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                Safety & Availability (Biologics)

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          Thimerosal and VaccinesSafety & Availability (Biologics) Thimerosal and Vaccines
  
  	
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    Print**Key Points**

All vaccines routinely recommended for children 6 years of age and younger in the U.S. are available in formulations that do not contain thimerosal.
	Vaccines that do not contain thimerosal as a preservative are also available for adolescents and adults.
	A robust body of peer-reviewed scientific studies conducted in the U.S. and other countries support the safety of thimerosal-containing vaccines.
	Preservatives prevent microbial growth.
	A preservative is required in multi-dose vials of vaccines.
	The use of thimerosal as a preservative in vaccines has markedly declined due to reformulation and development of new vaccines in single-use presentations.**Table of Contents**

Thimerosal as a Preservative
	Other Preservatives
	Rationale for Preservatives in Vaccines
	FDA Actions Pertaining to Thimerosal in Vaccines
	No Link between Thimerosal in Vaccines and Autism
	Current Status of Thimerosal in Vaccines
	Thimerosal Content of Available FDA-Approved Seasonal Influenza Vaccines
	References
	Bibliography - Notable Studies and Assessments Supporting the Safe Use of Thimerosal in Vaccines**Thimerosal as a Preservative**

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. The documented antimicrobial properties of thimerosal contribute to the safe use of vaccines in multi-dose vials, and the ability to package certain vaccines, such as those for seasonal and pandemic influenza, in multi-dose vials helps facilitate immunization campaigns in the United States and globally that save lives. However, the use of thimerosal as a preservative in U.S. FDA-licensed vaccines has significantly declined due to reformulation and development of new vaccines presented in single-dose containers.

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. Methylmercury is the type of mercury found in certain kinds of fish. At high exposure levels methylmercury can be toxic to people. In the United States, federal guidelines keep as much methylmercury as possible out of the environment and food, but over a lifetime, everyone is exposed to some methylmercury.

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. For comparison, this is roughly the same amount of elemental mercury contained in a 3 ounce can of tuna fish.

Prior to introduction of thimerosal 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 numerous studies (see Bibliography- Notable Studies and Assessments Supporting the Safe Use of Thimerosal in Vaccines) 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 due to the development of new products formulated into single-dose presentations that do not require preservatives, thimerosal has been used in some immune globulin preparations, anti-venins, skin test antigens, and ophthalmic and nasal products, in addition to some 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.

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**Other Preservatives**

Phenol is used in a variety of consumer products including mouthwashes, throat lozenges, and throat sprays.  It is also currently used as a preservative in three FDA-approved available vaccines, Pneumovax 23 (for prevention of pneumococcal disease caused by the 23 serotypes contained in the vaccine) and Typhim Vi (for prevention of typhoid fever) and ACAM2000 (for prevention of smallpox); each of these vaccines contains 0.25% phenol.  These vaccines are not recommended for routine use by the Centers for Disease Control and Prevention’s (CDC) Advisory Committee on Immunization Practices (ACIP).

2-Phenoxyethanol is an organic chemical compound that is sometimes used in cosmetics and antiseptics.  It is also currently used as a preservative in one FDA-approved available vaccine, Ipol, for the prevention of polio, at a concentration of 0.5%.

Benzethonium chloride is a chemical that has antimicrobial properties. It is used in over-the-counter hand and body washes.  This preservative is currently used in only one FDA-approved vaccine, BioThrax, for the prevention of disease caused by *Bacillus anthracis*.  BioThrax is not recommended for routine use by CDC’s ACIP.

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**Rationale for Preservatives in Vaccines**

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 with a needle. In some cases, preservatives are added during the manufacturing process to prevent microbial growth. However, improvements in manufacturing technology have markedly decreased the need to add preservatives during the manufacturing process.

The United States Code of Federal Regulations (the CFR) requires, in general, the addition of a preservative to multi-dose vials of vaccines; and, 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 an additional 21 children were injected. Of these children: eleven died on the 28th and one on the 29th. (Wilson 1967)

This incident 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.

The risk of contamination of vaccines cannot be completely eliminated even with the use of preservatives. 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.

It is important to note that the FDA does not license a particular preservative; rather, the FDA evaluates safety and effectiveness data for the vaccine containing the preservative and makes a determination whether to issue a license for the vaccine.

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**FDA Actions Pertaining to Thimerosal in Vaccines**

FDA has actively addressed the issue of thimerosal as a preservative in vaccines. The use of thimerosal as a preservative in U.S. FDA-licensed vaccines has significantly declined due to reformulation and development of new vaccines presented in single-dose containers. Under the FDA Modernization Act (FDAMA) of 1997, the FDA conducted a comprehensive review of the use of thimerosal in childhood vaccines. Conducted in 1999, this review found no evidence of harm from the use of thimerosal as a vaccine preservative, other than local hypersensitivity reactions (Ball et al. 2001).

