IOM Report, Mouse Study Continue Debate on Vaccine-Autism Link

Laurie Barclay, MD

June 11, 2004

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

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