Teresa
Binstock
Researcher in Developmental & Behavioral Neuroanatomy
December 04, 2009
Introduction: A new research paper by Aschner & Ceccatelli
is supposedly peer-reviewed but has sufficient omissions so as perhaps
to merit consideration as scientific fraud, perhaps to be considered as
injurious to children who have increased susceptibility -- whether
genetic and/or acquired -- for adverse effects from mercury,
methylmercury, and ethylmercury.
Michael Aschner, Ph.D., is a professor of neuroscience, pediatrics, and
pharmacology at Vanderbilt University (1) and has published more than
90 research articles about mercury (2). One of his more recent papers
(3) is coauthored with Sandra Ceccatelli, M.D., Ph.D. (4), who has
published at least 26 papers about mercury (5).
Despite these extensive backgrounds, Aschner & Ceccatelli 2009 (3)
omit studies which have found associations among thimerosal, autism,
and special education services (cites below). Furthermore, Aschner
& Ceccatelli err in stating (as if factual) that thimerosal in
vaccines "was removed from the US market in 2001." (3). Despite the
erroneous statement by Aschner & Ceccatelli, thimerosal has been
included in some U.S. vaccines in each of the years from 2002 to 2009
(6).
Indictment: Here is a list of errors and significant omissions
in Aschner & Ceccatelli 2009 (3).
1. Contrary to the supposedly peer-reviewed statement by Aschner &
Ceccatelli, thimerosal has been available in U.S. vaccines each and
every year since 2001 (6). In recent years and currently, most
influenza vaccines and most H1N1 vaccines contain thimerosal (6), which
is associated with autism and other developmental disabilities (cites
below).
2. Aschner & Ceccatelli dwell upon Pichichero et al's 2002 findings
regarding levels of ethylmercury injected as thimerosal into healthy
infants (7) but fail to cite and discuss Waly et al 2004, who found
that intra-body thimerosal levels lower than those described by
Pichichero et al were sufficient to impair methionine synthase, an
enzyme important in neurodevelopment (7). Ironically, contrary to
Aschner's & Ceccatelli's erroneous declaration that thimerosal was
removed in 2001, Pichichero et al 2002 used thimerosal-containing
vaccines, "diptheria-tetanus-acellular pertussis vaccine, hepatitis B
vaccine, and in some children Haemophilus influenzae type b vaccine"
(8), a research methodology consistent with thimerosal remaining in
various U.S. vaccines (6).
3. Aschner & Ceccatelli offer a summary entitled "Use of Thimerosal
in Vaccines" (3; p2) but omit peer-reviewed summaries which reported
thimerosal's lack of efficacy. For instance: "...mercurials are
ineffective in vivo and may be more toxic for tissue cells than
bacterial cells, as shown in mice, tissue culture and embryonic eggs
and with leucocytes " (10, ANYAS; listed in 9) and " Thimerosal is a
weak antibacterial agent that is rapidly broken down to products,
including ethylmercury residues, which are neurotoxic. Its role as a
preservative in vaccines has been questioned, and the pharmaceutical
industry itself considers its use historical." (11, Lancet; listed in
9).
Furthermore, Aschner & Ceccatelli cite Powell & Jamieson
1931 but fail to cite numerous studies whose findings call attention to
thimerosal's adverse effects and to thimerosal's quite imperfect
efficacy as bactericidal or bacteriostatic. Indeed, Aschner &
Ceccatelli failed to find or deliberately ignored a thorough
thimerosal-review published in the Journal of Toxicology and
Environmental Health (12). The review by Geier et al is in the PubMed
database, is free online (12), and summarizes findings which contradict
Aschner & Ceccatelli's glib oversimplification regarding
thimerosal.
4. Aschner & Ceccatelli omit CDC findings by Verstraeten et al
1999, the original CDC-sponsored study which found associations between
thimerosal injections and a range of developmental disabilities
including but not limited to autism, tics, and speech disorders (13).
After a series of deliberate dilutions of their own data, the CDC group
published a sanitized rendition as Verstraeten et al 2003 (14).
Obtained by Freedom of Information Act request (13), the CDC's 1999
findings stand in stark contrast to the diluted-data findings presented
in Pediatrics (14).
