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38 IMMUNIZA TION SAFETYREVIEW PLAUSIBILITY ASSESSMENT The Imm animation Safety Review Committee undertook its review to answer the following question: What is the causal relationship between tbimerosal- containing vaccines and the neurodevelopmental disorders of autism, attention deficitlhyperactivity disorder, and speech or language delay? The sources of evi- dence considered by the committee in its plausibility assessment include studies of biological mechanisms, reports of individual cases or series of cases, and epidemi- ological studies. Evidence Regarding Association: Biological Plausibility Biological plausibility rests on the existence of scientifically viable mecha- nisms by which exposure to thimerosal-containing vaccines from the recom- mended childhood immunization schedule could be associated with autism, ADHD, or speech or language delay. Evidence for such an association can come Dom demonstration of the mechanism through clinical, animal, or in vitro stud- ies. The evidence regarding thimerosal is indirect and incomplete, however. There are no direct studies, in either humans or srnrnals' of thimerosal exposures of a magnitude similar to those resulting from vaccines that would finely estab- lish a biological model connecting it to NDD. Only indirect evidence, from dec- ades of study of methylmercury and from high-dose thimerosal exposures, in- forms biological plausibility for neurodevelopmental effects from thirnerosal exposure ~ vaccines. The FDA risk assessment (Ball et al., 2001) included an extensive review of the available toxicity data on thimerosal and related data on ethyl- and methylmer- cury. The committee also reviewed much of these data, as well as published and unpublished reports that have become available since the FDA's review ~ 1999. 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 ex- amined are models of mercury accumulation and investigations related to concen- trabons 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. Mercu7y Toxicokinetics Mercury occurs in inorganic and organic forms. Inorganic mercury includes elemental, or metallic mercury (Hg), and the mercurous (Hg: and mercuric (Hg2~) salts. Organic mercury, defined as mercury compounds containing carbon bonds, includes ethylmercury (CH3CH2Hg: and me~ylmercury (CH3Hg), as well as over confounds. Mercury exposure can occur Trough inhalation of metallic mercury vapor, ingestion (with almost complete absorption of methyl-

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THIMEROSAL-CONTAINING VACCINES 39 mercury), and absorption through the skin, as well as through intravenous, in- tramuscular, and subcutaneous injections (ATSDR, 1999, NRC, 2000~. The toxicokinetic profile of mercury exposure can differ depending on the form of mercury, the route of exposure, the size of the dose, and age at exposure, but the toxicity of all mercury compounds is due to the mercury itself. Thimerosal is a thiosalicylate salt of ethylmercury. Upon administration, ethylmercury quickly dissociates from thiosalicylic acid and binds to blood or other tissue. The toxicological profile of ethylmercury from thimerosal is thought to be similar to that of ethylmercury from other sources (Magos, 2001b, Suzuki et al., 1963, 1973~. Mercury is clearly neurotoxic and nephrotoxic. Organic mercury forms of interest, ethyl- and methylmercury, are metabolized to mercuric mercury. The effects of mercuric mercury are greatest in the kidneys, whereas the effects of organic mercury are greatest in the central and peripheral nervous systems (Aschner and Aschner, 1990~. Generally, mercury is thought to induce cytotox- icity through inhibition of protein synthesis and cellular enzyme-mediated reac- tions, resulting in structural changes of cells, interference with cellular metabo- lism, and inhibition of cell migration (Clarkson, 1972~. More specifically, mercuric mercury exposure can cause acute renal failure and toxicity, charac- terized by proteinuria, oliguria, and hematuria. Case studies have also reported congested medulla, pale and swollen cortex, extensive necrosis, and degenera- tion of tubular epithelium (AT SDR, 1999~. Similar measures of toxicity such as necrosis of proximal tubules, proteinuria, and general renal nephropathy have been demonstrated in animal studies (AT SDR, 1999~. Comparisons of Ethylmercury and Methylmercury The limited data on the toxicology and pharmacokinetics of thimerosal and ethylmercury are summarized here, along with information about methylmercury, which has been studied extensively (see ATSDR, 1999, EPA, 1997, NRC, 2000, for detailed reviews). Many features of the toxicity of ethylmercury are thought likely to be qualitatively similar to those of Methylmercury (Ball et al., 2001~. Methylmercury has a whole-body half-life in the range of 70 to 80 days. The half-life of ethylmercury is not known, but may be shorter given its more rapid conversion to inorganic mercury. Methylmercury in blood appears to have a half-life of 50 days (WHO, 1990~. Methylmercury is excreted primarily in feces and bile, mostly in the form of inorganic mercury (NRC, 2000~. Organic and inorganic mercury complexed with glutathione are excreted in bile (Balla- tori and Clarkson, 1984~. Methylmercury secreted in bile undergoes subsequent re-absorption in the intestinal tract. 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. In general, based on studies of methylmercury in rodents (Ballatori and Clarkson,

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40 IMMUNIZATION SAFETY RE VIE W 1984), suckling infants do not excrete methylmercury. At weaning, the process of biliary excretion is suddenly activated. After ethylmercury administration in mice, more total mercury has been found in the blood and kidney compared with methylmercury and less in the brain (Suzuki et al., 1963~. Methylmercury can pass through the blood-brain barrier and into nerve cells as part of a methylmercury-cysteine complex (Ker- per et al., 1992~. It is unclear whether ethylmercury passes readily through the blood-brain barrier at the concentrations that result from exposure through vac- cines. This may result from lack of an amino acid transport system like that available to methylmercury. Glutathione, present in high concentrations inside cells, readily binds to methylmercury and may play a protective role. Methyl- mercury is transported out of cells probably as a complex with glutathione, as will be discussed later. Little is known about the transport mechanisms for eth- ylmercury out of cells, but it probably follows those of methylmercury. Ethyl- mercury also is converted more rapidly than methylmercury to mercuric mer- cury, which does not cross the blood-brain barrier as readily as the organic compounds (Magos, 2001b). It has also been postulated that mercury has a di- rect toxic effect on the blood-brain barrier at high doses, making it more perme- able (Aschner and Aschner, 1990~. Once present in brain tissue, organic mercury is converted into inorganic mercury. Studies have shown that ethylmercury has a significant and fast conver- sion to inorganic mercury and that the rate of conversion is slower for methyl- mercury. Suzuki and colleagues (1973) reviewed several studies and compared inorganic mercury levels in the brain after methylmercury or ethylmercury expo- sure. One study found that up to 75% of the total mercury in the brain was inor- ganic mercury three days after injection of ethylmercury or thimerosal. Other studies suggest that the percentage of inorganic mercury resulting from ethylmer- cury exposure is lower (11-46%~. In comparison, the total mercury in the brain at one to ten days after injection of methylmercury was 2.8% (reviewed in Suzuki et al., 1973~. Furthermore, the amounts of inorganic mercury in the brain increased over time following exposure to ethylmercury (Suzuki et al., 1973~. The charac- teristics of exposure also influence the conversion rate. Studies have found a higher fraction of inorganic mercury after chronic low dosing of methylmercury than after acute exposure (Aschner and Aschner, 1990~. Upon conversion from organic mercury, mercuric mercury does not as readily cross the blood-brain barrier to move into the blood stream for elimina- tion. Thus it is retained in the neural tissue for a longer period of time (ATSDR, 1999~. However, the relative contributions of inorganic and organic mercury to neural cytotoxicity are not known at this time. It is known that methylmercury can inhibit neuronal protein synthesis and several enzymatic processes that con- trol cell metabolism and respiration (Chang et al., 1980~. Unpublished data from in vitro studies presented to the committee suggest that ethylmercury from thi- merosal in vaccines binds to various neuronal cellular proteins (Haley, 2001~.

