How does the FDA evaluate vaccines to make sure they are safe?

FDA’s Center for Biologics Evaluation and Research is responsible for regulating vaccines in the U.S. Before new vaccines are licensed, they are tested extensively for safety in the laboratory, in animals, and in successive stages of human clinical trials called phases. When a new vaccine is first tested in humans, a sponsor (a vaccine manufacturer, academic investigator or other individual or organization) must first submit an Investigational New Drug Application to the FDA. If data at any stage of clinical development raise significant concerns regarding the safety of the product, FDA may request additional information or may halt ongoing or planned studies.

Phase 1 studies typically enroll less than 20 participants and are designed to look for very common adverse events. Phase 2 studies may include up to several hundred individuals and are designed to look at the overall safety profile of the vaccine for local reactions such as redness and swelling at the injection site as well as general side effects that may occur with some vaccines such as fever. For phase 3 studies, the sample size is often determined by the number required to establish efficacy of the new vaccine, which may be in the thousands or tens of thousands of subjects. Phase 3 studies are usually of sufficient size to detect less common adverse events, such as those occurring at rates of 1 in 100 to 1 in 1000. For vaccines given concomitantly with other vaccines under the routine immunization schedules, the safety of new vaccines typically is studied with concurrent administration of these other vaccines. In addition, the FDA carefully reviews information on the manufacturing process of new vaccines, and testing is performed on individual lots for safety and potency. If product development is successful, the completion of all three phases of clinical development can be followed by submission of a Biologics License Application (BLA).

Following FDA’s review of a license application for a new indication, the sponsor and the FDA present their findings to an expert advisory committee in an open public meeting for comment and advice. The advisory committee provides advice to the FDA on approval or disapproval. Vaccine approval also requires the provision of adequate information (labeling) to health care providers and the public on the vaccine’s proper use, including its potential benefits and risks, and its indications and contraindications.

The safety of new vaccines continues to be monitored following licensure in several ways. The Vaccine Adverse Event Reporting System, co-administered by the FDA and CDC, is a national passive surveillance system for the collection of all reports of adverse events following vaccination. As a spontaneous reporting system, VAERS has several limitations including under-reporting, incompleteness of reports, lack of consistent diagnostic criteria, and the inability to establish a cause and effect relationship. VAERS is useful, however, for raising “red-flags’” and subsequently generating hypotheses that can be tested further in controlled clinical trials or epidemiological studies. As part of a post-licensure commitment, the FDA often asks the manufacturer to conduct additional clinical studies (sometimes called phase 4 studies), to further evaluate safety, and to provide this information to the FDA in a timely manner. In addition, coordinated epidemiological studies may be conducted using pre-established large-linked databases, which have improved ability to detect the occurrence of more rare adverse events. One such system is the Vaccine Safety Datalink, administered by the CDC.

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What are preservatives and why are they added to vaccines?

Preservatives are compounds that kill or prevent the growth of microorganisms, such as bacteria or fungi. They are used in vaccines to prevent bacterial or fungal growth in the event that the vaccine is accidentally contaminated, as might occur with repeated puncture of multi-dose vials. Vaccines, both in the United States and throughout other parts of the world, are commonly packaged in multi-dose vials. In some cases, preservatives are added during manufacture to prevent microbial growth; with changes in manufacturing technology, however, the need to add preservatives during the manufacturing process has decreased markedly.

Preservatives have been used in vaccines for over 70 years. The requirement for a preservative in multi-dose, multi-entry vials was placed into the Code of Federal Regulations (21 CFR 610.15) in January 1968. There are exceptions to this requirement for preservative, primarily involving the live-attenuated viral vaccines.

The general need for preservatives in multi-dose vials has been attested to by a number of examples of multi-dose vials being formulated without preservatives becoming contaminated during use, and causing the death of vaccine recipients; cf. the Narrative Section on Thimerosal.

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What is thimerosal?

Thimerosal is a preservative that has been used in some vaccines since the 1930’s, when it was first introduced by Eli Lilly Company. It is 49.6% mercury by weight and is metabolized or degraded into ethylmercury and thiosalicylate. At concentrations found in vaccines, it meets the requirements for a preservative as set forth by the United States Pharmacopeia; that is, it kills the specified challenge organisms and is able to prevent the growth of the challenge fungi. Prior to its introduction in the 1930's, data were available in several animal species and humans providing evidence for its safety and effectiveness as a preservative. Since then, thimerosal has a long record of safe and effective use preventing bacterial and fungal contamination of vaccines, with no ill effects established other than minor local reactions at the site of injection.

