Immunization, Vaccines and Biologicals

Thiomersal - questions and answers

October 2011

What is the impact of mercury on health ?

Mercury is considered by WHO as one of the top 10 chemicals or groups of chemicals of major public health concern. Exposure to mercury, even in fairly small amounts, may cause serious health problems, and is a particular threat to the development of the child in utero and early in life. Mercury may have toxic effects on the nervous, digestive and immune systems, and on lungs, kidneys, skin and eyes. Individuals are mainly exposed to methylmercury, an organic compound, when they eat fish and shellfish that contain methylmercury. Mercury releases in the environment result mainly from human activity, particularly from coal-fired power stations, residential heating systems, waste incinerators and as a result of mining for mercury, gold and other metals.

What is thiomersal ?

Thiomersal is a compound containing ethyl mercury used to prevent bacterial and fungal growth in inactivated (in which the virus has been killed) vaccines presented in multi-dose vials. It is also used during vaccine production, both to inactivate certain organisms and toxins and to help maintain a sterile production line. Thiomersal has been used since the 1930s in the manufacture of some vaccines and other medicinal products. The manufacture of thiomersal is a very minor component (<0.1%) of the main sources of human exposure to mercury.

Why do vaccines need preservatives ?

Preservatives inhibit growth of bacterial and fungal contaminants, which may be introduced during repeated use of a multi-dose vial. Multi-dose vials are used in many countries because they require less storage space in the cold chain and lead to less wastage, both of which have a significant impact on programme costs. While a preservative is needed only for multi-dose presentations, a manufacturer will usually make one bulk formulation, so if the product has both multi-dose and single-dose presentations, the-single dose presentation would contain the same preservative. In many countries, for inactivated vaccines supplied in multi-dose vials, the presence of a preservative is a regulatory requirement.

Which vaccines contain thiomersal ?

Vaccines that contain thiomersal include those against diphtheria, tetanus and pertussis (DTP), hepatitis B, Haemophilus influenzae type b (Hib), rabies, influenza and meningococcal diseases. Usually, these vaccines have thiomersal added in varying concentrations (8 to 50 µg per dose) as a preservative. Also, some vaccines may contain trace amounts of thiomersal (<0.5 µg per dose) if it has been used in the production process as an inactivating agent, but has not been added to the final product as a preservative.

Thiomersal-containing vaccines are used widely across the world. A number of products containing thiomersal have been prequalified by WHO (i.e. they have been assessed by WHO as meeting international standards for assured quality, safety and efficacy) and are being supplied by United Nations procurement agencies. During 2010, UNICEF and the Pan American Health Organization Revolving Fund supplied 325 million doses of thiomersal-containing vaccines for routine vaccination activities and response to outbreaks of infectious diseases such as influenza or epidemic meningitis.

Which vaccines do not contain thiomersal ?

Live vaccines, such as oral poliovirus vaccine; yellow fever vaccine; and measles, mumps and rubella vaccines, do not contain thiomersal, because it would kill the immunizing component. In inactivated vaccines, when only single-dose presentations are available from a particular manufacturer, there is no thiomersal component in sufficient concentration required to prevent contamination of a vial because those presentations are not meant to be reused.

Does the amount of thiomersal in vaccines pose a health risk ?

WHO has closely monitored scientific evidence relating to the use of thiomersal as a vaccine preservative for over 10 years, in particular through its independent expert advisory group, the Global Advisory Committee on Vaccine Safety. The Committee has consistently reached the same conclusion: there is no evidence to suggest that the amount of thiomersal used in vaccines poses a health risk. Other expert groups (the U.S. Institute of Medicine, the American Academy of Pediatrics, the United Kingdom Committee on Safety of Medicines, and the European Agency for the Evaluation of Medicinal Products), have reached similar conclusions.

Why are the United States of America and other industrialized countries avoiding use of thiomersal in vaccines if there is no proven safety risk ?

The USA does use thiomersal-containing vaccines. During the 2010-2011 influenza season, more than 90 million doses of thiomersal-containing influenza vaccine in multi-dose vials were distributed for the vaccination of American citizens. Intensive safety studies showed that these vaccines were safe and effective. Other industrialized countries also used thiomersal-containing pandemic influenza vaccines.

