March 2008

NIAID Research on Thimerosal

OVERVIEW

Mercury is a naturally occurring chemical element found throughout the environment. Mercury is found in three forms: as a pure metal (as found in thermometers), as inorganic salts, and as an organic derivative. Humans and wildlife are exposed to all three forms. Most environmental mercury consists of the metallic and inorganic forms. Because mercury is everywhere, it is not possible to prevent all exposure to it. High levels of mercury, however, are toxic.

Methyl mercury, the most common organic derivative of mercury, is mainly produced by microorganisms in water and soil. Methyl mercury is of particular concern because it can accumulate in certain edible freshwater and saltwater fish, especially in larger and older fish, to levels that are much greater than levels in the surrounding water. Methyl mercury also can accumulate in humans who eat these fish. Exposure to high levels of methyl mercury is toxic and can cause mental retardation, cerebral palsy, and seizures. The fetus is especially sensitive to methyl mercury exposure and may suffer brain damage or even death if exposed to high levels.

Since the 1930s, thimerosal has been added to some vaccines and other products because it is effective in killing bacteria and in preventing bacterial contamination, particularly in multidose containers. When thimerosal is degraded or metabolized, one product is ethyl mercury, another organic derivative of mercury. Not much is known about the effects of thimerosal exposure on humans and how this compares to methyl mercury exposure. The only known side effects of receiving low doses of thimerosal in vaccines have been minor reactions such as redness and swelling at the injection site.

In July 1999, U.S. Department of Health and Human Service agencies, The American Academy of Pediatrics, and vaccine manufacturers agreed that thimerosal should be reduced or eliminated in vaccines as a precautionary measure and to reduce exposure to mercury from all sources. Today, all routinely recommended licensed pediatric vaccines currently being manufactured for the U.S. market are either thimerosal-free or contain markedly reduced amounts of thimerosal. Thimerosal, however, remains in some vaccines given to adults and adolescents, as well as some pediatric vaccines not on the Recommended Childhood and Adolescent Immunization Schedule. Thimerosal is still a common preservative found in vaccines used outside the United States.

The decision to move toward reduced or eliminated thimerosal in vaccines was based on the various Federal guidelines for methyl mercury exposure and the assumption that the health risks from methyl and ethyl mercury were the same. Methyl mercury exposure is primarily through fish consumption. People who regularly eat mercury-contaminated fish can accumulate methyl mercury in their body over time. Some of this methyl mercury may be passed from the mother to the fetus before birth and to infants through breast milk. The fetus is sensitive to damage from this exposure.

Prior to the removal of thimerosal from childhood recommended vaccines, infants were exposed to ethyl mercury by intramuscular injection during vaccination, not by ingestion. Furthermore, infants received thimerosal from childhood vaccines that were administered days or months apart. In contrast, methyl mercury exposure, primarily from foods, tends to occur over a longer sustained period of time. More research is needed to determine if the guidelines for methyl mercury exposure are also appropriate guidelines for thimerosal. Additionally, guidelines for maximal levels for short-term exposure need to be established.

The National Institute of Allergy and Infectious Diseases (NIAID) funds thimerosal research that focuses on better understanding what happens to thimerosal once it is introduced in the body and how this compares to current knowledge of methyl mercury pathways. NIAID-sponsored researchers from the University of Rochester in New York (one of NIAID's Vaccine Treatment and Evaluation Units) performed assessments of mercury levels in infants receiving routine immunizations. In addition, NIAID and the National Institute of Environmental Health Sciences (NIEHS) funded studies comparing the pharmacokinetics and tissue distribution of thimerosal and methyl mercury in non-human primates.

ASSESSMENT OF MERCURY LEVELS IN INFANTS RECEIVING ROUTINE IMMUNIZATIONS

NIAID-supported studies at the University of Rochester and the National Naval Medical Center in Bethesda, Maryland, assessed levels of mercury in the blood, hair, urine, and stool of 40 infants who received vaccines containing thimerosal and 21 infants who received vaccines without thimerosal, as controls. The infants studied were 6 months of age or younger. This study generated several important results.

• Mercury levels in blood and urine were low in all infants studied and, in many cases, too small to measure. There was no observed dose-dependent relationship between the level of thimerosal received through vaccination and the level of mercury in the body.
• Mercury levels in blood did not exceed, at any time, the blood levels that correspond to Environmental Protection Agency guidelines for exposure.
• Mercury levels in the stool of infants receiving vaccines containing thimerosal were relatively high compared to mercury levels in the stool of infants who were not exposed to thimerosal, providing evidence that mercury from thimerosal is eliminated in the stool of infants.