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THIMEROSAL-CONTAINING VACCINES 41 However, because many metals bind to cellular proteins, the significance of this finding with respect to biological plausibility is unclear. Following organic mer- cury injection in the mature brain, distribution of mercury (reviewed in Clark- son, 1972 and Chang et al., 1980) indicates greatest retention in the calcarine cortex, frontal, temporal, and occipital cortex, cerebellum, and the spinal dorsal root ganglions. In the developing brain, Methylmercury exposure leads to wide- spread damage, affecting virtually all areas of the brain (Clarkson, 1997~. Mercuric mercury accumulated in the kidney is bound to the protein metal- lothionein, which may play a protective role in renal toxicity. In the blood, ethyl- and Methylmercury are bound to cysteine residues of hemoglobin and to plasma proteins (Clarkson, 1972, NRC, 2000, Takeda et al., 1968~. Methylmer- cury 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. Methylmercury is avidly accumulated from the blood stream into scalp hair (for review, see WHO, 1990~. The average hair to blood concentration ratio is 250:1. Once incorporated into the formed elements of the hair strand, the con- centration remains unchanged. Thus, longitudinal analysis along the length of the hair strand will recapitulate previous blood levels (Amin-Zaki et al., 1976~. Hair grows at an approximate rate of 1 cm per month. Thus depending on the length of the hair strand, recapitulation can take place over many months or even years. Hair is especially useful as a biological monitor for prenatal exposure as a hair sample that covers the entire period of pregnancy can be collected from the mother at or soon after delivery. Thus hair has been used as the primary biologi- cal monitor in all epidemiological studies of prenatal exposure or in one case to complement the use of cord blood (NRC, 2000~. Especially important, it has recently been shown that levels in the mother's hair at delivery predict levels in autopsy brain samples from newborn infants that died of various causes (Cerni- chiari et al., 1995~. Organic mercury is also known to cross the placenta easily, allowing for prenatal mercury exposure. In addition, Methylmercury is excreted in breast milk (Sundberg and Oskarsson, 1992, Yoshida et al., 1992~. Health Effects of High-Dose Exposures to Thimerosal, Ethylmercury, and Methylmercury High-doses of thimerosal, ethylmercury, and Methylmercury have been found to produce severe health problems. High-dose thimerosal exposures have been iatrogenic or, in one case, resulting from a deliberate use in a suicide at- tempt. High-dose ethylmercury poisonings have resulted from environmental and occupational exposures, with poisoning from ethylmercury-containing fun- gicides being frequently fatal. Methylmercury poisoning has resulted from con- sumption of contaminated fish and grain. Neurological effects were prominent

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42 IMMUNIZATION SAFETY RE VIE W in all of these poisonings, and prenatal exposures to methylmercury resulted in birth defects and serious neurodevelopmental deficits. Although these exposures are at levels far higher than those resulting from vaccination, the evidence of neurotoxicity offers some support for, but does not establish, the biologic plau- sibility of neurotoxic effects at lower doses. Thimerosal Exposure. Several cases of high-dose exposure to thimerosal have been reported in the literature. Six patients (age 6 weeks to 39 years), who were given intramuscular injections of improperly formulated chloramphenicol, each received 71-330 mg/kg of thimerosal 1,000 times the correct level (Axton, 1972~. Symptoms were mainly neurological, including restlessness, slurred speech, hemiparesis, confusion, unsteady gait, hallucinations, and coma, five of the six patients died. An 18-month-old girl, who ingested 127 mg/kg of thimero- sal (in a merthiolate solution) over a one-month period, developed ataxia, hand tremors, vomiting, staring spells, and renal and hepatic failure before dying (Ro- hyans et al., 1984~. (Chelation therapy did not appear to be associated with clini- cal improvement in neurological function.) Ten of 13 infants treated with topical applications of a 0.1% tincture of thimerosal for omphaloceles (herniations of the bowel through the umbilicus) died (Fagan et al., 1977~. Autopsy studies of three infants found high levels of mercury in the liver (11.8-26.6 ,ug/g), the kidney (2.36-4.6 ,ug/g), and the brain (0.65-5.1 ,ug/g). A neurological follow-up at 10 years on a surviving patient found no abnormal focal neurological findings but included third-person reports of restlessness and easy distractibility in school. Ingestion of 5g of thimerosal in a suicide attempt resulted in delirium, sen- sorimotor polyneuropathy culminating in mechanical ventilation, and coma, along with acute renal failure (which resolved after 40 days), fever, oral exan- thema, and gingivitis (Pfab et al., 1996~. The patient recovered completely at 148 days post-ingestion, except for sensory defects in two toes. Toxicity was also reported in a 44-year-old male who had received ap- proximately 20 mg of thimerosal from HBV immunoglobulin, administered in- tramuscularly or intravenously, after a liver transplant for end-stage liver failure due to hepatitis B. C, and D infection (Lowell et al., 1996~. Beginning on the third postoperative day, the patient began developing symptoms that included paranoid thoughts, slurred speech, slowed movements, decreased muscle strength, inability to ambulate, and tremor in both hands. The patient's symp- toms completely resolved in five weeks following chelation therapy with DMSA (dimercaptsuccinic acid). The diagnosis of mercury toxicity in this case has been questioned because of the brief exposure period, the absence of visual field con- striction, and a blood-mercury level (104 ,ug/L on day nine) considered too low for the development of the symptoms described when compared with other cases (Magos, 2001b). In contrast to these reports of high-dose thimerosal toxicity, early studies in animals and humans failed to show neurotoxic effects (Jamieson and Powell, 1931~. Rabbits tolerated intravenous thimerosal doses of 25 mg/kg of body

