Jump to content

Thiomersal: Difference between revisions

From Wikipedia, the free encyclopedia
Content deleted Content added
added use in influenza vaccine
No edit summary
 
(60 intermediate revisions by 41 users not shown)
Line 1: Line 1:
{{Short description|Organomercury antiseptic and antifungal agent}}
{{Short description|Organomercury antiseptic and antifungal agent}}
{{use dmy dates |date=August 2021}}
{{use dmy dates |date=August 2021}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{chembox
{{chembox
| Watchedfields = changed
| Watchedfields = changed
Line 12: Line 13:
| IUPACName = Ethyl(2-mercaptobenzoato-(2-)-''O'',''S'') mercurate(1-) sodium
| IUPACName = Ethyl(2-mercaptobenzoato-(2-)-''O'',''S'') mercurate(1-) sodium
| OtherNames = Mercury((''o''-carboxyphenyl)thio)ethyl sodium salt, sodium ethylmercurithiosalicylate
| OtherNames = Mercury((''o''-carboxyphenyl)thio)ethyl sodium salt, sodium ethylmercurithiosalicylate

| Section1 = {{Chembox Identifiers
| Section1 = {{Chembox Identifiers
| CASNo_Ref = {{cascite|correct|CAS}}
| CASNo_Ref = {{cascite|correct|CAS}}
Line 38: Line 38:
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = RTKIYNMVFMVABJ-UHFFFAOYSA-L
| StdInChIKey = RTKIYNMVFMVABJ-UHFFFAOYSA-L
}}
}}

| Section2 = {{Chembox Properties
| Section2 = {{Chembox Properties
| Formula = [[carbon|C]]<sub>9</sub>[[hydrogen|H]]<sub>9</sub>[[Mercury (element)|Hg]][[sodium|Na]][[Oxygen|O]]<sub>2</sub>[[sulfur|S]]
| Formula = [[carbon|C]]<sub>9</sub>[[hydrogen|H]]<sub>9</sub>[[Mercury (element)|Hg]][[sodium|Na]][[Oxygen|O]]<sub>2</sub>[[sulfur|S]]
Line 48: Line 47:
| MeltingPtC = 232 to 233
| MeltingPtC = 232 to 233
| MeltingPt_notes = (decomposition)
| MeltingPt_notes = (decomposition)
}}
| BoilingPt =
| Section3 = {{Chembox Pharmacology
| pKa =
}}

| Section5 = {{Chembox Thermochemistry
| DeltaHf =
}}

| Section6 = {{Chembox Pharmacology
| ATCCode_prefix = D08
| ATCCode_prefix = D08
| ATCCode_suffix = AK06
| ATCCode_suffix = AK06
}}
}}
|Section4 = {{Chembox Hazards

|GHSPictograms = {{GHS06}}{{GHS08}}{{GHS09}}
| Section7 = {{Chembox Hazards
| GHSPictograms = {{GHS06}}{{GHS08}}{{GHS09}}
| GHSSignalWord = Danger
| GHSSignalWord = Danger
| HPhrases = {{H-phrases|300|310|330|373|410}}
| HPhrases = {{H-phrases|300|310|330|373|410}}
Line 70: Line 61:
| NFPA-R = 1
| NFPA-R = 1
| FlashPtC = 250
| FlashPtC = 250
| LD50 = 75 mg/kg (oral, rat)<ref>{{cite web|url=http://chem.sis.nlm.nih.gov/chemidplus/rn/54-64-8|title=ChemIDplus – 54-64-8 – RTKIYNMVFMVABJ-UHFFFAOYSA-L – Thimerosal [USP:JAN] – Similar structures search, synonyms, formulas, resource links, and other chemical information.|first=Michael|last=Chambers|website=chem.sis.nlm.nih.gov|access-date=3 April 2018}}</ref>
| LD50 = 75 mg/kg (oral, rat)<ref>{{cite web|url=https://chem.nlm.nih.gov/chemidplus/rn/54-64-8|title=ChemIDplus – 54-64-8 – RTKIYNMVFMVABJ-UHFFFAOYSA-L – Thimerosal [USP:JAN] – Similar structures search, synonyms, formulas, resource links, and other chemical information.| vauthors = Chambers M |website=chem.sis.nlm.nih.gov|access-date=3 April 2018}}</ref>
| ExternalSDS = [https://web.archive.org/web/20080625045712/http://www.conncoll.edu/offices/envhealth/MSDS/neuroscience/thimerosal.pdf External MSDS]
| ExternalSDS = [https://web.archive.org/web/20080625045712/http://www.conncoll.edu/offices/envhealth/MSDS/neuroscience/thimerosal.pdf External MSDS]
}}
}}
}}
}}
'''Thiomersal''' ([[International Nonproprietary Name|INN]]), or '''thimerosal''' ([[United States Adopted Name|USAN]], [[Japanese Accepted Name|JAN]]), is an [[organomercury]] compound. It is a well-established [[antiseptic]] and [[antifungal agent]].
'''Thiomersal''' ([[International Nonproprietary Name|INN]]), or '''thimerosal''' ([[United States Adopted Name|USAN]], [[Japanese Accepted Name|JAN]]), also sold under the name '''merthiolate'''<ref>{{Cite web |title=Merthiolate poisoning: MedlinePlus Medical Encyclopedia |url=https://medlineplus.gov/ency/article/002678.htm |access-date=2023-12-08 |website=medlineplus.gov |language=en}}</ref> is an [[organomercury]] compound. It is a well-established [[antiseptic]] and [[antifungal agent]].<ref>{{Cite web |date=2020-08-25 |title=Thimerosal and Vaccines {{!}} Vaccine Safety {{!}} CDC |url=https://www.cdc.gov/vaccinesafety/concerns/thimerosal/index.html |access-date=2023-05-04 |website=Centers for Disease Control and Prevention |language=en-us}}</ref>


