Thiomersal controversy

The thiomersal controversy is between claims that thiomersal-containing vaccines (TCVs) cause or contribute to the development of autism and other brain development disorders, and mainstream medical opinion, which is that no convincing scientific evidence supports these claims.

Thiomersal, also spelled thimerosal, is an organomercury preservative used in vaccines since the 1930s to prevent bacterial and fungal contamination. In July 1999, following a review of mercury-containing food and drugs, the Centers for Disease Control (CDC) and the American Academy of Pediatrics (AAP) asked vaccine makers to remove thiomersal from vaccines as quickly as possible, and it was rapidly phased out of most U.S. and European vaccines. The precautionary principle assumes that there is no harm in exercising caution even if it later turns out to be unwarranted, but this 1999 action sparked confusion and controversy that has diverted attention and resources away from other efforts to find the causes of autism.

Thousands of lawsuits have been filed in the U.S. to seek damages from alleged toxicity from vaccines, including those purportedly from thiomersal preservatives. The scientific consensus&mdash;including scientific and medical professional bodies and governmental agencies such as the Food and Drug Administration, the Centers for Disease Control and Prevention, and the World Health Organization &mdash;rejects the hypothesis that exposure to thiomersal causes or contributes to autism or other neurological disorders.

Scientific background
After the FDA Modernization Act of 1997 mandated a review and risk assessment of all mercury-containing food and drugs, vaccine manufacturers responded to FDA requests to provide detailed information about the thimerosal content of their preparations in December 1998 and April 1999. Upon conclusion of this review, the FDA, in conjunction with the other members of the US Public Health Service (USPHS), the National Institutes of Health (NIH), CDC and Health Resources and Services Administration (HRSA) in a joint statement with the American Academy of Pediatrics (AAP), concluded:

"'Our review revealed no evidence of harm caused by doses of thimerosal found in vaccines, except for local hypersensitivity reactions. At the time of our review, vaccines containing thimerosal as a preservative could expose infants to cumulative mercury at levels that exceed EPA recommendations during the first 6 months of life. The clinical significance of this conclusion is not currently known; EPA guidelines contain as much as a 10-fold safety factor and such guidelines are meant to be starting points for the evaluation of mercury exposure. However, reducing exposure to thimerosal from vaccines is merited given the goal of reducing human exposure to mercury from all sources, the feasibility of removing thimerosal as a vaccine preservative, and the desirability of ensuring public confidence in the safety of vaccines.'"

The FDA noted that while the vaccination schedule at that time might have exceeded EPA standards for mercury exposure during the first 6 months of life, it did not exceed those of the FDA, Agency for Toxic Substances and Disease Registry (ATSDR), or WHO. The FDA also noted some difficulty interpreting toxicity of the ethylmercury in thiomersal because guidelines for mercury toxicity were based primarily on studies of methylmercury. Despite the lack of convincing evidence of toxicity of thiomersal, the USPHS and AAP determined that thiomersal should be removed from vaccines as a purely preventative measure and to increase public confidence in vaccines.

Due to continued public concern, the Centers for Disease Control and the National Institutes of Health (NIH) asked the National Academy of Science's (NAS) Institute of Medicine (IOM) to establish an independent expert committee to review hypotheses about existing and emerging immunization safety concerns. In 2001 the committee reported:

"The committee concludes that although the hypothesis that exposure to thimerosal-containing vaccines could be associated with neurodevelopmental disorders is not established and rests on indirect and incomplete information, primarily from analogies with methylmercury and levels of maximum mercury exposure from vaccines given in children, the hypothesis is biologically plausible.

The committee also concludes that the evidence is inadequate to accept or reject a causal relationship between thimerosal exposures from childhood vaccines and the neurodevelopmental disorders of autism, ADHD, and speech or language delay."

Social and political background
The FDA actions prompted autism advocates to consider the possibility of thiomersal as a cause of autism. The indirect evidence included analogy with neurotoxic effects of mercury compounds, extrapolation from laboratory and animal studies, and comparisons between trends in vaccination and autism cases.

