MERCURY TOXICITY: Dependence on Dose, Diet and Genetic Susceptibility

1
MERCURY TOXICITY Dependence on Dose, Diet and
Genetic Susceptibility

• DR. BOYD E. HALEY
• PROFESSOR AND CHAIR
• DEPARTMENT OF CHEMISTRY
• UNIVERSITY OF KENTUCKY

2
VISUALIZATION OF MERCURY EMITTING FROM A DENTAL
AMALGAM

• From www. uninformed consent.com
• David Kennedys IAOMT tape

3
Measurement of Mercury Release from a Standard
Dental Filling

• Amalgams of known weight and surface area were
  placed in a sealed test tube in 50 milliliters of
  H2O. H2O was changed daily and Hg level measured
  by a mercury cold vapor analyzer.
• Without brushing the amalgams released 7.54?g
  Hg/cm2/day.
• With two 30 second brushings with a medium
  toothbrush the amalgams released 45.5?g
  Hg/cm2/day, a six-fold increase.
• This confirms the earlier observation of Dr.
  Stock in 1926 in Zeitschr. Angew. Chem. 39,
  461-466.

4
Hg THIMEROSAL DISPLAY ADDITIVE TOXICITIES TO
NEURONS IN CULTURE.
5
MERCURY BIRTH HAIR LEVELS VS. AMALGAM FILLINGS IN
AUTISTIC AND CONTROL GROUPS
Control
Hair Hg level (mcg/g)
Data from A. Holmes, M. Blaxill B. Haley, Int.
J. of Toxicology v22, in press, 2003
Autistic
Number of amalgams
4-5
6-7
8-9
gt10
0-3
Control autistic ratio
2.64
6.93
6.70
6.32
17.91
N
22
29
30
43
15
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ACTUAL VERSUS PREDICTED BIRTH HAIR MERCURY LEVELS
Hair Hg level (5.60)0.04(amalgam
volume)1.15(fish consumption)0.03(vaccine)
R2 0.79
Predicted hair Hg level (mcg/g)
Data from A. Holmes, M. Blaxill B. Haley, Int.
J. Toxicology, in press, 2003
Actual hair Hg level (ng/g)
7
BIRTH-HAIR MERCURY BY SEVERITY OF AUTISM
Hair Hg level (ppm)
Data from Amy Holmes, Mark Blaxill Boyd Haley,
Int. J. Tocicology v22, in press, 2003.
Mild Mean0.71 n27
Moderate Mean0.46 n43
Severe Mean0.21 n24
8
CONTRAST BETWEEN BIRH HAIR Hg LEVELS AND BODY Hg
LEVELS

• Autistic children have much lower Hg levels in
  their birth hair, yet
• Numerous physicians have reported that autistic
  children carry a 5 to 6-fold higher mercury body
  burden than control children.
• The obvious explanation is micro-mercuralism
  genetic susceptibility to retention toxicity.
• There is an obvious gender difference. This is
  explained by testosterone effects on T-toxicity.

9
ACROYDYNIA Pink Disease

• Acroydynia was prevalent from about 1880 until
  1940 affecting about 1 in 500 children. It was
  found to be caused by mercurous chloride
  (calomel) in baby teething powder. Removal of
  this teething powder from the market eliminated
  this disease which had some similarity to autism.

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MOST IMPORTANT CONCLUSIONS

• THERE APPEARS TO BE A SUBSET OF THE POPULATION
  THAT CANNOT EFFECTIVELY EXCRETE MERCURY AND ARE
  AT GREATER RISK TO EXPOSURES TO MERCURY THAN ARE
  THE GENERAL POPULATION.
• THIS SUSCEPTIBILITY IS LIKELY DUE TO GENETIC
  DIFFERENCES, DIET, EXPOSURE TO OTHER TOXICANTS,
  ANTIBIOTICS, ETC.
• DOES UNEXPLAINED LOW HAIR, NAIL, BLOOD OR URINE
  LEVELS APPEAR IN OTHER NEUROLOGICAL OR SYSTEMIC
  DISEASES?

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ELEVATED MERCURY IN IDIOPATHIC DILATED
CARDIOMYOPATHY (IDCM). WHERE DOES Hg COME FROM?

