1. Hepatitis B Vaccination of Male Neonates and Autism
Annals of Epidemiology , Vol. 19, No. 9 ABSTRACTS (ACE), September 2009: 651-680,
http://www.ncbi.nlm.nih.gov/pubmed/21058170
p. 659
CM Gallagher, MS Goodman, Graduate Program in Public Health, Stony Brook University Medical Center, Stony Brook, NY
PURPOSE: Universal newborn immunization with hepatitis B vaccine was recommended in 1991; however, safety findings are mixed. The Vaccine Safety Datalink Workgroup reported no association between hepatitis B vaccination at birth and febrile episodes or neurological adverse events. Other studies found positive associations between
hepatitis B vaccination and ear infection, pharyngitis, and chronic arthritis; as well as receipt of early intervention/special education services (EIS); in probability samples of U.S. children. Children with autistic spectrum disorder (ASD) comprise a growing caseload for EIS. We evaluated the association between hepatitis B vaccination of male neonates and parental report of ASD.
METHODS: This cross-sectional study used U.S. probability samples obtained from National Health Interview Survey 1997-2002 datasets. Logistic regression modeling was used to estimate the effect of neonatal hepatitis B vaccination on ASD risk among boys age 3-17 years with shot records, adjusted for race, maternal education, and two-parent household.
RESULTS: Boys who received the hepatitis B vaccine during the first month of life had 2.94 greater odds for ASD (nZ31 of 7,486; OR Z 2.94; p Z 0.03; 95% CI Z 1.10, 7.90)
compared to later- or unvaccinated boys. Non-Hispanic white boys were 61% less likely to have ASD (ORZ0.39; pZ0.04; 95% CIZ0.16, 0.94) relative to non-white boys.
CONCLUSION: Findings suggest that U.S. male neonates vaccinated with hepatitis B vaccine had a 3-fold greater risk of ASD; risk was greatest for non-white boys.
2. Porphyrinuria in childhood autistic disorder: Implications for environmental toxicity
Toxicology and Applied Pharmacology, 2006
http://www.ncbi.nlm.nih.gov/pubmed/16782144
Robert Natafa, Corinne Skorupkab, Lorene Ametb, Alain Lama, Anthea Springbettc and Richard Lathed, aLaboratoire Philippe Auguste, Paris, France, Association ARIANE, Clichy, France, Department of Statistics, Roslin Institute, Roslin, UK, Pieta Research,
This new study from France utilizes a new and sophisticated measurement for environmental toxicity by assessing porphyrin levels in autistic children. It provides clear and unequivocal evidence that children with autism spectrum disorders are more toxic than their neurotypical peers.
Excerpt: “Coproporphyrin levels were elevated in children with autistic disorder relative to control groups…the elevation was significant. These data implicate environmental toxicity in childhood autistic disorder.”
Abstract: To address a possible environmental contribution to autism, we carried out a retrospective study on urinary porphyrin levels, a biomarker of environmental toxicity, in 269 children with neurodevelopmental and related disorders referred to a Paris clinic (2002–2004), including 106 with autistic disorder. Urinary porphyrin levels determined by high-performance liquid chromatography were compared between diagnostic groups including internal and external control groups. Coproporphyrin levels were elevated in children with autistic disorder relative to control groups. Elevation was maintained on normalization for age or to a control heme pathway metabolite (uroporphyrin) in the same samples. The elevation was significant (P < 0.001). Porphyrin levels were unchanged in Asperger’s disorder, distinguishing it from autistic disorder. The atypical molecule precoproporphyrin, a specific indicator of heavy metal toxicity, was also elevated in autistic disorder (P < 0.001) but not significantly in Asperger’s. A subgroup with autistic disorder was treated with oral dimercaptosuccinic acid (DMSA) with a view to heavy metal removal. Following DMSA there was a significant (P = 0.002) drop in urinary porphyrin excretion. These data implicate environmental toxicity in childhood autistic disorder.
