|
|
Mercury concentrations and
metabolism in infants receiving vaccines containing thiomersal:
a descriptive study
|
After
reading this study please see
Safe
Minds Assessment of the Pichichero Thimerosal Study
Michael E
Pichichero, Elsa Cernichiari, Joseph
Lopreiato, John Treanor
The Lancet Volume 360, Number 9347
30 November 2002
http://www.thelancet.com/journal/vol360/iss9347/full/llan.360.9347.original_research.23350.1
 http://pdf.thelancet.com/pdfdownload?uid=llan.360.9347.original_research.23350.1&x=x.pdf
Departments of Microbiology/Immunology (Prof M
E Pichichero MD), Environmental Medicine (E
Cernichiari), and Medicine (J Treanor MD),
University of Rochester, Rochester, New York, NY, USA;
and National Naval Medical Center, Bethesda, MD (J
Lopreiato MD)
Correspondence to: Dr Michael E
Pichichero,
Department of Microbiology/Immunology, University of
Rochester Medical Center, 601 Elmwood Avenue, Box 672,
Rochester, NY 14642, USA (e-mail:michael_pichichero@urmc.rochester.edu)
Summary
Background
Thiomersal is
a preservative containing small amounts of ethylmercury
that is used in routine vaccines for infants and
children. The effect of vaccines containing thiomersal
on concentrations of mercury in infants' blood has not
been extensively assessed, and the metabolism of
ethylmercury in infants is unknown. We aimed to measure
concentrations of mercury in blood, urine, and stools of
infants who received such vaccines.
Methods
40 full-term infants
aged 6 months and younger were given vaccines that
contained thiomersal (diptheria-tetanus-acellular
pertussis vaccine, hepatitis B vaccine, and in some
children Haemophilus influenzae type b vaccine).
21 control infants received thiomersal-free vaccines. We
obtained samples of blood, urine, and stools 3-28 days
after vaccination. Total mercury (organic and inorganic)
in the samples was measured by cold vapour atomic
absorption.
Findings
Mean mercury
doses in infants exposed to thiomersal were 45·6 µg
(range 37·5-62·5) for 2-month-olds and 111·3 µg
(range 87·5-175·0) for 6-month-olds. Blood mercury in
thiomersal-exposed 2-month-olds ranged from less than
3·75 to 20·55 nmol/L (parts per billion); in
6-month-olds all values were lower than 7·50 nmol/L.
Only one of 15 blood samples from controls contained
quantifiable mercury. Concentrations of mercury were low
in urine after vaccination but were high in stools of
thiomersal-exposed 2-month-olds (mean 82 ng/g dry
weight) and in 6-month-olds (mean 58 ng/g dry weight).
Estimated blood half-life of ethylmercury was 7 days
(95% CI 4-10 days).
Interpretation
Administration of vaccines containing thiomersal does
not seem to raise blood concentrations of mercury above
safe values in infants. Ethylmercury seems to be
eliminated from blood rapidly via the stools after
parenteral administration of thiomersal in vaccines.
Lancet 2002; 360: 1737-41
Introduction
Thiomersal is a preservative used
in vaccines routinely administered to infants and
children. Its antimicrobial activity is due to small
amounts of ethylmercury; the usual dose of paediatric
vaccine contains 12·5-25 µg of mercury.1-3
When vaccines containing thiomersal are administered in
the recommended doses, allergic reactions have been
rarely noted, but no other harmful effects have been
reported.4 Massive overdoses from
inappropriate use of products containing thiomersal have
resulted in toxic effects.5-9
Mercury occurs in three forms:
the metallic element, inorganic salts, and organic
compounds (eg, methylmercury, ethylmercury, and
phenylmercury). The toxicity of mercury is complex and
dependent on the form of mercury, route of entry,
dosage, and age at exposure. Mercury is present in the
environment in inorganic and organic forms, and everyone
is exposed to small amounts.10,11 The main
route of environmental exposure to organic mercury is
consumption of predatory fish, especially shark and
swordfish. A 6-ounce can of tuna contains 2-127 µg
(average 17 µg) of mercury.12 Freshwater
fish (eg, walleye, pike, muskie, and bass) can also
contain high concentrations of mercury.
Most of the toxic effects of
organic mercury compounds take place in the central
nervous system, although the kidneys and immune system
can also be affected.10,11,13 Organic mercury
readily crosses the blood-brain barrier, and fetuses are
more sensitive to mercury exposure than are children or
adults. Data about potential differences in toxicity
between ethylmercury and methylmercury are few. Both are
associated with neurotoxicity in high doses; in-utero
poisoning with methylmercury causes problems that are
similar to cerebral palsy. Findings about the effect of
low-dose methylmercury exposure on neurodevelopment in
infants are contradictory.14,15 In-utero
exposure could be related to subtle neurodevelopmental
effects (eg, on attention, language, and memory) that
can be detected by sophisticated neuropsychometric
tests-- although the conclusion is confounded by
concomitant ingestion of polychlorinated biphenyls in
the patients investigated.14,15
No toxic effects of low-dose
exposure to thiomersal in children have been reported.3
The effect of the small amounts of mercury contained in
vaccines on concentrations of mercury in infants' blood
has not been extensively assessed, and the metabolism of
ethylmercury in infants is unknown. We aimed to assess
concentrations of mercury in full-term infants after
administration of routine vaccinations according to the
schedule used in the USA, and to obtain additional
information about the presence of mercury at other body
sites including urine and stool. Samples of hair and
breast milk were also obtained from some mothers of
infants participating in the study
Methods
Study populations
We studied two groups of full-term infants who
differed in their history of exposure to vaccines
containing thiomersal. Infants in the exposure group
were recruited at the Elmwood Pediatric Group, a large
paediatric practice in Rochester, NY, USA, where
vaccinations with thiomersal preservative were routinely
given. 20 infants aged 2 months and 20 aged 6 months
were studied at this practice to obtain information
about the range of total thiomersal exposures likely to
take place during infancy. The control group consisted
of 21 infants who did not receive vaccines containing
thiomersal and were recruited from the National Naval
Medical Center, Bethesda, MD. All the infants were
recruited during routine well-child examination and
vaccination visits by the investigators (between
November, 1999 and October, 2000). Written informed
consent was obtained from parents for all procedures.
Vaccines
Vaccines containing thiomersal that were given to
infants in the exposure group included Tripedia
(diphtheria-tetanus-acellular pertussis vaccine; Aventis
Pasteur, Swiftwater, PA; 0·01% thiomersal, 25 µg
mercury per dose) Engerix (hepatitis B vaccine;
GlaxoSmithKline, Rixensart, Belgium; 0·005% thiomersal,
12·5 µg mercury per dose), and in some children
HibTITER (Haemophilus influenzae type b conjugate
vaccine, Wyeth-Lederle, Pearl River, NY, USA; 0·01%
thiomersal, 25 µg mercury per dose). Vaccines
administered to the control group included Infanix (diptheria-tetanus-acellular
pertussis vaccine; GlaxoSmithKline, Rixensart, Belgium),
Recombivax HB (hepatitis B vaccine; Merck, West Point,
PA, USA), and ActHIB (Haemophilus influenzae b
conjugate vaccine, Aventis Pasteur, Swiftwater, PA,
USA).
Procedures
We obtained vaccination histories--including type of
vaccine, manufacturer, lot number, and dates of
administration--from the medical records. In the
exposure group, we obtained samples of heparinised whole
blood, stool, and urine, during a visit 3-28 days after
vaccination. Blood and urine were kept at 4°C, and
stools were frozen until assessment. Urine was sampled
by use of a urine bag at the clinic, and stool was taken
from a diaper (nappy) provided by the parent. Whole
blood and urine were obtained from the control children.
At both sites, we obtained at least 50 hairs from the
mother by cutting at the base near the scalp in the
occipital area, to assess potential transplacental
exposure of infants to mercury. Additionally, several
samples of breastmilk or formula were obtained from
mothers of infants at Elmwood Pediatric Group, as well
as stool samples from a few infants who were not exposed
to thiomersal.
