Thiomersal

Thiomersal (INN) (C₉H₉HgNaO₂S), formerly and still commonly known in the United States as thimerosal, is an organomercury compound (approximately 49% mercury by weight) used as an antiseptic and antifungal agent.

It was developed and registered under the trade name Merthiolate in 1929 by the pharmaceutical company Eli Lilly and Company, and has been used as a preservative in vaccines, immune globulin preparations, skin test antigens, antivenins, ophthalmic and nasal products, and tattoo inks.

The compound has been phased out from most childhood vaccinations in Europe and North America. Packaging the vaccines in single-dose vials eliminates the need for bacteriostatics such as thiomersal.

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Use

Thiomersal's main use is as an antiseptic and antifungal agent. In multi-dose injectable drug delivery systems, it prevents serious adverse effects such as the Staphylococcus infection that in one 1928 incident killed 12 of 21 children inoculated with a diphtheria vaccine that lacked a preservative.^[1] Unlike other vaccine preservatives used at the time, thiomersal does not reduce the potency of the vaccines that it protects.^[2] Thiomersal is not needed in more-expensive single-dose injectables.

In the U.S., the European Union, and a few other affluent countries, thiomersal is no longer used as a preservative in childhood vaccines.^[3] In the U.S., the only exceptions among vaccines routinely recommended for young children are most formulations of the inactivated influenza vaccine. Several vaccines not routinely recommended for young children contain thimerosal, 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.^[1] Also, four rarely-used treatments for pit viper, coral snake, and black widow venom still contain thimerosal.^[4] Outside North America and Europe, many vaccines contain thiomersal; the World Health Organization has concluded that there is no evidence of toxicity from thimerosal in vaccines and no reason on grounds of safety to change to more-expensive single-dose administration.^[5]

Toxicology

Thiomersal is very toxic by inhalation, ingestion, and in contact with skin (EC hazard symbol T+), with 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).^[6] In the body, it is metabolized or degraded to ethylmercury (C₂H₅Hg⁺) and thiosalicylate.^[1]

Few studies of the toxicity of thiomersal in humans have been performed. Animal experiments suggest that thimerosal rapidly dissociates to release ethylmercury after injection, that the disposition patterns of mercury are similar to those after exposure to equivalent doses of ethylmercury chloride, and that the central nervous system and the kidneys are targets, with lack of motor coordination being a common sign. Similar signs and symptoms have been observed in accidental human poisonings. The mechanisms of toxic action are unknown. Fecal excretion accounts for most of the elimination from the body. Ethylmercury clears from blood with a half-time of about 18 days, and from the brain in about 14 days. Inorganic mercury metabolized from ethylmercury has a much longer clearance, at least 120 days; it appears to be much less toxic than the inorganic mercury produced from mercury vapor, for reasons that are not understood.^[7]

Risk assessment for effects on the nervous system have been made by extrapolating from dose-response relationships for methylmercury, which is why thiomersal was removed from U.S. childhood vaccines starting in 1999. However, since then it has been found that ethylmercury is cleared from the body and the brain significantly faster than methylmercury, so the late-1990s risk assessments were overly conservative.^[7]

Allergies

Thiomersal is used in patch testing for people who have dermatitis, conjunctivitis and other potentially allergic reaction. A 2007 study in Norway found that 1.9% of adults had a positive patch test reaction to thiomersal.^[8] A higher prevalence of contact allergy (up to 6.6%) was observed in German populations. It is usually clinically irrelevant;^[9] thiomersal-sensitive individuals can receive intramuscular rather than subcutaneous immunization.^[10]

Autism

Main article: Thiomersal controversy

Many parents, and some scientists and doctors, believe there is a connection between thiomersal and autism. More than 5000 U.S. families have filed claims alleging autism was caused by vaccines, most implicating thiomersal; most claims are still being adjudicated and no awards have been given.^[11] Although there is no convincing evidence that thiomersal is a factor in the onset of autism, parents may first become aware of autistic symptoms in their child around the time of a routine vaccination, and parental concern about vaccines has led to a decreasing uptake of childhood immunizations and an increasing likelihood of measles outbreaks.^[12]

History

Thiomersal was developed by Dr. Morris S. Kharasch, a chemist and Eli Lilly and Company fellow at the University of Maryland and then at the University of Chicago.^{[citation needed]}

Eli Lilly and Company patented the compound under the trade name Merthiolate in 1928.^[2] In vitro tests conducted by Lilly's investigators H.M. Powell and W.A. Jamieson found that it was 40 to 50 times as effective as phenol against Staphylococcus aureus.^[2] It was used to kill bacteria and prevent contamination in antiseptic ointments, creams, jellies, and sprays used by consumers and in hospitals. Thiomersal was used in many such products (e.g. nasal sprays, eye drops, contact lens solutions, immunoglobulins, and vaccines). Thiomersal was used as a preservative (bactericide) so multi-dose 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.^[2]

Thiomersal's safety first came under question in the 1970s, when case reports demonstrated potential for neurotoxicity when given in large volumes as a topical antiseptic. At the time, the DPT vaccine was the only childhood vaccine that contained it; a 1976 FDA review concluded that this use of thiomersal was not dangerous.^[2] Concerns about mercury arising from Minamata disease and other cases of methylmercury poisoning led U.S. authorities to lower reference doses for methylmercury in the 1990s, about the same time that autism diagnoses began rising sharply. In 1999, a new FDA analysis concluded that infants could receive as much as 187.5 mg of ethylmercury during the first six months; lacking any standard for ethylmercury it used methylmercury-based standards to recommend that thiomersal be removed from routine childhood vaccines in the U.S., which was done by 2001.^[2] Some parents of autistic children seized upon thimerosal as an explanation for the increase in reported autism cases and sued vaccine makers, and the mercury-autism hypotheses is accepted widely among parents of autistic children, despite scientific studies rejecting it.^[2]

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