sodium ethylmercurithiosalicylate; Merthiolate
Status: used in a few vaccines and other products
Organizations involved:
Lilly, Eli & Co. – Manuf.; R&D; Tech.; World mark.; Former
Description: Thimerosal or sodium ethylmercurithio-sali-cylate is a mercury-containing organic compound (organomercurial) that has been used since about 1930 as an antimicrobial preservative in a number of biological and drug products, including many vaccines. Thimerosal effectively inhibits/-prevents bacterial and fungal growth, and is widely used as an preservative in aqueous biopharmaceutical and drug products, particularly those packaged in multiple use vials (needle repeated inserted to withdraw contents for injection), and in cosmetics and other products. [The only other antimicrobial preservatives used in currently approved vaccines are 2-phenoxyethanol with formaldehyde; 2-phenoxyethanol; phenol; and benzethonium chloride (Phemerol)].
With a formula of C8H9HgNaO3S2 and molecular weight of 404.82 Daltons, thimerosal is 49.6% mercury by weight. It is metabolized or degraded into ethylmercury, a highly toxic form of mercury, and thiosalicylate. Mercury is now widely considered a highly toxic heavy metal with cumulative toxicity, particularly neurotoxicity, for which any/all exposure, particularly in infants, should be eliminated. High levels of mercury in infants can cause serious neurological problems, and thimerosal in vaccines have been claimed to be linked to autism and other neurological adverse effects in vaccinated infants. Most of what is known about organomecury compound toxicity concerns methyl, rather than ethyl, mercury.
Since the 1930s, thimerosal use in vaccines has been shown effective for preventing infections from bacterial and fungal contamination of vaccines, particularly liquid vaccines packaged in multiple dose vials. Thimerosal is no longer widely used as a preservative and its use in vaccines and other injectables is being phased out, but it is still used in the manufacture of some vaccines (i.e,. used in manufacturing processes, leaving residual amounts, but not generally not added to the final formulated vaccine). Thimerosal in concentrations of 0.001% (1 part in 100,000) to 0.01% (1 part in 10,000) has been shown to be effective in clearing a broad spectrum of pathogens. A vaccine containing 0.01% thimerosal as a preservative contains 50 µg of thimerosal per 0.5 mL dose or ~25 micrograms of mercury per 0.5 mL dose.
As recently as a few years ago, the many vaccinations routinely received by infants during the first six months of life delivered 187.5 µg of mercury (as ethyl mercury). For example, in mid-1999, thimerosal was used at concentrations of 0.01% or less in over 30 vaccines marketed in the U.S., including many pediatric vaccines, and was used widely in other vaccines manufactured worldwide. Overall, U.S. pediatric vaccines reformulated without added thimerosal now deliver a maximum cumulative exposure during the first six months of life of less than 3 µg of mercury, a 98% reduction.
Thimerosal is highly effective, but is not a perfect preservative. In 1982, an FDA panel reported that thimerosal only prevents the growth of new bacteria, rather than killing all the organisms altogether. It reported mercury-based preservatives should be removed from topical products, and proposed that thimerosal was “not generally recognized as safe and effective.”
Nomenclature: thimerosal [BIO FDA]; Merthiolate [TR Lilly]; ethyl[2-mercaptobenzoato(2–)-O,-S]mercurate(1–) sodium [CAS]; [o-carboxyphenyl)thio]ethylmercury sodium salt [CAS]; sodium ethylmercurithiosalicylate [SY]
The term “trace” to describe levels of thimerosal is generally interpreted to mean 1 microgram (µg) of mercury per dose or less.
Companies.: Eli Lilly & Co. was developed thimerosal, including its use as a preservative in products other than vaccines. Thimerosal was originally developed in the 1920s by Eli Lilly primarily as an antiseptic. Lilly manufactured and marketed thimerosal from 1935-1974. Lilly continued to market thimerosal (Manufactured by other companies) in the U.S. until 1992. Since then, various manufacturers of pharmaceutical grade thimerosal continue to manufacture and market the product.
Lilly is the company most often associated with thimerosal-containing vaccine-related autism and related vaccine liability issues. As the original manufacturer and primary source for many decades, Lilly performed/sponsored the major toxicities studies supporting its safety and use. Lilly is now involved in a growing number of suits concerning thimerosal-related vaccine adverse effects. The company is not a target of suits claiming damage for non-thimerosal-associated vaccine adverse effects.
Status: Federal law [21 CFR 610.15(a)], requires, “Products in multi-dose containers shall contain a preservative, except that a preservative need not be added to Yellow Fever Vaccine; Polio-virus Vaccine, Live Oral; viral vaccine labeled for use with the jet injector; dried vaccines when the accompanying diluent contains a preservative; or to an Allergenic Product in 50 percent or more volume (v/v) glycerin.
The FDA maintains information about thimerosal, including charts presenting the current contents of marketed pediatric and adults vaccines, at http://www.fda.gov/cber/vaccine/thimerosal.htm.
