The AutismMercury Connection

1
The Autism-Mercury Connection

• Prof. James B. Adams, Ph.D.
• Chemical and Materials Engineering
• Arizona State University
• President, Greater Phoenix ASA
• Representative of national ASA to NIEHS
• Father of a 13-yr-old girl with autism

2
Genetic or Environmental Cause?

• Studies of identical twins reveal
• Co-occurrence is 40-80 if 100, then only due
  to genes so genes are important, but so are
  unknown environmental factors
• If a couple has one child with autism, then 5-10
  chance other children will have autism, and 25
  chance of major speech delay (so carefully
  monitor siblings)

3
What are the most likely environmental factors?

• More research is needed, but the most common
  hypotheses are
• Mercury and other heavy metals
• Measles virus
• GI bacteria
• Nutritional deficiencies

4
Summary of the Autism-Mercury Link

• Mercury is a deadly neurotoxin
• Mercury exposure at dangerous levels is common in
  the US
• Symptoms of mercury poisoning mimic autism
• Children with autism have limited ability to
  excrete mercury
• Children with autism have high levels of mercury
  in their bodies
• Severity of autism strongly correlates with
  mercury levels
• DMSA is a medication which has been proven to
  remove mercury from children with autism.
• Many physicians have reported on the safety and
  efficacy of DMSA therapy for children with autism.

5
Mercury is a deadly neurotoxin.

• Mercury damages and kills neurons.
• Mercury replaces zinc in enzymes, affecting over
  80 enzymatic reactions in the body.
• Mercury depletes glutathione.

6
Symptoms of Mercury Toxicity in Infants

• According to the ATSDR Toxicity Profile on
  mercury
• Mercury is considered to be a developmental
  toxicant. The symptoms observed in offspring of
  exposed mothers are primarily neurological in
  origin and have ranged from delays in motor and
  verbal development to severe brain damage.
• The infant may be born apparently normal, but
  later show effects that may range from the infant
  being slower to reach developmental milestones,
  such as the age of first walking and talking, to
  more severe effects including brain damage with
  mental retardation, incoordination, and inability
  to move.
• Other severe effects observed in children
  whose mothers were exposed to very toxic levels
  of mercury during pregnancy include eventual
  blindness, involuntary muscle contractions and
  seizures, muscle weakness, and inability to
  speak.
• It is important to remember, however, that the
  severity of these effects depends upon the level
  of mercury exposure and the time of dose.

7
Mercury exposure at dangerous levels is common
in the US.

• Seafood EPA estimates that 1 in 6 women in the
  US have mercury levels that place their infants
  at increased risk of neurological damage.
• Dental fillings release 1-10 mcg/day of
  mercury, close to the safe limit
• Thimerosal was injected into infants at levels
  25-100x the safe limits until 2001, when the FDA
  recommended removing it from childhood vaccines.

8
Mercury in Seafood - highest level

• SPECIES MEAN (PPM) RANGE (PPM) NO. OF SAMPLES
  
• Tilefish 1.45 0.65-3.73 60
• Swordfish 1.00 0.10-3.22 598
• Shark 0.96 0.05-4.54 324
• King Mackerel 0.73 0.30-1.67 213
• Grouper (Mycteroperca) 0.43 0.05-1.35 64
• commonly consumed
• data from US-Food and Drug Administration, 2001

9
Mercury in Seafood - Lower Levels

• SPECIES MEAN (PPM) RANGE (PPM) NO. OF SAMPLES
• Tuna (fresh or frozen) 0.32 ND-1.30 191
• Lobster Northern (American) 0.31 0.05-1.31 88
• Halibut 0.23 0.02-0.63 29
• Sablefish 0.22 ND-0.70 102
• Pollock 0.20 ND-0.78 107
• Tuna (canned) 0.17 ND-0.75 248
• Crab Blue 0.17 0.02-0.50 94
• Crab Dungeness 0.18 0.02-0.48 50
• Scallop 0.05 ND-0.22 66
• Catfish 0.07 ND-0.31 22
• Salmon ND ND-0.18 52
• Oysters ND ND-0.25 33
• Shrimp ND ND 22

10
FDA Recommendations - 2001

• Avoid fish from the highest category
• limit consumption to 12 ounces/week (2-3
  servings) of other fish
• Example 12 ounces (340 g) of canned tuna would
  contain 58 ug of mercury, roughly the amount
  excreted by a mouthful of old amalgams over a
  week, or the amount in 2-4 vaccines
• Note nearly 100 of mercury from seafood is
  absorbed into body

11
Genetic vulnerability to mercury

• Study by Hornig et al. of injection of thimerosal
  into infant mice, at doses equivalent to human
  infant exposure from childhood vaccines
• Hornig et al, Mol. Psych. (2004) 1-13.
• Two strains unaffected, but one strain (known to
  be sensitive to autoimmunity) was vulnerable,
  including
• growth delay
• reduced locomotion
• exaggerated response to novelty
• abnormal development of neurons and synapses
• Suggests that some humans may also be genetically
  vulnerable to mercury