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THIMEROSAL-CONTAINING VACCINES 43 weight, at higher doses, fatalities resulted from kidney and intestinal disease. In rats, the tolerated dose was 45 mg/kg body weight. A report on 22 human sub- jects who received total doses of up 180 ml of a 1% solution of merthiolate (10 mg/kg) noted only local skin irritation (Powell and Jamieson, 1931~. However, the study was not designed to test toxicity (Ball et al., 2001~. Other Ethylmercury Exposures. Mercury poisonings occurred in Iraq from consumption of bread made from grain treated with a fungicide containing 7.7% ethylmercury p-toluene sulphonanilide (Damluji, 1962, Jalili and Abbasi, 1961~. Symptoms generally occurred one to two months after consumption of the treated wheat, and patients differed in the mix and severity of their symptoms. Among the neurological symptoms seen were ataxia, difficulty in walking, speech disturbances, constriction of visual fields, and blindness. Effects were also seen on the renal system, the skin, the cardiac system, and the gastrointestinal system. In China, similar effects were seen from consumption of rice treated with ethylmercury chloride (2-2.5%) (Zhang, 1984~. Symptoms began one to two weeks following consumption of the rice and continued for several months. Common neurological symptoms included weakness, dizziness, numbness of extremities, paresthesia, ataxia, and unsteady gait. Fewer people experienced symptoms of impaired vision, coma, speech disturbance, or hand tremor. The mildest cases resulted from doses of 0.5-1 mg/kg body weight, moderate cases from 1-2 mg/kg, severe cases from 2-3 mg/kg, and lethal cases above 4.0 mg/kg body weight. Four cases of mercury poisoning occurred in Romania from consumption of pork from animals fed seed treated with ethylmercury chloride fungicides (Cinca et al., 1980~. Symptoms were similar to those seen in Iraq and China, including ataxia, dysarthria, dysphagia, increased tendon reflexes, inability to stand or walk, coma, and constricted visual fields. Autopsy results from two boys aged 10 and 15 showed the greatest nerve-cell loss and proliferation of neuroglia in the cerebral cortex, especially in the calcarine cortex, the midbrain, and the bul- bar reticular formation. Demyelination was apparent in the ninth and tenth cra- nial-nerve roots, and moderate cell loss and other lesions were found in the granular and Purkinje cells of the cerebellum. Motorneuron loss was evident in the ventral horns of the spinal cord. Fatal ethylmercury poisoning has also resulted from a seven-week occupa- tional exposure to ethylmercury in an insecticide factory (Hay et al., 1963~. The presenting symptoms included dysarthria, ataxia, leg weakness, bilateral nerve dearness, increased reflexes, and poor coordination. At autopsy, the brain showed loss of neurons from areas of the cerebral cortex (especially calcarine cortex) and some degeneration of Purkinje and granule cells of the cerebellum. In contrast to typical findings, a greater amount of mercury was found in the brain, especially in the corpus callosum, than in the liver. Methylmercury Exposures. Methylmercury at high doses is a well- documented neurotoxicant (NRC, 2000~. The most severe neurological effects

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44 IMMUNIZATION SAFETY RE VIE W reported in humans occurred after accidental methylmercury-poisoning episodes in Japan and Iraq. Major epidemics of methylmercury poisoning occurred in Minamata and Niigata, Japan, during the 1950s and 1960s following consump- tion of contaminated fish and seafood, and first raised awareness of the neuro- logical sequelae of high-dose exposures to methylmercury (Harada, 1995, Tsubaki and Irukayama, 1977~. Poisoning episodes in Iraq in the 1960s and 1970s resulted from consumption of homemade bread made from grain treated with a methylmercury-containing fungicide (Bakir et al., 1973~. In adults, these high-dose exposures to methylmercury resulted in symptoms that included paresthesia, ataxia, and impairments of speech, hearing, and vision. 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 ob- served in adults, and sometimes occurred at lower doses than in adults, indicating the increased susceptibility of the fetus to methylmercury exposure (NRC, 2000~. The exposures that produced these effects were very high, and precise dose- response relationships at low doses were not established (NRC, 2000~. Health Effects of Low-Dose Exposures to Thimerosal and Methylmercury Studies of low-dose exposures to thimerosal and methylmercury would be potentially more informative regarding the biological plausibility of neurodevel- opmental effects from thimerosal exposures from vaccination. The data on thi- merosal are limited, however, and the studies of the effect of ingested methyl- mercury are not directly applicable. Hypersensitivity Reactions to Thimerosal. Immune-mediated reactions to mercury-containing compounds are well documented in humans and in ex- perimental animals (for reviews see Enestron and Hultman, 1995, Griem and Gleichman, 1995, Pollard and Hultman, 1997~. The most common manifestation is contact allergy (i.e., delayed-type hypersensitivity), although immune- complex-mediated disorders, such as glomerulonephritis, and immediate-type hypersensitivity (i.e. allergy) reactions have also been reported. Thimerosal can induce contact hypersensitivity responses in humans. Positive patch tests have been seen in 1-16% of individuals tested (reviewed in Cox and Forsyth, 1988~. However, the frequency of clinically important contact hypersensitivity is much lower, and its significance is a matter of controversy (Ball et al., 2001~. Ethylmercury in vaccines and other pharmaceutical products may rarely cause immediate-type hypersensitivity reactions, including anaphylaxis, although conclusive proof that mercury in thimerosal is the causative component is lack- ing. In one case in which anaphylaxis occurred in association with hepatitis B

