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Suggested Citation:"Significance Assessment." Institute of Medicine. 2001. Immunization Safety Review: Thimerosal-Containing Vaccines and Neurodevelopmental Disorders. Washington, DC: The National Academies Press. doi: 10.17226/10208.
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Suggested Citation:"Significance Assessment." Institute of Medicine. 2001. Immunization Safety Review: Thimerosal-Containing Vaccines and Neurodevelopmental Disorders. Washington, DC: The National Academies Press. doi: 10.17226/10208.
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Suggested Citation:"Significance Assessment." Institute of Medicine. 2001. Immunization Safety Review: Thimerosal-Containing Vaccines and Neurodevelopmental Disorders. Washington, DC: The National Academies Press. doi: 10.17226/10208.
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Suggested Citation:"Significance Assessment." Institute of Medicine. 2001. Immunization Safety Review: Thimerosal-Containing Vaccines and Neurodevelopmental Disorders. Washington, DC: The National Academies Press. doi: 10.17226/10208.
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Suggested Citation:"Significance Assessment." Institute of Medicine. 2001. Immunization Safety Review: Thimerosal-Containing Vaccines and Neurodevelopmental Disorders. Washington, DC: The National Academies Press. doi: 10.17226/10208.
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Suggested Citation:"Significance Assessment." Institute of Medicine. 2001. Immunization Safety Review: Thimerosal-Containing Vaccines and Neurodevelopmental Disorders. Washington, DC: The National Academies Press. doi: 10.17226/10208.
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Suggested Citation:"Significance Assessment." Institute of Medicine. 2001. Immunization Safety Review: Thimerosal-Containing Vaccines and Neurodevelopmental Disorders. Washington, DC: The National Academies Press. doi: 10.17226/10208.
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Suggested Citation:"Significance Assessment." Institute of Medicine. 2001. Immunization Safety Review: Thimerosal-Containing Vaccines and Neurodevelopmental Disorders. Washington, DC: The National Academies Press. doi: 10.17226/10208.
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Suggested Citation:"Significance Assessment." Institute of Medicine. 2001. Immunization Safety Review: Thimerosal-Containing Vaccines and Neurodevelopmental Disorders. Washington, DC: The National Academies Press. doi: 10.17226/10208.
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66 IMMUNIZATION SAFETY RE VIE W response relationship. Furthermore, the findings between the two phases of this study are inconsistent. The committee therefore believes that the VSD study is inconclusive with respect to causality. The committee also found that an unpublished ecological analysis of trends in the prevalence of autism and in exposure to mercury from vaccines is uninformative with respect to causality. See Table 7 for a summary of the evidence reviewed by the committee. As stated above, the committee concludes that the hypothesized relationship is biologically plausible. However, the committee concludes that the evidence is inadequate to accept or reject a causal relationship between exposure to thimerosal from childhood vaccines and the NDDs of autism, ADHD, and speech or language delay. The committee's conclusion on causality is based on these factors: . The available case reports are uninformative with respect to causality. There are no published epidemiological studies examining the potential association between thimerosal-containing vaccines and neurodevelopmental disorders. . The unpublished and limited epidemiological studies provide weak and in- conclusive evidence regarding the hypothesis that exposure to thimerosal- containing vaccines may lead to certain neurodevelopmental disorders. SIGNIFICANCE ASSESSMENT In contrast to the majority of previous IOM vaccine safety studies, which limited conclusions to causality assessments and recommendations for future research, the Immunization Safety Review Committee has been asked to rec- ommend a public health response to immunization safety concerns. Such a re- sponse potentially encompasses a broad range of activities, including policy reviews, new research directions, and changes in communication to the public and to health care providers about issues of vaccine safety. In formulating the breadth and direction of the recommended public health response, the committee considers not only its conclusions regarding causality, but also the significance of the vaccine safety issues in a broader social context the context in which policy decisions must be made. These considerations can include, but are not limited to, the burden (the seriousness, risk, and treatability) of the adverse health events in question and of the diseases that the vaccines are intended to prevent, as well as the potential consequences of public concerns about the safety of vaccine use.

