Canada Communicable Disease Report
1 May 2002
Thimerosal is a mercury-containing
preservative that has been used as a vaccine additive
for > 60 years. High-dose, acute or chronic
mercury exposure of children and adults can cause neuro-
and nephrotoxicity(1-4). However, there are
limited data examining the effects of low-dose,
intermittent mercury exposure, for example, when infants
are immunized with thimerosal-containing vaccines.
Currently, the only thimerosal-containing vaccine in routine
use in the infant immunization schedules of some
Canadian jurisdictions is hepatitis B vaccine.
In a statement released in December 1999(5),
Canada’s National Advisory Committee on Immunization
recommended no change to existing infant immunization
programs for three reasons:
- absence of exposure (in eight provinces), or very
low cumulative exposure of Canadian infants to
vaccine-derived thimerosal (in two provinces and
both territories where thimerosal-containing
hepatitis B vaccine was, at that time, used in routine
infant immunization programs*);
- lack of evidence of harm from exposure to the dose
of mercury in thimerosal-containing hepatitis B
vaccine given to infants < 6 months age;
- no thimerosal-free hepatitis B vaccine was
licensed for use in Canada at that time.
Thimerosal-derived mercury in vaccines
remains a vaccine safety issue, with public attention
and scientific scrutiny focused on whether thimerosal
exposure from immunization in the first 6 months of age
causes neurodevelopmental disorders, such as autism,
attention deficit/hyperactivity disorder, or speech or
language problems(6-8). The purpose of this
review is to examine the risk of neurodevelopmental
disorders, including autism, in Canadian children as a
result of mercury exposure from thimerosal-containing
vaccines routinely used in some provincial/territorial
universal infant and early childhood immunization
An Internet-based search and review of
MEDLINE English language literature was conducted in
November and December 2001**. The
following Boolean key word combinations were used:
“(thimerosal or mercury) and (hepatitis B vaccine or
vaccine)”, and “(thimerosal or mercury) and (autism
or neurotoxicity or neurodevelopmental delay)”.
To minimize publication bias, an
identical electronic search using a commercial search
engine† was also
conducted. Additional relevant unpublished information
was sought from Health Canada and from sources
identified or cited in published literature. An
electronic survey of Canadian provincial/territorial
epidemiologists in jurisdictions with universal infant
hepatitis B immunization programs, was undertaken in
December 2001 and January 2002, to determine whether
thimerosal-free hepatitis B vaccine was used in their
Thimerosal – chemical properties
or ethylmercurithiosalicylic acid) is an organo-mercurial
compound (Figure 1) that dissociates
as 49.6% ethyl mercury by weight, and thiosalicylic acid(9,10).
Thimerosal has been added to drugs and vaccines
primarily as a preservative to prevent bacterial or
fungal contamination of these products. It is also used
as an inactivating or bacterio- static agent in the
manufacturing process of some vaccines(9,10).
Over 20 vaccines licensed in Canada contain thimerosal,
in concentrations ranging from 0.005% to 0.01%(11).
Figure 1. Thimerosal chemical
Regulatory agency reviews
Public concern about thimerosal-containing
vaccines first arose in Europe and the United States
(U.S.) in 1999. The European Agency for the Evaluation
of Medicinal Products (EMEA) issued a public statement
in July 1999, recommending elimination of organo-mercurial
preservatives in vaccines used for infants and toddlers,
with a view to limiting cumulative exposure to
ethylmercury from a range of sources, including food and
medicinal products(12). At the same time, a
U.S. congressional-mandated review by the U.S. Food and
Drug Administration (USFDA) revealed that the cumulative
vaccine- derived exposure by American infants in the
first 6 months of life to the ethylmercury metabolite of
thimerosal exceeded the recommended U.S. Environmental
Protection Agency (USEPA) exposure limit for a closely
related organic mercury compound, methylmercury(13-15).
