Review by B. Windham of
Prenatal methylmercury exposure from ocean fish consumption in the
The study methodology and
design ignored known facts about mercury and study methodology to the extent
that the study is flawed and the results are not very reliable or useful for
the purpose proposed by the authors. The
following 6 sections summarize the main problems with the study based on other
studies in the literature.
I. The
Scope and Usefulness of the Study Was Very Limited by Weak Design and Lack of
Controls
The authors and some quoting the study appear to imply broad
scope for the study although its scope is extremely limited by its lack of
attention to design and lack of attention to cofactors. The fact that several
of the assumptions underlying the study design are known not to be valid
presents serious problems in assessing its usefulness. By the design of the study the authors assume
that the cognitive measures used in the tests chosen for the study are only or
primarily affected by methyl mercury exposure. That this is not true is well
documented in the medical literature, and in this case there was no evidence
presented that methyl mercury from fish was the primary neurological factor
affecting this population. Other toxic metals including mercury vapor from
dental amalgam, ethyl mercury from vaccines, and other heavy metals such as
lead, arsenic, cadmium, aluminum, etc. are documented to have common
significant exposures and to cause significant neurological effects. And other
toxic exposures such as organochlorines, PCBs, dioxins, etc. are known to have
significant exposures in such populations and to have significant neurological
effects. Based on experience with such populations and other studies, many in
the study likely had significant neurological effects from other toxic
exposures. Many other studies have
considered such factors in their design to a larger extent than this one. As
will be demonstrated further in section II, there is no reason to assume that
methyl mercury from fish was the primary neurological toxic affecting many in
this population. And even if it were,
the effects of the other toxic exposures that were not measured would confound
the results significantly.
In Section
. In Section IV it will be shown
that the decision to exclude the results of some groups of those tested in the
study from consideration may have caused additional confounding of the study
results, since there is considerable evidence in the medical literature that
mercury exposure commonly causes some of the conditions of those whose test
results were excluded.
Another of the main assumptions
underlying the study that is known not to be valid is the assumption that the
neurological effects measured are directly or even primarily directly dose
related. It has been well demonstrated
in the medical literature that while exposure level is a factor, it is not the
primary factor in many cases. In Section
V it will be shown that susceptibility factors such as ability to detoxify or
excrete mercury and immune reactivity play a major role in the extent to which
a person is affected by mercury toxicity or immune reactive effects, and that
the degree to which effects are directly dose related in real life is not very
high.
In Section VI it will be shown that
many studies have found neurological effects and other effects at similar
levels of exposure, and many were better designed and controlled.
In Section VII it will be shown that the types of mercury
related effects tested for and the tests chosen were extremely limited, even
among neurological effects, given the well documented broad scope of neurological,
immune, and endocrine effects documented as related to low levels of mercury
exposure by the medical literature. Mercury has been documented to block basic
cellular enzymatic processes affecting all major functions of all major
organs-especially those related to neurological, immune, detoxification, and
endocrine functions. And immune effects or effects on other detoxification and
endocrine organs that occur at very low levels of exposure have been shown to
have long term neurological effects. Many
other studies have considered and demonstrated the significance of such effects
at levels of exposure such as those in this study
II. No Controls for Other Comparable
Synergistic and Perhaps Larger Mercury Exposure Sources and Other Synergistic
Toxic Exposures
A large flaw is that the
study ignored and did not control for other mercury or toxic metal exposures
such as dental amalgam fillings and vaccinations, which likely in many cases
were the largest mercury exposure to the mother and child (1-5). In general it
has been documented that dental amalgam is the largest source of total,
inorganic, and methyl mercury in most people who have several mercury amalgam
dental fillings in most populations (1,2). Mercury vapor and inorganic mercury
have been found to commonly be methylated by mouth and intestinal bacteria, as
well as yeast and other methyl donors (1,2). While the
Dental
amalgam from mother’s amalgam fillings has been documented to be a major source
of mercury exposure to the fetus and to infants (5,27). Mercury in breast milk is positively
correlated with the number of the mother’s amalgam fillings. Mercury in breast milk of mothers with more
than
Other
toxic metals including dental metals also are documented to have significant
synergistic neurological effects with mercury on children and to commonly have
significant exposures in such populations of children (3,4,8,9,12).
