Thiomersal-containing vaccines - a review of the current state of knowledge

Abstract

Thiomersal is an organomercury compound known for its antiseptic and antifungal properties and used as an antibacterial agent in pharmaceutical products, including vaccines and other injectable biological products. In recent years, concerns about the possible link between immunization with thiomersal-containing vaccines and autism development have grown. Many case-control and cohort studies have been conducted on a number of populations, and none of them have confirmed the hypothetical relation between thiomersal and increased risk of autism spectrum disorders (ASDs) development. It is also confirmed by the fact, that since 1999, number of thiomersal-containing vaccines used worldwide is decreasing year by year, while the prevalence of ASDs cases is rising. There are no contraindications to the use of vaccines with thiomersal in infants, children and non-pregnant women. The risk of serious complications associated with the development of diseases in unvaccinated individuals far outweighs the potential risk of adverse consequences associated with immunization with thiomersal-containing vaccines.

Full text

PRZEGL EPIDEMIOL 2015; 69: 59 - 64 Vaccines and vaccinations
© National Institute of Public Health – National Institute of Hygiene
Aleksandra Gołoś, Anna Lutyńska
THIOMERSAL-CONTAINING VACCINES
– A REVIEW OF THE CURRENT STATE OF KNOWLEDGE
Department of Sera and Vaccines Evaluation
National Institute of Public Health -National Institute of Hygiene in Warsaw
ABSTRACT
Thiomersal is an organomercury compound known for its antiseptic and antifungal properties and used as
an antibacterial agent in pharmaceutical products, including vaccines and other injectable biological products.
In recent years, concerns about the possible link between immunization with thiomersal-containing vaccines
and autism development have grown. Many case-control and cohort studies have been conducted on a number of
populations, and none of them have confirmed the hypothetical relation between thiomersal and increased risk
of autism spectrum disorders (ASDs) development. It is also confirmed by the fact, that since 1999, number of
thiomersal-containing vaccines used worldwide is decreasing year by year, while the prevalence of ASDs cases
is rising.
There are no contraindications to the use of vaccines with thiomersal in infants, children and non-pregnant
women. The risk of serious complications associated with the development of diseases in unvaccinated indi-
viduals far outweighs the potential risk of adverse consequences associated with immunization with thiomersal-
containing vaccines.
Key words: inactivated vaccines, thiomersal, mercury, autism
INTRODUCTION
Thiomersal, commonly known also as thimerosal or
Merthiolate (Eli Lilly and Company trade mark name)
is an organomercury compound providing antiseptic
and antifungal properties. Widely proven antimicrobial
activity of thiomersal resulted in its marketing in a
range of pharmaceutical products, including vaccines
and other injectable biological products since 1930s (1).
This pharmaceutical compound containing 49.55% of
mercury has been proven in effective clearing a broad
spectrum of pathogens in pharmaceutical products
in concentrations ranging from 0,001% to 0,01%. If
presents in vaccines recommended for children, its
concentration varies from 0,005% to 0,01% (12,5 μg
Hg to 25 μg Hg per 0,5 ml dose) (2). Thiomersal and
other organo-mercurial compounds are not used in
live vaccines due to their negative interactions on the
active substance. However in inactivated vaccines
they might be added during some of production steps,
such as harvest or formulation of final bulk, or their
residual content in the final formulation comes from
preservation of some production stages eg. inactivation
of some antigens (i.e. whole cell or acellular pertussis
vaccines) (1, 3).
In late-1990s the U.S. Food and Drug Administra-
tion after deep research issued a statement, pointing out
that infants during the first six months of life immunized
according to the U.S. recommended schedule might
receive, depending on the vaccine formulation used and
the infant weight, such amounts of ethylmercury that
exceed limits approved by Environmental Protection
Agency for exposure to methylmercury (0,0001 mg/
kg-day) (4). As a precautionary recommendation, the
American Academy of Pediatric and the Public Health
Service issued also a joint statement in 1999 calling for
removal of mercury-containing preservatives from all
vaccines administered to infants and children as soon
as possible and advised to conduct the study aimed to
investigate the potential risks associated with ethylmer-
cury exposure from thiomersal-containing vaccines (5).
