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New insights about interaction of thimerosal with blood components



Thimerosal (Thiomersal)
Due to its fungicidal and bactericidal properties, Thimerosal (THI) has been used since 1931 as a preservative mainly in multidose ampullae of drugs, vaccines and other medical products. The antimicrobial effect is based on its decomposition in aqueous medium to thiosalicylic acid and the monoethyl-mercury cation (EtHg+), which has a high binding affnity to thiol functions of proteins.

Due to the well known neurotoxicity of organomercury compounds, the question about possible toxic effects of THI reentered the public discussion in the 1990s, when an increasing number of vaccines was preserved with THI, including vaccines used for infants and children.

Due to suspected neurotoxic effects especially in children, the use of THI was banned in the European Union in 2001. Moreover, a connection between increasing occurrence of autism and usage of THI in vaccines is heavily discussed in the scientific world (see the EVISA News).

Despite the ongoing discussion, very little is known about the toxicity of ethylmercury in the human body. For this reason, data about methylmercury was often used for estimating the health risks imposed by ethylmercury.

In order to study the transport, distribution and metabolism of THI, researchers have done in vitro experiments with blood components,  in-vivo experiments with animals and followed the pharmacokinetics of THI in infants having received vaccines containing thimerosal. These studies have demonstrated the different half lifes of the two mercury species in the human body. While for the metabolism of methylmercury cations different mechanisms are suggested, only little is known about the metabolism of ethylmercury cations.

The new study:
The researchers from the University of Münster performed in-vitro incubation experiments with human and rat hemoglobin. From previous work (Trümpler et al.) it was already known, that about 80% of ethylmercury dosed to human blood can be recovered in red blood cells (RBC). Since hemoglobin is the most highly abundant constituent of RBC besides water, a reaction between EtHg+ and hemoglobin was expected, with thiol groups of hemoglobin being the expected binding sites.

The interaction between THI and hemoglobin was studied by using liquid chromatography coupled to electrospray ionization mass spectrometry (LC-ESI-MS). Using the high mass resolution of a TOF-MS instrument, adduct formation between THI and hemoglobin could be observed at low THI concentrations mimicking those relevant to vaccine application. Moreover, the binding stoichiometry correlated with the number of free thiol functions. Whereas human hemoglobin has six free thiol groups – one in each of the a-chains and two in each of the b-chains, hemoglobin of rats possess ten reactive thiol functions per hemoglobin, three in each a-chain and two in the b-chain.

The fact, that hemoglobin of rats can bind significantly more EtHg+ units compared to human hemoglobin leads to the conclusion that rat experiments for pharmacokinetics or toxicological studies and final health risk assessment of components like THI undergoing protein binding may not be easily transferred from rats to humans.

The original study

Rasmus Janzen, Miriam Schwarzer, Michael Sperling, Martin Vogel, Tanja Schwerdtle, Uwe Karst, Adduct formation of Thimerosal with human and rat hemoglobin: a study using liquid chromatography coupled to electrospray time-of-flight mass spectrometry (LC/ESI-TOF-MS),
Metallomics, 3/8 (2011) 847–852. doi: 10.1039/c1mt00043h

Instruments used for the study

Instrument Database: Bruker microTOF
Instrument Database: Stuart Aquatron water still

Related studies

J.G. Dorea, Integrating Experimental (In Vitro and In Vivo) Neurotoxic Studies of Low-dose Thimerosal Relevant to Vaccines, Neurochem. Res., 36 (2011) 927–938. DOI: 10.1007/s11064-011-0427-0

L. Barregard, D. Rekic, M. Horvat, L. Elmberg, T. Lundh, O. Zachrisson, Toxicokinetics of mercury after long-term repeated exposure to thimerosal-containing vaccine, Toxicol. Sci., 120 (2011) 499–506. doi: 10.1093/toxsci/kfr009

W.Y. Feng, M. Wang, M. Guan, Y. Hui, J. W. Shi, B. Wang, M. Zhu, O.Y. Hong, Y.L. Zhao, Z.F. Chai, Mercury speciation and mercury-binding protein study by HPLC-ICP-MS on the estimation of mercury toxicity between maternal and infant rats, J. Anal. At. Spectrom., 26/1 (2011) 156–164. DOI: 10.1039/c0ja00111b

J.L. Rodrigues, J.M. Serpeloni, B.L. Batista, S.S. Souza, F. Barbosa Jr, Identification and distribution of mercury species in rat tissues following administration of thimerosal or methylmercury, Arch. Toxicol., 2010, 84, 891–896. DOI 10.1007/s00204-010-0538-4

