IOM Report, Mouse Study Continue Debate on Vaccine-Autism Link
From: JWissmille (jwissmille_at_aol.com)
Date: 07/11/04
- Next message: JWissmille: "LATE AND CHRONIC LYME DISEASE"
- Previous message: A_Weisman: "Re: Reminder: Lyme Disease support meeting 7/13"
- Messages sorted by: [ date ] [ thread ]
Date: 11 Jul 2004 20:27:32 GMT
"We don't have an animal
model for autism and we don't understand exactly what causes autism or what
its exact pathophysiology is in humans. So we don't understand it completely
in either system at the moment, and we certainly don't understand to what
extent one is a model for the other."
"It is our privilege as an advanced society to not only have the means to
prevent death from and spread of infectious diseases, but to also have the
opportunity to carefully consider whether vaccines and other infection
control methods may be associated with any risks for a portion of the
population, including neurodevelopmental damage, and, if so, how to define
and manage these risks,"
"...........Other allegations are that some datasets that showed a
relationship between
thimerosal and neurologic disorders no longer exist, that independent
researchers have been denied access to CDC databases, that
government-sponsored studies have not evaluated genetic subgroups, and that
government public health agencies have ignored an increasing body of
clinical evidence on the connection of thimerosal to neurologic
disorders......."
http://www.medscape.com/viewarticle/480683
MEDSCAPE
IOM Report, Mouse Study Continue Debate on Vaccine-Autism Link
Laurie Barclay, MD
June 11, 2004 - Thimerosal, the ethylmercury-based preservative found in
childhood vaccines, can increase the risk of autism-like damage in mice,
according to a report published online June 8 in advance of publication in
Molecular Psychiatry. However, the Institute of Medicine (IOM) Immunization
Safety Review Committee released a statement on May 18 that scientific
evidence supports no association with autism for either
thimerosal-containing or measles-mumps-rubella (MMR) vaccines.
Since 2001, all universally recommended childhood vaccines have been
available in single-dose vials without thimerosal, but some influenza
vaccines still contain the preservative. The MMR vaccine has never contained
thimerosal.
The IOM report is the eighth, and said to be the final, report on vaccine
safety. It was intended to alleviate long-standing concerns that mercury in
vaccines could cause autism, and it was based on five large epidemiologic
studies conducted in the U.S., the U.K., Denmark, and Sweden since 2001,
which consistently provided evidence that there is no association between
thimerosal-containing vaccines and autism.
After reviewing results from the mouse model and other studies reporting
links between thimerosal and autism, the panel also concluded that
hypotheses regarding how the MMR vaccine and thimerosal could trigger autism
lack supporting evidence and are theoretical only.
"This type of study, while certainly interesting, in no way substitutes for
actual human evidence," IOM panelist Steven Goodman, MD, MHS, PhD, an
associate professor of oncology and epidemiology at the Johns Hopkins School
of Medicine in Baltimore, Maryland, told Medscape. "We don't have an animal
model for autism and we don't understand exactly what causes autism or what
its exact pathophysiology is in humans. So we don't understand it completely
in either system at the moment, and we certainly don't understand to what
extent one is a model for the other."
Some experts suggest that the 10-fold increase in the number of children
diagnosed with autism spectrum disorders since 1985 cannot be explained
solely by genetic factors, although about one third of children with autism
have increased immune disturbances and a family history of autoimmune
disease. The investigators in the mouse model study hypothesized that immune
response genes linked to mercury immunotoxicity would predict neurotoxicity
after exposure to low-dose thimerosal.
According to lead author Mady Hornig, MD, an associate professor of
epidemiology and director of translational research at the Jerome L. and
Dawn Greene Infectious Disease Laboratory of the Mailman School of Public
Health at Columbia University in New York City, this was the first animal
model providing evidence that postnatal administration of low-dose
ethylmercury can lead to behavioral and neurologic changes in the developing
brain of genetically susceptible mice.