While the use of mercury-containing preservatives has declined in recent years with the development of new products formulated with alternative or no preservatives, thimerosal is still used in certain antivenins, skin test antigens, and ophthalmic and nasal products, in addition to certain vaccines recommended for adults or older children. As a vaccine preservative it is used in concentrations of 0.003% to 0.01%. A vaccine containing 0.01% thimerosal as a preservative contains 50 micrograms of thimerosal per 0.5 ml dose or approximately 25 micrograms of mercury per 0.5 mL dose.

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What has the FDA done to address the issue of mercury containing preservatives in vaccines?

Under the FDA Modernization Act (FDAMA) of 1997, the FDA carried out a comprehensive review of the use of thimerosal in childhood vaccines. Conducted in 1999, this review found no evidence of harm from the use of thimerosal as a vaccine preservative, other than local hypersensitivity reactions.

As part of the FDAMA review, the FDA evaluated the amount of mercury an infant might receive in the form of ethylmercury from vaccines under the U.S. recommended childhood immunization schedule and compared these levels with existing guidelines for exposure to methylmercury, as there are no existing guidelines for ethylmercury, the metabolite of thimerosal. At the time of this review in 1999, the maximum cumulative exposure to mercury from vaccines in the recommended childhood immunization schedule was within acceptable limits for the methylmercury exposure guidelines set by FDA, Agency for Toxic Substances and Disease Registry (ATSDR), and the World Health Organization (WHO). However, depending on the vaccine formulations used and the weight of the infant, some infants could have been exposed to cumulative levels of mercury during the first six months of life that exceeded EPA recommended guidelines for safe intake of methylmercury. As a precautionary measure, the Public Health Service (including the FDA, National Institutes of Health [NIH], Centers for Disease Control and Prevention [CDC] and Health Resources and Services Administration [HRSA]) and the American Academy of Pediatrics issued a Joint Statement, urging vaccine manufacturers to reduce or eliminate thimerosal in vaccines as soon as possible. The U.S. Public Health Service agencies have collaborated with various investigators to initiate further studies to better understand any possible health effects from exposure to thimerosal in vaccines.

Available data has been reviewed in several public forums including the Workshop on Thimerosal, held in Bethesda in August 1999 and sponsored by the National Vaccine Advisory Committee, two meetings of the Advisory Committee on Immunization Practices of the CDC, held in October 1999 and June 2000, and by the Institute of Medicine’s Immunization Safety Review Committee in July 2001. Data reviewed did not demonstrate convincing evidence of toxicity from doses of thimerosal used in vaccines. In case reports of accidental high-dose exposures in humans to thimerosal or ethyl mercury toxicity was demonstrated only at exposures that were 100 or 1000 times that found in vaccines.

In its report of October 1, 2001, the IOM’s Immunization Safety Review Committee concluded that the evidence is inadequate to either accept or reject a causal relationship between thimerosal exposure from childhood vaccines and the neurodevelopmental disorders of autism, attention deficit hyperactivity disorder (ADHD), and speech or language delay. Thus, while the available scientific data do not establish that these neurodevelopmental disorders are caused by thimerosal, at the same time, they do not establish that these neurodevelopmental disorders are not caused by thimerosal. Additional studies are needed to establish or reject a causal relationship. The Committee did conclude that the hypothesis that exposure to thimerosal-containing vaccines could be associated with neurodevelopmental disorders was biologically plausible. The Committee stated that the effort to remove thimerosal from vaccines was “a prudent measure in support of the public health goal to reduce mercury exposure of infants and children as much as possible.”

The FDA is encouraging the reduction or removal of thimerosal from all existing vaccines. Much progress has been made to date. The FDA has been actively working with manufacturers, particularly those that manufacture childhood vaccines, to reach the goal of eliminating thimerosal from vaccines, and has been collaborating with other PHS agencies to further evaluate the potential health effects of thimerosal. In this regard, all of the routinely recommended pediatric vaccines are now manufactured as either thimerosal free or thimerosal reduced (less than 0.5 microgram of mercury per dose) presentations.

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Why did the FDA wait until mandated by Congress under FDAMA 1997 to examine the use of preservatives containing mercury?

