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Canada Communicable Disease Report
Volume 29 • ACS-1 1 March 2003 An Advisory Committee Statement (ACS)
STATEMENT ON THIMEROSALAdobe Downloadable
Document Introduction The National Advisory Committee on Immunization (NACI) has prepared this statement to provide recommendations on the use of vaccines licensed for use in Canada that contain the mercury-based preservative thimerosal, so that practitioners will have the information they need to make sound recommendations for vaccine administration to patients, and vaccine manufacturers will have guidance on the future development of vaccines for the Canadian market. The statement will also make recommendations on the management of patients who need vaccine that contains thimerosal but who report previous hypersensitivity to this constituent. Many vaccines licensed in Canada contain no thimerosal. Such vaccines are single-dose preparations in which thimerosal has not been used in any part of the manufacturing process. Other vaccines may contain trace amounts of thimerosal ( < 0.5 µg) if the preservative has been used in the production process, but have no added thimerosal. An example is one of the formulations of EngerixB™. A third group of vaccines have thimerosal added as a preservative. Such vaccines are typically those supplied in multi-dose vials, with thimerosal added in varying concentrations to prevent contamination with other serious infectious agents. Many of these vaccines are not in common use, but some, like influenza vaccine, are administered to millions of people in Canada with no evident adverse effect. In Canada, the vaccines currently used in routine infant immunization do not contain thimerosal (see Table 1). Some hepatitis B vaccines licensed in Canada do, but one formulation with no thimerosal and another with only trace amounts are now available in Canada, and NACI recommends their use in infants preferentially. The two hepatitis B vaccines in which thimerosal is added as a preservative are gradually being phased out. Influenza vaccine also contains thimerosal but is only recommended for use in Canada for those infants > 6 months of age. The other vaccines licensed in Canada that contain thimerosal are primarily used for people travelling to developing countries and are not routinely administered to infants.
The use of several different vaccines containing thimerosal as a preservative in the routine infant immunization program in the United States had led to concerns about the total amount given to infants. Several thimerosal-containing products may be given at one visit, and because of infants' low body weight (particularly in the case of premature infants) the total dosage administered to infants began to approach or marginally exceed the total recommended mercury exposure guideline of the U.S. Environmental Protection Agency, but not that of the World Health Organization (WHO) or the U.S. Food and Drug Administration. It has been calculated that a 6-month-old infant immunized in the United States may have received a cumulative dose of ethyl mercury as high as 187.5 µg . Given the use of combination vaccines that do not contain thimerosal, exposures to mercury through vaccines are negligible in Canada. The maximum allowable daily limits for mercury exposure and suggested cumulative limit of mercury from other sources are listed in Table 2.
As a result of these concerns in the United States, the American Academy of Paediatrics and the U.S. Public Health Service issued a joint statement in July 1999, recommending that the removal of thimerosal from vaccines be accomplished as soon as possible(3). In addition, the U.S. Institute of Medicine's Immunization Safety Review Committee was convened to review this issue. It released a report on thimerosal-containing vaccines and neurodevelopmental disorders in October 2001(4), concluding that “the evidence is inadequate to accept or reject a causal relationship between thimerosal exposures from childhood vaccines and neurodevelopmental disorders”, the primary concern that has been raised about thimerosal use. The report stated that “the hypothesis that thimerosal exposure through the recommended childhood immunization schedule (in the United States) has caused neurodevelopmental disorders is not supported by clinical or experimental evidence.” It suggested that biologic plausibility, though possible, is, at best, indirect. It did, however, recommend that, even in the absence of definite evidence of risk, the prudent approach is to seek alternatives to thimerosal for use in vaccines and to remove thimerosal-containing vaccines from use in the United States. Chemical Characteristics of Thimerosal Thimerosal is an organic mercury compound that is an effective preservative. It is used in some vaccines and in pharmaceutical and other consumer products, such as cosmetics. First introduced in the 1930s, it prevents bacterial and fungal contamination of these products. It may be used during the manufacture of the vaccine to inactivate organisms or added as a preservative to prevent contamination of the product after manufacture, particularly in multi-dose vials. Thimerosal is metabolized to ethyl mercury (CH3CH2Hg+2) and thiosalicylate. It contains 49.6% mercury by weight. In the final preparation of vaccines, the concentration of thimerosal is small, measured in micrograms (one millionth of a gram). When a person is immunized with a vaccine that contains thimerosal, the resultant concentration of metabolized ethyl mercury is reduced even further as it is diluted in the body. Health Effects of Mercury Mercury in large concentrations or with sustained exposure is a known neurotoxin, primarily in its organic form, methyl mercury, and a nephrotoxin in its inorganic form. Almost all research into mercury toxicity has been conducted on methyl mercury because it has been a major environmental contaminant, especially in the pulp and paper industry. The main concern in Canada has been methyl mercury exposure from the ingestion of fish containing high levels of the neurotoxin, especially in northern communities near pulp and paper mills. In such communities, fish as a food source has been a concern because of the large amounts of mercury that may be consumed if contaminated fish is a staple in the diet. Very little is actually known about ethyl mercury metabolism in humans, including whether it has the same potency as a neurotoxin, whether the blood concentration is ever significant, and even whether it crosses the blood-brain barrier. It is presumed that the majority of ethyl mercury metabolized from thimerosal is rapidly excreted in the stool. The risk, at best, can be described as theoretical. Although still preliminary, a recent study(5) suggested that the serum half-life of ethyl mercury in infants given thimerosal-containing vaccines was shorter than that suggested by work with methyl mercury, and did not seem to raise the blood concentrations of mercury above acceptable values. The detrimental health effects of high dose exposure to mercury have been well studied. In addition, acute accidental poisoning episodes with very high doses of thimerosal and improperly prepared medicines containing thimerosal have been documented. However, the amount of thimerosal in vaccines is small, and early studies of low dose exposure have not documented any adverse effects beyond the hypersensitivity reactions noted in the next section. The main theoretical concern is the use of thimerosal in vaccines for infants,
who, because of smaller body mass, will have a still small but higher concentration
of ethyl mercury than older children or adults when thimerosal is metabolized.
