Immunization Safety Review Thimerosal-Containing Vaccines and Neurodevelopmental Disorders (2001) / Chapter Skim
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Plausibility Assessment
Plausibility Assessment
Pages 38-64
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From page 38... ...
Presented here is a brief summary of data on mercury toxicity, He toxicokinetic comparability of e~ylmercury and methylmercury, and the documented effects of high-dose exposures to thimerosal, ethylmercury, and methy3mercury. Also examined are models of mercury accumulation and investigations related to concentrabons of mercury and heavy metals ~ children with autism The application of methylmercury-exposure guidelines to e~ylmercury exposures resulting from the use of thimerosal-containing vaccines is discussed as well.
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From page 39... ...
Urinary excretion plays a minor role in the elimination of methylmercury from the body. Urinary excretion may be higher after ethylmercury due to its more rapid conversion to inorganic mercury.
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From page 40... ...
Suzuki and colleagues (1973) reviewed several studies and compared inorganic mercury levels in the brain after methylmercury or ethylmercury exposure.
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From page 41... ...
Methylmercury exposure results in a greater ratio of mercury in the red blood cells to plasma compared with ethylmercury (reviewed in Suzuki et al., 1973~. The blood-distribution ratio of organic mercury is species-dependent.
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From page 42... ...
Ingestion of 5g of thimerosal in a suicide attempt resulted in delirium, sensorimotor polyneuropathy culminating in mechanical ventilation, and coma, along with acute renal failure (which resolved after 40 days) , fever, oral exanthema, and gingivitis (Pfab et al., 1996~.
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From page 43... ...
Methylmercury Exposures. Methylmercury at high doses is a welldocumented neurotoxicant (NRC, 2000~.
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From page 44... ...
In children exposed during fetal development, there were severe neurological dysfunctions and developmental abnormalities, including mental retardation, cerebral palsy, dearness, blindness, and dysarthria (Harada, 1995, Marsh et al., 1987, NRC, 2000~. In both Japan and Iraq, the neurological effects observed in children exposed to methylmercury in utero were more serious than those observed in adults, and sometimes occurred at lower doses than in adults, indicating the increased susceptibility of the fetus to methylmercury exposure (NRC, 2000~.
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From page 45... ...
Prenatal methylmercury exposure, as measured by umbilical cord blood levels, was associated with subtle neuropsychological deficits most notable in the areas of attention, memory, and language, and to a lesser extent in visuospatial and motor functions. Postnatal exposures, measured by the child's hair mercury concentration at ages 1 year and 7 years, were less useful risk predictors (Grandjean et al., 1997~.
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From page 46... ...
The committee carefully considered the significance of the evidence of subtle neurological deficits from the Faroe Islands study for its assessment of the biological plausibility of a causal association between exposure to thimerosalcontaining vaccines and the neurodevelopmental disorders of autism, ADHD, and speech or language delay. The conclusion was that those findings add indirect support to the biological plausibility of such an association but do not demonstrate a direct biological mechanism or provide evidence of causality.
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From page 47... ...
Three unpublished reports of chelation-based estimates of mercury in autistic children were presented to the committee (Bradstreet, 2001~. In one study, higher urinary mercury levels were found in autistic children than in neurologically normal children after provocation with the chelator DMSA.
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From page 48... ...
Although a consensus for safe mercury exposure does not exist, all of the recommended limits are within the same order of magnitude. The methylmercury exposure limits calculated by these agencies are not limits above which injury is sure to occur.
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From page 49... ...
Also discussed are sources of additional uncertainty that arise from the application of these methylmercury-based guidelines to ethylmercury exposures resulting from the use of thimerosal-containing vacc~nes. Computation of Federal Guidelines for Methylmercury Exposure.
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From page 50... ...
or adversely affected neurological function, were observed at lower levels of exposure than any other health effects, making them the most sensitive indicator of health risk. EPA estimated that with 95% confidence, the maternal mercury exposure that increased developmental risk for an unborn child by 10% corresponded to hair mercury concentrations of no less than 11 ppm (parts per million)
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From page 51... ...