THIMEROSAL-CONTAINING VACCINES TABLE 7 Summary of Evidence for Assessments of Causality and of Bio- logical Plausibility 67 Evidence Type of Direct/ Published/ PotentialRole in Study Indirect Unpublished Causality Assessment Potential Role in Biological Plausibility Assessment VSD Phase I, II Controlled observa- tional study Ecological Analyses of ASD rates2 Thimerosal and ethylmercury poisonings3 Hg levels after vaccinations Hg exposure guidelines5 Uncon- Indirect trolled ob- servational analysis Case re- ports, case series Clinical studies; theoretical modeling Modeling, theoretical calculations Methylmercury Epidemiol- Indirect poisonings6 ogical, clinical studies Epidemiol- Indirect Oglca1 studies Clinical studies of Case re- children with ports, clini- ASD~ cat studies TMS, EtHg, In vitro, MeHg toxicol- laboratory ogy and kinetics9 animal Direct evidence refers to evidence that specifically addresses a relationship between thimerosal in vaccines and neurodevelopmental disorders. All other evidence is therefore indirect. References are representative and are not a complete guide to the literature. 1. Verstraeten, 2001 2. Blaxill, 2001 3. Axton, 1972; Cinca et al., 1980; Fagan et al., 1977; Hay, 1963; Jalili and Abbasi, 1961 "Island Studies"7 Indirect Published Indirect Published; unpublished Indirect Published Published Published Indirect Published; unpublished Indirect Published; unpublished Direct Unpublished Evidence of this type N/A could be used to determine nature of causal relationship Unpublished Evidence of this N/A type could support causality Evidence of this Supports type could support causality Evidence of this type Supports could inform causal- ity assessments Evidence of this type Supports could inform causal- ity assessments Hypothesis genera- Supports lion only Hypothesis genera- Supports lion only Hypothesis genera- Supports lion only None Supports 4. Lowell et al., 1996; Pfab et al., 1996; Royhans et al., 1984; Zhang, 1984. Brown, 2001; Pichichiero et al, 2001; Sager, 2001; Stajich et al., 2000 5. Ball et al., 2001; Halsey, 1999; Halsey and Goldman, 2001; NRC, 2000 6. Bakir et al., 1973; Harada, 1995; Mahaffey, 1999; NRC, 2000; Tsubaki, 1977 7. Davidson et al., 2000; Grandjean et al., 1997; Grandjean, 2001; Myers, 2001; NRC, 2000 8. Bradstreet, 2001; Cave, 2000; Sykes, 2001; Walsh and Usman, 2001 9. Ball et al., 2001; Jamieson and Powell, 1931; Magos, 2001b; Suzuki et al., 1963

68 IMMUNIZATION SAFETY RE VIE W Public concerns about immunization safety are particularly important to un- derstand and to weigh, because most vaccines are given to healthy children not only for their direct protection but also to help protect others in the population. In fact, to achieve this broader level of protection, vaccinations are mandatory in all 50 states for school and daycare entry. Exemptions on medical grounds (contraindications) are allowed, although they are considered too limited by some (Fisher, 2001~. Exemptions are also allowed on religious grounds in 48 states and on philosophical grounds in 15 states (Evans, 1999~. However, such exemptions are rare, and it is argued that these public health mandates, particu- larly because they are imposed on healthy children, place a particular responsi- bility on the government for rigorous attention to safety issues, even for rare adverse outcomes. In the present case, the hypothesis that exposure to thimerosal-containing vaccines may be associated with neurodevelopmental disorders remains of pub- lic health significance, even though thimerosal has been removed from all vac- cines on the recommended childhood immunization schedule that are given to children six years of age or younger. First, neurodevelopmental disorders im- pose substantial burdens on the affected individuals, their families, and society, and because it is important to understand whether or not past vaccine use has increased the risks of such disorders. In addition, thimerosal continues to be used in other biological and pharmaceutical products. A better understanding of the potential risks may be useful to those countries that still use thimerosal- containing vaccines because they cannot easily or immediately switch to alter- natives. Furthermore, examination of the 1999 series of rapid changes in hepati- tis B immunization policy in response to concerns about thimerosal may provide lessons for improving future vaccine safety policymaking. Finally, the use of thimerosal in vaccines may have eroded trust in the safety of vaccines. Concern Regarding Neurodevelopmental Disorders The neurodevelopmental disorders that are addressed in this report autism' ADHD, and speech or language delay are of considerable concern. In the ag- gregate, these conditions affect a large number of children. Autism is a serious developmental disorder characterized by deficits in communication and behavioral, emotional, and social functioning. There are no agreed upon estimates of the prevalence or incidence of autism in the United States. Autism cannot be cured, but behavioral therapies are used to manage symptoms (Wing, 1997) and medication may help alleviate symptoms such as hyperactivity, anxiety, and repetitive behavior (Lainhart and Piven, 1995~. Fur- thermore, early educational and social interventions may improve functioning and integration into society for some autistic children (Harris and Handelman, 1997, Howlin and Goode, 1998~.