We measured total mercury in all
samples (and inorganic mercury in stool samples) by cold
vapour atomic absorption as previously described.16,17
The limit of reliable quantitation in this assay ranged
between 7·50 nmol/L and 2·50 nmol/L, dependant on
sample volume.
Population pharmacokinetic
calculations
To estimate the half-life of
thiomersal mercury in the blood, we developed a
prediction model for the expected concentrations of
mercury in blood for half-lives of mercury ranging from
1 day to 45 days, on the basis of bodyweight of the
infant, the doses of thiomersal administered, and the
times between the individual doses of thiomersal and
when the blood was obtained. To do these calculations,
we assumed that 5% of the mercury dose was distributed
to blood,7 that blood volume represented
about 8% of the infant's bodyweight, and that
elimination of mercury from blood followed a
single-compartment model with first-order kinetics. For
each possible half-life between 1 and 45 days, we then
calculated the difference between the predicted and
actual recorded concentrations in blood for each infant.
Only measurements within the range of reliable
quantitation were used in these calculations.
The best estimate of the blood
half-life of mercury was judged to be the hypothetical
half-life, which resulted in the smallest difference
between predicted and observed values. We constructed a
95% CI based on a likelihood ratio for this estimate
with the assumption that errors from the decay model
were independent, additive, and normally distributed.
The 95% confidence limits were the points where the
curve crossed the minimum sum of squares multiplied by
1+ 2(1)/(n-1)
where n is the number of data points and 2(1)
is the upper 5% point of the 2
distribution on one degree of freedom.
Statistical analysis
Because this was a descriptive study we did no formal
calculations for sample size. Student's t test
and Fisher's exact test were used to compare results for
the exposure and control group, with p 0·05
judged to be significant.
Role of the funding source
The sponsors of the study approved the study design
but had no other involvement in the in study design,
data collection, data analysis, data interpretation, or
writing of the report.
Results
61 infants were enrolled in this
study (table). Among infants aged 2 months in the
exposure group, samples were taken from eight within 7
days of vaccination, from five between 8 and 14 days
after vaccination, and from seven between 15 and 21 days
after vaccination. Among 6-month-old infants in the
exposure group, samples were taken from seven between 4
and 7 days after vaccination, from eight between 8 and
14 days after vaccination, and from five between 15 and
27 days after vaccination. Samples were obtained from
infants in the control group at regularly scheduled
visits at 2 or 6 months of age. All children remained
healthy throughout the study and during 24-36 months of
follow-up.
|
Infants aged 2 months |
|
Infants aged 6 months |
|
Thiomersal-exposed (n=20) |
Controls (n=11) |
Thiomersal-exposed (n=20) |
Controls (n=10) |
| Bodyweight (kg) |
| Mean (range) |
5·3 (4·0-6·4) |
NR |
8·1 (6·7-10·6) |
NR |
| Total mercury exposure
(µg)* |
| Mean (range) |
45·6 (37·5-62·5) |
0 |
111·3 (87·5-175·0) |
0 |
| Blood mercury (nmol/L) |
| Number of samples tested |
17 |
8 |
16 |
7 |
| Number with mercury in
range |
12 |
1 |
9 |
0 |
| Mean (SD)† |
8·20 (4·85) |
4·90 |
5·15 (1·20) |
.. |
| Median (IQR)† |
6·15 (4·60-10·85) |
4·90 |
5·30 (4·55-6·10) |
.. |
| Range† |
4·50-20·55 |
.. |
2·85-6·90 |
.. |
| Urinary mercury (nmol/L) |
| Number of samples tested |
12 |
6 |
15 |
8 |
| Number with mercury in
range |
1 |
0 |
3 |
0 |
| Mean (SD)† |
3·8‡ |
.. |
5·75 (1·05) |
.. |
| Median (range)† |
3·8‡ |
.. |
6·2 (4·55-6·45) |
.. |
| Stool mercury (ng/g dry
weight) |
| Number of samples tested |
12 |
NT |
10 |
NT |
| Number with mercury in
range |
12 |
.. |
10 |
.. |
| Mean (SD)† |
81·8 (40·3) |
.. |
58·3 (21·2) |
.. |
| Median (IQR)† |
83·5 (47·0-121·3) |
.. |
58·0 (42·0-68·5) |
.. |
| Range† |
23·0-141·0 |
.. |
29·0-102·0 |
.. |
| NR=Not
recorded. NT=not tested. *Via vaccination.
†All calculations done only with samples
within range of accurate quantitation. ‡Only
one value so SD and range are not applicable. |
| Concentrations
of mercury in blood, urine, and stool of infants
who received vaccines containing thiomersal and
those who did not |
Sufficient volumes of blood ( 1
mL) for the measurement of mercury by the atomic
absorption technique were obtained from 17 infants aged
2 months and 16 aged 6 months in the exposure group.
Mercury concentrations were below the range of reliable
quantitation in five of 17 blood samples from
2-month-olds, and seven of 16 blood samples from 6-month
olds (p=0·48). The mean concentration of blood mercury
in samples with quantifiable mercury was higher in
2-month-olds than in 6-month olds (difference 3·05 nmol/L,
95% CI 0·03-1·24, p=0·06), but was low in both these
groups (table). Sufficient blood volumes for measurement
of mercury were obtained from 15 infants in the control
group, including eight aged 2 months and seven aged 6
months. Blood mercury was below the level of reliable
quantitation in seven of the eight samples from the
2-month-olds and in all seven samples from 6-month-olds.
The only detectable value from the control group was
4·65 nmol/L.
Overall, mercury concentrations
were below the range of quantitation in 12 of 33 samples
from thiomersal-exposed infants and in 14 of 15
unexposed infants (p=0·04). The highest level of blood
mercury detected in any infant in this study was 20·55
nmol/L, which was measured 5 days after vaccination in a
2-month-old infant weighing 5·3 kg, who had received
vaccines (Tripedia and Engerix B) containing a total
dose of 37·5 µg mercury. The relation between time
between vaccination and sampling and the concentration
of mercury in the blood in the exposed group is shown in
figure 1. Although mercury concentrations were uniformly
low, the highest levels were recorded soon after
vaccination.
http://image.thelancet.com/lancet/issues/vol360no9347/article1737/tn02art4136_1.gif
Figure 1: Blood mercury
concentrations in infants aged 2 months (diamonds) and 6
months (squares) by time of sampling
Filled symbols represent measured
values and open symbols represent samples at the limit
of quantitation, either 7·50 nmol/L, 3·75 nmol/L, or
2·5 nmol/L, dependent on sample volume.
Mercury was undetectable in most
of the urine samples from the infants in this study.
Only one of 12 urine samples from 2-month-olds, and
three of 15 from 6-month-olds in the exposure group, and
none of the 14 samples from the controls, contained
detectable mercury. The highest concentration of urinary
mercury detected was 6·45 nmol/L, in a 6-month old
infant in the exposure group (table).
Stool samples were collected
from infants in the exposure group. All of the stool
samples from infants who received thiomersal-containing
vaccines had detectable mercury, with concentrations in
stools from 2-month-old infants slightly higher than
those in 6-month-olds (p=0·098, table). As expected,
most of the mercury in stools was inorganic. Stool
samples were not obtained from control infants;
therefore, to determine whether dietary intake could
contribute to the mercury content of stools, we also
obtained samples from nine infants at Elmwood Pediatric
Group who were age-matched with the infants in the
exposure group and were not exposed to vaccines
containing thiomersal. The mean mercury concentration in
the stools of these infants was 22 ng/g dry weight (SD
16), which was significantly lower (p=0·002) than the
mean of the samples collected from thiomersal-exposed
infants.
