Τρίτη 12 Νοεμβρίου 2013

THIOMERSAL - mercury as preservative in vaccines

Thiomersal

From Wikipedia, the free encyclopedia
Thiomersal
Identifiers
CAS number54-64-8 Yes
PubChem16684434
ChemSpider10772045 Yes
UNII2225PI3MOV Yes
EC number200-210-4
ChEBICHEBI:9546 Yes
ChEMBLCHEMBL508338 Yes
RTECS numberOV8400000
ATC codeD08AK06
Jmol-3D imagesImage 1
Properties
Molecular formulaC9H9HgNaO2S
Molar mass404.81 g/mol
AppearanceWhite or slightly yellow powder
Density2.508 g/cm³[1]
Melting point
232–233 °C (decomposition)
Solubility inwater1000 g/l (20 °C)
Hazards
MSDSExternal MSDS
EU classificationVery toxic (T+)
Dangerous for the environment (N)
Repr. Cat. 1
R-phrasesR26/27/28 R33 R40 R50/53 R60R61
S-phrasesS13 S28 S36 S45 S53 S60 S61
NFPA 704
NFPA 704.svg
1
3
1
Flash point250 °C
 Yes (verify) (what is: Yes/?)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references
Thiomersal (INN), commonly known in the US as thimerosal, is an organomercury compound. This compound is
a well establishedantiseptic and antifungal agent.
The pharmaceutical corporation Eli Lilly and Company gave thiomersal the trade name Merthiolate. It has been
 used as a preservativein vaccines, immunoglobulin preparations, skin test antigens, antivenins, ophthalmic and 
nasal products, and tattoo inks.[2] 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.[3]

Structure[edit]

Thiomersal features mercury(II) with a coordination number 2, i.e. two ligands are attached to Hg, the thiolate and
 the ethyl group. Thecarboxylate group is not coordinated, but 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]

Use[edit]

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 diphtheriavaccine that lacked a preservative.[4] Unlike other vaccine preservatives used 
at the time, thiomersal does not reduce the potency of the vaccines that it protects.[5] Bacteriostatics like 
thiomersal are not needed in more-expensive single-dose injectables.[6]
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.[3] 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.[7] 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.[4] Also, four rarely used treatments 
for pit viper, coral snake, and black widow venom still contain thiomersal.[8] 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.[9] The United Nations Environment Program backed away from an earlier proposal of adding 
thimerosal in vaccines to the list of banned compound in a treaty aimed at reducing exposure to mercury worldwide
.[10] Citing medical and scientific consensus that thimerosal in vaccines posed no safety issues, but eliminating 
the preservative in multi-dose vaccines, primarily used in developing countries, will lead to high cost and
 requirement of refrigeration which the developing countries can ill afford, the UN’s final decision is to exclude 
thimerosal from the treaty.[11]

Toxicology[edit]

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).[12] In the body, it is metabolized or degraded to ethylmercury (C2H5Hg+) and thiosalicylate.[4]
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.[13] Animal experiments suggest t
hat 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. Risk assessment for effects

 on the nervous system have been made by extrapolating from dose-response relationships

 for methylmercury.[14] 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.[15] 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.[14] 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.[14]

Allergies[edit]

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;[16] a higher prevalence of contact allergy (up to 6.6%) was observed in German populations.[17] Thiomersal-sensitive individuals can receive intramuscular rather than subcutaneousimmunization,[18] 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.[17] Thiomersal allergy has decreased in Denmark, probably because of its exclusion from vaccines there.[19] 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.[20]

Autism[edit]

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.[5][21] Many 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.[5] The scientific consensus is that there is no scientific evidence supporting these claims, including the observation that the rate of autism continues to climb despite elimination of thiomersal from routine childhood vaccines.[22][23][24] Major scientific and medical bodies such as the Institute of Medicine[24] and World Health Organization[25] as well as governmental agencies such as the Food and Drug Administration[4] and the CDC[26] reject any role for thiomersal in autism or other neurodevelopmental disorders.[27] 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[28] and diverting resources away from research into more promising areas for the cause of autism.[29] 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.[30]

History[edit]

