Neurochemical Research

, Volume 36, Issue 6, pp 927–938 | Cite as

Integrating Experimental (In Vitro and In Vivo) Neurotoxicity Studies of Low-dose Thimerosal Relevant to Vaccines

Overview

Abstract

There is a need to interpret neurotoxic studies to help deal with uncertainties surrounding pregnant mothers, newborns and young children who must receive repeated doses of Thimerosal-containing vaccines (TCVs). This review integrates information derived from emerging experimental studies (in vitro and in vivo) of low-dose Thimerosal (sodium ethyl mercury thiosalicylate). Major databases (PubMed and Web-of-science) were searched for in vitro and in vivo experimental studies that addressed the effects of low-dose Thimerosal (or ethylmercury) on neural tissues and animal behaviour. Information extracted from studies indicates that: (a) activity of low doses of Thimerosal against isolated human and animal brain cells was found in all studies and is consistent with Hg neurotoxicity; (b) the neurotoxic effect of ethylmercury has not been studied with co-occurring adjuvant-Al in TCVs; (c) animal studies have shown that exposure to Thimerosal-Hg can lead to accumulation of inorganic Hg in brain, and that (d) doses relevant to TCV exposure possess the potential to affect human neuro-development. Thimerosal at concentrations relevant for infants’ exposure (in vaccines) is toxic to cultured human-brain cells and to laboratory animals. The persisting use of TCV (in developing countries) is counterintuitive to global efforts to lower Hg exposure and to ban Hg in medical products; its continued use in TCV requires evaluation of a sufficiently nontoxic level of ethylmercury compatible with repeated exposure (co-occurring with adjuvant-Al) during early life.

