Thiomersal

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Thiomersal
Thiomersal.svg
Thiomersal-from-xtal-3D-balls.png
Names
IUPAC name
Ethyl(2-mercaptobenzoato-(2-)-O,S) mercurate(1-) sodium
Other names
Mercury((o-carboxyphenyl)thio)ethyl sodium salt, sodium ethylmercurithiosalicylate
Identifiers
3D model (JSmol)
8169555
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.000.192 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 200-210-4
1677155
KEGG
PubChem CID
RTECS number
  • OV8400000
UNII
  • InChI=1S/C7H6O2S.C2H5.Hg.Na/c8-7(9)5-3-1-2-4-6(5)10;1-2;;/h1-4,10H,(H,8,9);1H2,2H3;;/q;;2*+1/p-2 Yes check.svgY
    Key: RTKIYNMVFMVABJ-UHFFFAOYSA-L Yes check.svgY
  • InChI=1/C7H6O2S.C2H5.Hg.Na/c8-7(9)5-3-1-2-4-6(5)10;1-2;;/h1-4,10H,(H,8,9);1H2,2H3;;/q;;2*+1/p-2/rC9H10HgO2S.Na/c1-2-10-13-8-6-4-3-5-7(8)9(11)12;/h3-6H,2H2,1H3,(H,11,12);/q;+1/p-1
    Key: RTKIYNMVFMVABJ-TYXNQWANAP
  • [Na+].[O-]C(=O)c1ccccc1S[Hg]CC
Properties
C 9 H 9 Hg Na O 2 S
Molar mass 404.81 g/mol
AppearanceWhite or slightly yellow powder
Density 2.508 g/cm3 [1]
Melting point 232 to 233 °C (450 to 451 °F; 505 to 506 K) (decomposition)
1000 g/L (20 °C)
Pharmacology
D08AK06 ( WHO )
Hazards
GHS labelling:
GHS-pictogram-skull.svg GHS-pictogram-silhouette.svg GHS-pictogram-pollu.svg
Danger
H300, H310, H330, H373, H410
P260, P273, P280, P301, P302, P304, P310, P330, P340, P352 [2]
NFPA 704 (fire diamond)
NFPA 704.svgHealth 3: Short exposure could cause serious temporary or residual injury. E.g. chlorine gasFlammability 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g. canola oilInstability 1: Normally stable, but can become unstable at elevated temperatures and pressures. E.g. calciumSpecial hazards (white): no code
3
1
1
Flash point 250 °C (482 °F; 523 K)
Lethal dose or concentration (LD, LC):
75 mg/kg (oral, rat) [3]
Safety data sheet (SDS) External MSDS
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

Thiomersal (INN), or thimerosal (USAN, JAN), also sold under the name merthiolate [4] is an organomercury compound. It is a well-established antiseptic and antifungal agent. [5]

The pharmaceutical corporation Eli Lilly and Company named it Merthiolate. It has been used as a preservative in vaccines, immunoglobulin preparations, skin test antigens, antivenins, ophthalmic and nasal products, and tattoo inks. [6] In spite of the scientific consensus that fears about its safety are unsubstantiated, [7] [8] [9] [10] its use as a vaccine preservative has been called into question by anti-vaccination groups.

A 1999 statement issued in CDC's Morbidity and Mortality Weekly Report announced that "the Public Health Service (PHS), the American Academy of Pediatrics (AAP), and vaccine manufacturers agree that thimerosal-containing vaccines should be removed as soon as possible" and that these groups would collaborate to replace them while manufacturers committed "to eliminate or reduce as expeditiously as possible the mercury content of their vaccines." [11] [12] [13]

It remains in use as a preservative for certain annual flu vaccines, mostly those stored in multi-dose vials. [14] [15]

History

Morris Kharasch, a chemist then at the University of Maryland filed a patent application for thiomersal in 1927; [16] Eli Lilly later marketed the compound under the trade name Merthiolate. [17] 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 . [17] 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. [17]

Structure

Thiomersal features mercury(II) with a coordination number 2, i.e. two ligands are attached to Hg, the thiolate and the ethyl group. The carboxylate group confers solubility in water. Like other two-coordinate Hg(II) compounds, the coordination geometry of Hg is linear, with a 180° S-Hg-C angle. Typically, organomercury thiolate compounds are prepared from organomercury chlorides. [1]

Uses

Antiseptic/antifungal

Thiomersal's main use is as an antiseptic and antifungal agent, due to its oligodynamic effect. 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 vaccinated with a diphtheria vaccine that lacked a preservative. [18] Unlike other preservatives at the time, such as phenol and cresol, thiomersal does not reduce the potency of the vaccines that it protects. [17] Bacteriostatics such as thiomersal are not needed in single-dose injectables. [19]