THIMEROSAL-CONrTA - LOG VACCINES 69 Autism leads to substantial challenges for the families of affected individu- als, many of whom remain dependent throughout their lives. In addition to the substantial financial strains, families of children with autism must meet other demands, such as arranging for around-the-clock efforts to care for their child. They face the difficult tasks of finding knowledgeable and sympathetic health- care providers and of finding high-quality information, and they must endure the frustrations of seeing their children develop abnormally or regress from being active and engaged to being aloof and nonresponsive. ADHD, one of the most common of the psychiatric disorders that appears in childhood, usually becomes evident in preschool or early elementary years Am, 2001~. Children may have problems functioning in school and other social settings. There are often impairments in memory, cognitive processing, motor skills, social skills, and response to discipline ASH, 2001~. People with ADHD often have other disorders as well, such as learning disabilities, language disor- ders, conduct disorder, oppositional-defiant disorder, and mood and anxiety dis- orders Am, 2001~. ADHD is incurable, but medications and behavioral inter- ventions may Prove functioning for 80% of the people with the disorder (CDC, l999b). Treatment for ADHD may not be covered by health insurance, however, and two recent studies found mat the cost and use of medical care for children with ADHD is significantly higher than for other children (Guevara et al, 2001; Leibson et al., 2001~. Special educational services are often needed. The national public school system's additional costs for students with ADHD was more than $3 billion in 1995 ASH, 1998~. The prevalence of speech or language delay is difficult to estimate. Speech and language delay refers to a group of symptoms resulting from many different causes. Some causes are [mown, such as mental retardation, genetic deformities, deafness, and structural abnormalities like cleft palate (Shriberg et al., 1999~. In other cases, no specific cause can be identified. Children with speech and lan- guage delay often experience additional problems, including poor school per- formance, psychological and behavioral disturbances, and, later, speech and language problems (Whitehurst and Herschel, 1994~. Continued Exposure to Thimerosal In the United States, currently manufactured or marketed vaccines on the recommended childhood i~,ni~ation schedule and given to children six years of age or younger contain no ~imerosal, or only Face amounts (<0.5 fig Hg per dose) of tt~irnerosal left over from the manufacturing process (CDC, 2000c). However, given the public health goal of reducing children's exposure to mer- cury as much as possible, concerns have been raised about the continued pres- ence of thimerosal in other vaccines and biological and pha~Tnaceutical products. Some vaccines that are not part of the recommended childhood imm~,ni~a- tion schedule still contain thimerosal as a preservative and may be given to some

70 IMMUNIZATION SAFETY RE VIE W children. These include diphtheria-tetanus toxoid (DT), tetanus toxoid (TT), influenza, and Pnu-Immune 23 pneumococcal (recommended only for children 2 years or older) vaccines. Other thimerosal-containing vaccines, given only to older children and adults, are tetanus-diphtheria (Td), meningococcal vaccine, and the adult formulation for one hepatitis B vaccine (Recombivax-B). There is also a lingering concern that there remains "on the shelf" an un- known quantity of thimerosal-containing Hib, hepatitis B. and DTaP vaccines. However, because of turnover and of the expiration date of current vaccines, it is estimated by CDC that few, if any, of those containing thimerosal as a preserva- tive are still being administered (CDC, 2001f). Other biological products that have traditionally contained thimerosal may be used in infants, children, and pregnant women. (A list of all drug and food prod- ucts containing mercury identified during the 1997 FDAMA review can be ac- cessed at the following website: http://www.fda.gov/cber/genadmin/merclst.htm. An updated list is not available, but some of the products on this list may no longer contain thimerosal.) For example, some preparations of Rho (D) Immune Globu- lin, which are given to Rh-negative mothers during pregnancy, contain thimerosal. Approximately 15% of the population is Rh-negative, and use of these thimerosal- containing products exposes the fetus to ethylmercury. The amount of thimerosal in these products ranged from 0.003 to 0.01% thimerosal (PDR, 