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MarkR.Geier,M.D.,Ph.D.DavidA.GeierIntroduction
Abstract
In this study, we evaluated doses of mercury from thimerosal-containingchildhood immunizations in compari-son to US Federal Safety Guidelinesand the effects of increasing doses of mercury on the incidence of neurodevelopment disorders andheart disease. This study showed thatchildren received mercury from thissource in excess of the Federal SafetyGuidelines for the oral ingestion of methylmercury. Our analyses showedincreasing relative risks forneurodevelopment disorders andheart disease with increasing doses of mercury. This study provides strongepidemiological evidence for a linkbetween mercury exposure fromthimerosal-containing childhoodvaccines and neurodevelopmentdisorders.
Many sources now confirm an autismepidemic in the United States. The prevalence of autism has risen from one inabout 2,500 children in the mid-1980s toone in about 300 children in 1996.Several studies report that there is anassociation between mercury exposure andan increased risk of heart disease. Manyin the scientific/medical community have,initially, been highly skeptical thatthimerosal, an ethylmercury preservative,in childhood vaccines could be associatedwithneurodevelopmentdisorders.Thimerosal is an organic mercurycompound. It is metabolized toethylmercury and thiosalicylate and has been present since the 1930s as a preserva-tive in many vaccines and pharmaceutical products to prevent bacterial and fungalcontamination.In 2001, the Institute of Medicine(IOM) of the US National Academy of Sciencesconcludedthatthehypothesisthatexposure to thimerosal-containingvaccines could be associated with
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neurodevelopment disorders is notestablished and rests on indirect andincomplete information, primarily fromanalogieswithmethylmercuryandlevelsof maximummercuryexposurefromvaccinesgiven in children. They concluded that thehypothesis is biologically possible, but the possible relationship between thimerosalfrom vaccines and neurodevelopmentdisorders of autism, attention defi-cit/hyperactivity disorder (ADHD), andspeech or language delay remainedseriouslysuspect.As the first part of this study, weevaluated the doses of mercury thatchildren received from thimerosal-containing vaccines, as part of the routineUS childhood immunization schedule, incomparison to the US Federal SafetyGuidelines for the oral ingestion of methylmercury. In 1999, the US Food andDrug Administration (FDA) determinedthat under the recommended childhoodimmunization schedule infants might beexposed to cumulative doses of ethylmercury that exceed some federalsafety guidelines established for the oralingestionofmethylmercury.Secondly,inordertoanalyzetheeffectsof thimerosal in vaccine recipients, weanalyzed the incidence rates of neurodevelopment disorders and heartdisease reported following thimerosal-containing vaccines in comparison tothimerosal-free vaccines based uponanalysis of the Vaccine Adverse EventsReporting System (VAERS) database. Weanalyzed thimerosal-containingDiphtheria-Tetanus-whole-cell-Pertussis(DTwcP) and Diphtheria-Tetanus-acellular-Pertussis (DTaP) vaccines incomparison to thimerosal-free DTaPvaccines.
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SincethepublicationoftheIOMreport,we published the first epidemiologicalevidence showing a direct association between thimerosal-containing childhoodvaccines and neurodevelopment disordersin children. We showed that there wasfrom a 2 to 6-fold increased incidence of neurodevelopment disorders following anadditional 75-100µg dosage of mercuryfrom thimerosal-containing childhoodvaccines in comparison to thimerosal-freechildhoodvaccines.
