Limiting Infant Exposure to Thimerosal in
Vaccines and Other Sources of Mercury
A. Halsey, MD
In late June of this year, the Food and Drug
Administration (FDA) revealed that some infants who receive multiple doses
of vaccines containing thimerosal could be exposed to total amounts of
mercury that exceed some federal guidelines.1
Thimerosal is a mercury-containing preservative used in some Haemophilus
influenzae type b (Hib), diphtheria and tetanus toxoids with acellular
pertussis (DTaP), hepatitis B, influenza, and other vaccines.2
Federal agencies, the American Academy of Pediatrics (AAP), international
agencies, and vaccine manufacturers have responded quickly to address the
5 However, more can be done to maintain public
confidence in vaccines and to reduce childhood exposures to mercury from all
Some confusion has occurred because of uncertainty regarding the
applicability of guidelines for long-term exposures to methylmercury from
environmental sources to intermittent exposures to ethylmercury, a breakdown
product from thimerosal. Based on the limited data available, experts have
concluded that the toxicity of ethylmercury may be similar to methylmercury.
Guidelines for limiting exposure to methylmercury in foods (primarily fish)
are based on the assumption that exposure will continue over long periods of
time. The long half-life of methylmercury (average, 50 days) results in
accumulation that could be harmful to the developing fetal brain, which is
much more susceptible to organomercurial compounds than the adult brain.2
The doses thought to be able to be consumed on a daily basis without harm
vary among agencies: 0.1 µg/kg per day for the Environmental Protection
Agency (EPA),6 0.3 µg/kg per
day for the Agency for Toxic Substances Disease Registry,7
and 0.4 µg/kg per day for the FDA.8
The World Health Organization provides a provisional tolerable weekly intake
of 3.3 µg/kg for the general population, but the dose for pregnant women and
infants would be smaller.9
The EPA estimates that 7% of women of childbearing age in the United States
consume 0.1 µg/kg per day or more of mercury from fish harvested in high
risk areas, and 1% of women consume 0.37 µg/kg per day or more.6
Mercury accumulated in these women is transferred to their children
prenatally and in breast milk; subsequent exposures to organomercurials from
other sources, including biologic products, are presumed to be additive to
their baseline body loads.
Exposure to ethylmercury from vaccines containing thimerosal in the first
6 months of life ranges from 0 to 187 µg based on which vaccines are
administered.2 Since many vaccines do not
contain thimerosal, most children receive less than the total amount of
mercury indicated in the guidelines during the first 6 months of life. If
all thimerosal-containing vaccines are given, the total exposures exceed the
EPA guidelines, and possibly other guidelines, for the smallest infants.
There are safety or uncertainty factors (10-fold for the EPA) built into the
guidelines, and experts believe there is no evidence of harm from exposure
to thimerosal in vaccines.1, 2
However, clinicians are uncertain as to how much mercury can be safely given
at 1 time when multiple thimerosal-containing vaccines are administered
Data from 2 recent studies examining the relationship between
methylmercury exposure and neuropsychological outcome in children suggest
that intermittent large exposures may pose more risk than small daily doses.
Faeroese children at age 7 years who had been exposed in utero to
intermittent bolus doses of methylmercury were found to have subtle
neurologic impairments based on domain-specific neuropsychological testing.10
The total exposures during pregnancy were in the range that was not
associated with impairments by global IQ testing in Seychelloises children
aged 5.5 years who had been exposed to smaller daily doses.11
The investigators from the 2 studies disagree over what exposures are safe,
but a review by a panel of independent scientists found no major
methodological problems in either of the studies.12-14
Differences in testing methods and age at evaluation might explain some of
the differences; follow-up studies will provide more information. The
controversy resembles that in studies of lead toxicity where sequential
studies over many years provided evidence for subtle effects with
progressively lower exposures and resulted in increasingly lower acceptable
limits of exposure.15
Additional studies are being planned to evaluate the possible effects of
mercury exposure from vaccines.