2001, Physicians' GenRx, 1993~. Rho(D) Immune Globulin is currently being manufactured without thimerosal in the United States. Other such products that contain thimerosal and are available over-the-counter include some nasal sprays, contact lens solutions, and antibacterial/anti-itch creams (FDA, 1999~. The committee is not aware, how- ever, of any risk assessments of the use of these products in infants, children, and pregnant women. Nevertheless, the NHANES survey indicates that 10% of women have mercury levels within one-tenth of the potentially hazardous levels estimated in the NRC toxicological review of methylmercury, indicating a poten- tial benefit for some women from efforts to reduce mercury exposure (CDC, 2001 d, NRC, 2000~. Use of Thimerosal-Containing Vaccines in Other Countries In contrast to the rapid removal of thimerosal from vaccines in the United States, many other countries have taken a less urgent approach to removing thi- merosal from vaccines. In a July 1999 statement, the European Agency for the Evaluation of Medicinal Products (EMEA) recommended as a precautionary measure, that the use of thimerosal-free products should be promoted and efforts should be made to eliminate mercury preservative in vaccines in the shortest possible time frame (EMEA, 1999~. However, the EMEA recommended that vaccination proceed in accordance with normal schedules while vaccine

THIMEROSAL-CONTAINING VACCINES 71 reformulation proceeded. Overall, reducing or eliminating thimerosal in Europe was considered to be a "middle and long term effort" (EMEA, 2001~. Several factors may have contributed to the difference in the risk assess- ments conducted by the United States and European countries. First, the poten- tial exposure to thimerosal through vaccines was less in European countries than in the United States, given the differences in recommended childhood immuni- zation schedules. Second, the EMEA compared cumulative ethylmercury expo- sures from vaccines to the WHO's recommended level of intake for methylmer- cury (3.3 ,ug/kg/week or 0.47 ,ug/kg/day), which is less stringent than the U.S. federal standards for methylmercury intake (e.g., EPA's is 0.1 ,ug/kg/day). Third, other vaccine safety concerns (e.g., the hypothesized link between mea- sles-mumps-rubella vaccine and autism) may have figured more prominently in these countries (Freed and Andreae, 2001~. Many other nations, particularly developing countries, continue to rely on multi-dose vaccine vials which contain thimerosal as a preservative. Although the World Health Organization (WHO) supports the July 1999 statement by the AAP and U.S. PHS to phase out use of thimerosal in vaccines, the WHO recommends the continued use of thimerosal-containing vaccines because of the benefits of thimerosal as a preservative and the benefits of continued immunization (WHO, 2000~. The WHO notes that removing thimerosal from vaccines worldwide is a complex process. Removing thimerosal from multidose vials is not a viable op- tion given the lack of alternative preservatives, thus, removal of thimerosal could increase the risk of bacterial contamination which could lead to toxic shock syn- drome or other illnesses. In addition, switching from multi-dose to single-dose vials imposes practical constraints. Most notably, switching to single-dose vials could impose a significant burden on the cold chain making this strategy prohibi- tive for developing countries. Furthermore, even if a mercury-free preservative were developed in the future, many local vaccine producers may not have easy access to it. This is important since, for example, 60% of the whole-cell DTP vaccine used in developing countries is produced locally (WHO, 2000~. In the interim, the WHO believes that the known risks of morbidity and mortality from vaccine-preventable diseases and contaminated multi-dose vaccine vials out- weigh the potential risk of thimerosal (Clements et al., 2000~. The committee concluded that it was important to more fully research the possible effects of thimerosal in vaccines in order to provide evidence that could be useful to countries facing a decision of whether or not to continue using thi- merosal-containing vaccines. While the United States chose to remove thimero- sal as a precautionary measure and because it was feasible to do so, the com- mittee understands that practical considerations and an assessment of the risks and benefits in other countries may lead those countries to reach different con- clusions regarding continued use of thimerosal in vaccines. Analyses of the costs associated with reducing the potential risk from thimerosal, and comparisons of