Several factors led to examination of mercury-containing preservatives in childhood vaccines. Over the past decade there has been increased attention focused on the health effects of human exposure to mercury, particularly methyl mercury. In 1994, the EPA revised its Reference Dose (RfD) for methylmercury exposure, lowering its guideline for safe exposure from 0.3 to 0.1 microgram per kilogram body weight per day. Prospective studies (in the Seychelles, Faroe Islands and others) of the effects of low dose exposure to methylmercury in the diet have been published during the past few years. Some studies have raised concern that neurodevelopmental outcomes in children may be subtly affected when their mothers were exposed methylmercury from dietary sources at levels that were previously thought to be safe. Also in the past decade, the CDC’s Advisory Committee on Immunization Practices (ACIP) and other recommending bodies have added new vaccines containing thimerosal as a preservative such as hepatitis B and Hib vaccines to the routine childhood immunization schedule. Additionally, beginning in 1996, the replacement of whole cell DTP-Hib combination vaccines with separately administered DTaP and Hib vaccines increased the amount of thimerosal that some infants might receive (depending on vaccine formulation(s) received). In light of efforts by various federal agencies to decrease human exposure to mercury from all sources, and the potential increase in infant exposure to thimerosal from vaccines, FDA undertook review of this issue.

Thus, while enactment of FDAMA 1997 provided an official mechanism for review of this issue, the use of thimerosal as a preservative in vaccines had already begun to be considered by the FDA. During the past ten years, the FDA has provided informal and formal advice to manufacturers recommending that new vaccines under development be formulated without thimerosal as a preservative.

The FDA had previously reviewed thimerosal use in biological products, including vaccines, in 1976. This review evaluated exposure to thimerosal from biological products using the 1974 American Academy of Pediatrics “Red Book” immunization schedule and concluded that, with the exception of long term immune globulin replacement therapy, “no dangerous quantity of mercury is likely to be received from biologic products in a lifetime.” Of note, immune globulin products manufactured in the U.S. no longer use thimerosal as a preservative.

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What progress has been made towards the goal of eliminating thimerosal from vaccines?

All routinely administered pediatric vaccines are now being manufactured either in thimerosal-free or thimerosal-reduced (> 95% reduction) presentations. FDA expedited reviews of manufacturers’ supplements to their product license applications to eliminate or reduce the mercury content vaccines to help assure that the PHS goal of replacement of thimerosal-containing vaccines takes place as quickly as possible. In August 1999 the FDA approved a thimerosal-free hepatitis B vaccine and in March 2000 a hepatitis B vaccine containing only trace thimerosal (less than 0.5 micrograms mercury per dose) was approved. Thus, as of March 2000, all U.S children had access to hepatitis B vaccines that are free of thimerosal as a preservative. All Haemophilus influenzae type b (Hib) vaccines currently distributed in the U.S. do not contain thimerosal. With the March 2001 approval of a second diphtheria and tetanus toxoid and pertussis vaccine (DTaP) that does not contain thimerosal as a preservative (Aventis Pasteur’s Tripedia, trace thimerosal), all DTaP vaccines currently being produced in the U.S. are either thimerosal free or contain greatly reduced amounts (less than 0.5 micrograms of mercury per vaccine dose.)

Based on this progress, the most likely maximum amount of ethyl mercury that an infant may be exposed to from the routine vaccination schedule has been reduced from approximately 187.5 mcg to <3 mcg. The measles, mumps, rubella, varicella, inactivated polio, and pneumococcal conjugate vaccines that are now in use have never contained thimerosal.

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Why are some vaccines noted to be “thimerosal-free” while some are “thimerosal-reduced”? What is the difference between “thimerosal-free” and “preservative-free”?

Thimerosal may be added at the end of the manufacturing process to act as a preservative to prevent bacterial or fungal growth in the event that the vaccine is accidentally contaminated, as might occur with repeated puncture of multi-dose vials. When thimerosal is used as preservative in vaccines, it is present in concentrations up to 0.01% (50 micrograms thimerosal per 0.5 mL dose or 25 micrograms mercury per 0.5 mL dose). In some cases, preservatives are added during manufacture to prevent microbial growth. Use of thimerosal during the manufacturing process contributes considerably less to the final content of vaccines (less than 0.5 micrograms mercury per 0.5 mL dose).

Vaccines may be termed “thimerosal-free” if no thimerosal can be measured; i.e., thimerosal content is below the limit of detection. The term “thimerosal-reduced” usually indicates that thimerosal is not added as a vaccine preservative, but trace amounts (less than 0.5 micrograms mercury per 0.5 mL dose) may remain from use in the manufacturing process. Such trace amounts are not felt to be clinically significant, nor would they result in exposure exceeding any federal guideline for mercury exposure. The term “preservative-free” indicates that no preservative (thimerosal or otherwise) is used in the vaccine; however, traces used during the manufacturing process may be present in the final formulation. For example, some vaccines may be preservative-free but may contain traces of thimerosal (less than 0.5 micrograms mercury per 0.5 mL dose); in such settings, this information is noted in the package insert.

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Why is exposure to mercury a concern?