Exposure to the fetus or infant in the first 6 months
after birth is of particular concern because of
susceptibility of the developing nervous system to
Similarities between autism and
neurologic effects of mercury (discussed below) have led
some to argue that vaccine-derived thimerosal might
cause autism(15). Autism is a life-long
developmental disability, characterized by impaired
social interaction and communication and a pattern of
restrictive, repetitive and stereotypic behaviours,
interests and activities(16). These
characteristics present across a wide spectrum of
clinical severity and most commonly are recognized in
children 18 to 30 months of age. Boys are more commonly
The cause(s) of autism is/are unknown
although a variety of different factors have been
implicated(17). A genetic component is
suggested by studies that show an identical twin of a
child with autism having a 75% to 90% chance of having
autism, compared with a fraternal twin of a child with
autism having only a 5% to 10% chance. Families with
autism have a 10% to 40% increase in diagnosis of other
developmental or learning disabilities. Cited
environmental causes include: exposure to heavy metals
such as lead or mercury; nutritional deficiency (e.g.,
iodine); metabolic disease (e.g., iron overload); or
infectious diseases (e.g., congenital rubella syndrome
or meningitis caused by Haemophilus influenzae or
Neisseria meningitidis). Another theory posits a
genetic predisposition to unspecified heavy metal
intoxication in some children, related to
metallothionein protein dysfunction, which has been
suggested to have a role in metabolism of these
Health effects of methylmercury and
ethylmercury – acute or chronic high-dose exposures
Both methylmercury and ethylmercury can
cause peripheral and central nervous system injury in
adults and children following acute or chronic,
high-dose dietary exposure(1,10,19). Symptoms
may include tremors, spasms, numbness and tingling of
extremities, and a range of psychomotor and psychologic
effects including irritability, restlessness, difficulty
concentrating, decreased memory, and depression. Many of
these symptoms and signs resemble those found in
autistic children. Studies of the effects of
ethylmercury and methylmercury in rats suggest
comparable observable neurologic effects of intoxication
between these two compounds(14,20,21).
Cases of acute, high-dose thimerosal
poisoning are also reported in the literature, involving
oral or injection exposures to thimerosal in the range
of 100 mg/kg or higher, among children and adults(22-24).
Several deaths attributable to acute mercury toxicity,
and a similar range of neurologic symptoms as cited
above, were reported. Animal experiments of acute
thimerosal toxicity reveal an oral lethal dose for half
of exposed mice (LD50) (oral) to be 91 mg/kg
body weight and an LD50 (subcutaneous) in
exposed rats of 98 mg/kg body weight(25).
Other documented reports of high-dose
oral ethylmercury poisoning relate to consumption, over
periods of weeks to several months, of grains or foods
contaminated by mercury-containing fungicide (e.g.,
rice, bread, or meat from grain-fed animals). Neurologic
symptoms included ataxia, unsteady gait and balance,
speech disturbances, and tremors(26-28).
Health effects of methylmercury and
ethylmercury – chronic (e.g., dietary) or intermittent
low-dose (e.g., vaccination) exposures
To date, the most common
vaccine-associated adverse event to which thimerosal has
been possibly implicated is minor, contact allergy
(delayed-type hypersensitivity) skin reactions(9,29).
Between 1% and 16% of tested individuals have exhibited
such a reaction on skin patch testing(30).
Immediate hypersensitivity (e.g.,
anaphylaxis) and immune complex-mediated disorders
(e.g., glomerulonephritis) have been reported in
association with exposure to thimerosal-containing
products although it is uncertain if thimerosal was the
There is currently no direct evidence
that thimerosal-containing vaccines causes autism or any
other neurodevelopmental disorder in humans(10,14,29,31).
No long-term, prospective, controlled epidemiologic
studies of the neurologic or neurodevelopmental effects
of intermittent, low-dose exposure to thimerosal or
ethylmercury are reported in the scientific literature.