Amounts of mercury measured in
maternal hair are shown in figure 2. The mean
concentration of hair mercury in mothers of the exposure
group was 0·45 µg/g hair, whereas the mean amount in
mothers of the control infants was 0·32 µg/g
(p=0·22). Eight mothers of infants in the 6-month-old
cohort provided breast milk samples. Concentrations of
mercury in these samples were low (mean=0·30 µg/g,
range 0·24-0·42 µg/g).
http://image.thelancet.com/lancet/issues/vol360no9347/article1737/tn02art4136_2.gif
Figure 2: Mercury
concentrations in hair from mothers of infants
Bar represents mean
concentration of mercury in maternal hair.
We estimated the half-life of
mercury in blood after vaccination to be 7 days, since
this result gave the smallest difference between the
expected and recorded (measured) concentration (figure
3). The 95% CI around this estimate was 4-10 days. The
half-life estimate was very similar when only
measurements in 2-month-olds (7 days, 95% CI 4-11) or
6-month-olds (5 days, 3-9) were included, suggesting
that the rate of elimination of thiomersal mercury from
blood was similar in both age-groups.
http://image.thelancet.com/lancet/issues/vol360no9347/article1737/tn02art4136_3.gif
Figure 3: Estimated blood
half-life of mercury in infants who were exposed to
thiomersal
Lines represent sum of square of
differences between observed concentrations of blood
mercury (nmol/L) and those predicted for every
individual infant on the basis of bodyweight and time of
sampling, with a series of hypothetical half-lives shown
on x axis. Arrow shows point with lowest value for
squared difference, indicating best estimate for serum
half-life.
Discussion
We have shown that very low concentrations of blood
mercury can be detected in infants aged 2-6 months who
have been given vaccines containing thiomersal. However,
no children had a concentration of blood mercury
exceeding 29 nmol/L (parts per billion), which is the
concentration thought to be safe in cord blood;18
this value was set at ten times below the lower 95% CI
limit of the minimal cord blood concentration associated
with an increase in the prevalence of abnormal scores on
cognitive function tests in children. Blood mercury
concentrations indicate concentrations in organs well.18
Although our study was not designed as a formal
assessment of the pharmacokinetics of mercury, we did
obtain samples of blood at various time points after
exposure. Assessment of these samples suggested that the
blood half-life of ethylmercury in infants might differ
from the 40-50 day half-life of methylmercury (range
20-70 days) in adults and breastfeeding infants.10,19
The concentrations of blood mercury 2-3 weeks after
vaccination noted in our study were not consistent with
such a long half-life, but suggested a half-life of less
than 10 days. However, this conclusion is based on
several assumptions and a very simple model, and does
not take into account the fact that at least some of the
mercury detected in the blood of the infants in this
study is likely to have been derived from exposures
other than vaccination. Because of the short period
between vaccination and sampling, the findings of
Strajich and colleagues20 could be consistent
with either a 6-day or 40-day half-life, but are
otherwise consistent with the assumptions made in our
model. Because we expected a 45-day half-life on the
basis of methylmercury pharmacokinetics, the first blood
samples were obtained 3 days after vaccination. Blood
samples taken in the first 72 hours after vaccination,
stool samples obtained every 24 h, and samples from
premature newborn babies (weighing2000
g) given a birth dose of hepatitis B vaccine would have
helped us to reach stronger conclusions. Thus,
additional studies of the pharmacology of thiomersal in
infants are underway.
At the times tested after vaccination, mercury
excretion in urine in our study population was low. By
contrast, concentrations of mercury in stool were high,
and combined with the finding that stool mercury
concentrations in infants who were not exposed to
thiomersal were significantly lower is consistent with
the hypothesis that the gastrointestinal tract
represents a possible mode of elimination of thiomersal
mercury in infants.
Overall, the results of this study show that amounts
of mercury in the blood of infants receiving vaccines
formulated with thiomersal are well below concentrations
potentially associated with toxic effects. Coupled with
60 years of experience with administration of thiomersal-containing
vaccines, we conclude that the thiomersal in routine
vaccines poses very little risk to full-term infants,
but that thiomersal-containing vaccines should not be
administered at birth to very low birthweight premature
infants. Decisions about the elimination of thiomersal
from these vaccines must balance the potential benefit
of reduced exposure to mercury against the risks of
decreased vaccine coverage because of higher costs, the
risk of sepsis in recipients because of bacterial
contamination of preservative-free formulations, and the
risks of exposure to alternative preservatives that
might replace thiomersal.
Conflict of interest statement
None declared.
M Pichichero and J Treanor contributed to the study
conception and design; obtained, assessed, and
interpreted data; drafted and revised the manuscript;
and provided statistical expertise and supervision. E
Cernichiari contributed to analysis and interpretation
of data, revision of the manuscript, and technical
support. J Lopreiato contributed to revision of the
manuscript, and obtained data.
Contributors
Acknowledgments
We thank Tom Clarkson for advice about the
interpretation of mercury assays, David Oakes for
statistical advice, Doreen Francis for recruiting
participants and obtaining samples, and Margaret Langdon
and Nicole Zur for technical assistance. The
investigation was funded by the US National Institutes
of Health (NIH), Bethesda, MD, under contract 1
AF-45248.
References
1 Clements CJ, Ball LK, Ball R,
Pratt D. Thiomersal in vaccines. Lancet 2000; 355: 1279-79. [Text]
2 American Academy of
Pediatrics, Committee on Infectious Diseases, and
Committee on Environmental Health. Thimerosal in
vaccines--An interim report to clinicians. Pediatrics
1999; 104: 570-74. [PubMed]
3 Ball LK, Ball R, Pratt, RD. An
assessment of thimerosal use in childhood vaccines.
Pediatrics 2001; 107: 1147-54. [PubMed]
4 Cox NH, Forsyth A. Thimerosal
allergy and vaccination reactions. Contact
Dermatitis 1988; 18: 229-33. [PubMed]
5 Axton JH. Six cases of
poisoning after a parenteral organic mercurial compound
(merthiolate). Postgrad Med J 1972; 561: 417-21. [PubMed]
6 Fagan DG, Pritchard JS,
Clarkson TW, Greenwood MR. Organ mercury levels in
infants with omphaloceles treated with organic mercurial
antiseptic. Arch Dis Child 1977; 52: 962-64. [PubMed]
7 Matheson DS, Clarkson TW,
Gelfand EW. Mercury toxicity (acrodynia) induced by
long-term injection of gammaglobulin. J Pediatr
1980; 97: 153-55. [PubMed]
8 Lowell JA, Burgess S, Shenoy
S, Curci JA, Peters M, Howard TK. Mercury poisoning
associated with high-dose hepatitis-B immune globulin
administration after liver transplantation for chronic
hepatitis B. Liver Transpl Surg 1996; 2: 475-78. [PubMed]
9 Pfab R, Muckter H, Roider G,
Zilker T. Clinical course of severe poisoning with
thimerosal. J Toxicol Clin Toxicol 1996; 34:
453-60.
10 Clarkson TW. Mercury: major
issues in environmental health. Environ Health
Perspect 1992; 100: 31-38. [PubMed]
11 Clarkson TW. The toxicology
of mercury. Crit Rev Clin Lab Sci 1977; 34: 369-403. [PubMed]
12 Yess NJ. US food and Drug
Administration survey of methylmercury in canned tuna.
J AOAC Int 1993; 76: 36-38. [PubMed]
13 Shenker BJ, Guo TL, Shapiro
IM. Low-level methylmercury exposure causes human
T-cells to undergo apoptosis: evidence of mitochondrial
dysfunction. Environ Res 1998; 77: 149-59. [PubMed]
14 Grandjean P, Weihe P, White
RF, et al. Cognitive deficit in 7-year-old children with
prenatal exposure to methylmercury. Neurotoxicol
Teratol 1997; 6: 417-28. [PubMed]
15 Davidson PW, Myers GJ, Cox C,
et al. Effects of prenatal and postnatal methylmercury
exposure from fish consumption on neurodevelopment:
outcomes at 66 months of age in the Seychelles child
development study. JAMA 1998; 280: 701-07. [PubMed]
16 Cernichiari E, Toribara TY,
Liang L, et al. The biological monitoring of mercury in
the Seychelles study. Neurotoxicology 1995; 16: 613-28. [PubMed]
17 Cernichiari E, Brewer R,
Myers GJ, et al. Monitoring methylmercury during
pregnancy: maternal hair predicts fetal brain exposure.