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THIMEROSAL-CONTAINING VACCINES 45 vaccine administration, a repeat challenge suggested that thimerosal was not re- sponsible (Ball et al., 2001~. Similarly, one report of laryngeal obstruction after a patient used a throat spray containing thimerosal (Maibach, 1975) might reflect the corrosive effect of mercury rather than a hypersensitivity reaction. Acrodynia has been reported in a patient receiving gammaglobulin injec- tions containing .01% thimerosal (Matheson et al., 1980~. Acrodynia, or pink disease, occurs in a small fraction of exposed individuals, primarily children, and may represent a hypersensitivity response to mercury. It presents with a pink, pruritic skin rash, especially on the soles and palms. Other symptoms can include photophobia, irritability, and lethargy. Acrodynia is most closely associ- ated with infants exposed to inorganic mercury in products like teething pow- ders, which are no longer marketed. The 20-year-old patient receiving gamma- globulin had congenital agammaglobulinemia and a history of allergic reactions and sensitivity to sulphonamide drugs. He had been receiving gammaglobulin shots over the course of 15 years. It was estimated that the patient was exposed to 40-50 mg of mercury during the year in which he presented with symptoms. Methylmercury Exposure. The lack of data on the effects of low-dose ethylmercury exposure has led those concerned about thimerosal-containing vaccines to examine studies of chronic low-dose exposures to methylmercury, occurring primarily through consumption of fish and marine mammals. The neu- rodevelopmental effects in children resulting from moderate to low-level prena- tal and postnatal exposures to methylmercury are less clear than the serious ef- fects seen in high-dose poisonings (see NRC, 2000 for a review of epidemiological studies). Two large prospective cohort studies are currently under way to evaluate the more subtle endpoints of neurotoxicity resulting from low-dose prenatal ex- posure to methylmercury. The first study is being conducted in the Faroe Is- lands, in the North Sea, and the second in the Republic of the Seychelles, a na- tion of islands in the Indian Ocean off the coast of East Africa. In the Faroe Islands, the predominant source of mercury exposure is from consumption of pilot whale meat. In the Seychelles, mercury exposure comes from consumption of ocean fish. To date, the two studies have reached different conclusions. The Faroe Islands study is following a cohort of approximately 1,000 chil- dren born in 1986-1987. Developmental outcomes were assessed for 917 of the children at age 7 using a battery of domain-specific neuropsychological and neu- rophysiological tests. Prenatal methylmercury exposure, as measured by umbili- cal 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~. The Seychelles study is following two cohorts of children, a Pilot Study co- hort (N = 789) and a Main Study cohort (N = 779), enrolled in 1987 and 1989,

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46 IMMUNIZATION SAFETY RE VIE W respectively. The cohorts have been followed longitudinally and outcomes have been assessed at multiple ages. Prenatal and postnatal mercury exposures were measured in maternal hair and child hair cut at each testing, respectively. Evaluations conducted through 5.5 years of age, using global assessments, found no adverse associations between prenatal or postnatal exposure to methylmer- cury and childhood developmental outcomes (Davidson et al., 1995, 1998, 2000~. Preliminary analyses from evaluations of pilot cohort members at age nine using domain-specific tests also show no adverse associations (Davidson et al., 2000, Myers, 2001~. The discrepant findings in these two studies may reflect differences in study design or in the characteristics of the populations examined. There were differ- ences in exposure measures (cord blood versus maternal hair), types of neuro- logical and psychological tests administered (domain-specific versus global de- velopmental outcomes), the age of testing (7 years versus 5.5 years of age), possible confounders (PCB exposure or genetic differences in the populations studied), and biostatistical issues related to data analysis (NRC, 2000~. Addi- tional analyses of the Seychelle Islands data are under way and will address some ofthese differences (Myers, 2001~. The committee carefully considered the significance of the evidence of sub- tle neurological deficits from the Faroe Islands study for its assessment of the biological plausibility of a causal association between exposure to thimerosal- containing vaccines and the neurodevelopmental disorders of autism, ADHD, and speech or language delay. The conclusion was that those findings add indi- rect support to the biological plausibility of such an association but do not dem- onstrate a direct biological mechanism or provide evidence of causality. As was stated in the recent FDA risk assessment of thimerosal in vaccines (Ball et al., 2001), extrapolating the toxicity of methylmercury exposure to ethylmercury exposure in thimerosal-containing vaccines is problematic. Data on the com- parative toxicology of ethyl- and methylmercury are limited. In addition, data on the metabolism and excretion of ethylmercury compared with methylmercury have not been well established. The comparability of the effects of chronic low- dose exposure to methylmercury via ingestion versus those of intermittent expo- sure to ethylmercury via intramuscular injection is unknown. The relative sus- ceptibility of the fetus compared with the infant is also unknown. Furthermore, the neuropsychological deficits detected in the Faroe Island studies are not reli- able predictors for the specific neurodevelopmental diagnoses of autism, ADHD, and speech or language delay. Investigations Related to Mercury and Heavy Metals in Children with Autism Similarities between autism and mercury intoxication have been offered as evidence that thimerosal in childhood vaccines could cause autism (Bernard et

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THIMEROSAL-CONTAINING VACCINES 47 al., 2001, El-Dahr, 2001~. The identified similarities include psychiatric distur- bances, speech or language deficits, sensory abnormalities, motor disorders, cognitive impairments, unusual behaviors (such as head banging and sleep diffi- culties), physical disturbances (such as rashes, diarrhea, abnormal feeding be- haviors), and biological indices (such as metal metabolism, immune system ef- fects, CNS structure, neurochemistry, and neurophysiology). However, the analogy is weakened by differences in mechanistic understanding of some of the symptoms of mercury intoxication and of autism. For example, impaired visual fixation associated with mercury toxicity is due to problems with motor control of eye muscles. This is unrelated mechanistically to problems in joint attention associated with autism, which are most likely a problem of social reciprocity, not motor control (Tanguay, 2000~. In addition, there are manifestations from ethylmercury toxicity not seen in autism, for example, polyoria, ataxia, and tremor. Analogies like these are important for hypothesis generation, but they have limited value in causality assessments. Others have argued that thimerosal may cause autism based on the observa- tion that some autistic children have abnormal blood-metal profiles. One method being used to indicate levels of mercury in autistic children is chelation therapy. 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 neurologi- cally normal children after provocation with the chelator DMSA. In a case re- port that also used DMSA provocation, mercury levels in an autistic boy were much more elevated than those of his mother, father, or brother. Finally, in a study of 27 autistic children in Indonesia, 70% had detectable mercury levels, with the levels in 30% of the children exceeding adult mercury levels. Some have reported improvements in functioning of autistic children after chelation therapy (Cave, 2000, Sykes, 2001~. Chelation therapy has not been established to improve renal or nervous sys- tem symptoms of chronic mercury toxicity (Sandborgh Englund et al., 1994) and has had no effect on cognitive function when used for excretion of another heavy metal, lead (Rogan et al., 2001~. Because it is unlikely to remove mercury from the brain, it is useful only immediately after exposure, before damage has oc- curred (Evans, 1998~. Moreover, chelation therapy is not without risks, for exam- ple, some chelation therapies might cause the release of mercury from soft-tissue stores, thus leading to increased exposure of the nervous system to mercury (Wentz,2000~. In addition, chelation therapies are not specific to one metal. The presence of abnormal metal profiles in autistic children does not mean that the metal burden is the cause of autism. It could indicate a comorbidity be- tween autism and an inability to handle heavy metals. Further, a favorable re- sponse to chelation therapy is not proof that the mercury levels caused the neu- rological dysfunction. Chelation therapy is non-specific, and the observed effects could be caused by other metals or other factors.