Dose-response relationships to low-dose methylmercury or
ethylmercury exposures are unknown, although two
population-based studies conducted in the Seychelles
Islands(32) and Faroe Islands(33),
are evaluating the neurotoxic effects of exposure to
methylmercury in utero as a result of mothers’
dietary intake of mercury-contaminated seafood. The
mercury exposure profiles in utero and infancy
differed in these two settings. In the Seychelles,
mothers’ daily diet consisted of fish with lower
levels of mercury contamination, resulting in chronic,
low level mercury exposure to their infants, whereas
Faroese mothers exposed their unborn children to
intermittent, higher dose exposures as a result of
periodic consumption of more highly contaminated pilot
The Seychelles study, which used
maternal and child hair to evaluate prenatal and
childhood mercury exposure respectively, and primarily
global neuropsychiatric scales to assess outcome, has
found no neurologic impairment among children <= 9
years of age(29,34). The Faroe Islands study,
which used umbilical cord blood and child hair to
evaluate prenatal and postnatal mercury exposure
respectively, and domain-specific neuropsychiatric
testing to assess outcome, reported subtle neurologic
deficits in memory, attention and language scores among
7-year-old children tested. Postnatal mercury exposure
was less predictive of these effects than prenatal
exposure(35). Further study is required to
properly evaluate these discordant findings,
particularly in view of the fact that infant
neurodevelopment test results have not consistently been
shown to predict later dysfunction(31).
One unpublished retrospective cohort
study was reported in 2001 in a review of thimerosal-containing
vaccines by the U.S. Institute of Medicine’s
Immunization Safety Review Committee(29).
This study examined 10 years of data from the Vaccine
Safety Datalink (VSD), a large U.S. database, covering
approximately 2.5% of the U.S. population. The VSD links
vaccination, clinic, hospital discharge and demographic
data from seven health maintenance organizations
(HMO’s). A statistically significant, but weak,
association (relative risk ratio < 2) was found
between various cumulative exposures to thimerosal and
some neurodevelopmental diagnoses, such as speech delay
and attention deficit disorder, but not autism. No
significant difference in risk of any neurologic or
neurodevelopmental disorder was identified, although
small sample size limited the power of the study to
detect a small effect. Potential limitations of this
analysis include biases related to healthcare-seeking
behaviour, diagnostic ascertainment, and
misclassification biases and lack of data on familial or
genetic predispositions to neurodevelopmental outcomes(29).
One study examined blood mercury levels
in infants vaccinated with thimerosal-containing
hepatitis B vaccine(36). Blood mercury
increased from a baseline (prevaccination) level < 1
µg/L to 2.24 µg/L (standard deviation
[SD] ± 0.58) and 7.36 µg/L (SD ± 4.99) for
preterm and term infants respectively, within 48 to 72
hours after a single dose of vaccine. However, maternal
hair mercury level (an indicator of in utero
exposure) was not examined, and neurodevelopmental
testing was not done, to evaluate the clinical
significance of this increase in blood mercury. The
toxicologic relevance of this is further complicated by
uncertainty of the pharmacokinetics (e.g., rates of
metabolism and excretion) of mercury in blood(23),
and reports from other studies that maternal blood
levels of 100 µg/L to 200 µg/L were not
associated with detectable abnormalities in infants
exposed in utero(37,38).
Sources of environmental mercury
Mercury is a ubiquitous element in the
natural environment(1). Mercury is present in
soil at average concentrations between 0.05 µg/g
and 0.08 µg/g of soil and 0.2 µg/L in
fresh water lakes(2). Mercury vapour is
present in ambient air, with concentrations in
uncontaminated areas averaging < 10 ng/m3
(39). Natural sources contribute an estimated
2,700 to 6,000 tonnes per year to global emissions,
compared with <= 3,000 tonnes per year from
Table 1 shows that
the main population sources of exposure to elemental and
methylmercury are dental amalgam and dietary fish,
respectively(41). Organic mercury compounds
occur in high concentrations in certain species of
dietary fish. For example, in a survey of U.S. food
market baskets conducted between 1991 and 1999 by the
USFDA, canned tuna, packed in oil was reported to
contain an average 0.165 µg/g of mercury(42).
