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Thiomersal and vaccines

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The thiomersal controversy is between critics of vaccines, who allege that thiomersal-containing vaccines contribute to autism and other brain development disorders, and mainstream medical opinion, which is that no convincing scientific evidence supports the critics' claim.[1] Thiomersal, also spelled thimerosal, is an organomercury compound used in vaccines since the 1930s as a preservative to prevent contamination by bacteria and fungi.[2] Since the passage of the 1997 FDA Modernization Act and a subsequent review of mercury containing compounds, a number of critics of vaccines and autism advocacy groups have alleged thiomersal-containing vaccines contribute to, or cause, a range of neurodevelopmental disorders in children, most notably autism and related pervasive developmental disorders (PDDs),[3] or other cognitive disorders, including attention deficit hyperactivity disorder (ADHD).[4] Subsequently, over 4,800 lawsuits have been filed in the Omnibus Autism court to seek damages from alleged toxicity from vaccines, including those purportedly from thiomersal preservatives. [5] The scientific consensus, including scientific and medical professional bodies and governmental agencies such as the Food and Drug Administration,[2] Centers for Disease Control and Prevention,[6] and World Health Organization,[7] uniformly rejects the concept that exposure to thiomersal causes, or contributes to, autism.

Background of controversy

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. [8] 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." [9]

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. [2]

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 IOM committee concluded:

"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."[10]

Social and political background

During this period, the actions by the FDA prompted autism advocates, such as Lyn Redwood, to consider the possibility of thiomersal as a possible causative agent of autism beginning in 1999. The autism and vaccine critic communities began to support the concept that thiomersal is associated with autism based on the coinciding of increases in both the number of thiomersal-containing vaccines administered to newborns in the vaccination schedule and perceived autism incidence in the early 1990s. [11]

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"[4]

Those calling for more research into a potential connection between thimerosal and autism include people who are against all vaccinations but also people who believe in vaccinating but who believe that thimerosal in vaccines contributed to the increased rate of autism.[citation needed]

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.[2][12]
  • In vitro tests: cultured cells in laboratory show adverse effects when exposed to ethylmercury[13][14]
  • In vivo tests: experiments on animal models show wide range of adverse effects[15]
  • 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 the rest of us and that increasingly, the Amish do receive at least some vaccinations.[16]
  • Epidemiologic data: epidemiologic studies (all by Mark Geier) to examine population level correlation between thiomersal and autism[17]
  • Concern that mercury might have synergistic effects with other metals and toxicants.[18]

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.[19] 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.[20]

Scientific consensus on controversy

The scientific consensus is reflected in the 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."[This quote needs a citation]

Based on a 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."[This quote needs a citation] [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."[This quote needs a citation]

Thus, the committee feels money should be invested in other areas of autism research, as the vaccine-autism avenue of research does not appear promising[21]

Large-scale epidemiologic studies rejecting an autism-thiomersal link include a study from Denmark which notes no decrease in autism rates despite cessation of thiomersal containing vaccinations,[22] a study based on the Vaccine Safety Datalink which showed analysis of this dataset did not show an association between thiomersal and autism,[23] and a study from the UK which found that thiomersal containing vaccines actually had a protective effect with respect to autism,[24] in addition to some smaller studies finding no association.[25][26][27] Another smaller study also found the opposite result: 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).[28]

The research of Mark Geier, which is the main source of epidemiologic data used by supporters of a link between thiomersal and autism, has received considerable criticism in the past, including charges of not presenting methods and statistical analyses for others to be able to verify,[29] improperly analyzing data taken from Vaccine Adverse Event Reporting System,[29][21] as well as either mislabelling or confusing fundamental statistical terms in his papers.[21]

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,[30] the American Academy of Pediatrics,[31] the National Academy of Sciences,[21] the Food and Drug Administration,[2] Centers for Disease Control and Prevention,[6] the World Health Organization,[7] the Public Health Agency of Canada,[32] and the European Medicines Agency.[33]

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. In response, about 10% of hospitals suspended the use of the vaccine for all newborns. 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.[34]

Timeline

  • 1930s - first added to vaccines and other products as a bactericide.[35]
  • 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 - 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".[36]
  • 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.[36]
  • 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[citation needed] give these in a shorter time period.[citation needed]
  • 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.[37]
  • 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.