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Thimerosal in Childhood Vaccines,Neurodevelopment Disorders, andHeart Disease in the United States
Finally, we analyzed data from the USDepartment of Education on the number of children of various ages in US schools whowere reported with various types of disabilities in comparison to the mercurydosethatchildrenreceivedfromthimerosalintheirchildhoodvaccines.In this study, the amount of mercurychildren received as part of their routinechildhood immunization schedule and theEPAand FDAmaximum permissible dosesfor the oral ingestion of methylmercurywere determined from the IOM report.The maximum permissible doses for theoralingestionofmethylmercurybytheEPAand FDA are 0.1 µg /kg body weight/dayand 0.4 µg /kg body weight/day, respec-tively.TheaveragesizeofinfantsatvariousageswasdeterminedfromGeigyScientificTables.The incidence of neurodevelopmentdisorders and heart disease followingthimerosal-containing DTaP and DTwcPvaccines in comparison to thimerosal-freeDTaP vaccines was based upon analysis of the VAERS database, using MicrosoftAccess.®The VAERS database is anepidemiologic database maintained by theCentersforDiseaseControlandPrevention(CDC)since1990.Alladversereactionsareto be reported to the VAERS database asrequired by US law. The CDC requireswritten and telephonic confirmation of serious adverse reactions and follows upthese patients one year later. The FDAinquires into deaths reported to theVAERSdatabase by contacting the patient'shealthcare provider and physician. TheFDA also continually monitors reports tothe VAERS database to determine whether anyvaccineorvaccinelothasahigherthanexpected incidence rate of events. TheVAERS Working Group of the CDC, theFDA, and we analyze and publishepidemiologic studies based upon analysisoftheVAERSdatabase.
Methods
EPA/FDAExposureLimitsTheVAERSDatabase
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The neurodevelopment disorders andheart disease conditions we analyzed wereautism, speech disorders, and heart arrest.These categories of adverse events were based upon descriptions of adversereactions by those reporting them and bydefined fields contained in the VAERSdatabase. In addition, as control adverseevents we analyzed the number of febrileseizures,fevers,pain,edema,andvomitingfollowingeachofthevaccinesunderstudy.We determined the number of each type of adverse event reported following doses for twogroupsofpatients,thefirstreceivinganaverage of 37.5 µg of mercury and thesecond, an average of 87.5 µg of mercuryThis grouping allowed us to be able toascertainlargernumbersforouranalyses.
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We hypothesize that DTaP or DTwcPvaccines, whether containing thimerosal or not, should have a similar incidence rate of adverse events. The assumption of similar reactogenicity following the vaccinesunder study forms the basis of our nullhypothesis.We analyzed DTaP and DTwcPvaccines by manufacturer, so that we couldcompare thimerosal-containing DTaP andDTwcP vaccines administered from 1992through2000againstthimerosal-freeDTaPvaccines administered from 1997 through2000.Weuseddenominatorsobtainedfromthe Biological Surveillance Summaries of the CDC to determine the number of dosesof each manufacturer administered. Basedupon this information, we were able tocalculate incidence rates of adverse eventsfollowingvaccination.Weareprecludedfromgivingincidencerates, the number of doses administered, or types of DTaP or DTwcP vaccine, becausethis information could reveal the identitiesof the manufacturers and the CDC claimsthatthisinformationisproprietary.We compared the incidence rates of adverse events following thimerosal-containing DTaP and DTwcP vaccinesagainst thimerosal-free DTaP vaccines inorder to determine relative risk. Therelativeriskvaluewasobtainedbydividingthe incidence rate of the adverse eventfollowing thimerosal-containing DTaP or DTwcP vaccines by the incidence rate of theadverseeventfollowingthimerosal-freeDTaP vaccines. The relative risks of theadverse events analyzed were plottedagainst the amount of mercury that eachchild had received. By definition, since weassumethatthepopulationsunderstudyaresimilarandwearetrackingonlytheamountof mercury that children received from thethimerosal-containing or thimerosal-freevaccines under study, the initial point
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Table 1.
