderly American population. A total of 1,821,663 weighted-persons between 60-80 years old with detectable blood ethyl-Hg levels within the 2011-2012 National Health and Nutritional Examination Survey were examined. Those persons with blood ethyl-Hg levels greater than the median were deemed the higher ethyl-Hg exposure group and those with ethyl-Hg levels less than the median were deemed the lower ethyl-Hg exposure group. Three tests were utilized to measure cognitive function: 1) Consortium to Establish a Registry for Alzheimer's Disease - Word List Learning (CERAD W-L) delayed recall test, 2) animal fluency test, and 3) Digit Symbol Substitution Test. Each cognitive test score was categorized as higher for those with scores greater than the median and lower for those with scores less than the median. Survey logistic regression modeling with covariates was used to analyze the data for the relationship between blood ethyl-Hg levels and cognitive function scores. Significantly increased risks for lower animal fluency test (odds ratio (OR) = 13.652, p = 0.0029) and CERAD W-L delayed recall test (OR = 6.401, p = 0.0433) scores were observed among the higher ethyl-Hg exposure group as compared to the lower ethyl-Hg exposure group. This study supports the hypothesis that increased ethyl-Hg exposure is associated with significant cognitive decline in older adult and elderly Americans.

The risk of neurodevelopmental disorders following Thimerosal-containing Hib vaccine in comparison to Thimerosal-free Hib vaccine administered from 1995 to 1999 in the United States.

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

A cross-sectional study of the relationship between infant Thimerosal-containing hepatitis B vaccine exposure and attention-deficit/hyperactivity disorder.

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

A Cross-Sectional Study of the Association between Infant Hepatitis B Vaccine Exposure in Boys and the Risk of Adverse Effects as Measured by Receipt of Special Education Services.

The National Center for Education Statistics reported that between 1990-2005 the number of children receiving special education services (SES) rose significantly, and then, from 2004-2012, the number declined significantly. This coincided with the introduction of Thimerosal-containing hepatitis B vaccine in 1991, and the subsequent introduction of Thimerosal-reduced hepatitis B vaccine in the early 2000s. This study examined the potential relationship between infant exposure to mercury from three doses of Thimerosal-containing hepatitis B vaccine and the risk of boys being adversely affected (as measured by receipt of SES). This cross-sectional study examined 1192 boys (weighted n = 24,537,123) 7-8 years of age (born: 1994-2007) from the combined 2001-2014 National Health and Nutritional Examination Survey (NHANES). Survey logistic regression modeling revealed that an exposed population receiving three doses of infant Thimerosal-containing hepatitis B vaccine (weighted n = 11,186,579), in comparison to an unexposed population (weighted n = 704,254), were at an increased risk of receipt of SES. This association was robust (crude odds ratio = 10.143, p = 0.0232), even when considering covariates, such as race and socioeconomic status (adjusted odds ratio = 9.234, p = 0.0259). Survey frequency modeling revealed that receipt of SES for the population that was exposed to three doses of Thimerosal-containing hepatitis B vaccine in infancy (12.91%) was significantly higher than the unexposed population (1.44%) (prevalence ratio = 8.96, p = 0.006, prevalence attributable rate = 0.1147). Despite the limitation of this cross-sectional study not being able to ascribe a direct cause-and-effect relationship between exposure and outcome, it is estimated that an additional 1.2 million boys received SES with excess education costs of about United States (US) $180 billion associated with exposure to Thimerosal-containing hepatitis B vaccine. By contrast, exposure to Thimerosal-reduced hepatitis B vaccine was not associated with an increased risk of receiving SES. Therefore, routine childhood vaccination is important to reduce the morbidity and mortality of infectious diseases, but every effort should be made to eliminate Thimerosal from all vaccines.

Abnormal Brain Connectivity Spectrum Disorders Following Thimerosal Administration: A Prospective Longitudinal Case-Control Assessment of Medical Records in the Vaccine Safety Datalink.

BACKGROUND: Autism spectrum disorder (ASD), tic disorder (TD), and hyperkinetic syndrome of childhood (attention deficit disorder [ADD]/attention deficit hyperactivity disorder [ADHD]) are disorders recently defined as abnormal connectivity spectrum disorders (ACSDs) because they show a similar pattern of abnormal brain connectivity. This study examines whether these disorders are associated with exposure to thimerosal, a mercury (Hg)-based preservative. METHODS: A hypothesis testing case-control study evaluated the Vaccine Safety Datalink for the potential dose-dependent odds ratios (ORs) for diagnoses of ASD, TD, and ADD/ADHD compared to controls, following exposure to Hg from thimerosal-containing Haemophilus influenzae type b vaccines administrated within the first 15 months of life. Febrile seizures, cerebral degeneration, and unspecified disorders of metabolism, which are not biologically plausibly linked to thimerosal, were examined as control outcomes. RESULTS: On a per 25 µg Hg basis, cases diagnosed with ASD (OR = 1.493), TD (OR = 1.428), or ADD/ADHD (OR = 1.503) were significantly (P < .001) more likely than controls to have received increased Hg exposure. Similar relationships were observed when separated by gender. Cases diagnosed with control outcomes were no more likely than controls to have received increased Hg exposure. CONCLUSION: The results suggest that Hg exposure from thimerosal is significantly associated with the ACSDs of ASD, TD, and ADD/ADHD.