Morris Kharasch, a chemist at the University of Maryland, filed a patent application for thiomersal in 1927;[31] Eli Lilly later marketed the compound under the trade name Merthiolate.[5] 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.[5] 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.[5]

See also[edit]

References[edit]

  1. ^ Jump up to: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. Jump up^ Sharpe, M. A.; Livingston, A. D.; Baskin, D. S. (2012). "Thimerosal-Derived Ethylmercury is a Mitochondrial Toxin in Human Astrocytes: Possible Role of Fenton Chemistry in the Oxidation and Breakage of mtDNA". Journal of Toxicology 2012: 1.doi:10.1155/2012/373678. edit
  3. ^ Jump up to: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.
  4. ^ Jump up to:a b c d "Thimerosal in vaccines". Center for Biologics Evaluation and Research, U.S. Food and Drug Administration. 2008-06-03. Retrieved 2008-07-25.
  5. ^ Jump up to: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.
  6. Jump up^ "Thimerosal in Vaccines: Frequently Asked Questions". Food and Drug Administration. Retrieved 2008-03-09.
  7. Jump up^ 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. Retrieved 2008-04-02.
  8. Jump up^ "Mercury in plasma-derived products". U.S. Food and Drug Administration. 2004-09-09. Archived from the original on 2007-09-29. Retrieved 2007-10-01.
  9. Jump up^ Global Advisory Committee on Vaccine Safety (2006-07-14). "Thiomersal and vaccines". World Health Organization. Retrieved 2007-11-20.
  10. Jump up^ Hamilton, Jon (17 December 2012). "Doctors Argue Against Proposed Ban on Vaccine Preservative". NPR. Retrieved 25 February 2013.
  11. Jump up^ Bryant, Alison (24 January 2013). "U.N. excludes vaccine preservative from mercury treaty". fiercevaccine.com. Retrieved 25 February 2013.
  12. Jump up^ "Safety data sheet, Thiomersal Ph Eur, BP, USP" (PDF). Merck. 2005-06-12. Retrieved 2010-01-01.
  13. Jump up^ Clarkson TW (2002). "The three modern faces of mercury". Environ Health Perspect110 (S1): 11–23. doi:10.1289/ehp.02110s111. PMC 1241144. PMID 11834460.
  14. ^ Jump up to: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.
  15. Jump up^ 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.
  16. Jump up^ Dotterud LK, Smith-Sivertsen T (2007). "Allergic contact sensitization in the general adult population: a population-based study from Northern Norway". Contact Dermatitis56 (1): 10–5. doi:10.1111/j.1600-0536.2007.00980.x. PMID 17177703.
  17. ^ Jump up to: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.
  18. Jump up^ Aberer W (1991). "Vaccination despite thimerosal sensitivity". Contact Dermatitis 24(1): 6–10. doi:10.1111/j.1600-0536.1991.tb01621.x. PMID 2044374.
  19. Jump up^ 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.
  20. Jump up^ 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.
  21. Jump up^ "Thimerosal in vaccines: frequently asked questions (FAQs)". Center for Biologics Evaluation and Research, U.S. Food and Drug Administration. 2007-06-07. Retrieved 2008-07-22.
  22. Jump up^ 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.
  23. Jump up^ Doja A, Roberts W (2006). "Immunizations and autism: a review of the literature". Can J Neurol Sci 33 (4): 341–6. PMID 17168158.
  24. ^ Jump up to: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.
  25. Jump up^ World Health Organization (2006). "Thiomersal and vaccines: questions and answers". Retrieved 2009-05-19.
  26. Jump up^ Centers for Disease Control (2008-02-08). "Mercury and vaccines (thimerosal)". Retrieved 2009-05-19.
  27. Jump up^ 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.
  28. Jump up^ Harris G, O'Connor A (2005-06-25). "On autism's cause, it's parents vs. research".New York Times. Retrieved 2010-07-02.
  29. Jump up^ Offit PA (2007). "Thimerosal and vaccines—a cautionary tale". N Engl J Med 357(13): 1278–9. doi:10.1056/NEJMp078187. PMID 17898096.
  30. Jump up^ Autism cases in vaccine court:
  31. Jump up^ U.S. Patent 1,672,615 "Alkyl mercuric sulphur compound and process of producing it".
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