Thiomersal

Thiomersal
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 Y
ChemSpider	10772045 Y
UNII	2225PI3MOV Y
EC number	200-210-4
ChEBI	CHEBI:9546 N
ChEMBL	CHEMBL508338 Y
RTECS number	OV8400000
Jmol-3D images	Image 1
SMILES [Na+].[O-]C(=O)c1ccccc1S[Hg]CC
InChI 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 Y Key: RTKIYNMVFMVABJ-UHFFFAOYSA-L Y 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
Properties
Molecular formula	C9H9HgNaO2S
Molar mass	404.81 g/mol
Appearance	White or slightly yellow powder
Density	2.508 g/cm³[1]
Melting point	232–233°C (decomposition)
Solubility in water	1000 g/l (20°C)
Hazards
MSDS	External MSDS
EU classification	Very toxic (T+) Dangerous for the environment (N) Repr. Cat. 1
R-phrases	R26/27/28 R33 R50/53
S-phrases	S13 S28 S36 S45 S60 S61
NFPA 704	1 3 1
Flash point	250°C
N (verify) (what is: Y/N?) Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

Thiomersal (INN), and commonly known in the US as thimerosal, is an organomercury compound. This compound is a well established antiseptic and antifungal agent.

The pharmaceutical corporation Eli Lilly and Company gave thiomersal the trade name Merthiolate and it has been used as a preservative in vaccines, immunoglobulin preparations, skin test antigens, antivenins, ophthalmic and nasal products, and tattoo inks. Its use as a vaccine preservative is controversial, and it is being phased out from routine childhood vaccines in the United States, the European Union, and a few other countries.^[2]

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 is not coordinated, but confers solubility in water. Like other two-coordinate Hg(II) compounds, the coordination geometry is linear, with a 180° S-Hg-C angle. Typically, organomercury thiolate compounds are prepared from organomercury chlorides.^[1]

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] Bacteriostatics like thiomersal are not needed in more-expensive single-dose injectables.^[5]

In the United States, countries in the European Union and a few other affluent countries, thiomersal is no longer used as a preservative in routine childhood vaccination schedules.^[2] 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.^[6] 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.^[7] 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.^[8]

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).^[9] 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. Cases have been reported of severe poisoning by accidental exposure or attempted suicide, with some fatalities.^[10] 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-life of about 18 days in adults. Ethylmercury is eliminated from the brain in about 14 days in infant monkeys. Inorganic mercury metabolized from ethylmercury has a much longer half-life, at least 120 days; though it appears to be much less toxic than the inorganic mercury produced from mercury vapor, for reasons not yet understood.^[11]

Risk assessment for effects on the nervous system have been made by extrapolating from dose-response relationships for methylmercury.^[11] Methylmercury and ethylmercury distributes to all body tissues, crossing the blood-brain barrier and the placental barrier, and ethylmercury also moves freely throughout the body.^[12] Concerns based on extrapolations from methylmercury caused thiomersal to be removed from U.S. childhood vaccines, starting in 1999. Since then, it has been found 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.^[11]

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;^[13] a higher prevalence of contact allergy (up to 6.6%) was observed in German populations.^[14] Thiomersal-sensitive individuals can receive intramuscular rather than subcutaneous immunization,^[15] so contact allergy is usually clinically irrelevant.^[14] Thiomersal allergy has decreased in Denmark, probably because of its exclusion from vaccines there.^[16] 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 have received six thiomersal-preserved vaccines during their life course, with the last immunization taking place 2–3 years before the mentioned study, younger children received only four thiomersal-preserved vaccines, with the last one applied 5 years before the study, while further immunizations were performed with new thiomersal-free vaccines.^[17]