Other toxic exposures such as pesticides,
PCBs, and other neurotoxic and endocrine disrupting substances are common
exposures that could confound these results(18,29). In one study of Inuit
children, potential covariates were documented including demographic and
familial characteristics, other prenatal neurotoxicants (alcohol, tobacco) and
nutrients (selenium (Se), Omega-3 polyunsaturated fatty acids (n-3 PUFA))(29). Concentrations of polychlorinated biphenyls
(PCBs) and mercury were respectively three- and twofold higher, significantly
greater, in the subsistence fishing group than in the reference group(33).
For
some of the test outcomes, neuromotor effects of Pb exposure are observed at
blood concentrations below 10 microg/dl.
Together the lack of taking into
account of these common neurotoxic exposures in this study resulted in a major
confounding of the stated conclusions. Nor did the study mention the protective
effects of selenium in some of the fish species that were eaten, or attempt to
measure selenium levels to assess its differential protective effects on the
population. Although methyl mercury is documented to be extremely neurotoxic at
low levels of exposure, many species of fish are documented to contain
significant levels of selenium which is known to be protective against
neurotoxic effects of mercury(23).
Selenium protects from mercury and methyl mercury toxicity by preventing
damage from free radicals or by forming inactive selenium mercury complexes (20). Other nutritional factors are also documented
to have significant effects on neurotoxicity of mercury(11,20).
III. Hair Mercury Level
Used as a Measure of Mercury Exposure in the Study is Not a Reliable Indicator
of Either Mercury Body Burden or Mercury Toxicity
The authors assumed that hair test mercury levels of mother
and infant are reliable indicators of current or future body burden, which
isn't supported by experience or research.
A study by Dr. Haley(PhD) and Dr. Holmes(MD) found that among some mercury affected
populations, those with high mercury body burdens and diagnosed mercury
toxicity effects tend to have lower hair levels, not higher(7). Other
researchers based on extensive clinical experience treating mercury toxic
patients have found similar results(8,9).
Also since the population likely had significant mercury exposure from
dental amalgam and vaccinations, the fact that hair mercury level mostly
measures methyl mercury, whereas urine mercury levels are a better measure of
dental amalgam exposure but weren’t measured, further confounds the results(10).
Another study concluded that for the so-called normal population, the interpretation potential of heavy
metal concentrations in blood, urine, and hair must be qualified: on a group basis, they can provide us with
some useful information under the limitation that not every monitor is suitable
for every metal. But despite statistical significant
rank correlation, the confidence intervals of the regressions are
so large that it is rather pointless to conclude the heavy metal burden of the
target or storage tissue of an individual from the concentration in blood,
muscle, urine, or hair(21).
A Japanese study
with average maternal hair mercury level of 2.24 ppm found a positive
correlation between fetal cord tissue methylmercury level and indicators of
cardiac parasympathetic activity and sympathovagal shift indicating
cardiovascular effects. However cord
mercury level was not significantly correlated with child hair mercury level,
and hair mercury level was not significantly correlated with cardiovascular
effects. (28)
In regression analysis failure to adjust for imprecision in
the exposure variable is likely to lead to underestimation of the exposure
effect(26). It is shown that, if the exposure error is ignored, then the
benchmark approach produces results that are biased toward higher and less
protective levels. It is therefore important to take exposure measurement error
into account when calculating benchmark doses. . The calculated total
imprecision much exceeded the known laboratory variation: the CV was 28-30% for
the cord-blood concentration and 52-55% for the maternal hair concentration.
The dietary questionnaire response was even more imprecise. These findings
illustrate that measurement error may be greatly underestimated if judged
solely from reproducibility or laboratory quality data. Adjustment by
sensitivity analysis is meaningful only if realistic measurement errors are
applied. When exposure measurement errors are overlooked or underestimated,
decisions based on the precautionary principle will not appropriately reflect
the degree of precaution that was intended.
IV. Deletion from the Study Results of Infants
Suffering from Health Conditions Known to be Commonly Caused by Mercury
Toxicity
Study Participants. The authors write:
“We excluded mothers and
children with disorders highly associated with adverse neurodevelopment such as
traumatic brain injury, meningitis, epilepsy, and severe neonatal illnesses. No
data exist to suggest they are associated with MeHg exposure.”
The authors however
clearly were mistaken, as some of these conditions for which children were
excluded from the study results have been well documented to be commonly caused
by mercury toxicity (12-15,5,7).
The following Table is a
summary of data from a large epidemiological study by the National Institute of
Health of health statistics related to number of dental amalgam surfaces.
Table 1.