The concerns that were raised in 1999 in the USA regarding exposure to mercury following immunization with thiomersal-containing vaccines were based on the calculation that the cumulative amount of mercury in infant immunization schedules potentially exceeded the recommended threshold for methyl mercury set by a U.S. government agency. At the time the concerns were raised, there was scientific uncertainty over the issue and the regulator (the United States Food and Drug Administration), taking a precautionary approach, requested manufacturers to consider development of thiomersal-free products for routine immunization. However, thiomersal contains ethyl mercury, not methyl mercury, and ethyl and methyl mercury are quite different. Studies have subsequently shown that withdrawal of thiomersal-containing vaccines had no effect on conditions, such as autism, which had been linked by some advocates to use of thiomersal-containing vaccines.

Can you provide more information on the studies reviewed by the Global Advisory Committee on Vaccine Safety ?

Since August 2000, the WHO Global Advisory Committee on Vaccine Safety (GACVS), responsible for advising WHO on vaccine safety issues of potential global importance, has periodically reviewed available information on thiomersal pharmacokinetic studies in humans (including low birth-weight infants) and in monkeys and has assessed the validity of animal models in studying associations between thiomersal and neuro-developmental disorders (such as autism) in humans.

Expert consultation and data presented to GACVS indicate that the pharmacokinetic profile of ethyl mercury is substantially different to that of methyl mercury. In particular, the half-life of ethyl mercury is short (6 days; 95% CI: 3-10 days) compared with 40-50 days for methyl mercury, making exposure to ethyl mercury in blood comparatively brief and preventing accumulation when vaccines are administered at least four weeks apart. Further, ethyl mercury is actively excreted via the gut, unlike methyl mercury, which accumulates in the body. This rapid elimination of ethyl mercury has been confirmed in all studies reviewed, even those that looked at low birth-weight infants.

Four independent epidemiological studies investigating associations and frequency of neuro-developmental disorders in relation to vaccination with thiomersal-containing vaccines from the United Kingdom and Denmark did not challenge the safety of existing thiomersal-containing vaccines in infants.

GACVS also reviewed a series of studies by Geier and Geier alleging reduction of neuro-developmental disorders in the USA following discontinuation of thiomersal-containing vaccines in the national immunization programme. The Committee found a number of methodological limitations, such that published outcomes regarding neurodevelopment and heart disease following administration of thiomersal-containing vaccines do not meet the scientific criteria required to suggest a causal relationship. The Committee therefore found the conclusions made by these authors both unconvincing and unsubstantiated.

On that basis the GACVS considers that pharmacokinetic and developmental studies undertaken do not support concerns over the safety of thiomersal in vaccines.

The Committee has concluded that there is no reason on grounds of safety to change current immunization practices with thiomersal-containing vaccines, as the alleged risks are unproven.

What would be the public health impact of restricting manufacture, distribution or use of thiomersal-containing vaccines ?

Immunization with thiomersal-containing multi-dose vaccines currently protects at least 64% of all infants and children against four diseases with high mortality rates: diphtheria, tetanus, pertussis and Haemophilus influenzae type b. It is estimated that use of thiomersal-containing vaccines to protect against these diseases averted at least 1 400 000 child deaths in 2010. Thiomersal-containing vaccines are being used in over 120 countries. Removing thiomersal completely from vaccines would require either using alternative preservatives or using preservative-free single-dose vaccines exclusively. Alternative presentations (with other preservatives, or preservative-free) would incur significant costs for development and regulatory approval, thereby limiting the ability to offer affordable vaccines.

Use of multi-dose vials is the most efficient and cost-effective presentation for protection of populations in instances when vaccines need to be administered to large numbers of people in a short space of time, such as in epidemic or pandemic situations.

Are there alternative preservatives that could be used for vaccines ?

Yes, there are two approved for use. 2-phenoxyethanol (used for inactivated polio vaccine) and phenol (used for typhoid vaccine). A few studies have been done to compare the effectiveness of the different preservatives but the data is limited and inconclusive. Extrapolation from a few examples that an alternative preservative can be used for all vaccines is speculation. Practically, any vaccine presentation for which another preservative is to be used for the first time will require new clinical evaluation to test for safety and efficacy.

Is there research ongoing to evaluate the relative effectiveness of alternative preservatives to thiomersal ?

