Thiomersal (INN) (C9H9HgNaO2S), or sodium ethylmercurithiosalicylate, 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 invented and patented by Morris Kharasch. The pharmaceutical corporation Eli Lilly and Company gave it the trade name Merthiolate and it has been used as a preservative in vaccines, immunoglobulin preparations, skin test antigens, antivenins, ophthalmic and nasal products, and tattoo inks. Its use as a vaccine preservative is controversial, and it is being phased out from routine childhood vaccines in the United States, the European Union, and a few other countries.
4.0 See also
Thiomersal’s main use is as an antiseptic and antifungal agent. In multidose injectable drug delivery systems, it prevents serious adverse effects such as the Staphylococcus infection that, in one 1928 incident, killed 12 of 21 children inoculated with a diphtheria vaccine that lacked a preservative. Unlike other vaccine preservatives used at the time, thiomersal does not reduce the potency of the vaccines that it protects. Bacteriostatics like thiomersal are not needed in more-expensive single-dose injectables.
In the United States, countries in the European Union and a few other affluent countries, thiomersal is no longer used as a preservative in routine childhood vaccination schedules. 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. 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. Also, four rarely used treatments for pit viper, coral snake, and black widow venom still contain thiomersal. 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.
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). In the body, it is metabolized or degraded to ethylmercury (C2H5Hg+) and thiosalicylate.
Few studies of the toxicity of thiomersal in humans have been performed. 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. Fecal excretion accounts for most of the elimination from the body. Ethylmercury clears from blood with a half-life 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 not yet understood.
Risk assessment for effects on the nervous system have been made by extrapolating from dose-response relationships for methylmercury. Methylmercury and ethylmercury distributes to all body tissues, crossing the blood-brain barrier and the placental barrier, and ethylmercury also moves freely throughout the body.
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 cleared from the body and the brain significantly faster than methylmercury, so the late-1990s risk assessments turned out to be overly conservative. A 2008 study found that the half-life of blood mercury after vaccination averages 3.7 days for newborns and infants, much shorter than the 44 days for methylmercury.
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; a higher prevalence of contact allergy (up to 6.6%) was observed in German populations. Thiomersal-sensitive individuals can receive intramuscular rather than subcutaneous immunization, so contact allergy is usually clinically irrelevant. Thiomersal allergy has decreased in Denmark, probably because of its exclusion from vaccines there.
It was voted Allergen of the Year in 2002 by the American Contact Dermatitis Society.
Main article: Thiomersal controversy
There is no convincing evidence that thiomersal is a factor in the onset of autism. Despite this, many parents, and some scientists and doctors, believe there is a connection. 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.
More than 5,000 U.S. families have filed claims in a federal vaccine court alleging autism was caused by vaccines, most implicating thiomersal; the majority of these claims are still being adjudicated.
The U.S. federal government agreed to award damages in one case, to a girl with a mitochondrial enzyme deficiency who developed autistic-like symptoms after receiving a series of vaccines, some of which contained thiomersal. Many parents view this ruling as confirming that vaccines cause regressive autism; however, most children with autism do not seem to have mitochondrial disorders, and the case was conceded without proof of causation.
Morris Kharasch, a chemist at the University of Maryland, filed a patent application for thiomersal in 1927; Eli Lilly later marketed the compound under the trade name Merthiolate. In vitro tests conducted by Lilly investigators H.M. Powell and W.A. Jamieson found that it was forty to fifty times as effective as phenol against Staphylococcus aureus. It was used to kill bacteria and prevent contamination in antiseptic ointments, creams, jellies, and sprays used by consumers and in hospitals, including nasal sprays, eye drops, contact lens solutions, immunoglobulins, and vaccines. Thiomersal was used as a preservative (bactericide) so that multidose vials of vaccines could be used instead of single-dose vials, which are more expensive. By 1938, Lilly’s assistant director of research listed thiomersal as one of the five most important drugs ever developed by the company.
Thiomersal’s safety for its intended uses 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 United States Food and Drug Administration review concluded that this use of thiomersal was not dangerous. 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 micrograms 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 infant vaccines in the U.S., which was largely complete by summer 2001. Some parents of autistic children adopted thiomersal as an explanation for the increase in reported autism cases and sued vaccine makers; the mercury-autism hypothesis is accepted widely among parents of autistic children, despite scientific studies rejecting it.
1. ^ a b Bigham M, Copes R (2005). “Thiomersal in vaccines: balancing the risk of adverse effects with the risk of vaccine-preventable disease”. Drug Saf 28 (2): 89–101. doi:10.2165/00002018-200528020-00001. PMID 15691220.
2. ^ a b c d “Thimerosal in vaccines”. Center for Biologics Evaluation and Research, U.S. Food and Drug Administration. 2008-06-03. Retrieved 2008-07-25.