This concept also gained support in the political sphere, with Rep. Dan Burton and Rep. David Weldon openly supporting this movement as well. A number of hearings were held in the Subcommittee on Human Rights and Wellness, Committee on Government Reform, chaired by Rep. Burton, on the topic of autism and vaccines. His staff concluded:

"'Thimerosal used as a preservative in vaccines in [sic] likely related to the autism epidemic. This epidemic in all probability may have been prevented or curtailed had the FDA not been asleep at the switch regarding the lack of safety data regarding injected thimerosal and the sharp rise of infant exposure to this known neurotoxin. Our public health agencies’ failure to act is indicative of institutional malfeasance for self-protection and misplaced protectionism of the pharmaceutical industry'"

Rationale for concern
Supporters of a link between thiomersal and autism cite several lines of reasoning for their concerns, including:


 * Appeal for caution: precise thresholds for ethylmercury toxicity have not been fully studied, and methylmercury is a poor surrogate for studying the toxicity of thiomersal.
 * In vitro tests: cultured cells in laboratory show adverse effects when exposed to ethylmercury.
 * An in vivo study reported in 2004 that autoimmune disease-sensitive mice exposed to thiomersal had growth delay, reduced locomotion, exaggerated response to new stimuli, and uncommon neuronal structure in some brain areas. The exposure attempted to replicate the one-year schedule for U.S. infants in 2001, adjusted for weight and age. However, a similar 2007 study found no pervasive developmental neurotoxicity in the same mouse strain. Also, while the intervals between vaccination in human infants assure nearly complete clearance of the organic species from the brain and blood, significant accumulation would be expected for the accelerated schedule in the mouse pups.
 * Unscientific reports that autism is rarer in the Amish community and other non-vaccinated groups. The reports are undercut by the fact that Amish genes may differ from those in the general community, that people in the Amish community have low exposures to many other potential hazards (for example, pesticides and plastics) and that increasingly, the Amish do receive at least some vaccinations.
 * Epidemiologic data: epidemiologic studies (all by Mark Geier) examined population level correlation between thiomersal and autism.
 * Concern that mercury might have synergistic effects with other metals and toxicants.

Despite the 1999 recommendation by the USPSH and AAP, some vaccines continue to contain non-trace amounts of thiomersal, mainly in vaccines targeted against influenza and tetanus. Other products that may contain thimerosal include products derived from blood plasma such as Rho(D) Immune Globulin, pit viper antivenin and coral snake antivenin, as well as black widow spider antivenin.

Scientific consensus on controversy
The scientific consensus is reflected in another committee report commissioned by the CDC by the Institute of Medicine that follows up on the initial 2001 report. Since the 2001 report, the IOM committee took into account new data that had been published in the interim, including a number of large scale epidemiologic studies focusing on the relationship between thiomersal and autism in a number of countries including the US, Sweden, Denmark, and the UK.

The committee noted, in response to those who cite in vitro or animal models as evidence for the link between autism and thiomersal:

"However, the experiments showing effects of thimerosal on biochemical pathways in cell culture systems and showing abnormalities in the immune system or metal metabolism in people with autism are provocative; the autism research community should consider the appropriate composition of the autism research portfolio with some of these new findings in mind. However, these experiments do not provide evidence of a relationship between vaccines or thimerosal and autism.

In the absence of experimental or human evidence that vaccination (either the MMR vaccine or the preservative thimerosal) affects metabolic, developmental, immune, or other physiological or molecular mechanisms that are causally related to the development of autism, the committee concludes that the hypotheses generated to date are theoretical only."

Based on an exhaustive review of the scientific literature, the committee concludes:

"'Thus, based on this body of evidence, the committee concludes that the evidence favors rejection of a causal relationship between thimerosal-containing vaccines and autism.' [bold in original]"

This committee felt so strongly about this conclusion that they state:

"'The committee concludes that much more research must be conducted on autism. However, research should be directed towards those lines of inquiry most supported by the current state of knowledge. The vaccine hypotheses are not currently supported by the evidence.'"

Three large-scale controlled observational studies have been reported on this issue; none have found an association between thiomersal-containing vaccines (TCVs) and autism. A study from Denmark noted no decrease in autism rates despite cessation of TCVs and a UK study found that TCVs actually had a protective effect with respect to autism. Because the Danish and UK studies involved only diphtheria-tetanus-pertussis (DTP) or diphtheria-tetanus (DT) vaccines, they are less relevant for the higher thiomersal exposure levels that occurred in the U.S. For the U.S., a study based on the Vaccine Safety Datalink found no association between TCVs and autism. Some smaller studies have also found no association between TCVs and autism and a study found no association between thimerosal and the neurological signs of autism. Another smaller study also found a protective effect: it reported a significantly lower prevalence of autism spectrum disorders among children exposed to thimerosal (5.95 per 1,000 versus 8.27 per 1,000).

