Mercury (Thimerosal) in Vaccines FDA report

Main Category: Infectious Diseases / Bacteria / Viruses
Article Date: 08 Aug 2004 - 0:00 PDT

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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 have 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.

In the U.S at present, all of the routinely administered pediatric vaccines are being produced in either thimerosal-reduced (less than 1 microgram of thimerosal per dose; less than 0.5 micrograms of mercury per dose) or thimerosal-free presentations; see Table 1. 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 Institute of Medicine's 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.

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.

More……

Table of Contents

Introduction

Preservatives in Vaccines

Thimerosal as a Preservative

Guidelines on Exposure to Organomercurials

Thimerosal Toxicity

Recent and Future FDA Actions

The Safety Review of Thimerosal-containing Vaccines and Neurodevelopmental Disorders Conducted by the Institute of Medicine

Table 1. Thimerosal Content of the Routinely Recommended Pediatric Vaccines

Table 2. Preservatives in U.S. Licensed Vaccines

Table 3. Thimerosal and Expanded List of vaccines

References

Bibliography

Frequently Asked Questions (FAQs)

• Additional
• References
• Citations