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THIMEROSAL-CONTAINING VACCINES RECOMMENDATIONS REGARDING THE PUBLIC HEALTH RESPONSE 75 Prompt action by federal agencies, medical professionals, and vaccine manu- facturers to remove thimerosal from vaccines has ensured that any risk thimerosal exposure may pose has been substantially reduced for the future. However, the committee sees significant reasons for continued public health attention to con- cerns about thimerosal exposure and neurodevelopmental disorders. . The committee has found inadequate evidence to accept or reject a causal relationship between thimerosal-containing vaccines and neurodevelopmental disorders. Although the available evidence is indirect and incomplete, and the relationship is not established, it is biologically plausible. Because thimerosal was used in millions of vaccine doses over several decades, it is important that additional research be done to understand the nature of the risk, if any, from this exposure to thimerosal. There is a need for more evidence on the risks and benefits associated with thimerosal-containing vaccines and biological and pharmaceutical products in use in the United States and elsewhere. . . As concerns continue to emerge about other vaccines it is likely that poli- cymakers will again be faced with the need to consider action regarding vaccine safety in the face of great uncertainty, as they were with thimerosal. It is critical that policymakers be better prepared to handle these concerns. . It is important to do everything possible to restore, maintain, and build trust . . in vaccines. The committee provides recommendations in three areas of public health response: policy review and analysis, public health and biomedical research, and communications. Policy Review and Analysis The committee supports prior decisions by ACIP, AAP, and AAFP to call for the removal of thimerosal from vaccines as a precautionary step in the effort to minimize children's exposure to mercury. Fortunately, technology was avail- able to manufacturers in this country to do so in a timely manner. Vaccine manufacture is a complex process, and the committee understands that to re- move a constituent, reformulate and repackage a vaccine, and receive FDA ap- proval in a short time is no small feat. The committee was unable to conclude, however, from the existing evi- dence whether thimerosal does or does not cause neurodevelopmental disorders. In the United States, thimerosal has been removed from most vaccines and some biological products to which infants, children, and pregnant women are exposed. Although mercury exposures from currently available thimerosal-containing products may not exceed estimated exposure limits for methylmercury derived

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76 IMMUNIZATION SAFETY RE VIE W from federal guidelines, further action to remove thimerosal from all vaccines and other biological and pharmaceutical products might be warranted to ensure that exposures to thimerosal do not contribute to combined mercury exposures that could exceed guidelines for safe exposure. This is consistent with the pre- cautionary principle (Goldstein, 2001, Kriebel and Tickner, 2001) which states that, "When an activity raises threats of harm to human health or the environ- ment, precautionary measures should be taken even if some cause and effect relationships are not fully established scientifically." Finally, these actions could do a great deal to simplify decision-making by clinicians and parents regarding the use of vaccines, other biologicals, or pharmaceuticals without potentially compromising the health of the child. A decision not to remove thimerosal from other products in the United States should be based on an assessment of the risks and benefits which demonstrates that action is unwarranted. Risk-benefit as- sessments conducted on U.S. populations might not be valid for other popula- tions and caution should be exercised when generalizing these recommendations to other countries. However, an unknown number of thimerosal-containing DTaP, Hib, and hepatitis B vaccine doses are still on the shelves. Given that alternatives are now available, the committee recommends the use of the thimerosal-free DTaP, Hib, and hepatitis B vaccines in the United States, despite the fact that there might be remaining supplies of thimerosal-containing vaccine available. Re- maining