C.S. Price, W.W. Thompson, B. Goodson, E.S. Weintraub, L.A. Croen, V. L. Hinrichsen, M. Marcy, A. Robertson, E. Eriksen, E. Lewis, P. Bernal, D. Shay, R.L. Davis, F. DeStefano, Prenatal and Infant Exposure to Thimerosal From Vaccines and Immunoglobulins and Risk of Autism, Pediatrics, 126 (2010) 656–664. DOI: 10.1542/peds.2010-0309

S. Trümpler, W. Lohmann, B. Meermann, W. Buscher, M. Sperling, U. Karst, Interaction of thimerosal with proteins—ethylmercury adduct formation of human serum albumin and b-lactoglobulin A, Metallomics, 1 (2009) 87–91. DOI: 10.1039/b815978e

M.E. Pichichero, A. Gentile, N. Giglio, V. Umido, T. Clarkson, E. Cernichiari, G. Zareba, C. Gotelli, M. Gotelli, L. Yan, J. Treanor, Mercury Levels in Newborns and Infants After Receipt of Thimerosal-Containing Vaccines, Pediatrics, 21 (2008) e208–e214. DOI: 10.1542/peds.2006-3363

G. Zareba, E. Cernichiari, R. Hojo, S. M. Nitt, B. Weiss, M.M.Mumtaz, D. E. Jones, T.W. Clarkson, Thimerosal distribution and metabolism in neonatal mice: comparison with methyl mercury, J. Appl. Toxicol., 27/5 (2007) 511–518. DOI: 10.1002/jat.1272

D.A. Geier, L.K. Sykes, M.R. Geier, A Review of Thimerosal (Merthiolate) and its Ethylmercury Breakdown Product: Specific Historical Considerations Regarding Safety and Effectiveness, J. Toxicol. Environ. Health, Part B, 10 (2007) 575–596. DOI: 10.1080/10937400701389875

T.M. Burbacher, D.D. Shen, N. Liberato, K.S. Grant, E. Cernichiari, T. Clarkson, Comparison of Blood and Brain Mercury Levels in Infant Monkeys Exposed to Methylmercury or Vaccines Containing Thimerosal, Environ. Health Perspect., 2005, 113, 1015–1021. doi:10.1289/ehp.7712

G.J. Harry, M.W. Harris, L.T. Burka, Mercury concentrations in brain and kidney following ethylmercury, methylmercury and Thimerosal administration to neonatal mice, Toxicol. Lett., 2004, 154, 183–189. doi:10.1016/j.toxlet.2004.07.014

L. Magos, Neurotoxic Character of Thimerosal and the Allometric Extrapolation of Adult Clearance Half-time to Infants,  J. Appl. Toxicol., 23 (2003) 263–269. DOI: 10.1002/jat.918

Related EVISA Resources

Brief Summary: ESI-MS: The tool for the identification of chemical species
Link Database: All about thimerosal
Link database: Toxicity of organic mercury compounds

Related EVISA News

November 12, 2017: Mercury and Autism: Is there a Link ?
May 5, 2014: Global policy on the use of mercury as a preservative in vaccine called discriminatory
January 21, 2013: UNEP mercury treaty exempts vaccines for children 
January 14, 2013: United Nations Global Mercury Treaty: Fifth and final session
December 18, 2012: Pediatricians Argue to Keep Thimerosal in Some Vaccines
October 12, 2012: Prenatal mercury intake linked to ADHD
July 15, 2012: World Health Organization Fails In Its Effort To Defend Mercury In Vaccines Before United Nations 
June 19, 2012: Vaccine ingredient causes brain damage; some nutrients prevent it
October 28, 2011: WHO worries mercury treaty could affect costs and availability of vaccines
August 15, 2011: New insights about interaction of thimerosal with blood components
August 8, 2011: UNEP Global Mercury Treaty May Include Ban on Mercury in Medicine
March 17, 2011: Researchers Urge the Removal of Mercury From Flu Shots
September 24, 2009: Huge field experiment for assessing human ethylmercury risk starting in october
July 15, 2009: New Study Finds: Thimerosal Induces Autism-like Neurotoxicity
May 15, 2008: New study will investigate the influence of environmental factors in autism
May 3, 2006: Texas Study Relates Autism to Environmental Mercury
March 24, 2006: Mercury Containing Preservative Alters Immune Function
March 24, 2006: American lawmakers initiate mercury probe for vaccines
April 27, 2005: New results about toxicity of thimerosal
February 11, 2005: New findings about Thimerosal Neurotoxicity

last time modified: May 17, 2024


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