As of April 2006, the only vaccines approved for pediatric use (≤6 years of age) and containing significant amounts of added thimerosal were: Fluzone influenza vaccine, 0.01% (12.5 µg/0.25 mL dose, 25 µg/0.5 mL dose), although a thimerosal-free formulation is available; and Fluvirin, 0.01% (25 µg/0.5 mL dose)
Issues regarding the safety of thimerosal in vaccines, its potential association as a cause of autism and serious neurological damage in infants, and related lawsuits have become complex and highly controversial and politicized in the U.S. and other countries. Thimerosal has been and is being removed as a vaccine preservative from many vaccines, not based upon evidence of harm, but rather as a precautionary measure at the request of governments, physicians, activists, and other groups. Much of the toxicity and concerns regarding thimerosal, which results in release of ethyl mercury, are extrapolated from methyl mercury. Methyl mercury stays in the body for some time, while ethyl mercury leaves the body more rapidly and does not accumulate over time to the extent of methyl mercury. While there is a considerable body of toxicological and other studies of methyl mercury clearly documenting its dangers, including neurotoxicity, relatively little is known about the toxicity of ethyl mercury. A University of Rochester Medical Center study reported that ethyl mercury has a half-life in the blood of about 7 days vs. methyl mercury with a half-life of 45 days, suggesting ethyl mercury exposure results in less body accumulation and toxicity. Also, some activists and those suing Eli Lilly allege that the company withheld and misrepresented toxicity studies for many decades showing thimerosal to pose a higher risk than presumed. Lilly is also accused of conducting human toxicity studies with thimerosal, now considered unethical, but a common practice at the time.
In 1997, as part of the FDA Modernization Act, Congress required the FDA to compile an inventory of mercury in all of its licensed drugs and vaccines. The FDA requested vaccine manufacturers supply information about their use of thimerosal in Dec. 1998 and April 1999. European and U.S. manufacturers and regulators met and agreed that thimerosal should be removed from vaccines. In July 1999, the CDC issued a joint statement with the American Academy of Pediatrics (AAP) noting that a safety margin is incorporated into the regulatory limits on vaccine-related mercury exposure, there is no evidence of any harm in children caused by the current level of exposure, and there have been no specific cases reported of mercury poisoning due to vaccines. However, following current vaccination guidelines, “some children could be exposed to a cumulative level of mercury over the first 6 months of life that exceeds one of the federal [Environmental Protection Agency] guidelines on methyl mercury.” The EPA guidelines were developed as guidelines for food consumption and other environment exposure/-intake of mercury, and were primarily based on methyl mercury toxicity.
In Oct. 2001, an Institute of Medicine, National Academy of Sciences, study concluded that administration to infants and children of vaccines containing thimerosal should be avoided, and that the link between thimerosal and autism and other developmental disorders was “biologically plausible,” but not proven. The report found insufficient evidence to either support or reject the association of thimerosal-containing vaccines with brain damage in children. The linkage is considered possible, since high doses of thimerosal are known to be neurotoxic, and a small percentage of the population might be hypersensitive to the adverse effects of mercury. Although long-used in vaccines, there has been relatively little study of the toxicity of thimerosal, and like other studies of thimerosal’s safety, the reviewers extrapolated assessments from studies of the environmental pollutant methyl mercury.
The rapid removal of thimerosal from U.S. pediatric vaccines further damaged public perceptions of the risk-benefits of vaccines, giving the impression of a substantial, validated health hazard.
A study published in the Nov. 30, 2002 issue of Lancet reported that mercury levels in infants who received thimerosal-containing vaccines were well within federal safety limits, and that infants excrete mercury at a much faster rate than previously believed. Most infants studied had blood mercury levels below 2 nanograms/mL after vaccinations, and the highest level in one infant was 4.11 ng/ml. (while the EPA safety limit is 5.9 nanograms/mL).
Some parents of autistic children assert that thimerosal in pediatric vaccines has caused autism in their children, and have filed lawsuits against vaccine companies, Lilly (developer and former manufacturer of thimerosal) and the federal government. By the end of 2002, 800 or more families in over a dozen states had filed lawsuits seeking compensation for autism in children allegedly due to thimerosal in pediatric vaccines. About 200 or more cases included Lilly as a dependent. The federal vaccine court expects an eventual 3,000 to 5,000 filings for damages claiming autism due to thimerosal/vaccines.
On Nov. 25, 2002, the Homeland Security Act (HSA; P.L. 107-296) was signed into law. Included in this major legislation were several paragraphs restricting damages due to thimerosal. Vaccine ingredients were essentially defined as including in the definition of “vaccine.” This provision was added by Republican Senator Frist (became Majority Leader) as part of a post-September 11, 2001 motivated effort to help keep the U.S. vaccine industry viable (with the vaccine industry composed of just a few remaining manufacturers operating on low profit margins and increasingly the target of costly lawsuits). The HSA requires processing of thimerosal-related claims through the National Vaccine Injury Compensation Program (see the Vaccine Products entry #400) before cases can be filed in civil (state) courts. This will severely restrict parents’ chances of prosecuting and winning thimerosal-related cases in civil courts, and will severely restrict monetary awards to parents of autistic children, with the federal program’s compensation for pain, suffering and even death limited to $250,000 (while state court jury awards have generally been in the millions). The Department of Justice also filed a motion to restrict the use and disclosure of information gathered in the federal program’s “vaccine court,” so it can not be used in civil court cases. On Dec. 19, 2002, the Dept. of Justice withdraw its motion to the U.S. Court of Federal Claims Office of Special Master to seal all documents related to present thimerosal-autism claims.