In the United States, the European Union, and a few other affluent countries, thiomersal is no longer used as a preservative in routine childhood vaccination schedules. [13] In the U.S., all vaccines routinely recommended for children 6 years of age and younger are available in formulations that do not contain thimerosal. Two vaccines (a TD and the single-dose version of the trivalent influenza vaccine Fluvirin) that may contain a trace of thiomersal from steps in manufacture, but less than 1 microgram of mercury per dose. [18] The multi-dose versions of some trivalent and quadrivalent influenza vaccines can contain up to 25 micrograms of mercury per dose from thiomersal. Also, four rarely used treatments for pit viper, coral snake, and black widow venom contain thiomersal. [20]

Outside North America and Europe, many vaccines contain thiomersal; the World Health Organization reported no evidence of toxicity from thiomersal in vaccines and no reason on safety grounds to change to more expensive single-dose administration. [21] The United Nations Environment Program backed away from an earlier proposal of putting thiomersal on the list of banned vaccine compounds as part of its campaign to reduce mercury exposure. [22] It stated that eliminating it in multi-dose vaccines, primarily used in developing countries, would lead to high cost and a refrigeration requirement that developing countries could ill afford. At the Minamata Convention on Mercury in 2013 thiomersal was excluded from the treaty. [23]

Toxicology

General toxicity

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). [24]

In the body, it is metabolized or degraded to ethylmercury (C2H5Hg+) and thiosalicylate. [18]

Cases have been reported of severe mercury poisoning by accidental exposure or attempted suicide, with some fatalities. [25] Animal experiments suggest that thiomersal rapidly dissociates to release ethylmercury after injection; that mercury's disposition patterns are similar to those after exposure to equivalent doses of ethylmercury chloride; and that the central nervous system and the kidneys are targets. Loss of motor coordination is a common sign. Similar signs and symptoms have been observed in accidental human poisonings. The mechanisms of toxic action are unknown. [25]

Fecal excretion accounts for most of the elimination from the body. Ethylmercury clears from blood with a half-life of about 18 days in adults by breakdown into other chemicals, including inorganic mercury. [26] The half-life of ethylmercury in the brains of infant monkeys is 14 days. [27] Risk assessment for effects on the nervous system have been made by extrapolating from dose-response relationships for methylmercury. [27] Methylmercury and ethylmercury distribute to all body tissues, crossing the blood–brain barrier and the placental barrier, and ethylmercury also moves freely throughout the body. [28]

Concerns based on extrapolations from methylmercury caused thiomersal to be removed from U.S. childhood vaccines, starting in 1999. Later it was reported that ethylmercury is eliminated from the body and the brain significantly faster than methylmercury, so the late-1990s risk assessments turned out to be overly conservative. [27] Though inorganic mercury metabolized from ethylmercury has a much longer half-life in the brain, at least 120 days, it appears to be much less toxic than the inorganic mercury produced from mercury vapor, for reasons not yet understood. [27]

As an allergen

Patch test Epikutanni-test.jpg
Patch test

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; [29] a higher prevalence of contact allergy (up to 6.6%) was observed in German populations. [30] Thiomersal-sensitive individuals can receive intramuscular rather than subcutaneous immunization, [31] though there have been no large sample sized studies regarding this matter to date. In real-world practice on vaccination of adult populations, contact allergy does not seem to elicit clinical reaction. [30]

Thiomersal allergy has decreased in Denmark, probably because of its exclusion from vaccines there. [32] In a recent study of Polish children and adolescents with chronic/recurrent eczema, positive reactions to thiomersal were found in 11.7% of children (7–8 y.o.) and 37.6% of adolescents (16–17 y.o.). This difference in the sensitization rates can be explained by changing exposure patterns: The adolescents received six thiomersal-preserved vaccines during their life course, with the last immunization taking place 2–3 years before the study. Younger children received only four thiomersal-preserved vaccines, with the last one applied five years before the study, while further immunizations were performed with thiomersal-free vaccines. [33]

Removal from vaccines

The Center for Biologics Evaluation and Research (CBER) at the FDA initiated a formal risk assessment of thiomersal in vaccines beginning in 1998. [34] After determining the levels of ethylmercury exposure from the currently recommended vaccine schedule, the CBER found these amounts exceeded new standards for methylmercury exposure recently established by the Environmental Protection Agency. [17] On July 7, 1999, both the American Academy of Pediatrics and the US Public Health Service issued a statement calling for the removal of thiomersal-containing vaccines “as expeditiously as possible.” [35] [36] By March 2001, thiomersal-free versions of all the recommended childhood vaccines for children up to age 6 were available in the United States following the introduction of the new DtAP vaccine. [34]

