thiomersal

Morris Kharasch, a chemist then at the University of Maryland filed a patent application for thiomersal in 1927;{{US patent|1672615}} "Alkyl mercuric sulphur compound and process of producing it". Eli Lilly later marketed the compound under the trade name Merthiolate. 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. 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.

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.{{cite journal | vauthors = Melnick JG, Yurkerwich K, Buccella D, Sattler W, Parkin G | title = Molecular structures of thimerosal (Merthiolate) and other arylthiolate mercury alkyl compounds | journal = Inorganic Chemistry | volume = 47 | issue = 14 | pages = 6421–6426 | date = July 2008 | pmid = 18533648 | doi = 10.1021/ic8005426 }}

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. Unlike other preservatives at the time, such as phenol and cresol, thiomersal does not reduce the potency of the vaccines that it protects.{{cite journal | vauthors = Baker JP | title = Mercury, vaccines, and autism: one controversy, three histories | journal = American Journal of Public Health | volume = 98 | issue = 2 | pages = 244–253 | date = February 2008 | pmid = 18172138 | pmc = 2376879 | doi = 10.2105/AJPH.2007.113159 }} Bacteriostatics such as thiomersal are not needed in single-dose injectables.{{cite web |url=https://www.fda.gov/cber/vaccine/thimfaq.htm |archive-url=https://web.archive.org/web/20081231152114/http://www.fda.gov/CbER/vaccine/thimfaq.htm | archive-date=31 December 2008 |title=Thimerosal in Vaccines: Frequently Asked Questions |publisher=Food and Drug Administration |access-date=9 March 2008 }}

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.{{cite journal | vauthors = Bigham M, Copes R | title = Thiomersal in vaccines: balancing the risk of adverse effects with the risk of vaccine-preventable disease | journal = Drug Safety | volume = 28 | issue = 2 | pages = 89–101 | year = 2005 | pmid = 15691220 | doi = 10.2165/00002018-200528020-00001 | s2cid = 11570020 }} 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) may contain a trace of thiomersal from steps in manufacture, but less than 1 microgram of mercury per dose.{{cite web |date=2018-01-02 |title=Thimerosal and vaccines |url=https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/thimerosal-and-vaccines |access-date=2023-04-09 |publisher=Center for Biologics Evaluation and Research, U.S. Food and Drug Administration |language=en}} 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.{{cite web |date=September 9, 2004 |url=https://www.fda.gov/cber/blood/mercplasma.htm |access-date=October 1, 2007 |title=Mercury in plasma-derived products |publisher=U.S. Food and Drug Administration |archive-url=https://web.archive.org/web/20070929122259/https://www.fda.gov/cber/blood/mercplasma.htm |archive-date=September 29, 2007 }}

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.{{cite web |title=Thiomersal and vaccines |author=Global Advisory Committee on Vaccine Safety |publisher=World Health Organization |url=https://www.who.int/vaccine_safety/topics/thiomersal/en/index.html |archive-url=https://web.archive.org/web/20030820170557/http://www.who.int/vaccine_safety/topics/thiomersal/en/index.html |url-status=dead |archive-date=20 August 2003 |date=July 14, 2006 |access-date=November 20, 2007 }} 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.{{cite web|url=https://www.npr.org/blogs/health/2012/12/17/167280941/experts-argue-against-proposed-ban-on-vaccine-preservative|title=Doctors Argue Against Proposed Ban on Vaccine Preservative | vauthors = Hamilton J |publisher=NPR |date=17 December 2012|access-date=25 February 2013}} 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.{{cite journal |url=https://www.aappublications.org/content/early/2013/01/22/aapnews.20130122-1 | archive-url = https://web.archive.org/web/20160113080618/https://www.aappublications.org/content/early/2013/01/22/aapnews.20130122-1 | archive-date = 13 January 2016 |date=January 22, 2013 |title=Global ban on mercury grants exception to thimerosal-containing vaccines | vauthors = Wyckoff AS |journal=AAP News |publisher=American Academy of Pediatrics |access-date=August 24, 2019 }}