Mercury is an element that is dispersed widely around the earth. Most of the mercury in the water, soil, plants and animals is found as inorganic mercury salts. Mercury accumulates in the aquatic food chain, primarily in the form of the methylmercury, an organomercurial. Methylmercury is more easily absorbed and is less readily eliminated from the body than inorganic mercury. Exposure to methylmercury has been shown to pose a variety of health risks to humans. Extremely high levels, such as that observed in poisoning episodes in Japan and Iraq, has caused neurological damage and death. The fetus is considered more sensitive to health effects of methylmercury than adults. In recent years some studies have found adverse health effects of methylmercury at levels previously thought to be safe. Other studies, however, have shown conflicting results.

It is important to note that the preservative thimerosal contains ethylmercury, a related though distinct organomercurial from methylmercury. Information on the toxicity of ethylmercury, especially at low doses, is limited.

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Is mercury from thimerosal a major source of mercury exposure in infants?

To answer this question, one must compare an infant’s environmental exposure (primarily the diet) to mercury exposure from vaccines. However, limited information is available on dietary exposure to mercury in infants less than 6 months of age. In addition, dietary exposure of infants to organic mercury occurs in the form of methylmercury, while exposure to mercury in vaccines occurs as ethylmercury, which may have different toxicity. Recognizing these limitations, available information has suggested that exposure of infants to mercury from vaccines is in the same order of magnitude as exposure to mercury in the diet. Reports of total exposures to mercury (inorganic and organic) in the diet have ranged from less than 0.05 micrograms/kg/day to 0.1 micrograms/kg/day. One investigator calculated that approximately half of mercury in breast milk was in the form of organic mercury, of a total 0.6 micrograms mercury per L. (Oskarsson 1996). At the time of the FDA risk assessment in 1999, exposure of infants to mercury from vaccines during the first six months of life under the routine immunization schedule range from 0 to 187.5 micrograms mercury as a cumulative total dose.

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I understand that the Institute of Medicine (IOM) recently reviewed the issue of thimerosal in vaccines. What were the IOM’s findings?

This past year, the Institute of Medicine convened a committee (the Immunization Safety Review Committee) to review selected issues related to immunization safety and their most recent review focused on a potential relationship between thimerosal use in vaccines and neurodevelopmental disorders (IOM 2001). This issue was brought to the fore primarily as the result of the hypothesis, formulated by S. Bernard and others from Cure Autism Now, that autism is a novel form of mercury poisoning (Bernard et al. 2001); this hypothesis, linking autism to mercury, was based on a comprehensive review of the scientific literature on mercury toxicity.

In its report of October 1, 2001, the IOM’s Immunization Safety Review Committee concluded that the evidence is inadequate to either accept or reject a causal relationship between thimerosal exposure from childhood vaccines and the neurodevelopmental disorders of autism, attention deficit hyperactivity disorder (ADHD), and speech or language delay. Thus, while the available scientific data do not establish that these neurodevelopmental disorders are caused by thimerosal, at the same time, they do not establish that these neurodevelopmental disorders are not caused by thimerosal. Additional studies are needed to establish or reject a causal relationship. The Committee did conclude that the hypothesis that exposure to thimerosal-containing vaccines could be associated with neurodevelopmental disorders was biologically plausible.

The Committee believed that the effort to remove thimerosal from vaccines was “a prudent measure in support of the public health goal to reduce mercury exposure of infants and children as much as possible.” Furthermore, in this regard, the Committee urged that “full consideration be given to removing thimerosal from any biological product to which infants, children, and pregnant women are exposed.”

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The IOM recommends the use of thimerosal-free DTaP, hepatitis B, and Hib vaccines in the United States, despite the fact that there might be remaining supplies of thimerosal-containing vaccines available. Why doesn’t the FDA recall all thimerosal-containing vaccines intended for use in infants and small children?

The FDA believes a recall of thimerosal-containing vaccines is not warranted because data show that these products are safe. In addition, with the approval of new thimerosal-free and thimerosal-reduced products, all vaccines routinely administered childhood vaccines are manufactured without thimerosal as a preservative and thus infant exposure to mercury from vaccines is unlikely to exceed any federal guidelines. However, we concur with the IOM that it is prudent to avoid mercury exposure from vaccines, indeed, from all sources. Accordingly, we have worked with manufacturers to remove or reduce thimerosal from vaccines.

