Thimerosal exposure and increased risk for diagnosed tic disorder in the United States: a case-control study

Geier, David A.; Kern, Janet K.; Hooker, Brian S.; King, Paul G.; Sykes, Lisa K.; Homme, Kristin G.; Geier, Mark R.

doi:10.1515/intox-2015-0011

Abstract

A hypothesis testing, case-control study evaluated automated medical records for exposure to organic-Hg from Thimerosal-containing hepatitis B vaccines (TM-HepB) administered at specific intervals in the first six-months-of-life among cases diagnosed with a tic disorder (TD) or cerebral degeneration (CD) (an outcome not biologically plausibly linked to TM exposure) in comparison to controls; both cases and controls were continuously enrolled from birth (born from 1991–2000) within the Vaccine Safety Datalink (VSD) database. TD cases were significantly more likely than controls to have received increased organic-Hg from TM-HepB administered within the first month-of-life (odds ratio (OR)=1.59, p<0.00001), first two-months-of-life (OR=1.59, p<0.00001), and first six-months-of-life (OR=2.97, p<0.00001). Male TD cases were significantly more likely than male controls to have received increased organic-Hg from TM-HepB administered within the first month-of-life (OR =1.65, p<0.0001), first two-months-of-life (OR=1.64, p<0.0001), and first six months-of-life (OR=2.47, p<0.05), where as female TD were significantly more likely than female controls to have received increased organic-Hg from TM-HepB administered within the first six-months-of-life (OR=4.97, p<0.05). By contrast, CD cases were no more likely than controls to have received increased organic-Hg exposure from TM-HepB administered at any period studied within the first six-months-of-life. Although routine childhood vaccination is considered an important public health tool to combat infectious diseases, the present study associates increasing organic-Hg exposure from TM-HepB and the subsequent risk of a TD diagnosis.