3. Theoretical aspects of autism: Causes—A review
Journal of Immunotoxicology, January-March 2011, Vol. 8, No. 1 , Pages 68-79
http://www.ncbi.nlm.nih.gov/pubmed/21299355
Helen V. Ratajczak, PhD
Autism, a member of the pervasive developmental disorders (PDDs), has been increasing dramatically since its description by Leo Kanner in 1943. First estimated to occur in 4 to 5 per 10,000 children, the incidence of autism is now 1 per 110 in the United States, and 1 per 64 in the United Kingdom, with similar incidences throughout the world. Searching information from 1943 to the present in PubMed and Ovid Medline databases, this review summarizes results that correlate the timing of changes in incidence with environmental changes. Autism could result from more than one cause, with different manifestations in different individuals that share common symptoms. Documented causes of autism include genetic mutations and/or deletions, viral infections, and encephalitis following vaccination. Therefore, autism is the result of genetic defects and/or inflammation of the brain. The inflammation could be caused by a defective placenta, immature blood-brain barrier, the immune response of the mother to infection while pregnant, a premature birth, encephalitis in the child after birth, or a toxic environment.
4. Uncoupling of ATP-mediated Calcium Signaling and Dysregulated IL-6 Secretion in Dendritic Cells by Nanomolar Thimerosal
Environmental Health Perspectives, July 2006.
http://www.ncbi.nlm.nih.gov/pubmed/16835063
Samuel R. Goth, Ruth A. Chu Jeffrey P. Gregg
This study demonstrates that very low-levels of Thimerosal can contribute to immune system disregulation.
Excerpt: “Our findings that DCs primarily express the RyR1 channel complex and that this complex is uncoupled by very low levels of THI with dysregulated IL-6 secretion raise intriguing questions about a molecular basis for immune dyregulation and the possible role of the RyR1 complex in genetic susceptibility of the immune system to mercury.”
Abstract
Dendritic cells (DCs), a rare cell type widely distributed in the soma, are potent antigen
presenting cells that initiate primary immune responses. DCs rely on intracellular redox
state and calcium (Ca2+) signals for proper development and function, but the relationship
between these two signaling systems is unclear. Thimerosal (THI) is a mercurial used to
preserve vaccines, consumer products, and experimentally to induce Ca2+ release from
microsomal stores. We tested ATP-mediated Ca2+ responses of DCs transiently exposed
nanomolar THI. Transcriptional and immunocytochemical analyses show murine
myeloid immature and mature DC (IDCs, MDCs) express inositol 1, 4, 5-trisphosphate
and ryanodine receptor (IP3R, RyR) Ca2+ channels, known targets of THI. IDCs express
the RyR1 isoform in a punctate distribution that is densest near plasma membranes and
within dendritic processes whereas IP3Rs are more generally distributed. RyR1 positively
and negatively regulates purinergic signaling since ryanodine (Ry) blockade (1) recruited
80 percent more ATP responders, (2) shortened ATP-mediated Ca2+ transients >2-fold,
(3) and produced a delayed and persistent rise (≥2-fold) in baseline Ca2+. THI (100nM,
5min) recruited more ATP responders, shortened the ATP-mediated Ca2+ transient (≥1.4-
fold) and produced a delayed rise (≥3-fold) in the Ca2+ baseline, mimicking Ry. THI and
Ry, in combination, produced additive effects leading to uncoupling of IP3R and RyR1
signals. THI altered ATP-mediated IL-6 secretion, initially enhancing the rate of but
suppressing overall cytokine secretion in DCs. DCs are exquisitely sensitive to THI, with
one mechanism involving the uncoupling of positive and negative regulation of Ca2+
signals contributed by RyR1.
5. Gender-selective toxicity of thimerosal.
Exp Toxicol Pathol. 2009 Mar;61(2):133-6. Epub 2008 Sep 3.
Branch DR, Departments of Medicine and Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada.
Abstract
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 present study was originally undertaken to determine the maximum tolerated dose (MTD) of thimersosal in male and female CD1 mice. However, during the limited MTD studies, it became apparent that thimerosal has a differential MTD that depends on whether the mouse is male or female. At doses of 38.4-76.8mg/kg using 10% DMSO as diluent, seven of seven male mice compared to zero of seven female mice tested succumbed to thimerosal. Although the thimerosal levels used were very high, as we were originally only trying to determine MTD, it was completely unexpected to observe a difference of the MTD between male and female mice. Thus, our studies, although not directly addressing the controversy surrounding thimerosal and autism, and still preliminary due to small numbers of mice examined, provide, nevertheless, 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.