Federal law is specific about the criteria that must be met before FDA can enforce a mandatory recall of a regulated product. Under section 351(d) of the Public Health Service Act, a licensed vaccine (or other biological product) shall be recalled if FDA determines that it “… presents an imminent or substantial hazard to the public health...” The FDA does not believe that thimerosal-containing vaccines “present an imminent or substantial hazard to the public health" because available scientific data do not provide adequate evidence that exposure to thimerosal in vaccines can cause neurodevelopmental disorders. In a recent comprehensive review of this subject, the IOM found inadequate evidence to accept or reject a causal relationship between thimerosal-containing vaccines and neurodevelopmental disorders. Therefore, a mandatory recall under § 351(d) is not warranted.

FDA regulations also provide for a voluntary recall of products regulated by the FDA (21 CFR, Part 7). A firm may withdraw a product from the market, of its own volition, at any time. In addition, FDA may request a firm to recall a product that is in violation of FDA laws and regulations and that presents a risk of injury or gross deception, or is otherwise defective; an agency request for recall is reserved for urgent situations such as those that are necessary to protect the public health. FDA has concluded that voluntary recall is not warranted because vaccines that contain thimerosal as a preservative are not violative products and there is no conclusive data that they present a risk of injury. Additional studies on the potential for adverse effects of mercury in vaccines are continuing. Results of these studies will be closely monitored by FDA.

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The IOM urged that “full consideration be given to removing thimerosal from any biological product to which infants, children, and pregnant women are exposed.” (IOM 2001) Routine administration of influenza vaccine is recommended in pregnant women, yet currently available U.S. licensed influenza vaccines contain thimerosal. Why are pregnant women receiving influenza vaccine containing thimerosal?

This issue was reviewed by the CDC’s Advisory Committee on Immunization Practices (ACIP) in 1999 and again in 2001. The ACIP recommended no changes in the influenza vaccination guidelines, including those for children and pregnant women. The ACIP stated that “because pregnant women are at increased risk for influenza complications and because a substantial safety margin has been incorporated into health guidance values for organic mercury exposure, the benefit of influenza vaccine outweighs the potential risks for thimerosal”. FDA is in discussions with manufacturers regarding the development of thimerosal-free or reduced influenza vaccines.

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Although thimerosal is no longer used as a preservative in routinely recommended childhood vaccines manufactured in the US, what is being done about the thimerosal content of less commonly administered vaccines and other biological products given to infants, children, and pregnant women?

The FDA is continuing its efforts to reduce exposure to infants, children, and pregnant women to mercury from all sources. Discussions with the manufacturers of influenza virus vaccines (which are routinely recommended for pregnant women) regarding thimerosal-reduced and thimerosal-free presentations are ongoing. Discussions are also underway with regard to other vaccines, in particular, the diphtheria and tetanus vaccines and one manufacturer’s adolescent/adult formulation of the hepatitis B vaccine (a second manufacturer’s hepatitis B vaccine is formulated without thimerosal as a preservative for both the pediatric and adult presentations.)

At present time all immune globulin preparations including hepatitis B immune globulin, and Rho(D) immune globulin preparations are manufactured without thimerosal.

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When thimerosal was removed as a preservative in vaccines, what replaced it? How do we know that the new formulations are safe?

Two options are available to manufacturers seeking to remove thimerosal as a vaccine preservative: reformulating the vaccine in single dose containers that do not contain a preservative, or replacing thimerosal with an alternative preservative.

Since 1999, license supplements have been approved for one DTaP (Tripedia; Aventis Pasteur) and two pediatric formulations of hepatitis B vaccine (Recombivax HB [Merck] and Engerix-B [Glaxo SmithKline]). In each of these cases removal of thimerosal as preservative has been accomplished by changing presentations from multi-dose to single dose vials that do not require a preservative. Preservatives are used in multi-dose vials to prevent bacterial or fungal growth in the event that the vaccine is accidentally contaminated, as might occur with repeated puncture. When thimerosal is removed as a preservative, the manufacturer submits relevant information to the FDA to demonstrate the safety and effectiveness of this product has not been affected by the change in formulation.

A manufacturer may seek to replace thimerosal with an alternate preservative; however, additional data establishing its safety and effectiveness may be required.

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What kind of evidence would be needed to demonstrate that autism or other neurodevelopmental disorders are caused by exposure to thimerosal?

Several general considerations, patterned after those proposed by Hill in 1965 and adapted by others have been generally accepted in the field of epidemiology for causal inference, i.e., determination of whether a disease is caused by an exposure. The IOM used the following criteria for assessing whether evidence indicates the presence of an association between an adverse event and vaccine exposure (IOM 1991). Similar criteria were used recently by the IOM’s Immunization Safety Review Committee in their assessment of thimerosal-containing vaccines and neurodevelopmental disorders (IOM 2001).