References

American Academy of Pediatrics. (1999). Thimerosal in vaccines – An interim report to clinicians. American Academy of Pediatrics. Committee on Infectious Diseases and Committee on Environmental Health. Pediatrics104: 570–574.
Search in Google Scholar
American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders (Fifth edition). Washington, DC, American Psychiatric Association.
Search in Google Scholar
Andrews N, Miller E, Grant A, Stowe J, Osborne V, Taylor B. (2004). Thimerosal exposure in infants and developmental disorders: a retrospective cohort study in the United kingdom does not support a causal association. Pediatrics114: 584–591.
Search in Google Scholar
Barile JP, Kuperminc GP, Weintraub ES, Mink JW, Thompson WW. (2012). Thimerosal exposure in early life and neuropsychological outcomes 7–10 years later. Journal of Pediatric Psychology37: 106–118.
Search in Google Scholar
Boyle CA, Boulet S, Schieve LA, Cohen RA, Blumberg SJ, Yeargin-Allsopp M, Visser S, Kogan MD. (2011). Trends in the prevalence of developmental disabilities in US children, 1997–2008. Pediatrics 127(6): 1034–1042.
Search in Google Scholar
Burbacher TM, Shen DD, Liberato N, Grant KS, Cernichiari E, Clarkson T. (2005). Comparison of blood and brain mercury levels in infant monkeys exposed to methylmercury or vaccines containing thimerosal. Environ Health Perspect113: 1015–1021.
Search in Google Scholar
Castellanos FX, Margulies DS, Kelly C, Uddin LQ, Ghaffari M, Kirsch A, Shaw D, Shehzad Z, Di Martino A, Biswal B, Sonuga-Barke EJ, Rotrosen J, Adler LA, Milham MP. (2008). Cingulate-precuneus interactions: a new locus of dys-function in adult attention-deficit/hyperactivity disorder. Biol Psychiatry63(3): 332–337.
Search in Google Scholar
Centers for Disease Control. (1991). Hepatitis B virus: a comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination. Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR Recomm Rep40(RR-13): 1–25.
Search in Google Scholar
Chen RT, DeStefano F, Davis RL, Jackson LA, Thompson RS, Mullooly JP, Black SB, Shinefield HR, Vadheim CM, Ward JI, Marcy SM. (2000). The vaccine safety datalink: immunization research in health maintenance organizations in the USA. Bull World Health Organ78(2): 186–194.
Search in Google Scholar
Chen RT, Glasser JW, Rhodes PH, Davis RL, Barlow WE, Thompson RS, Mullooly JP, Black SB, Shinefield HR, Vadheim CM, Marcy SM, Ward JI, Wise RP, Wassilak SG, Hadler SC. (1997). Vaccine Safety Datalink: project: a new tool for improving vaccine safety monitoring in the United States. The Vaccine Safety Datalink Team. Pediatrics99(6): 765–773.
Search in Google Scholar
Church JA, Fair DA, Dosenbach NU, Cohen Al, Miezin FM, Petersen SE, Schlaggar BL. (2009). Control networks in paediatric Tourette syndrome show immature and anomalous patterns of functional connectivity. Brain132: 225–238.
Search in Google Scholar
Cubo E. (2012). Review of prevalence studies of tic disorders: methodological caveats. Tremor Other Hyperkinet Mov (N Y) 2: pii: tre-02-61-349-1.
Search in Google Scholar
DeStefano F, Vaccine Safety Datalink Research Group. (2001). The Vaccine Safety Datalink project. Pharmacoepidemiol Drug Safe10: 403–406.
Search in Google Scholar
Ellenberg SS, Braun MM. (2002). Monitoring the safety of vaccinees: assessing the risks. Drug Safety25: 145–152.
Search in Google Scholar
Fair DA, Dosenbach NU, Church JA, Cohen AL, Brahmbhatt S, Miezin FM, Barch DM, Raichle ME, Petersen SE, Schlaggar BL. (2007). Development of distinct control networks through segregation and integration. Proc Natl Acad Sci U S A104: 13507–13512.
Search in Google Scholar
Fawcett JW. (1992). Intrinsic neuronal determinants of regeneration. Trends in Neurosci15: 5–8.
Search in Google Scholar
Fine PE, Chen RT. (1992). Confounding in studies of adverse reactions to vaccines. Am J Epidemiol136: 121–135.
Search in Google Scholar
Freeman RD, Tourette Syndrome International Database Consortium. (2007). Tic disorders and ADHD: answers from a world-wide clinical dataset on Tourette syndrome. Eur Child Adolesc Psychiatry16(Suppl 1): 15–23.
Search in Google Scholar
Geier MR, Geier DA. (2002). The state of polio vaccination in the world: the case for continuing routine vaccination. Toxicol Mech Methods12: 221–228.
Search in Google Scholar
Geier DA, Geier MR. (2004). A review of the Vaccine Adverse Event Reporting System database. Expert Opin Pharmacother5: 691–698.
Search in Google Scholar
Geier DA, Geier MR. (2005). A two-phased population epidemiological study of the safety of thimerosal-containing vaccines: a follow-up analysis. Med Sci Monit11: CR160–CR170.
Search in Google Scholar
Geier DA, Geier MR. (2006). A meta-analysis epidemiological assessment of neurodevelopmental disorders following vaccines administered from 1994 through 2000 in the United States. Neuro Endocrinol Lett27(4): 401–413.
Search in Google Scholar
Geier DA, Hooker BS, Kern JK, King PG, Sykes LK, Geier MR. (2013). 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. Transl Neurodegener2: 25.
Search in Google Scholar
Grzadzinski R, Di Martino A, Brady E, Mairena MA, O’Neale M, Petkova E, Lord C, Castellanos FX (2011). Examining autistic traits in children with ADHD: does the autism spectrum extend to ADHD? J Autism Dev Disord41(9): 1178–1191.10.1007/s10803-010-1135-3312340121108041
Search in Google Scholar
Hariz MI, Robertson MM. (2010). Gilles de la Tourette syndrome and deep brain stimulation. Eur J Neurosci32: 1128–1134.
Search in Google Scholar
Jones TA. (1999). Multiple synapse formation in the motor cortex opposite uni-lateral sensorimotor cortex lesions in adult rats. J Comp Neurol414: 57–66.
Search in Google Scholar