The pharmaceutical corporation [[Eli Lilly and Company]] gave thiomersal the trade name '''Merthiolate'''. It has been used as a [[preservative]] in [[vaccine|vaccines]], [[immunoglobulin]] preparations, [[Allergy#Diagnosis|skin test antigens]], [[antivenin]]s, [[ophthalmology|ophthalmic]] and nasal products, and [[tattoo]] inks.<ref>{{Cite journal |last1=Sharpe |first1=M. A. |last2=Livingston |first2=A. D. |last3=Baskin |first3=D. S. |title=Thimerosal-Derived Ethylmercury is a Mitochondrial Toxin in Human Astrocytes: Possible Role of Fenton Chemistry in the Oxidation and Breakage of mtDNA |doi=10.1155/2012/373678 |journal=Journal of Toxicology |volume=2012 |pages=1–12 |year=2012 |pmid=22811707 |pmc=3395253 |quote="...widely used in medical products, including as a preservative in vaccines, immunoglobulin preparations, skin test antigens, antivenins, ophthalmic and nasal products, and tattoo inks..."|doi-access=free }}</ref> In spite of the [[scientific consensus]] that fears about its safety are unsubstantiated,<ref>{{cite book|last=Immunization Safety Review Committee, Board on Health Promotion and Disease Prevention, Institute of Medicine |title=Immunization Safety Review: Vaccines and Autism |year=2004 |publisher=The National Academies Press |location=Washington, DC |isbn=978-0-309-09237-1 }}</ref><ref>{{cite journal |last1=Doja |first1=Asif |last2=Roberts |first2=Wendy |title=Immunizations and autism: a review of the literature |journal=[[Canadian Journal of Neurological Sciences|Can J Neurol Sci]] |date=November 2006 |volume=33 |issue=4 |pages=341–46 |pmid=17168158 |doi=10.1017/s031716710000528x |doi-access=free }}</ref><ref name="CDC concerns">{{Cite web |title=Vaccines Do Not Cause Autism |url=https://www.cdc.gov/vaccinesafety/concerns/autism.html |website=cdc.gov |access-date=29 November 2015 }}</ref><ref>{{cite journal |last1=Gołoś |first1=A |last2=Lutyńska |first2=A |title=Thiomersal-containing vaccines - a review of the current state of knowledge |journal=Przeglad Epidemiologiczny |date=2015 |volume=69 |issue=1 |pages=59–64, 157–61 |pmid=25862449 }}</ref> its use as a vaccine preservative has been [[Thiomersal controversy|called into question]] by [[vaccine hesitancy|anti-vaccination]] groups. Due to this public pressure the substance was phased out of routine childhood vaccines in the United States, the European Union, and a few other countries in response to popular fears.<ref name=drugsaf/> It remains in use as a preservative for annual [[Influenza vaccine|flu vaccines]].<ref>{{Cite web |last=Nast |first=Condé |date=2015-02-08 |title=Not Immune |url=https://www.newyorker.com/magazine/2015/02/16/immune-3 |access-date=2022-10-02 |website=The New Yorker |language=en-US}}</ref>
The pharmaceutical corporation [[Eli Lilly and Company]] named it Merthiolate. It has been used as a [[preservative]] in [[vaccine]]s, [[immunoglobulin]] preparations, [[Allergy#Diagnosis|skin test antigens]], [[antivenin]]s, [[ophthalmology|ophthalmic]] and nasal products, and [[tattoo]] inks.<ref>{{cite journal | vauthors = Sharpe MA, Livingston AD, Baskin DS | title = Thimerosal-Derived Ethylmercury Is a Mitochondrial Toxin in Human Astrocytes: Possible Role of Fenton Chemistry in the Oxidation and Breakage of mtDNA | journal = Journal of Toxicology | volume = 2012 | pages = 373678 | year = 2012 | pmid = 22811707 | pmc = 3395253 | doi = 10.1155/2012/373678 | quote = "...widely used in medical products, including as a preservative in vaccines, immunoglobulin preparations, skin test antigens, antivenins, ophthalmic and nasal products, and tattoo inks..." | doi-access = free }}</ref> In spite of the [[scientific consensus]] that fears about its safety are unsubstantiated,<ref name = "IOM2004" /><ref>{{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 }}</ref><ref name="CDC concerns">{{Cite web |title=Vaccines Do Not Cause Autism |url=https://www.cdc.gov/vaccinesafety/concerns/autism.html |website=cdc.gov |access-date=29 November 2015 }}</ref><ref>{{cite journal | vauthors = Gołoś A, Lutyńska A | title = Thiomersal-containing vaccines - a review of the current state of knowledge | journal = Przeglad Epidemiologiczny | volume = 69 | issue = 1 | pages = 59–64, 157–61 | date = 2015 | pmid = 25862449 }}</ref> its use as a vaccine preservative has been [[Thiomersal controversy|called into question]] by [[vaccine hesitancy|anti-vaccination]] groups.

