DOI: http://dx.doi.org/10.18203/2319-2003.ijbcp20173268

A review on thimerosal: an irreplaceable element of long-term immunisation strategy in low income countries

Ritika Singla, Anita K. Gupta, Anjleen Kaur

Abstract


Thimerosal, an organic-mercury (Hg) compound containing 49.55% Hg by weight, is added to vaccines as a preservative permitting formulation of multi-dose vaccine vials. Being a derivative of ethylmercury, it has been linked with autism as a possible risk factor based on the assumption that exposure to ethylmercury would have similar neurotoxic effects as another mercurial compound, methylmercury. In 1999, AAP issued a joint statement emphasising the removal of thimerosal from vaccines. Subsequently, several studies have been conducted; those showing positive association between thimerosal exposure and autism have been recognised to be fraught with methodological flaws. On the other hand, many well controlled studies have failed to find any such causal relation and there are others that have clearly demonstrated a much favourable kinetic profile of ethylmercury as compared to methylmercury. Owing to the lack of data, AAP retired its original statement in 2002. Recently, thimerosal has been exempted from regulation by Minamata Convention on Mercury resulting in the continued use of low cost thimerosal containing vaccines in low income countries which cannot afford to run their immunisation program using single dose thimerosal free vaccines, that comparatively cost much higher, as is the case in high income countries. Some bodies view this as a discrimination on the basis of wealth of a nation and have opposed this decision. This review presents various studies regarding the causal association between thimerosal containing vaccines and autism. The current evidence fails to support any such association. Hence this review supports the exemption of thimerosal from regulation and also justifies its use in LICs for uninterrupted vaccination of the most vulnerable population.


Keywords


Ethylmercury, Low income countries, Methylmercury, Thimerosal, Thimerosal containing vaccines, Thimerosal free vaccines

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References


Orenstein WA, Paulson JA, Brady MT, Cooper LZ, Seib K. Global Vaccination Recommendations and Thimerosal. Pediatrics. 2013 Jan;131(1):149-51.

Immunization Safety Review Committee; Board on Health Promotion and Disease Prevention, Institute of Medicine. Immunization Safety Review: Vaccines and Autism. Washington, DC: The National Academies Press; 2004.

US Food and Drug Administration. Vaccines, Blood and Biologics: Thimerosal in Vaccines. US Department of Health and Human Services. [Cited 2016 Sep 24]; Available at: http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/VaccineSafety/ucm096228.htm

Ball LK, Ball R, Pratt RD. An assessment of thimerosal use in childhood vaccines. Pediatrics. 2001;107(5):1147-54.

Sykes LK, Geier DA, King PG, Kern JK, Haley BE, Chaigneau CG et al. Thimerosal as discrimination: vaccine disparity in the UN Minamata Convention on mercury. Indian Journal of Medical Ethics. 2014;11(4):206-18.

Geier DA, Hooker BS, Kern JK, King PG, Sykes LK, Geier MR. A two-phase study evaluating the relationship between Thimerosal-containing vaccine administration and the risk for an autism spectrum disorder diagnosis in the United States. Translational Neurodegeneration. 2013;2(25).

Schultz ST. Does thimerosal or other mercury exposure increase the risk for autism? Acta Neurobiol Exp. 2010;70:187-95.

Budzyn DM, Majewska R, Kiełtyka A. Early exposure to thimerosal-containing vaccines and children’s cognitive development. A 9-year prospective birth cohort study in Poland. Eur J Pediatr. 2015;174:383-91.

Geier DA, Geier MR. A meta-analysis epidemiological assessment of neurodevelopmental disorders following vaccines administered from 1994 through 2000 in the United States. Neuro Endocrinol Lett. 2006;27(4):401-13.

De Stefano F. Vaccines and autism: evidence does not support a causal association. Clin Pharmacol Ther. 2007;82(6):756-9.

Heron J, Golding J. ALSPAC Study Team. Thimerosal exposure in infants and developmental disorders: a prospective cohort study in the United Kingdom does not support a causal association. Pediatrics. 2004;114(3):577-83.

AAP (American Academy of Pediatrics) and USPHS (U.S. Public Health Service). Joint statement of the American Academy of Pediatrics (AAP) and the United States Public Health Service (PHS). Pediatrics. 1999;104(3):568-9.

Tamma PD, Ault KA, Rio CD, Steinhoff MC, Halsey NA, Omer SB. Safety of influenza vaccination during pregnancy. Am J Obstet Gynecol. 2009;1-6.

Berman RF, Pessah IN, Mouton PR, Mav D, Harry J. Low-Level Neonatal Thimerosal Exposure: Further Evaluation of Altered Neurotoxic Potential in SJL Mice. Toxicol Sci. 2008;101(2):294-309.