The results were published in the November 30, 2002, issue of the The Lancet.
Reference: Pichichero ME, Cernichiari E, Lopreiato J, and Treanor J. Mercury concentrations and metabolism in infants receiving vaccines containing thimerosal: a descriptive study. Lancet 360:1737-1741 (2002).

For more information see www.niaid.nih.gov/factsheets/thimerosalqa.htm.

NIAID conducted a follow-up of the Rochester study in Argentina with 216 newborns and infants. The purpose of this study was to

• Measure blood levels of mercury in infants receiving thimerosal-containing vaccines as part of their routine care
• Determine the excretion of mercury in feces
• Expand the time points for sampling in a larger group of infants

Preliminary results confirmed findings of the first study done at the University of Rochester.

• Blood mercury levels did not show accumulation between vaccinations in children; the levels drop to pre-vaccination levels within 30 days.
• Excretion of mercury in stools followed vaccination with thimerosal-containing vaccines.

These results were published in the February 2008 issue of Pediatrics. Reference: Pichichero ME, Gentile A, Giglio N, Umido V, Clarkson T, Cernichiari E, Zareba G, Gotelli C, Gotelli M, Yan L, Treanor J. Mercury levels in newborns and infants after receipt of thimerosal-containing vaccines. Pediatrics 121(2):e208-214 (2008).

NIAID is also conducting an additional study in Argentina that focuses on premature (32 to 37 weeks gestational age) and low birth weight (2000 to <3000 grams) infants. Enrollment for this study is now complete.

PHARMACOKINETICS AND TISSUE DISTRIBUTION OF THIMEROSAL, ETHYL MERCURY, AND METHYL MERCURY IN ANIMALS

NIAID and NIEHS cosponsored studies in adolescent and infant monkeys to compare the pharmacokinetics and tissue distribution of thimerosal and methyl mercury. One group of animals in this study received a dose of thimerosal and a dose of thimerosal-free infant vaccines by injection weekly beginning at birth and continuing for 3 weeks. The vaccines were included in the study to mimic infant exposure as closely as possible. A second group of animals received methyl mercury orally on a weekly basis beginning at birth and continuing for 3 weeks. Blood levels of mercury were determined for each animal after each of the four exposures. After the fourth dose, animal tissues were analyzed to determine levels of mercury in target tissues, such as brain and kidney. Assays to determine mercury levels measure inorganic vs. organic mercury but do not distinguish whether the organic mercury is in the form of ethyl mercury from thimerosal or methyl mercury.

Results from these studies indicate

• Mercury, in the form of methyl mercury (oral ingestion) and thimerosal (intramuscular injection with vaccines) were both readily absorbed and distributed into blood and brain.
• Total (organic plus inorganic) mercury was cleared from both blood and brain faster after thimerosal exposure than after methyl mercury exposure.
• Levels of total mercury measured in blood and in brain were lower after thimerosal exposure than after methyl mercury exposure.
• The proportion of brain mercury that was inorganic was higher in animals exposed to thimerosal compared with methyl mercury.
• The absolute amount of inorganic mercury was higher in thimerosal exposed animals compared with methyl mercury.
• During weekly doses of methyl mercury, total mercury in blood continued to accumulate, while during weekly doses of thimerosal, there was little accumulation of total mercury in blood.

This study indicates that methyl mercury is not a suitable reference for risk assessment from exposure to thimerosal. This study was not designed to measure any type of damage due to mercury exposure. The mechanisms by which organic mercury is converted to inorganic mercury in the brain are unknown. There is not a consensus as to whether inorganic mercury in brain causes damage or to what extent compared to organic mercury.

These results were recently published in. Environmental Health Perspectives, Volume 113, Number 8, August 2005.

Comparison of Mercury Exposures

MORE INFORMATION

National Institute of Allergy and Infectious Diseases
Division of Microbiology and Infectious Diseases

U.S. Department of Health and Human Services
National Vaccine Program Office
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Washington, DC 20201
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Centers for Disease Control and Prevention
National Immunization Program
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Atlanta, GA 30333
1-800-CDC-INFO (1-800-232-4636)

Food and Drug Administration
Center for Biologics Evaluation and Research
CBER Ombudsman (HFM-4)
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Rockville, MD 20852-1448
1-800-835-4709 or 301-827-1800

Health Resources and Services Administration
National Vaccine Injury Compensation Program
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Rockville, MD 20857
1-800-338-2382

NIAID is a component of the National Institutes of Health. NIAID supports basic and applied research to prevent, diagnose and treat infectious diseases such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis, malaria and illness from potential agents of bioterrorism. NIAID also supports research on transplantation and immune-related illnesses, including autoimmune disorders, asthma and allergies.

The National Institutes of Health (NIH)-The Nation's Medical Research Agency-includes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

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