Keywords

Children Infants Neurodevelopment Pregnancy Ethylmercury Thimerosal 

References

  1. 1.
    Grandjean P, Landrigan PJ (2006) Developmental neurotoxicity of industrial chemicals. Lancet 368(9553):2167–2178PubMedCrossRefGoogle Scholar
  2. 2.
    Palmer RF, Blanchard S, Stein Z et al (2006) Environmental mercury release, special education rates, and autism disorder: an ecological study of Texas. Health Place 12:203–209PubMedCrossRefGoogle Scholar
  3. 3.
    Ishitobi H, Stern S, Thurston SW (2010) Organic and inorganic mercury in neonatal rat brain after prenatal exposure to methylmercury and mercury vapor. Environ Health Perspect 118:242–248PubMedCrossRefGoogle Scholar
  4. 4.
    Warkany J, Hubbard DM (1953) Acrodynia and mercury. J Pediatr 42:365–386PubMedCrossRefGoogle Scholar
  5. 5.
    HO W (2000) Thiomersal as a vaccine preservative. Weekly Epidemiol Record 75:12–16Google Scholar
  6. 6.
    da Costa SL, Malm O, Dórea JG (2005) Breast-milk mercury concentrations and amalgam surface in mothers from Brasília, Brazil. Biol Trace Elem Res 106:145–151PubMedCrossRefGoogle Scholar
  7. 7.
    Seal D, Ficker L, Wright P et al (1991) The case against thiomersal. Lancet 338:315–316PubMedCrossRefGoogle Scholar
  8. 8.
    Karincaoglu Y, Aki T, Erguvan-Onal R et al (2007) Erythema multiforme due to diphtheria-pertussis-tetanus vaccine. Pediatr Dermatol 24:334–335PubMedCrossRefGoogle Scholar
  9. 9.
    Halsey NA, Goldman L (2001) Balancing risks and benefits: primum non nocere is too simplistic. Pediatrics 108:466–467PubMedCrossRefGoogle Scholar
  10. 10.
    Clements CJ (2004) The evidence for the safety of thiomersal in newborn and infant vaccines. Vaccine 22:1854–1861PubMedCrossRefGoogle Scholar
  11. 11.
    Lapphra K, Huh L, Scheifele DW (2010) Adverse neurologic reactions after both doses of pandemic H1N1 influenza vaccine with optic neuritis and demyelination. Pediatr Infect Dis J (in press)Google Scholar
  12. 12.
    Ratajczak HV (2011) Theoretical aspects of autism: causes? A review. J Immunotoxicol 8:68–79PubMedCrossRefGoogle Scholar
  13. 13.
    Dórea JG (2010) Research into mercury exposure and health education in subsistence fish-eating communities of the Amazon Basin: potential effects on public health policy. Int J Environ Res Public Health 7:3467–3477PubMedCrossRefGoogle Scholar
  14. 14.
    Knezevic I, Griffiths E, Reigel F (2004) Thiomersal in vaccines: a regulatory perspective WHO Consultation, Geneva, 15–16 April 2002. Vaccine 22:1836–1841PubMedCrossRefGoogle Scholar
  15. 15.
    Freed GL, Clark SJ, Butchart AT et al (2010) Parental vaccine safety concerns in 2009. Pediatrics 125:654–659PubMedCrossRefGoogle Scholar
  16. 16.
    Sears R (2010) The autism book: what every parent needs to know about early detection, treatment, recovery, and prevention. Little BrownGoogle Scholar
  17. 17.
    Austin DW, Shandley KA, Palombo EA (2010) Mercury in vaccines from the Australian childhood immunization program schedule. J Toxicol Environ Health A 73:637–640PubMedCrossRefGoogle Scholar
  18. 18.
    Siegrist CA (2010) Vaccine update 2009: questions around the safety of the influenza A (H1N1) vaccine. Rev Med Suisse 6:67–70PubMedGoogle Scholar
  19. 19.
    Stetler HC, Garbe PL, Dwyer DM et al (1985) Outbreaks of group A streptococcal abscesses following diphtheria-tetanus toxoid-pertussis vaccination. Pediatrics 75:299–303PubMedGoogle Scholar
  20. 20.
    Puziss M, Wright GG (1963) Studies on immunity in anthrax. X. Gel-adsorbed protective antigen for immunization of man. J Bacteriol 85:230–236PubMedGoogle Scholar
  21. 21.
    Nelson EA, Gottshall RY (1967) Enhanced toxicity for mice of pertussis vaccines when preserved with Merthiolate. Appl Microbiol 15:590–593PubMedGoogle Scholar
  22. 22.
    Geier DA, Jordan SK, Geier MR (2010) The relative toxicity of compounds used as preservatives in vaccines and biologics. Med Sci Monitor 16:SR21–SR27Google Scholar
  23. 23.
    Mayrink W, Tavares CA, de Deus RB (2010) Comparative evaluation of phenol and thimerosal as preservatives for a candidate vaccine against American cutaneous leishmaniasis. Mem Inst Oswaldo Cruz 105:86–91PubMedCrossRefGoogle Scholar