• LEVELS ng/g Hg Sb
• Controls 8.0 1.5
• IDCM 178,400 19.260
• This is a 22,300 fold increase in Hg!
• Frustaci et al., J. of American College of
  Cardiology, 33, (6) 1578, 1999. Controls were
  patients with valvular or ischemic heart disease.
  Athletic youth die of IDCM.

12
M. Bauman K. Nelson Paper

• In contrast, in the Sechylles study of gt700
  children, exposure was to marine fish only, and
  boys with higher levels of hair mercury performed
  better on some tests, including the Boston Naming
  Test and 2 tests of visual motor coordination.
• The above observation has lead some to dismiss Hg
  as being causal for any neurological problems in
  youth.
• However, it is likely in light of the autistic
  observations that the boys with higher hair Hg
  levels were the best at excreting Hg or Methyl-Hg.

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CARDIOVASCULAR DISEASE AND MERCURY

• Two studies have found a correlation between
  cardiovascular disease and Hg. Guallar et al.
  NEJM v347,1747,2003 Salonen et al.
  Atherosclerosis v148, 265, 2000.
• However, a Faeroe Island study found that blood
  pressure was increased in 7 year old children
  when the blood Hg levels were BELOW 10?g/liter,
  but not when it was higher! Sorensen et al.
  Epidemiology v10, 370, 1999 as reported by
  Clarkson et al. NEJM 2003.
• If ingestion rates of mercury were the same then
  the above results imply that low blood levels of
  Hg are caused by failure to excrete the mercury.

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Hg Levels in Human Brain

• Saxe et al, determined Hg levels in the brains
  of 101 human subjects, both AD and normals,
  mostly Catholic Nuns (Alzheimers Disease, Dental
  Amalgam and Mercury, JADA v130, p191-199, 1999).
• The histogram in this paper showed 6 of 101
  subjects with brain Hg levels above 200 ng/g wet
  weight (C236, 248, 319 AD394, 622, 698). This
  represents between 1.2 3.5 micromolar, or
  highly toxic levels of Hg in 6 of these
  subjects. At 100 ng/g Hg this increases to about
  15 of subjects with highly toxic levels of brain
  mercury.
• Hg levels were double in the control olfactory
  tissue!
• Where does this Hg come from? Why is it elevated
  in certain individuals? This also appears to be
  an inability to excrete the mercury as the
  authors state Hg levels were not correlated with
  number of amalgam fillings.

15
Hg levels in AD brain

• Ehmann, Markesbery, et al. Transactions of the
  American Nuclear Society, 41, 206-207, 1982
  entitled Brain Trace Element Studies of Aging
  and Disease by INAA INAA instrumental neutron
  activation analysis.
• Tested for Ag, Br, Co, Cr, Cs, Fe, Hg, Rb, Sb,
  Sc, Se and Zn.
• Quote In the comparison of Alzheimers disease
  and control brains, the largest differences were
  observed for bromine and mercury, both being
  enriched in Alzheimers brains (p lt 0.05).

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Hg levels in hair nails of AD

• Ehmann, Markesbery et al. Neurotoxicology
  9(2)197-208. Trace Element Imbalances in Hair
  and Nails of Alzheimers Diseased Patients.
• Quote The concentrations of 17 elements in the
  hair and nails of 180 Alzheimers disease (AD)
  and control subjects have been determined by
  instrumental neutron activation analysis (INAA).
• Mercury is decreased in the nail of AD subjects
  compared to controls
• Perhaps one reason for the lowering of nail Hg
  in AD subjects could be the presumably lower
  exposure rate of the AD patients to environmental
  Hg. This would not explain the elevated brain
  Hg, however.

17
Hg in nails of AD subjects

• Ehman, Markesbery et al. Biological Trace
  Element Research, pp461-470. EditorG.N.
  Schrauzer, 1990 by the Humana Press, Inc.
• A Search for Longitudinal Variations in Trace
  Element Levels in Nails of Alzheimers disease
  patients.
• Quote Mercury tended to decrease in nail with
  increasing age of patient, and with the duration
  and severity of the dementia.