1. Strength of Association - The strength of an association refers to the magnitude of the measure of effect of an exposure, usually the relative risk or odds ratio, in a study comparing an exposed and an unexposed group. The larger the magnitude of the effect the less likely any observed effect is due to chance, bias or confounding. In general in observational studies, relative risks of 2 or less are considered to be evidence of a weak association, because the likelihood the effect is due to chance, bias or confounding is greater than if the effect is larger).
2. Dose-Response Relation - The existence of a dose-response relation strengthens an inference that an association is causal. A dose-response relation is defined as an increased strength of association with increased magnitude of exposure.
3. Temporally Correct Association - Exposure must precede the event by at least the duration of disease induction. This consideration may be limited by the fact that knowledge of the pathogenesis and natural history of an adverse event may be insufficient.
4. Consistency of Association - This consideration requires that an association be found regularly in a variety of studies, using different study populations and study methods.
5. Specificity of an Association -Uniqueness of an association between an exposure and an outcome provides a stronger justification for a causal interpretation than when the association is nonspecific. However, perfect specificity between an exposure and an effect cannot be expected in all cases because of the multifactorial etiology of many disorders.
6. Biological Plausibility - The existence of a possible mechanism of action that fits existing biologic or medical knowledge is thought to increase the likelihood that an association is causal.

The final judgment on whether there is a causal relationship between an exposure, such as thimerosal, and an outcome, such as autism, is made by balancing between the strength of above considerations supporting a causal interpretation against the strength of alternative explanations.

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How can these considerations applied when assessing whether autism is caused by thimerosal?

One can apply these considerations in the following way:

1. Strength of Association - When evaluating this consideration 3 types of studies are generally included, controlled trials, cohort studies, and case-control studies. These studies have in common the ability to calculate an estimate of the relative risk of an effect from an exposure.

   There have been no controlled trials of the relationship between thimerosal and autism, and those controlled trials that have been done using thimerosal containing vaccines have not been conducted in a way that would allow an evaluation of the relationship between thimerosal and autism. There have been two retrospective cohort studies conducted recently by the CDC using data from 2 different health maintenance organization (HMO) databases. The first study did not show a statistically significant association between thimerosal exposure and autism. There were not enough cases of autism in the second database to study. There have been no case control studies of autism and thimerosal.

   An association that has been noted by some concerned parents of autistic children is that the increase in the prevalence of autism over the last few decades “closely matches the introduction and spread of thimerosal-containing vaccines”. This type of comparison is known as an ecological study. Ecological studies alone are generally not accepted as strong evidence of causality, because they do not link individual exposure to individual outcome, and can be subject to confounding by unknown or uncontrollable factors. In addition, it has been noted that some children with autism have high levels of mercury in hair, urine and blood. This observation cannot be interpreted without information on the levels of mercury in individuals without autism (i.e. case-control study). However, such observations do indicate that the hypothesis should be studied further.

2. Dose-Response Relation - In the CDC cohort study that was conducted to examine the relationship between thimerosal and autism, no increase in relative risk of autism was observed with increasing doses of thimerosal, making a causal relationship less likely.

3. Temporally Correct Association - A detailed understanding of the time course of the pathological changes that lead to autism is not available. Since autism is not usually diagnosed at least until 18 months of age, it is difficult to judge whether the exposure to the highest levels of thimerosal on a body weight basis in the first 6 months to a year of life is consistent with a causal relationship between thimerosal exposure and autism.

4. Consistency of Association - The one CDC cohort study in which autism could be examined failed to show an association between thimerosal and autism, but because only one study has been conducted we cannot evaluate consistency across studies. Thus, a causal relationship between thimerosal and autism is neither supported nor refuted by this consideration.

5. Specificity of Association - There is not a clearly identified unique relationship between thimerosal and autism, or for methylmercury exposure and autism.

6. Biological Plausibility - In a general sense it is biologically plausible that thimerosal could cause autism since thimerosal has caused neurological abnormalities at high doses. However, it has not been shown that mercury at the much lower doses found in childhood vaccines can cause the specific neurological injuries that are found in autism.

   In summary, the CDC cohort study did not show an association between thimerosal exposure and autism and no dose-response relationship was observed, thus the existing evidence does not support a causal relationship between thimerosal and autism. However, additional studies to fill in gaps in our knowledge, such as whether the regressive subtype of autism is causally related to thimerosal in vaccines, may be warranted.

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Some individuals have pointed out that the clinical features of individuals with autism are similar to those found following mercury poisoning. Does this indicate that autism is caused by exposure to mercury?