Neurotoxicology 1995; 16: 705-10. [PubMed]
18 Nielsen JB, Andersen O,
Grandjean P. Evaluation of mercury in hair, blood and
muscle as biomarkers for methylmercury exposure in male
and female mice. Arch Toxicol 1994; 68: 317-21. [PubMed]
19 National Academy of Sciences.
Toxicologic effects of methylmercury. Washington DC:
National Research Council, 2000.
20 Stajich GV, Lopez GP, Harry
SW, Sexson WR. Iatrogenic exposure to mercury after
hepatitis B vaccination in preterm infants. J
Pediatr 2000; 136: 679-81. [PubMed]
After
reading this study please see
Safe
Minds Assessment of the Pichichero Thimerosal Study
Commentary
Mercury in
vaccines--reassuring news
The
Lancet Volume 360, Number 9347
30 November 2002
http://www.thelancet.com/journal/vol360/iss9347/full/llan.360.9347.editorial_and_review.23382.1
The mass media and alternative-medicine publications
increasingly report that exposure to and the build-up of
mercury within the body is associated with chronic
ill-health, particularly conditions such as myalgic
encephalitis. Mercury is widespread in the environment;
it is found naturally in rocks, soils, and plants and as
a contaminant in air, water, and food. The element is
used a lot in the electrical industry, and in many
domestic products, including paints, pesticides, fabric
softeners, waxes, and polishes. Mercury is often used as
a preservative in vaccines, skin creams, cosmetics, and
other medications. Mercury is the major component of
dental amalgams and there is a growing lobby against its
use.1 Everyone is exposed to small amounts of
mercury as elemental metallic vapour from dental
amalgams or organic mercury from fish, sea foods, and
vaccines, or to inorganic salts from other food stuffs,
water, and air. Faecal excretion is the major route of
elimination of inorganic or organic mercury.
Elemental mercury from amalgams is
lipid-soluble and freely passes through cell membranes.2
By contrast, organic and inorganic mercury from the diet
and other sources are charged and must be complexed with
other counter-ions or low-molecular-weight sulphur
compounds to pass through cell membranes. The major
targets in proteins susceptible to binding of metals,
including mercury, are the sulphydryl group of cysteine
and the iminonitrogen of histidine. The aromatic ring
nitrogens of the nucleotide bases form mercury
complexes, with thymine and uracil being more reactive
than cytosine, guanine, and adenine.3,4 The
most abundant single nucleophile reactant is the
antioxidant glutathione, typically present at
concentrations of 5 mmol/L in cells, serum, and bile.5
Glutathione mops up ionised mercury derived from
oxidation of elemental mercury and from organic and
inorganic mercury. There may be an inverse relation
between the concentration of intracellular glutathione
and mercury toxicity.6 Once bound to
glutathione, mercury can leave the cell and circulate
freely in serum and lymph from where it can be deposited
in other organs and tissues. Glutathione-complexed
mercury is eventually eliminated via the kidney or
downloaded via bile into the intestinal lumen from where
it is excreted in faeces. After mercury is released from
tissues, faecal excretion is the predominant route for
elimination.
In this issue of The Lancet,
Michael
Pichichero and colleagues investigate mercury levels
and excretion in infants receiving vaccines containing
thiomersal (ethyl mercury). Little is known about the
harmful effects of mercury in infants and children and
at what level these effects occur. At between 12·5 and
25 mg mercury per vaccine dose, the infants may be
receiving over 100 mg ethyl mercury in the first 6
months of life. Pichichero and colleagues show that the
levels in blood are much lower than the prescribed
limits and that much of the ethyl mercury appears to be
eliminated rapidly in faeces. This study gives
comforting reassurance about the safety of ethyl mercury
as a preservative in childhood vaccines.
D C Henderson
Department of Immunology, Faculty of Medicine,
Imperial College of Science Technology and Medicine,
Chelsea & Westminster Hospital, London SW10 9NH, UK
(e-mail:d.henderson@ic.ac.uk)
1 Henderson DC, Clifford R, Young
DM. Mercury-reactive lymphocytes in peripheral blood are
not a marker for dental amalgam associated disease.
J Dentistry 2001; 29: 469-74. [PubMed]
2 Lorscheider FL, Vimy MJ,
Summers AO. Mercury exposure from "silver"
tooth fillings: emerging evidence questions a dental
paradigm. FASEB J 1995; 9: 504-08. [PubMed]
3 Magos L, Halbach S, Clarkson
TW. Role of catalase in the oxidation of mercury vapour.
Biochem Pharmacol 1978; 27: 1373-77. [PubMed]
4 O'Halloran TV. Transition
metals in control of gene expression. Science 1993; 261: 715-25. [PubMed]
5 Meister A, Anderson ME.
Glutathione. Annu Rev Biochem 1983; 52: 711-60. [PubMed]
6 Naganuma A, Anderson ME,
Meister A. Cellular glutathione as a determinant of
sensitivity to mercuric chloride toxicity. Biochem
Pharmacol 1990; 40: 693-97. [PubMed]
http://www.urmc.rochester.edu/gebs/faculty/Michael_Pichichero.htm
Michael
Pichichero
Professor of Microbiology &
Immunology
M.D. (1976) Rochester
Primary Appointment:
Microbiology
& Immunology
GEBS
Cluster Affiliations:
Immunology,
Microbiology, and Vaccine Biology - IMV
Contact Information:
- University of Rochester
School of Medicine and Dentistry
601 Elmwood Ave, Box 672
Rochester, New York 14642
Medical Center 2-5431
Phone: (585) 275-1534
E-Mail: mepo@uhura.cc.rochester.edu
Research:
- Vaccine Development
and Evaluation
Research
Overview
Dr. Pichichero and his colleagues' vaccine
studies helped define the key variables that
determine immunogenicity of the Haemophilus
influenzae b (Hib) conjugate vaccines in the young
infant. Encouraging findings have been made with
Streptococcus pneumoniae capsular polysaccharide
vaccines of several serotypes employing the
conjugate vaccine technology. Continuation of
these studies should further define structural
factors governing immunogenicity of conjugate
vaccines, analyze the role of epitopes of the
carrier component, and pursue structure-immunogenicity
relationships in conjugates of specific
pneumococcal serotypes.
Combination vaccines are a necessity for the
future of human vaccine development. The
immunogenicity of acellular pertussis (DTaP)
vaccines combined with various Hib conjugate
vaccines, Hepatitis B vaccine, and inactivated
poliovirus vaccine results in reduced
immunogenicity for some of the included antigens.
The mechanism(s) and biological relevance of this
immunologic interference phenomena is an area of
active research in Dr. Pichichero's lab.
Bacteria resistant to standard antibiotic
therapy are causing acute otitis media with
increasing frequency. New antibiotics are needed
to cure these infections and to prevent long-term
middle ear disease and associated hearing loss.
Dr. Pichichero's group studies the epidemiology,
etiology, and optimal treatment of otitis media.
Sore throat caused by Group A beta hemolytic
streptococci occur with concomitant colonization
by organisms that may protect the streptococci
through beta lactamase inactivation of penicillin
at the site of infection. Dr. Pichichero's group
evaluates alternative treatments to decrease the
relapse rate of streptococcal infections.
Recent
Publications
 |
Publication
list, as provided by PubMed.