72 IMMUNIZATION SAFETY RE VIE W the risks and benefits of current vaccines with more expensive thimerosal-free alternatives, could help inform decisions in other countries. Confusion from Changes in Hepatitis B Immunization Policy Public health agencies, the medical community, and vaccine manufacturers acted swiftly to reduce the potential risk from thimerosal exposure when the FDA risk assessment revealed that vaccines could expose some children to cu- mulative levels of ethylmercury that exceeded one of the three federal guidelines on methylmercury exposure. Although no evidence showed that thimerosal in vaccines had caused harm, AAP and PHS in July 1999 recommended as a pre- cautionary step the removal of thimerosal from vaccines as soon as possible (CDC, 1999a). To reduce exposure to thimerosal in the smallest infants, the joint statement also recommended postponing the first dose of hepatitis B vaccine from birth until two to six months of age for infants born to low-risk mothers who were hepatitis B-surface antigen negative. (The birth dose of hepatitis B was still rec- ommended for infants whose mothers had a positive or unknown hepatitis B surface antigen status, thereby continuing to reduce the risk of vertical transmis- sion of hepatitis B tCDC, l999a].~. Within two months, however, the CDC an- nounced the availability of a new thimerosal-free hepatitis B vaccine and also recommended resumption of routine hepatitis B vaccination of all newborns, reversing the initial recommendation (CDC, l 999c). Concerns have been raised by some about the sudden shifts in hepatitis B vaccination policy and the general decision-making process that led to the change (Freed and Andreae, 2001, Offit, 2000, Plotkin, 2000, Seal and Daum, 2001~. One criticism centered on the rapidity of the process, which caught some members of the medical and scientific community by surprise and led to a per- ception that decisions to issue policy guidelines were made in haste (Freed and Andreae, 2001, Plotkin, 2000, Seal and Daum, 2001~. Another controversial aspect of the process was the lack of agreement among members of the key or- ganizations issuing the policy statement (AAP, AAFP, PHS) regarding the na- ture and level of the risk from thimerosal. Some believed it posed only a theo- retical risk, while others perceived it to be an actual risk (Freed and Andreae, 2001, Halsey, l999b, Offit, 2000, Seal and Daum, 2001~. In addition, the exis- tence of three different federal standards on methylmercury exposure (EPA, FDA, ATSDR) resulted in confusion about the potential risks of thimerosal and questions about the relevance of the guidelines in assessing the risk from thi- merosal in vaccines (Freed and Andreae, 2001~. There are debates on whether or not policymakers adequately gauged the potentially negative effects on the hepatitis B newborn-immunization program when implementing the policy changes (Halsey and Goldman, 2001, Seal and

THIMEROSAL-CONTAINING VACCINES 73 Daum, 2001~. Recent surveys indicate that as a result of the initial recommenda- tion, some hospitals did not have appropriate policies in place for vaccinating infants whose mothers' hepatitis B surface antigen status was positive or un- known (Hurie et al., 2001), and that many hospitals had failed to resume hepati- tis B vaccination after the CDC recommendation to do so (CDC, 2001 c, Hurie et al., 2001, Gram et al., 2001~. The committee believes that the AAP, AAFP and PHS had clearly acted with the best interest of children in mind both in issuing the guidelines to sus- pend the hepatitis B birth dose, and reversing them shortly thereafter once a thi- merosal-free alternative was approved. The experience may offer lessons for improving future vaccine safety policymaking, however. Trust in the Safety of Vaccines Concerns related to the potential adverse effects of thimerosal-containing vaccines and continued use of thimerosal in some vaccines have the potential to erode public trust. The presence of thimerosal in some vaccines can raise doubts about the entire system for ensuring vaccine safety. Although vaccine packaging included information about thimerosal content, the amount of mercury in indi- vidual vaccine doses and the cumulative exposure were not calculated until the FDAMA-required risk assessment. This late recognition of the amount of mer- cury in vaccines may contribute to a perception among some that careful atten- tion to vaccine components has been lacking. The issue of thimerosal in vaccines has been the focus of media stories (At- kins, 2001, Manning, 2000), Congressional hearings (U.S. House of Represen- tatives, Committee