Understanding Thiomerosal, Mercury, and Vaccine Safety. Center of Disease Control. USA. 2013 Feb. [Cited 2016 Sep 24]; Available at: http://www.cdc.gov/vaccines/hcp/patient-ed/conversations/downloads/vacsafe-thimerosal-color-office.pdf

Fombonne E, Zakarian R, Bennett A, Meng L, Heywood DML. Pervasive Developmental Disorders in Montreal, Quebec, Canada: Prevalence and Links with Immunizations. Pediatrics. 2006;118:e139-50.

Geier MR, Geier DA. Neurodevelopmental disorders after thimerosal-containing vaccines: a brief communication. Exp Biol Med (Maywood). 2003;228(6):660-4.

Bradstreet J, Geier DA, Kartzinel JJ, Adams JB, Geier MR. A case-control study of mercury burden in children with autistic spectrum disorders. J Am Phys Surg. 2003;8(3):76-9.

Geier DA, Geier MR. An assessment of the impact of thimerosal on childhood neurodevelopmental disorders. Pediatr Rehabil. 2003;6(2):97-102.

Geier DA, Geier MR. Neurodevelopmental disorders following thimerosal-containing childhood immunizations: a follow-up analysis. Int J Toxicol. 2004;23(6):369-76.

Geier DA, Geier MR. A two-phased population epidemiological study of the safety of thimerosal-containing vaccines: a follow-up analysis. Med Sci Monit. 2005;11(4):CR160-70.

Geier DA, Geier MR. An evaluation of the effects of thimerosal on neurodevelopmental disorders reported following DTP and Hib vaccines in comparison to DTPH vaccine in the United States. Journal of Toxicology and Environmental Health 2006;69:1481-95.

Geier DA, Geier MR. Early downward trends in neurodevelopmental disorders following removal of thimerosal-containing vaccines. Journal of American Physicians and Surgeons. 2006;11(1):8-13.

Geier DA, Geier MR. A Case Series of Children with Apparent Mercury Toxic Encephalopathies Manifesting with Clinical Symptoms of Regressive Autistic Disorders. Journal of Toxicology and Environmental Health. 2007;70(10):837-51.

Gallagher C, Goodman M. Hepatitis B triple series vaccine and developmental disability in US children aged 1–9 years. Journal of Toxicology and Environmental Health. 2008;90(5):997-1008.

DeLong G. A Positive Association found between Autism Prevalence and Childhood Vaccination uptake across the U.S. Population. Journal of Toxicology and Environmental Health. 2011;74(14):903-16.

Dorea JG, Marques RC, Isejima C. Neurodevelopment of Amazonian infants: antenatal and postnatal exposure to methyl- and ethylmercury. J Biomed Biotechnol. 2012;132876.

Budzyn DM, Majeswska R, Kieltyka A, Augustyniak M. Neonatal exposure to Thimerosal from vaccines and child development in the first 3 years of life. Neurotoxicol Teratol. 2012 Nov-Dec;34(6):592-7.

Geier DA, Hooker BS, Kern JK, King PG, Sykes LK, Geier MR. A Dose-Response Relationship between Organic Mercury Exposure from Thimerosal-Containing Vaccines and Neurodevelopmental Disorders. Int. J. Environ. Res. Public Health. 2014;11:9156-70.

Baskin DS, Ngo H, Didenko VV. Thimerosal induces DNA breaks, caspase-3 activation, membrane damage, and cell death in cultured human neurons and fibroblasts. Toxicol Sci. 2003;74(2):361-8.

Laurente J, Remuzgo F, Ávalos B, Chiquinta J, Ponce B, Avendaño R, et al. Neurotoxic effects of thimerosal at vaccines doses on the encephalon and development in 7 days-old hamsters. An Fac Med Lima. 2007;68(3):222-37.

Eke D, Celik A. Genotoxicity of thimerosal in cultured human lymphocytes with and without metabolic activation sister chromatid exchange analysis proliferation index and mitotic index. Toxicol In Vitro. 2008;22:927-34.

Minami T, Miyata E, Sakamato Y, Yamazaki H, Ichida S. Induction of metallothionein in mouse cerebellum and cerebrum with low-dose thimerosal injection. Cell Biol Toxicol. 2010;26:143-52.

Geier DA, King PG, Geier MR. 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. Toxicological and Environmental Chemistry. 2009;91(4):735-49.

Ida-Eto M, Oyabu A, Ohkawara T, Tashiro Y, Narita N, Narita M. Prenatal exposure to organomercury, thimerosal, persistently impairs the serotonergic and dopaminergic systems in the rat brain: implications for association with developmental disorders. Brain Dev. 2013 Mar;35(3):261-4.

Pichichero ME, Cernichiari E, Lopreiato J, Treanor J. Mercury concentrations and metabolism in infants receiving vaccines containing thiomersal: a descriptive study. Lancet. 2002 Nov 30;360(9347):1737-41.