PubMed is maintained by the National Library of
Medicine and provides complete abstracts of all
publications, as well as links to the full text of
many articles (at journal homepages).
|
| Rennels MB, Deloria MA, Pichichero ME, Englund
JA, Anderson EL, Steinhoff MC, Decker MD, Edwards
KM. Lack of consistent relationship between
quantity of aluminum in diphtheria-tetanus-acellular
pertussis vaccines and rates of extensive swelling
reactions. Vaccine. 20 Suppl 3:S44-7, 2002. http://www.ncbi.nlm.nih.gov/entrez/query.Retrieve&db=PubMed&list_uids=12184364&dopt=Abstract
|
| Pichichero ME, Casey JR. Otitis media. Expert
Opin Pharmacother. 3:1073-90, 2002. |
| Pichichero ME. Dynamics of antibiotic
prescribing for children. JAMA. 287:3133-5, 2002. |
| Shelly MA, Pichichero ME, Treanor JJ. Low
baseline antibody level to diphtheria is
associated with poor response to conjugated
pneumococcal vaccine in adults. Scand J Infect
Dis. 33:542-4, 2001. |
| Pichichero ME, Anderson EL, Rennels MB, Edwards
KM, England JA. Fifth vaccination with dipthteria,
tetanus and acellular pertussis is beneficial in
four- to six-year-olds.Pediatr Infect Dis J
20:427-33, 2001. |
| Pichichero ME, Marsocci SM, Murphy ML, Hoeger
W, Francis AB, Green JL. A prospective
observational study of 5-, 7-, and 10-day
antibiotic treatment for acute otitis media.
Otolaryngol Head Neck Surg 124:381-7, 2001. |
| Pichichero ME, Gooch WM 3rd. Comparison of
cefdinir and penicillin V in the treatment of
pediatric streptococcal tonsillopharyngitis.
Pediatr Infect Dis 19:S171-3, 2000. |
| Hoe NP, Kordari P, Cole R, Liu M, Palzkill T,
Huang W, McLellan D, Adams GJ, Hu M,
Vuopio-Varkila J, Cate TR, Pichichero ME, Edwards
KM, Eskola J, Low DE, Musser JM. Human immune
response to streptococcal inhibitor of complement,
a serotype M1 group A streptococcus extracellular
protein involved in epidemics. J Infect Dis.
182:1425-36, 2000. |
| Anderson P, Ingram DL, Pichichero ME, Peter G.
A high degree of natural immunologic priming to
the capsular polysaccharide may not prevent
Haemophilus influenzae type b meningitis. Pediatr
Infect Dis J. 19:589-91, 2000. |
| Novotny LA, Jurcisek JA, Pichichero ME,
Bakaletz LO. Epitope mapping of the outer membrane
protein P5-homologous fimbrin adhesin of
nontypeable Haemophilus influenzae. Infect Immun.
68:2119-28, 2000. |
| Pichichero ME, Edwards KM, Anderson EL, Rennels
MB, Englund JA, Yerg DE, Blackwelder WC, Jansen
DL, Meade BD. Safety and immunogenicity of six
acellular pertussis vaccines and one whole-cell
pertussis vaccine given as a fifth dose in four-
to six-year-old children. Pediatrics. 105:e11,
2000. |
Medscape Medical News
Mercury in Vaccines:
A Newsmaker Interview With Michael E. Pichichero, MD
Laurie Barclay, MD
Medscape Medical News 2002.
http://www.medscape.com/viewarticle/445538_print
Dec. 3, 2002 — Editor's Note: There has been
much debate about the safety of thimerosal, which is
used as a preservative in childhood vaccines and also in
adult influenza vaccines. Although studies generally
have shown that mercury levels after vaccination are not
a problem, the American Academy of Pediatrics (AAP)
successfully lobbied to have thimerosal removed from all
childhood vaccines. The first detailed analysis of
blood, stool, and urine mercury levels in 61 infants who
received vaccines containing thimerosal, published in
the Nov. 30 issue of The Lancet, indicates that
blood levels of mercury in children are well below
current safety limits established by the Environmental
Protection Agency (EPA). Surprisingly, the elimination
of mercury in these children was much faster than
predicted from studies of mercury toxicity from seafood.
Based in part on these findings, the World Health
Organization (WHO) put forth guidelines saying that
thimerosal is safe and should continue to be used.
To clarify these findings and their implications,
Medscape's Laurie Barclay interviews lead author and
lead investigator of The Lancet article, Michael
E. Pichichero, MD, a professor of microbiology,
immunology, pediatrics, and medicine at the University
of Rochester Medical Center in New York.
Medscape: Please summarize your Lancet study
results and their implications for the safety of
vaccines containing thimerosal.
Dr. Pichichero: We looked at the [blood] level
of mercury in children who received
thimerosal-containing vaccines. Not a single child had a
blood mercury level approaching the lower safety limit
established by the EPA. Former predictions of possible
pediatric problems with mercury in vaccines, which led
to removal of thimerosal from U.S. vaccines, were based
on the notion that metabolism of ethyl mercury in the
vaccine was the same as that of methyl mercury in fish.
But our study showed that elimination of ethyl mercury
from the vaccine was about six times as fast as that of
methyl mercury. The rapid metabolism probably accounts
for the very low blood levels in the children we
studied.
Medscape: Could blood levels of mercury be
misleading in that blood levels could be low even while
mercury is accumulating in bone or in organs?
Dr. Pichichero: We accounted for virtually all
the mercury contained in the vaccine in the stool of
these children, with not much excretion in the urine. So
there really is no evidence that there is any mercury
unaccounted for which could be accumulating in bone or
elsewhere, although this study was not a toxicity study
and did not examine this issue directly.
Medscape: Although these results appear to be
reassuring, are there any study limitations to consider
in interpreting the findings?
Dr. Pichichero: This was a small study of 61
children: 20 two-month-olds who got thimerosal, 20
six-month-olds who got thimerosal, and 21 controls.
Because we didn't anticipate the rapid clearance of
ethyl mercury with half-life of only six to seven days,
we predicted the sampling times on the basis of an
assumed 45-day half-life.
Medscape: On what basis did the EPA set public
safety limits for mercury levels?
Dr. Pichichero: The EPA levels were largely
based on studies from the Faroe Islands which looked at
the toxicity of methyl mercury ingestion from whale
blubber. Mild neurodevelopmental problems occurred at
blood levels of 200 to 300 ng/mL, and the mildest
detectable neurodevelopmental toxicity occurred at blood
levels of 58 ng/mL. So the EPA decided they'd add in a
safety factor of 10, and they reasoned that levels
should not exceed 5.8 ng/mL to be totally safe. In our
study, most children had levels of 1 to 2 ng/mL; two had
levels of 2-3 ng/mL, and one had a level of 4 ng/mL. No
child approached the EPA safety limit.
Medscape: Do you think that the Faroe Islands
studies form an adequate basis on which the EPA can
determine safe blood levels as they pertain to infants
who receive vaccines containing thimerosal?
Dr. Pichichero: Actually, it's not an adequate
basis because the situations are not strictly
comparable. First of all, the Faroe Islands study looked
at levels of mercury in fetal cord blood when mothers
ingested mercury from whale blubber. If anything, the
fetus has been shown in human studies to be more
susceptible to the toxic effects of mercury than are
infants, because mercury easily penetrates into the
fetal brain and kidneys and causes damage.
The other issue is that the Faroe Islands study
looked at methyl mercury exposure, but thimerosal
contains ethyl mercury. The FDA [Food and Drug
Administration] assumed that metabolism of these two
organic forms of mercury was closely correlated, but
this was not validated by our study. We now know that
the two forms are metabolized and eliminated
differently. But our data are very reassuring in that
the metabolism of ethyl mercury appears to be six times
faster than that of methyl mercury.
An editorial accompanying the Lancet paper
suggests that another study will soon be published
comparing the effects of ethyl and methyl mercury. But
from a toxicity point of view, once mercury is freed
from its organic bonds, mercury is mercury, and it's the
free form that enters the brain and kidneys and can
cause damage. Our study did not examine toxicity, but we
measured blood levels of free mercury, not of ethyl
mercury.