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48 IMMUNIZATION SAFElrYREVIEW Application of Methylmercz~ry Exposure Guidelines to Thimerosal Exposurefrom Vaccines Concern over the use of thimerosal in childhood vaccines was originally triggered by calculations showing that vaccines on the recommended childhood imm~mi~ation schedule might result in cumulative ethylmercury exposures that exceed estimated limits of safe exposure based on some federal guidelines for methylmercury intake. Three U.S. federal agencies EPA, ATSDR, and FDA- have developed guidelines for assessing exposure to methylmercury. The EPA is responsible for monitoring mercury concentrations in the environment and regulating industrial releases of mercury to air and surface water. The FDA is responsible for regulating commercially sold fish and seafood based on mercury concentrations. Although ATSDR does not have regulatory authority, it moni- tors the potential for h,iman exposure to methylmercury and investigates re- ported health effects (NRC, 2000~. Currently, each of the agencies has a differ- ent guideline for assessing safe exposure to mercury, and different [units of methylmercury intake, ranging from 0.1 ,uglkg/day for EPA (EPA, 2001), to 0.3 ~g/kg/day for ATSDR (ATSDR, 1999), to approximately 0.4 ~g/kg/day for FDA (FDA, 1979~.3 The differences ~ the agencies' recommended limits can be attributed to the use of different nsk-assessment methods and uncertainty fac- tors, variation ~ primary data sources, and the different mandates of each agency (NRC, 2000~. 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. Rather, they should be interpreted as general levels of exposure below which there is confidence that adverse effects will be absent, although the margin of safety reflected in those limits is uncertain (EPA, 1997~. Definitions of the exposure measures used in the three federal guidelines are provided in Box 4. It is important to understand the specific data and assumptions on which these guidelines are based, however, when considering the possible implications of thi- merosal exposures that exceed Me guidelines on methylmercury intakes. As a re- sult, the computation of the federal guidelines is briefly reviewed here, although an in-depth discussion of the development of We guidelines is beyond Me scope of this report. (The interested reader is referred to a recent review in NRC, 2000.) The estimates of Me maximum mercury exposures associated with reco~nended childhood Motion are then compared against the recommended exposure 3 FDA's acceptable daily intake (ADI) of methylmercury is 30 ~g/day (FI)A, 1 979). FDA has never officially expressed its standard on a body weight basis. For general corr~anson purposes with the EPA's and ATSDR's guidelines, FDA's ADI of 30 1lg/day has been converted to a 1lg/lcg/day basis, assuming a 70 kg average body weight, which is roughly equivalent to 0.4 ~gfkg/day. Varying the assumptions about average body weight will affect the conversion.

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54 IMMUNIZATION SAFETY RE VIE W be more fully developed to be useful in risk assessments of thimerosal- . . . containing vaccines. In a recent published observational study (Stajich et al., 2000), total blood mercury levels were measured before and after the administration of the birth dose of hepatitis B (containing 12.5 ,ug of ethylmercury) in a group of 15 pre- term infants and a control group of 5 term infants. Measurements of mercury levels were taken within 48 to 72 hours after vaccination. Comparisons of pre- and post-vaccination mercury levels demonstrated elevated blood mercury levels after a single dose of hepatitis B vaccine in both preterm and term infants. Pre- term infants (mean = .54 ,ug/L, +/-.79 SD) had a tenfold higher mean blood mer- cury level at baseline compared with term infants (mean = .04 ,ug/L, +/-.09 SD), although the difference was not significant. Post-vaccination mean blood mer- cury 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), and differ- ences were significant. Unpublished observational data funded by NIAID (Pichichero et al., 2001, Sager, 2001) show lower blood mercury levels than Brown's model-based esti- mates or the observational study by Stajich et al. (2000~. Among two-month- olds (N = 16) receiving an average of 45.6 ,ug of mercury (range 37.5-62.5 fig), blood mercury concentrations at 3 to 20 days after vaccination (average 11.25 days) averaged 1.5 ,ug/L (range < 0.75-4.11 ,ug/L). Among six-month-olds (N = 20) receiving an average cumulative dose of 111.3 ,ug mercury (range 87.5-175 fig), blood mercury concentrations 4 to 27 days post vaccination (average 13.3 days) averaged 0.98,ug/L (range < 0.05-1.5,ug/L). Two differences among the three studies should be noted. The delay be- tween vaccination and blood mercury sampling in the NIAID data means that these measurements are not directly equivalent to the peak levels estimated by Brown or the measures by Stajich et al. (2000) taken within 48 to 72 hours. The delay was not substantial, given mercury's relatively long half-life, but the half- life of ethylmercury is probably shorter than the half-life of methylmercury (Brown, 2001), implying that earlier observation would have shown higher blood mercury levels. The findings of the NIAID study are consistent with ex- cretion of ethylmercury. The children in the NIAID study also received lower cumulative mercury doses from their vaccines than the theoretical maximums modeled by Brown. Once again, however, this difference in dose (roughly a factor of 2) does not explain the differences between the modeled and measured blood mercury levels reported by Brown and NIAID, respectively. However, Brown's model is preliminary and is based on assumptions about methylmer- cury, which may explain why the results differ substantially from the empirical findings by Stajich et al. (2000) and NIAID. Furthermore, given the small size of the study populations in the two observational studies, the significance of the findings cannot be assessed.