The FDA sent a letter to vaccine manufacturers on July 1, 1999,
requesting plans to remove thimerosal from vaccines or justify the continued
use of this preservative.1 The AAP and the US
Public Health Service issued a statement on July 7 calling for elimination
or reduction of thimerosal in vaccines for children and recommending
deferral of the first dose of hepatitis B vaccine for infants born to
hepatitis B virus surface antigen (HBsAg) negative women until age 2 to 6
months.1 A parallel review of these issues in
Europe resulted in the European Agency for the Evaluation of Medicinal
Products issuing a statement on July 8 promoting the use of vaccines without
thimerosal for infants and toddlers within the shortest possible time frame.3
The AAP issued a more detailed statement on July 144
that provided physicians with the mercury content in vaccines, background
information on mercury toxicity, advice for reducing mercury exposures from
all sources, and specific guidelines for the use of hepatitis B vaccines.
The AAP also urged the FDA and manufacturers to rapidly reduce the mercury
content of vaccines.2 In a remarkably short
time, the FDA approved a request from Merck on August 27 to market a
thimerosal-free hepatitis B vaccine for use in infants. SmithKline Beecham
also has submitted a request for approval of products with little or no
thimerosal.5 The Centers for Disease Control
and Prevention (CDC) and the AAP have strongly encouraged physicians to
resume neonatal hepatitis B vaccination of infants born to HBsAg negative
women with products that have reduced or no thimerosal.2,
Some clinicians apparently were confused by the rapid changes in
hepatitis B guidelines. Infants born to women who are HBsAg positive or
whose hepatitis status is unknown should be vaccinated at birth regardless
of the availability of thimerosal-free vaccines because the high risk of
acquiring hepatitis B infection and increased likelihood of becoming a
carrier far outweigh theoretical concerns about the amount of mercury in a
single dose of this vaccine.1-5 The CDC has
emphasized the need for immunization of all newborns in populations at
increased risk for hepatitis B infections from contacts early in life.5
Most countries have initiated programs to administer hepatitis B
immunization at birth or in the first few weeks of life because this is the
optimal strategy for preventing hepatitis B transmission.16,
17 Immunization at birth provides early and
long-term protection of neonates against infection by HBsAg positive mothers
who were missed by screening programs and HBsAg carriers among families,
friends, and other contacts.18
In this issue of THE JOURNAL, Lauderdale and colleagues19
present evidence that neonatal hepatitis B vaccination may have additional
benefits. They found that children given the first dose of vaccine in the
first month of life, presumably mostly at birth, were more likely to
complete the 3-dose series and to receive their first dose of DTaP vaccine
at age 2 months than children who began hepatitis B immunization at an older
age. Since the availability of hepatitis B vaccine in nurseries is a
hospital decision, the data suggest that the birth dose helps influence
parents to complete the series and seek other vaccines on time. Prospective
controlled studies are needed to determine if early immunization truly
increases on-time immunization at older ages or if this is a result of
enrollment in a more proactive health care program.
Are preservatives like thimerosal necessary in vaccines? The FDA
regulations require preservatives in multidose vials of most vaccines (with
the exception of certain live viral vaccines) to protect against inadvertent
contamination from repeated puncture of the seal.20
Thimerosal does not prevent all bacterial contamination, as evidenced by
clusters of disease from group A streptococcus infections traced to
multidose diphtheria toxoid, tetanus toxoid, and pertussis (DTP) vaccine
vials that were contaminated after opening.21
The use of single-dose vials or prefilled syringes for vaccines should be
encouraged because this eliminates errors in preparation as well as the need
for preservatives for most vaccines. Thimerosal is used during production of
some vaccines and in many cases can be removed leaving trace amounts (<0.3
µg) of mercury that have no biologic effect.22
Such products should be considered equivalent to thimerosal-free products.