NHanesIII Condition
Graphs, 35,000 Americans
(Conditions highly
correlated with number of amalgam fillings: fewer of those with this condition
have zero fillings than those of the general population while more of those
with the condition have 17 or more surfaces than in the general population)
Infectious and parasitic diseases (001-139)
Disorders of thyroid gland (240-246)
Mental disorders (290-319)
Diseases of the nervous system and sense organs (320-389)
Other disorders of the central nervous system(Epilepsy, Seizures, MS) (340-349)
Incidence
of the category of neurological conditions made up primarily of Epilepsy and MS
was found to be highly correlated with the number of dental amalgam surfaces by
the NHANES
Likewise, the NHANES study and other studies have
found that there is a significant correlation between mercury exposure and
infectious conditions such as meningitis so exclusion of these children without
further consideration may have also been problematic. (13,16abc)
Mercury
is documented to significantly suppress the immune system, and a suppressed
immune system is known to result in higher susceptibility to infectious
diseases(24). High levels of mercury
exposure has been found to result in meningitis in animal studies and
humans(22)
Mercury and toxic
substances effects on suppressing the immune system also are documented to
cause increased susceptibility to other pathogens such as viruses, mycoplasma,
bacterial infections, and parasites. The majority of those with autoimmune
conditions like
Likewise
mercury has been documented to commonly cause birth defects and neonatal
developmental conditions and illnesses, so excluding some of these children
without further investigation might also be a further confounding
factor(3,4,8,9,14).
V. Neurological effects are not primarily directly
dose related as
Susceptibility factors are known to have a major effect
The Study did not
take into account that mercury effects on children and adults are well documented
in the literature to be highly influenced by susceptibility factors, with
effects primarily on significant groups
that have known and testable susceptibility factors(17). Some of the common
significant susceptibility factors that determine the extent of mercury
toxicity effects on an individual include immune reactivity, ability of the individual’s
detoxification systems to detoxify and excrete mercury and other toxics, nutritional
factors, etc.
VI. Other Studies Finding
Neurological Effects from Similar Levels of Exposure
One study was of a Faroese birth
cohort prenatally exposed to methylmercury from maternal intake of contaminated
pilot whale meat. At seven years of age, clear dose-response relationships were
observed for deficits in attention, language, and memory. An increase in blood
pressure was also associated with the prenatal exposure level. The exposure
limit for mercury has therefore been decreased(30). A follow-up for the same population at age 14
found that the child's hair mercury level at age 14 years was associated with
prolonged
Another study of Greenland infants at exposure
levels slightly less than the Seychelles study found that “data from the
present study therefore appears in accordance with other evidence that prenatal
or early postnatal exposures to methylmercury may cause subtle neurobehavioral
deficits” (31). In a study of Inuit
children, cord blood, maternal blood, and maternal hair mercury concentrations
averaged 18.5 microg/L, 10.4 microg/L, and 3.7 microg/g, respectively, and were
similar to those found in the Faeroe Islands but lower than those documented in
the Seychelles Islands and New Zealand cohorts(29). Concentrations of PCB
congener 153 averaged 86.9, 105.3, and 131.6 microg/kg (lipids) in cord plasma,
maternal plasma, and maternal milk, respectively; prenatal exposure to PCBs in
the Nunavik cohort is similar to that reported in the Dutch but much lower than
those in other Arctic cohorts. Levels of n3-PUFA in plasma phospholipids and
selenium in blood are relatively high. Tremor
amplitude was related to blood Hg concentrations at testing time, which
corroborate an effect already reported among adults.
Cord blood Hg in a study of a population living
along the
Another study assessed infant
cognition by the percent novelty preference on visual recognition memory (VRM)
testing at 6 months of age. An increase
of 1 ppm in mercury was associated with a decrement in VRM score of 7.5 (95%
CI, -13.7 to -1.2) points. (11) VRM scores were highest among infants of
women who consumed greater than 2 weekly fish servings but had mercury levels
less than 1.2 ppm. Levels of mercury in
mothers greater than 1.2 ppm were found to have negative health effects on
infants. And without the positive omega
3 effects, this level of exposure likely would produce even more adverse
effects.
Concentrations
of polychlorinated biphenyls (PCBs) and mercury were respectively three- and
twofold higher, significantly greater, in the subsistence fishing group than in
the reference group(33). Compared to the reference group, the subsistence
fishing group showed significant decreases in the proportion of the naive
helper T-cell subset CD4+CD45RA, T-cell proliferation following an in vitro
mitogenic stimulation, and plasma immunoglobulin M (IgM) level, while plasma
IgC level was increased. NK cytolytic activities were similar in both groups.