Using the U.S. immunization schedule for children, Dr. Hornig's group
calculated the timing and quantity of thimerosal dosing based on 10th
percentile weight of U.S. boys at age two, four, six, and twelve months, and
they administered the ethylmercury to a strain of mice susceptible to
autoimmune disease.
"The same immune response genes in mice that predict mercury-related
immunotoxicity also predict neurodevelopmental damage in our model and are
associated with the development of features reminiscent of those observed in
autism," Dr. Hornig told Medscape. "These include generalized impoverishment
of behavioral responses and abnormal reactions to novel environments; brain
enlargement, correlated closely with the observed behavioral abnormalities
in exploration and anxiety; increased cell packing in the hippocampus; and
disturbances in glutamate receptors and transporters."
The investigators suggest that these findings may allow identification of
autism cases associated with environmental factors, design of treatment
strategies, and development of rational immunization programs.
Immune response genes in humans homologous to those implicated in the mouse
model could be the human leukocyte antigen (HLA) alleles located in the
major histocompatibility complex (MHC) on chromosome 6, but genes that
modulate susceptibility might also include those coding for the heavy metal
binding protein metallothionein or the detoxifying enzyme
glutathione-S-transferase, or genes involved in DNA methylation and
epigenetic modulation.
"Even without knowledge of a specific gene association, we can consider the
impact of gene prevalence on our statistical capacity to demonstrate effects
of potential toxins in a population, should they exist," Dr. Hornig said.
"Thus, our animal model findings have important implications for the design
of epidemiologic studies capable of evaluating the role of gene-environment
interactions in the pathogenesis of autism."
However, the IOM panel already considered findings from the mouse model in
February when they drafted their report, according to panel chair Marie C.
McCormick MD, ScD, the Sumner and Esther Feldberg Professor of Maternal and
Child Health at the Harvard School of Public Health in Boston,
Massachusetts.
"Although this model uses thimerosal...it assumes that autism is caused by
an autoimmune reaction," Dr. McCormick told Medscape. "[The IOM report]
discussed the lack of evidence of autoimmune-mediated [central nervous
system] damage in the brains of autistic patients."
The IOM panel acknowledged that mercury is a neurotoxin and that autism is a
devastating disorder meriting additional research into its pathophysiology
and treatments. However, they concluded that pursuing the link between the
two is unlikely to be productive, at least until susceptible subgroups can
be defined based on some meaningful biologic hypothesis.
"We didn't say that investigations shouldn't continue in the lab on the
effects of mercury, on the effects of thimerosal, and on the causes and
profiles of autism," Dr. Goodman said. "Where the committee thought that
research dollars probably shouldn't go, at least for the moment, are these
large-scale epidemiologic studies linking autism and thimerosal exposure."
But Dr. Hornig countered that the design of published epidemiologic studies
may have been inadequate to appropriately estimate risk. Although MHC and
non-MHC genes, age, sex, nutrition, route and frequency of administration,
and maturity of the metabolic, immune, and nervous systems are known to
affect mercury toxicokinetics, previous studies have not evaluated such
factors.
Despite the profound implications of her research for understanding outcomes
of exposure not only to mercury but to a wide variety of xenobiotics ranging
from toxins to infectious agents, Dr. Hornig is concerned that funding is in
jeopardy, because the IOM conclusions will guide decisions by the National
Institutes of Health (NIH) and by foundations supporting autism research.
"The pronouncement that research funds are better applied elsewhere
effectively forecloses any possibility of federal funding for an entire
field of research," she said. "The timing is particularly unfortunate given
that we are only just beginning to define the mechanisms by which
environmental factors such as thimerosal interact with immune response genes
during early development."
According to Dr. McCormick, the IOM committee recommended that "available
funding for autism research be channeled to the most promising areas, of
which the link with vaccines does not appear to be one." However, they did
recommend continued surveillance of autistic spectrum disorder as exposure
to thimerosal declined.
Parents' advocacy groups such as the National Vaccine Information Center are
distressed by the firm position that the IOM panel has taken on the issue.
Compared with earlier IOM reports in 1991, 1994, and 2001, which concluded
there was insufficient evidence to accept or reject a link between vaccines
and autism, the present report uses stronger language.