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).{{cite web |url=http://www.merck-chemicals.com/documents/sds/emd/int/en/8170/817043.pdf |date=June 12, 2005 |access-date=January 1, 2010 |publisher=Merck |title=Safety data sheet, Thiomersal Ph Eur, BP, USP |archive-date=15 September 2009 |archive-url=https://web.archive.org/web/20090915050341/http://www.merck-chemicals.com/documents/sds/emd/int/en/8170/817043.pdf |url-status=dead }}

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

Cases have been reported of severe mercury poisoning by accidental exposure or attempted suicide, with some fatalities.{{cite journal | vauthors = Clarkson TW | title = The three modern faces of mercury | journal = Environmental Health Perspectives | volume = 110 | issue = Suppl 1 | pages = 11–23 | date = February 2002 | pmid = 11834460 | pmc = 1241144 | doi = 10.1289/ehp.02110s111 | url = http://www.ehponline.org/members/2002/suppl-1/11-23clarkson/clarkson-full.html | url-status = dead | archive-url = https://web.archive.org/web/20080906092329/http://www.ehponline.org/members/2002/suppl-1/11-23clarkson/clarkson-full.html | archive-date = September 6, 2008 }} 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.

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.{{cite journal | vauthors = Magos L | title = Neurotoxic character of thimerosal and the allometric extrapolation of adult clearance half-time to infants | journal = Journal of Applied Toxicology | volume = 23 | issue = 4 | pages = 263–269 | year = 2003 | pmid = 12884410 | doi = 10.1002/jat.918 | s2cid = 20703489 }} The half-life of ethylmercury in the brains of infant monkeys is 14 days. Risk assessment for effects on the nervous system have been made by extrapolating from dose-response relationships for methylmercury. 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.{{cite journal | vauthors = Clarkson TW, Vyas JB, Ballatori N | title = Mechanisms of mercury disposition in the body | journal = American Journal of Industrial Medicine | volume = 50 | issue = 10 | pages = 757–764 | date = October 2007 | pmid = 17477364 | doi = 10.1002/ajim.20476 }}

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. 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.{{cite journal |vauthors=Clarkson TW, Magos L |date=September 2006 |title=The toxicology of mercury and its chemical compounds |url=https://www.tandfonline.com/doi/full/10.1080/10408440600845619 |journal=Critical Reviews in Toxicology |volume=36 |issue=8 |pages=609–662 |doi=10.1080/10408440600845619 |pmid=16973445 |s2cid=37652857|url-access=subscription }}

File:Epikutanni-test.jpg]]

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;{{cite journal | vauthors = Dotterud LK, Smith-Sivertsen T | title = Allergic contact sensitization in the general adult population: a population-based study from Northern Norway | journal = Contact Dermatitis | volume = 56 | issue = 1 | pages = 10–15 | date = January 2007 | pmid = 17177703 | doi = 10.1111/j.1600-0536.2007.00980.x | s2cid = 25765635 }} a higher prevalence of contact allergy (up to 6.6%) was observed in German populations.{{cite journal | vauthors = Uter W, Ludwig A, Balda BR, Schnuch A, Pfahlberg A, Schäfer T, Wichmann HE, Ring J | title = The prevalence of contact allergy differed between population-based and clinic-based data | journal = Journal of Clinical Epidemiology | volume = 57 | issue = 6 | pages = 627–632 | date = June 2004 | pmid = 15246132 | doi = 10.1016/j.jclinepi.2003.04.002 }} Thiomersal-sensitive individuals can receive intramuscular rather than subcutaneous immunization,{{cite journal | vauthors = Aberer W | title = Vaccination despite thimerosal sensitivity | journal = Contact Dermatitis | volume = 24 | issue = 1 | pages = 6–10 | date = January 1991 | pmid = 2044374 | doi = 10.1111/j.1600-0536.1991.tb01621.x | s2cid = 43264826 }} 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.