A 1999 statement issued in [[Centers for Disease Control and Prevention|CDC]]'s [[Morbidity and Mortality Weekly Report]] announced that "the Public Health Service ([[United States Public Health Service Commissioned Corps|PHS]]), the American Academy of Pediatrics ([[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 (element)|mercury]] content of their vaccines."<ref>{{cite news |title=Thimerosal in Vaccines: A Joint Statement of the American Academy of Pediatrics and the Public Health Service |url=https://www.cdc.gov/mmwr/PDF/wk/mm4826.pdf |access-date=May 8, 2024 |work=Morbidity and Mortality Weekly Report Vol. 48 No. 26 |agency=Centers for Disease Control and Prevention |date=July 9, 1999 |pages=563–65}}</ref><ref>{{cite journal | vauthors = Hurley AM, Tadrous M, Miller ES | title = Thimerosal-containing vaccines and autism: a review of recent epidemiologic studies | journal = The Journal of Pediatric Pharmacology and Therapeutics | volume = 15 | issue = 3 | pages = 173–181 | date = July 2010 | doi = 10.5863/1551-6776-15.3.173 | pmid = 22477809 | pmc = 3018252 }}</ref><ref name=drugsaf/>

It remains in use as a preservative for certain annual [[Influenza vaccine|flu vaccines]], mostly those stored in multi-dose vials.<ref>{{Cite magazine |date=2015-02-08 |title=Not Immune |url=https://www.newyorker.com/magazine/2015/02/16/immune-3 |access-date=2022-10-02 |magazine=The New Yorker |language=en-US}}</ref><ref>{{cite web | url=https://www.cdc.gov/flu/prevent/thimerosal.htm | title=Thimerosal in Flu Vaccine &#124; CDC | date=22 August 2023 }}</ref> Single-dose vial flu shots are an option for those who prefer vaccines with no thiomersal, although no scientific data supports claims that there is any link between thiomersal and autism.

__TOC__


==History==
==History==
[[Morris Kharasch]], a [[chemist]] then at the [[University of Maryland, College Park|University of Maryland]] filed a patent application for thiomersal in 1927;<ref>{{US patent|1672615}} "Alkyl mercuric sulphur compound and process of producing it".</ref> Eli Lilly later marketed the compound under the trade name Merthiolate.<ref name="Baker"/> [[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]]''.<ref name="Baker"/> 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, [[immunoglobulin]]s, 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.<ref name="Baker"/>
[[Morris Kharasch]], a [[chemist]] then at the [[University of Maryland, College Park|University of Maryland]] filed a patent application for thiomersal in 1927;<ref>{{US patent|1672615}} "Alkyl mercuric sulphur compound and process of producing it".</ref> Eli Lilly later marketed the compound under the trade name Merthiolate.<ref name="Baker"/> [[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]]''.<ref name="Baker"/> 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, [[immunoglobulin]]s, 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.<ref name="Baker"/>


==Structure==
== Structure ==
Thiomersal features [[Mercury (element)|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.<ref name="molstruct">{{ cite journal |first1=J. G. |last1=Melnick |first2=K. |last2=Yurkerwich |first3=D. |last3=Buccella |first4=W. |last4=Sattler |first5=G. |last5=Parkin |title=Molecular Structures of Thimerosal (Merthiolate) and Other Arylthiolate Mercury Alkyl Compounds |journal=[[Inorganic Chemistry (journal)|Inorg. Chem.]] |year=2008 |volume=47 |issue=14 |pmid=18533648 |pages=6421–26 |doi=10.1021/ic8005426 }}</ref>
Thiomersal features [[Mercury (element)|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.<ref name="molstruct">{{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 }}</ref>


==Uses==
==Uses==
=== Antiseptic/antifungal ===
Thiomersal's main use is as an antiseptic and antifungal agent, due to the [[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 [[vaccinate]]d with a [[diphtheria]] vaccine that lacked a preservative.<ref name=T-in-vaccines/> Unlike other vaccine preservatives used at the time, thiomersal does not reduce the potency of the vaccines that it protects.<ref name=Baker>{{cite journal |journal=Am J Public Health |year=2008 |title=Mercury, Vaccines, and Autism: One Controversy, Three Histories |last=Baker |first=JP |doi=10.2105/AJPH.2007.113159 |pmid=18172138 |volume=98 |issue=2 |pages=244–53 |pmc=2376879}}</ref>{{clarify|reason=And what of the preservatives in use at this time?|date=February 2021}} [[Bacteriostatic]]s such as thiomersal are not needed in single-dose injectables.<ref>{{cite web |url=https://www.fda.gov/cber/vaccine/thimfaq.htm |title=Thimerosal in Vaccines: Frequently Asked Questions |publisher=[[Food and Drug Administration (United States)|Food and Drug Administration]] |access-date=9 March 2008 }}</ref>
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 [[vaccinate]]d with a [[diphtheria]] vaccine that lacked a preservative.<ref name="T-in-vaccines" /> Unlike other preservatives at the time, such as [[phenol]] and [[cresol]], thiomersal does not reduce the potency of the vaccines that it protects.<ref name="Baker">{{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 }}</ref> [[Bacteriostatic]]s such as thiomersal are not needed in single-dose injectables.<ref>{{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 (United States)|Food and Drug Administration]] |access-date=9 March 2008 }}</ref>