Policy implications of the IOM report include not only research priorities,
but immunization policies.
"It was clear from the report that we were not giving thimerosal a clean
bill of health. Mercury is definitely a neurotoxin," Dr. Goodman said. "We
didn't say that thimerosal is something that we should want in vaccines; we
said that the safest vaccines are indeed thimerosal-free vaccines. We only
said that the evidence favored that there was not a connection between
autism and thimerosal exposure."
An additional concern regarding mercury exposure from thimerosal is that any
potentially neurotoxic effect could be cumulative with that of other mercury
exposures, such as maternal ingestion of seafood. Dr. Hornig explained that
ethylmercury, the form of mercury in thimerosal, is more rapidly converted
to inorganic mercury than methylmercury, the form found in contaminated
fish. Oral administration of thimerosal to adult, genetically sensitive mice
results in a severe autoimmune syndrome similar to that of inorganic
mercury. Such autoimmune reactions are less potent with methylmercury in
mercury-equivalent doses.
"The issue about minimizing exposure to thimerosal on top of the other
mercury exposures I think is a legitimate one," Dr. Goodman said. "We live
in a world where there is exposure to mercury from multiple sources, and
some of it may be unavoidable. To the extent that there is mercury in the
air, we can't stop breathing. To the extent that there is mercury in certain
foods, obviously we can avoid fish, but anything else we may not know
about."
Although a comparison of mercury exposure from thimerosal-based vaccines
with that from other environmental sources was outside the scope of the IOM
report, the panel recommended increased efforts to quantify the level of
prenatal and postnatal exposure to thimerosal and other forms of mercury in
infants, children, and pregnant women.
"Thimerosal was removed from vaccines as a precautionary measure to reduce
the exposure to mercury from all sources. There is no evidence that the
amount of mercury present in vaccines resulted in health problems," Dr.
McCormick said. "Clearly, thimerosal-free vaccines would be preferred on
this cautionary principle. Equally clearly, thimerosal-containing vaccines
would be preferred to no vaccination; the hypothetical risk posed by
exposure to thimerosal is far outweighed by the very real risk of the
preventable diseases, which I might add are only one plane ride away."
Cost is the major advantage of thimerosal-containing vaccine because the
preservative prevents contamination and allows packaging in multiple-dose
vials, whereas thimerosal-free vaccine has to be put in single-dose vials
and costs approximately $4 more per dose. But the IOM panel was not assigned
the task of cost-benefit analysis or its application to immunization policy.
"I don't think anybody, presented with the choice of thimerosal-free vaccine
versus thimerosal-containing vaccine that was equally effective, that
anybody would say that the thimerosal-containing vaccine was the preferable
one." Dr. Goodman said. "The committee continued to recommend that
thimerosal-free vaccines should be created where possible and that exposure
to this preservative be minimized, with recognition that there are special
circumstances where the risks and benefits related to inclusion or exclusion
might lead certain countries or policy-makers to accept its inclusion."
Dr. Hornig urged consideration of autism-related disability in any
cost-benefit analysis, and points out that expense, timely production, and
distribution of thimerosal-free vaccines are tractable issues.
"It is our privilege as an advanced society to not only have the means to
prevent death from and spread of infectious diseases, but to also have the
opportunity to carefully consider whether vaccines and other infection
control methods may be associated with any risks for a portion of the
population, including neurodevelopmental damage, and, if so, how to define
and manage these risks," Dr. Hornig said. "To maintain public confidence in
immunization programs, we must provide sound assurance through solid science
that such confidence is warranted."
The 2004 IOM report does not recommend a policy review of the current
schedule and recommendations for the administration of routine childhood
vaccines, but it does recommend that cost-benefit assessments regarding the
use of thimerosal in vaccines, whether in the U.S. or elsewhere, should not
include autism as a potential risk.