These recommendations have raised however general
concerns, even if the potential harmful effects of vac-
cines with thiomersal have not been confirmed (1, 6).

Aleksandra Gołoś, Anna Lutyńska
60 No 1
TOXICITY OF MERCURY
The toxicity of mercury is complex and depends on
the form, route of entry, dosage and age of the person at
exposure. Mercury might occur in three forms: the me-
tallic element, inorganic salts and organic compounds
(i.e. methylmercury, ethylmercury and phenylmercury).
According to the chemical nomenclature given by Inter-
national Union of Pure and Applied Chemistry (IUPAC)
thiomersal is an ethyl(2-mercaptobenzoato-(2-)-O,S)
mercurate(1-) sodium metabolized to ethyl form of
mercury and thiosalicylate. The association between
possibility of causing autism by thiomersal-containing
vaccines has been raised mainly by public media in
recent years. It has been originated from biological
plausibility of ethylmercury with methylmercury, where
initial data published on methylmercury showed some
potential risk of toxic effects resulting from its adsorp-
tion and accumulation in brain (7). This controversial
data raised further suspicions of induction of adverse
effect risk in children who were exposed to methyl-
mercury at levels previously considered as safe (7). It
should be remembered that in 1999 the toxicological
profile of ethylmercury was unknown and expected to
resemble at observed for methylmercury (8). Since then
a lot of scientific evidence has been gathered proving
that ethylmercury (metabolite of thiomersal) has not
been associated with such consequences as caused by
methylmercury due to its shorter half-life in the human
body and differences in pharmacodynamic and phar-
macokinetic properties (9, 10, 11). The main difference
between ethyl- and methylmercury relates to active
excretion of ethylmercury into the gut (8). The thresh-
olds for neurologic effects due to methylmercury and
ethylmercury were estimated to be approx. 200 mcg/L
and from 1000 to 2000 mcg/L respectively (12). Re-
search aimed to measure concentrations of mercury
in blood, urine and stool of infants aged 2-6 months
who received vaccines containing thiomersal clearly
indicated that administration of thiomersal-containing
vaccines does not raise blood concentrations of mer-
cury above widely accepted safe values. Elimination
of ethylmercury from blood via the stool was found
quite effective, with estimated blood half-life ranging
from 4 to 10 days (13). Nevertheless, lack of the data
on the possibilities of blood-brain barrier crossing by
ethylmercury raise public doubt (8).
There are a few reports available on the neuro- and
nephro-toxicity caused by accidental poisoning of
ethylmercury, however induced with doses of several
times exceeding the lethal dose in rats (LD50: 60 mg/
kg) – thus significantly and enormously higher than
those presented in vaccines in use (14).
Up to now, there is no proven evidence that thi-
omersal may cause any potential harm except an aller-
gic responses e.g. delayed-type local hypersensitivity
reactions such as redness and swelling at the injection
site, mainly regarded as mild and lasting only for a few
days. Sensitization to this compound was estimated in an
about 1-5% of vaccinated adolescents and adults (1, 2).
In the scope of the current knowledge and available
data published, general attention should be rather paid
into its positive effects i.e. reducing the risk of contami-
nation of opened multi-dose vaccines rather than into
unproven negative effects of thiomersal (8).
SAFETY OF THIOMERSAL-CONTAINING
VACCINES
Over the past several years much concern has
been raised regarding the potential links of childhood
vaccination with the development of autism or autism
spectrum disorders (ASD) (6). Autism classified as a
pervasive developmental disorder (PDD) is character-
ized by impaired social interaction and verbal/non-
verbal communication (15). Although a causation of
autism is still unknown, its genetics and environmental
factors might hypothetically be involved (9, 11). The
available data suggesting, that genetic variation in
neuronal circuitry might affect synaptic development,
further imply that pathogenesis of autism has rather
nothing in common with exaggerated or inappropriate
immune response to vaccination (15).
