www.phac-aspc.gc.ca/publicat/ccdr-rmtc/07vol33/acs-06/index-eng.phpCanada Communicable Disease Report
Volume 33 • ACS-6
1 July 2007
An Advisory Committee Statement (ACS)
National Advisory Committee on Immunization (NACI)†,††
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13 Pages - 680 KB PDF
Preamble
The National Advisory Committee on Immunization (NACI) provides the Public Health Agency of Canada with ongoing and timely medical, scientific and public health advice relating to immunization. The Public Health Agency of Canada acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and is disseminating this document for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph(s). Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) of the Canadian manufacturer(s) of the vaccine(s). Manufacturer(s) have sought approval of the vaccine(s) and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of the Public Health Agency of Canada's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.
Introduction
In 2003 the National Advisory Committee on Immunization (NACI) published recommendations on the use of vaccines approved for use in Canada that contained the mercury-based preservative thimerosal, so that practitioners would have the necessary information to make sound recommendations for vaccine administration to patients and vaccine manufacturers would have guidance on the future development of vaccines for the Canadian market(1). The statement also made recommendations on the management of patients who needed vaccine(s) containing thimerosal but who had reported previous hypersensitivity to this constituent.
With the availability of additional evidence on the safety of thimerosal as a preservative in vaccines, NACI published a brief statement updating its recommendations in December 2005(2) in conjunction with the annual influenza vaccine campaign, promising to follow up with a completely revised statement. This document should be considered a replacement of both the 2003 and 2005 statements, with new evidence added as appropriate and content from both that is still considered current retained.
Background
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 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 ethylmercury (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 (µg), one millionth of a gram. When a person is immunized with a vaccine that contains thimerosal, the resultant concentration of metabolized ethylmercury 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, methylmercury, and a nephrotoxin in its inorganic form, consisting of salts containing mercury combined with chlorine, sulfur or oxygen(3). Almost all research into mercury toxicity has been conducted on methylmercury because it has been a major environmental contaminant, especially in the pulp and paper industry. The main concern in Canada has been methylmercury 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.
By contrast, little is actually known about ethylmercury 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 ethylmercury metabolized from thimerosal is rapidly excreted in the stool. The risk, at best, can be described as theoretical. Although the numbers were small, one study(4) suggested that the serum half-life of ethylmercury in infants given thimerosal-containing vaccines was shorter than that suggested by work with methylmercury and did not seem to raise the blood concentrations of mercury above acceptable values. A more recent study(5) used infant monkeys to compare, in a limited way, the pharmacokinetic profiles of ethylmercury following exposure to thimerosal-containing vaccines and methylmercury following administration by nasogastric feeding tube. There were 17 animals in each group, and exposures were repeated at 0, 7, 14 and 21 days of age. The absorption and initial distribution of the two mercury compounds were similar. However, in comparison to methylmercury, ethylmercury was eliminated faster (half-life of 8.6 days versus 21.5 days for methylmercury), did not accumulate between doses, unlike methylmercury, and resulted in lower total brain mercury levels. The firmest conclusion to be drawn from these pharmacokinetic studies is that methylmercury and ethylmercury are handled very differently in the body and that safety limits regarding methylmercury cannot simply be extrapolated to ethylmercury.
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 no studies have documented any associated adverse effects beyond the hypersensitivity reactions noted in the next section.
Removing thimerosal from vaccines available in single-dose vials is a relatively easy measure to reduce exposure to mercury, however small, as compared with reducing dietary and environmental exposures. NACI continues to endorse the long-term goal of removing thimerosal from vaccines when there are safe alternatives to establish sterility in multi-dose vials, since this is one achievable way to reduce total environmental exposure to mercury.
Hypersensitivity reactions
Low-dose exposure to thimerosal has been associated with hypersensitivity reactions(6). Thimerosal was previously present in various eye preparations and contact lens solutions and has been proven to cause delayed hypersensitivity reactions resulting in conjunctivitis and eyelid dermatitis. Thimerosal is also used as a preservative in vaccines, antitoxins, parenteral medications and preparation of antigens for allergy tests. 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.
Delayed hypersensitivity to thimerosal is usually diagnosed with patch testing. Up to 16% to 18% of patients undergoing routine patch testing are identified as being reactive to thimerosal. However, the significance of this positivity is unknown in the absence of clinical reactivity. Positive patch tests are generally poor predictors of the likelihood of reaction to thimerosal-containing vaccines. Most individuals with demonstrable delayed hypersensitivity to thimerosal tolerate thimerosal-containing vaccines with no untoward reaction, although some individuals may experience either a large local reaction, a delayed generalized dermatitis reaction that can be long lasting or exacerbation of an existing skin disease, such as atopic dermatitis.