As part of the FDAMA review, the FDA evaluated the amount of mercury an infant might receive in the form of ethylmercury from vaccines under the U.S. recommended childhood immunization schedule and compared these levels with existing guidelines for exposure to methylmercury, as there are no existing guidelines for ethylmercury, the metabolite of thimerosal. At the time of this review in 1999, the maximum cumulative exposure to mercury from vaccines in the recommended childhood immunization schedule was within acceptable limits for the methylmercury exposure guidelines set by FDA, the Agency for Toxic Substances and Disease Registry, and the World Health Organization. However, depending on the vaccine formulations used and the weight of the infant, some infants could have been exposed to cumulative levels of mercury during the first six months of life that exceeded Environmental Protection Agency (EPA) recommended guidelines for safe intake of methylmercury.

Other than allergic responses in some individuals, there was no known health risk from thimerosal-preservative at the concentration used in vaccines, but in 1999, the Public Health Service (including the FDA, National Institutes of Health (NIH), CDC, and Health Resources and Services Administration (HRSA)), along with the American Academy of Pediatrics (AAP) and the American Academy of Family Physicians (AAFP) concluded that because of scientific uncertainty at the time, as a precautionary measure, that it was prudent to reduce childhood exposure to mercury from all sources, including vaccines, as feasible. On July 1, 1999, the FDA sent a letter to all licensed manufacturers of vaccines requesting their plans to remove thimerosal from U.S. licensed vaccines. This step was taken because the elimination or reduction of mercury in vaccines was a feasible means of reducing an infant’s total exposure to mercury in a world where other environmental sources of mercury are challenging to eliminate.

Much progress has been made in removing or reducing thimerosal in vaccines. All vaccines routinely recommended for children 6 years of age and younger in the U.S. are available in formulations that do not contain thimerosal. In addition, vaccines that do not contain thimerosal as a preservative are available for adolescents and adults.

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**No Link between Thimerosal in Vaccines and Autism**

Although all vaccines routinely recommended for children 6 years of age and younger in the U.S. are available in formulations that do not contain thimerosal, thimerosal has a long record of safe and effective use in preventing bacterial and fungal contamination of vaccines, with no ill effects established other than hypersensitivity and minor local reactions at the site of injection.

There is a robust body of peer-reviewed, scientific studies conducted in the United States and countries around the world that support the safety of thimerosal-containing vaccines. The scientific evidence collected over the past 15 years does not show any evidence of harm, including serious neurodevelopmental disorders, from use of thimerosal in vaccines. Specifically, the Institute of Medicine (now known as the National Academy of Medicine), and others have concluded that the evidence favors rejection of a link between thimerosal and autism. Scientific studies of the risk of other serious neurodevelopmental disorders have failed to support a causal link with thimerosal. (see Bibliography- Notable Studies and Assessments Supporting the Safe Use of Thimerosal in Vaccines)

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**Current Status of Thimerosal in Vaccines**

The use of thimerosal as a preservative in U.S. FDA-licensed vaccines has significantly declined due to reformulation and development of new vaccines presented in single-dose containers.

All vaccines routinely recommended for children 6 years of age and younger in the U.S. are available in formulations that do not contain thimerosal.

As with pediatric vaccines, vaccines for adolescents and adults are available in formulations that do not contain thimerosal. (Note- one vaccine, Tetanus and Diphtheria Toxoids Adsorbed, single-dose presentation, manufactured by Mass Biologics utilizes thimerosal as part of its manufacturing process, not as a preservative, and a trace remains in the final presentation).

FDA-approved seasonal influenza vaccines are available in single-dose presentations that do not contain thimerosal as a preservative for use in infants, children, adults, the elderly and pregnant women. (Note- one vaccine, Fluvirin’s single-dose presentation utilizes thimerosal as part of its manufacturing process, not as a preservative, and a trace remains in the final presentation). Vaccines with trace amounts of thimerosal contain 1 microgram or less of mercury per dose.

The CDC’s ACIP does not preferentially recommend vaccines that do not contain thimerosal for any populations.