Autism

Main article: Thiomersal controversy

Following a review of mercury-containing food and drugs mandated in 1999, the Centers for Disease Control (CDC) and the American Academy of Pediatrics asked vaccine manufacturers to remove thiomersal from vaccines as a purely precautionary measure, and it was rapidly phased out of most U.S. and European vaccines.^[4][18] Many parents took 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.^[4] The current scientific consensus is that no convincing scientific evidence supports these claims, based on various lines of evidence including the observation that the rate of autism continues to climb despite elimination of thiomersal from routine childhood vaccines.^[19][20][21] Major scientific and medical bodies such as the Institute of Medicine^[21] and World Health Organization^[22] as well as governmental agencies such as the Food and Drug Administration^[3] and the CDC^[23] reject any role for thiomersal in autism or other neurodevelopmental disorders.^[24] This controversy has caused harm due to parents attempting to treat their autistic children with unproven and possibly dangerous treatments, discouraging parents from vaccinating their children due to fears about thiomersal toxicity^[25] and diverting resources away from research into more promising areas for the cause of autism.^[26] Thousands of lawsuits have been filed in a U.S. federal court to seek damages from alleged toxicity from vaccines, including those purportedly caused by thiomersal.^[27]

History

Morris Kharasch, a chemist at the University of Maryland, filed a patent application for thiomersal in 1927;^[28] Eli Lilly later marketed the compound under the trade name Merthiolate.^[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]