5. Aschner & Ceccatelli omit findings by Goodman & Gallagher,
Stony Brook medical school researchers who found that, among boys,
early life thimerosal injections are associated with an increased
likelihood of autism-spectrum disorder and with an increased need for
special education services (15-16).
6. Aschner & Ceccatelli omit findings by James SJ & colleagues,
who have reported associations among thimerosal, autism, and metabolic
pathways related to glutathione (eg, 17-18) and omit other studies
documenting the bidirectional genetics of thimerosal detoxification
(eg, 19-20).
7. Aschner & Ceccatelli omit findings about thimerosal's adverse
effects upon mitochondria (eg, 17, 21-24), despite the autism
significance of mitochondrial disorders (eg, 25-27) and mitochondrial
dysfunction not necessarily genetic in origin (reviewed in 28).
8. Aschner & Ceccatelli omit findings about porphyrins and mercury
in autism (eg, 29-30).
Discussion: The erroneous and misleading article by Aschner
& Ceccatelli (3) prompts questions. How or why did such
experienced professors, the article's reviewers, and the journal's
editor (31) err in regard to thimerosal's continued presence in some
vaccines injected into children in the United States? How and why did
Aschner & Ceccatelli choose to omit studies with findings which
contradict the rationale the authors chose to impose?
Ceccatelli & Aschner have considerable experience in writing about
mercury, thus their seemingly well documented rationale about
ethylmercury creates a convincing but misleading illusion. Clearly, the
content and omissions in Aschner & Ceccatelli suggest that the
journal Neurotoxicity Research needs publish a correction of factual
errors in Ceccatelli & Aschner and ought publish a paper which
remedies the omissions and rebuts the implications cleverly but
inaccurately presented by Aschner & Ceccatelli.
Physicians, researchers, and others are encouraged to read Aschner's
and Ceccatelli's summary entitled "Use of Thimerosal in Vaccines" (p2
in 3) and to compare their overview with thimerosal findings
summarized by Geier et al (12).
Given these flaws in Aschner & Ceccatelli 2009, two caveats are
merited. Firstly, the abstract states, "In this review, we have
discussed the hypothesis that exposure to thimerosal during childhood
may be a primary cause of autism. The conclusion is that there are no
reliable data indicating that administration of vaccines containing
thimerosal is a primary cause of autism." [sic, eg, 15-17] Secondly, in
their abstract the authors qualify the gist of their skillfully
misleading presentation by admitting, "...one cannot rule out the
possibility that the individual gene profile and/or gene–environment
interactions may play a role in modulating the response to acquired
risk by modifying the individual susceptibility." Despite the authors'
declaration of this "possibility", Aschner's and Ceccatelli's
deliberate omissions and their masterfully crafted illusion of science
suggest the authors have made the moral equivalent of a Faustian
bargain.
References :
1. Michael Aschner, Ph.D.
http://kc.vanderbilt.edu/site/people/8993/aschner-michael.aspx
2. Pubmed, Nov 20, 2009
Aschner M AND (mercury OR methylmercury OR ethylmercury OR
thimerosal)
3. Are Neuropathological Conditions
Relevant to Ethylmercury Exposure?
Michael Aschner and Sandra Ceccatelli
http://www.springerlink.com/content/3398g44388158630/fulltext.pdf
4. Sandra Ceccatelli, M.D.,
Ph.D.
http://ki.se/ki/jsp/polopoly.jsp?d=21984&a=54602&l=en
5. PubMed, Nov 20, 2009
Ceccatelli S AND (mercury OR methylmercury OR ethylmercury OR
thimerosal)
6. Thimerosal content in some US vaccines
(yearly summaries, 2002 through 2009)
Institute for Vaccine Safety (IVS); Johns Hopkins
Bloomberg School of Public Health
http://www.vaccinesafety.edu/
IVS data summaries dated: 02-21-2002; 12-17-2002; 6/20/2003;
04/22/2004; October 2004; February 2005; Sept 13; 2005; Oct 16, 2006;
7/11/07; 5/15/08; 8/6/08; 10/19/09/ 11/19/09.
7. Mercury concentrations and metabolism in
infants receiving vaccines containing thiomersal: a descriptive
study
Pichichero ME, Cernichiari E, Lopreiato J, Treanor J.
Lancet. 2002 Nov 30;360(9347):1737-41.