6. Comparison of Blood and Brain Mercury Levels in Infant Monkeys Exposed to Methylmercury or Vaccines Containing Thimerosal
Environmental Health Perspectives, Aug 2005.
http://www.ncbi.nlm.nih.gov/pubmed/16079072
Thomas Burbacher, PhD [University of Washington].
This study demonstrates clearly and unequivocally that ethyl mercury, the kind of mercury found in vaccines, not only ends up in the brain, but leaves double the amount of inorganic mercury as methyl mercury, the kind of mercury found in fish. This work is groundbreaking because little is known about ethyl mercury, and many health authorities have asserted that the mercury found in vaccines is the “safe kind.” This study also delivers a strong rebuke of the Institute of Medicine’s recommendation in 2004 to no longer pursue the mercury-autism connection.
Excerpt: “A recently published IOM review (IOM 2004) appears to have abandoned the earlier recommendation [of studying mercury and autism] as well as back away from the American Academy of Pediatrics goal [of removing mercury from vaccines]. 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.”
7. 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
Charleston JS, Bolender RP, Mottet NK, Body RL, Vahter ME, Burbacher TM., Department of Pathology, School of Medicine, University of Washington
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. All other cell types, including the neurons, showed no significant change in number at the prescribed exposure level and durations. The identities of the reactive glial cells and the implications for the long-term function and survivability of the neurons due to changes in the glial population following subclinical long-term exposure to mercury are discussed.
8. Neuroglial Activation and Neuroinflammation in the Brain of Patients with Autism
Annals of Neurology, Feb 2005.
Diana L. Vargas, MD [Johns Hopkins University].
This study, performed independently and using a different methodology than Dr. Herbert (see above) reached the same conclusion: the brains of autistic children are suffering from inflammation.
Excerpt: “Because this neuroinflammatory process appears to be associated with an ongoing and chronic mechanism of CNS dysfunction, potential therapeutic interventions should focus on the control of its detrimental effects and thereby eventually modify the clinical course of autism.”
9. Autism: A Brain Disorder, or A Disorder That Affects the Brain?
Clinical Neuropsychiatry, 2005
Martha R. Herbert M.D., Ph.D., Harvard University
Autism is defined behaviorally, as a syndrome of abnormalities involving language, social reciprocity and hyperfocus or reduced behavioral flexibility. It is clearly heterogeneous, and it can be accompanied by unusual talents as well as by impairments, but its underlying biological and genetic basis in unknown. Autism has been modeled as a brain-based, strongly genetic disorder, but emerging findings and hypotheses support a broader model of the condition as a genetically influenced and systemic. These include imaging, neuropathology and psychological evidence of pervasive (and not just specific) brain and phenotypic features; postnatal evolution and chronic persistence of brain, behavior and tissue changes (e.g. inflammation) and physical illness symptomatology (e.g. gastrointestinal, immune, recurrent infection); overlap with other disorders; and reports of rate increases and improvement or recovery that support a role for modulation of the condition by environmental factors (e.g. exacerbation or triggering by toxins, infectious agents, or others stressors, or improvement by treatment). Modeling autism more broadly encompasses previous work, but also encourages the expansion of research and treatment to include intermediary domains of molecular and cellular mechanisms, as well as chronic tissue, metabolic and somatic changes previously addressed only to a limited degree. The heterogeneous biologies underlying autism may conceivably converge onto the autism profile via multiple mechanisms on the one hand and processing and connectivity abnormalities on the other may illuminate relevant final common pathways and contribute to focusing on the search for treatment targets in this biologically and etiologically heterogeneous behavioral syndrome.
10. Activation of Methionine Synthase by Insulin-like Growth Factor-1 and Dopamine: a Target for Neurodevelopmental Toxins and Thimerosal
Molecular Psychiatry, July 2004.
Richard C. Deth, PhD [Northeastern University].
This study demonstrates how Thimerosal inhibits methylation, a central driver of cellular communication and development. Excerpt:
“The potent inhibition of this pathway [methylation] by ethanol, lead, mercury, aluminum, and thimerosal suggests it may be an important target of neurodevelopmental toxins.”
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