Medscape: Why did the AAP urge vaccine manufacturers
to remove thimerosal from U.S. vaccines? Do you think
that this recommendation should be changed or updated?
Dr. Pichichero: It's very reassuring for
America's children that the hypothetical concerns which
led to thimerosal removal were not validated by our
study. The AAP and the FDA are not likely to reverse
their decision based on our findings, now that
thimerosal has been replaced with other preservatives.
Although this drove up the cost of vaccines, we as a
wealthy nation have absorbed this cost. But the FDA and
the AAP should be very pleased with our findings, which
speak to the millions of children who have already
received vaccines containing thimerosal. Our findings
were also pivotal in the WHO's recommendation that
thimerosal will remain in all vaccines provided by them
to other countries.
Medscape: What are the advantages of using
thimerosal in vaccines?
Dr. Pichichero: Cost is a major issue. If you
don't use preservatives at all, you have to dispense
vaccine in single-dose vials, which is not only more
expensive but which may lead to more errors in
administration. In underdeveloped countries where
millions of children die of whooping cough, tetanus and
measles, switching to a thimerosal-free vaccine would
raise the price so high that millions of children would
not be vaccinated.
The potential toxicity of using newer preservatives,
as we now do in the U.S., is unknown, so we're trading
the very small, known risk of thimerosal for an unknown
one. The new preservatives in U.S. vaccines are presumed
to be safe, but I'm not an expert on vaccine
preservatives, and I don't know the extent of background
research supporting this presumption.
Medscape: Is any additional research planned to
clarify safety issues for thimerosal?
Dr. Pichichero: We are collaborating with a
laboratory in Seattle to look at nonhuman primate models
to study possible mercury accumulation and other
potential toxicity of thimerosal in vaccines. We're also
doing a large follow-up in Buenos Aires, Argentina, in
which we'll more carefully examine and quantitate these
findings in larger numbers of children.
Medscape: Please comment on the provision in the
Homeland Security Bill that protects pharmaceutical
manufacturers from lawsuits related to adverse effects
of childhood vaccines.
Dr. Pichichero: The three major manufacturers
of thimerosal-containing vaccines are GlaxoSmithKline,
Aventis-Pasteur, and Wyeth. The Childhood Vaccine
Protection Act is a long-standing piece of legislation
which protects the pharmaceutical manufacturers against
lawsuits involving vaccines recommended by the
government. This legislation came into effect about a
decade ago because all the lawsuits led to vaccine
shortages. I'm not aware of any specific provisions in
the Homeland Security Act dealing with this issue, but I
haven't studied it specifically.
Lancet. 2002;360:1711-1712, 1737-1741
Reviewed by Gary D. Vogin, MD
Safe
Minds Assessment of the Pichichero Thimerosal Study
December 3, 2002
Contact: Sallie Bernard, Executive
Director, Safe Minds
sbernard@arcresearch.com;
908 295-6648; www.safeminds.org
INTRODUCTION
This analysis describes the concerns which Safe Minds
has over a recently published study in The Lancet by
Michael Pichichero et al.(1) in which blood measurements
were taken of infants after administration of vaccines
containing thimerosal. The article and accompanying
commentary contain several sweeping statements about
thimerosal safety:
* "Overall, the results of this study show that
amounts of mercury in the blood of infants receiving
vaccines formulated with thiomersal are well below
concentrations potentially associated with toxic
effects."
* "Administration of vaccines containing
thimerosal does not seem to raise blood concentrations
of mercury above safe values in infants."
* "This study gives comforting reassurance about
the safety of ethyl mercury as a preservative in
childhood vaccines." The design and results of the
study do not support these statements. In fact, the
results suggest that thimerosal exposure from vaccines
may have caused neurological damage in some children.
Safe Minds questions the objectivity of the study
authors, due to their ties to vaccine research and
vaccine manufacturers, which may have resulted in a
biased study design and biased interpretation of the
results.
OBJECTIVITY OF THE AUTHORS
* Pichichero has an acknowledged financial tie to Eli
Lilly, the developer of thimerosal and the main target
of thimerosal litigation. He has also claimed
financial ties to a number of vaccine manufacturers,
including manufacturers of thimerosal-containing
vaccines.(2) For example, in an article in the American
Academy of Family Physicians newsletter of
April 2000, Dr. Pichichero makes this disclosure
statement (3):
"The author has received research grants
and/or honoraria from the following pharmaceutical
companies: Abbott Laboratories, Inc.; Bristol-Myers
Squibb Company; Eli Lilly & Company; Merck &
Co.; Pasteur Merieux Connaught; Pfizer Labs; Roche
Laboratories; Roussel-Uclaf; Schering Corporation;
Smith Kline Beecham Pharmaceuticals; Upjohn Company;
and Wyeth-Lederle."
* Pichichero's work has been cited in 21 vaccine
patent applications He was involved in the
recommendation for the Wyeth rotavirus vaccine and
failed to anticipate its risks.
(4) This vaccine was withdrawn soon after licensure
due to adverse reactions.
* A substantial proportion of Dr. Pichichero's work
involves vaccines. Safe Minds conducted a simple Medline
search of publications listing M Pichichero as an
author.(5) A breakdown of these publications by subject
area shows that many focus on vaccines, especially those
which contained thimerosal.
| 161 publications |
| 23 DPT |
| 7 Hib |
| 1 HepB |
| 1 Polio |
| 3 Pneumococcal Conjugate |
| 3 Rotavirus |
| 4 New combination vaccines or
general vaccine discussions |
| The remainder deal with
otitis media and use of antibiotics |
| Note some articles were
counted more than once because they addressed more
than one vaccine |
* Similarly, the University of Rochester web site
provides biographical information on Dr. Pichichero,
which describes his focus on vaccine research. (6) It
describes him as an immunologist, not a toxicologist.
None of his work involves safety assessment of a heavy
metal or other toxicant. One paragraph cites his work on
the Haemophilus influenzae type B vaccine, one of the
thimerosal-containing vaccines that was added to the CDC/AAP-recommended
infant schedule in 1991, nearly doubling the thimerosal
load.
* John Treanor, another author, has also conducted
substantial research into thimerosal-containing
vaccines, and the University of Rochester is one of a
few sites designated by NIH for evaluating new vaccines.
Investigators at the University of Rochester helped
develop the Haemophilus influenzae B vaccine. Per its
web site, "Rochester has become a national
model...in ensuring that as many people as possible are
immunized." (7)
STUDY DESIGN ISSUES
Sample
* The sample size was small. Although the overall
sample size was stated as 61 infants, there were only 33
exposed children who were used for the blood mercury
assessment upon which the safety conclusions were made.
One major shortcoming of a small sample size is the low
chance of including infants who are especially sensitive
to mercury's effects, or who may have detoxification
difficulties. We know from the mercury literature that
there is wide variability in the population in regard to
mercury sensitivity and clearance. Since vaccines are
given to virtually all infants, even if 1% retained
mercury to a much greater degree than the
"norm", this would represent a large number of
injured children.
* The small sample size means that the study lacks
sufficient power to establish safety claims.
* The sample was not randomly drawn, but was a
convenience sample, and therefore not representative of
all infants in terms of health status, socio-economic
status, ethnicity, and other potentially important
factors.
Dose
* Given that the half life of ethylmercury appears to
be 6-7 days, virtually all, if not all, blood draws
missed the peak blood concentrations of mercury. It is
evident that earlier peaks existed because the feces
contained high mercury values, and feces reflect earlier
blood levels. It is impossible to state what the peak
values are if they were not measured. It is also
impossible to calculate average blood concentrations
unless peak concentrations are measured. Standard
methylmercury pharmacokinetic (PK) studies consider peak
and average blood concentrations, along with tissue
distribution, as necessary components of toxicity
assessment. It is disingenuous to compare the blood
levels in this study with past methylmercury ones
without any type of adjustment factor, because the
methylmercury studies incorporated peak levels into
their values, whereas this study only included the
smaller values.