Hviid A, Stellfeld M, Wohlfahrt J, Melbye M. Association Between Thimerosal-Containing Vaccine and Autism. JAMA. 2003;290(13):1763-6.

Madsen KM, Lauritsen MB, Pedersen CB, Thorsen P, Plesner AM, Andersen PH, et al. Thimerosal and the Occurrence of Autism: Negative Ecological Evidence From Danish Population-Based Data. Pediatrics. 2003 Sep;112(3):604-6.

Verstraeten T, Davis RL, DeStefano F, Lieu TA, Rhodes PH, Black SB, et al. Safety of Thimerosal-Containing Vaccines: A Two-Phased Study of Computerized Health Maintenance Organization Databases. Pediatrics. 2003 Nov;112(5):1039-48.

Stehr-Green P, Tull P, Stellfeld M, Mortenson PB, Simpson D. Autism and thimerosal-containing vaccines: lack of consistent evidence for an association. Am J Prev Med. 2003 Aug;25(2):101-6.

Parker SK, Schwartz B, Todd J, Pickering LK. Thimerosal-containing vaccines and autistic spectrum disorder: a critical review of published original data. Pediatrics. 2004 Sep;114(3):793-804.

Andrews N, Miller N, Grant A, Stowe J, Osborne V, Taylor B. Thimerosal Exposure in Infants and Developmental Disorders: A Retrospective Cohort Study in the United Kingdom Does Not Support a Causal Association. Pediatrics. 2004;114(3):584-91.

Taylor B. Vaccines and the changing epidemiology of autism. Child Care Health Dev. 2006 Sep;32(5):511-9.

Thompson WW, Price C, Goodson B, Shay DK, Benson P, Hinrichsen VL, et al. Early Thimerosal Exposure and Neuropsychological Outcomes at 7 to 10 Years. N Engl J Med. 2007 Sep;357(13):1281-92.

Miles JH, Takahashi TN. Lack of association between Rh status, Rh immune globulin in pregnancy and autism. Am J Med Genet A. 2007;143A:1397-407.

Schechter R, Grether JK. Continuing increases in autism reported to California’s Developmental Services System: mercury in retrograde. Arch Gen Psychiatry. 2008;65(1):19-24.

Price CS, Thompson WW, Goodson B, Weintraub ES, Croen LA, Hinrichsen VL, et al. Prenatal and Infant Exposure to Thimerosal From Vaccines and Immunoglobulins and Risk of Autism. Pediatrics. 2010 Oct;126(4):656-64.

Budzyn DM, Majeswska R, Kieltyka A, Augustyniak M. Lack of association between thiomersal-containing vaccines and autism. Przeglad Epidemiologiczny. 2011;65(3):491-5.

Barregard L, Rekic D, Horvat M, Elmberg L, Lundh T, Zachrisson O. Toxicokinetics of mercury after long-term repeated exposure to thimerosal-containing vaccine. Toxicol Sci. 2011 Apr;120(2):499-506.

Barile JP, Kuperminc GP, Weintraub ES, Mink JW, Thompson WW. Thimerosal Exposure in Early Life and Neuropsychological Outcomes 7–10 Years Later. J Pediatr Psychol. 2012;37(1):106-18.

Yoshimasu K, Kiyohara C, Takemura S, Nakai K. A meta-analysis of the evidence on the impact of prenatal and early infancy exposures to mercury on autism and attention deficit/hyperactivity disorder in the childhood. Neuro Toxicol. 2014;44:121-31.

Burbacher TM, Shen DD, Liberato N, Grant KS, Cernichiari E, Clarkson T. Comparison of Blood and Brain Mercury Levels in Infant Monkeys Exposed to Methylmercury or Vaccines Containing Thimerosal. Environmental Health Perspectives. 2005 Aug;113(8):1015-21.

Ueha-Ishibashi T, Oyama Y, Nakao H, Umebayashi C, Hirama S, Ishida S, et al. Flow-cytometric analysis on cytotoxic effect of thimerosal, a preservative in vaccines, on lymphocytes dissociated from rat thymic glands. Toxicol In Vitro. 2005 Mar;19(2):191-8.

World Health Organization. Global Advisory Committee on Vaccine Safety. 2012;87(30):277-88. Available at: http://www.who.int/wer/2012/wer8730.pdf?ua=1

Goodman MJ, Nordin J. Vaccine adverse event reporting system reporting source: a possible source of bias in longitudinal studies. Pediatrics. 2006 Feb;117(2):387-90.

American Academy of Pediatrics. Policy Statement-AAP Publications Reaffirmed and Retired. Pediatrics. 2010;126(1). Available at: http://pediatrics.aappublications.org/content/pediatrics/126/1/177.full.pdf

King K, Paterson M, Green SK. Global Justice and the Proposed Ban on Thimerosal-Containing Vaccines. Pediatrics. 2013;131:154-6.