8. Activation of methionine synthase by
insulin-like growth factor-1 and dopamine: a target for
neurodevelopmental toxins and thimerosal
Waly M et al.
Mol Psychiatry. 2004 Apr;9(4):358-70.
9. Thimerosal is an Ineffective Vaccine
Preservative
http://www.autismboulder.org/pdf/IneffectivePreservative.pdf
10. Evaluation of mercurial compounds as
antiseptics
Engley FB
Annals of New York Academy of Sciences. 53:197-2-6, 1950.
11. The case against thimerosal
use
Seal D et al.
Lancet, 1991;338:315-316.
12. A review of Thimerosal (Merthiolate)
and its ethylmercury breakdown product: specific historical
considerations regarding safety and effectiveness
Geier DA, Sykes LK, Geier MR.
J Toxicol Environ Health B Crit Rev. 2007 Dec;10(8):575-96.
{free online}
http://www.informaworld.com/smpp/content~db=all?content=10.1080/10937400701389875
Thimerosal (Merthiolate) is an ethylmercury-containing pharmaceutical
compound that is 49.55% mercury and that was developed in 1927.
Thimerosal has been marketed as an antimicrobial agent in a range of
products, including topical antiseptic solutions and antiseptic
ointments for treating cuts, nasal sprays, eye solutions, vaginal
spermicides, diaper rash treatments, and perhaps most importantly as a
preservative in vaccines and other injectable biological products,
including Rho(D)-immune globulin preparations, despite evidence, dating
to the early 1930s, indicating Thimerosal to be potentially hazardous
to humans and ineffective as an antimicrobial agent. Despite this,
Thimerosal was not scrutinized as part of U.S. pharmaceutical products
until the 1980s, when the U.S. Food and Drug Administration finally
recognized its demonstrated ineffectiveness and toxicity in topical
pharmaceutical products, and began to eliminate it from these.
Ironically, while Thimerosal was being eliminated from topicals, it was
becoming more and more ubiquitous in the recommended immunization
schedule for infants and pregnant women. Furthermore, Thimerosal
continues to be administered, as part of mandated immunizations and
other pharmaceutical products, in the United States and globally. The
ubiquitous and largely unchecked place of Thimerosal in
pharmaceuticals, therefore, represents a medical crisis.
13. [analysis] Generation
Zero
Blaxill M, Safeminds 2004
http://www.safeminds.org/research/library/GenerationZeroPowerPoint.pdf
14. Safety of thimerosal-containing
vaccines: a two-phased study of computerized health maintenance
organization databases
Verstraeten T, Davis RL, DeStefano F, Lieu TA, Rhodes PH, Black SB,
Shinefield H, Chen RT; Vaccine Safety Datalink Team.
Epidemic Intelligence Service Program, Epidemiology Program Office
Centers for Disease Control and Prevention
Pediatrics. 2003 Nov;112(5):1039-48.
http://pediatrics.aappublications.org/cgi/content/full/112/5/1039
15. Hepatitis B vaccination of male
neonates and autism
[conference abstract as published]
CM Gallagher, MS Goodman, Graduate Program in Public
Health, Stony Brook University Medical Center, Stony Brook, NY
Annals of Epidemiology, p659
Vol. 19, No. 9 Abstracts (ACE) September 2009: 651–680
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 ASDrisk amongboys age 3–17 years
with shot records, adjusted for race, maternal education, and
two-parent household.
RESULTS:Boyswho 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-Hispanicwhite 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.
16. Hepatitis B triple series vaccine and
developmental disability in US children aged 1-9
years
Gallagher C, Goodman M. Toxicol Environ Chem 2008 90(5):997-1008.
{free online}
http://fourteenstudies.org/pdf/hep_b.pdf
This study investigated the association between vaccination with the
Hepatitis B triple series vaccine prior to 2000 and developmental
disability in children aged 1-9 years (n = 1824), proxied by parental
report that their child receives early intervention or special
education services (EIS). National Health and Nutrition Examination
Survey 1999-2000 data were analyzed and adjusted for survey design by
Taylor Linearization using SAS version 9.1 software, with SAS callable
SUDAAN version 9.0.1. The odds of receiving
EIS were approximately nine times as great for vaccinated boys (n = 46)
as for unvaccinated boys (n = 7), after adjustment for
confounders. This study found statistically significant evidence to
suggest that boys in United States who were vaccinated with the triple
series Hepatitis B vaccine, during the time period in which vaccines
were manufactured with thimerosal, were more susceptible to
developmental disability than were unvaccinated boys.