In the same survey, USFDA reported mean mercury
concentrations of 0.070 µg/g for pan-fried
haddock, 0.029 µg/g for salmon, and 0.027 µg/g
for boiled shrimp.
Table 1. Estimated daily
intake and retention (µg /day) of
elemental and mercuric compounds in the general
population not occupationally exposed to
Elemental mercury vapour, µg
Food – fish
Food – non-fish
* Environmental Health
Criteria 101: Methylmercury. Geneva: World
Health Organization, 1990.
Sources of mercury exposure in
Typical dietary consumption of fish,
including species mentioned above, by pregnant or
lactating women, can result in fetal or infant mercury
exposure far exceeding those from thimerosal-containing
vaccines, since these compounds can cross the placenta
and are also excreted in breast milk(10,19,31,43).
The U.S. EPA estimates that 7% of U.S. women of
childbearing age consume >= 0.1 µg/kg
per day of mercury from fish harvested in high risk
Potential thimerosal exposure through
Canadian routine infant immunization
As of January 2002, three provinces (New
Brunswick, Prince Edward Island and British Columbia),
along with Yukon, Northwest Territories and Nunavut, had
incorporated hepatitis B vaccine into their routine
infant immunization schedules (Dr. T. Tam, Health
Canada, Ottawa: personal communication, 2002). Across
these six jurisdictions, five different schedules of
infant hepatitis B vaccination have been implemented,
offering three doses of hepatitis B vaccine at various
times between birth and 15 months of age.
Two licensed recombinant hepatitis B
vaccines (Engerix BTM [Glaxo Smithkline] and
Recombivax BTM [Merck Frosst Canada]) have
been available in Canada since these programs were
initiated, containing thimerosal at a concentration of
0.005% or 50 µg/mL. A regular infant dose of 0.5
mL Engerix BTM contains 12.5 µg of
ethylmercury, while a regular infant dose of 0.25 mL of
Recombivax BTM contains 6.25 µg.
Depending on the product and hepatitis B immunization
schedule, Canadian infants from the above six Canadian
jurisdictions could have been exposed to between 12.5 µg
and 37.5 µg of ethylmercury in the first 6
months of life (or an average of 0.069 µg/day to
0.206 µg/day), from thimerosal-containing
hepatitis B vaccine.
All Canadian provinces and territories
also offer hepatitis B immunoprophylaxis to high-risk
infants whose mother is identified through antenatal
testing as a hepatitis B carrier. Such infants
(approximately 2,000 per year in Canada) are routinely
immunized with three doses of hepatitis B vaccine in the
first 6 months of life, and in this circumstance, the
recommended dose of either recombinant hepatitis B
vacccine is 0.5 mL. Consequently, immunized, high-risk
infants will have been exposed to 37.5 µg of
ethylmercury in the first 6 months of life, from
Organic mercury metabolism in humans
Limited human toxicologic and
pharmacokinetic data are available for ethylmercury,
particularly from episodic, low-dose, intramuscular
exposure. Comparison is made to methylmercury, for which
gastrointestinal exposure in particular has been studied
more extensively(1,19,25,29). Although
methylmercury binds with cysteine to form a complex that
readily crosses the blood-brain barrier and enters
neurons, it is unknown if a similar transport mechanism
exists for ethylmercury(45). The biologic
half-life of methylmercury in humans is about 70 days(25,29),
but it is likely less for ethylmercury due to more rapid
conversion in the lungs, liver and red blood cells to
inorganic mercury – which does not cross the
blood-brain barrier as readily(20,46-48). On
the other hand, once in the brain, ethylmercury is
converted to its inorganic form, resulting in higher
cumulative neural exposure to mercury, again due to less
efficient inorganic mercury transport across the
blood-brain barrier(20). Organic mercury also
binds to glutathione, which may play a protective role
in transporting mercury out of cells, as well as to
metallothionein and other plasma proteins(19).
The metabolic and toxicologic effects of these
mercury-containing complexes are poorly understood(19).
Methylmercury is absorbed from blood and
incorporated into scalp hair in a fixed concentration
that is highly correlated to blood levels, at an
approximate ratio of hair to blood mercury of 250:1(41).