* The dose of ethylmercury given to subjects varied
greatly and was less than what a typical child in the
1990s could receive. In a rationally designed PK study,
the dose is kept constant. In the Pichichero study, the
2 month old subjects were injected with between 37.5 mcg
and 62.5 mcg of ethylmercury reflecting a 67% difference
between the lowest and highest dose. The mean was 45.6
mcg. The typical child in the 1990s could receive 62.5
mcg of mercury at age 2 months and an additional 12.5
mcg at birth (from the Hepatitis B vaccine), or 37% and
64% more Hg, respectively, than the children in this
study. The 6 month old subjects were injected with
between 87.5 mcg and 175 mcg of ethylmercury reflecting
a 100% difference between the lowest and highest dose.
The mean was 111.3 mcg. By 6 months of age, the typical
child in the 1990s would have received 187.5 mcg Hg, or
68% more than the Pichichero study group average.
* The total recorded dose of ethylmercury was not
administered during the study data collection period.
According to the national immunization schedule that
existed during the data collection period (November 1999
to October 2000), it is not possible for a six month old
infant to receive 175 mcg of ethyl mercury at only the
six month visit. Rather, at 6 months of age, an infant
would receive a maximum of 62.5 mcg Hg, from a DTaP, a
HiB, and a Hep B vaccine. Thus, the Pichichero study, in
calculating dose, included exposures which occurred
months prior to the last injection. Thus, when the study
characterizes blood draws as being "X" days
after the mercury exposure, this is misleading, because
it refers only to the last injection. Thus, the reader
really doesn't know how much dose any infant received at
that last exposure from the data presented in the table
in the study.
* In a properly designed PK study, multiple blood
draws should be taken from each subject, and blood
collection times should be consistent for all subjects.
In this study, there was a single draw per child, and
the collection times varied from 3 to 21 days for two
month old infants, a 700% difference, and from 4 to 27
days for six month old infants, a 675% difference.
Modeling
* The single compartment model and safety assumptions
looked at blood levels as the determinant of safety.
However, a more important measure is mercury
distribution into tissue, particularly the brain.
Estimation of brain accumulation would require a two
compartment model and measurement of peak blood levels,
neither of which were components of this study. Yet it
is apparent that the mercury is moving through the body
and is redistributing because it is in the feces at
substantial levels.
STUDY INTERPRETATION
* Improper use of methylmercury safety levels as a
marker for ethylmercury risk: the Pichichero study
compares ethylmercury blood levels with levels from
methylmercury risk assessments, but obviously,
ethylmercury is a different molecule than methylmercury,
and therefore it needs its own safety assessment. A
slight change in molecular structure can have very
different effects in the body. There has never been a
full safety assessment of thimerosal, as the FDA has
admitted.
The only way to do this is to conduct a series of
cellular or molecular level studies as well as
population studies consisting of either (a) animal
studies which measure behavioral, neuropsychological, or
physiological outcomes (that is, does "x" dose
result in "y" aberrant behavior or
"z" reduction on memory tests, etc.), or (b)
human studies on exposed populations, again looking at
behavioral, neuropsychological, or physiological
outcomes. These types of studies have been done
extensively for methylmercury, and this is why
methylmercury blood levels can be correlated with
certain outcomes or risk, but it has never been done
thoroughly for thimerosal. The Pichichero study does not
address adverse outcomes at all, and therefore does not
constitute a true safety assessment.
* Improper interpretation of 1994 Grandjean study to
assess safety: the Lancet study authors cite a 1994
article by Philippe Grandjean as saying that a 29 nMol/L
blood concentration is the level for methylmercury which
is thought to be safe, since it is ten times lower than
the levels at which adverse effects have been found in
methylmercury research. (Ten times 29 nMol/L equates to
290 nMol/L, or 59 part per billion.) Actually, as the
EPA explains (8), the EPA incorporated a ten-fold factor
into their safety assessments due to "uncertainty
factors" because the methylmercury studies are
small, have a high margin of error, and there is immense
variability in human response to mercury.
Thus, to be truly protective of the population, blood
levels should not exceed 29 nMol/L (which equates to 5.8
parts per billion, or the 6 mcg/L the EPA refers to in
their document). The EPA was concerned when a national
study (NHANES) showed that 10% of the US women of child
bearing age had blood mercury over 6 ppb. Thus, a level
of 6 ppb or over, equivalent to 29+ nMol/L, is
considered by EPA to be cause for alarm.
In the Pichichero study, there is one infant blood
level out of the 17 2-month old blood samples (12%)
which was 20.55 nMol/L, or 4.1 ppb. This infant had its
blood drawn at day 5, received 37.5 mcg/Hg, and weighed
5.3 kg.
a) Day 5 is past the peak value in blood, meaning
that at days 1-3, levels would be much higher.
b) A 37.5 mcg dose is (conservatively) 60% of what a
typical 1990s infant may have received (37.5/62.5=60%).
c) A 5.3 kg infant is at the 95th percentile of
weight for a 2 month old, that is, a large, heavy baby.
Since blood Hg concentrations are in part dependent on
weight, a child with a lower weight than this infant
(that is, 95% of the 2 month old population) would have
had a higher blood level than this infant.
The implications of points a, b, and c are that (1)
if the study infant's blood were taken at 1-3 days, it
is more than likely that the Hg levels would have
exceeded 6 ppb; (2) it is likely that the peak levels of
more than 12% of 2 month old children children given the
full 62.5 mcg of mercury would exceed 6 ppb; and (3) a
larger percentage of smaller infants - but still those
of "normal" weight - would be likely to have
blood levels exceeding 6 ppb.
In addition, there were two other 2 year olds with
mercury levels at between 10 and 15 nMol/L. These values
are with 1/2-1/3 of the EPA margin of safety, with blood
draws on days 6-7.
For these reasons alone, the results of the
Pichichero study are anything but "reassuring"
to parents whose children were exposed to thimerosal as
infants.
LEARNING FROM THE STUDY
Despite its many limitations, the Pichichero study
does provide new or confirming information about the
pharmacokinetics of ethylmercury injected into infants.
* The half life of ethymercury in infants appears to
be shorter than methytlmercury, approximately 6-7 days.
Pharmacologically, this period would be considered a
very long half life and a long time for a toxic
substance to be circulating in the body. In fact, the
single blood draw after 20 days for which mercury
quantitation could be made showed mercury being
circulated at about 5 nMol/L. In a developing brain a
few days are significant time periods for an agent that
interferes with cell division and organization.
* The control group had no detectable mercury,
indicating that the mercury in the exposed group was due
to the thimerosal in the vaccines.
SUMMARY
The Pichichero is a small-scale descriptive study
with many design limitations, which has moderate value
in advancing understanding of ethylmercury
pharmacokinetics. It has little if no value as a safety
assessment of thimerosal from vaccines, and its
conclusions are overreaching, perhaps reflecting a bias
on the part of its lead author towards absolving
lisenced vaccines of any adverse effects.
References
(1) Mercury concentrations and metabolism in infants
receiving vaccines containing thiomersal: a descriptive
study, by Michael E Pichichero, Elsa Cernichiari, Joseph
Lopreiato, John Treanor. The Lancet. November 30, 2002.
(2) UpToDate.com web site. Accessed 11/29/02. http://www.utdol.com/application/help/conflict.asp
(3) Acute Otitis Media Part I. Improving Diagnostic
Accuracy, by Michael E. Pichichero, M.D. American
Academy of Family Physicians newsletter, April 2000.