Thimerosal exposure and disturbance of emotions specific to childhood and adolescence: A case-control study in the Vaccine Safety Datalink (VSD) database.

BACKGROUND: This study evaluated Thimerosal-containing childhood vaccines and the risk of a diagnosis called disturbance of emotions specific to childhood and adolescence (ED). Thimerosal is an organic-mercury (Hg)-containing compound used in some vaccines. METHODS: A hypothesis-testing prospective, longitudinal case-control study evaluated Hg exposure from Thimerosal in hepatitis B vaccines administered at specific times within the first 6 months of life and its association with medically diagnosed ED (313.xx) (n = 517) in children born between 1991-2000 in comparison to controls (n = 27 491) in the Vaccine Safety Datalink (VSD) database. RESULTS: Cases diagnosed with ED were significantly more likely than controls to have received increased Hg exposure within the first month of life (odds ratio (OR) = 1.3384), the first 2 months of life (OR = 1.3367) and the first 6 months of life (OR = 2.37). When the data were separated by gender, similar significant adverse effects were observed for males, but not females. On a per microgram Hg basis, cases diagnosed with ED were significantly more likely than controls to have received increased exposure within the first 6 months of life (OR = 1.025 per microgram Hg). CONCLUSIONS: The results show a significant relationship between Hg exposure from Thimerosal-containing childhood vaccines and the subsequent risk of an ED diagnosis.

Developmental neurotoxicants and the vulnerable male brain: a systematic review of suspected neurotoxicants that disproportionally affect males.

The prevalence of neurodevelopmental disorders (NDs), including autism spectrum disorder, attention­deficit/hyperactivity disorder, tic disorder, obsessive­compulsive disorder, and emotional disturbances, has increased notably in the past few decades. To date, debate continues as to the origins of NDs. Increases in widespread exposure to and bioaccumulation of chemical neurotoxicants have paralleled the upsurge in NDs, and are suggested to be causal agents for NDs. One consistent aspect of NDs is the male preponderance. This review considers the issue of male preponderance by reviewing the gender­specific neurotoxic effects of recognized neurotoxicant chemicals to assess their possible etiology in NDs. This investigation consisted of a systematic literature review of original studies published from 1970-2016 on suspected neurotoxicants, to examine whether they have a disproportionate adverse effect based on gender. Based on that review, the neurotoxicants exhibiting consistent gender­specific effects, with exposed males being more affected (than similarly exposed females), were: lead, Thimerosal/ethylmercury, some organochlorine pesticides (e.g., dieldrin, endosulfan, and heptachlor), and air pollution. The next group identified were neurotoxicants exhibiting gender­specific neurotoxic effects, with males being somewhat (but not consistently) more affected than females: mercury vapor, polychlorinated biphenyls (PCBs), and organophosphate pesticides. Finally, there was a group of studies in which the neurotoxicants exhibited apparent gender­related neurotoxic effects but failed to show whether exposed males were consistently more affected than females: inorganic mercury salts, methylmercury species, and certain endocrine disruptors (e.g., phthalates and BPA). The overall conclusion from the studies reviewed was that the brain in males is more vulnerable to many toxic exposures than it is in females. Evidence suggests that the reasons for the male brain being more vulnerable include: (1) greater glutathione availability in females; (2) greater sulfate­based detoxification capacity in females; (3) potentiating effects of co­exposure to neurotoxicants and testosterone; (4) greater neuroinflammatory response in males; (5) reduced vulnerability to oxidative stress in females; and (6) neuroprotective effects of female hormones (estrogen and progesterone), especially in the reduction of inflammation and oxidative stress.

Thimerosal-containing Hepatitis B Vaccine Exposure is Highly Associated with Childhood Obesity: A Case-control Study Using the Vaccine Safety Datalink.