See also

References

  1. ^ Doja A, Roberts W (2006). "Immunizations and autism: a review of the literature". Can J Neurol Sci. 33 (4): 341–6. PMID 17168158.
  2. ^ a b c d e "Thimerosal in vaccines". Center for Biologics Evaluation and Research, U.S. Food and Drug Administration. 2007-09-06. Retrieved 2007-10-01. {{cite web}}: Check date values in: |date= (help)
  3. ^ http://www.mrc.ac.uk/consumption/idcplg?IdcService=GET_FILE&dID=4970&dDocName=MRC002394&allowInterrupt=1
  4. ^ a b "Mercury in Medicine Report". Congressional Record. 149: E1011–30. 2003.
  5. ^ US Courts of Federal Claims (2007-07-17). "Vaccine Program/Office of Special Masters Omnibus Autism Proceeding". Retrieved 2007-07-22.{{cite web}}: CS1 maint: year (link)
  6. ^ a b Centers for Disease Control (2007-01-08). "Mercury and Vaccines (Thimerosal)". Retrieved 2007-07-22.{{cite web}}: CS1 maint: year (link)
  7. ^ a b World Health Organization (2006-07-01). "Thiomersal and vaccines: questions and answers". Retrieved 2007-07-22.{{cite web}}: CS1 maint: year (link)
  8. ^ American Academy of Pediatrics (1999-09-01). "Joint Statement of the American Academy of Pediatrics and the US Public Health Service (USPHS)". Retrieved 2007-07-22.{{cite web}}: CS1 maint: year (link)
  9. ^ Ball LK, Ball R, Pratt RD (2001). "An assessment of thimerosal use in childhood vaccines". Pediatrics. 107 (5): 1147–54. PMID 11331700.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ^ Stratton, Kathleen (2001). Immunization Safety Review: Thimerosal - Containing Vaccines and Neurodevelopmental Disorders. The National Academies Press. ISBN 0-309-09008-3. {{cite book}}: Cite has empty unknown parameter: |month= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)National Academies Press
  11. ^ Testimony by Lyn Redwood (July 18, 2000). "Mercury in Medicine - Are We Taking Unnecessary Risks?". 106th Congress, Committee on Government Reform, Serial No. 106-232.{{cite journal}}: CS1 maint: year (link) http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=106_house_hearings&docid=f:72722.wais
  12. ^ Burbacher TM; et al. (2005). "Comparison of Blood and Brain Mercury Levels in Infant Monkeys Exposed to Methylmercury or Vaccines Containing Thimerosal". Environmental Health Perspectives. 113 (8): 1015–1021. PMID 16079072. {{cite journal}}: Explicit use of et al. in: |author= (help)http://www.ehponline.org/members/2005/7712/7712.html
  13. ^ James SJ; et al. (2005). "Thimerosal Neurotoxicity is Associated with Glutathione Depletion: Protection with Glutathione Precursors". NeuroToxicology. 26: 1–8. PMID 15527868. {{cite journal}}: Explicit use of et al. in: |author= (help); line feed character in |title= at position 44 (help)http://www.generationrescue.org/pdf/james.pdf
  14. ^ Baskin DS; et al. (2003). "Thimerosal induces DNA breaks, caspase-3 activation, membrane damage, and cell death in cultured human neurons and fibroblasts". Toxicological Sciences. 74 (2): 361–368. PMID 12773768. {{cite journal}}: Explicit use of et al. in: |author= (help)http://www.generationrescue.org/pdf/baskin.pdf
  15. ^ Ueha-Ishibashi T; et al. (2004). "Effect of thimerosal, a preservative in vaccines, on intracellular Ca(2+) concentration of rat cerebellar neurons". Toxicology. 195 (1): 77–84. PMID 14698570. {{cite journal}}: Explicit use of et al. in: |author= (help)
  16. ^ Olmsted D (2007-07-18). "The age of autism: the last word". UPI. Retrieved 2007-07-23.
  17. ^ Geier studies:
    • Geier DA, Geier MR (2006). "A meta-analysis epidemiological assessment of neurodevelopmental disorders following vaccines administered from 1994 through 2000 in the United States". Neuro Endocrinol Lett. 27 (4): 401–13. PMID 16807526.
    • Geier DA, Geier MR (2006). "An assessment of downward trends in neurodevelopmental disorders in the United States following removal of Thimerosal from childhood vaccines". Med Sci Monit. 12 (6): CR231–9. PMID 16733480.
    • Geier DA, Geier MR (2006). "An evaluation of the effects of thimerosal on neurodevelopmental disorders reported following DTP and Hib vaccines in comparison to DTPH vaccine in the United States". J Toxicol Environ Health A. 69 (15): 1481–95. PMID 16766480.
    • Geier DA, Geier MR (2006). "Early downward trends in neurodevelopmental disorders following removal of thimerosal-containing vaccines" (PDF). J Am Phys Surg. 11 (1): 8–13.
    • Geier DA, Geier MR (2007). "A prospective study of mercury toxicity biomarkers in autistic spectrum disorders". J Toxicol Environ Health A. 70 (20): 1723–30. doi:10.1080/15287390701457712. PMID 17885929.