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THIMEROSAL-CONTAINING VACCINES 55 Sources of Uncertainty. As the previous discussion shows, comparing mercury exposures from vaccines with federal mercury-exposure guidelines does not provide proof of either excess risk or adequate safety. In addition to considerations like the choice of an appropriate averaging duration, there are several other key factors that make comparisons between vaccine doses of eth- ylmercury and federal exposure guidelines uncertain. Many of these points are also raised elsewhere in this report. The EPA and ATSDR exposure guidelines were set based on adverse ef- fects of prenatal exposures to methylmercury resulting from maternal consump- tion of contaminated food. This means that vaccine exposures differ in terms of the age of exposure, the route of exposure, and the type of mercury. The devel- oping fetal brain is known to be highly susceptible to toxic exposures, but data on the effects of early postnatal exposures are limited, for both methylmercury and ethylmercury. There is also little basis for determining whether the effects of exposures through injection are comparable to those from ingestion. Furthermore, because the pharmacokinetics of ethylmercury are not well documented, it is difficult to know whether the biomarkers used in establishing the methylmercury guidelines can be applied to ethylmercury exposures. Magos (2001b) points out that blood mercury levels following exposure to ethylmer- cury 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. Although data from animal tests and data on methylmercury excretion in infants suggest little excretion in infants, the preliminary data from the NIAID study suggest significant mercury elimination in children given thimerosal-containing vaccines. However, abnormalities or genetic variations in mercury metabolism might lead to an underestimate of mercury levels from thimerosal-containing vaccines. The preliminary report that autistic children have a higher risk than non-autistic children for metallothionein metabolic disturbances (Walsh and Usman, 2001), together with case reports from some pediatric practices that some autistic chil- dren have high mercury and other heavy-metal profiles, might contribute to the concern of some that a subgroup of children with NDDs might be at risk for mercury toxicity at levels of exposure that are safe for other children. This does not, however, imply that mercury exposures have caused the NDDs. Due to differences in drug distribution or clearance, concentrations of mer- cury reached in specific tissues may vary between individuals receiving the same amount of mercury (or whose intake of mercury is similar). Other individuals may have genetic differences that make them more susceptible to mercury-induced injury at a given concentration of mercury in a particular tissue. It might be pru- dent to reduce mercury exposure as much as possible in these children. The role of the mercury metabolism (or other metabolic defects) in the genesis of concomitant NDDs is unclear, however, and cause and effect should not be inferred.

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56 IMMUNIZATION SAFETY RE VIE W Biological Plausibility Argument The hypothesis that thimerosal exposure through the recommended child- hood immunization schedule has caused neurodevelopmental disorders is not supported by clinical or experimental evidence because: . low-dose thimerosal exposure in humans has not been demonstrated to be associated with effects on the nervous system, . neurodevelopmental effects have been demonstrated for prenatal but not postnatal exposures to low doses of methylmercury, . the toxicological information regarding ethylmercury, particularly at low doses, is limited, . thimerosal exposure from vaccines has not been proven to result in mercury levels associated with toxic responses, signs and symptoms of mercury poisonings are not identical to autism, ADHD, or speech or language delay, . . autism is thought primarily to originate from prenatal injury, and . there is no evidence that ethylmercury causes any of the pathophysiological changes known to be associated with autism, such as genetic defects, and there are no well-developed pathological markers of ADHD or delay of speech or language that could be compared to effects of ethylmercury on the nervous sys- tem. The information related to biological plausibility is indirect because: high-dose thimerosal exposures are associated with neurological damage, . an extensive toxicological and epidemiological literature establishes meth- ylmercury, a close chemical relative, as a toxicant to the developing nervous system, . some children who received the maximum number of thimerosal-containing vaccines on the recommended childhood immunization schedule had exposures to ethylmercury that exceeded some estimated limits of exposure based on fed- eral guidelines for methylmercury intake, and . 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 neurodevelopmen- tal disorders is not established and rests on indirect and incomplete infor- mation, primarily from analogies with methylmercury and levels of maxi- mum mercury exposure from vaccines given in children, the hypothesis is biologically plausible.

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THIMEROSAL-CONTAINING VACCINES Evidence Regarding Association: Case Reports, Case Series, and Uncontrolled and Controlled Epidemiological Studies 57 Considered in this section are the case reports and epidemiological studies related to thimerosal-containing vaccines and neurodevelopmental disorders. Case Reports and Case Series VAERS. A search of the Vaccine Adverse Event Reporting System (VAERS), for the period from its inception in November 1990 through May 2001, identified 176 unique reports based on the following search strategy. During this 11-year period, about 120,000 reports were submitted to VAERS, including approximately 5,000 foreign reports (CDC, 2001b). Reports of interest were identified by searching all text fields using the terms "thimerosal," "thiomersal," "mercury," or "merthiolate," or a portion thereof (e.g., for "mer- cury," the text string "mere" was used). The reports referred to the following thimerosal-containing vaccines: hepa- titis B (79), influenza (48), diphtheria-tetanus (DT) (3), diphtheria-tetanus- pertussis (DTP) (4), Haemophilus influenzue type b (Hib) (1), tetanus-diphtheria (Td)~9), DTP-Hib (5), pneumococcal (3), tetanus (4), rabies (1) and concurrent but separate administration of influenza and pneumococcal (3), influenza and TD (1), DTwP and hepatitis B (1), DTP and Hib (5), and DTaP, Hib, and hepa- titis B (1~. Eight reports listed an adverse event in response to the cumulative childhood vaccine schedule. Reports involving only non-thimerosal-containing vaccines (e.g., MMR or OPV) were excluded from the reporting. Thirty-three reports were for children ages 15 years and younger and were distributed as follows: 6 months and younger (6 reports), 7 months to 2 years (1 1 reports), 3 to 5 years (9 reports), and 6 to 15 years (7 reports). The reported adverse reactions were categorized into three groups: the neuro- developmental outcomes addressed in this report (autism, ADHD, speech or lan- guage problems), other neurological outcomes, and non-neurological outcomes. Table 4 details the type and number of outcomes reported in these three categories. In the first category, there were nine reports of autism and nine reports of speech or language problems. There were no reports of ADHD, although there was one report of attention problems (not otherwise specified) for a child with autism. In the second category, the types of neurological outcomes reported include: headache (15), paresthesia (11), dizziness (9), asthenia (6), non-febrile seizure (4), developmental delay (3), cognitive abnormality (2), and hypertonia (2~. Five reports describe mercury poisoning in the patient, but not did not identify a spe- cific outcome. See Table 4 for less frequently reported neurological outcomes.