  24. 24.
    Chanez C, Flexor MA, Bourre JM (1989) Effect of organic and inorganic mercuric salts on Na+K+ATPase in different cerebral fractions in control and intrauterine growth-retarded rats: alterations induced by serotonin. Neurotoxicology 10:699–706PubMedGoogle Scholar
  25. 25.
    Rush T, Hjelmhaug J, Lobner D (2009) Effects of chelators on mercury, iron, and lead neurotoxicity in cortical culture. Neurotoxicology 30:47–51Google Scholar
  26. 26.
    Ueha-Ishibashi T, Oyama Y, Nakao H et al (2004) Effect of thimerosal, a preservative in vaccines, on intracellular Ca2+ concentration of rat cerebellar neurons. Toxicology 195:77–84PubMedCrossRefGoogle Scholar
  27. 27.
    James SJ, Slikker W, Melnyk S et al (2005) Thimerosal neurotoxicity is associated with glutathione depletion: protection with glutathione precursors. Neurotoxicology 26:1–8PubMedCrossRefGoogle Scholar
  28. 28.
    Minami T, Miyata E, Sakamoto Y (2009) Expression of metallothionein mRNAs on mouse cerebellum microglia cells by thimerosal and its metabolites. Toxicology 261:25–32PubMedCrossRefGoogle Scholar
  29. 29.
    Baskin DS, Ngo H, Didenko VV (2003) Thimerosal induces DNA breaks, caspase-3 activation, membrane damage, and cell death in cultured human neurons and fibroblasts. Toxicol Sci 74:361–368PubMedCrossRefGoogle Scholar
  30. 30.
    Yel L, Brown LE, Su K et al (2005) Thimerosal induces neuronal cell apoptosis by causing cytochrome c and apoptosis-inducing factor release from mitochondria. Int J Mol Med 16:971–977PubMedGoogle Scholar
  31. 31.
    Humphrey ML, Cole MP, Pendergrass JC et al (2005) Mitochondrial mediated thimerosal-induced apoptosis in a human neuroblastoma cell line (SK-N-SH). Neurotoxicology 26:407–416PubMedCrossRefGoogle Scholar
  32. 32.
    Herdman ML, Marcelo A, Huang Y et al (2006) Thimerosal induces apoptosis in a neuroblastoma model via the cJun N-terminal kinase pathway. Toxicol Sci 92:246–253PubMedCrossRefGoogle Scholar
  33. 33.
    Geier DA, King PG, Geier MR (2009) Mitochondrial dysfunction, impaired oxidative-reduction activity, degeneration, and death in human neuronal and fetal cells induced by low-level exposure to thimerosal and other metal compounds. Toxicol Environ Chem 91:735–749CrossRefGoogle Scholar
  34. 34.
    Parran DK, Barker A, Ehrich M (2005) Effects of thimerosal on NGF signal transduction and cell death in neuroblastoma cells. Toxicol Sci 86:132–140PubMedCrossRefGoogle Scholar
  35. 35.
    Waly M, Olteanu H, Banerjee R et al (2004) Activation of methionine synthase by insulin-like growth factor-1 and dopamine: a target for neurodevelopmental toxins and thimerosal. Mol Psychiatry 9:358–370PubMedCrossRefGoogle Scholar
  36. 36.
    James SJ, Rose S, Melnyk S et al (2009) Cellular and mitochondrial glutathione redox imbalance in lymphoblastoid cells derived from children with autism. FASEB J 23:2374–2383PubMedCrossRefGoogle Scholar
  37. 37.
    Jin Y, Kim DK, Khil LY et al (2004) Thimerosal decreases TRPV1 activity by oxidation of extracellular sulfhydryl residues. Neurosci Lett 369:250–255PubMedCrossRefGoogle Scholar
  38. 38.
    Song J, Jang YY, Shin YK et al (2000) Inhibitory action of thimerosal, a sulfhydryl oxidant, on sodium channels in rat sensory neurons. Brain Res 864:105–113PubMedCrossRefGoogle Scholar
  39. 39.
    Lawton M, Iqbal M, Kontovraki M et al (2007) Reduced tubulin tyrosination as an early marker of mercury toxicity in differentiating N2a cells. Toxicol In Vitro 21:1258–1261PubMedCrossRefGoogle Scholar
  40. 40.
    Zieminska E, Toczylowska B, Stafiej A et al (2010) Low molecular weight thiols reduce thimerosal neurotoxicity in vitro: modulation by proteins. Toxicology 276:154–163PubMedCrossRefGoogle Scholar
  41. 41.
    Wyrembek P, Szczuraszek K, Majewska MD et al (2010) Intermingled modulatory and neurotoxic effects of thimerosal and mercuric ions on electrophysiological responses to GABA and NMDA in hippocampal neurons. J Physiol Pharmacol 61:753–768PubMedGoogle Scholar
  42. 42.
    Toimela T, Tahti H (2004) Mitochondrial viability and apoptosis induced by aluminum, mercuric mercury and methylmercury in cell lines of neural origin. Arch Toxicol 78:565–574PubMedCrossRefGoogle Scholar