Because infants are still in the phase of neurodevelopment, it is theoretically
possible that the potential effects of organic mercury may be greater, although
this finding has not been observed and remains theoretical. Finally, it has
been postulated that the use of thimerosal in vaccines may lead to certain
neurologic conditions for which, to date, there has been no etiology determined,
such as autism and attention deficit and hyperactivity disorder (ADHD). No
clear scientific evidence has been published to substantiate this theory,
and the conclusion of the U.S. Institute of Medicine was that, whatever the
evidence, it is speculative. The WHO also responded in a review published
in the Weekly Epidemiologic Record(6), summarizing that
“thimerosal poses [only] a theoretical low risk of neurodevelopmental
toxicity in infants. The known risk of morbidity and mortality from vaccine-preventable
diseases and of contaminated multi-dose vaccine vials far outweigh any potential
risk posed by thimerosal.” More recently however, the WHO's Global
Advisory Committee on Vaccine Safety, which had been reviewing evidence since
the issue was raised, concluded that there is no evidence of toxicity in infants,
children or adults exposed to thimerosal (containing ethyl mercury) in vaccines. Hypersensitivity Reactions Low dose exposure to thimerosal has been associated with hypersensitivity reactions(7). Most reports of adverse immunologic reactions to thimerosal in vaccines involve small numbers of patients. Both delayed hypersensitivity (allergic contact) and immediate hypersensitivity (IgE mediated) reactions have been reported. The former mechanism is the more common of the two. Between 1% and 6% of tested individuals have exhibited this type of reaction on skin patch testing. Immediate hypersensitivity, including anaphylaxis and immune complex mediated disorders, have been reported with some products that contain thimerosal, but it is uncertain whether thimerosal was the responsible agent. Anaphylaxis has not been shown to occur as a result of thimerosal in vaccines and remains a theoretical risk. Although the amount of mercury that has been associated with these reactions from cosmetic and other commercial products is low, it is still much higher than the amounts found in vaccines. Of greater concern, however, are individuals who give a history compatible with sensitization to thimerosal through the use of now discontinued contact lens cleaning solutions. In such individuals, the nature of the hypersensitivity reaction must be characterized before a vaccine containing thimerosal is administered. An anaphylactic reaction to thimerosal from such products would constitute an absolute contraindication to vaccine containing thimerosal. Although positive patch tests and, possibly, intradermal tests to thimerosal
are risk factors for allergic reaction, they are generally poor predictors
of the likelihood of reaction to thimerosal-containing vaccine. Most individuals
with demonstrable sensitization to thimerosal tolerate thimerosal-containing
vaccines with no untoward reaction, although some individuals may experience
reactions ranging from mild to serious. Thus, it is advisable that patients
with a definite history of hypersensitivity to thimerosal or a demonstrable
hypersensitivity reaction be immunized in a setting that has resuscitation
capability. If there is no definite and proved history of hypersensitivity,
such precautions are not necessary. If there is a definite history of anaphylaxis
to thimerosal in any product, vaccines containing thimerosal should not be
given. Vaccines, like other injectable products, should be free of inadvertent microbial contamination. During the manufacturing process, great care is taken to ensure that vaccines are sterile. Failure to do this can lead to serious illness and death(8). Bacterial and fungal contamination can result in a variety of conditions, from local abscesses to septicemia. The use of preservatives in general, and thimerosal specifically, prevents microbial infection and contributes significantly to the safety profile of vaccines. Although single-dose vials of vaccines need not contain preservative if sterilization is effective, the use of a preservative is required for multi-dose vials, because the multiple entries into the vial to retrieve the vaccine may permit microbial contamination. Despite the fact that preservatives such as thimerosal have been used since the 1930s, there have been no common adverse effects observed, and vaccine safety has been enhanced. If a thimerosal preservative-free product is not available, it is clearly better to administer a vaccine containing thimerosal than to allow a susceptible person to suffer the disease that the vaccine will prevent. Vaccines Containing Thimerosal In Canada, many licensed vaccines contain thimerosal as a preservative (see Table 3). Most of these vaccines are not widely used, however, either because they have been replaced by newer vaccines or have very specialized use (DT adsorbed). Some, such as influenza, are used in provincial/territorial immunization programs. Every vaccine recommended for routine infant immunization programs in Canada either does not contain thimerosal as a preservative or has formulations available for use in infants that contain only trace amounts left over from the production process.