Immediate hypersensitivity, including anaphylaxis and immune-complex-mediated disorders, has been reported with some products that contain thimerosal, but it is uncertain whether thimerosal was the responsible agent. Anaphylaxis has not been proven to occur as a result of thimerosal in vaccines and thus remains a theoretical risk.
If an individual is suspected of being hypersensitive to thimerosal, the nature of the hypersensitivity reaction must be characterized before a vaccine containing thimerosal is administered. If there is no proven history of hypersensitivity, vaccination can proceed without particular precaution. If there is a definite history of anaphylaxis to thimerosal, vaccines containing this component should not be given. Although such reactions have never been reported, prior history of erythema multiforme, Stevens-Johnson syndrome or toxic epidermal necrolysis from thimerosal exposure would be an absolute contraindication to future exposure. In cases of proven delayed hypersensitivity to thimerosal, vaccination can proceed but the patient should be advised that long-lasting local or systemic cutaneous reactions can occur.
Thimerosal as a preservative
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. Single-dose vials of vaccines need not contain preservative if sterilization is effective. However, multiple entries into multi-dose vials to retrieve vaccine can result in bacterial or fungal contamination if proper technique is not strictly followed. Before the routine addition of preservative to multi-dose vials used for immunization purposes, microbial contamination was shown to result in a variety of conditions, from local abscesses to septicemia. In 1928, during a diphtheria immunization campaign, staphylococcal contamination of a multidose vial led to the septic deaths of 12 of 42 immunized children(7). Tragic events such as this led to the introduction of preservatives in general, and thimerosal specifically, to prevent microbial infection, thereby enhancing the safety profile of vaccines.
Millions of vaccines containing preservatives such as thimerosal have been administered since the 1930s, and there have been no common adverse effects observed. 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.
Thimerosal Content of Vaccines Used in Canada
Vaccines approved for use in Canada may contain the following:
* no thimerosal: these are single-dose preparations in which thimerosal has not been used in any part of the manufacturing process;
* trace amounts of thimerosal (< 1.0 µg/dose) if the preservative has been used in the production process but not added to serve a preservative function in the final product;
* 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. The amount of mercury per dose varies from 2 to 50 µg per 0.5 mL dose.
Table 1 identifies vaccines currently approved for use in Canada in terms of thimerosal content. Most of the listed vaccines containing thimerosal as a preservative are not widely used, either because they have been replaced by newer vaccines or have very specialized use (e.g. DT adsorbed). Some, such as influenza vaccines, are used in provincial/territorial immunization programs. A more detailed table of vaccine contents is published in the 2006 Canadian Immunization Guide(8), and updates will be posted, as appropriate, at <www.naci.gc.ca>. These would include any changes to the preservative content of vaccines listed in Table 1 as well as changes in vaccines approved for use in Canada after this statement has been published.
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*A more detailed and, as appropriate, updated table of vaccine contents, including preservatives such as thimerosal, can be found at <www.naci.gc.ca>.
Before 1999 several different vaccines containing thimerosal as a preservative were used in routine infant immunization programs in the United States (US). It was calculated that a 6-month-old infant immunized in the US before 1999 may have received a cumulative dose of ethylmercury as high as 187.5 µg. For infants with a low body weight (particularly premature infants) the total dosage administered as part of routine immunization began to approach or marginally exceed the total recommended mercury exposure guideline of the US Environmental Protection Agency (Table 2) but not that of the World Health Organization or the US Food and Drug Administration. As discussed further in the next section, a theoretical concern was raised that the levels of mercury could be high enough to cause neurologic damage, and thus the American Academy of Pediatrics and the US Public Health Service issued a joint statement in July 1999 recommending that thimerosal be removed from vaccines as soon as possible(9).