  43. 43.
    Campbell A, Hamai D, Bondy SC (2001) Differential toxicity of aluminum salts in human cell lines of neural origin: implications for neurodegeneration. Neurotoxicol 22:63–71CrossRefGoogle Scholar
  44. 44.
    Redwood L, Bernard S, Brown D (2001) Predicted mercury concentrations in hair from infant immunizations: cause for concern. Neurotoxicology 22:691–697PubMedCrossRefGoogle Scholar
  45. 45.
    Aschner M, Ceccatelli S (2010) Are neuropathological conditions relevant to ethylmercury exposure? Neurotox Res 18:59–68PubMedCrossRefGoogle Scholar
  46. 46.
    Echeverria D, Woods JS, Heyer NJ et al (2010) The association between serotonin transporter gene promoter polymorphism (5-HTTLPR) and elemental mercury exposure on mood and behavior in humans. J Toxicol Environ Health 73:552–569CrossRefGoogle Scholar
  47. 47.
    Ceccatelli S, Daré E, Moors M (2010) Methylmercury-induced neurotoxicity and apoptosis. Chem Biol Interact 188:301–308PubMedCrossRefGoogle Scholar
  48. 48.
    Clarkson TW, Nordberg GF, Sager PR (1985) Reproductive and developmental toxicity of metals. Scand J Work Environ Health 11:145–154PubMedGoogle Scholar
  49. 49.
    Blair A, Clark B, Clarke A et al (1975) Tissue concentrations of mercury after chronic dosing of squirrel monkeys with thimerosal. Toxicology 3:171–176CrossRefGoogle Scholar
  50. 50.
    Burbacher TM, Shen DD, Liberato N et al (2005) Comparison of blood and brain mercury levels in infant monkeys exposed to methylmercury or vaccines containing thimerosal. Environ Health Perspect 113:1015–1021PubMedCrossRefGoogle Scholar
  51. 51.
    Vahter M, Mottet NK, Friberg L et al (1994) Speciation of mercury in the primate blood and brain following long-term exposure to methyl mercury. Toxicol Appl Pharmacol 124:221–229PubMedCrossRefGoogle Scholar
  52. 52.
    Gassett AR, Itoi M, Ishii Y et al (1975) Teratogenicities of ophthalmic drugs II. Teratogenicities and tissue accumulation of thimerosal. Arch Ophthalmol 93:52–55Google Scholar
  53. 53.
    Minami T, Oda K, Gima N et al (2007) Effects of lipopolysaccharide and chelator on mercury content in the cerebrum of thimerosal-administered mice. Environ Toxicol Pharmacol 24:316–332CrossRefGoogle Scholar
  54. 54.
    Minami T, Miyata E, Sakamoto Y et al (2010) Induction of metallothionein in mouse cerebellum and cerebrum with low-dose thimerosal injection. Cell Biol Toxicol 26:143–152PubMedCrossRefGoogle Scholar
  55. 55.
    Orct T, Blanusa M, Lazarus M et al (2006) Comparison of organic and inorganic mercury distribution in suckling rat. J Appl Toxicol 26:536–539PubMedCrossRefGoogle Scholar
  56. 56.
    Zareba G, Cernichiari E, Hojo R et al (2007) Thimerosal distribution and metabolism in neonatal mice: comparison with methyl mercury. J Appl Toxicol 27:511–518PubMedCrossRefGoogle Scholar
  57. 57.
    Rodrigues JL, Serpeloni JM, BL Batista et al (2010) Identification and distribution of mercury species in rat tissues following administration of thimerosal or methylmercury. Arch Toxicol 84:891–896PubMedCrossRefGoogle Scholar
  58. 58.
    Ekstrand J, Nielsen JB, Havarinasab S et al (2010) Mercury toxicokinetics-dependency on strain and gender. Toxicol Appl Pharmacol 243:283–291PubMedCrossRefGoogle Scholar
  59. 59.
    Branch DR (2009) Gender-selective toxicity of thimerosal. Exp Toxicol Pathol 61:133–136PubMedCrossRefGoogle Scholar
  60. 60.
    Harry GJ, Harris MW, Burka LT (2004) Mercury concentrations in brain and kidney following ethylmercury, methylmercury and Thimerosal administration to neonatal mice. Toxicol Lett 154:183–189PubMedCrossRefGoogle Scholar
  61. 61.
    Gibičar D, Logar M, Horvat N et al (2007) Simultaneous determination of trace levels of ethylmercury and methylmercury in biological samples and vaccines using sodium tetra(n-propyl)borate as derivatizing agent. Anal Bioanal Chem 388:329–340PubMedCrossRefGoogle Scholar
  62. 62.
    Dórea JG, Wimer W, Marques RC et al. (2010) Automated speciation of mercury in hair of breastfed infants exposed to ethylmercury from Thimerosal-containing vaccines. Biol Trace El Res (in press)Google Scholar