The enormous benefit of vaccine use over the decades cannot be overstated. Thousands upon thousands of deaths have been prevented, and many more thousands of people have not had to suffer the consequences of disability caused by vaccine-preventable diseases. The balance of benefit versus risk is highly weighted toward the use of vaccines. Vaccines are an extraordinarily safe product, when compared with other medical interventions. Notwithstanding this, it is critically important for there to be confidence in the safety of vaccines among the public and health professionals, for vaccines to be accepted, and for immunization programs to be successful. Vaccines are used much more widely in populations than any other medical product or procedure, and so any remote or rare adverse effect will appear in population-based programs. Thus, any possible adverse effect must be reduced to the lowest possible level. Although thimerosal used in vaccines has not been shown to cause harm, such use is being phased out, as it is from other medical products, in order to reduce all unnecessary exposures to mercury and to maintain public confidence in immunization programs. Alternatives to Thimerosal in Vaccines The issue of ensuring that vaccines are completely free from contamination is not trivial. Preservatives play an important role in vaccine safety, particularly in multi-dose vials. Vaccines in single-dose vials generally do not need a preservative provided they are produced under modern conditions of good manufacturing practices. However, single-dose vials are significantly more expensive and less convenient to use in large-scale immunization programs. Research is continuing globally to develop alternatives to thimerosal as a preservative. It is important that research into alternative preservatives and their suitability for vaccines as a replacement for thimerosal be supported. It is also important that these alternatives increase the safety profile of the vaccine by acting as an equally effective preservative while not interfering with efficacy or safety. Alternatives, such as phenoxyethanol, are available but are generally less effective than thimerosal. Recommendations As vaccines are so critically important to disease control programs in Canada, it is essential that the confidence of the public and health professionals in vaccines is firm. NACI reaffirms the importance of vaccines in disease prevention and the importance of vaccine safety. Although vaccines are among the safest of medical interventions, every measure should be taken to ensure that the safety of vaccine products is as high as technologically possible. Almost none of the vaccines recommended for universal use in infants in Canada contains thimerosal; one formulation of hepatitis B vaccine contains only trace amounts. Some vaccines that may be given to infants for specific preventive purposes, such as influenza vaccine for medically compromised infants, do contain added thimerosal. Although it is preferable to use thimerosal-free vaccines in infants, such vaccines should not be withheld if they are required to prevent serious illness. Furthermore, thimerosal-containing vaccines offered in other countries that are needed to prevent serious illness need not be refused because of this preservative. NACI makes the following specific recommendations on the use of thimerosal in vaccines:
Acknowledgements The authors and NACI gratefully acknowledge the contribution and assistance of Dr. Peter Vadas, Director of Allergy and Clinical Immunology, St. Michael's Hospital, and Dr. Eric Leith, President of the Canadian Society of Allergy and Clinical Immunology, in the writing of this paper, and Dr. Robert Pless for his review of the manuscript. References
Further Reading
* Members: Dr. V. Marchessault (Chairperson), Dr. A. King (Executive Secretary), J. Rendall (Administrative Secretary), Dr. I. Bowmer, Dr. G. De Serres, Dr. S. Dobson, Dr. J. Embree, Dr. I. Gemmill, Dr. J. Langley, Dr. A. McGeer, Dr. P. Orr, Dr. B. Tan, A. Zierler. Liaison Representatives: S. Callery (CHICA), Dr. J. Carsley (CPHA), Dr. M. Douville-Fradet (ACE), Dr. T. Freeman (CFPC), Dr. A. Gruslin (SOGC), Dr. V. Lentini (DND), Dr. R. Massé (CCMOH), Dr. A. McCarthy (CIDS), K. Pielak (CNCI), Dr. J. Salzman (CATMAT), Dr. L. Samson (CPS), Dr. D. Scheifele (CAIRE), Dr. M. Wharton (CDC). Ex-Officio Representatives: Dr. M. Dawar (FNIHB), Drs. H. Rode and A. Klein (BREC), Dr. T. Tam (CIDPC). † This statement was prepared by Dr. Ian Gemmill and approved by NACI.
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