thimerosal-containing vaccines should be reserved for use only in re- sponse to serious shortages or emergencies, when failure to vaccinate would increase the risk of vaccine-preventable disease. The committee understands that this could result in a financial loss. However, it is confusing to the public to continue to use thimerosal-containing vaccines when alternatives are available. The committee did not explore the mechanisms by which this could be accom- plished. But, the committee is concerned that, because of meeting schedules and other requirements for example, the development of official statements on this issue by advisory groups such as the Red Book Committee or the ACIP might delay action. Other mechanisms might be available: "Dear Doctor" letters could be sent, for instance, or existing supplies could be bought back from providers by vaccine makers or the CDC (in the case of doses purchased for the Vaccines for Children program). The removal of thimerosal as a preservative from vaccines on the recom- mended childhood immunization schedule does not eliminate exposure to thi- merosal from the other vaccines, such as DT or influenza, that some infants, children, and pregnant women receive. Therefore, the committee recommends that full consideration be given by appropriate professional societies and gov- ernment agencies to removing thimerosal from vaccines administered to in- fants, children, or pregnant women in the United States. However, the com- mittee draws attention to the recent recommendation of the ACIP that high-risk children and women beyond their first trimester of pregnancy during the influ-

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THIMEROSAL-CONTAINING VACCINES 77 enza season should tee vaccinated. The ACIP states, "Because pregnant women are at increased risk for influenza-related complications and because a substan- tial safety margin has been incorporated into the health guidance values for or- ganic mercury exposure, the benefit of influenza vaccine outweighs the potential risks for thimerosal" (CDC, 2001e). Thimerosal is also present in some pharmaceuticals, such as nasal sprays, used by infants, children, and pregnant women. The committee is unaware of risk-benefit analyses or risk assessments of thimerosal in pharmaceutical prod- ucts, nor is it aware of the status of research into alternative preservatives. It seems prudent, however, that alternatives to thimerosal in these products be ex- plored and, if risk analyses suggest a need to do so, be used. Therefore, the committee recommends that appropriate professional societies and govern- ment agencies review their policies about the non-vaccine biological and pharmaceutical products that contain thimerosal and are used by infants, children, and pregnant women in the United States. This recommendation is consonant with a recent statement by the Committee on Environmental Health of the American Academy of Pediatrics that advocated reducing mercury expo- sure in children (Goldman et al., 2001~. The confusion that resulted among some providers following the rapid changes in recommendations regarding the birth dose of hepatitis B vaccine suggests not that the policy decision was fundamentally flawed, but that im- provements could be made in the formulation, communication, and implemen- tation of vaccine policies. As the immunization schedule becomes more com- plex, and as vaccine safety concerns continue to emerge, it is likely that the public health community, medical professionals, and vaccine manufacturers will again be faced with the need to consider action regarding vaccine safety in the face of great uncertainty and of theoretical rather than demonstrated risks. . The committee recommends that policy analyses be conducted that will inform these discussions in the future. First, the committee recommends a review and assessment of how pub- lic health policy decisions are made under uncertainty, in order to develop suggestions to improve the decisionmaking process about vaccines in the future. These studies might consider, for example, how costs should be weighed against uncertain risks, who should bear the cost of added safety, and the impact of de- cisions on trust in the vaccine or health care system. . In addition, the committee recommends a review of the strategies used to communicate rapid changes in vaccine policy, and it recommends re- search on how to improve those strategies.