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 schedule]]s.<ref name="drugsaf">{{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 }}</ref> In the U.S., all vaccines routinely recommended for children 6 years of age and younger are available in [[Pharmaceutical formulation|formulations]] that do not contain thimerosal. Two vaccines (a [[Tetanus vaccine|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.<ref name="T-in-vaccines">{{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}}</ref> 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.<ref>{{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 <!-- Bot retrieved archive --> |archive-date=September 29, 2007 }}</ref>


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 schedule]]s.<ref name="drugsaf">{{cite journal |journal=Drug Saf |year=2005 |volume=28 |issue=2 |pages=89–101 |title=Thiomersal in vaccines: balancing the risk of adverse effects with the risk of vaccine-preventable disease |last1=Bigham |first1=M |last2=Copes |first2=R |pmid=15691220 |doi=10.2165/00002018-200528020-00001 |s2cid=11570020 }}</ref> 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.<ref>{{cite web |title=Thimerosal in seasonal influenza vaccine |url=http://cdc.gov/FLU/ABOUT/QA/thimerosal.htm |date=October 26, 2007 |access-date=April 2, 2008 |author=Coordinating Center for Infectious Diseases |publisher=Centers for Disease Control and Prevention |archive-url=https://web.archive.org/web/20080411133237/http://www.cdc.gov/FLU/ABOUT/QA/thimerosal.htm |archive-date=April 11, 2008 }}</ref> 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.<ref name=T-in-vaccines>{{cite web |date=June 3, 2008 |url=https://www.fda.gov/cber/vaccine/thimerosal.htm |access-date=July 25, 2008 |title=Thimerosal in vaccines |publisher=Center for Biologics Evaluation and Research, U.S. Food and Drug Administration}}</ref> The multi-dose versions of the [[influenza vaccine]]s Fluvirin and [[Fluzone]] can contain up to 25 micrograms of mercury per dose from thiomersal.<ref>{{Cite web |url=https://www.cdc.gov/flu/about/qa/vaxsupply.htm |title=Seasonal Influenza Vaccine Supply for the U.S. 2016-2017 Influenza Season &#124; Seasonal Influenza (Flu) &#124; CDC |website=cdc.gov|access-date=March 16, 2017 }}</ref><ref>{{Cite journal|last1=Grohskopf|first1=Lisa A. |last2=Sokolow|first2=Leslie Z.|last3=Broder|first3=Karen R.|last4=Olsen|first4=Sonja J.|last5=Karron|first5=Ruth A. |last6=Jernigan|first6=Daniel B.|last7=Bresee|first7=Joseph S.|date=2016|title=Prevention and Control of Seasonal Influenza with Vaccines|url=https://www.cdc.gov/mmwr/volumes/65/rr/rr6505a1.htm|journal=MMWR. Recommendations and Reports|volume=65|issue=5|pages=1–54|doi=10.15585/mmwr.rr6505a1|pmid=27560619 |issn=1057-5987 |doi-access=free }}</ref> Also, four rarely used treatments for pit viper, coral snake, and black widow venom still contain thiomersal.<ref>{{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 <!-- Bot retrieved archive --> |archive-date=September 29, 2007 }}</ref> 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.<ref>{{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 }}</ref> The [[United Nations Environment Programme|United Nations Environment Program]] backed away from an earlier proposal of putting thiomersal, when used as a component in vaccines, on the list of banned compounds, in its campaign to reduce exposure to mercury worldwide.<ref>{{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 |last=Hamilton |first=Jon |publisher=[[NPR]] |date=17 December 2012|access-date=25 February 2013}}</ref> Citing that eliminating the preservative in multi-dose vaccines, primarily used in developing countries, would lead to high cost and a requirement for refrigeration which the developing countries can ill afford, the UN's final decision at the [[Minamata Convention on Mercury]] in 2013 was to exclude thiomersal from the treaty.<ref>{{cite journal |url=https://www.aappublications.org/content/early/2013/01/22/aapnews.20130122-1 |date=January 22, 2013 |title=Global ban on mercury grants exception to thimerosal-containing vaccines |first=Alyson |last=Sulaski Wyckoff |journal=AAP News |publisher=[[American Academy of Pediatrics]] |access-date=August 24, 2019 }}</ref>
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.<ref>{{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 }}</ref> The [[United Nations Environment Programme|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.<ref>{{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}}</ref> 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.<ref>{{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 }}</ref>


==Toxicology==
==Toxicology==
===General toxicity===
===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).<ref>{{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 }}</ref> In the body, it is metabolized or degraded to [[ethylmercury]] (C<sub>2</sub>H<sub>5</sub>Hg<sup>+</sup>) and [[thiosalicylate]].<ref name=T-in-vaccines/>
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).<ref>{{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 }}</ref>