Analogous clinical features have been described between autistic individuals and those suffering from mercury toxicity (Bernard et al. 2001). Hill (1965) included “analogy” as an additional consideration in his original discussion of causal inference. This consideration has not been accepted as strong evidence of causality, and was not used by the Institute of Medicine in its evaluation, because it is quite easy to draw analogies among exposure disease relationships, even when causal relationships do not exist. The analogies between the neurological illness of mercury poisoning on the one hand and autism and thimerosal exposure on the other are not strong evidence of a causal relationship, but suggest more definitive studies should be conducted.

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Does the available evidence address the possibility that exposure to thimerosal causes a particular type of autism, termed “regressive autism” in a subset of genetically susceptible children?

Most experts believe that the majority of autism cases are genetically determined. One piece of evidence supporting this view is that studies of videotapes of autistic children before and after their diagnosis show that most children already have behavioral abnormalities before they manifest all the signs and symptoms of autism. However, in these studies a minority of children appear to develop normally and then suddenly manifest all the signs and symptoms of autism, leading to the diagnosis of "regressive" autism. These children may have a genetic predisposition to autism that requires an environmental stimulus to trigger. The environmental agents that may trigger regression are not known. The children with regressive autism may be more sensitive to certain environmental agents than normal children, as has been suggested by some members of Cure Autism Now (CAN). Since the details of the biological mechanism and genetics behind regressive autism are not clear, another approach to the question is through a "case-control" study. Cases of regressive autism would be identified, and a variety of environmental exposures including vaccines and thimerosal would be compared with children who do not have regressive autism ("controls"). A difference in exposures between the two groups would suggest that those exposures might cause regressive autism. Such a study can be conducted as part of a larger study of the causes of autism.

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Central nervous system lesions and neurochemical abnormalities following exposure to mercury have been compared to that found in individuals with autism. Do these studies prove that the organic mercury metabolite of thimerosal (ethylmercury) found in some vaccines can cause autism?

Intrauterine and postnatal development of the nervous system can be affected by many different toxins. Mercury, typically in the form of ingested methylmercury compounds, has been shown to induce abnormalities in the brain of humans and experimental animals. Physical damage to the areas of brain undergoing development at the time of exposure has been found in autopsy studies and in experimental animal models. Neurochemical transmitter abnormalities in the brain associated with toxic compounds, such as mercury, has been identified in experimental animal systems, and, indirectly, in human samples of blood or cerebral spinal fluid.

Available evidence indicates that autism is a developmental disorder of the nervous system. Many etiologies have been suggested or proven to lead to autism or autism spectrum disorders, from genetic (e.g., Rett's Syndrome, Fragile X Syndrome) to drugs exposure in utero (e.g., thalidomide). Only a small number of brains from autistic individuals have been available for pathological studies. Those studies reveal some consistency of damage in specific areas (e.g., the cerebellum and hippocampus). Further, brain imaging studies have been performed in autism, and the results suggest similar brain areas are affected, but these studies are less consistent. How the reported neuroanatomical damage relates to the expression of autistic disease is unknown. Indirect assessments of neurochemical changes from the cerebral spinal fluid, blood or by special brain scans (PET) of autistic subjects also suggest a variety of neurochemical abnormalities. However, in part because these indirect measurements (e.g., blood levels of norepinephrine) may not reflect accurately changes in the brain neurochemistry, the relationship of the proposed neurochemical abnormalities to disease expression is unknown.

Determining cause and effect relationships of early toxin exposures to the developing nervous system is very difficult. Subtle changes in exposure doses and timing of exposure of a single toxin (e.g., methylmercury) can cause a variety of different outcomes in the nervous system. Moreover, exposure to many different toxic treatments can result in similar types of damage to the brain (e.g., ethanol, X-irradiation). Currently, little information is available on the outcome of exposure of the developing human nervous system to toxic levels of ethylmercury.

In sum, the data are not sufficient to support the causal relationship between ethylmercury exposure and autism. More information is needed about autism and mercury toxicity in order to understand the relationship, if any, between thimerosal and autism.

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Is it possible that genetic and non-genetic factors establish a predisposition among some children to adverse effects from thimerosal?

The only well-recognized adverse effect associated with use of thimerosal in drugs and vaccines is a transient skin allergy or local hypersensitivity reaction. In most cases when such reactions are reported, it cannot be definitely established that thimerosal is the cause of the allergy. Serious hypersensitivity reactions following vaccinations such as anaphylaxis are rare. A predisposition to allergic reactions probably is linked to genetic factors, although such factors are not well understood.

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Could there be a subset of genetically susceptible children predisposed to develop autism following exposure to thimerosal?