Table 2. Guidelines on the maximum allowable daily limits* for methyl** mercury intake in infants < 7 months
Date issued
Agency/department
TDI of Hg (μg)/kg body weight† daily
Suggested cumulative limit of Hg (μg)
1997
EPA-USA‡
0.10
81
1999
ATSDR-USA‡
0.30
242
1999
FDA-USA‡
0.48
387
1998
Health Canada¶
(Foods Directorate)
0.20
162
TDI: tolerable daily intake; EPA: Environmental Protection Agency, USA; FDA: Food and Drug Agency, USA; ATSDR: Agency for Toxic Substances and Disease Registry, USA
* Based on TDI estimates: «The daily intake of a substance from all sources during a person's entire lifetime which appears to be without appreciable risk to health on the basis of all known facts»(10)
** These maximum allowable limits are based on exposure to methyl mercury, a related organomercurial.There are no established guidelines for ethyl mercury.
†Assume average of 5th percentile for body weight at each month of age for girls: 3.84 kg.
‡Based on USA and WHO TDI standards/guidelines(11)
¶Based on proposed Canadian TDI standards
Vaccine-related exposure to thimerosal and neurodevelopment disorders
The theoretical concerns regarding an association between thimerosal exposure and subsequent development of autism or other neurologic disorders led to a review of the available evidence by the Immunization Safety Review Committee of the US Institute of Medicine (IOM) in 2001, which was repeated in 2004 as new evidence became available. The October 2001 report(12) concluded that "the evidence is inadequate to accept or reject a causal relationship between thimerosal exposures from childhood vaccines and neurodevelopmental disorders." It went on to state that "the hypothesis that thimerosal exposure through the recommended childhood immunization schedule [in the US] has caused neurodevelopmental disorders is not supported by clinical or experimental evidence." It also suggested that biologic plausibility, though possible, was at best indirect. Despite the absence of definite evidence of risk, the Committee still concluded that the prudent approach was to seek alternatives to thimerosal for use in vaccines and to remove thimerosal-containing vaccines from use in the US.
In 2004 the IOM reconvened to consider newly published evidence bearing on the proposed association between thimerosal-containing vaccines and autism(13). This included epidemiologic studies from several countries (Denmark(14), Great Britain(15,16), Sweden(17) and the US(18)) using cohort and/or ecologic designs, as well as studies using passive surveillance data from the US Vaccine Adverse Events Reporting System. For those interested in further details, the report provides tabular summaries of all studies reviewed and a discussion in the text of key findings as well as the methodologic strengths and weaknesses of the different study designs. With these added data the Committee was able to conclude that "the evidence favors rejection of a causal relationship between thimerosal containing vaccines and autism." The IOM added that since "all well designed epidemiological studies provide evidence of no association between thimerosal and autism, the Committee recommends that risk-benefit assessments regarding the use of thimerosal-containing versus thimerosal-free vaccines and other biological or pharmaceutical products, whether in the United States or other countries, should not include autism as a potential risk."
Since the 2004 IOM report additional publications have underscored the lack of association between thimerosal and neurodevelopmental disorders(15,16,19,20).
Detailed studies involving multiple developmental analyses of school-aged children exposed to ethylmercury as part of US immunization programs before 1999 are under way, and publication of results is expected in 2007. A commentary on the theoretical association between thimerosal and autism was published in 2003 by two pediatric neurologists(21). This report clearly points out that the profile of neuroanatomic pathology and of clinical signs and symptoms associated with autism is different in many key aspects from that associated with mercury toxicity.
Canadian data from Quebec supporting the lack of association between thimerosal and pervasive developmental disorders (PDD) were recently published(19). A total of 180 children with PDD were identified out of 27,749 children attending 55 schools in the province's largest anglophone school board from 1987 through 1998. This translated to an overall prevalence of 64.9 cases per 10,000 children, which is similar to the rate observed in the US and other countries where there has been concern about a rising occurrence of autism. The study analyzed the association between possible thimerosal exposure through routine childhood immunization and the PDD prevalence using annual school enrolments as a birth cohort proxy. From 1987 through 1998 the maximal possible exposure to ethylmercury from vaccines recommended during the first 2 years of life initially rose and then plummeted as follows: 100 µg in 1987 (DPT, 2, 4, 6 and 18 months); 125 µg from1988 to1991 (Hib vaccine added at 18 months); 200 µg from 1992 to1995 (Hib added at 2, 4, 6 and 18 months); and 0 µg from 1996 to 1998 (DTaP-IPV-Hib substituted for all previous vaccines). During the same interval the PDD prevalence increased from 45.7 (1987) to 107.8 (1998) cases per 10,000 children. There was no correlation between ethylmercury exposure from immunization and the rising prevalence of PDD, the first increase in PDD occurring in 1991 with continued increases in 1997 and 1998 despite complete removal of thimerosal from routinely administered vaccines. The prevalence of PDD per 10,000 children in the thimerosal-exposed cohort (1987-1995) was 59.5 cases (95% confidence interval [CI] 49.6-70.8) and in the thimerosal-free cohort (1996-1998) was 82.7 (95% CI 62.0-108.0). The higher PDD prevalence observed in the thimerosal-free cohort was statistically significant (odds ratio [OR] 1.39; 95% CI 1.01-1.92).