In the body, it is metabolized or degraded to [[ethylmercury]] (C<sub>2</sub>H<sub>5</sub>Hg<sup>+</sup>) and [[thiosalicylate]].<ref name=T-in-vaccines/>
Cases have been reported of severe [[mercury poisoning]] by accidental exposure or attempted suicide, with some fatalities.<ref name = "Clarkson2">{{cite journal |journal=Environ Health Perspect |year=2002 |volume=110 |issue=S1 |pages=11–23 |title=The three modern faces of mercury |last=Clarkson |first=TW |pmid=11834460 |pmc=1241144 |url=http://www.ehponline.org/members/2002/suppl-1/11-23clarkson/clarkson-full.html |doi=10.1289/ehp.02110s111 |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 }}</ref> 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.<ref name = "Clarkson2"/>


Cases have been reported of severe [[mercury poisoning]] by accidental exposure or attempted suicide, with some fatalities.<ref name = "Clarkson2">{{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 }}</ref> 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 [[Kidney|kidneys]] are targets. [[Ataxia|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.<ref name = "Clarkson2"/>
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 compound|inorganic]] mercury.<ref>{{cite journal | title=Neurotoxic character of thimerosal and the allometric extrapolation of adult clearance half-time to infants | journal=Journal of Applied Toxicology | year=2003 | pmid=12884410 | url=https://pubmed.ncbi.nlm.nih.gov/12884410/ | access-date=2021-01-19| last1=Magos | first1=L. | volume=23 | issue=4 | pages=263–269 | doi=10.1002/jat.918 | s2cid=20703489 }}</ref> 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]].<ref name=Clarkson/> 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.<ref>{{cite journal |last1=Clarkson |first1=TW |last2=Vyas |first2=JB |last3=Ballatori |first3=N |title=Mechanisms of mercury disposition in the body |journal=Am J Ind Med |volume=50 |issue=10 |pages=757–64 |year=2007 |pmid=17477364 |doi=10.1002/ajim.20476 }}</ref>


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 compound|inorganic]] mercury.<ref>{{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 }}</ref> The [[Biological half-life|half-life]] of ethylmercury in the brains of infant monkeys is 14 days.<ref name=Clarkson/> Risk assessment for effects on the [[nervous system]] have been made by extrapolating from dose-response relationships for [[methylmercury]].<ref name=Clarkson/> 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.<ref>{{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 }}</ref>
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.<ref name=Clarkson/> 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.<ref name=Clarkson>{{cite journal |journal=Crit Rev Toxicol |year=2006 |volume=36 |issue=8 |pages=609–62 |title=The toxicology of mercury and its chemical compounds |last1=Clarkson |first1=TW |last2=Magos |first2=L |doi=10.1080/10408440600845619 |pmid=16973445 |s2cid=37652857 }}</ref>

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.<ref name=Clarkson/> 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.<ref name="Clarkson">{{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}}</ref>


===As an allergen===
===As an allergen===
[[File:Epikutanni-test.jpg|thumb|[[Patch test]]]]
[[File:Epikutanni-test.jpg|thumb|left|[[Patch test]]]]

Thiomersal is used in [[patch test]]ing 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;<ref>{{cite journal |journal=Contact Dermatitis |year=2007 |volume=56 |issue=1 |pages=10–15 |title=Allergic contact sensitization in the general adult population: a population-based study from Northern Norway |last1=Dotterud |first1=LK |last2=Smith-Sivertsen |first2=T |doi=10.1111/j.1600-0536.2007.00980.x |pmid=17177703|s2cid=25765635 }}</ref> a higher prevalence of contact allergy (up to 6.6%) was observed in German populations.<ref name=Uter>{{cite journal |journal=J Clin Epidemiol |year=2004 |volume=57 |issue=6 |pages=627–32 |title=The prevalence of contact allergy differed between population-based and clinic-based data |last1=Uter |first1=W |last2=Ludwig |first2=A |last3=Balda |first3=BR |doi=10.1016/j.jclinepi.2003.04.002 |pmid=15246132}}</ref> Thiomersal-sensitive individuals can receive [[Intramuscular injection|intramuscular]] rather than [[Subcutaneous injection|subcutaneous]] immunization,<ref>{{cite journal |journal=Contact Dermatitis |year=1991 |volume=24 |issue=1 |pages=6–10 |title=Vaccination despite thimerosal sensitivity |last=Aberer |first=W |doi=10.1111/j.1600-0536.1991.tb01621.x |pmid=2044374|s2cid=43264826 }}</ref> 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.<ref name=Uter/>
Thiomersal is used in [[patch test]]ing 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;<ref>{{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 }}</ref> a higher prevalence of contact allergy (up to 6.6%) was observed in German populations.<ref name=Uter>{{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 }}</ref> Thiomersal-sensitive individuals can receive [[Intramuscular injection|intramuscular]] rather than [[Subcutaneous injection|subcutaneous]] immunization,<ref>{{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 }}</ref> 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.<ref name=Uter/>

Thiomersal allergy has decreased in Denmark, probably because of its exclusion from vaccines there.<ref>{{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 }}</ref> 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.<ref>{{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 }}</ref>