on Government Reform, 2000, 2001), lawsuits (Joseph Counter, et al. v. Abbott Laboratories, Inc., et al. Cause No. GN100866 ), and Internet sites, all which indicate some level of public concern and distrust about vaccine safety. However, with few exceptions (Gellin et al., 2000), there is a paucity of studies that have objectively and routinely assessed public and physi- cian opinions about vaccine safety. Unpublished findings from one recent CDC- sponsored survey of pediatricians and family physicians suggest that thimerosal in vaccines is a concern for physicians and parents (Freed and Andreae, 2001~. This cross-sectional survey administered by mail during spring 2000 to a na- tional random sample of 750 pediatricians and 750 family physicians (response rate of 70%), asked physicians about their perceptions of parents' views and their self-perceptions regarding vaccine safety. The findings show that 27% of pediatricians and 18% of family physicians surveyed perceived that parents were more concerned about vaccine safety as a result of the thimerosal issue. In addi- tion, the practitioners themselves had some doubts 13% of pediatricians and 24% of family physicians and reported that they were more concerned about vaccine safety as a result of thimerosal issues.

74 IMMUNIZATION SAFETY RE VIE W The committee emphasizes that confidence in the safety of vaccines is es- sential to an effective immunization program one that provides maximum protection against vaccine-preventable diseases with the safest vaccines possi- ble. Questions about vaccine safety must be addressed responsibly by public health officials, health professionals, and vaccine manufacturers. Conclusion The committee sees significant reasons for continued public health attention to concerns about thimerosal exposure and neurodevelopmental disorders. The committee considered the burden of the potential adverse neurodevelopmental outcomes and of vaccine-preventable disorders, and it considered the extent of continued use of thimerosal-containing products. Diphtheria, tetanus, pertussis, Haemophilus influence type b, and hepatitis B are serious infectious diseases that can lead to significant morbidity and mortality. It is imperative that immu- nizations continue against these and other serious vaccine-preventable diseases. Historically, several concerns about the safety of vaccines have led to declines in immunization coverage rates and outbreaks of disease, as observed during the pertussis outbreaks in the United Kingdom during the 1970s. Similar disease outbreaks could easily occur, with devastating effects, were immunization rates to decline as a result of fears that our childhood vaccines are not as safe as ab- solutely possible. Neurodevelopmental disorders are pervasive and impose a significant bur- den on affected children, their families, and society. Mercury is a well-known neurotoxicant and efforts are being made to reduce the exposure of vulnerable populations to this environmental contaminant. There are no data that elucidate how much, if any, mercury exposure from all sources contributes to the prevalence of autism, ADHD, or speech or language delay. Thus, it is not possible to predict whether or not removing thimerosal from vaccines will reduce the prevalence of these neurodevelopmental disorders. There is no reason to believe, however, that removing thimerosal by switching to pre- servative-free single dose vials of vaccine will pose a risk to children's health. It is possible that replacing thimerosal with a less effective preservative in multi- dose vials could increase risk to children's health. It is also likely that decreased immunization rates due to fears about the risks of thimerosal could increase the risk of serious and even fatal vaccine-preventable diseases. Therefore, the committee considers the presence of thimerosal in pediatric vaccines to be a significant issue, and it supports precautionary public health efforts to reduce mercury exposure. It is important to resolve whether or not children might have experienced neurodevelopmental disorders because of an unrecognized incremental mercury burden from thimerosal given the responsi- bility for assuring the safest vaccines possible.

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In this report, the Immunization Safety Review committee examines the hypothesis of whether or not the use of vaccines containing the preservative thimerosal can cause neurodevelopmental disorders (NDDs), specifically autism, attention deficit/hyperactivity disorder (ADHD), and speech or language delay.

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