See also

• Mercury (element)
• Nitromersol, a related antimicrobial

References

1. ^ ^{a b} Melnick, J. G.; Yurkerwich, K.; Buccella, D.; Sattler, W.; Parkin, G. (2008). "Molecular Structures of Thimerosal (Merthiolate) and Other Arylthiolate Mercury Alkyl Compounds". Inorg. Chem. 47 (14): 6421–6426. doi:10.1021/ic8005426. PMID 18533648. 
2. ^ ^{a b} 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. doi:10.2165/00002018-200528020-00001. PMID 15691220. 
3. ^ ^{a b c d} "Thimerosal in vaccines". Center for Biologics Evaluation and Research, U.S. Food and Drug Administration. 2008-06-03. http://www.fda.gov/cber/vaccine/thimerosal.htm. Retrieved 2008-07-25. 
4. ^ ^{a b c d e f} Baker JP (2008). "Mercury, Vaccines, and Autism: One Controversy, Three Histories". Am J Public Health 98 (2): 244–53. doi:10.2105/AJPH.2007.113159. PMC 2376879. PMID 18172138. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2376879. 
5. ^ "Thimerosal in Vaccines: Frequently Asked Questions". Food and Drug Administration. http://www.fda.gov/cber/vaccine/thimfaq.htm. Retrieved 2008-03-09. 
6. ^ Coordinating Center for Infectious Diseases (2007-10-26). "Thimerosal in seasonal influenza vaccine". Centers for Disease Control and Prevention. Archived from the original on 2008-04-11. http://web.archive.org/web/20080411133237/http://www.cdc.gov/FLU/ABOUT/QA/thimerosal.htm. Retrieved 2008-04-02. 
7. ^ "Mercury in plasma-derived products". U.S. Food and Drug Administration. 2004-09-09. Archived from the original on 2007-09-29. http://web.archive.org/web/20070929122259/http://www.fda.gov/cber/blood/mercplasma.htm. Retrieved 2007-10-01. 
8. ^ Global Advisory Committee on Vaccine Safety (2006-07-14). "Thiomersal and vaccines". World Health Organization. http://www.who.int/vaccine_safety/topics/thiomersal/en/index.html. Retrieved 2007-11-20. 
9. ^ "Safety data sheet, Thiomersal Ph Eur, BP, USP" (PDF). Merck. 2005-06-12. http://www.merck-chemicals.com/documents/sds/emd/int/en/8170/817043.pdf. Retrieved 2010-01-01. 
10. ^ Clarkson TW (2002). "The three modern faces of mercury". Environ Health Perspect 110 (S1): 11–23. doi:10.1289/ehp.02110s111. PMC 1241144. PMID 11834460. http://www.ehponline.org/members/2002/suppl-1/11-23clarkson/clarkson-full.html. 
11. ^ ^{a b c} Clarkson TW, Magos L (2006). "The toxicology of mercury and its chemical compounds". Crit Rev Toxicol 36 (8): 609–62. doi:10.1080/10408440600845619. PMID 16973445. 
12. ^ Clarkson TW, Vyas JB, Ballatori N (2007). "Mechanisms of mercury disposition in the body". Am J Ind Med 50 (10): 757–64. doi:10.1002/ajim.20476. PMID 17477364. 
13. ^ 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. doi:10.1111/j.1600-0536.2007.00980.x. PMID 17177703. 
14. ^ ^{a b} 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. doi:10.1016/j.jclinepi.2003.04.002. PMID 15246132. 
15. ^ Aberer W (1991). "Vaccination despite thimerosal sensitivity". Contact Dermatitis 24 (1): 6–10. doi:10.1111/j.1600-0536.1991.tb01621.x. PMID 2044374. 
16. ^ 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. doi:10.1111/j.1600-0536.2007.01220.x. PMID 17937743. http://www.blackwell-synergy.com/doi/full/10.1111/j.1600-0536.2007.01220.x. 
17. ^ Czarnobilska E, Obtulowicz K, Dyga W, Spiewak R (2011). "The most important contact sensitizers in Polish children and adolescents with atopy and chronic recurrent eczema as detected with the extended European Baseline Series". Pediatr Allergy Immunol 22 (2): 252–6. doi:10.1111/j.1399-3038.2010.01075.x. PMID 20969635. 
18. ^ "Thimerosal in vaccines: frequently asked questions (FAQs)". Center for Biologics Evaluation and Research, U.S. Food and Drug Administration. 2007-06-07. http://www.fda.gov/cber/vaccine/thimfaq.htm. Retrieved 2008-07-22. 
19. ^ DeStefano F (2007). "Vaccines and autism: evidence does not support a causal association". Clin Pharmacol Ther 82 (6): 756–9. doi:10.1038/sj.clpt.6100407. PMID 17928818. 
20. ^ Doja A, Roberts W (2006). "Immunizations and autism: a review of the literature". Can J Neurol Sci 33 (4): 341–6. PMID 17168158. 
21. ^ ^{a b} Immunization Safety Review Committee, Board on Health Promotion and Disease Prevention, Institute of Medicine (2004). Immunization Safety Review: Vaccines and Autism. Washington, DC: The National Academies Press. ISBN 0-309-09237-X. http://www.nap.edu/catalog/10997.html. 
22. ^ World Health Organization (2006). "Thiomersal and vaccines: questions and answers". http://who.int/vaccine_safety/topics/thiomersal/questions/en/. Retrieved 2009-05-19. 
23. ^ Centers for Disease Control (2008-02-08). "Mercury and vaccines (thimerosal)". http://www.cdc.gov/vaccinesafety/updates/thimerosal.htm. Retrieved 2009-05-19. 
24. ^ Sugarman SD (2007). "Cases in vaccine court—legal battles over vaccines and autism". N Engl J Med 357 (13): 1275–7. doi:10.1056/NEJMp078168. PMID 17898095. http://content.nejm.org/cgi/content/full/357/13/1275. 
25. ^ Harris G, O'Connor A (2005-06-25). "On autism's cause, it's parents vs. research". New York Times. http://nytimes.com/2005/06/25/science/25autism.htm. Retrieved 2010-07-02. 
26. ^ Offit PA (2007). "Thimerosal and vaccines—a cautionary tale". N Engl J Med 357 (13): 1278–9. doi:10.1056/NEJMp078187. PMID 17898096. http://content.nejm.org/cgi/content/full/357/13/1278. 
27. ^ Autism cases in vaccine court:
    • Sugarman SD (2007). "Cases in vaccine court—legal battles over vaccines and autism". N Engl J Med 357 (13): 1275–7. doi:10.1056/NEJMp078168. PMID 17898095. http://content.nejm.org/cgi/content/full/357/13/1275. 
    • U.S. Court of Federal Claims (2007-09-28). "Vaccine Program/Office of Special Masters Omnibus Autism Proceeding". Archived from the original on 2007-10-23. http://web.archive.org/web/20071023235955/http://www.uscfc.uscourts.gov/OSM/OSMAutism.htm. Retrieved 2007-11-24. 
28. ^ U.S. Patent 1,672,615 "Alkyl mercuric sulphur compound and process of producing it".