===Removal from vaccines===
Thiomersal allergy has decreased in Denmark, probably because of its exclusion from vaccines there.<ref>{{cite journal |journal=Contact Dermatitis |year=2007 |volume=57 |issue=5 |pages=287–99 |title=The epidemiology of contact allergy in the general populationprevalence and main findings |last1=Thyssen |first1=JP |last2=Linneberg |first2=A |last3=Menné |first3=T |last4=Johansen |first4=JD |doi=10.1111/j.1600-0536.2007.01220.x |pmid=17937743 |s2cid=44890665 }}</ref> 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 five years before the study, while further immunizations were performed with new thiomersal-free vaccines.<ref>{{cite journal |journal=Pediatr Allergy Immunol |year=2011 |volume=22 |issue=2 |pages=252–56 |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 |last1=Czarnobilska |first1=E |last2=Obtulowicz |first2=K |last3=Dyga |first3=W |last4=Spiewak |first4=R |pmid=20969635 |doi=10.1111/j.1399-3038.2010.01075.x |s2cid=22195669 }}</ref>
The Center for Biologics Evaluation and Research ([[Center for Biologics Evaluation and Research|CBER]]) at the FDA initiated a formal risk assessment of thiomersal in vaccines beginning in 1998.<ref name = "Stratton_2001">{{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/ }}</ref> 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.<ref name="Baker" /> 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.”<ref>{{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 }}</ref><ref name="pmid10418806">{{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) }}</ref> 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.<ref name = "Stratton_2001" />


===Disproven autism hypothesis===
===Disproven autism hypothesis===
{{main|Thiomersal and vaccines}}
{{main|Thiomersal and vaccines}}
Following a review of mercury-containing food and drugs mandated in 1999, the [[Centers for Disease Control and Prevention]] (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.<ref name="Baker"/><ref>{{cite web |url=https://www.fda.gov/cber/vaccine/thimfaq.htm |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}}</ref> 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.<ref name="Baker" /> The [[scientific consensus]] is that there is no evidence supporting these claims, and the rate of autism continues to climb despite elimination of thiomersal from routine childhood vaccines.<ref name="CDC concerns" /><ref name=DeStefano>{{cite journal |journal=Clin Pharmacol Ther |year=2007 |volume=82 |issue=6 |pages=756–59 |title=Vaccines and autism: evidence does not support a causal association |last=DeStefano |first=F |doi=10.1038/sj.clpt.6100407 |pmid=17928818|s2cid=12872702 }}</ref><ref name=Doja>{{cite journal |journal=Can J Neurol Sci |year=2006 |volume=33 |issue=4 |pages=341–46 |title=Immunizations and autism: a review of the literature |last1=Doja |first1=A |last2=Roberts |first2=W |pmid=17168158 |doi=10.1017/s031716710000528x |doi-access=free }}</ref><ref name=IOM2004/> Major scientific and medical bodies such as the [[Institute of Medicine]]<ref name=IOM2004>{{cite book |author=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 |isbn=978-0-309-09237-1 |url=http://www.nap.edu/catalog/10997.html}}</ref> and [[World Health Organization]],<ref name=WHO>{{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 }}</ref><ref>{{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}}</ref> as well as governmental agencies such as the [[Food and Drug Administration]]<ref name=T-in-vaccines/> and the CDC<ref name=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 }}</ref> reject any role for thiomersal in autism or other neurodevelopmental disorders.<ref name=Sugarman>{{cite journal |journal=N Engl J Med |year=2007 |volume=357 |issue=13 |pages=1275–77 |title=Cases in vaccine court legal battles over vaccines and autism |last=Sugarman |first=SD |pmid=17898095 |url=http://content.nejm.org/cgi/content/full/357/13/1275 |doi=10.1056/NEJMp078168 }}</ref> 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,<ref name="Harris">{{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|last1=Harris |first1=G |last2=O'Connor |first2=A |access-date=March 11, 2016 }}</ref> and diverting resources away from research into more promising areas for the [[cause of autism]].<ref name=Offit>{{cite journal |journal=N Engl J Med |year=2007 |volume=357 |issue=13 |pages=1278–79 |title=Thimerosal and vaccines – a cautionary tale |last=Offit |first=PA |doi=10.1056/NEJMp078187 |pmid=17898096 |url=http://content.nejm.org/cgi/content/full/357/13/1278 |author-link=Paul Offit}}</ref> Thousands of lawsuits have been filed in a [[vaccine court|U.S. federal court]] to seek damages from alleged toxicity from vaccines, including those purportedly caused by thiomersal.<ref>Autism cases in vaccine court:
Following the phasing out of thiomersal from most U.S. and European vaccines,<ref name="Baker"/><ref>{{cite web |url=https://www.fda.gov/cber/vaccine/thimfaq.htm |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}}</ref> 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.<ref name="Baker" /> 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.<ref name="CDC concerns" /><ref name=DeStefano>{{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 }}</ref><ref name=Doja>{{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 }}</ref><ref name=IOM2004/>
*{{cite journal |journal=N Engl J Med |year=2007 |volume=357 |issue=13 |pages=1275–77 |title=Cases in vaccine court – legal battles over vaccines and autism |last=Sugarman |first=SD |pmid=17898095 |url=http://content.nejm.org/cgi/content/full/357/13/1275 |doi=10.1056/NEJMp078168 }}
*{{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 }}</ref>