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78 IMMUNIZATION SAFETY RE VIE W Public Health and Biomedical Research Although the risk of exposure to thimerosal through recommended child- hood vaccinations has been mostly eliminated, questions remain as to whether or not thimerosal-containing vaccines may have previously contributed to neurode- velopmental disorders in some children. The committee recommends a diverse public health and biomedical research portfolio. This will be most effective if it involves several different agencies (thus maximizing resources), provides some findings fairly quickly, and utilizes a variety of approaches. These recom- mendations for additional research, some of which are underway or in develop- ment by CDC, NIH, FDA, universities, and the vaccine manufacturers, could support evidence-based decisions in other countries regarding whether or not to continue using thimerosal-containing vaccines. Research should be designed to accommodate the switch to non-thimerosal-containing products as soon as it is beneficial to change formulations. Specific recommendations on epidemiologi- cal, clinical, and basic science research are as follows. Epidemiological Studies . The committee recommends case-control studies examining the poten- tial link between neurodevelopmental disorders and thimerosal-containing vaccines. The studies should use clearly defined outcomes, specifically diagno- ses (e.g., identified in terms of ICD-9 coding) that correspond to current prac- tice. Gradients of performance on neurodevelopmental tests should be used as outcome measures only if they can be linked to specific diagnoses. Furthermore, the committee recommends examining multiple cognitive outcomes, including autism. In addition, because thimerosal poisonings were associated with adverse renal effects, renal outcomes should also be included in the epidemiological, clinical, and basic science studies of thimerosal exposure recommended in this report. Although there are many challenges that will arise in planning and con- ducting these studies (e.g., appropriate control group selection, conducting a retrospective assessment of mercury exposure from other sources), the commit- tee believes that multiple case-control studies are an efficient approach for seeking answers to the causality questions. The committee is aware of several cohorts of children outside the United States who did not receive thimerosal-containing doses as part of a clinical trial of DTaP vaccine. The committee recommends further analysis of neurode- velopmental outcomes in these populations. Although the exposure levels to thimerosal in these children are lower than exposure levels in the United States, these cohorts have the powerful analytic benefit of randomized assignment to thimerosal-free or thimerosal-containing vaccines. Studies using these already- defined cohorts could probably be completed more quickly than a study that

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THIMEROSAL-CONTAINING VACCINES 79 would have to define and recruit some other population in the United States or elsewhere. . The removal of thimerosal from vaccines on the recommended childhood immunization schedule in the United States presents a unique opportunity to study whether this change affected the rates of neurodevelopmental disorders in children. The committee recommends conducting epidemiological studies that compare the incidence and prevalence of neurodevelopmental disor- ders before and after the removal of thimerosal from vaccines. These studies should focus on multiple renal and cognitive outcomes, including autism. Col- laborations with existing research studies, such as NIMH's Epidemiological Catchment Area studies or the Collaborating Program of Excellence in Autism, might be efficient and should be explored. Ecological studies are not well-suited to making individual-level causal inferences and comparisons before and after the removal of the thimerosal are problematic when the criteria for diagnosis, or the manner in which the criteria are applied, change over time, as they have with autism. However, the committee believes that well-designed ecological studies can provide support to other epidemiological studies. . The committee recommends an increased effort to identify the primary sources and levels of prenatal and postnatal background exposure to thi- merosal (e.g., Rho (D) Immune Globulin) and other forms of mercury (e.g., maternal consumption of fish) in infants, children, and pregnant women. Data on background exposures to mercury are sparse, additional studies may identify populations or quantify the number of children at higher risk for mer- cury toxicity. A feasibility assessment should be done to see if a meaningful study could be conducted regarding the risk of neurodevelopmental disorders due to thimerosal exposures through Rh immunoglobulin during pregnancy. Where possible, studies of the rates of specific neurodevelopmental diagno- ses in cohorts of children exposed to varying levels of thimerosal would be of interest. Such studies have to be large enough to have sufficient variation in ex- posure and in incidence rates of the diagnoses of interest to detect an associa- tion. They also should include uniform data on thimerosal exposure, clear defi- nitions of neurodevelopmental disorders using current diagnostic rubrics, the use of standard clinical protocols for diagnosing neurodevelopmental disorders, and assessment of neurodevelopmental diagnoses by professionals who do not know the patients' exposure status. The committee is aware of the planning under way for a two-stage follow- up study (Phase III) to the findings from the Phase I and II VSD studies. The plans for Phase III have been presented to several groups, including the com- mittee at its July 2001 meeting (Stehr-Green, 2001~. The Phase III study is con- ceived as a two-part retrospective cohort study in which participants, seven- to nine-year-old children, would be enrolled into one of three groups, based on exposure to thimerosal-containing vaccines at specified points in the past. The