17. Cellular and mitochondrial glutathione
redox imbalance in lymphoblastoid cells derived from children with
autism
James SJ et al.
FASEB J. 2009 Aug;23(8):2374-83.
Research into the metabolic phenotype of autism has been relatively
unexplored despite the fact that metabolic abnormalities have been
implicated in the pathophysiology of several other neurobehavioral
disorders. Plasma biomarkers of oxidative stress have been reported in
autistic children; however, intracellular redox status has not yet been
evaluated. Lymphoblastoid cells (LCLs) derived from autistic children
and unaffected controls were used to assess relative concentrations of
reduced glutathione (GSH) and oxidized disulfide glutathione (GSSG) in
cell extracts and isolated mitochondria as a measure of intracellular
redox capacity. The results indicated that the GSH/GSSG redox ratio was
decreased and percentage oxidized glutathione increased in both cytosol
and mitochondria in the autism LCLs. Exposure to oxidative stress via the sulfhydryl
reagent thimerosal resulted in a greater decrease in the GSH/GSSG ratio
and increase in free radical generation in autism compared to control
cells. Acute exposure to physiological levels of nitric
oxide decreased mitochondrial membrane potential to a greater extent in
the autism LCLs, although GSH/GSSG and ATP concentrations were
similarly decreased in both cell lines. These results suggest that the
autism LCLs exhibit a reduced glutathione reserve capacity in both
cytosol and mitochondria that may compromise antioxidant defense and
detoxification capacity under prooxidant conditions.
18. Metabolic endophenotype and related
genotypes are associated with oxidative stress in children with
autism
James SJ et al.
Am J Med Genet B Neuropsychiatr Genet. 2006 Dec 5;141B(8):947-56.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2610366/?tool=pubmed
Autism is a behaviorally defined neurodevelopmental disorder usually
diagnosed in early childhood that is characterized by impairment in
reciprocal communication and speech, repetitive behaviors, and social
withdrawal. Although both genetic and environmental factors are thought
to be involved, none have been reproducibly identified. The metabolic
phenotype of an individual reflects the influence of endogenous and
exogenous factors on genotype. As such, it provides a window through
which the interactive impact of genes and environment may be viewed and
relevant susceptibility factors identified. Although abnormal
methionine metabolism has been associated with other neurologic
disorders, these pathways and related polymorphisms have not been
evaluated in autistic children. Plasma levels of metabolites in
methionine transmethylation and transsulfuration pathways were measured
in 80 autistic and 73 control children. In addition, common polymorphic
variants known to modulate these metabolic pathways were evaluated in
360 autistic children and 205 controls. The metabolic results indicated
that plasma methionine and the ratio of S-adenosylmethionine (SAM) to
S-adenosylhomocysteine (SAH), an indicator of methylation capacity,
were significantly decreased in the autistic children relative to
age-matched controls. In addition, plasma levels of cysteine,
glutathione, and the ratio of reduced to oxidized glutathione, an
indication of antioxidant capacity and redox homeostasis, were
significantly decreased. Differences in allele frequency and/or
significant gene-gene interactions were found for relevant genes
encoding the reduced folate carrier (RFC 80G > A), transcobalamin II
(TCN2 776G > C), catechol-O-methyltransferase (COMT 472G > A),
methylenetetrahydrofolate reductase (MTHFR 677C > T and 1298A >
C), and glutathione-S-transferase (GST M1). We propose that an
increased vulnerability to oxidative stress (endogenous or
environmental) may contribute to the development and clinical
manifestations of autism.
19. Homozygous gene deletions of the
glutathione S-transferases M1 and T1 are associated with thimerosal
sensitization
Westphal GA et al.
Int Arch Occup Environ Health. 2000 Aug;73(6):384-8.