Scientific and medical bodies such as the [[Institute of Medicine]]<ref name="IOM2004">{{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}}</ref> and [[World Health Organization]],<ref name="WHO">{{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 }}</ref><ref>{{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}}</ref> as well as governmental agencies such as the [[Food and Drug Administration]]<ref name="T-in-vaccines" /> and the CDC<ref name="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 }}</ref> reject any role for thiomersal in autism or other neurodevelopmental disorders.<ref name="Sugarman">{{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 }}</ref> 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.<ref name="Harris">{{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 }}</ref> Studying thiomersal potentially diverts resources away from research into more promising areas for [[cause of autism|autism]].<ref name="Offit">{{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 }}</ref> Thousands of lawsuits have been filed in [[vaccine court|U.S. federal court]] to seek damages from allegedly toxic vaccines, including those purportedly caused by thiomersal.<ref>Autism cases in vaccine court:
==See also==
* {{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 }}
*{{annotated link|Nitromersol}}, a related antimicrobial
* {{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 }}</ref>
* [[Phenylmercuric nitrate]] - an organomercury compound with powerful antiseptic and antifungal effects


==References==
== See also ==
* {{Annotated link|Nitromersol}}, a related antimicrobial
* [[Phenylmercuric nitrate]] Organomercury compound with powerful antiseptic and antifungal effects

== References ==
{{Reflist}}
{{Reflist}}


{{Mercury compounds}}
{{Mercury compounds}}
{{vaccines}}
{{Vaccines}}
{{Antiseptics and disinfectants}}
{{Antiseptics and disinfectants}}
{{sodium compounds}}
{{Sodium compounds}}


[[Category:Thiolates]]
[[Category:Benzoates]]
[[Category:Eli Lilly and Company brands]]
[[Category:Drugs developed by Eli Lilly and Company]]
[[Category:Organomercury compounds]]
[[Category:Excipients]]
[[Category:Excipients]]
[[Category:Organic sodium salts]]
[[Category:Organic sodium salts]]
[[Category:Benzoates]]
[[Category:Organomercury compounds]]
[[Category:Thiolates]]

Latest revision as of 05:36, 2 December 2024

Thiomersal
Thiomersal
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 Edit this at Wikidata
EC Number
  • 200-210-4
1677155
KEGG
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 checkY
    Key: RTKIYNMVFMVABJ-UHFFFAOYSA-L checkY
  • 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
C9H9HgNaO2S
Molar mass 404.81 g/mol
Appearance White 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:
GHS06: ToxicGHS08: Health hazardGHS09: Environmental hazard
Danger
H300, H310, H330, H373, H410
P260, P273, P280, P301, P302, P304, P310, P330, P340, P352[2]
NFPA 704 (fire diamond)
NFPA 704 four-colored diamondHealth 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).
checkY verify (what is checkY☒N ?)

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] Single-dose vial flu shots are an option for those who prefer vaccines with no thiomersal, although no scientific data supports claims that there is any link between thiomersal and autism.

History

[edit]

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

[edit]

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

[edit]

Antiseptic/antifungal

[edit]

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

[edit]

General toxicity

[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).[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

[edit]
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

[edit]

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

[edit]

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

[edit]
  • Nitromersol – Organomercury antiseptic and antifungal agent, a related antimicrobial
  • Phenylmercuric nitrate – Organomercury compound with powerful antiseptic and antifungal effects