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58 IMMUNIZATION SAFETY RE VIE W TABLE 4 Summary of Outcomes Attributed on VAERS Reports to Th merosal 11 - Outcome Autism Speech or Language Problems ADHD Other Neurological Outcome Headache Paresthesia Dizziness Asthenia Myasthenia Seizure (not febrile) Behavior changes Developmental delay Number of Cases Reported 9 9 o 15 11 9 6 4 4 3 Hypokinesia Loss of eye focus Amnesia Cognitive abnormality Confusion Guillain-Barre syndrome Hypertonia Neuropathy 1 remor Twitch Atrophy muscle Auditory processing disorder Buzzing in head Catalonia CSF abnormality Coordination abnormality Enc ephal op athy Febrile seizure Learning impairment Mitochondrial disorder Neuralgia Neuralgic amyotrophy Sound and light sensitive Strabismus Unspecified neurological sequelae Vertigo Mercury poisoning (no specific outcome identified) Non-Neurological Outcome (1 of which with autism and mercury toxicity) 2 2 2 2 2 2 2 2 (also reported autism) (also reported mercury toxicity) 5 155

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THIMEROSAL-CONTAINING VACCINES 59 In the third category, 155 people reported non-neurological outcomes. The most commonly reported event was delayed hypersensitivity reactions. Because the focus of this report is on neurodevelopmental outcomes, non-neurological outcomes are not reported in detail here. There were 12 rechallenge cases identified involving 11 non-neurological outcomes, and one neurological outcome (headache). The one neurological- related rechallenge case reported a headache after receiving the first and second doses of the hepatitis B vaccine. The committee concluded that these reports were uninformative with respect to causality. VAERS and other case reports submitted to the committee are useful for hypothesis generation, but they are generally inadequate to establish causality. 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. None. Unpublished Studies. Controlled Observational Studies. One unpub- lished controlled epidemiological study, funded by CDC, has tested whether or not certain neurodevelopmental and renal disorders are related to exposure to thimerosal-containing vaccines. The study was based on data from the Vaccine Safety Datalink (VSD), a large-linked database that includes vaccination, clinic, hospital discharge, and demographic data. The VSD, formed as a partnership between CDC and seven health maintenance organizations (HMOs), was initi- ated in 1991 and covers approximately 2.5 percent of the U.S. population (Ver- straeten, 2001~. The study was conducted in two phases. Phase I was designed to screen data for potential associations between exposures to mercury from thimerosal- containing vaccines and selected neurodevelopmental and renal outcomes. Phase II was designed to test the hypotheses generated in the first phase. Both phases were designed as retrospective cohort studies. In Phase I, the original study population included children born between 1992 and 1997 who were enrolled continuously during their first year of life in one of two large West Coast HMOs and who received at least two polio vacci- nations by one year of age. Excluded from the study were infants with diagnoses of congenital or severe perinatal disorders or who were receiving hepatitis B immunoglobulins, and premature infants with gestational ages less than 38 com- pleted weeks. Of the approximately 213,000 infants born into these HMOs be- tween 1992 and 1997, approximately 110,000 met the eligibility criteria for in- clusion in the analyses. (The eligible children from both HMOs were combined

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60 IMMUNIZATION SAFETY RE VIE W into a single cohort in the original Phase I analysis.) Separate analyses were conducted for the premature infants (Stehr-Green, 2000~. 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), 25.0 ,ug, hepatitis B. 12.5 ,ug, Haemophilus influence type b, 25.0 ,ug, measles- mumps-rubella, polio, pneumococcal, and varicella, 0.0,ug. The level of mercury exposure was categorized in increments of 12.5 ,ug. The outcomes studied in- cluded a range of plausible neurological and renal disorders identified in the mer- cury toxicity literature, and defined by specific ICD-9 diagnostic codes. Cox proportional hazard models were used to compare the risk of adverse developmental outcomes. The endpoint of the observation period for each child was defined as the date of the first of the following events: first diagnosis, first disenrollment, or the close of the study period (December 31, 1998~. The analy- sis was stratified by HMO, year, and month of birth, adjustments were made for sex. To obtain sufficient power to detect any association, the study examined only outcomes with more than 50 identified cases. Preliminary results of the Phase I analysis produced statistically significant but weak associations (relative risk ratios < 2.00 per 12.5 ,ug increment of mer- cury) between various cumulative exposures to thimerosal and the following neu- rodevelopmental diagnoses: unspecified developmental delays, tics, attention defi- cit disorder (ADD), language and speech delay, and general neurodevelopmental delays. No association was found for renal disorders or other neurological disor- ders with more than 50 cases, including autism (Stehr-Green, 2000, 2001~. The researchers interpreted the analysis as showing a possible association between certain neurological developmental disorders and exposure to mercury from thi- merosal-containing vaccines prior to six months of age (Stehr-Green,2000~. An outside review panel (known as the Simpsonwood Panel), convened in June 2000, concluded that the Phase I VSD screening analyses did not provide adequate evidence to support or refute a causal relationship between exposure to thimerosal-containing vaccines and specific neurodevelopmental disorders, but recommended that these issues be vigorously investigated. The Simpsonwood panel also noted several concerns about factors that could affect the interpret- ability of the Phase I study results (Stehr-Green, 2000, 2001~: . An ascertainment or health-care-seeking bias could exist. Children whose parents make greater use of health care services may be more likely to have re- ceived all recommended vaccinations and therefore the highest doses of thi- merosal-containing vaccines and to have had a greater opportunity to receive a diagnosis for a neurodevelopmental disorder.

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THIMEROSAL-CONTAINING VACCINES 61 . The inexactness in the diagnosis of neurodevelopmental disorders, espe- cially for young children, and inconsistencies in diagnoses across clinicians, clinics, and HMOs could result in misclassifications or biases that affect the clinical significance of the findings. . The lack of data on known familial and genetic predispositions to the neu- robehavioral outcomes could mask factors that confound the relationship be- tween thimerosal exposure and the outcomes being studied. . The data and analyses are limited in their ability to distinguish any effects of thimerosal exposure from excess risks attributable to other vaccine compo- nents or other vaccine-related associations. 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~. Among the modifications made in the re-analysis were: conducting separate analyses for each HMO (referred to as HMO A and HMO B), adjusting for additional vari- ables in the models, making additional controls and adjustments to avoid a health-care-utilization bias, and checking for outcome misclassification through chart review of select diagnoses. Of the 22,647 children born from 1992 through 1997 into HMO A, 15,309 children were eligible and retained in the final cohort for analysis. Of the 184,723 children born from 1992 through 1998 into HMO B. 114,966 children were eligible and were retained in the final cohort. Table 5 shows the neurologi- cal and renal outcomes with more than 50 identified cases that were examined in the analysis. Two control diagnoses, flat feet/toe deformities and injury at un- specified site, were also included in the analysis to check for a potential health- care-seeking bias. These diagnoses were thought to be associated with the worry of parents and increased health-seeking behavior, but a priori were not expected to be associated with thimerosal exposure. Because the final cohort at HMO B is about eight times as large as the cohort at HMO A, there are relatively more children included in the outcome categories at HMO B. Not all of the outcomes that were examined at HMO B could be examined at HMO A due to insufficient numbers of cases in some outcome categories at HMO A. As in the original Phase I analysis, the re-analysis identified positive but weak associations (relative risk ratios < 2.00) with several neurodevelopmental diagnoses (see Table 6~. Results from unadjusted and adjusted models were pre- sented to the committee. The adjusted models, which are used in epidemiology to control for potential confounders, included the following additional variables: birthweight, gestational age, mother's age at delivery, race and ethnicity, and