The proportion of CD4+CD45RA cells was inversely correlated to mercury and
PCBs, while T-cell clonal expansion was negatively associated with PCBs and
p,p'-DDE. Mercury was inversely correlated to plasma IgM. Data show that subtle functional alterations
of the developing human immune system may result from in utero exposure to OrganoChlorines
and mercury.
A Polish study found that the
mean blood mercury level of the mothers of a group of normal infants was
significantly lower than that of a group of neurocognitively delayed infants
and the cord blood mercury level of the normal infants was significantly less
than for the group with delayed cognitive performance (34). The relative risk of delayed performance for
those with cord blood level greater than 0.8 micrograms per liter was 3.5 times
that of those with level less than 0.5 ug/L.
Autopsy studies have also found that
chronic mercury exposures result in cumulative increases in mercury in the
brain and other body organs over time, and that mercury damage is cumulative
and often only noticed later in life(24).
Studies have also found that neurotoxic effects of developmental mercury
exposures are often delayed(35). Mercury exposures in a population of adults
studied were associated with fish consumption(36). The hair mercury
concentration in the 129 subjects ranged from 0.56 to 13.6 microg/g; the mean
concentration was 4.2 +/- 2.4 micrograms/g and the median was 3.7 microg/g.
Hair mercury levels were associated with detectable alterations in performance
on tests of fine motor speed and dexterity, and concentration. Some aspects of
verbal learning and memory were also disrupted by mercury exposure. This study found
that adults exposed to MeHg may be at risk for deficits in neurocognitive
function. The functions disrupted in adults, namely attention, fine-motor
function and verbal memory, are similar to some of those previously reported in
children with prenatal exposures(36).
The
paper used a limited number of neurological tests and did not include other tests
for neurological conditions or other types of conditions and effects that
mercury has been documented to cause. Yet the authors tend to imply that the
study represents a broad generally applicable assessment of mercury effects on
children due to prenatal exposures. This
is clearly not the case and is counter to extensive documentation in the
medical literature of chronic effects due to mercury at comparable or lower
levels of exposure. (3-9, 11-15,24)
Chronic
exposure to mercury has been documented in the medical literature to result in
distribution of mercury in the blood to all parts of the body where it accumulates
in major organs receiving large amounts of blood and damages or blocks all
bodily enzymatic or hormonal processes(24,etc.). These effects have been documented in the
medical literature to commonly result in neurological, immune, and endocrine system
effects. The mechanisms by which mercury
commonly causes over 30 chronic health conditions has been documented by
thousands of peer-reviewed studies(24,etc.), with susceptibility factors having
a major role in the resulting conditions affecting an individual(17).
Mercury
has several forms and exists in solid, liquid, and gaseous states that are
converted to other forms and states in the body, moving rapidly through the
blood, crossing cell membranes, and forming compounds in the cells that result
in accumulation in major organs, depending on the individuals systematic
ability to detoxify and excrete mercury. For these reasons as has been
documented in the literature, there is no simple test that is a reliable
indicator of mercury body burden or mercury toxicity effects(37). Because the
effects of mercury are systematic and diverse it is not possible to do a simple
epidemiological study to develop a benchmark exposure level that is reliable
for all of the diverse systematic effects of mercury which affect different
individuals in very different ways depending on their individual
susceptibilities. And the many other
toxic exposures that most populations are exposed to and the fact that
susceptibility and nutritional factors have major impacts on mercury toxicity
effects further complicates any effort in using an epidemiological study to
develop a benchmark or baseline exposure level below which exposures are
unlikely to have significant effects. The many bodily processes and organs
affected by mercury are affected at different exposure levels depending on the
organ/function and the individual. It
has been documented for example that some who are immune reactive to mercury
have very significant effects at extremely low levels of exposure. The following provides documentation on the
mechanisms by which mercury causes significant systematic effects on all
enzymatic processes in all organs of the body.
Studies
have found heavy metals such as mercury
to deplete glutathione and bind to protein-bound sulfhydryl SH groups,
resulting in inhibiting SH-containing enzymes and production of reactive oxygen
species such as superoxide ion, hydrogen peroxide, and hydroxyl
radical(40-44). In addition to forming
strong bonds with SH and other groups like OH,NH2, and Cl in amino acids and
thus interfering with basic enzymatic processes, toxic metals exert part of
their toxic effects by replacing essential metals such as zinc and magnesium at
their sites in enzymes (45-47,14). . Mercury has also been found to play a part
in neuronal problems through blockage of the P‑450 enzymatic process(48,43). Such
affects have been found to commonly result in mental retardation, lowered IQ,
and learning disabilities (40).