To address the criticism of lack of individual-level immunization data, the authors repeated the analysis on the subgroup of 158 children (87.8% of total) with PDD who were born in Quebec. The results were essentially the same, in that the PDD prevalence was significantly higher in the thimerosal-free cohort (74.9 cases; 95% CI 55.3-99.1) than the thimerosal-exposed cohort (51.6 cases; 95% CI 42.6-62.1) with an OR of 1.46 (95% CI 1.04-2.05). The study concluded that the PDD prevalence in Montreal is high, similar to that found in most other countries, and that there is no association between PDD and thimerosal (i.e. ethylmercury) exposure. Although not relevant to this discussion, the study also concluded that there was no association between one or two doses of MMR and PDD. As has been suggested by many others, the authors considered that the factors most likely responsible for the increasing prevalence of PDD were a combination of broadened diagnostic criteria, increased awareness of and thus a greater likelihood of PDD being diagnosed and greater availability of school-based services to meet the special needs of children with PDD.
In summary, the weight of evidence to date clearly refutes an association between thimerosal and neurodevelopmental disorders.
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 such as the annual influenza immunization campaign.
Research is continuing globally to develop alternatives to thimerosal as a preservative. It is important that research into alternative preservatives as a replacement for thimerosal and their suitability for vaccines be supported. It is also important that these alternatives increase the perceived 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.
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Recommendations
Currently, in Canada, some multi-dose preparations of influenza or hepatitis B vaccines are the only thimerosal-containing products that might be offered to children as part of the routine childhood immunization schedule. Thimerosal-free influenza and hepatitis B vaccines have also become available in recent years. Having reviewed all the available evidence NACI reaffirms its recommendations:
* There is no legitimate safety reason to avoid the use of thimerosal-containing products for children or older individuals, including pregnant women.
* A previous episode of anaphylaxis attributed to thimerosal is an absolute contraindication to the use of thimerosal-containing vaccines. While at least one such event has been described, the link to thimerosal was not proven. Prior history of erythema multiforme, Stevens-Johnson syndrome or toxic epidermal necrolysis from thimerosal exposure would also be an absolute contraindication to future exposure. Thimerosal has never been reported to cause such reactions.
* If there is a documented history of a delayed hypersensitivity reaction to thimerosal (as manifest by a large local reaction or an eczematous rash) or a positive patch test reaction to thimerosal, immunization with thimerosal-containing vaccines can proceed, but individuals should be advised that long-lasting local or systemic cutaneous reactions can occur. They should report any reaction of concern following immunization so that it can be managed appropriately.
* The long-term goal of removing thimerosal from vaccines, provided there are safe alternatives to ensure that multi-dose vials are sterile, still applies, since this is one achievable way to reduce total environmental exposure to mercury.
Conclusion
Public confidence in vaccines and high rates of vaccine uptake are critical to the continued effectiveness of immunization programs. Even when risks are purely theoretical, experience has shown that unaddressed public concerns can drastically decrease immunization coverage, to the detriment of public health. Thus the call to remove thimerosal from vaccines seeks to maintain public confidence by avoiding even theoretical risk.
NACI makes recommendations based on the best available scientific evidence. Vaccine safety is an essential consideration in any recommendation made by NACI. Concerns regarding thimerosal, as reviewed in the 2003 statement, were purely theoretical. Nevertheless, NACI identified them as important issues for further consideration and study. The weight of evidence now available, however, refutes any link between thimerosal and autism. Therefore, NACI concludes that there is no reason for vaccine providers or other health care professionals who may counsel individuals regarding immunization to raise any concerns about exposure to thimerosal.
References
1.
The National Advisory Committee on Immunization. Statement on Thimerosal. Canada Communicable Disease Report 2003;29(ACS-1):1-10.
2.
The National Advisory Committee on Immunization. Updated Recommendations of the Use of Thimerosal-containing Vaccines in Canada. Canada Communicable Disease Report 2005;31(ACS-12):1-4.
3.