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**Thimerosal Content of Available FDA-Approved Seasonal Influenza Vaccines**

**Thimerosal Content of Available FDA-Approved Seasonal Influenza Vaccines**
	Vaccine
			Tradename
			(Manufacturer)
			Thimerosal Status Concentration**(Mercury)Trivalent Influenza Vaccine
			Afluria (multi-dose presentation)
			Seqirus Pty Ltd
			0.01% (24.5 mcg/0.5 mL dose)Afluria (single-dose presentation)
			Seqirus Pty Ltd
			NoneFluad (single-dose presentation)
			Seqirus Vaccines Ltd
			NoneFlublok (single dose presentation)
			Protein Sciences Corporation
			NoneFluvirin (multi-dose presentation)
			Seqirus Vaccines Ltd
			0.01% (25 mcg/0.5 mL dose)Fluvirin (single-dose presentation)
			Seqirus Vaccines Ltd
			Trace (<1 mcg/0.5mL dose) 1Fluzone High Dose (single-dose presentation)
			Sanofi Pasteur Inc.
			NoneQuadrivalent Influenza Vaccine
			Afluria Quadrivalent (multi-dose presentation)
			Seqirus Pty Ltd
			0.01% (24.5 mcg/0.5 mL dose)Afluria Quadrivalent (single-dose presentation)
			Seqirus Pty Ltd
			NoneFluarix Quadrivalent (single-dose presentation)
			GlaxoSmithKline Biologicals
			NoneFlublok Quadrivalent (single-dose presentation)
			Protein Sciences Corporation
			NoneFlucelvax Quadrivalent (single-dose presentation)
			Seqirus, Inc
			NoneFluLaval Quadrivalent (multi-dose presentation)
			vID Biomedical Corporation of Quebec
			0.01% (25 mcg/0.5 mL dose)2FluLaval Quadrivalent (single-dose presentation)
			Biomedical Corporation of Quebec
			NoneFluMist Quadrivalent (single-dose presentation)
			MedImmune LLC
			NoneFluzone Quadrivalent (multi-dose presentation)
			Sanofi Pasteur Inc.
			0.01% (12.5 mcg/0.25 mL dose, 25 mcg/0.5 mL dose)3Fluzone Quadrivalent (single-dose presentation)
			Sanofi Pasteur Inc.
			NoneFluzone Intradermal Quadrivalent (single-dose presentation)
			Sanofi Pasteur Inc.
			None

**Thimerosal is approximately 50% mercury (Hg) by weight. A 0.01% solution (1 part per 10,000) of thimerosal contains 50 μg (micrograms) of Hg per 1 mL dose or 25 μg of Hg per 0.5 mL dose.

1 The term "trace" has been taken in this context to mean 1 microgram of mercury per dose or less

2 Individuals 6 months of age and older receive a full-dose of vaccine, i.e., 0.5 mL

3 Children 6 months of age to less than 3 years of age receive a half-dose of vaccine, i.e., 0.25 mL; children 3 years of age and older receive 0.5 mL dose

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**References**

Title 21 of the Code of Federal Regulations, Part 610.15(a) [21 CFR 610.15(a)]

Ball LK, Ball R, Pratt RD. An assessment of thimerosal use in childhood vaccines. Pediatrics 2001;1147-1154.

Bernier RH, Frank JA, Nolan TF. Abscesses complicating DTP vaccination. Am J Dis Child 1981;135:826-828.

Federal Register. November 19, 1999;64:63323-63324.

Powell HM, Jamieson WA. Merthiolate as a Germicide. Am J Hyg 1931;13:296-310.

Simon PA, Chen RT, Elliot JA, Schwartz B. Outbreak of pyogenic abscesses after diphtheria and tetanus toxoids and pertussis vaccine. Pediatr Infect Dis J 1993;12:368-371.

U.S. Pharmacopeia 24, Rockville, MD: U.S. Pharmacopeial Convention; 2001.

Wilson GS. The Hazards of Immunization. New York, NY: The Athlone Press; 1967:75-84.

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**Bibliography**

**Notable Studies and Assessments Supporting the Safe Use of Thimerosal in Vaccines**

Agency for Toxic Substances and Disease Registry (ATSDR). Toxicological profile for mercury. Atlanta, GA: 1999.

American Academy of Pediatrics. Vaccine Safety: Examine the Evidence. April 2013

Ball LK, Ball R, Pratt RD. (2001) An assessment of thimerosal use in childhood vaccines.
Pediatrics 107(5):1147-54.

Barregard L, Rekic D, Horvat M, Elmberg L, Lundh T, Zachrisson O. 2011. Toxicokinetics of mercury after long-term repeated exposure to thimerosal-containing vaccine. Toxicol Sci 120(2):499-506.

Berman RF, Pessah IN, Mouton PR, Mav D, Harry J. (2008) Low-level neonatal thimerosal exposure: further evaluation of altered neurotoxic potential in SJL mice.
Toxicol Sci 101(2):294-309.