Alternative preservatives are one option for multidose vials, especially in
developing countries where the need to keep costs low is an essential
component of the success of the World Health Organization's Expanded Program
on Immunization. The use of new combination products will reduce exposure to
preservatives by decreasing the number of injections needed to deliver
How should physicians deal with the uncertainties during the transition
to the elimination or reduction of thimerosal in vaccines? On October 20,
1999, the Advisory Committee on Imunization Practices of the CDC decided not
to give a general preference for thimerosal-free vaccines for administration
to infants. The CDC and AAP have indicated that hepatitis B vaccines
containing no or trace amounts of thimerosal should be preferentially used
for infants during the first 6 months of life. I believe that this
preference should be extended to Hib and DTaP vaccines for infants
(especially premature infants) whenever possible. The list of mercury
content in vaccines is kept up-to-date on the Institute for Vaccine Safety
Web site (http://www.vaccinesafety.edu)
to assist physicians in vaccine choices. If supplies are limited, exposure
to no more than 1 thimerosal-containing vaccine at each visit would reduce
exposures while ensuring that infants are fully protected against diseases,
including influenza in high-risk infants. Elimination of thimerosal or other
preservatives will be more difficult for influenza vaccines produced in eggs
because a preservative helps ensure protection against contamination. The
small amount of thimerosal in influenza vaccines does not constitute an
undue risk for older children and adults, especially for high-risk
individuals in whom complications from influenza constitute a major health
The AAP encourages parents to follow local fish advisories to reduce
children's exposure to mercury.2 Since mercury
exposures from other sources may be additive, special care should be taken
not to administer additional mercury from vaccines to small infants in
populations in which pregnant women may consume more than the maximum
recommended amounts of mercury. Thimerosal has been eliminated from latex
paints, and merthiolate, a concentrated form of thimerosal used as an
antiseptic, is no longer used because of serious toxic effects from these
products in infants.23
Congress deserves credit for mandating the review of thimerosal in
biological products, but needs to ensure that the agencies responsible for
vaccine safety have the resources and freedom from undue regulation to allow
them to carry out their mandates. The FDA needs highly qualified scientists
and resources to address the increasingly complex scientific issues involved
in vaccine production. Therefore, health care professionals should be
concerned that the research budget for the Center for Biologics and
Evaluation Research has been reduced to one third the level that it was in
1994.24 Availability of the
safest vaccines now and in the future requires support for scientists
working at federal agencies responsible for vaccine safety. In late June and
early July, when decisions needed to be made rapidly, officials from the CDC
could not officially consult with the Advisory Committee on Immunization
Practices because statutes prevent such meetings without posting a notice in
the Federal Register.25
Exceptions should be made to allow the CDC and other agencies to address
The public has become intolerant of unnecessary exposure to real and
theoretical risks for children from all sources as evidenced by demands to
make food products, toys, seat belts, and air bags as safe as possible.26
Reducing or eliminating exposure to mercury from all sources, including
industrial contamination of waterways that leads to accumulation of mercury
in fish, should be a national priority.27
Further reductions or elimination of mercury in vaccines will help maintain
public confidence by demonstrating a commitment to provide the safest
vaccines possible for protecting children against disease.
Author Affiliation: Institute for Vaccine Safety, Johns Hopkins
School of Hygiene and Public Health, Baltimore, Md.
Corresponding Author and Reprints: Neal A. Halsey, MD, Division of
Disease Control, Johns Hopkins School of Hygiene and Public Health, 615 N
Wolfe St, Baltimore, MD 21205 (e-mail:
Editorials represent the opinions of the authors and THE JOURNAL and not
those of the American Medical Association.
Acknowledgment: I am grateful to Leslie Ball and Robert Ball for
comments and technical support.
Financial Disclosure: The Institute for Vaccine Safety has
received research grant support from the Food and Drug Administration, the
World Health Organization, and SmithKline Beecham; educational grant support
from Merck & Co, SmithKline Beecham, North American Vaccine, and Pasteur
Mérieux Connaught. Dr Halsey has received honoraria for a manuscript on
hepatitis B vaccine from Ross Products Division, Abbott Laboratories Inc,
Abbott Park, Ill.
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