A 2008 study found that autism rates for children in California increased each quarter from January 1995 through March 2007, despite the removal of all but trace amounts of thimerosal from childhood vaccines since the 1999 national recommendation. The study analyzed data from the California Department of Developmental Services database, which had been systematically used by proponents of the thimerosal hypothesis to argue that the rising number of children accessing these services was linked to increased use of thimerosal in vaccines.

The research of Mark Geier, the main source of epidemiologic data used by supporters of a link between thiomersal and autism, has received considerable criticism, including charges of not presenting methods and statistical analyses to others for verification, improperly analyzing data taken from Vaccine Adverse Event Reporting System, as well as either mislabelling or confusing fundamental statistical terms in his papers.

Further evidence of the position of the scientific consensus includes the rejection of a causal link between thimerosal and autism by the main scientific and medical professional bodies including the American Medical Association, the American Academy of Pediatrics, the American College of Medical Toxicology, the National Academy of Sciences, the Food and Drug Administration, Centers for Disease Control and Prevention, the World Health Organization, the Public Health Agency of Canada, and the European Medicines Agency.

Effects of the controversy
In July 1999 the CDC and the AAP asked vaccine makers to remove thiomersal from vaccines as quickly as possible, and asked doctors to delay the birth dose of hepatitis B vaccine in children not at risk for hepatitis. The CDC and the AAP followed the precautionary principle, which assumes that there is no harm in exercising caution even if it later turns out to be unwarranted, but their action sparked confusion, controversy and some harm. About 10% of hospitals suspended the use of hepatitis B vaccine for all newborns, and one child born to a Michigan mother infected with hepatitis B virus died of it. The notion that thiomersal causes autism caused some parents to have their children treated with chelation therapy; about 10,000 autistic children in the U.S. receive mercury-chelating agents every year, and in August 2005 a 5-year-old autistic boy died from an arrhythmia caused by injection of the chelating agent EDTA. The notion has also diverted attention and resources away from efforts to determine the causes of autism.

Timeline

 * 1930s - first added to vaccines and other products as a bactericide.
 * Mid-1980s - used as a preservative in virtually all whole-cell DPT vaccines, which were routinely administered four times each to children before eighteen months of age, starting at two months.
 * Late 1980s - Hib vaccines are recommended for administration to children at eighteen months. They contain thiomersal.
 * Early 1990s - In the USA three doses of Hepatititis B vaccine (at that time containing Thiomersal) are recommended for infants under six months of age, beginning on the day of birth; four doses of Hib are recommended within an eighteen month period, beginning at age two.
 * Late 1990s - three of the vaccines included in Vaccination schedules for children between six and eighteen months of age contain thiomersal.
 * 1999 - The American Academy of Pediatrics requests removal of thiomersal from all pediatric vaccines.
 * 2001 - Thiomersal is no longer used in routine childhood vaccines in the U.S.
 * 2001 - The Institute of Medicine, citing insufficient evidence, is unable to prove or disprove any link between thiomersal and autism. However, they conclude that a causal connection between thiomersal and autism is "biologically plausible".
 * 2002 - The USA Centers for Disease Control (CDC) and the USA Food and Drug Administration (FDA) state that: although thiomersal was to be discontinued in some paediatric vaccines, they would not be recalling any unused stocks, as there is no proof that low doses of thiomersal is dangerous, and that the change was purely cautionary.
 * 2004 - The Institute of Medicine, based on new information from epidemiological studies undertaken since its 2001 report, rejects the hypothetical causative link between thiomersal and autism.
 * 2006 - Some vaccines provided by the World Health Organization for children in developing countries contain the same amounts of thiomersal as vaccines used previously for American children. Current vaccination schedules give these in a shorter time period.
 * 2006 - In the latest review by the WHO committee, the conclusion previously reached was reaffirmed that there is no evidence of toxicity in infants, children or adults exposed to thiomersal in vaccines.
 * 2007 - Theresa and Michael Cedillo, the parents of 12-year-old Michelle Cedillo asked a federal court Monday June 11, to find that their child's autism was caused by common childhood vaccines.
 * 2007 - Mike Enzi, the ranking member on the United States Senate Committee on Health, Education, Labor, and Pensions, issued a report assessing allegations about thimerosal and autism. The report substantiated allegations that there were shortcomings in the Institute of Medicine's conflict screening procedures, that thimerosal is used in third-world childhood vaccines, and that late-1990s EPA mercury guidelines were inappropriate for vaccines and caused many individuals to conclude that ethyl mercury can be linked to autism. Several other allegations were not substantiated.