Mercury induced lipid peroxidation has been found to be a major factor in
mercury’s neurotoxicity, along with leading to
decreased levels of glutathione peroxidation and
superoxide dismustase(SOD)(41,42,47-53). Mercury also
blocks the enzyme functions of magnesium and zinc (45-47,14), whose
deficiencies are known to cause significant neurological effects(54,55,14). The
low Zn levels result in deficient CuZnSuperoxide dismustase (CuZnSOD), which in turn leads to increased levels of
superoxide due to toxic metal exposure. This condition can result in zinc
deficient SOD and oxidative damage involving
nitric oxide, peroxynitrite, and lipid peroxidation(50-52,56), which have been found to affect
glutamate mediated excitability and apoptosis of nerve cells and effects on
mitochondria
(45,51,52,56,59,61). Additional cellular level enzymatic
effects of mercury’s binding with proteins include blockage of sulfur oxidation
processes such as cysteine dioxygenase,
gamma‑ glutamyltranspeptidase(GGT), and
sulfite oxydase, along with neurotransmitter amino
acids which have been found to be significant factors in many autistics(57-60),
plus enzymatic processes involving vitamins B6 and B12, with effects on the cytochrome-C energy processes as well.
Mercury by forming strong bonds with
and modification of the-SH
groups
of proteins and enzymes causes mitochondrial release of calcium
(45,61),as
well as changing the permeability of cell membranes(62),
damaging
mitochondria (45,59,61,51,52) altering molecular function of
amino
acids and damaging enzymatic process(59,62-64). This results
in
improper
cysteine regulation(63,65), inhibited glucose
transfer and
uptake(62,49),
damaged sulfur oxidation processes (59,62,65), reduced
glutathione availability (necessary for
detoxification) (41,67), and
damaging
DNA(66).
TNFa(tumor necrosis factor-alpha) is a
cytokine that controls a wide range of immune cell response in mammals,
including cell death(apoptosis). This
process is involved in inflamatory and degenerative
neurological conditions like
Metalloprotein(MT) are involved in metals transport and
detoxification(69,14). Mercury inhibits sulfur ligands
in MT and in cell membranes inactivates MT that normally bind cuprous ions(70),
thus allowing buildup of copper to toxic levels in many people and malfunction
of the Zn/Cu SOD function. Exposure to
mercury results in changes in
metalloprotein compounds that have
genetic effects, having both structural and catalytic effects on gene
expression(66,69-71,14,51,). Some of the
processes affected by such MT control of genes include cellular respiration,
metabolism, enzymatic processes, metal-specific homeostasis, and adrenal stress
response systems. Significant physiological changes occur when metal ion
concentrations exceed threshold levels. Copper is an essential trace metal
which plays a fundamental role in the biochemistry of the nervous system
through the SOD and MT functions(50,51,14). Mutations in the copper/zinc enzyme
superoxide dismustase(SOD) have been shown to be a
major factor in the motor neuron degeneration in conditions like familial
Such
MT formation and disfunction also appears to have a
relation to
autoimmune reactions in significant numbers
of people (64,69,71-73,14).
The enzymatic processes blocked by
such toxic substances as mercury also
result in chronic formation of metal‑protein
compounds (HLA antigens or
antigen-presenting
macrophages) that the body’s immune
system(T-
lymphocytes)
does not recognize, resulting in autoimmune reactions and
autoimmune conditions (64,68,71-73). Of the over 3,000 patients with
chronic conditions tested using the
MELISA test for lymphocyte reactivity to
metals(72), 20% tested positive for
inorganic mercury and 8% for methyl
mercury.
For people with autoimmune conditions such as
or Multiple Chemical
Sensitivity, the percentage testing
immune reactive to
mercury was higher-
23% to inorganic mercury, and 12% to methyl
mercury, as compared to less than 5% for
controls.
And the percentage of those with
MS testing positive to mercury was over
70%, with significant reductions
in reactivity and symptoms when mercury
levels were reduced(73). The mechanisms
by which mercury exposure
causes over 30 chronic conditions has
been documented in the medical
literature(24), as well as documentation of
common recovery from these
conditions after treatment for mercury
toxicity(25,9.14).
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