Thiomersal

Template:Short description Template:Use dmy dates Template:Cs1 config Template:Chembox Thiomersal (INN), or thimerosal (USAN, JAN), also sold under the name merthiolate,<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> is an organomercury compound. It is a well-established antiseptic and antifungal agent.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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.<ref>Template:Cite journal</ref> In spite of the scientific consensus that fears about its safety are unsubstantiated,<ref name = "IOM2004" /><ref>Template:Cite journal</ref><ref name="CDC concerns">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite journal</ref> 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."<ref>Template:Cite news</ref><ref>Template:Cite journal</ref><ref name=drugsaf/>

It remains in use as a preservative for certain annual flu vaccines, mostly those stored in multi-dose vials.<ref>Template:Cite magazine</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</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.

History

Morris Kharasch, a chemist then at the University of Maryland filed a patent application for thiomersal in 1927;<ref>{{#if:1672615 |[{{#ifeq:|uspto|http://patft.uspto.gov/netacgi/nph-Parser?patentnumber=%7Chttps://patents.google.com/patent/US}}{{#iferror:{{#expr:1672615 }}|1672615}} U.S. patent {{#ifeq:Template:Replace|Template:Digits|Template:Replace|1672615}}] |{{US patent|123456|link text}}}} "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, 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.<ref name="Baker"/>

Structure

Thiomersal features mercury(II) with a coordination number 2, i.e. two ligands are attached to Hg, the thiolate and the ethyl group. The carboxylate group confers solubility in water. Like other two-coordinate Hg(II) compounds, the coordination geometry of Hg is linear, with a 180° S-Hg-C angle. Typically, organomercury thiolate compounds are prepared from organomercury chlorides.<ref name="molstruct">Template:Cite journal</ref>

Uses

Antiseptic/antifungal

Thiomersal's main use is as an antiseptic and antifungal agent, due to its oligodynamic effect. In multidose injectable drug delivery systems, it prevents serious adverse effects such as the Staphylococcus infection that, in one 1928 incident, killed 12 of 21 children vaccinated with a diphtheria vaccine that lacked a preservative.<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">Template:Cite journal</ref> Bacteriostatics such as thiomersal are not needed in single-dose injectables.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</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 schedules.<ref name="drugsaf">Template:Cite journal</ref> 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.<ref name="T-in-vaccines">{{#invoke:citation/CS1|citation |CitationClass=web }}</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>{{#invoke:citation/CS1|citation |CitationClass=web }}</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>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</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>Template:Cite journal</ref>

Toxicology

General toxicity

Thiomersal is very toxic by inhalation, ingestion, and in contact with skin (EC hazard symbol T+), with a danger of cumulative effects. It is also very toxic to aquatic organisms and may cause long-term adverse effects in aquatic environments (EC hazard symbol N).<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

In the body, it is metabolized or degraded to ethylmercury (C₂H₅Hg⁺) 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">Template:Cite journal</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 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.<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 mercury.<ref>Template:Cite journal</ref> The 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>Template:Cite journal</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">Template:Cite journal</ref>

As an allergen

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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;<ref>Template:Cite journal</ref> a higher prevalence of contact allergy (up to 6.6%) was observed in German populations.<ref name=Uter>Template:Cite journal</ref> Thiomersal-sensitive individuals can receive intramuscular rather than subcutaneous immunization,<ref>Template:Cite journal</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>Template:Cite journal</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>Template:Cite journal</ref>

Removal from vaccines

The Center for Biologics Evaluation and Research (CBER) at the FDA initiated a formal risk assessment of thiomersal in vaccines beginning in 1998.<ref name = "Stratton_2001">Template:Cite book</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>Template:Cite journal</ref><ref name="pmid10418806">Template:Cite journal</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

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} Following the phasing out of thiomersal from most U.S. and European vaccines,<ref name="Baker"/><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</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>Template:Cite journal</ref><ref name=Doja>Template:Cite journal</ref><ref name=IOM2004/>

Scientific and medical bodies such as the Institute of Medicine<ref name="IOM2004">Template:Cite book</ref> and World Health Organization,<ref name="WHO">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> as well as governmental agencies such as the Food and Drug Administration<ref name="T-in-vaccines" /> and the CDC<ref name="CDC">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> reject any role for thiomersal in autism or other neurodevelopmental disorders.<ref name="Sugarman">Template:Cite journal</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">Template:Cite news</ref> Studying thiomersal potentially diverts resources away from research into more promising areas for autism.<ref name="Offit">Template:Cite journal</ref> Thousands of lawsuits have been filed in U.S. federal court to seek damages from allegedly toxic vaccines, including those purportedly caused by thiomersal.<ref>Autism cases in vaccine court:

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See also

• Template:Annotated link, a related antimicrobial
• Phenylmercuric nitrate – Organomercury compound with powerful antiseptic and antifungal effects