BACKGROUND: Obesity among children and adolescents in the United States has tripled since 1980, and has become a major public health concern. AIMS: The purpose of this study was to evaluate the potential relationship between exposure to organic mercury from Thimerosal-containing hepatitis B vaccines and the children's subsequent risk of an obesity diagnosis. MATERIALS AND METHODS: A hypothesis-testing, case-control study was undertaken to evaluate exposure to organic mercury from Thimerosal-containing hepatitis B vaccines, which were administered at specific intervals in the first 6 months of life, among cases diagnosed with childhood obesity and controls by examining automated medical records for children born from 1991 to 2000 who were continuously enrolled in the Vaccine Safety Datalink database. RESULTS: This study found highly significant associations as follows. Cases diagnosed with obesity were significantly (P < 0.00001) more likely to have received greater exposure to organic mercury from Thimerosal-containing hepatitis B vaccines administered within the first month of life (odds ratio (OR) =1.511), first 2 months of life (OR = 1.486), and first 6 months of life (OR = 3.795) than the controls. Similar outcomes were observed when the overall data were separated by gender. In a dose-response manner, cases diagnosed with obesity were significantly more likely than controls to have received greater exposure to organic mercury from Thimerosal-containing hepatitis B vaccines, which were administered within the first 6 months of life (OR = 1.0375 per µg of mercury, P < 0.00001). CONCLUSIONS: In a dose-response manner, the present study associates an increased organic mercury exposure from Thimerosal-containing hepatitis B vaccines with an increased risk of obesity diagnosis, and suggests that Thimerosal is an obesogen. The results are biologically plausible and future studies are needed to examine this phenomenon.

Thimerosal exposure and increased risk for diagnosed tic disorder in the United States: a case-control study.

A hypothesis testing, case-control study evaluated automated medical records for exposure to organic-Hg from Thimerosal-containing hepatitis B vaccines (TM-HepB) administered at specific intervals in the first six-months-of-life among cases diagnosed with a tic disorder (TD) or cerebral degeneration (CD) (an outcome not biologically plausibly linked to TM exposure) in comparison to controls; both cases and controls were continuously enrolled from birth (born from 1991-2000) within the Vaccine Safety Datalink (VSD) database. TD cases were significantly more likely than controls to have received increased organic-Hg from TM-HepB administered within the first month-of-life (odds ratio (OR)=1.59, p<0.00001), first two-months-of-life (OR=1.59, p<0.00001), and first six-months-of-life (OR=2.97, p<0.00001). Male TD cases were significantly more likely than male controls to have received increased organic-Hg from TM-HepB administered within the first month-of-life (OR =1.65, p<0.0001), first two-months-of-life (OR=1.64, p<0.0001), and first six months-of-life (OR=2.47, p<0.05), where as female TD were significantly more likely than female controls to have received increased organic-Hg from TM-HepB administered within the first six-months-of-life (OR=4.97, p<0.05). By contrast, CD cases were no more likely than controls to have received increased organic-Hg exposure from TM-HepB administered at any period studied within the first six-months-of-life. Although routine childhood vaccination is considered an important public health tool to combat infectious diseases, the present study associates increasing organic-Hg exposure from TM-HepB and the subsequent risk of a TD diagnosis.

New science challenges old notion that mercury dental amalgam is safe.

Mercury dental amalgam has a long history of ostensibly safe use despite its continuous release of mercury vapor. Two key studies known as the Children's Amalgam Trials are widely cited as evidence of safety. However, four recent reanalyses of one of these trials now suggest harm, particularly to boys with common genetic variants. These and other studies suggest that susceptibility to mercury toxicity differs among individuals based on multiple genes, not all of which have been identified. These studies further suggest that the levels of exposure to mercury vapor from dental amalgams may be unsafe for certain subpopulations. Moreover, a simple comparison of typical exposures versus regulatory safety standards suggests that many people receive unsafe exposures. Chronic mercury toxicity is especially insidious because symptoms are variable and nonspecific, diagnostic tests are often misunderstood, and treatments are speculative at best. Throughout the world, efforts are underway to phase down or eliminate the use of mercury dental amalgam.

Evidence supporting a link between dental amalgams and chronic illness, fatigue, depression, anxiety, and suicide.

The purpose of this review is to examine the evidence for a relationship between mercury (Hg) exposure from dental amalgams and certain idiopathic chronic illnesses--chronic fatigue syndrome (CFS), fibromyalgia (FM), depression, anxiety, and suicide. Dental amalgam is a commonly used dental restorative material that contains approximately 50% elemental mercury (Hg0) by weight and releases Hg0 vapor. Studies have shown that chronic Hg exposure from various sources including dental amalgams is associated with numerous health complaints, including fatigue, anxiety, and depression--and these are among the main symptoms that are associated with CFS and FM. In addition, several studies have shown that the removal of amalgams is associated with improvement in these symptoms. Although the issue of amalgam safety is still under debate, the preponderance of evidence suggests that Hg exposure from dental amalgams may cause or contribute to many chronic conditions. Thus, consideration of Hg toxicity may be central to the effective clinical investigation of many chronic illnesses, particularly those involving fatigue and depression.