Disproven autism hypothesis

Following the phasing out of thiomersal from most U.S. and European vaccines, [17] [37] some parents saw the action to remove thiomersal—in the setting of a perceived increasing rate of autism as well as increasing number of vaccines in the childhood vaccination schedule—as indicating that the preservative was the cause of autism. [17] The scientific consensus is that no evidence supports these claims, while the rate of autism continued to climb in children who did not take the thiomersal-preserved childhood vaccines. [9] [38] [39] [7]

Scientific and medical bodies such as the Institute of Medicine [7] and World Health Organization, [40] [41] as well as governmental agencies such as the Food and Drug Administration [18] and the CDC [42] reject any role for thiomersal in autism or other neurodevelopmental disorders. [43] Unconvinced parents attempted to treat their autistic children with unproven and possibly dangerous treatments, and refused to vaccinate them due to fears about thiomersal toxicity. [44] Studying thiomersal potentially diverts resources away from research into more promising areas for autism. [45] Thousands of lawsuits have been filed in U.S. federal court to seek damages from allegedly toxic vaccines, including those purportedly caused by thiomersal. [46]

See also

Related Research Articles

<span class="mw-page-title-main">Vaccination</span> Administration of a vaccine to protect against disease

Vaccination is the administration of a vaccine to help the immune system develop immunity from a disease. Vaccines contain a microorganism or virus in a weakened, live or killed state, or proteins or toxins from the organism. In stimulating the body's adaptive immunity, they help prevent sickness from an infectious disease. When a sufficiently large percentage of a population has been vaccinated, herd immunity results. Herd immunity protects those who may be immunocompromised and cannot get a vaccine because even a weakened version would harm them. The effectiveness of vaccination has been widely studied and verified. Vaccination is the most effective method of preventing infectious diseases; widespread immunity due to vaccination is largely responsible for the worldwide eradication of smallpox and the elimination of diseases such as polio and tetanus from much of the world. However, some diseases, such as measles outbreaks in America, have seen rising cases due to relatively low vaccination rates in the 2010s – attributed, in part, to vaccine hesitancy. According to the World Health Organization, vaccination prevents 3.5–5 million deaths per year.

<span class="mw-page-title-main">Vaccine</span> Pathogen-derived preparation that provides acquired immunity to an infectious disease

A vaccine is a biological preparation that provides active acquired immunity to a particular infectious or malignant disease. The safety and effectiveness of vaccines has been widely studied and verified. A vaccine typically contains an agent that resembles a disease-causing microorganism and is often made from weakened or killed forms of the microbe, its toxins, or one of its surface proteins. The agent stimulates the body's immune system to recognize the agent as a threat, destroy it, and recognize further and destroy any of the microorganisms associated with that agent that it may encounter in the future.

<span class="mw-page-title-main">Mercury poisoning</span> Poisoning caused by mercury chemicals

Mercury poisoning is a type of metal poisoning due to exposure to mercury. Symptoms depend upon the type, dose, method, and duration of exposure. They may include muscle weakness, poor coordination, numbness in the hands and feet, skin rashes, anxiety, memory problems, trouble speaking, trouble hearing, or trouble seeing. High-level exposure to methylmercury is known as Minamata disease. Methylmercury exposure in children may result in acrodynia in which the skin becomes pink and peels. Long-term complications may include kidney problems and decreased intelligence. The effects of long-term low-dose exposure to methylmercury are unclear.

Ethylmercury (sometimes ethyl mercury) is a cation composed of an organic CH3CH2— species (an ethyl group) bound to a mercury(II) centre, making it a type of organometallic cation, and giving it a chemical formula C2H5Hg+. The main source of ethylmercury is thimerosal.

The 2000 Simpsonwood CDC conference was a two-day meeting convened in June 2000 by the Centers for Disease Control and Prevention (CDC), held at the Simpsonwood Methodist retreat and conference center in Norcross, Georgia. The key event at the conference was the presentation of data from the Vaccine Safety Datalink examining the possibility of a link between the mercury compound thimerosol in vaccines and neurological problems in children who had received those vaccines.