Thiomersal allergy has decreased in Denmark, probably because of its exclusion from vaccines there.{{cite journal | vauthors = Thyssen JP, Linneberg A, Menné T, Johansen JD | title = The epidemiology of contact allergy in the general population--prevalence and main findings | journal = Contact Dermatitis | volume = 57 | issue = 5 | pages = 287–299 | date = November 2007 | pmid = 17937743 | doi = 10.1111/j.1600-0536.2007.01220.x | s2cid = 44890665 | doi-access = free }} 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.{{cite journal | vauthors = Czarnobilska E, Obtulowicz K, Dyga W, Spiewak R | title = The most important contact sensitizers in Polish children and adolescents with atopy and chronic recurrent eczema as detected with the extended European Baseline Series | journal = Pediatric Allergy and Immunology | volume = 22 | issue = 2 | pages = 252–256 | date = March 2011 | pmid = 20969635 | doi = 10.1111/j.1399-3038.2010.01075.x | s2cid = 22195669 }}

The Center for Biologics Evaluation and Research (CBER) at the FDA initiated a formal risk assessment of thiomersal in vaccines beginning in 1998.{{cite book | vauthors = ((Institute of Medicine (US) Immunization Safety Review Committee)) | veditors = Stratton K, Gable A, McCormick MC | title = Immunization Safety Review: Thimerosal-Containing Vaccines and Neurodevelopmental Disorders. | chapter = Thimerosal-Containing Vaccines and Neurodevelopmental Disorders | location = Washington (DC) | publisher = National Academies Press (US) | date = 2001 | url = https://www.ncbi.nlm.nih.gov/books/NBK223724/ }} 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. 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.”{{cite journal | pmc=1308509 | date=1999 | title=AAP and PHS Urge Reduction of Mercury in Vaccines | journal=Public Health Reports | volume=114 | issue=5 | pages=394–395 | doi=10.1093/phr/114.5.394 | doi-broken-date=1 November 2024 }}{{cite journal | title = Thimerosal in vaccines: a joint statement of the American Academy of Pediatrics and the Public Health Service | journal = MMWR. Morbidity and Mortality Weekly Report | volume = 48 | issue = 26 | pages = 563–565 | date = July 1999 | pmid = 10418806 | doi = | url = https://www.cdc.gov/mmwr/preview/mmwrhtml/mm4826a3.htm | author1 = Centers for Disease Control and Prevention (CDC) }} 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.

{{main|Thiomersal and vaccines}}

Following the phasing out of thiomersal from most U.S. and European vaccines,{{cite web |url=https://www.fda.gov/cber/vaccine/thimfaq.htm |archive-url=https://web.archive.org/web/20011203181733/http://www.fda.gov/cber/vaccine/thimfaq.htm |url-status=dead |archive-date=3 December 2001 |date=June 7, 2007 |access-date=July 22, 2008 |title=Thimerosal in vaccines: frequently asked questions (FAQs) |publisher=Center for Biologics Evaluation and Research, U.S. Food and Drug Administration}} 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. 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.{{cite journal | vauthors = DeStefano F | title = Vaccines and autism: evidence does not support a causal association | journal = Clinical Pharmacology and Therapeutics | volume = 82 | issue = 6 | pages = 756–759 | date = December 2007 | pmid = 17928818 | doi = 10.1038/sj.clpt.6100407 | s2cid = 12872702 }}{{cite journal | vauthors = Doja A, Roberts W | title = Immunizations and autism: a review of the literature | journal = The Canadian Journal of Neurological Sciences. Le Journal Canadien des Sciences Neurologiques | volume = 33 | issue = 4 | pages = 341–346 | date = November 2006 | pmid = 17168158 | doi = 10.1017/s031716710000528x | doi-access = free }}

