The Problem

Recent scientific evidence has begun to link the presence of thimerosal in childhood vaccines to autism and other childhood neurological and behavioral disorders.  Thimerosal is a preservative that contains mercury, a compound known to cause brain damage.  The U.S. FDA has encouraged pharmaceutical companies to remove thimerosal from their vaccines as soon as possible.  A product liability lawsuit may help injured children recover damages from this situation in the future, and attorneys are expected to organize such a class-action lawsuit.  The information that follows is from the FDA's Center for Biologics Evaluation and Research.  It contains information about the research on thimerosal and autism as well as information about the content of vaccines.

Introduction

Thimerosal is a mercury-containing organic compound (an organomercurial). Since the 1930s, it has been widely used as a preservative in a number of biological and drug products, including many vaccines, to help prevent potentially life threatening contamination with harmful microbes. Over the past several years, because of an increasing awareness of the theoretical potential for neurotoxicity of even low levels of organomercurials and because of the increased number of thimerosal containing vaccines that had been added to the infant immunization schedule, concerns about the use of thimerosal in vaccines and other products have been raised. Indeed, because of these concerns, the Food and Drug Administration has worked with, and continues to work with, vaccine manufacturers to reduce or eliminate thimerosal from vaccines.

Thimerosal has been removed from or reduced to trace amounts in all vaccines routinely recommended for children 6 years of age and younger, with the exception of inactivated influenza vaccine (see Table 1). A preservative-free version of the inactivated influenza vaccine (contains trace amounts of thimerosal) is available in limited supply at this time for use in infants, children and pregnant women. Some vaccines such as Td, which is indicated for older children (> 7 years of age) and adults, are also now available in formulations that are free of thimerosal or contain only trace amounts. Vaccines with trace amounts of thimerosal contain 1 microgram or less of mercury per dose.

In the following pages, a discussion of preservatives, the use of thimerosal as a preservative, guidelines on exposure to organomercurials (primarily methylmercury), thimerosal toxicity, recent and future FDA actions, and the conclusions of the Institute of Medicine’s most recent review of thimerosal in vaccines are presented. This narrative on thimerosal contains references to the literature and links to other sites for readers who wish additional information; for quick reference, a number of frequently asked questions (FAQs) and answers are provided.

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Preservatives in Vaccines

To begin, we need to answer two questions-what are preservatives and why are they used in vaccines. For our purposes, preservatives may be defined as compounds that kill or prevent the growth of microorganisms, particularly bacteria and fungi. They are used in vaccines to prevent microbial growth in the event that the vaccine is accidentally contaminated, as might occur with repeated puncture of 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.

The United States Code of Federal Regulations (the CFR) requires, in general, the addition of a preservative to multi-dose vials of vaccines; indeed, worldwide, preservatives are routinely added to multi-dose vials of vaccine. Tragic consequences have followed the use of multi-dose vials that did not contain a preservative and have served as the impetus for this requirement. One particularly telling incident from Australia is described by Sir Graham S. Wilson in his classic book, The Hazards of Immunization

In January 1928, in the early stages of an immunization campaign against diphtheria, Dr. Ewing George Thomson, Medical Officer of Health of Bundaberg, began the injection of children with toxin-antitoxin mixture. The material was taken from an India-rubber-capped bottle containing 10 mL of TAM. On the 17th, 20th, 21, and 24th January, Dr. Thomson injected subcutaneously a total of 21 children without ill effect. On the 27th a further 21 children were injected…Of these children …eleven died on the 28th and one on the 29th. (Wilson 1967)

This disaster was investigated by a Royal Commission and the final sentence in the summary of their findings reads as follows:

The consideration of all possible evidence concerning the deaths at Bundeberg points to the injection of living staphylococci as the cause of the fatalities.

From this experience, the Royal Commission recommended that biological products in which the growth of a pathogenic organism is possible should not be issued in containers for repeated use unless there is a sufficient concentration of antiseptic (preservative) to inhibit bacterial growth.

The U.S. requirement for preservatives in multi-dose vaccines was incorporated into the CFR in January 1968, although many biological products had contained preservatives, including thimerosal, prior to this date. Specifically, the CFR states:

Products in multi-dose containers shall contain a preservative, except that a preservative need not be added to Yellow Fever Vaccine; Polio-virus Vaccine, Live Oral; viral vaccine labeled for use with the jet injector; dried vaccines when the accompanying diluent contains a preservative; or to an Allergenic Product in 50 percent or more volume (v/v) glycerin. [21 CFR 610.15(a)]

The CFR also requires that the preservative used

…[s]hall be sufficiently non-toxic so that the amount present in the recommended dose of the product will not be toxic to the recipient, and in combination used it shall not denature the specific substance in the product to result in a decrease below the minimal acceptable potency within the dating period when stored at the recommended temperature. [21 CFR 610.15(a)]

Preservatives cannot completely eliminate the risk of contamination of vaccines. The literature contains several reports of bacterial contamination of vaccines despite the presence of a preservative, emphasizing the need for meticulous attention to technique in withdrawing vaccines from multi-dose vials. (Bernier et al 1981; Simon et al. 1993). The need for preservatives in multi-dose vials of vaccines is nonetheless clear. Several preservatives are used in U.S. licensed vaccines, and these are listed in Table 2. It is important to note that the FDA does not license a particular preservative; rather, the product containing that preservative is licensed, with safety and efficacy data generally collected in the context of a license application for a particular product.

