SAN FRANCISCO, Nov. 10 (UPI) -- Exactly what and even how much doctors know about autism and its causes is a matter of debate.
Vaccine makers and most public health authorities thought long ago the piles of evidence they had gathered in support of their case were sufficient to convince the public no harm would come from the small amounts of the mercury-based preservative thimerosal once commonly found in children's shots and still present in some booster and flu vaccines.
They certainly expected the issue to be settled when the authoritative Institute of Medicine of the National Academy of Sciences came out with its 215-page assessment, backed by 215 references, of published and unpublished clinical and epidemiological research relevant to thimerosal's role in autism.
Acknowledging the firestorm flaring around the issue, the IOM stressed it took pains to keep the process clear of vested interests. It excluded from the review panel of 13 experts anyone with financial ties to vaccine makers or who had served as an expert witness on vaccine safety issues.
In a follow-up to an analysis that excused the measles-mumps-rubella vaccine as a cause of a broad range of neruodevelopmental disorders but was unable to reach a verdict on thimerosal's role, the IOM panel focused solely on autism.
It looked at large population surveys of children exposed to various amounts of thimerosal and to no thimerosal at all.
Similar investigations had raised red flags about a serious side effect occurring in one of every 100,000 Americans who received the swine-flu shot in the mid-1970s. If thimerosal was at the root of the increase in autism diagnoses, a retrospective study would pick out such an association just as well, mainstream scientists maintained.
Over three years the panel heard from researchers and parents and evaluated five surveys that showed no thimerosal link to autism, seven that did, 14 that found no MMR connection to the disorder and three that did.
The surveys that discounted a tie-in involved hundreds of thousands of children in the United States, Britain, Denmark and Sweden.
One study examined the records of all 467,450 babies born in Denmark from Jan. 1, 1990, to Dec. 31, 1996, in search of any developmental variations between youngsters who had received a thimerosal-containing vaccine and those inoculated with a mercury-free formulation of the same shot. It found none.
Thimerosal is nearly half a neurotoxin known as ethylmercury, which differs in certain ways from methylmercury, the type of mercury found in polluted fish.
"Furthermore there was no indication of a dose-response association between autism and the amount of ethylmercury received through thimerosal," the authors concluded.
The finding indicated children exposed to higher levels of mercury appeared to face a similar risk of developing a disorder as did those receiving lower amounts, they said.
The authors also said the hypothesis of such a link is based primarily on inappropriate analogies with methylmercury.
In addition, researchers reviewed the medical histories of the 537,303 children born in Denmark from January 1991 through December 1998 to determine whether the baby's age at the time of MMR vaccination, the time elapsed since or the date on which the shot was received had any bearing on their developmental health.
"We ... considered vaccination and autism in much the same study population," said Anders Hviid, investigator on both surveys. "In neither of these studies did we find any support for an association between vaccination and autism."
Skeptics discount the research as irrelevant because Denmark's children have had a different vaccine schedule and, thus, a different thimerosal exposure than their American counterparts. To them, it's akin to studying malaria in Minnesota.
In addition, the studies relied primarily on the records of hospitalized patients to draw their conclusions, but the vast majority of individuals with autism are treated and released, they note.
"One recent Danish study revealed that 93 percent of autistic records were for outpatients," Mark Blaxill, director of the mercury-opposing advocacy group SafeMinds, wrote to the American Journal of Preventive Medicine. "Clearly, the small remaining group of inpatient registrations has little value in trend assessment."
Most mainstream specialists are of a different mind.
"Studies conducted in the United States and abroad looking at the relationship between vaccination and autism provide irrefutable evidence there is no connection," said Dr. Charles Prober, professor of pediatrics, microbiology and immunology and associate chair of pediatrics at the Stanford University School of Medicine.
"The Danish studies repudiate any link," added Prober, scientific director of the Glaser Pediatric Research Network and infectious-disease specialist who worked with the American Academy of Pediatrics to devise recommendations on childhood vaccination and infection control.
For its part, the IOM panel, after weighing all the evidence, came to the conclusion that "favors rejection of a causal relationship between" thimerosal-containing vaccines and MMR shots and autism.
The committee also found no scientific substance to suggestions that the measles virus in the MMR vaccine might lodge in the gut and trigger autism, that the shot might stimulate the release of immune factors that damage the central nervous system or that thimerosal may interfere with biochemical systems in the brain, causing the disorder.
The report held little sway with the critical minority.
Even some mainstream researchers bristled at the "abandonment" of IOM's earlier call for a ban on mercury in medicines and a boost of research into this area.
They deemed the move "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."
Since their release, the IOM findings have been backed by a series of reports -- with which skeptics find equal fault.
One study, by the World Health Organization, examined the medical records of 109,863 children born in Britain from 1988 to 1997.
The investigation looked for a connection between thimerosal in vaccines and general developmental disorders, language or speech delay, tics, attention-deficit disorder, autism, unspecified developmental delays, behavior problems, encopresis, or involuntary bowel movement, and enuresis, better known as bedwetting.
Other than glimpsing a tenuous link to tics, it came up empty.
Another major review covered similar ground -- searching for a link between thimerosal and various health risks, thimerosal-containing vaccines and a type of leukemia, aluminum-containing vaccines and immune problems, vaccines and autoimmune disease, the MMR vaccine and autism -- and came out on the side of vaccine safety.
No adverse health effects have been noted in the general population during more than 60 years of thimerosal use, except at levels much higher than those found in drugs or shots, the report said.
However, it acknowledged there is a dearth of studies looking at the potential risks thimerosal-preserved vaccines pose to the fetus and premature and low-weight infant.
Critics took issue with the study, published in November 2005. They voiced concern that many of the authors were affiliated with the Centers for Disease Control and Prevention, which recommends the childhood immunization schedule, and the WHO, which oversees the vaccination of 104 million children every year.
They also raised questions about a portion of the research funding coming from vaccine-making giants GlaxoSmithKline Biologicals and Sanofi Pasteur MSD.
Another team, this one mixing scientists from the CDC and pediatricians from Children's Hospital and University of Colorado Health Sciences Center in Denver, came to vaccines' defense after analyzing 12 studies that had looked for any thimerosal-developmental disability ties.
"We reviewed the quality of science in various studies that suggested there was an association and in those that said there was no association," said co-author Dr. Ben Schwartz, senior science adviser to the U.S. vaccine program.
"We looked at a number of accepted measures of scientific quality such as whether the outcome was clearly defined, whether exposure could be appropriately quantified, whether the investigator had taken precautions to detect bias in the study results," he added.
"When we looked at these quality measures, one thing that became apparent was the studies that identified an association met very few of those accepted criteria whereas the studies that did not support such an association were (scientifically) better studies."
When a controversial hypothesis of an MMR connection to autism -- proposed in 1998 by British researcher Andrew Wakefield -- fell flat, the focus shifted to thimerosal as a target, Schwartz said.
"This represents a very natural desire of parents with autistic children to find a cause, a potentially preventable cause," he said, expressing a view that miffs many of said parents. "However, neither hypothesis bears strict scientific scrutiny."
(Note: In this multi-part installment, based on dozens of reports, conferences and interviews, Ped Med is keeping an eye on autism, taking a backward glance at its history and surrounding controversies, facing facts revealed by research and looking forward to treatment enhancements and expansions.)
Next: Doctors take on their critics
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