Thiomersal containing vaccines, especially diphthe-
ria, tetanus and whole-cell pertussis vaccines, frequently
blamed as one of possible environmental source of
mercury, are constantly receiving widespread critical
media interest (6, 9, 11). It should be stressed out, that
theoretical association between vaccination and autism
is getting far form the truth consequently, as the number
of thiomersal-containing vaccines used worldwide is
decreasing year by year, while the prevalence of ASDs
cases is rising (15). Such observation was found in re-
search conducted in Denmark where number of autism
cases did not decrease even after the discontinuation
of thiomersal use in vaccines administered to children
between mid-1980s and late-1990s (16).
In the meantime, several case-control and cohort
studies have been conducted on a very numerous popu-
lations and none of them supported a causal relationship
between the use of thiomersal-containing vaccines in
children and development of autistic spectrum disorders
or found higher risk of autism (10, 16 - 21). Moreover,
according to the available data, a vaccine dose-response
association with autism was also not confirmed. One
of the US case-control study, using immunization reg-
istries, medical charts and parents interviews of 246
children with spectrum disorders of autism, compared
with 752 controls organized in 3 medical centers pub-

Thiomersal-containing vaccines 61No 1
lished in 2010 did not find an increased risk of ASDs
in children vaccinated with thiomersal-containing vac-
cines (19). Other study performed in a large population
of children delivered in 1991-1992 in United Kingdom
also did not revealed any link between thiomersal and
neurological or psychological disorders and finally
proved no autism risk in children younger than 6 months
vaccinated with thiomersal-containing vaccines (17).
From the other side, it was found that the risk associ-
ated with the use of contaminated multidose vials in the
absence of thiomersal far outweigh any other potential
risks. Subsequently, dozens of studies published from
countries around the world, did not confirm the pos-
sibility of any linkage between vaccines containing
thiomersal and neurodevelopmental disorders (22).
Recently published meta-analysis of case-control and
cohort studies on potential autism rates and childhood
vaccination from various countries, showed also no
evidence of any risk of development of autism or autis-
tic spectrum disorders after administration of vaccines
containing thiomersal (6).
Despite the above arguments, media discussion,
doubting thiomersal safety and supporting again a link
between vaccinations and autism, began to appear in
March 2014. This attention was resulted from looking
up upon the results on the negative effects of thiomersal-
containing vaccines on children, conducted in the nine-
ties by the Center for Disease Control and Prevention
(CDC) epidemiologist Dr. Thomas Verstraeten. These
results presented on the conference of Epidemic Intel-
ligence Service (EIS), when reassessed once again in
detail, were found lacking many interfering factors
(bias), influencing the final analysis result. Many had
forgotten that in 2003 improved and in-depth analysis
of this controversial study confirming no relationship
between thiomersal in vaccines and the incidence of
autism in children was finally published in “Pediatrics”
(21). Moreover, the revaluation of T. Verstraeten study
by an independent commission from Emory University
finally resulted in official statement of Dr Verstraeten,
rejecting his initial thesis as not supported (21, 23, 24).
All together, scientific data coming from analyses
performed by different study groups were expressed
in a position paper of the expert panel of Institute of
Medicine of The National Academies (23). In Immuni-
zation Safety Review: Vaccines and Autism, the above
mentioned Committee concluded: “The committee
also concludes that the body of epidemiological evi-
dence favors rejection of a causal relationship between
thiomersal-containing vaccines and autism. The com-
mittee further finds that potential biological mechanisms
for vaccine-induced autism that have been generated
to date are theoretical only. The committee does not
recommend a policy review of the current schedule and
recommendations for the administration of either the
MMR vaccine or thiomersal-containing vaccines.” (25).