  63. 63.
    Mutter J, Curth A, Naumann J et al. (2010) Does inorganic mercury play a role in alzheimer’s disease? A systematic review and an integrated molecular mechanism. J Alzheimers Dis (in press)Google Scholar
  64. 64.
    Dórea JG, Marques RC (2010) Infants’ exposure to aluminum from vaccines and breast milk during the first 6 months. J Expo Sci Environ Epidemiol 20:598–601Google Scholar
  65. 65.
    Burrell SA, Exley C (2010) There is (still) too much aluminium in infant formulas. BMC Pediatr 10:63PubMedCrossRefGoogle Scholar
  66. 66.
    Petrik MS, Wong MC, Tabata RC et al (2007) Aluminum adjuvant linked to Gulf War illness induces motor neuron death in mice. Neuromolecular Med 9:83–100PubMedCrossRefGoogle Scholar
  67. 67.
    Flarend RE, Hem SL, White JL et al (1997) In vivo absorption of aluminium-containing vaccine adjuvants using 26Al. Vaccine 15:1314–1318PubMedCrossRefGoogle Scholar
  68. 68.
    Shaw CA, Petrick MS (2009) Aluminum hydroxide injections lead to motor deficits and motor neuron degeneration. J Inorg Biochem 103:1555–1562PubMedCrossRefGoogle Scholar
  69. 69.
    Olczak M, Duszczyk M, Mierzejewski P et al (2010) Neonatal administration of thimerosal causes persistent changes in mu opioid receptors in the rat brain. Neurochem Res 35:1840–1847PubMedCrossRefGoogle Scholar
  70. 70.
    Olczak M, Duszczyk M, Mierzejewski P et al (2010) Lasting neuropathological changes in rat brain after intermittent neonatal administration of thimerosal. Folia Neuropathol 48:258–269PubMedGoogle Scholar
  71. 71.
    Hornig M, Chian D, Lipkin WI (2004) Neurotoxic effects of postnatal thimerosal are mouse strain dependent. Mol Psychiatry 9:833–845PubMedCrossRefGoogle Scholar
  72. 72.
    Berman RF, Pessah IN, Mouton PR et al (2008) Low-level neonatal thimerosal exposure: further evaluation of altered neurotoxic potential in SJL mice. Toxicol Sci 101:294–309PubMedCrossRefGoogle Scholar
  73. 73.
    Olczak M, Duszczyk M, Mierzejewski P et al (2009) Neonatal administration of a vaccine preservative, thimerosal, produces lasting impairment of nociception and apparent activation of opioid system in rats. Brain Res 1301:143–151PubMedCrossRefGoogle Scholar
  74. 74.
    Hewitson L, Lopresti BJ, Stott C et al (2010) Influence of pediatric vaccines on amygdala growth and opioid ligand binding in rhesus macaque infants: a pilot study. Acta Neurobiol Exp 70:147–164Google Scholar
  75. 75.
    Hewitson L, Houser LA, Stott C et al (2010) Delayed acquisition of neonatal reflexes in newborn primates receiving a thimerosal-containing hepatitis B vaccine: influence of gestational age and birth weight. J Toxicol Environ Health A 73:1298–1313PubMedCrossRefGoogle Scholar
  76. 76.
    Dórea JG (2010) Making sense of epidemiological studies of young children exposed to thimerosal in vaccines. Clin Chim Acta 411:1580–1586PubMedCrossRefGoogle Scholar
  77. 77.
    Marques RC, Dórea JG, Bernardi JV (2010) Thimerosal exposure (from tetanus-diphtheria vaccine) during pregnancy and neurodevelopment of breastfed infants at six months. Acta Paediatr 99:934–939PubMedCrossRefGoogle Scholar
  78. 78.
    Marques RC, Dórea JG, Bernardi JV et al (2009) Pre- and post-natal mercury exposure, breastfeeding and neurodevelopment during the first five years. Cognit Behav Neurol 22:134–141CrossRefGoogle Scholar
  79. 79.
    Dórea JG, Marques RC, Brandão KG (2009) Neonate exposure to thimerosal mercury from hepatitis B vaccines. Am J Perinatol 26:523–527PubMedCrossRefGoogle Scholar
  80. 80.
    Judson RS, Houck KA, Kavlock RJ et al (2010) In vitro screening of environmental chemicals for targeted testing prioritization: the ToxCast project. Environ Health Perspect 118:485–492PubMedCrossRefGoogle Scholar
  81. 81.
    Hunter JW, Mullen GP, McManus JR, Heatherly JM, Duke A, Rand JB (2010) Neuroligin-deficient, mutants of C. elegans have sensory processing deficits and are hypersensitive to oxidative stress and mercury toxicity. Dis Model Mech 3:366–376PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Faculty of Health SciencesUniversidade de BrasíliaBrasíliaBrazil

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