<span class="mw-page-title-main">Richard Deth</span>

Richard Carlton Deth is an American neuropharmacologist, a former professor of pharmacology at Northeastern University in Boston, Massachusetts, and is on the scientific advisory board of the National Autism Association. Deth has published scientific studies on the role of D4 dopamine receptors in psychiatric disorders, as well as the book, Molecular Origins of Human Attention: The Dopamine-Folate Connection. He has also become a prominent voice in the controversies in autism and thiomersal and vaccines, due to his hypothesis that certain children are more at risk than others because they lack the normal ability to excrete neurotoxic metals.

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<span class="mw-page-title-main">Mersalyl</span> Organomercury compound once used diuretic

Mersalyl (Mersal) is an organomercury compound and mercurial diuretic. It is only rarely used as a drug, having been superseded by thiazides and loop diuretics that are less toxic because they do not contain mercury. It features a Hg(II) centre. Mersalyl was originally adapted from calomel (Hg2Cl2), a diuretic discovered by Paracelsus.

<span class="mw-page-title-main">Organomercury chemistry</span> Group of chemical compounds containing mercury

Organomercury chemistry refers to the study of organometallic compounds that contain mercury. Typically the Hg–C bond is stable toward air and moisture but sensitive to light. Important organomercury compounds are the methylmercury(II) cation, CH3Hg+; ethylmercury(II) cation, C2H5Hg+; dimethylmercury, (CH3)2Hg, diethylmercury and merbromin ("Mercurochrome"). Thiomersal is used as a preservative for vaccines and intravenous drugs.

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References

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  30. 1 2 Uter W, Ludwig A, Balda BR, Schnuch A, Pfahlberg A, Schäfer T, et al. (June 2004). "The prevalence of contact allergy differed between population-based and clinic-based data". Journal of Clinical Epidemiology. 57 (6): 627–632. doi:10.1016/j.jclinepi.2003.04.002. PMID   15246132.
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  34. 1 2 Institute of Medicine (US) Immunization Safety Review Committee (2001). "Thimerosal-Containing Vaccines and Neurodevelopmental Disorders". In Stratton K, Gable A, McCormick MC (eds.). Immunization Safety Review: Thimerosal-Containing Vaccines and Neurodevelopmental Disorders. Washington (DC): National Academies Press (US).
  35. ↑ "AAP and PHS Urge Reduction of Mercury in Vaccines". Public Health Reports. 114 (5): 394–395. 1999. doi:10.1093/phr/114.5.394 (inactive 1 November 2024). PMC   1308509 .{{cite journal}}: CS1 maint: DOI inactive as of November 2024 (link)
  36. ↑ Centers for Disease Control and Prevention (CDC) (July 1999). "Thimerosal in vaccines: a joint statement of the American Academy of Pediatrics and the Public Health Service". MMWR. Morbidity and Mortality Weekly Report. 48 (26): 563–565. PMID   10418806.
  37. ↑ "Thimerosal in vaccines: frequently asked questions (FAQs)". Center for Biologics Evaluation and Research, U.S. Food and Drug Administration. 7 June 2007. Retrieved 22 July 2008.
  38. ↑ DeStefano F (December 2007). "Vaccines and autism: evidence does not support a causal association". Clinical Pharmacology and Therapeutics. 82 (6): 756–759. doi:10.1038/sj.clpt.6100407. PMID   17928818. S2CID   12872702.
  39. ↑ Doja A, Roberts W (November 2006). "Immunizations and autism: a review of the literature". The Canadian Journal of Neurological Sciences. Le Journal Canadien des Sciences Neurologiques. 33 (4): 341–346. doi: 10.1017/s031716710000528x . PMID   17168158.
  40. ↑ World Health Organization (2006). "Thiomersal and vaccines: questions and answers". Archived from the original on 12 October 2003. Retrieved 19 May 2009.
  41. ↑ WHO. "Statement on thiomersal". www.who.int. Archived from the original on 29 October 2012. Retrieved 3 April 2018.
  42. ↑ Centers for Disease Control (8 February 2008). "Mercury and vaccines (thimerosal)". Archived from the original on 18 April 2018. Retrieved 19 May 2009.
  43. ↑ Sugarman SD (September 2007). "Cases in vaccine court--legal battles over vaccines and autism". The New England Journal of Medicine. 357 (13): 1275–1277. doi: 10.1056/NEJMp078168 . PMID   17898095.
  44. ↑ Harris G, O'Connor A (25 June 2005). "On autism's cause, it's parents vs. research". New York Times. Retrieved 11 March 2016.
  45. ↑ Offit PA (September 2007). "Thimerosal and vaccines--a cautionary tale". The New England Journal of Medicine. 357 (13): 1278–1279. doi: 10.1056/NEJMp078187 . PMID   17898096.
  46. ↑ Autism cases in vaccine court:
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