Thus, hair represents a reliable biologic monitor of
past mercury exposure(3). Ninety per cent of
methylmercury is excreted through bile in feces, mostly
as inorganic mercury(10).
Exposure limits to methylmercury
There are no relevant studies for
evaluating a “no observed effect level” (NOEL) for
thimerosal and, no “allowable daily intake” (ADI)
has been proposed(25). Various agencies’
“worst-case” scenarios of calculated cumulative
exposure limit to methylmercury exposure for infants in
the first 6 months of life are depicted in Table 2(14).
Such scenarios assume administration of three doses of
hepatitis B vaccine containing 12.5 µg of
ethylmercury per dose to a female infant in the lowest 5th
percentile of mean body weight during the first 6 months
It should be pointed out that the
suggested exposure limits in Table 2
do not represent absolute levels above which toxicity
occurs but, reflect an average daily
intake of methylmercury from all sources over a
lifetime, below which there is no known, appreciable
health risk(29,49). The differences in
suggested methylmercury exposure limit between the
various agencies reflects the limited epidemiologic data
available, differing data sources used and differing
risk assessment methodologies that incorporate a range
of exposure and health effect variables(14,29).
For example, the Health Canada figure is based on an
approximated bench-mark dose of 10 parts per million (ppm)
maternal hair concentration for women of child bearing
age and children. The hair mercury concentration is
converted to an equivalent blood mercury concentration
and daily mercury intake. An uncertainty factor of five
is applied to give the interim tolerable daily intake (TDI).
The USEPA follows a similar review of the scientific
information on dose-response, but applies an uncertainty
factor of 10 to derive their reference dose (RfD). It is
worth noting that the variability between the suggested
limits is less than one order of magnitude. In general,
these limits are intended to be protective of the fetus,
whose developing brain is presumed to be most
susceptible to mercury toxicity(4,10,14,50).
Exposures early in life are reasonably
of greater health concern, not only because of greater
brain organ susceptibility, but also due to
methylmercury’s extended biological half-life in the
central nervous system(51). It is unknown
whether organic mercury exposure in the first 6 months
after birth poses as great a risk as in utero
exposure(10,29). The validity of the
suggested limits is also constrained by the few studies
undertaken and the sensitivity of methods utilized to
detect and measure cumulative low-dose exposures to
methylmercury or ethylmercury or subtle
neurodevelopmental effects in young children.
Table 2 “Worst-case
scenario” cumulative exposure limit to
methylmercury for infants <= 6 months
age, based on 5th
percentile of female infant body weight*
Suggested daily dietary
exposure limit to methyl- mercury -µg/kg
body weight per Day/week
exposure limit to methylmercury for infant
<= 6 months of age (µg)†
ethylmercury content of three doses hepatitis b
vaccine (12.5 µg per dose)
% ratio of cumulative
hepatitis B vaccine-derived ethylmercury to
agencies’ calculated cumulative
exposure limits for methylmercury
World Health Organization
U.S. Environmental Protection
Agency (U.S. EPA)
U.S. Food and Drug
* Based on: Ball LK, Ball R,
Pratt RD. An assessment of thimerosal use in
childhood vaccines. Pediatrics
† Calculated as
dose/kg body weight/week x mean weight x 26
weeks and based on the mean of lowest 5th
percentile of weight for a female infant between
birth (2.36 kg) and 6 months age (5.25 kg) –
i.e., 3.81 kg.
** Clarkson TW. Mercury:
major issues in environmental health.
Environ Hlth Perspect 1993;100:31-8.
Adverse neurodevelopmental effects
following vaccine-related ethylmercury exposures – if
these adverse effects do exist – are either extremely
subtle and difficult to measure or occur at a frequency
that is so low that they have escaped reliable detection(14,29,31).