OBJECTIVE: Thimerosal is an important preservative in vaccines and
ophthalmologic preparations. The substance is known to be a type IV
sensitizing agent. High sensitization rates were observed in
contact-allergic patients and in health care workers who had been
exposed to thimerosal-preserved vaccines. There is evidence for the
involvement of the glutathione system in the metabolism of thimerosal
or its decomposition products (organomercury alkyl compounds). Thus
detoxification by polymorphically expressed glutathione S-transferases
such as GSTT1 and GSTM1 might have a protective effect against
sensitization by these substances. METHODS: To address this question, a
case control study was conducted, including 91 Central European
individuals with a positive patch-test reaction to thimerosal. This
population was compared with 169 healthy controls and additionally with
114 individuals affected by an allergy against para-substituted aryl
compounds. The latter population was included in order to test whether
possible associations were due to substance-specific effects, or were a
general feature connected with type IV immunological diseases.
Homozygous deletions of GSTT1 and GSTM1 were determined by polymerase
chain reaction. RESULTS: Glutathione S-transferase M1 deficiency was
significantly more frequent among patients sensitized to thimerosal
(65.9%, P = 0.013) compared with the healthy control group (49.1%) and
the "para-compound" group (48%, P = 0.034). Glutathione S-transferase
T1 deficiency in the thimerosal/mercury group (19.8%) was barely
elevated versus healthy controls (16.0%) and the "para-compound" group
(14.0%). The combined deletion (GSTT1-/GSTM1-) was markedly more
frequent among thimerosal-sensitized patients than in healthy controls
(17.6% vs. 6.5%, P = 0.0093) and in the "para-compound" group (17.6%
vs. 6.1%, P =0.014), revealing a synergistic effect of these enzyme
deficiencies (healthy controls vs. thimerosal GSTM1 negative
individuals, OR = 2.0 [CI = 1.2-3.4], GSTT1-, OR = 1.2 [CI = 0.70-2.1],
GSTM1/T1-, OR = 3.1 [CI = 1.4-6.5]). CONCLUSIONS: Since the
glutathione-dependent system was repeatedly shown to be involved in the
metabolism of thimerosal decomposition products, the observed
association may be of functional relevance.
20. Inhibition of the human erythrocytic
glutathione-S-transferase T1 (GST T1) by thimerosal
Müller M, Westphal G, Vesper A, Bünger J, Hallier E.
Int J Hyg Environ Health. 2001 Jul;203(5-6):479-81.
We have investigated the interaction of thimerosal, a widely used
antiseptic and preservative, with the human erythrocytic GST T1
(glutathione-S-transferase T1). This detoxifying enzyme is expressed in
the erythrocytes of solely the human species and it displays a genetic
polymorphism. Due to this polymorphism about 25% of the individuals of
the caucasian population lack this activity ("non-conjugators"), while
75% show it ("conjugators") (Hallier, E., et al., 1993). Using our
newly developed HPLC-fluorescence detection assay (Müller, M., et al.,
2001) we have profiled the kinetics of enzyme inhibition in erythrocyte
lysates of two individuals previously identified as "normal conjugator"
(medium enzyme activity) and "super-conjugator" (very high activity).
For the normal conjugator we have determined a 2.77 mM thimerosal
concentration to inhibit 50% of the GST T1 activity. In the case of the
super-conjugator a 2.3 mM thimerosal concentration causes a 50%
inhibition of the enzyme activity. For both phenotypes a 14.8 mM
thimerosal concentration results in residual enzyme activities equal to
those typically detected in non-conjugator lysates. Thus, sufficiently
high doses of thimerosal may be able to change the phenotypic status of
an individual--at least in vitro--by inhibition of the GST T1
enzyme.
21. Biochemical and molecular basis of
thimerosal-induced apoptosis in T cells: a major role of mitochondrial
pathway
Makani S et al.
Division of Basic and Clinical Immunology, University of California
Genes Immun. 2002 Aug;3(5):270-8.
http://www.nature.com/gene/journal/v3/n5/abs/6363854a.html
The major source of thimerosal (ethyl mercury thiosalicylate) exposure
is childhood vaccines. It is believed that the children are exposed to
significant accumulative dosage of thimerosal during the first 2 years
of life via immunization. Because of health-related concerns for
exposure to mercury, we examined the effects of thimerosal on the
biochemical and molecular steps of mitochondrial pathway of apoptosis
in Jurkat T cells. Thimerosal and not thiosalcylic acid (non-mercury
component of thimerosal), in a concentration-dependent manner, induced
apoptosis in T cells as determined by TUNEL and propidium iodide
assays, suggesting a role of mercury in T cell apoptosis. Apoptosis was
associated with depolarization of mitochondrial membrane, release of
cytochrome c and apoptosis inducing factor (AIF) from the mitochondria,
and activation of caspase-9 and caspase-3, but not of caspase-8. In
addition, thimerosal in a concentration-dependent manner inhibited the
expression of XIAP, cIAP-1 but did not influence cIAP-2 expression.