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80 IMMUNIZATION SAFETY RE VIE W three groups would be defined according to two exposure factors: level of mer- cury exposure at birth, based on whether the birth dose of hepatitis B vaccine was received, and cumulative level of exposure to all thimerosal-containing vac- cines during the first three months of life. The decision to group participants on the basis of levels of exposure during the earliest ages of life reflects the advice of expert consultants and a review of the methylmercury literature. The study will collect data on all vaccine exposures so as to permit analyses based on cu- mulative exposure at any age. The study would focus on specific primary diagnostic outcomes identified from the Phase I screening analysis, including ADD, language and speech deficits, and tics. Autism is not included as an outcome in this study because of the high cost of the large sample size that would be needed to identify a sufficient number of cases of autism for a retrospective cohort design. A separate case-control study of autism has been proposed, although no study protocol has been developed. The proposed follow-up study uses a two-part approach to assessing out- comes. In the first stage, a standardized set of neuropsychological tests would be administered to all study participants to identify children whose performance sug- gests the presence of selected neurodevelopmental disorders (NDD). In the second stage, confirmatory neuropsychological tests would be administered for ADD and speech or language delay specifically. The study would also develop measures of potential confounders (e.g., exposures to mercury, lead, PCBs, alcohol and other drugs, genetic predisposition, family medical history) and would attempt to evalu- ate the independent contribution of other vaccine antigens and components. The committee recognizes that this study is still in the planning phase. Three issues loom large regarding the proposed Phase III study: feasibility, re- sources, and several technical design issues. The committee has reservations about such an ambitious and therefore resource-intensive study. It will be a few years until results and meaningful analyses are available. In addition, the power of the study to detect small relative risks is limited. The proposed Phase III study could thus be contributory, but would best be undertaken as part of an overall package of research and only if it accurately identifies neurodevelop- mental conditions of concern. Clinical Studies . Very little is known about the pharmacokinetics of ethylmercury exposure in humans. Better understanding of these mechanisms would have greatly fa- cilitated the risk assessment of thimerosal in vaccines. The committee recom- mends research on how children, including those diagnosed with neurode- velopmental disorders, metabolize and excrete metals particularly mercury. Studies of proteins known to be associated with metal metabolism, such as glutathione and metallothionein, could be undertaken. Some of this re-

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THIMEROSAL-CONTAINING VACCINES 81 search could be done expeditiously through autism research centers, which have great expertise in identifying and working with autistic children. . The committee recommends continued research on theoretical model- ing of ethylmercury exposures, including the incremental burden of thi- merosal with background mercury exposure from other sources. It would be particularly helpful to have such theoretical modeling done in conjunction with empiricists, so that the models could be better constructed. The committee is aware of several specialized pediatric practices that use chelation therapy to treat autistic children. These practitioners report unusual metal profiles in their patients as well as clinical improvement following chela- tion. However, chelation therapy is currently indicated only for acute, high-dose mercury poisonings. Given that chelation therapy is not a benign treatment, the committee recommends careful, rigorous, and scientific investigations of chelation when used in children with neurodevelopmental disorders, espe- cially autism. Although studies of chelation would not be able to link excreted metal specifically with vaccine exposure, and therefore would not contribute to causality assessments, it is important to pursue these uncontrolled clinical ob- servations in order to establish an evidence base for appropriate therapeutic uses of chelation. . Basic Science Studies . Many countries continue to use thimerosal-containing vaccines given the proven benefits of thimerosal as a vaccine preservative for many years and the benefits of continued immunization. Complete risk assessments have not been done for other countries that would indicate the need to switch to thimerosal-free vaccines. However, the committee recommends research to identify a safe, effective, and inexpensive alternative to thimerosal for countries that decide they need to switch. Comparative animal studies of the toxicity of ethylmercury and methylmer- cury are limited, though the teratological effects of methylmercury in rodents and primates is well established. Several important questions regarding the po- tential risk of thimerosal exposure could have been informed by a wider and deeper literature from studies in laboratory animals. The committee recom- mends research in appropriate animal models on neurodevelopmental ef- fects of ethylmercury. These would help elucidate the comparability and valid- ity for ethylmercury of the risk assessments based on methylmercury. . Communications The committee identified three specific impediments to effectively commu- nicating the risks and benefits of thimerosal-containing vaccines to parents and practitioners. The first is the challenge of communicating policy changes given