12
Aluminum in Vaccines

• Often added to vaccines to increase immune
  reaction to vaccine
• Study by Boyd Haley and collaborators found that
  aluminum in vaccines was not toxic by itself, but
  greatly increased toxicity of thimerosal

13
Symptoms of mercury poisoning mimic autism

• Bernard et. al. Autism A Novel Type of Mercury
  Poisoning
• Medical Hypothesis 56(4) 462-471 (2001)
• They found many similarities between autism and
  mercury toxicity, including
• speech/language deficit
• mental retardation
• social withdrawal
• poor coordination
• unusual behaviors
• higher sensitivity in males than females

14
Children with autism have a limited ability to
excrete mercury.

• Glutathione is the bodys primary mechanism for
  excretion of mercury.
• Two studies found that children with autism have
  only 50 of the normal amount of glutathione.
• Two studies by our group found that children with
  autism had 2-4x higher usage of oral antibiotics
  (plt0.0001), which (in rats) increase the
  half-life for excretion of mercury from 10 days
  to over 100 days.
• Holmes found very low levels of mercury in baby
  hair of children with autism, consistent with an
  impaired ability to excrete mercury. Our study
  with NIEHS and MIT supports their findings.

15
HAIR MERCURY OF AUTISTIC VS. CONTROL GROUPS
Hair Hg level (ppm)
Autistic Mean0.47 n94
Non-autistic Mean3.79 n34
16
HAIR MERCURY BY SEVERITY OF AUTISM
Hair Hg level (ppm)
Mild Mean0.71 n27
Moderate Mean0.46 n43
Severe Mean0.21 n24
17
ASU-NIEHS replication of Holmes et al. Baby Hair
Study

• Preliminary Results partial agreement
• Median level of mercury is 50 lower in autism
• However, 10 of autistics have extremely high
  levels of mercury
• Our autism mercury levels generally match Holmes
  levels, but our controls are much lower
• However, important to note that typical children
  have mercury levels 4x above that of mothers in
  NHANES study and in our previous study
• Also, oral antibiotic usage roughly 2x higher in
  autism vs. controls plt0.01

18
Children with autism have high levels of mercury
in their bodies.

• Our study of levels of Hg, Pb, Zn in baby teeth
  of children found
• Mercury levels were 3x higher in children with
  autism vs. controls, p0.05
• Lead levels only slightly elevated, zinc levels
  were normal.

19
T. Audhya Toxic Metals in Red Cells of Children
(ng/ml)

• Control
  Autistic High
• (n 29) (n46)
• Aluminum 1-140 (55) 56-280 (170)
  14.3
• Arsenic 3-14 (8) 11-48
  (32) 32.1
• Cadmium 0.4-1.9 (1.0) 1.5-4.6(3.4)
  16.3
• Lead 40-122 (74) 66-380
  (230) 29.3
• Mercury (total) 11-34 (20) 26-103 (68)
  17.3
• Mercury (org.) 5-16 (9) 8-56 (35)
  21.2
• Mercury (inorg.) 8-22 (12) 4-94 (59)
  28.5

20
Toxic Chemical in Red Cells of Children (ng/ml)

• Control (n 29)
  Autistic (n 46) High
• Aroclors 1-4 (2)
  50-84 (70) 19.4
• Benzene 65-140 (98)
  240-540 (400) 41.3
• Methyl Benzene 25-84 (51) 50-230
  (150) 32.4
• Isopro. Acetone 90-194 (138) 140-890
  (505) 48.6
• Pentane 30-110 (67)
  60-688 (384) 56
• Perchloroethylene 30-50 (36) 70-200
  (142) 34
• Diflurobexzamide none trace
• Methylated DFB none trace
• Hexane (mg/ml) 2.8-7.9 (5)
  5-14 (10) 67.3
• Xylene (mg/ml) 1.0-2.9 (1.8)
  3.6-8.4 (6.5) 21.3

21
Epidemiology of Thimerosal-Autism

• Geier Geier analyzed national Vaccine Adverse
  Effect Reporting System (VAERS)
• Children who received DTaP with thimerosal vs
  thimerosal-free DTaP had
• 6x chance of autism
• 6x risk of mental retardation
• 2x risk of speech disorder
• 3 published studies by Geiers find strong link
• 4 other published studies find no link 1 study
  inconclusive however, 3 of those studies were in
  countries with very low use of thimerosal and low
  incidence of autism
• 1 US study originally found 7-11x relative risk,
  but altered methodology until risk disappeared

22
Cu, Zn and Metallothionein

• Pfeiffer Labs found high CuZn ratio in autism
  (1.7 vs 1.1 in controls, n 503 and 20, plt0.001)
• Supplementation with high-dose Zn has modest
  effect
• Suggests a defect in metallothionein, which
  regulates Cu and Zn
• Since metallothionein works with glutathione for
  excretion of heavy metals, suggests impairment in
  ability to excrete heavy metals
• Treatments to raise metallothionein levels now
  being tried on over 1000 children with autism

23
DMSA Challenge

• Bradstreet et al. used a 3-day, 9-dose, 10
  mg/kg-dose DMSA treatment in 221 children with
  autism and 18 controls.
• Autism 4.1 mcg Hg / g creatinine
• Controls 1.3 mcg Hg / g creatinine
• RI 3.15 95 CI 1.43-4.11 p0.0002
• Lead, cadmium levels were similar
• Bradstreet, Geier, Kartzinel, Adams, Geier., J.
  Am Phys. Surg 8(3) 2003 76-79.