Furthermore, thimerosal enhanced intracellular reactive oxygen species
and reduced intracellular glutathione (GSH). Finally, exogenous
glutathione protected T cells from thimerosal-induced apoptosis by
upregulation of XIAP and cIAP1 and by inhibiting activation of both
caspase-9 and caspase-3. These data suggest that thimerosal induces
apoptosis in T cells via mitochondrial pathway by inducing oxidative
stress and depletion of GSH.
22. Mitochondrial mediated
thimerosal-induced apoptosis in a human neuroblastoma cell line
(SK-N-SH)
Humphrey ML, Cole MP, Pendergrass JC, Kiningham KK.
Neurotoxicology. 2005 Jun;26(3):407-16.
Environmental exposure to mercurials continues to be a public health
issue due to their deleterious effects on immune, renal and
neurological function. Recently the safety of thimerosal, an ethyl
mercury-containing preservative used in vaccines, has been questioned
due to exposure of infants during immunization. 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, and
more specifically, to elucidate signaling pathways which might serve as
pharmacological targets. Within 2 h of thimerosal exposure (5 microM)
to the human neuroblastoma cell line, SK-N-SH, morphological changes,
including membrane alterations and cell shrinkage, were observed. Cell
viability, assessed by measurement of lactate dehydrogenase (LDH)
activity in the medium, as well as the
3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT)
assay, showed a time- and concentration-dependent decrease in cell
survival upon thimerosal exposure. In cells treated for 24 h with
thimerosal, fluorescence microscopy indicated cells undergoing both
apoptosis and oncosis/necrosis. To identify the apoptotic pathway
associated with thimerosal-mediated cell death, we first evaluated the
mitochondrial cascade, as both inorganic and organic mercurials have
been reported to accumulate in the organelle. Cytochrome c was shown to
leak from the mitochondria, followed by caspase 9 cleavage within 8 h
of treatment. In addition, poly(ADP-ribose) polymerase (PARP) was
cleaved to form a 85 kDa fragment following maximal caspase 3
activation at 24 h. Taken together these findings suggest deleterious
effects on the cytoarchitecture by thimerosal and initiation of
mitochondrial-mediated apoptosis.
23. Thimerosal induces neuronal cell
apoptosis by causing cytochrome c and apoptosis-inducing factor release
from mitochondria
Yel L et al.
Int J Mol Med. 2005 Dec;16(6):971-7.
There is a worldwide increasing concern over the neurological risks of
thimerosal (ethylmercury thiosalicylate) which is an organic mercury
compound that is commonly used as an antimicrobial preservative. In
this study, we show that thimerosal, at nanomolar concentrations,
induces neuronal cell death through the mitochondrial pathway.
Thimerosal, in a concentration- and time-dependent manner, decreased
cell viability as assessed by calcein-ethidium staining and caused
apoptosis detected by Hoechst 33258 dye. Thimerosal-induced apoptosis
was associated with depolarization of mitochondrial membrane,
generation of reactive oxygen species, and release of cytochrome c and
apoptosis-inducing factor (AIF) from mitochondria to cytosol. Although
thimerosal did not affect cellular expression of Bax at the protein
level, we observed translocation of Bax from cytosol to mitochondria.
Finally, caspase-9 and caspase-3 were activated in the absence of
caspase-8 activation. Our data suggest that thimerosal causes apoptosis
in neuroblastoma cells by changing the mitochondrial
microenvironment.
24. Are toxic biometals destroying your
children's future?
Drum DA.
Biometals. 2009 Oct;22(5):697-700. Epub 2009 Feb 11.
http://www.springerlink.com/content/7k502300609t72v4/
Cadmium, arsenic, lead, and mercury have been linked to autism,
attention deficit disorder, mental retardation and death of children.