A summary of the instantaneous mercury exposure levels of US infants at varioustimesaspartoftheirchildhoodimmunizationscheduleincomparisontothemaximumdaily EPAestablishedlimits.
analyzed was zero micrograms of mercuryandhadarelativeriskofone.The 2001 US Department of Educationreport was analyzed to determine thenumberofchildrenatvariousageswhohaddeveloped various conditions. Theconditions analyzed included: autism,speech disorders, orthopedic impairments,visual impairments, and deaf-blindness.We determined the prevalence of each of these conditions based upon the number of  births in each birth cohort as per the CDC'syearly live birth surveillance data. The birth cohort years analyzed were 1984,1985,1990,1991,1992,1993,and1994.We then calculated the amount of mercury that had been administered onaverage to each child in a birth cohort,UnitedStatesDepartmentofEducationReport
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 based upon the Biologic SurveillanceSummaries of the CDC. Then the preva-lence of the various conditions analyzedwas plotted against the amount of mercurythateachchildreceived.Table 1 presents a summary of theinstantaneous mercury exposure of USinfants at various times as part of their childhood immunization schedule incomparison to the EPA established limits.This table shows that the instantaneousrelative excess mercury that US childrenreceived from their childhood immuniza-tions ranged from 11 to 150-fold at a givenage in comparison to the US EPA safetyguidelines for the daily maximum oralingestion of methylmercury. In addition,these data show that children received aninstantaneous relative excess mercurydoses in comparison to the FDA safety
Results
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Figure1.(A)(B)
Neurodevelopmentdisordersandheartdiseaseconditionsreportedfollowingthimerosal-containingDTaPincomparisonto thimerosal-free DTaP vaccines for increasing mercury dosage that children received from thimerosal; Control adverse events reportedacutelyfollowingthimerosal-containingDTaPincomparisontothimerosal-freeDTaPvaccinesforincreasingmercurydosagefromthimerosal 
guidelines for the oral ingestion of methylmercury,rangingfrom2.7to37-foldatagivenage.Figure 1A plots the relative risk of speech disorders, autism, and heart arrestreported after thimerosal-containing DTaPin comparison to thimerosal-free DTaPvaccines for increasing doses of mercury.We found that the data points for eachcondition closely followed exponentialdistributions.Figure 1B plots the relative risks of febrile seizure, fever, pain, edema, andvomiting reported after thimerosal-containing DTaP in comparison tothimerosal-free DTaP vaccines. We foundthat administration of thimerosal-containing DTaP vaccines slightly raisedthe rate of adverse events compared tothimerosal-free DTaP vaccines, but theincreased relative risks did not correlatewith the total amount of mercury thechildrenreceived.Figure 2A shows the relative risk of speech disorders, autism, and heart arrestreported after thimerosal-containingDTwcP in comparison to thimerosal-freeDTaP vaccines for increasing dosage of mercury. We found that the data pointscloselyfollowedexponentialdistributions.Figure 2B shows the relative risk of febrile seizure, fever, pain, edema, andvomiting after thimerosal-containingDTwcP in comparison to thimerosal-freeDTaPvaccinesfordifferentmercurydoses.We found that administration of thimerosal-containing DTwcP vaccinessignificantly raised the rate of adverseevents compared to thimerosal-free DTaPvaccines,buttheincreasedrelativerisksdidnot correlate with the total amount of mercurythechildrenreceived.Figures 3A-B show the prevalence of autismandspeechdisordersasafunctionof the mercury dose that children receivedfrom thimerosal contained in their child-hood vaccines. We found that the condi-tions analyzed closely followed linear distributions with an increase of about onecase of autism per 100,000 children for every microgram present in childhoodvaccines and about one case of speech
Figure 2. (A)(B)
Neurodevelopment disorders and heart disease conditions reported following thimerosal-containing DTwcP incomparison to thimerosal-free DTaP vaccines for increasing mercury dosage that children received from thimerosal; Control  adverseeventsreportedacutelyfollowingthimerosal-containingDTwcPincomparisontothimerosal-freeDTaPvaccinesforincreasing mercurydosagefromthimerosal 
8 Journal ofAmerican Physicians and Surgeons Volume 8 Number 1 Spring 2003
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