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Thimerosal as a Preservative

Thimerosal, which is approximately 50% mercury by weight, has been one of the most widely used preservatives in vaccines. It is metabolized or degraded to ethylmercury and thiosalicylate. Ethylmercury is an organomercurial that should be distinguished from methylmercury, a related substance that has been the focus of considerable study (see "Guidelines on Exposure to Organomercurials" and "Thimerosal Toxicity", below).

At concentrations found in vaccines, thimerosal 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 (U.S. Pharmacopeia 2004). Thimerosal in concentrations of 0.001% (1 part in 100,000) to 0.01% (1 part in 10,000) has been shown to be effective in clearing a broad spectrum of pathogens. 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.

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 (Powell and Jamieson 1931). Since then, thimerosal has been the subject of several studies (see Bibliography) and 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 has been used in some immune globulin preparations, anti-venins, skin test antigens, and ophthalmic and nasal products, in addition to certain vaccines. Under the FDA Modernization Act of 1997, the FDA compiled a list of regulated products containing mercury, including those with thimerosal (Federal Register 1999). It is important to note that this list was compiled in 1999; some products listed are no longer manufactured and many products have been reformulated without thimerosal. Updated lists of vaccines and their thimerosal content can be found in Table 1 (routinely recommended pediatric vaccines) and Table 3 (expanded list of vaccines).

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Guidelines on Exposure to Organomercurials

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. Organic forms of mercury are more easily absorbed when ingested and are less readily eliminated from the body than are inorganic forms mercury. Humans are exposed to methylmercury primarily from the consumption of seafood (Mahaffey et al. 1997).

Methylmercury is a neurotoxin. The toxicity of methylmercury was first recognized during the late 1950s and early 1960s when industrial discharge of mercury into Minimata Bay, Japan led to the widespread consumption of mercury-contaminated fish (Harada 1995). Epidemics of methylmercury poisoning also occurred in Iraq during the 1970s when seed grain treated with a methylmercury fungicide was accidentally used to make bread (Bakir et al. 1973). During these epidemics, fetuses were found to be more sensitive to the effects of methylmercury than adults. Maternal exposure to high levels of methylmercury resulted in infants exhibiting severe neurologic injury including a condition resembling cerebral palsy, while their mothers showed little or no symptoms. Sensory and motor neurologic dysfunction and developmental delays were observed among some children who were exposed in utero to lower levels of methylmercury.

More recently, several epidemiological studies have examined the effect of low dose dietary exposure to methylmercury, with inconsistent results. Studies from the Faroe Islands reported that subtle cognitive deficits (e.g., performance on attention, language, and memory tests), detectable by sophisticated neuropsychometric testing, were associated with methylmercury levels previously thought to be safe (Grandjean et al 1997). Studies in the Seychelles, evaluating more global developmental outcomes, did not reveal any correlation between abnormalities and methylmercury levels (Davidson et al. 1998).

Various agencies have developed guidelines for safe exposure to methylmercury, including the U.S. Environmental Protection Agency (Mahaffey et al. 1997), U.S. Agency for Toxic Substances and Disease Registry (ATSDR 1999), the FDA (Federal Register 1979)¹, and the World Health Organization (WHO 1996). These exposure levels range from 0.1 µg/kg body weight/day (EPA) to 0.47 µg/kg body weight/day (WHO)². The range of recommendations is due to varying safety margins, differing emphasis placed on various sources of data, the different missions of the agencies and the population that the guideline is intended to protect. All guidelines, however, fall within the same order of magnitude. While these guidelines may be used as screening tools in risk assessment to evaluate the "safety" of mercury exposures, they are not meant to be bright lines above which toxicity will occur. However, as exposure levels increase in multiples of these guidelines, there is increasing concern on the part of the public health community that adverse health consequences may occur (Mahaffey 1999).

To address the issue of conflicting methylmercury exposure guidelines, Congress asked the National Academy of Sciences to study the toxicological effects of methylmercury and provide recommendations on the establishment of a scientifically appropriate methylmercury reference dose (RfD) (National Research Council 2000; http://www.nap.edu/catalog/9899.html). Their report concluded that the EPA’s current reference dose, the RfD, for methylmercury, 0.1 µg/kg/day is a scientifically justifiable level for the protection of human health. The FDA is considering this and other data relevant to its exposure guideline for methylmercury.

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Updated July 18, 2005

With the exception of the section labeled "The Problem" this document was produced by the FDA / Center for Biologics Evaluation and Research in July of 2005.  This document is in the public domain as a work-for-hire created by U.S. Government employees and can be freely reproduced.