Site accessed 11-29-02. http://www.aafp.org/afp/20000401/2051.html
(4) Rotavirus vaccines and vaccination in Latin
America, by A. C. Linhares and J. S. Bresee. Pan Am J
Public Health. 8(5) 2000. Accessed 11-30-02. http://www.paho.org/english/dbi/es/ARTI--Linares.pdf
(5) Pichichero Publications based on Medline Search
of November 30, 2002, by Safe Minds
(6) Biographical Information on M. Pichichero,
University of Rochester web site. Accessed 11-29-02. http://www.urmc.rochester.edu/gebs/faculty/Michael_Pichichero.htm
(7) Vaccine Technology Takes Center Stage in
Rochester, University of Rochester press release,
October 8, 1998. Accessed 11-30-02. http://www.rochester.edu/pr/releases/med/vaccines.htm
(8) Development of Methylmercury Reference Dose, by
Dr. Kathryn Mahaffey, Office of Prevention, Pesticides
and Toxic Substances, U.S. Environmental Protection
Agency. Site accessed November 30, 2002. http://www.masgc.org/mercury/abs-mahaffey.html
A few comments may
be added to this excellent review:
By Per Dalen MD
The Lancet article starts, somewhat disingenuously,
with the following sentence:
"Thiomersal is a preservative containing small
amounts of ethylmercury that is used in routine vaccines
for infants and children."
Thiomersal contains 50% Hg by weight!
According to a University of Rochester Medical Center
press release http://www.newswise.com/articles/2002/11/VACCINES.URM.html?sc=wire)
the study was initiated as follows:
"In response to the debate, the National
Institute of Allergy and Infectious Diseases (NIAID)
asked vaccine researchers at the University of
Rochester Medical Center to investigate. With funding
from NIAID, the Rochester team measured mercury
concentrations in urine, blood, and stools of 61
infants ..."
<snip>
"The research was done at the Vaccine
Treatment and Evaluation Unit that the NIAID funds at
the University of Rochester Medical Center."
The Lancet article contains the following, under the
subheading "Role of the funding source":
"The sponsors of the study approved the study
design but had no other involvement in the in study
design, data collection, data analysis, data
interpretation, or writing of the report."
Control of the design goes a long way in controlling
the results in a study like this.
Per
Per Dalen MD E-mail: pdalen@algonet.se
Mercury in Vaccines Is at Safe Levels
University of Rochester Medical Center
29-Nov-02
http://www.newswise.com/articles/2002/11/VACCINES.URM.html
Library: MED
Keywords: VACCINES MERCURY THIMEROSAL
Description: The first detailed analysis of
blood mercury levels in infants who received vaccines
containing the preservative thimerosal indicates that
blood levels of mercury in children are comfortably
below current safety limits. (Lancet, 30-Nov-2002)
For more information, contact:
Tom Rickey
(585) 275-7954
trickey@admin.rochester.edu
Embargoed for release at 6:30 p.m. Eastern Time
Thursday, Nov. 28, per Lancet embargo
Mercury in Vaccines Is at Safe Levels, Study Suggests
The first detailed analysis of blood mercury levels
in infants who received vaccines containing the
preservative thimerosal indicates that blood levels of
mercury in children are comfortably below current safety
limits. The study of 61 children by physicians and
scientists at the University of Rochester Medical
Center, published in the Nov. 30 issue of The Lancet,
also found that the form of mercury in vaccines is
eliminated from the blood much more quickly than
scientists had predicted.
"The results are very reassuring," says
pediatrician Michael E. Pichichero, M.D., the lead
investigator of the study and professor of microbiology
and immunology, pediatrics, and medicine. "The
amount of mercury is well below all established safety
levels."
The issue is at the core of a national debate over
the safety of vaccines. While some parents and
politicians have asserted that the minuscule amounts of
mercury used in vaccines could be responsible for a
range of disorders including autism in some children, no
scientific study has found a link. The current study
adds evidence to the argument by most pediatricians and
public health officials that vaccines are safe.
"Every day we see families who are reluctant to
have their children vaccinated because of this
issue," says Pichichero. "We work with them,
and many decide to go ahead with vaccinations, but some
do not, and so they put their children at increased risk
for developing serious diseases. It's no longer a
routine office visit."
During the 1990s the number of vaccines given to
infants increased markedly, with the addition of
immunizations against diseases like hepatitis B and
meningitis. Though each vaccine contained only a small
amount of thimerosal and a minute amount of mercury,
some became concerned that perhaps the cumulative
amounts might harm children.
In 1999, the American Academy of Pediatrics and
public health officials urged vaccine manufacturers to
remove thimerosal from vaccines administered in the
United States. The compound has since been removed from
nearly all vaccines given to U.S. children, though there
is no scientific evidence that the compound has harmed
children. The preservative is still used widely in other
countries to make vaccines available to millions of
children at a lower cost.
In response to the debate, the National Institute of
Allergy and Infectious Diseases (NIAID) asked vaccine
researchers at the University of Rochester Medical
Center to investigate. With funding from NIAID, the
Rochester team measured mercury concentrations in urine,
blood, and stools of 61 infants -- 40 received vaccines
containing thimerosal, and 21 received thimerosal-free
vaccines. All the children in the study had received
diphtheria-tetanus-acellular pertussis vaccine and
hepatitis B vaccine, and some also received Haemophilus
influenzae type B vaccine. The immunizations are
typically given to children at the ages of two months,
four months, and six months.
Most of the children in the study had blood mercury
levels of 1 or 2 nanograms per milliliter; the highest
level, found in one child, was 4.11 ng/ml. By
comparison, the most stringent public safety limit,
established by the Environmental Protection Agency, is
above 5.8 nanograms per milliliter. That number itself
is a small fraction of the amount that scientists
believe is the level of mercury that would actually harm
a child.
The team also found that children eliminate
thimerosal mercury from the blood six times faster than
predicted from data on methyl mercury, mostly through
the stools. The compound's "half life" in the
blood is 6 or 7 days, compared to the 45 days that
scientists had assumed. Thus, by the time a child
receives another round of vaccines containing mercury,
virtually all of the compound from the previous doses
has been eliminated.
Removing
thimerosal from U.S. vaccines has had several effects,
Pichichero says. Since vaccines don't last as long
without a preservative, the elimination of thimerosal
caused some vaccine makers to produce single-dose vials,
which are more expensive to produce, store, and ship.
For some vaccines, manufacturers use thimerosal
throughout the manufacturing process, then remove the
compound, which also adds to the cost of the vaccine.
Such actions raised the cost of vaccines, making it less
likely that they'll be used as widely as possible.
Thimerosal is still part of vaccines widely used in
other nations. In October the World Health Organization
announced guidelines suggesting that
thimerosal-containing vaccines are safe and should
continue to be used, a conclusion based partly on
Pichichero's findings.
"In countries that are still confronting
diseases like whooping cough and tetanus and measles,
where millions of children die of the disease, there is
no argument. Where people are dying of these diseases,
switching to a thimerosal-free vaccine would raise the
prices such that millions of children would go
unvaccinated.
"Although America can afford to pay a higher
price for newly formulated vaccines, much of the rest of
the world cannot afford the increased cost of
thimerosal-free vaccines. For them, it's a critical
issue of life and death."
While mercury is known to be toxic in high amounts,
scientists continue to debate the health effects of
exposure to very low levels. Everyone on Earth has some
mercury in the blood stream -- the chemical is present
naturally, from the belching of volcanoes, and is also
present in power-plant emissions. Everyone who smokes
cigarettes contributes a bit of mercury to the air we
breathe. Mercury is found especially in seafood like
swordfish and tuna; a tuna sandwich contains much more
mercury than a typical vaccine dose.
The University of Rochester team has just begun a
similar but larger study -- of about 200 children --
with funding from NIAID, to elaborate on the results of
the study published in the Lancet. The work is being
conducted with colleagues in Buenos Aires, Argentina,
since most vaccines now given to children in the United
States no longer contain thimerosal.
The research was done at the Vaccine Treatment and
Evaluation Unit that the NIAID funds at the University
of Rochester Medical Center. Also taking part in the
study were John Treanor, M.D., associate professor of
medicine and director of the Rochester VTEU; Elsa
Cernichiari, assistant professor in the Department of
Environmental Medicine; and Joseph Lopreiato, M.D., of
the National Naval Medical Center in Bethesda, Md.
|
|
 |
|
|
|
|
|
Dental
Information