  18. ^ Mutter J, Naumann J, Schneider R, Walach H, Haley B (2005). "Mercury and autism: accelerating evidence?" (PDF). Neuro Endocrinol Lett. 26 (5): 439–46. PMID 16264412. Retrieved 2007-08-15.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  19. ^ Institute for Vaccine Safety (2007-07-12). "Thimerosal Content in Some US Licensed Vaccines". Retrieved 2007-07-23.{{cite web}}: CS1 maint: year (link)
  20. ^ Food and Drug Administration (2004-09-09). "Mercury in Plasma-Derived Products". Retrieved 2007-07-23.{{cite web}}: CS1 maint: year (link)
  21. ^ a b c d Immunization Safety Review Committee (2004). Immunization Safety Review: Vaccines and Autism. The National Academies Press. ISBN 0-309-09237-X. {{cite book}}: Cite has empty unknown parameters: |coauthors= and |month= (help); line feed character in |title= at position 28 (help)National Academies Press
  22. ^ Hviid A, Stellfeld M, Wohlfahrt J, Melbye M (2003). "Association between thimerosal-containing vaccine and autism". JAMA. 290 (13): 1763–6. PMID 14519711.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  23. ^ Verstraeten T, Davis RL, DeStefano F; et al. (2003). "Safety of thimerosal-containing vaccines: a two-phased study of computerized health maintenance organization databases". Pediatrics. 112 (5): 1039–48. PMID 14595043. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  24. ^ Andrews N, Miller E, Grant A, Stowe J, Osborne V, Taylor B (2004). "Thimerosal exposure in infants and developmental disorders: a retrospective cohort study in the United kingdom does not support a causal association". Pediatrics. 114 (3): 584–91. doi:10.1542/peds.2003-1177-L. PMID 15342825.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  25. ^ Heron J, Golding J, ALSPAC Study Team (2004). "Thimerosal exposure in infants and developmental disorders: a prospective cohort study in the United kingdom does not support a causal association". Pediatrics. 114 (3): 577–83. doi:10.1542/peds.2003-1176-L. PMID 15342824.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  26. ^ Madsen KM, Lauritsen MB, Pedersen CB; et al. (2004). "Thimerosal and the occurrence of autism: negative ecological evidence from Danish population-based data". Pediatrics. 112 (3): 604–6. PMID 12949291. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  27. ^ Thompson WW, Price C, Goodson B; et al. (2007). "Early thimerosal exposure and neuropsychological outcomes at 7 to 10 years". N Engl J Med. 357 (13): 1281–92. PMID 17898097. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |laydate= ignored (help); Unknown parameter |laysource= ignored (help); Unknown parameter |laysummary= ignored (help)CS1 maint: multiple names: authors list (link)
  28. ^ Fombonne E, Zakarian R, Bennett A, Meng L, McLean-Heywood D (2006). "Pervasive developmental disorders in Montreal, Quebec, Canada: prevalence and links with immunizations". Pediatrics. 118 (1): e139–50. doi:10.1542/peds.2005-2993. PMID 16818529.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  29. ^ a b Parker SK, Schwartz B, Todd J, Pickering LK (2004). "Thimerosal-containing vaccines and autistic spectrum disorder: a critical review of published original data". Pediatrics. 114 (3): 793–804. doi:10.1542/peds.2004-0434. PMID 15342856. {{cite journal}}: Cite has empty unknown parameter: |1= (help)CS1 maint: multiple names: authors list (link) Erratum (2005) Pediatrics 115 (1), 200. doi:10.1542/peds.2004-2402. PMID 15630018.
  30. ^ American Medical Association (2004-05-18). "AMA Welcomes New IOM Report Rejecting Link Between Vaccines and Autism". Retrieved 2007-07-23.{{cite web}}: CS1 maint: year (link)
  31. ^ American Academy of Pediatrics (2004-05-18). "What Parents Should Know About Thimerosal". Retrieved 2007-07-23.{{cite web}}: CS1 maint: year (link)
  32. ^ National Advisory Committee on Immunization (2007). "Thimerosal: updated statement. An Advisory Committee Statement". Can Commun Dis Rep. 33 (ACS-6): 1–13. PMID 17663033.
  33. ^ European Medicines Agency (2004-03-24). "EMEA Public Statement on Thiomersal in Vaccines for Human Use" (PDF). Retrieved 2007-07-22.{{cite web}}: CS1 maint: year (link)
  34. ^ Offit PA (2007). "Thimerosal and vaccines—a cautionary tale". N Engl J Med. 357 (13): 1278–9.
  35. ^ "Mercury and vaccines (thimerosal)". Centers for Disease Control and Prevention. 2007-06-05. Retrieved 2007-10-01. {{cite web}}: Check date values in: |date= (help)
  36. ^ a b "Thimerosal in vaccines". Center for Biologics Evaluation and Research, U.S. Food and Drug Administration. 2007-09-06. Retrieved 2007-10-01. {{cite web}}: Check date values in: |date= (help)
  37. ^ Statement on thiomersal (World Health Organization, July 2006)
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