A major problem for parents asserting autism due to thimerosal in vaccines is that autism often is diagnosed three or more years after vaccinations, a period after the 3-year time limit (statute of limitation) for which claims can be filed with the federal compensation program. By the end of 2002, all thimerosal-related cases filed with the federal program had been put on hold to allow further study of links between vaccines and autism. Many issues concerning trial discovery, access, and dissemination of court, government agency, and corporate documents arising from ongoing litigation have not been resolved (how much and what information will plaintiffs and the public have access to).
A study published in the Oct. 1, 2003 Journal of the American Medical Association reported finding no causal relationship between childhood vaccination with thimerosal-preserved vaccines and autistic disorder, examining 440 autism cases and 787 autistic-related disorders among 2,986,654 person-years.
In May 2004, the eighth and final report of the Immunization Safety Review Committee of the Institute of Medicine (IOM) was published concerning published and unpublished epidemiological studies regarding causality, and studies of potential biological mechanisms by which these thimerosal-containing vaccines might cause autism. The committee concluded that the body of epidemiological evidence favors rejection of a causal relationship between the thimerosal-containing vaccines and autism; and that potential biological mechanisms for vaccine-induced autism that have been generated to date are theoretical only. The Centers for Disease Control and Prevention (CDC) plans a more robust study to fully understand the reasons behind the rise in autism in the 1990s.
The World Health Organization continues to endorse the use of thimerosal as a vaccine preservative.
In Sept. 2004, a law was enacted in California that restricts the mercury content in vaccines for expectant mothers and children under three years as of July 2006. The law bans vaccines with more than trace levels of thimerosal. With essentially all vaccines reformulated in recent years, this only affects influenza vaccine from Sanofi Aventis Inc., the only influenza vaccine specifically approved for children under two years of age.
In April 2005, “Evidence of Harm: Mercury in Vaccines and the Autism Epidemic: A Medical Controversy” by David Kirby, yet another book highly critical of vaccines and thimerosal in particular, was published by St. Martin’s Press with much publicity/hype.
In the April 2005 issue of Environmental Health Perspectives, a primate study reported that ethylmercury may (or may not, depending on interpretation) be more toxic in the brain/nervous system than methylmercury. Injected thimerosal reacted differently from methylmercury, clearing from infants monkeys’ blood much more quickly, but ethylmercury was shown to cross the blood-brain barrier and enter the brain at a quicker rate than methylmercury.
In Aug. 2006, the State of California banned administration of thimerosal-containing vaccines to children under age three and to pregnant women. An exception was made for Japanese encephalitis virus vaccine. The new law also allows for exceptions when no other alternatives are available and during public health emergencies.
In Oct. 2006, FDA rejected a petition filed by the Coalition for Mercury-free Drugs in 2004 calling for the restrictions on thimerosal due to linkage to autism. A spokesman noted, “Only a small number of licensed and approved products still contain thimerosal, and the available evidence supports FDA’s conclusion that all currently licensed vaccines and other pharmaceutical drug products containing thimerosal are safe.”
In spring 2007, the federal vaccine court (see the Vaccine Products entry, #400) began deliberations concerning damages claiming autism development in infants/children due to thimerosal/vaccines. While the scientific and medical communities’ consensus is that thimerosal and vaccines are not linked to autism, this court only requires a likely, i.e,. presumed greater than 50% probability, of linkage in order to award damages.
Tech. transfer: Eli Lilly & Co. discovered and developed the vaccine and other preservative uses of thimerosal. It holds patents including U.S. 2,864,844 (long expired). It has been reported that licensing agreements with current manufacturers worldwide provide Lilly with royalties until at least 2010, another reason why thimerosal-related lawsuits are targeting Lilly.
Companies involvement:
Full monograph
939 Thimerosal Preservative
Nomenclature:
thimerosal [BIO FDA]
Merthiolate [TR Lilly]
ethyl[2-mercaptobenzoato(2–)-O,-S]mercurate(1–) sodium [CAS]
[o-carboxyphenyl)thi]ethylmercury sodium salt [CAS]
mercury-based preservative [SY]
sodium ethylmercurithiosalicylate [SY]
Year of approval (FDA) = 1935
Date of 1st FDA approval = 19350000
(in format YYYYMMDD)
Index Terms:
non-Hodgkin's lymphoma (NHL)
PrefGel
ethyl mercury
meningitis prophylaxis
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
North American coral snake
North American coral snake
EU200 Currently Approved in EU
UM999 Not Available/Not Marketed in US
US200 Currently Approved in US
EM999 Not Available/Not Marketed in EU
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