As part of the FDA risk assessment of thimerosal, Ball and colleagues (2001) sought to compare the maximum mercury exposures resulting from the recommended childhood immunization schedule with the estimated cumulative limits for mercury exposure based on the three federal guidelines, as well as those of the World Health Organization (WHo)
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From page 52... ...
Alternatively, if the exposure is averaged over a single day, it amounts to approximately 3.1 ,ug/kg/day, which exceeds EPA's standard by more than a factor of 30. Figure 2 shows Halsey's estimates of maximum single-day mercury exposure from recommended vaccines given at birth and ages 2, 4, and 6 months, for a range of body weights at each age.
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From page 53... ...
Hair measurements provide a historical record of methylmercury exposure but do not accurately reflect exposure to inorganic mercury (NRC, 2000)
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From page 54... ...
Post-vaccination mean blood mercury levels in preterm infants (mean = 7.36 ,ug/L., +/- 4.99 SD) were 3 times higher than those in term infants (mean = 2.24 ,ug/L, +/- .58 SD)
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From page 55... ...
points out that blood mercury levels following exposure to ethylmercury appear to correspond to lower concentrations of mercury in the brain, and therefore perhaps less risk of neurotoxicity, than are found with similar blood levels resulting from methylmercury exposure. A key uncertainty is the rate of excretion of ethylmercury in infants.
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From page 56... ...
some children could be particularly vulnerable or susceptible to mercury exposures due to genetic or other differences. The committee concludes that although the hypothesis that exposure to thimerosal-containing vaccines could be associated with neurodevelopmental disorders is not established and rests on indirect and incomplete information, primarily from analogies with methylmercury and levels of maximum mercury exposure from vaccines given in children, the hypothesis is biologically plausible.
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From page 57... ...
. The reported adverse reactions were categorized into three groups: the neurodevelopmental outcomes addressed in this report (autism, ADHD, speech or language problems)
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From page 58... ...
Non-Neurological Outcome (1 of which with autism and mercury toxicity) 2 2 2 2 2 2 2 2 (also reported autism)
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From page 59... ...
The analytical value of data from passive surveillance systems is limited by such problems as underreporting, lack of detail, inconsistent diagnostic criteria, and inadequate denominator data (Ellenberg and Chen, 1997, Singleton et al., 1999~. Epidemiological Studies Published Studies.
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From page 60... ...
For each child, cumulative vaccine-related mercury exposure was calculated at the end of the first, second, third, and sixth months of life from individual automated vaccination records. Each vaccine a child received was assumed to contain the mean amount of thimerosal reported by manufacturers to the FDA, meaning that the ethylmercury content per dose of each childhood vaccine was assumed to be as follows: diphtheria-tetanus-pertussis (whole-cell or acellular)
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From page 61... ...
The Simpsonwood panel also expressed reservations about the applicability of findings from the studies of methylmercury exposures to possible effects of thimerosal exposures from vaccines (Stehr-Green, 2000, 2001~. Re-analyses of the Phase I data, reflecting modifications to address some of the concerns of the Simpsonwood panel and others, were reported at the TOM committee's scientific meeting in July 2001 (Verstraeten, 2001~.
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From page 62... ...
79 69 (15) 604 76 HMO B 2989 150 76 299.0 299.8 307.0 307.2 307.4 Sleep disorders 307.5 Eating disorders Emotional disturbances 313 314.0 315.39 Attention deficit disorder 315.31 Language delay Speech delay Coordination disorder 315.4 75 121 123 74 203 517 494 1448 (31)
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From page 63... ...
It should also be noted that the chances of finding an association between thimerosal exposure and these outcomes, if it exists, depends on the range of thimerosal exposures in the population, an HMO that is particularly successful in vaccinating its children would have less range of exposure and ability to detect positive findings. The Phase II study was conducted in mid-2000 to examine more closely the significant associations identified in the original Phase I analysis by replicating the Phase I study design with data from an East Coast HMO.
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From page 64... ...
An unpublished ecological analysis comparing aggregate trends in autism rates in California with the trends in mercury exposure from thimerosal-containing vaccines was presented to the committee (Blaxill, 2001~. To estimate the average level of mercury exposure for children 19-35 months of age in a given year, the mercury content of all recommended vaccine doses (assumed to be 37.5,ug for 3 doses of hepatitis B
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