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 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 algam fillings in one population studied was more than 10 times the average for those with no amalgam fillings(27). As previously noted, there is no direct way of knowing exactly which mercury in mother’s milk came from amalgam or from fish.
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.
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)
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
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
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
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
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
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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