References

[edit]
  1. ^ a b Melnick JG, Yurkerwich K, Buccella D, Sattler W, Parkin G (July 2008). "Molecular structures of thimerosal (Merthiolate) and other arylthiolate mercury alkyl compounds". Inorganic Chemistry. 47 (14): 6421–6426. doi:10.1021/ic8005426. PMID 18533648.
  2. ^ "Thimerosal T5125".
  3. ^ Chambers M. "ChemIDplus – 54-64-8 – RTKIYNMVFMVABJ-UHFFFAOYSA-L – Thimerosal [USP:JAN] – Similar structures search, synonyms, formulas, resource links, and other chemical information". chem.sis.nlm.nih.gov. Retrieved 3 April 2018.
  4. ^ "Merthiolate poisoning: MedlinePlus Medical Encyclopedia". medlineplus.gov. Retrieved 8 December 2023.
  5. ^ "Thimerosal and Vaccines | Vaccine Safety | CDC". Centers for Disease Control and Prevention. 25 August 2020. Retrieved 4 May 2023.
  6. ^ Sharpe MA, Livingston AD, Baskin DS (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: 373678. doi:10.1155/2012/373678. PMC 3395253. PMID 22811707. ...widely used in medical products, including as a preservative in vaccines, immunoglobulin preparations, skin test antigens, antivenins, ophthalmic and nasal products, and tattoo inks...
  7. ^ a b c 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. doi:10.17226/10997. ISBN 978-0-309-09237-1. PMID 20669467.
  8. ^ 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.
  9. ^ a b "Vaccines Do Not Cause Autism". cdc.gov. Retrieved 29 November 2015.
  10. ^ Gołoś A, Lutyńska A (2015). "Thiomersal-containing vaccines - a review of the current state of knowledge". Przeglad Epidemiologiczny. 69 (1): 59–64, 157–61. PMID 25862449.
  11. ^ "Thimerosal in Vaccines: A Joint Statement of the American Academy of Pediatrics and the Public Health Service" (PDF). Morbidity and Mortality Weekly Report Vol. 48 No. 26. Centers for Disease Control and Prevention. 9 July 1999. pp. 563–65. Retrieved 8 May 2024.
  12. ^ Hurley AM, Tadrous M, Miller ES (July 2010). "Thimerosal-containing vaccines and autism: a review of recent epidemiologic studies". The Journal of Pediatric Pharmacology and Therapeutics. 15 (3): 173–181. doi:10.5863/1551-6776-15.3.173. PMC 3018252. PMID 22477809.
  13. ^ a b Bigham M, Copes R (2005). "Thiomersal in vaccines: balancing the risk of adverse effects with the risk of vaccine-preventable disease". Drug Safety. 28 (2): 89–101. doi:10.2165/00002018-200528020-00001. PMID 15691220. S2CID 11570020.
  14. ^ "Not Immune". The New Yorker. 8 February 2015. Retrieved 2 October 2022.
  15. ^ "Thimerosal in Flu Vaccine | CDC". 22 August 2023.
  16. ^ U.S. patent 1,672,615 "Alkyl mercuric sulphur compound and process of producing it".
  17. ^ a b c d e f g Baker JP (February 2008). "Mercury, vaccines, and autism: one controversy, three histories". American Journal of Public Health. 98 (2): 244–253. doi:10.2105/AJPH.2007.113159. PMC 2376879. PMID 18172138.
  18. ^ a b c d "Thimerosal and vaccines". Center for Biologics Evaluation and Research, U.S. Food and Drug Administration. 2 January 2018. Retrieved 9 April 2023.
  19. ^ "Thimerosal in Vaccines: Frequently Asked Questions". Food and Drug Administration. Archived from the original on 31 December 2008. Retrieved 9 March 2008.
  20. ^ "Mercury in plasma-derived products". U.S. Food and Drug Administration. 9 September 2004. Archived from the original on 29 September 2007. Retrieved 1 October 2007.
  21. ^ Global Advisory Committee on Vaccine Safety (14 July 2006). "Thiomersal and vaccines". World Health Organization. Archived from the original on 20 August 2003. Retrieved 20 November 2007.
  22. ^ Hamilton J (17 December 2012). "Doctors Argue Against Proposed Ban on Vaccine Preservative". NPR. Retrieved 25 February 2013.
  23. ^ Wyckoff AS (22 January 2013). "Global ban on mercury grants exception to thimerosal-containing vaccines". AAP News. American Academy of Pediatrics. Archived from the original on 13 January 2016. Retrieved 24 August 2019.
  24. ^ "Safety data sheet, Thiomersal Ph Eur, BP, USP" (PDF). Merck. 12 June 2005. Archived from the original (PDF) on 15 September 2009. Retrieved 1 January 2010.
  25. ^ a b Clarkson TW (February 2002). "The three modern faces of mercury". Environmental Health Perspectives. 110 (Suppl 1): 11–23. doi:10.1289/ehp.02110s111. PMC 1241144. PMID 11834460. Archived from the original on 6 September 2008.
  26. ^ Magos L (2003). "Neurotoxic character of thimerosal and the allometric extrapolation of adult clearance half-time to infants". Journal of Applied Toxicology. 23 (4): 263–269. doi:10.1002/jat.918. PMID 12884410. S2CID 20703489.
  27. ^ a b c d Clarkson TW, Magos L (September 2006). "The toxicology of mercury and its chemical compounds". Critical Reviews in Toxicology. 36 (8): 609–662. doi:10.1080/10408440600845619. PMID 16973445. S2CID 37652857.
  28. ^ Clarkson TW, Vyas JB, Ballatori N (October 2007). "Mechanisms of mercury disposition in the body". American Journal of Industrial Medicine. 50 (10): 757–764. doi:10.1002/ajim.20476. PMID 17477364.
  29. ^ Dotterud LK, Smith-Sivertsen T (January 2007). "Allergic contact sensitization in the general adult population: a population-based study from Northern Norway". Contact Dermatitis. 56 (1): 10–15. doi:10.1111/j.1600-0536.2007.00980.x. PMID 17177703. S2CID 25765635.
  30. ^ a b 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.
  31. ^ Aberer W (January 1991). "Vaccination despite thimerosal sensitivity". Contact Dermatitis. 24 (1): 6–10. doi:10.1111/j.1600-0536.1991.tb01621.x. PMID 2044374. S2CID 43264826.
  32. ^ Thyssen JP, Linneberg A, Menné T, Johansen JD (November 2007). "The epidemiology of contact allergy in the general population--prevalence and main findings". Contact Dermatitis. 57 (5): 287–299. doi:10.1111/j.1600-0536.2007.01220.x. PMID 17937743. S2CID 44890665.
  33. ^ Czarnobilska E, Obtulowicz K, Dyga W, Spiewak R (March 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". Pediatric Allergy and Immunology. 22 (2): 252–256. doi:10.1111/j.1399-3038.2010.01075.x. PMID 20969635. S2CID 22195669.
  34. ^ a b 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: