Thiomersal

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Thiomersal
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IUPAC name Ethyl(2-mercaptobenzoato-(2-)-O,S)
mercurate(1-) sodium
Other names Mercury((o-carboxyphenyl)thio)ethyl sodium salt
Identifiers
CAS number 54-64-8
EINECS number 200-210-4
RTECS number OV8400000
Properties
Molecular formula C9H9HgNaO2S
Molar mass 404.81 g/mol
Appearance White or slightly yellow powder
Density 500 kg/m³
Melting point

232–233°C (decomposition)

Solubility in water 1000 g/l (20°C)
Hazards
MSDS External MSDS
NFPA 704

NFPA 704.svg

1
3
1
 
R-phrases R26/27/28R33R50/53
S-phrases S13S28S36S45S60S61
Flash point 250°C
Except where noted otherwise, data are given for
materials in their standard state
(at 25 °C, 100 kPa)

Infobox disclaimer and references


Overview

Thiomersal (INN) (C9H9HgNaO2S), commonly known in the United States as thimerosal, is an organomercury compound (approximately 49% mercury by weight) used as an antiseptic and antifungal agent.

It was developed and registered under the trade name Merthiolate in 1928 by the pharmaceutical corporation Eli Lilly and Company and has been used as a preservative in vaccines, immunoglobulin preparations, skin test antigens, antivenins, ophthalmic and nasal products, and tattoo inks.

In the U.S., the European Union, and a few other affluent countries, the compound is being phased out from vaccines routinely given to children.[1] Packaging the vaccines in single-dose vials eliminates the need for bacteriostatics such as thiomersal.[2]

Use

Thiomersal's main use is as an antiseptic and antifungal agent. In multidose injectable drug delivery systems, it prevents serious adverse effects such as the Staphylococcus infection that, in one 1928 incident, killed 12 of 21 children inoculated with a diphtheria vaccine that lacked a preservative.[3] Unlike other vaccine preservatives used at the time, thiomersal does not reduce the potency of the vaccines that it protects.[4] Thiomersal is not needed in more-expensive single-dose injectables.

In the U.S., the European Union, and a few other affluent countries, thiomersal is no longer used as a preservative in routine childhood vaccination schedules.[1] In the U.S., the only exceptions among vaccines routinely recommended for children are some formulations of the inactivated influenza vaccine for children older than two years.[5] Several vaccines that are not routinely recommended for young children do contain thiomersal, including DT (diphtheria and tetanus), Td (tetanus and diphtheria), and TT (tetanus toxoid); other vaccines may contain a trace of thiomersal from steps in manufacture.[3] Also, four rarely used treatments for pit viper, coral snake, and black widow venom still contain thiomersal.[6] Outside North America and Europe, many vaccines contain thiomersal; the World Health Organization has concluded that there is no evidence of toxicity from thiomersal in vaccines and no reason on safety grounds to change to more-expensive single-dose administration.[7]

Toxicology

Thiomersal is very toxic by inhalation, ingestion, and in contact with skin (EC hazard symbol T+), with a danger of cumulative effects. It is also very toxic to aquatic organisms and may cause long-term adverse effects in aquatic environments (EC hazard symbol N).[8] In the body, it is metabolized or degraded to ethylmercury (C2H5Hg+) and thiosalicylate.[3]

Few studies of the toxicity of thiomersal in humans have been performed. Animal experiments suggest that thiomersal rapidly dissociates to release ethylmercury after injection; that the disposition patterns of mercury are similar to those after exposure to equivalent doses of ethylmercury chloride; and that the central nervous system and the kidneys are targets, with lack of motor coordination being a common sign. Similar signs and symptoms have been observed in accidental human poisonings. The mechanisms of toxic action are unknown. Fecal excretion accounts for most of the elimination from the body. Ethylmercury clears from blood with a half-time of about 18 days, and from the brain in about 14 days. Inorganic mercury metabolized from ethylmercury has a much longer clearance, at least 120 days; it appears to be much less toxic than the inorganic mercury produced from mercury vapor, for reasons that are not understood.[9]

Risk assessment for effects on the nervous system have been made by extrapolating from dose-response relationships for methylmercury, which is why thiomersal was removed from U.S. childhood vaccines, starting in 1999. However, since then, it has been found that ethylmercury is cleared from the body and the brain significantly faster than methylmercury, so the late-1990s risk assessments turned out to be overly conservative.[9] A 2008 study found that the half-life of blood mercury after vaccination averages 3.7 days for newborns and infants, much shorter than the 44 days for methylmercury.[10]

Allergies

Thiomersal is used in patch testing for people who have dermatitis, conjunctivitis, and other potentially allergic reactions. A 2007 study in Norway found that 1.9% of adults had a positive patch test reaction to thiomersal;[11] a higher prevalence of contact allergy (up to 6.6%) was observed in German populations.[12] Thiomersal-sensitive individuals can receive intramuscular rather than subcutaneous immunization,[13] so contact allergy is usually clinically irrelevant.[12] Thiomersal allergy has decreased in Denmark, probably because of its exclusion from vaccines there.[14]

Autism

Many parents, and some scientists and doctors, believe there is a connection between thiomersal and autism.[15] More than 5,000 U.S. families have filed claims alleging autism was caused by vaccines, most implicating thiomersal; the majority of these claims are still being adjudicated, and no awards have been issued.[15] Although there is no convincing evidence that thiomersal is a factor in the onset of autism, parents may first become aware of autistic symptoms in their child around the time of a routine vaccination, and parental concern about vaccines has led to a decreasing uptake of childhood immunizations and an increasing likelihood of measles outbreaks.[16]

History

Morris S. Kharasch, a chemist at the University of Maryland, filed a patent application for thiomersal in 1927;[17] Eli Lilly was granted the patent for the compound under the trade name Merthiolate in 1928.[4] In vitro tests conducted by Lilly investigators H.M. Powell and W.A. Jamieson found that it was forty to fifty times as effective as phenol against Staphylococcus aureus.[4] It was used to kill bacteria and prevent contamination in antiseptic ointments, creams, jellies, and sprays used by consumers and in hospitals, including nasal sprays, eye drops, contact lens solutions, immunoglobulins, and vaccines. Thiomersal was used as a preservative (bactericide) so that multidose vials of vaccines could be used instead of single-dose vials, which are more expensive. By 1938, Lilly's assistant director of research listed thiomersal as one of the five most important drugs ever developed by the company.[4]

Thiomersal's safety for its intended uses first came under question in the 1970s, when case reports demonstrated potential for neurotoxicity when given in large volumes as a topical antiseptic. At the time, the DPT vaccine was the only childhood vaccine that contained it; a 1976 FDA review concluded that this use of thiomersal was not dangerous.[4] Concerns about mercury arising from Minamata disease and other cases of methylmercury poisoning led U.S. authorities to lower reference doses for methylmercury in the 1990s, about the same time that autism diagnoses began rising sharply. In 1999, a new FDA analysis concluded that infants could receive as much as 187.5 mg of ethylmercury during the first six months; lacking any standard for ethylmercury, it used methylmercury-based standards to recommend that thiomersal be removed from routine childhood vaccines in the U.S., which was done by 2001.[4] Some parents of autistic children adopted thiomersal as an explanation for the increase in reported autism cases and sued vaccine makers; the mercury-autism hypothesis is accepted widely among parents of autistic children, despite scientific studies rejecting it.[4]

References

  1. 1.0 1.1 Bigham M, Copes R (2005). "Thiomersal in vaccines: balancing the risk of adverse effects with the risk of vaccine-preventable disease". Drug Saf. 28 (2): 89–101. PMID 15691220. 
  2. Thimerosal in Vaccines: Frequently Asked Questions, from the United States Food and Drug Administration. Accessed March 9 2008.
  3. 3.0 3.1 3.2 "Thimerosal in vaccines". Center for Biologics Evaluation and Research, U.S. Food and Drug Administration. 2007-09-06. Retrieved 2007-10-01. 
  4. 4.0 4.1 4.2 4.3 4.4 4.5 4.6 Baker JP (2008). "Mercury, vaccines, and autism: one controversy, three histories". Am J Public Health. 98 (2): 244–53. PMID 18172138. doi:10.2105/AJPH.2007.113159. 
  5. Coordinating Center for Infectious Diseases (2007-10-26). "Thimerosal in seasonal influenza vaccine". Centers for Disease Control and Prevention. Retrieved 2008-04-02. 
  6. "Mercury in plasma-derived products". U.S. Food and Drug Administration. 2004-09-09. Retrieved 2007-10-01. 
  7. Global Advisory Committee on Vaccine Safety (2006-07-14). "Thiomersal and vaccines". World Health Organization. Retrieved 2007-11-20. 
  8. "Thiomersal Ph Eur, BP, USP material safety data sheet" (PDF). Merck. 2005-06-12. Retrieved 2007-10-01. 
  9. 9.0 9.1 Toxicology of thiomersal:
  10. Pichichero ME, Gentile A, Giglio N; et al. (2008). "Mercury levels in newborns and infants after receipt of thimerosal-containing vaccines". Pediatrics. 121 (2): e208–14. PMID 18245396. doi:10.1542/peds.2006-3363. Lay summaryUniversity of Rochester Medical Center (2008-01-30). 
  11. Dotterud LK, Smith-Sivertsen T (2007). "Allergic contact sensitization in the general adult population: a population-based study from Northern Norway". Contact Dermatitis. 56 (1): 10–5. PMID 17177703. doi:10.1111/j.1600-0536.2007.00980.x. 
  12. 12.0 12.1 Uter W, Ludwig A, Balda BR (2004). "The prevalence of contact allergy differed between population-based and clinic-based data". J Clin Epidemiol. 57 (6): 627–32. PMID 15246132. doi:10.1016/j.jclinepi.2003.04.002. 
  13. Aberer W (1991). "Vaccination despite thimerosal sensitivity". Contact Dermatitis. 24 (1): 6–10. PMID 2044374. doi:10.1111/j.1600-0536.1991.tb01621.x. 
  14. Thyssen JP, Linneberg A, Menné T, Johansen JD (2007). "The epidemiology of contact allergy in the general population—prevalence and main findings". Contact Dermatitis. 57 (5): 287–99. PMID 17937743. doi:10.1111/j.1600-0536.2007.01220.x. 
  15. 15.0 15.1 Sugarman SD (2007). "Cases in vaccine court—legal battles over vaccines and autism". N Engl J Med. 357 (13): 1275–7. PMID 17898095. doi:10.1056/NEJMp078168. 
  16. Vaccines and autism:
    • "Thimerosal in vaccines". Center for Biologics Evaluation and Research, U.S. Food and Drug Administration. 2008-03-14. Retrieved 2008-03-21. 
    • Doja A, Roberts W (2006). "Immunizations and autism: a review of the literature". Can J Neurol Sci. 33 (4): 341–6. PMID 17168158. 
    • Taylor B (2006). "Vaccines and the changing epidemiology of autism". Child Care Health Dev. 32 (5): 511–9. PMID 16919130. doi:10.1111/j.1365-2214.2006.00655.x. 
  17. US patent 1672615

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