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Hg in nails of AD subjects

• Ehman, Markesbery et al. Biological Trace
  Element Research, pp461-470. EditorG.N.
  Schrauzer, 1990 by the Humana Press, Inc.
• A Search for Longitudinal Variations in Trace
  Element Levels in Nails of Alzheimers disease
  patients.
• Quote This decrease is counter to the elevated
  levels of Hg observed in AD brain, as compared to
  age-matched controls.

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Hg Brain/Nail or Hair Ratios in AD versus Normal
Subjects

• In a manner similar to that observed for autistic
  children the body burden of mercury in AD
  subjects appears to be elevated compared to
  controls whereas the mercury levels in the hair
  and nails was found to be significantly lower.
• Perhaps these AD subjects could not excrete Hg as
  effectively as the normal subjects.
• Do other experiments show any correlation between
  amalgam and brain Hg levels? Yes.

20
Brain Hg levels versus Number Amalgam Surfaces
From Dr. Magnus Nylanders Research. The scatter
in this graph, where high levels of Hg are
observed with low amalgam surface count and low
levels are observed with high amalgam count, and
vice versa, is what would be expected if the
individual subjects were differentially capable
of excreting mercury. Similar results are seen
doing similar analysis on fetal tissue and
comparing Hg levels to birth mothers amalgam
count. The low Hg levels found in alcohol abusers
also implies that diet may play a role in mercury
retention.
21
SYNERGISTIC TOXICITIES on NEURONS IN CULTURE
AlNEOMYCINTESTERONE EFFECTS
50 NANOMOLAR
DR. MARK LOVELL COLLABORATOR
TESTOSTERONE
22
Antibiotics, Milk and Hg Half-Life

• In a study where rats were given high doses of
  oral antibiotics the half-life for excretion of
  mercury increased from 10 days to gt100 days.
• If the rats were also on a milk diet the
  excretion half-life increased to over 300 days.
• (Rowland, Archives of Environmental Health 1984
  39(6) 401-408)
• It appears obvious that the cellular retention of
  Hg is dependent on genetics, diet and medical
  treatment. Increased cellular retention is an
  excretion problem.

23
Axonal Transport - A Process Essential for the
Survival of Neurons
Dendrite
Membrane Bound Organelle
Axon
Dynien
Microtubule, made of polymerized tubulin dimers.
Kinesin
24
Autoradiogram of 32P8N3GTP Photolabeled
Control AD Brain Hippocampus Homogenates
25
EDTA Prevents Cd, Cu Zn, But Not Hg,
Inhibition of 32P8N3GTP Photolabeling of Brain
ß-Tubulin
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Partitioning of ß-Tubulin is Aberrant in
Alzheimers Diseased Brain Homogenates
NORMALS
NORMALS
ALZHEIMERS
NORMALS
ANTIBODY DETECTION OF BETA-TUBULIN
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MERCURY AND ALZHEIMERS DISEASE

• Exposure of neuroblastoma cells to 10-9 molar
  mercury increases Tau phosphorylation and
  secretion of beta-amyloid. Both of these events
  occur in Alzheimers diseased brain. Amyloid
  plaque formation is the diagnostic hallmark of
  Alzheimers disease. Olivieri et al. J.
  Neurochemistry, 74, 231, 2000.
• Exposure of cultured neurons to 10-7 to 10-10
  molar mercury rapidly causes the stripping of
  tubulin from the neurofibrils forming the neurite
  processes leading to the formation of
  neurofibillary tangles, a diagnostic hallmark
  of Alzheimers disease. Leong et al.
  NeuroReports 12(4), 733, 2001
• Therefore, Hg exposure can create these
  diagnostic hallmarks of Alzheimers Disease!

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HgEDTA Induces Aberrant 32P8N3GTP-ß-Tubulin
Interactions Indicative of AD
29
EFFECT OF SEQUENTIAL AMALGAM EXTRACTION SOLUTIONS
ON THE VIABILITY OF BRAIN TUBULIN
Active
Hours of Amalgam Soak
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PROTEINS INVOLVED IN Hg EXCRETION

• GLUTATHIONE (carries Hg through bilary transport,
  rapidly oxidized by excess Hg2. Note Hg2 must
  go intracellular to interact with GSH, then be
  excreted for clearance in the bilary transport
  system of the liver.
• GLUTATHIONE TRANSFERASE, a recent gene product
  identified with AD risk.
• METALLOTHIONINE (Dr. W.Walshs work, regulated by
  estrogen and testosterone). This may explain
  gender susceptibility.
• APO-E (apo-lipoprotein-E, a brain housekeeping
  protein that carries cholesterol from the brain
  through the CSF, through the blood-brain barrier
  for excretion by the liver bilary transport
  system.) This may explain additional excretion
  deficit.