Mercury in thimerosal found in many vaccines and flu shots contributes
significantly to these problems. Decomposition of the thimerosal can
produce more toxic compounds, either methylethylmercury or
diethylmercury, in the body. These compounds have a toxicity level
similar to dimethylmercury. Within the human body, a mitochondrial
disorder may release the more toxic form of mercury internally. Young
children and pregnant women must minimize internal exposure to the
vaccines and flu shots containing mercury.
25. Developmental regression and
mitochondrial dysfunction in a child with autism
Poling JS, Frye RE, Shoffner J, Zimmerman AW.
J Child Neurol. 2006 Feb;21(2):170-2.
{free online}
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2536523/?tool=pubmed
26. Mitochondrial dysfunction in autism
spectrum disorders: a population-based study
Oliveira G et al.
Dev Med Child Neurol. 2005 Mar;47(3):185-9.
27. Mitochondrial disease in autism
spectrum disorder patients: a cohort analysis
Weissman JR et al.
PLoS One. 2008;3(11):e3815. Epub 2008 Nov 26.
{free online}
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0003815
28. Evidence of Mitochondrial Dysfunction
in Autism and Implications for Treatment
Daniel A. Rossignol, J. Jeffrey Bradstreet
American Journal of Biochemistry and Biotechnology 4 (2): 208-217,
2008
{free online}
http://www.scipub.org/fulltext/ajbb/ajbb42208-217.pdf
29. Porphyrinuria in childhood autistic
disorder: implications for environmental toxicity
Nataf R et al.
Toxicol Appl Pharmacol. 2006 Jul 15;214(2):99-108.
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.
30. A prospective study of mercury toxicity
biomarkers in autistic spectrum disorders
Geier DA, Geier MR.
J Toxicol Environ Health A. 2007 Oct;70(20):1723-30.
Porphyrins are derivatives formed in the heme synthesis pathway and
porphyrins afford a measure of xenobiotic exposure. The steps in the
heme pathway most vulnerable to heavy metal inhibition are uroporphyrin
decarboxylase (UROD) and coproporphyrinogen oxidase (CPOX) reactions.
Mercury toxicity was associated with elevations in urinary
coproporphyrin (cP), pentacarboxyporphyrin (5cxP), and
precoproporphyrin (prcP) (also known as keto-isocoproporphyrin) levels.
Two cohorts of autistic patients in the United States and France had
urine porphyrin levels associated with mercury toxicity. A prospective
study of urinary porphyrin testing at LabCorp (United States) and the
Laboratoire Philippe Auguste (France) involving 71 autism spectrum
disorder (ASD) patients, neurotypical sibling controls, and general
population controls was undertaken. ASD patients had significant
elevations in urinary levels of cP, 5cxP, and prcP relative to
controls, and > 50% of ASD patients had urinary cP levels more than
2 standard deviations above the mean values for neurotypical sibling
controls. Significant reductions in urinary 5cxP and cP levels were
observed in ASD patients following chelation. A significant correlation
was found between urinary porphyrins measured at LabCorp and those
measured at the Laboratoire Philippe Auguste on individual ASD
patients. The established developmental neurotoxicity attributed to
mercury and biochemical/genomic evidence for mercury
susceptibility/toxicity in ASDs indicates a causal role for mercury.
Urinary porphyrin testing is clinically available, relatively
inexpensive, and noninvasive. Porphyrins need to be routinely measured
in ASDs to establish if mercury toxicity is a causative factor and to
evaluate the effectiveness of chelation therapy.
31. Richard M. Kostrzewa
Editor-in-chief of Neutotoxicity Research
Department of Pharmacology, Quillen College of Medicine
East Tennessee State University, Johnson City, TN, USA
http://www.springer.com/biomed/neuroscience/journal/12640?detailsPage=aboutTheEditor
32. "Jeffrey R. Balser, M.D., Ph.D." <jeff.balser@vanderbilt.edu>
Associate Vice Chancellor for Health Affairs
Dean, School of Medicine
Vanderbilt
University
http://www.vanderbilt.edu/
33. Harriet Wallberg-Henriksson <rektorssekreterare@ki.se>
President of Karolinska Institutet
Karolinska Institutet
http://info.ki.se/index_en.html
34. NIH: Center for Scientific
Review
http://cms.csr.nih.gov/ContactCSR/
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