For most individuals diagnosed with autism, the specific factors associated with expression of this disorder are not known. Genetic studies of autistic children have failed to identify a single gene responsible for autism and no chromosomal anomalies have been associated with autism. Nevertheless, studies among twins with autism strongly suggest that genetic influences underlie the development of autism. Among non-identical twins, if one twin is autistic, the other twin becomes autistic about 5% of the time, while among identical twins, if one twin is autistic, the other twin becomes autistic about 60% of the time. The strong genetic influence thus argues against a toxic exposure as the sole cause of autism. It is possible that the ability to metabolize and eliminate mercury from the body may depend on genetic factors. However, at this time, little information is available to indicate what those genetic factors might be.

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Autism and autism-spectrum disorders have been steadily increasing, especially during the 80’s and 90’s. During this time period the number of vaccines that children have received has more than tripled. Doesn’t this implicate vaccinations as a cause of autism?

The reasons for the apparent increase in the number of cases of autism over the past two decades are complex. In part, the increase can be traced to a broadening of the case definition to include less severe and more atypical presentations of autism. However, the increased number of childhood vaccinations and increased vaccine coverage in recent years in no way constitutes evidence of an association with autism or any other diseases which may have increased in recent years. To the contrary, childhood vaccinations today protect children from devastating illnesses such as meningitis. (The rubella vaccine administered in infancy protects the fetus of the next generation from neurological deficits, and may arguably be described as an anti-autism vaccine).

The association that has been noted by some concerned parents of autistic children that the increase in the prevalence of autism over the last few decades “closely matches the introduction and spread of thimerosal-containing vaccines” is known as an ecological study. Ecological studies alone are generally not accepted as strong evidence of causality, because they do not link individual exposure to individual outcome, and can be subject to confounding by unknown or uncontrollable factors. In addition, it has been noted that some children with autism have high levels of mercury in hair, urine and blood. This observation cannot be interpreted without information on the levels of mercury in individuals without autism (i.e. case-control study). However, such observations do suggest that the hypothesis should be studied further.

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Is it true that some autistic children experience neurobehavioral improvements after chelation therapies? Doesn’t this prove that mercury causes autism if autistic children improve after chelation?

Individual case histories, while worth noting, do not constitute compelling evidence a treatment effect for chelation therapy or a causal association of mercury in autism.

Convincing evidence comes from well-designed, randomized, well-controlled studies. We are not aware of any evidence from such studies demonstrating a treatment effect of chelation therapy in autism.

It is also important to point out that the use of chelation therapy for organic mercury poisoning is controversial, with some experts questioning its benefit. In addition, there are risks associated with chelation therapy.

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What can you tell me about other additives to vaccines besides preservatives?

In addition to the immunogen (the active component of the vaccine) and, at times, a preservative, vaccines may also contain adjuvants and stabilizers; residual materials from the manufacturing process may also be present. The focus of this answer will be on vaccine adjuvants. Adjuvants are chemical entities that are added to vaccines to enhance or direct the immune response. At present, the only adjuvants that are present in any of the U.S.-licensed vaccines are the aluminum salts - aluminum hydroxide, aluminum phosphate, alum (aluminum potassium phosphate) derivative salts, or a mixed aluminum hydroxide/phosphate salt. Among the routine pediatric vaccines, aluminum salts are used in all of the DTaP vaccines, some Hib conjugate vaccines, the pneumococcal conjugate vaccine, and both of the hepatitis B vaccines. Depending on the vaccines that were administered, an infant might receive between approximately 1.5 and 3.5 milligrams of aluminum during the first half year of life. The primary concern with aluminum is that it is neurotoxin. The Agency for Toxic Substances and Disease Registry (ATSDR) has set a minimal risk level (MRL) for aluminum of 2 milligrams/kilogram of body weight/day; the MRL is, however, for oral intake of aluminum [link to ATSDR and aluminum]. Seemingly, the allowed aluminum intake is many times in excess of that received through vaccines. However, the MRL has been established for oral intake and aluminum salts are only poorly absorbed through the gut; in contrast, vaccines are injected into the muscle. We can, however, try to compare these numbers. The ATSDR has estimated an uptake factor of approximately 0.006 for aluminum (the fraction of orally ingested aluminum that becomes systemic). Using this number, we can estimate a systemic MRL of 12 micrograms/kg of body weight/day ([2 milligrams/kilogram bodyweight/day] x 0.006]). Over a period of 6 months, taking an average weight of 5 kilograms for a child, this would translate into an allowed accumulation of 10.8 milligrams of aluminum. This number is in excess of the 1.5 - 3.5 milligrams of aluminum that a child would receive from vaccines. Whether there is, or is not, any synergistic biological interaction between aluminum and mercury is unknown.

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