Scientific and medical bodies such as the Institute of Medicine{{cite book | vauthors = ((Immunization Safety Review Committee)), ((Board on Health Promotion and Disease Prevention)), ((Institute of Medicine)) |title=Immunization Safety Review: Vaccines and Autism |publisher=The National Academies Press |location=Washington, DC |year=2004 |doi=10.17226/10997 |pmid=20669467 |isbn=978-0-309-09237-1 |url=http://www.nap.edu/catalog/10997.html}} and World Health Organization,{{cite web |author=World Health Organization |year=2006 |url=http://who.int/vaccine_safety/topics/thiomersal/questions/en/ |archive-url=https://web.archive.org/web/20031012231839/http://www.who.int/vaccine_safety/topics/thiomersal/questions/en/ |url-status=dead |archive-date=12 October 2003 |title=Thiomersal and vaccines: questions and answers |access-date=May 19, 2009 }}{{cite web|url=https://www.who.int/vaccine_safety/committee/topics/thiomersal/statement_jul2006/en|archive-url=https://web.archive.org/web/20121029124603/http://www.who.int/vaccine_safety/committee/topics/thiomersal/statement_jul2006/en/|url-status=dead|archive-date=29 October 2012|title=Statement on thiomersal|author=WHO|website=www.who.int|access-date=3 April 2018}} as well as governmental agencies such as the Food and Drug Administration and the CDC{{cite web |author=Centers for Disease Control |date=February 8, 2008 |url=https://www.cdc.gov/vaccinesafety/updates/thimerosal.htm |title=Mercury and vaccines (thimerosal) |access-date=May 19, 2009 |archive-url=https://web.archive.org/web/20180418041930/https://www.cdc.gov/vaccinesafety/updates/thimerosal.htm |archive-date=April 18, 2018 |url-status=dead }} reject any role for thiomersal in autism or other neurodevelopmental disorders.{{cite journal | vauthors = Sugarman SD | title = Cases in vaccine court--legal battles over vaccines and autism | journal = The New England Journal of Medicine | volume = 357 | issue = 13 | pages = 1275–1277 | date = September 2007 | pmid = 17898095 | doi = 10.1056/NEJMp078168 | doi-access = free }} 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.{{cite news|url=https://www.nytimes.com/2005/06/25/science/on-autisms-cause-its-parents-vs-research.html|title=On autism's cause, it's parents vs. research|date=June 25, 2005 |work=New York Times| vauthors = Harris G, O'Connor A |access-date=March 11, 2016 }} Studying thiomersal potentially diverts resources away from research into more promising areas for autism.{{cite journal | vauthors = Offit PA | title = Thimerosal and vaccines--a cautionary tale | journal = The New England Journal of Medicine | volume = 357 | issue = 13 | pages = 1278–1279 | date = September 2007 | pmid = 17898096 | doi = 10.1056/NEJMp078187 | author-link = Paul Offit | doi-access = free }} Thousands of lawsuits have been filed in U.S. federal court to seek damages from allegedly toxic vaccines, including those purportedly caused by thiomersal.Autism cases in vaccine court:

• {{cite journal | vauthors = Sugarman SD | title = Cases in vaccine court--legal battles over vaccines and autism | journal = The New England Journal of Medicine | volume = 357 | issue = 13 | pages = 1275–1277 | date = September 2007 | pmid = 17898095 | doi = 10.1056/NEJMp078168 | doi-access = free }}
• {{cite web |author=U.S. Court of Federal Claims |author-link=U.S. Court of Federal Claims |date=September 28, 2007 |url=http://www.uscfc.uscourts.gov/OSM/OSMAutism.htm |title=Vaccine Program/Office of Special Masters Omnibus Autism Proceeding |access-date=November 24, 2007 |archive-url=https://web.archive.org/web/20071023235955/http://www.uscfc.uscourts.gov/OSM/OSMAutism.htm |archive-date=October 23, 2007 }}

• {{Annotated link|Nitromersol}}, a related antimicrobial
• Phenylmercuric nitrate – Organomercury compound with powerful antiseptic and antifungal effects

{{Reflist}}

{{Mercury compounds}}

{{Vaccines}}

{{Antiseptics and disinfectants}}

{{Sodium compounds}}

Category:Benzoates

Category:Drugs developed by Eli Lilly and Company

Category:Excipients

Category:Organic sodium salts

Category:Organomercury compounds

Category:Thiolates