Nevertheless, additional studies are being undertaken to
further evaluate whether there is any association
between neurodevelopmental disorders and exposure to
It is worth emphasizing that agencies’
recommended limits to methylmercury shown in Table
2 are based on critical mercury concentrations in
hair or blood that are measures of ongoing mercury
exposure. With a half-life in blood of about 70 days,
two or three discrete exposures of ethylmercury from
thimerosal-containing hepatitis B vaccine will not
produce the same steady-state blood mercury
concentration as an ongoing exposure to this as a daily
dose. Therefore for example, it is not correct to infer
from agencies’ guidelines that a single dose of 12.5 µg
ethylmercury from thimerosal-containing hepatitis B
vaccine administered to a 2-month-old, 3 kg infant,
(i.e., 4.2 µg/kg) represents a 1-day exposure to
ethylmercury that is 21 times the suggested daily limit
for methylmercury set by Health Canada.
A thimerosal-free hepatitis B vaccine,
Recombivax BTM (Merck Frosst Canada) was
licensed in Canada on 16 March 2001, and licensure of a
second such product is anticipated in early 2002. By
December 2001, four of six Canadian jurisdictions
(British Columbia, New Brunswick, Prince Edward Island
and Yukon) which routinely immunize all infants with
hepatitis B vaccine, had switched to thimerosal-free
vaccine. Other routine childhood vaccines used in
Canada, such as those for measles, mumps, and rubella (MMR)
and PENTACELTM (for diphtheria, tetanus,
acellular pertussis, H. influenzae type b, and
inactivated polio) do not contain thimerosal
Therefore, at this time, exposure of
Canadian infants in the first 6 months of life to
ethylmercury from thimerosal-containing vaccines used in
the routine immunization schedule, has been eliminated.
This does not mean that all thimerosal-containing
vaccines have been eliminated in Canada. A number of
other thimerosal-containing vaccines are licensed that
are used in special circumstances, that could continue
to expose infants < 6 months of age to
These include some single antigen
acellular pertussis and conjugate H. influenzae
vaccines, diphtheria-tetanus, and diphtheria- tetanus-acellular
pertussis combination vaccines, all of which contain
thimerosal in a concentration of 0.01%, and represent an
exposure of 25 µg ethylmercury per 0.5 mL dose(11).
Thimerosal- containing hepatitis B vaccine continues to
be used in some Canadian jurisdictions to protect high
risk infants born to chronic hepatitis B infected
mothers. Influenza vaccines that are licensed in Canada
also contain 0.01% thimerosal but are not recommended or
used in infants < 6 months of age because of lack of
effectiveness early in life.
In part, media and public concern about
thimerosal likely reflects increasing public intolerance
of avoidable exposure of children to real or even
theoretical risks from all sources. The balance of
benefit versus risk strongly favours continued use of
thimerosal-containing vaccines, where no alternatives
exist. As thimerosal-free vaccines come to market, it is
prudent for Canada to incorporate these products into
immunization programs, to minimize to the extent
possible, the total burden of organic mercury exposure
to children. Suitable thimerosal-free alternatives
include preservative-free single dose vaccines, or
products that use nonmercurial preservatives, such as
Important lessons can be learnt from the
confusing process of implementing transition to
thimerosal-free childhood vaccines in the U.S. during
1999-2000, which in some instances resulted in
inappropriate deferral of hepatitis B immunization for
high-risk infants(52-54). A carefully defined
and co-ordinated policy, and effective communication to
practitioners and the public, are essential components
of a successful transition. In the meantime, thimerosal-containing
vaccines should continue to be offered to children in
all instances where no thimerosal-free alternative is
The authors thank Dr. Paul Varughese,
Population and Public Health Branch, and Dr. Jerry
Calver, Biologics and Genetic Therapies Directorate,
Health Products and Food Branch, Health Canada, Ottawa,
Ontario, for summarizing data on thimerosal- containing
vaccines used in Canada and Ms Kulvinder Atwal, British
Columbia Centre for Disease Control, for assisting in
proofreading and typing of manuscript.
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** PubMed, National Library of Medicine at: : www.ncbi.nlm.nih.gov
† AltaVista, Palo Alto, CA, at: www.altavista.com :