The position papers on safety of vaccines con-
taining thiomersal were also sequentially released by
other international agencies and competent authorities
including:
- A statement of the European Agency for the
Evaluation of Medicinal Products (now European
Medicines Agency) published on 24 March 2004
on thiomersal in vaccines for human use based on
latest evidence relating to the safety of thiomersal-
containing vaccines. The Committee for Proprietary
Medicinal Products (CPMP) concluded that the latest
epidemiological studies show no negative associa-
tion between the vaccination with thiomersal-con-
taining vaccines and autism. Possibility of develop-
ment of specific neurodevelopmental disorders and
the benefits of vaccination to the general population,
including infants, far outweigh the risk, if any, of
exposure to vaccines with thiomersal. Additionally
CPMP stated that in order to reduce exposure to
mercury, the development of vaccines containing
the lowest possible level or no thiomersal or other
mercury containing preservatives should continue
to be promoted (26).
- The statement of the Global Advisory Committee
on Vaccine Safety (GACVS) – an expert clinical
and scientific advisory body established by WHO
in 2012 proclaimed, that based on current evidence
and published studies it is confirmed that half-life
of ethyl mercury in blood is between 3 and 7 days.
Thus levels on ethyl mercury attained in the blood
and brain from cumulative doses of vaccines do not
reach toxic levels and available evidence strongly
supports the safety of the use of thiomersal as a
preservative for vaccines administered to infants
and children (27).
In order to determine the rules for identifying
thiomersal content in medicinal products, in January
2007, the Committee for Medicinal Products for Hu-
man Use (CHMP) presented the necessity of updating
of warning statement regarding the Summary of Product
Characteristic (SPC) and Package Leaflet (PL), with
regard to possible sensitization for medicinal products
containing thiomersal. For vaccines in which thiomersal
was used as a preservative, SPC was claimed to include
the following information: In Section 4.8. Undesirable
Effects: “This medicinal product contains thiomersal
(an organomercuric compound) as a preservative and
therefore, it is possible that sensitization reactions may
occur (see Section 4.3.).” and in Section 4.3. Contra-
indications: “Hypersensitivity to any compound of the
medicinal product”. In PL the CHMP recommendations
were expressed by following statements: “This medici-
nal product contains thiomersal as a preservative and

Aleksandra Gołoś, Anna Lutyńska
62 No 1
it is possible that <you/your child> may experience an
allergic reaction.” and “Tell your doctor if <you/your
child> have/has any known allergies.”.
For vaccines in which thiomersal was used dur-
ing the manufacturing process, resulting in levels of
thiomersal in the vaccine content below 40 nanograms
per dose or undetectable levels, sensitization reactions
to this compound are not expected to occur and no state-
ments are recommended for SPC and PL. If residue of
thiomersal used in the manufacturing process is greater
than or equal to 40 nanograms per dose, the following
information should be included in SPC: in Section
4.4 Special warnings and special precautions for use:
“Thiomersal (an organomercuric compound) has been
used in the manufacturing process of this medicinal
product and residues of it are present in the final prod-
uct. Therefore, sensitization reactions may occur.” and
in PL: “Thiomersal is present (in trace amounts) in this
product, and it is possible that <you/your child> may
experience an allergic reaction.” and “Tell your doctor if
<you/your child> have/has any known allergies.” (28).
All vaccines with thiomersal available on Polish market
should be identified and described in accordance with
the above guidelines.
THIOMERSAL-CONTAINING VACCINES
AVAILABLE IN POLAND
Currently in Poland whole-cell vaccine against
pertussis, diphtheria and tetanus (DTP; IBSiS BIOMED
S.A.) is the only thiomersal-containing vaccines used
in children during the first two years of life.
Derivatives of DTwP such as DT, D, T – containing
thiomersal are used in children in special circumstances
such as contraindications to vaccination against pertus-
sis (see tab. I).