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62 IMMUNIZATION SAFETY RE VIE W TABLE 5 Neurodevelopmental, renal outcomes, and control diagnoses > 50 children Neurodevelopmental outcomes > 50 children ICD 9 Disorders Any neurodevelopment disorder Autism Childhood psychosis Stammering Tics HMO A 869 (19) (1 1) 54 (32) 56 (5) 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) Renal outcomes and control diagnoses > 50 children ICD 9 Disorders Any renal disorder Unspecified kidney or ureter disease 14 Flat feet or toe deformities HMO A HMO B 197 80 24 5939 734, 735 959.9 Injury at unspecified site 86 848 112 2428 Numbers in brackets indicate outcomes for which there were insufficient numbers of children at HMO A or B. Provisional Results may be subject to change. Verstraeten, 2001. Apgar score at 5 minutes (the last at HMO A only). The adjusted models in- cluded only approximately 80 percent of the eligible children because variables were missing for some children. For HMO A, positive but weak associations were found between exposures to thimerosal and stammering, sleep disorders, and emotional disturbances. The association with sleep disorders did not persist in the adjusted models, and the association with emotional disturbances appeared only in the adjusted models. For HMO B. positive but weak associations were found for: any neurodevelopmental disorder, stammering, language delay, speech delay, attention deficit disorder, and tics. The association with attention deficit disorder and tics did not persist in the adjusted models. In both rounds of analysis of Phase I data. the results failed to show a consistent dose-response pattern.

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THIMEROSAL-CONTAINING VACCINES 63 The inconsistent findings between HMO A and B in the re-analysis could be due to several factors. At HMO B. a positive association was found in both un- adjusted and adjusted models between thimerosal exposure and the control diag- nosis of flat feet/toe deformities, indicating a potential health-care-seeking bias at HMO B. In addition, the sample size was considerably larger at HMO B. pro- viding more power to detect small differences in risk, if they exist. 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. However, the study population had only approximately 17,500 eligible children, providing a suffi- cient number of cases for analysis of only two of the outcomes, ADD and speech delays. The Phase II analysis identified no significant differences in risk with the receipt of thimerosal-containing vaccines and these two outcomes, TABLE 6 Relative risks by increase of 12.5 ,ug ethylmercury Summary of positive associations *: p < 0.05 **: p < 0.01. HMO A HMO B Outcome Unadjusted Adjustedi Unadjusted Adjustedi Any neurodevelop- ** ** mental disorder Stammering * * * * * * Tics * Sleep disorders * Emotional * disturbances Attention deficit ** disorder Language delay ** ** Speech delay ** ** Flat feet or toe * * deformities "Adjusted for birthweight, gestational age, mother's age at delivery, race and ethnicity, and Apgar score at 5 minutes [the last in HMO A only]. Notes: Final cohort size - HMO A: 15,309 and HMO B: 114,966. The diagnosis of flat feet or toe deformities was included as control for health-care-seeking be- havior. Because the analyses in this study are not yet complete and are as yet unpublished, the com- mittee has chosen to show only summary information about the significant findings, not detailed quantitative results. Provisional results may be subject to change. Verstraeten, 2001.

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64 IMMUNIZATION SAFETY RE VIE W however, the small sample size limited the power of the study to detect a small effect, if it exists (Verstraeten, 2001~. As a result of the inconsistent findings from the first two phases, a protocol for a Phase III follow-up study has been developed, although funding for the study is not confirmed. As described to the committee at its scientific meeting in July 2001 (Stehr-Green, 2001), the study will use a retrospective cohort design and will focus on primary diagnoses from the Phase I analysis, including ADD, language and speech deficits, and tics. Autism is not included because a substan- tially larger study population (and therefore a substantially more expensive study) would be needed to identify a sufficient number of cases for a retrospective co- hort study. A separate case-control study of thimerosal exposure and autism has been proposed, but no study protocol has been developed. The Phase III protocol is discussed further in the research recommendations section of this report. The committee notes several limitations of the Phases I and II of the VSD study. First, the consistency and accuracy of the diagnoses have not been estab- lished. Second, the variation between HMOs in the results of the updated Phase I analysis indicates an ascertainment or health-care-seeking bias could exist at HMO B among parents of study subjects who received the highest doses of thi- merosal-containing vaccines. The exclusion of children who disenrolled from the HMOs is another potential source of bias. In addition, the effect sizes are small and thus difficult to interpret. Furthermore, with an observation period of only one year for some children, diagnoses usually made at older ages may be under- represented. With its restriction to diagnoses with at least 50 cases, the study is uninformative about other important but less common diagnoses. In addition, there is not a consistent dose-response relationship. Also, information on prenatal exposure to mercury is sparse. Finally, the findings from Phase I and Phase II of the study are inconsistent. Given these caveats, the committee believes that the Phase I and II VSD analyses are inconclusive with respect to causality. Uncontrolled Observational Studies. An unpublished ecological analysis comparing aggregate trends in autism rates in California with the trends in mer- cury exposure from thimerosal-containing vaccines was presented to the com- mittee (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 rec- ommended vaccine doses (assumed to be 37.5,ug for 3 doses of hepatitis B. 75 ,ug for 3 doses of Hib, and 75-lOO,ug for 3 or 4 doses of DTP) was weighted by estimates from the National Health Interview Survey of coverage rates for the specific vaccines for the specified year. Estimates of the number of children with autism were obtained from annual caseload data from the California De- partment of Developmental Services database. These data were retabulated by year of birth, and birth-cohort prevalence rates were calculated using census data on births by year in California. The presenter concluded that the increasing trends seen in these data, in both the prevalence of autism and the levels of mer- cury exposure from thimerosal-containing vaccines, are consistent with the hy-