Blair, AMJN, Clark B, Clarke AJ, Wood P. (1975) Tissue concentrations of mercury after chronic dosing of squirrel monkeys with thiomersal. Toxicology 3(2):171-6.

Burbacher, TM, DD Shen, N Liberato, KS Grant, E Cernichiari, and T Clarkson. (2005)
Comparison of Blood and Brain Mercury Levels in Infant Monkeys Exposed to Methylmercury or Vaccines Containing Thimerosal. Environ Health Perspect 113(8):1015-21.

Christensen DL, Baio J, Van Naarden Braun K, et al. Prevalence and Characteristics of Autism Spectrum Disorder Among Children Aged 8 Years--Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2012. MMWR Surveill Summ 2016;65:1-23.

Clarkson TW. (2002) The three modern faces of mercury. Environ Health Perspect 110 Suppl 1:11-23.

Clarkson, TW, and L Magos. (2006) The Toxicology of Mercury and Its Chemical Compounds. Crit Rev Tox 36:609-62.

Fombonne, E., et al., (2006) Pervasive Developmental Disorders in Montreal, Quebec, Canada: Prevalence and Links With Immunizations. Pediatrics 118;e139-e150.

Hviid A, Stellfeld M, Wohlfahrt J, Melbye M. Association between thimerosal-containing vaccine and autism. JAMA. 2003;290:1763–6.

Hornig M, Chian D, Lipkin WI. (2004) Neurotoxic effects of postnatal thimerosal are mouse strain dependent. Mol Psychiatry 9(9):833-45.

IOM (Institute of Medicine). Immunization Safety Review: Vaccines and Autism. Washington, D.C.: National Academy Press: 2004 (Executive Summary, at 7).

Madsen KM, Hviid A, Vestergaard M, Schendel D, Wohlfahrt J, et al. A population-based study of measles, mumps, and rubella vaccination and autism. N Engl J Med. 2002;347 (19):1477–1482.

Magos, L, AW Brown, S Sparrow, E Bailey, RT Snowden, and WR Skipp. (1985)
The Comparative Toxicology of Ethyl- and Methylmercury. Arch Toxicol 57:260-7.

Magos L. (2001) Review on the toxicity of ethylmercury, including its presence as a preservative in biological and pharmaceutical products. J Appl Toxicol 21(1):1-5. Review on the toxicity of ethylmercury, including its presence as a preservative in biological and pharmaceutical products.

Mitkus RJ, King DB, Walderhaug MO, Forshee RA. A comparative pharmacokinetic estimate of mercury in U.S. Infants following yearly exposures to inactivated influenza vaccines containing thimerosal. Risk Anal 2014; 34:735.

Olczak M, Duszczyk M, Mierzejewski P, Wierzba-Bobrowicz T, Majewska MD (2010) Lasting neuropathological changes in rat brain after intermittent neonatal administration of thimerosal. Folia Neuropathol. 48(4): 258-69.

Pichichero, ME, E Cernichari, J Lopreiato, and J Treanor. (2002) Mercury Concentrations and Metabolism in Infants Receiving Vaccines Containing Thiomersal: A Descriptive Study. The Lancet 360:1737-41.

Pichichero ME, Gentile A, Giglio N, Umido V, Clarkson T, Cernichiari E, Zareba G, Gotelli C, Gotelli M, Yan L, and Treanor J. (2008) Mercury Levels in Newborns and Infants After Receipt of Thimerosal-Containing Vaccines. Pediatrics. 121(2):e208 14.

Pichichero ME, Gentile A, Giglio N, Alonso MM, Fernandez Mentaberri MV, Zareba G, Clarkson T, Gotelli C, Gotelli M, Yan L, Treanor J. (2009) Mercury levels in premature and low birth weight newborn infants after receipt of thimerosal-containing vaccines J Pediatr.; 155(4):495-9.

Price C. et al. (2010) Prenatal and Infant Exposure to Thimerosal from Vaccines and Immunoglobulins and Risk of Autism. Pediatrics. 126: 656-664.

Schechter, R., et al., (2008) Continuing Increases in Autism Reported to California’s Developmental Services System. Arch Gen Psychiatry. 65(1):19-24.

Thompson, WW., et al. (2007) Early thimerosal exposure and neuropsychological outcomes at 7 and 10 years. N. Engl. J. Med 2007. 357:1281-92.

Tryphonas L. and Nielsen NO. (1973) Pathology of Chronic Alkylmercurial Poisoning in Swine. Am J Vet Res. 34(3):379-92.

World Health Organization, Global Advisory Committee on Vaccine Safety. (2006). Statement on Thiomersal.

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                                                                                  Content current as of:
      02/01/2018
              
              
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