In Poland, according the annually updated Im-
munization Schedule, vaccination against diphtheria,
tetanus and pertussis is mandatory. The compulsory
vaccination with DTP vaccines consist of four doses
at the second, 3-4, and 5-6 months of age as a primary
vaccination and then at the 16-18 months of age fourth
dose is administered as a booster (29). Because of the
intervals between successive doses and rapid removal
of ethylmercury from the organism, even four doses of
DTwP vaccine during two first years of life, cause no
possibility of its negative cumulative effect.
Clodivac and Tetana vaccines, recommended for
teenagers and adults contain thiomersal only in trace
amounts, as the residue of the manufacturing process
(see tab. II).
Thiomersal is not present in vaccines against hepa-
titis B and influenza (single doses – prefilled syringe).
Influenza vaccines may contain thiomersal as a pre-
servative only in multidose presentations, which are
currently not released on Polish market.
CONCLUSIONS
There are no contraindications to the use of thi-
omersal-containing vaccines in infants, children and
non-pregnant adults. Any reliably and independently
performed epidemiological studies, generally proved the
lack of the link between vaccine-originated exposure to
thiomersal and development of autism spectrum disor-
ders. Before drawing the conclusion or interpretation of
any of the study published, it should be remembered that
only widely accepted methodology and pre-established
criteria for reliable and valid epidemiological studies
should be taken into account.
Growing number of autism cases seen in recent
decades might be associated with increased attention
Table I. Vaccines containing thiomersal as a preservative registered in Poland
Trade name Manufacturer Thiomersal content
per dose
Mercury content
per dose
DTP Diphtheria, tetanus and pertussis
(whole cell) vaccine (adsorbed) IBSiS BIOMED S.A. (Cracow) max. 50 μg max. 25 μg
DT Diphtheria and tetanus vaccine
(adsorbed) IBSiS BIOMED S.A. (Cracow) max. 50 μg max. 25 μg
D Diphtheria vaccine (adsorbed) IBSiS BIOMED S.A. (Cracow) max. 50 μg max. 25 μg
dDiphtheria vaccine (adsorbed,
reduced antigen content) IBSiS BIOMED S.A. (Cracow) max. 50 μg max. 25 μg
T Tetanus vaccine WSiS BIOMED Sp. z o. o.
(Warsaw) max. 50 μg max. 25 μg
Table II. Vaccines registered in Poland in which thiomersal is used during the manufacturing process
Trade name: Manufacturer: Thiomersal content
per dose:
Mercury content
per dose:
Clodivac Diphtheria and tetanus vaccine
(adsorbed, reduced antigen content) IBSiS BIOMED S.A. (Cracow) max. 1 μg max. 0,5 μg
Tetana Tetanus vaccine (adsorbed) IBSiS BIOMED S.A. (Cracow) max. 1 μg max. 0,5 μg

Thiomersal-containing vaccines 63No 1
paid to the symptoms of autism and changes in autism
disorders diagnostic criteria. Nevertheless, all available
and reliable results shows independently that autism
has nothing in common with thiomersal-contained
vaccines, which quantity on the market since 1999
critically decreased.
Routine vaccinations provide protection against
many serious diseases. Childhood vaccination should be
performed in accordance with the Annual Immunization
Schedule as early as possible to ensure the maximum
protection.
It is extremely important to speak to the public
about the facts, not about the myths of thiomersal-
containing vaccines safety, using the results of reliable
studies, in order to sustain the population confidence
in the efficacy and safety of immunization programs.
Risk associated with deaths and serious complications
associated with the development of diseases in unvac-
cinated individuals far outweighs the potential risk of
adverse consequences associated with immunization
with thiomersal-containing vaccines.
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Received: 12.11.2014
Accepted for publication: 17.12.2014
Address for correspondence:
Mgr inż. Aleksandra Gołoś
Department of Sera and Vaccines Evaluation
National Institute of Public Health
-National Institute of Hygiene
24 Chocimska Street, 00-791 Warsaw,Poland
e-mail: agolos@pzh.gov.pl
tel.: (22) 5421347