The Office of Special Counsel (OSC) is concerned that the IOM report will
provide the impetus for government and industry to eliminate autism from
cost-benefit analyses of thimerosal risks. The OSC is an independent federal
investigative and prosecutorial agency that functions as a secure channel
for disclosures of whistleblower complaints and abuse of authority. It is
currently questioning potential conflicts of interests underlying the
composition of the IOM panel.
Dr. McCormick described the Committee on Immunization Safety Review as an
independent group of 13 scientists from public health and medical
disciplines established in January 2001 in response to a request from the
Centers for Disease Control and Prevention (CDC) and the NIH. An IOM news
release describes this body as a private nonprofit institution providing
health policy advice under a congressional charter granted to the National
Academy of Sciences, and notes that the panel report was sponsored by the
CDC and the National Institute of Allergy and Infectious Diseases.
On May 20, the OSC forwarded to congressional oversight committees hundreds
of disclosures alleging public health and safety concerns regarding the
possible link between thimerosal-containing vaccines and autism, many from
parents of children with autism or other neurologic disorders. However, the
OSC does not have jurisdiction over disclosures from private citizens, and
none of the disclosures were from federal employees. Contrary to statements
from DHHS agencies, the DHHS Office of Investigations, and the American
Academy of Pediatrics, the disclosures claim that some childhood vaccines
with expiration dates of 2005 contain 25 µg of mercury and continue to be
produced and administered.
Other allegations are that some datasets that showed a relationship between
thimerosal and neurologic disorders no longer exist, that independent
researchers have been denied access to CDC databases, that
government-sponsored studies have not evaluated genetic subgroups, and that
government public health agencies have ignored an increasing body of
clinical evidence on the connection of thimerosal to neurologic disorders.
The citizens making these allegations call for immediate safeguarding of the
Vaccine Safety Datalink database and other relevant CDC data information.
They further claim that the CDC and the Food and Drug Administration
colluded with pharmaceutical companies at a conference in Norcross, Georgia,
in June 2000, to prevent the release of data showing a statistically
significant correlation between thimerosal exposure via pediatric vaccines
and neurologic disorders including autism.
The allegation is that study author Thomas Verstraeten, MD, who presented
these data at the conference, published a different version of the study in
the November 2003 issue of Pediatrics that did not show a statistical
correlation. An erratum in Pediatrics in January 2004 indicates that when he
worked on the study, Dr. Verstraeten was a CDC employee, and that he is
currently employed by GlaxoSmithKline (GSK).
In April, Dr. Verstraeten wrote a letter to the editor of Pediatrics, which
was published in the April issue (2004;113[4]:932), voicing his opinions
that the CDC did not "water down the original results." He stated that the
CDC screening study of thimerosal-containing vaccines "was perceived at
first as a positive study that found an association between thimerosal and
some neurodevelopmental outcomes."
According to his letter, the study was a first phase conducted in two health
maintenance organizations (HMO), with the original plan being to conduct the
second phase as a case-control study, which the investigators realized would
be too time-consuming. Dr. Verstraeten urged that the second phase be
performed instead at a third HMO; it was, and this second phase did not
replicate the findings of the first phase.
"The investigators could neither confirm nor exclude an association, and
therefore more study is required," Dr. Verstraeten writes. "The CDC has
taken its responsibility and is currently undertaking such additional
study." Dr. Verstraeten further denied any allegation that GSK "hired [him]
away to manipulate the data before publication," and explained that he and
GSK "had a very clear deal from the start of my employment that I would
finalize my involvement in the study on my own time and keep this
involvement entirely separated from my work at GSK."
As a next step, the IOM panel recommends developing programs to increase
public participation in vaccine safety research and policy decisions, and to
promote constructive dialogue between scientists, government officials, and
the public about research findings and their implications for policy
development.
Molec Psychiatry. Posted online June 8, 2004.
Reviewed by Gary D. Vogin, MD
- Next message: JWissmille: "LATE AND CHRONIC LYME DISEASE"
- Previous message: A_Weisman: "Re: Reminder: Lyme Disease support meeting 7/13"
- Messages sorted by: [ date ] [ thread ]
Relevant Pages
|