Pichichero ME, Cernichiari E, Lopreiato J., Treanor J, Mercury concentrations and metabolism in infants receiving vaccines containing thimerosal: a descriptive study. Lancet 2002;360 (9347):1737-41.
4.
Burbacher TM, Shen DD, Liberaton, et al. Comparison of Blood and Brain Mercury Levels in Infant Monkeys Exposed to methylmercury or Vaccines Containing Thimerosal. Environ Health Perspect 2005;113:1015-21.
5.
Cox NH, Forsyth A. Thimerosal allergy and vaccination reactions. Contact Dermatitis 1988;18:229-33.
6.
Wilson G. The hazards of immunization. London: Athone Press, 1967.
7.
The National Advisory Committee on Immunization. Canadian Immunization Guide, 7th ed. Ottawa: Public Health Agency of Canada; 2006.
8.
CDC. Thimerosal in vaccines: a joint statement of the American Academy of Pediatrics and the Public Health Service. MMWR 1999;48:563-5.
9.
Ontario Ministry of Health. Health and environment: a handbook for health professionals. Toronto: 1995.
10.
Ball LK, Ball R, Pratt RD. An assessment of thimerosal use in childhood vaccines. Pediatrics 2001;107:1147-54.
11.
Institute of Medicine. Immunization safety review: thimerosal-containing vaccines and neurodevelopmental disorders. 2001. National Academy Press.
12.
Institute of Medicine. Immunization Safety Review: Vaccines and Autism. 2004. National Academy Press.
13.
Madsen KM, Lauritsen MB, Pedersen CB. Thimerosal and the occurence of autism: negative ecological evidence from Danish population-based data. Pediatrics 2003;112:604-6.
14.
Andrews N, Miller E, Grant A, Stowe, et al. Thimerosal exposure in infants and development disorders: a retrospective cohort study in the United Kingdom does not support a causal association. Pediactrics 2004;114:584-91.
15.
Heron J, Golding J and the Alspac Study Team. Thimerosal exposure in infants and developmental disorders: A prospective cohort study in the United Kingdom does not support a causal association. Pediatrics 2004;114:577-83.
16.
Stehr-Green P, Tull P, Stellfeld M, et al. Autism and thimerosal-containing vaccines: lack of consistent evidence for an association. American Journal of Preventative Medicine 2003;25:101-6.
17.
Verstraeten T, Davis RL, DeStefano F, et al. Safety of Thimerosal-Containing Vaccines: A two-phased study of computerized health maintenance organization databases. Pediatrics 2003;112: 1039-48.
18.
Fombonne E, Zakarian R, Bennett A, et al. Pervasive developmental disorders in Montreal, Quebec Canada: Prevalence and Links with Immunizations. Pediatrics 2006;118:139-50.
19.
Parker SK, Schwartz B, Todd J, Pickering LK. Thimerosal-containing vaccines and autistic spectrum disorder: A critical review of published original data. Pediatrics 2004;114:793-804.
20.
Agency for Toxic Substances and Disease Registry. ToxFAQsTM :Chemical Agents Briefing Sheets (CABS) Mercury. 2006.
www.atsdr.cdc.gov/toxfaq.html 21.
Nelson KB, Bauman ML. Thimerosal and autism? Pediatrics 2003;111:674-9.
†Members: Dr. J. Langley (Chairperson), Dr. S. Deeks (Executive Secretary), Dr. K. Laupland, Dr. S. Dobson, Dr. B. Duval, Ms. A. Hanrahan, Dr. A. McGeer, Dr. S. McNeil, Dr. M-N Primeau, Dr. B. Tan, Dr. B. Warshawsky.
Liaison Representatives: Ms. S. Callery (CHICA), Dr. P. Hudson (CPHA), Dr. B. Bell (CDC), Dr. D. Money (SOGC), Ms. E. Holmes (CNCI), Dr. B. Larke (CCMOH), Dr. P. Orr (AMMI Canada) Dr. M. Salvadori (CPS), Dr. S. Rechner (CFPC), Dr. J. Salzman (CATMAT), Dr. D. Scheifele (CAIRE).
Ex-Officio Representatives: Dr. H. Rode (BGTD), Dr. M. Lem (FNIHB), Lt. Col. J.W. Anderson (DND), Dr. B. Law (IRID).
††This statement was prepared by Dr. Barbara Law and Dr. Marie-Noël Primeau, and approved by NACI and the Public Health Agency of Canada.
[Canada Communicable Disease Report]