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Biochemical Differences Between the Three Most
Common Apolipoprotein E Isoforms is Reflected in
Hg Binding Capacity
2 Mercury binding sites
LOW RISK FOR EARLY AD
1 Mercury binding site
No Mercury binding sites
HIGH RISK FOR EARLY AD
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RELATIONSHIP TO NUMBER OF APO-E SH GROUPS AND
AGE OF AD ONSET

• APO-E? 2 3 4
• ?
• 2 4 (gt90) 3 (gt90) 2 (80-90)
• 3 3 (gt90) 2 (80-90) 1 (70-80)
• 4 2 (80-90) 1 (70-80) 0 (lt70)

RED APO-E GENOTYPE COMBINATION YELLOW NUMBER
OF SH GROUPS IN COMBINATION WHITE APPROXIMATE
AGE OF ONSET OF AD
33
M. Godfrey, et al. APO-E Geneotyping as a
Potential Biomarker for Mercury Neurotoxicity. J.
of Alzheimers Disease (June 2003)

• 400 subjects with a mean of 13.7 amalgams, with
  previously diagnosed neurological problems, were
  compared to 426 blood donors with regards to
  APO-E geneotype.
• It was found that the symptomatic cohort was
  significantly elevated in percentages of 4/4 (3.5
  vs 1.0 ) and low in the 2/2 (0.25 vs 1.4) in
  comparison to the blood donors.
• In mixed geneotypes 2/3 (9.5 vs 20) and 3/4 (30.8
  vs 25) similar skewed ratios were found.
• The 3/3 homozygote was found at 54.8 and 51.4 in
  the symptomatic and blood donor groups,
  respectively.

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Effect of Removal of Amalgams Antioxidant
Therapy on Patient Symptoms and Blood Hg Levels.
Controls matched with test groups in age, gender
socio-economic conditions. They were
subjectively healthy persons not suffering from
any disease.
U. Lindh et al., Neuroendocrinology Letters, v23,
459, 2002.
35
CONCLUSIONS WITH REGARD TO AD

• MOST, IF NOT ALL, ABERRANT BIOCHEMISTRY IN AD
  BRAIN CAN BE MIMICKED BY Hg.
• THE DIAGNOSTIC HALLMARKS OF AD BRAIN CAN BE
  PRODUCED BY Hg CONCENTRATIONS LOWER THAN REPORTED
  IN HUMAN BRAIN.
• THE BIOLOGICAL PLAUSIBILITY OF Hg BEING CAUSAL IN
  AD IS MORE COMPLETE THAN THIMEROSAL CAUSATION OF
  AUTISM.
• WHILE THERE HAS BEEN NO SIGNIFICANT
  EPIDEMIOLOGICAL STUDY ON Hg EXPOSURE AND AD, AND
  REASONABLE PEOPLE COULD DISAGREE ABOUT THE
  CAUSALITY, THERE IS NO DOUBT THAT EXPOSURE TO Hg
  WOULD EXACERBATE AD!

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CONCLUSION REGARDING AMALGAM FILLINGS

• DUE TO THE ENHANCEMENT OF Hg TOXICITY AND
  RETENTION BY FACTORS FOUND IN THE DIET,
  ANTIBIOTICS, OTHER TOXICANTS SUCH AS Pb2 Cd2,
  AND GENETIC SUSCEPTIBILITY THERE CANNOT BE ANY
  REASONABLE PREDICITION OF A SAFE LEVEL OF MERCURY
  EXPOSURE WITHIN THE LEVELS PRODUCED BY HAVING
  AMALGAM FILLINGS.
• MERCURY FROM THE BIRTH MOTHERS AMALGAMS IS FOUND
  IN THE CHILD ON BIRTH.