WHO does not have a research programme for evaluating alternatives to the use of thiomersal in vaccines, given the lack of scientific evidence suggesting that there is a need to do so. Vaccine manufacturers have conducted research into alternative preservatives but, except for research on inactivated polio vaccine and a pneumococcal conjugate vaccine, there has been a conspicuous lack of success.

Could supplying vaccines in single-dose vials only be an option ?

Vaccines could be supplied in preservative-free single-dose vials as is the case for the majority of vaccines used in industrialized countries. However, this option requires a significant increase in manufacturers' filling capacity. This would be time consuming and expensive to implement and it may not be possible to produce sufficient single-dose product to ensure uninterrupted global supply.

There is also the vaccine cost element: vaccines supplied in single-dose vials are more expensive than a dose of vaccine from a multi-dose vial.

In addition, single-dose vials require significantly larger cold storage space as well as increased transport capacity, which is currently not feasible for the majority of countries. Current WHO estimates suggest that the vaccine storage requirements would at least double if only single-dose presentations were used (WHO vaccine volume calculator, March 2011). Upgrading the cold chains of those countries is limited by local resources and the additional maintenance requirements that would render many existing systems vulnerable.

Replacing thiomersal in vaccines would require regulatory approval. There is no guarantee of obtaining a vaccine of equivalent quality, safety and efficacy following replacement of thiomersal as an inactivating agent or replacement or removal of thiomersal as the preservative from an existing licensed product. This would require a new licensing application, including conducting of new manufacturing validation studies; and pre-clinical and clinical studies. Such processes take time and money, could lead to an increase in vaccine cost and could interrupt global supply of the vaccines, thereby leading to increased disease and death from vaccine-preventable diseases.

Could supplying vaccines in multi-dose vials without a preservative be an option ?

No, this is not an option because it would be dangerous. Bacterial and fungal contaminants, which may be introduced during repeated use of a multi-dose vial, would have an opportunity to grow in the partially-used vials. This is why the presence of a preservative is a regulatory requirement.

What would be the environmental impact of switching to single-dose vials only ?

The environmental cost of replacing all multi-dose vials with single-dose vials must be taken into consideration. Such a switch would involve more raw materials, more energy for manufacturing processes and transport, and more waste. Although a formal environmental impact assessment has not yet been done, it should not be assumed that thiomersal-free presentations of vaccines will yield a positive net effect on the environment.

Why is thiomersal in vaccines considered safe by WHO whereas mercury in some cosmetics is considered unsafe ?

Mercury in cosmetics exists in two forms: inorganic and organic mercury. The form of mercury used in skin lightening soaps and creams is inorganic mercury. Many countries have banned mercury skin lightening products because they are hazardous to human health. Organic mercury compounds (thiomersal (ethyl mercury) and phenyl mercuric salts) are used as cosmetic preservatives in eye makeup cleansing products and mascara. As with vaccines that contain thiomersal, safe limits have been defined for organic mercury compounds in these products.

What is WHO's position on the use of thiomersal in vaccines ?

WHO supports continued use of thiomersal as an inactivating agent and preservative for vaccines.

The reasons for this position are as follows:

  • regular review by WHO's Global Advisory Committee on Vaccine Safety of new studies relating to the safety of thiomersal in vaccines over more than a decade has not provided any evidence to suggest a possible health hazard with the amounts of thiomersal currently used in vaccines; and
  • the use of multi-dose vials remains the best option for routine immunization programmes in many countries because they are safe and effective, they limit the required storage capacity and waste, and help reduce vaccine costs.

What is WHO's role in the process of the Intergovernmental Negotiating Committee to prepare a global legally binding instrument on mercury (INC) ?

WHO participates in the treaty process as an observer. As well as being present at the INC sessions, the Organization can provide submissions, technical briefings, and contributions to Secretariat meeting documents.

What is the overall goal of the treaty ?

The overall goal of the treaty is to protect human health and the environment by reducing mercury releases.

What is WHO's position on thiomersal-containing vaccines, as they pertain to the treaty ?

WHO supports continued use of thiomersal as an inactivating agent and preservative for vaccines. In this context, WHO is concerned about the potential inclusion of vaccines in the scope of the treaty given the lack of evidence that thiomersal presents a risk to human health.