3. ^ a b c d e f g Baker JP (2008). “Mercury, vaccines, and autism: one controversy, three histories”. Am J Public Health 98 (2): 244–53. doi:10.2105/AJPH.2007.113159. PMID 18172138.
4. ^ “Thimerosal in Vaccines: Frequently Asked Questions”. Food and Drug Administration. Retrieved 2008-03-09.
5. ^ Coordinating Center for Infectious Diseases (2007-10-26). “Thimerosal in seasonal influenza vaccine”. Centers for Disease Control and Prevention. Retrieved 2008-04-02.
6. ^ “Mercury in plasma-derived products”. U.S. Food and Drug Administration. 2004-09-09. Retrieved 2007-10-01.
7. ^ Global Advisory Committee on Vaccine Safety (2006-07-14). “Thiomersal and vaccines”. World Health Organization. Retrieved 2007-11-20.
8. ^ “Thiomersal Ph Eur, BP, USP material safety data sheet” (PDF). Merck. 2005-06-12. Retrieved 2007-10-01.
9. ^ a b c Toxicology of thiomersal:
▪ Clarkson TW (2002). “The three modern faces of mercury”. Environ Health Perspect 110 (S1): 11–23. PMID 11834460.
▪ Clarkson TW, Magos L (2006). “The toxicology of mercury and its chemical compounds”. Crit Rev Toxicol 36 (8): 609–62. doi:10.1080/10408440600845619. PMID 16973445.
10. ^ Clarkson TW, Vyas JB, Ballatori N (2007). “Mechanisms of mercury disposition in the body”. Am J Ind Med 50 (10): 757–64. doi:10.1002/ajim.20476. PMID 17477364.
11. ^ Pichichero ME, Gentile A, Giglio N et al. (2008). “Mercury levels in newborns and infants after receipt of thimerosal-containing vaccines”. Pediatrics 121 (2): e208–14. doi:10.1542/peds.2006-3363. PMID 18245396. Lay summary – University of Rochester Medical Center (2008-01-30).
12. ^ Dotterud LK, Smith-Sivertsen T (2007). “Allergic contact sensitization in the general adult population: a population-based study from Northern Norway”. Contact Dermatitis 56 (1): 10–5. doi:10.1111/j.1600-0536.2007.00980.x. PMID 17177703.
13. ^ a b Uter W, Ludwig A, Balda BR (2004). “The prevalence of contact allergy differed between population-based and clinic-based data”. J Clin Epidemiol 57 (6): 627–32. doi:10.1016/j.jclinepi.2003.04.002. PMID 15246132.
14. ^ Aberer W (1991). “Vaccination despite thimerosal sensitivity”. Contact Dermatitis 24 (1): 6–10. doi:10.1111/j.1600-0536.1991.tb01621.x. PMID 2044374.
15. ^ Thyssen JP, Linneberg A, Menné T, Johansen JD (2007). “The epidemiology of contact allergy in the general population—prevalence and main findings”. Contact Dermatitis 57 (5): 287–99. doi:10.1111/j.1600-0536.2007.01220.x. PMID 17937743.
16. ^ a b Doja A, Roberts W (2006). “Immunizations and autism: a review of the literature”. Can J Neurol Sci 33 (4): 341–6. PMID 17168158.
17. ^ a b Sugarman SD (2007). “Cases in vaccine court—legal battles over vaccines and autism”. N Engl J Med 357 (13): 1275–7. doi:10.1056/NEJMp078168. PMID 17898095.
18. ^ Taylor B (2006). “Vaccines and the changing epidemiology of autism”. Child Care Health Dev 32 (5): 511–9. doi:10.1111/j.1365-2214.2006.00655.x. PMID 16919130.
19. ^ Offit PA (2008). “Vaccines and autism revisited—the Hannah Poling case”. N Engl J Med 358 (20): 2089–91. doi:10.1056/NEJMp0802904. PMID 18480200.
20. ^ Harris G (2008-03-08). “Deal in an autism case fuels debate on vaccine”. NY Times.
21. ^ Honey K (2008). “Attention focuses on autism”. J Clin Invest 118 (5): 1586–7. doi:10.1172/JCI35821. PMID 18451989.
22. ^ U.S. Patent 1,672,615 “Alkyl mercuric sulphur compound and process of producing it”.
23. ^ Ball LK, Ball R, Pratt RD (2001). “An assessment of thimerosal use in childhood vaccines”. Pediatrics 107 (5): 1147–54. doi:10.1542/peds.107.5.1147. PMID 11331700.
24. ^ DeStefano F (2007). “Vaccines and autism: evidence does not support a causal association”. Clin Pharmacol Ther 82 (6): 756–9. doi:10.1038/sj.clpt.6100407. PMID 17928818.