Jones TA, Schallert T. (1992). Overgrowth and pruning of dendrites in adult rats recovering from neocortical damage. Brain Res581: 156–160.
Search in Google Scholar
Kern JK, Geier DA, Audhya T, King PG, Sykes LK, Geier MR. (2012). Evidence of parallels between mercury intoxication and the brain pathology in autism. Acta Neurobiol Exp (War)72: 113–153.
Search in Google Scholar
Kern JK, Geier DA, Ayzac F, Adams JB, Mehta JA, Geier MR. (2011). Toxicity biomarkers among US children compared to a similar cohort in France: a blinded study measuring urinary porphyrins. Toxicol Environ Chem93: 396–405.
Search in Google Scholar
Kern JK, Geier DA, Sykes LK, Geier MR, Deth RC. (2015). Are ASD and ADHD a continuum? A comparison of pathophysiological similarities between the disorders. J Atten Disord19(9): 805–27.
Search in Google Scholar
Kern JK, Haley BE, Geier DA, Sykes LK, King PG, Geier MR. (2013). Thimerosal exposure and the role of sulfation chemistry and thiol availability in autism. Int J Environ Res Public Health10: 3771–3800.
Search in Google Scholar
Laks DR. (2009). Assessment of chronic mercury exposure within the U.S. population, National Health and Nutrition Examination Survey, 1999–2006. Biometals22: 1103–1114.
Search in Google Scholar
Li AM, Chan MH, Leung TF, Cheung RC, Lam CW, Fok TF. (2000). Mercury intoxication present with tics. Arch Dis Childhood83: 174–175.
Search in Google Scholar
Liu Y, Miao W, Wang J, Gao P, Yin G, Zhang L, Lv C, Ji Z, Yu T, Sabel BA, He H, Peng Y. (2013). Structural abnormalities in early Tourette syndrome children: a combined voxel-based morphometry and tract-based spatial statistics study. PLoS One8(9): e76105.
Search in Google Scholar
Marques RC, Dórea JG, Fonseca MF, Bastos WR, Malm O. (2007). Hair mercury in breast-fed infants exposed to thimerosal-preserved vaccines. Eur J Pediatr166(9): 935–941.
Search in Google Scholar
National Institute of Neurological Disorders and Stroke. National Institutes of Health. Tourette Syndrome Fact Sheet 2013 [updated 10/19/2012]. Available from [accessed on: 4/12/2014]: http://www.ninds.nih.gov/disorders/tourette/detail_tourette.htm#220453231.
Search in Google Scholar
Neuner I, Kupriyanova Y, Stöcker T, Huang R, Posnansky O, Schneider F, Tittgemeyer M, Shah NJ. (2010). White-matter abnormalities in Tourette syndrome extend beyond motor pathways. Neuroimage51(3): 1184–1193.
Search in Google Scholar
Pichichero ME, Gentile A, Giglio N, Umido V, Clarkson T, Cernichiari E, Zareba G, Gotelli C, Gotelli M, Yan L, Treanor J. (2008). Mercury levels in newborns and infants after receipt of thimerosal-containing vaccines. Pediatrics121(2): e208–e214.
Search in Google Scholar
Pichichero ME, Gentile A, Giglio N, Alonso MM, Fernandez Mentaberri MV, Zareba G, Clarkson T, Gotelli C, Gotelli M, Yan L, Treanor J. (2009). Mercury levels in premature and low birth weight newborn infants after receipt of thimerosal-containing vaccines. J Pediatr155(4): 495–499.
Search in Google Scholar
Redwood L, Bernard S, Brown D. (2001). Predicted mercury concentrations in hair from infant immunizations: cause for concern. Neurotoxicology22: 691–697.
Search in Google Scholar
Roessner V, Hoekstra PJ, Rothenberger A. (2011). Tourette’s disorder and other tic disorders in DSM-5: a comment. Eur Child Adolesc Psychiatry20: 71–74.
Search in Google Scholar
Stajich GV, Lopez GP, Harry SW, Sexson WR. (2000). Iatrogenic exposure to mercury after hepatitis B vaccination in preterm infants. J Pediatr136: 679–681.
Search in Google Scholar
Tan M, Parkin JE. (2000). Route of decomposition of thiomersal (thimerosal). Int J Pharm208: 23–34.
Search in Google Scholar
Thompson WW, Price C, Goodson B, Shay DK, Benson P, Hinrichsen VL, et al. (2007). Early thimerosal exposure and neuropsychological outcomes at 7 to 10 years. N Engl J Med357: 1281–1292.
Search in Google Scholar
Verstraeten T, Davis RL, DeStefano F, Lieu TA, Rhodes PH, Black SB, Shinefield H, Chen RT; Vaccine Safety Datalink Team. (2003). Safety of thimerosal-containing vaccines: a two-phased study of computerized health maintenance organization databases. Pediatrics112: 1039–1048.
Search in Google Scholar
Wang L, Zhu C, He Y, Zang Y, Cao Q, Zhang H, Zhong Q, Wang Y. (2009). Altered small-world brain functional networks in children with attention-deficit/hyperactivity disorder. Hum Brain Mapp30: 638–649.
Search in Google Scholar
Wass S. (2011). Distortions and disconnections: disrupted brain connectivity in autism. Brain Cogn75: 18–28.
Search in Google Scholar
Wassilak SG, Glasser JW, Chen RT, Hadler SC. (1995). Utility of large-linked databases in vaccine safety, particularly in distinguishing independent and synergistic effects. The Vaccine Safety Datalink Investigators. Ann NY Acad Sci754: 377–382.
Search in Google Scholar
Wehe CA, Pieper I, Holtkamp M, Thyssen GM, Sperling M, Schwerdtle T, Karst U. (2014). On-line species-unspecific isotope dilution analysis in the picomolar range reveals the time- and species-depending mercury uptake in human astrocytes. Anal Bioanal Chem406(7): 1909–1916.
Search in Google Scholar
Young HA, Geier DA, Geier MR. (2008). Thimerosal exposure in infants and neurodevelopmental disorders: an assessment of computerized medical records in the Vaccine Safety Datalink. J Neurol Sci271: 110–118.
Search in Google Scholar
Zimmermann LT, Santos DB, Naime AA, Leal RB, Dórea JG, Barbosa F Jr, Aschner M, Rocha JB, Farina M. (2013). Comparative study on methyl- and ethyl-mercury-induced toxicity in C6 glioma cells and the potential role of LAT-1 in mediating mercurial-thiol complexes uptake. Neurotoxicology38: 1–8.
Search in Google Scholar

Thimerosal exposure and increased risk for diagnosed tic disorder in the United States: a case-control study

Abstract

Paradigm

My account