24
Results of Single-dose DMSA study

• Change of urinary excretion of metals after DMSA
  
• (provoked urine vs. baseline urine)
• Metal Autism Controls
• Al 7500 0
• As 4 19
• Cd 52 1
• Pb 315 478
• Hg 328 90
• Ni 51 -11
• Sn 1900 85
• U 2100 515

25
Support of Autism Research Institute (oldest
autism research center in US)

• Directed by Bernard Rimland, Ph.D.
• detoxification of mercury from autistic children
  can bring about enormous improvement in a
  considerable number of these children. DMSA is a
  remarkably effective, and very safe, drug.
• Based on his survey data, the percentage of
  parents who report that the child got better,
  73, is by far the highest percentage improvement
  reported for any of the biomedical treatments

26
Many physicians have reported on the safety and
efficacy of DMSA therapy for children with
autism, and support the proposed study.

• Jane El-Dahr, M.D., Professor of Pediatrics,
  Tulane Medical School
• very positive results in terms of clinical
  improvement, with no adverse events, in over 100
  children with autism treated with DMSA.
• Sid Baker, M.D. over 100 patients
• No child developed a major adverse effect.
• 50-75 experienced improvement that could be
  reasonably attributed to treatment.

27

• James Neubrander, M.D. over 100 patients
• no significant side effects or significantly
  atypical laboratory studies were ever found.
• 25-30 of my children improved to some degree,
  and it was not uncommon for some children to have
  remarkable success, unparalleled by anything else
  they had ever done.
• David Berger, M.D. over 500 patients
• I have never seen a serious side effect from
  DMSA
• About 1/3 of the families report that their
  children seem to improve with each cycle of DMSA.
  About 1/3 report that there is a general
  improvement noted over the time that the child is
  using DMSA. About 1/3 of the families report no
  improvement in symptoms.

28

• Stephanie Cave, M.D. over 2700 patients
• DMSA is one of the safest drugs that I have used
  to date.
• DMSA treatment has been the pivotal point in the
  treatment for many children in the autism
  spectrum.
• Until I treated them with DMSA, I did not see
  the level of improvement that I am now seeing.
• I have seen children progress from no speech or
  eye contact to full dialogue mainstreamed in
  school within eight months.

29
Conclusion

• Children with autism have a decreased ability to
  excrete mercury, resulting in a high body burden
  of mercury.
• DMSA is proven to be able to remove mercury and
  other toxic metals.
• There is strong clinical support for the safety
  and efficacy of DMSA in treating children with
  autism.
• DMPS is another alternative for removing mercury,
  after DMSA.

30
Recommendations for Prevention

• Larger, more controlled studies are needed to
  confirm results
• However, if the results are correct, then many
  cases of autism might be prevented by
• reduced use of oral antibiotics (especially many
  repeated uses for ear infections)
• removal of thimerosal from vaccines
• limiting maternal seafood consumption (warning
  labels on fish)
• No mercury fillings (especially none placed
  during pregnancy)

31
2005 DAN! Consensus Report on Treating Mercury
Toxicity in Children with Autism

• 25 Physicians and Scientists worked in 2001 to
  draft and sign the Mercury Detoxification
  Consensus Group Position Paper, which advocates
  the use of DMSA for treating children with
  autism.
• 30 Physicians and Scientists just completed the
  2005 Consensus Report, which recommends DMSA,
  DMPS, and TTFD
• available from www.eas.asu.edu/autism

32
Acknowledgements

• Many autism families who participated in our
  studies.
• Funded by Autism Research Institute, ICDRC,
  Arizona State University, Greater Phoenix Chapter
  of ASA, and Pima County Chapter of ASA
• www.eas.asu.edu/autism
• for copy of talk and other information

33
Preliminary Results of 3rd DMSA Study

• James B. Adams, Matthew Baral (P.I.), Sanford
  Newmark, Liz Geis, Andrea Hensley, Julie Ingram,
  Jessica Mitchell, Ken Mitchell, Jeff Bradstreet,
  Jane El-Dahr
• Southwest College of Naturopathic Medicine
• Funded by Wallace Foundation and
• Autism Research Institute

34
Two previous studies of DMSA treatment for
children with autism

• Single dose, 10 mg/kg
• Found higher excretion of toxic metals in
  children with autism (n16) vs. controls (n15),
  but not statistically significant (sample size
  too small)
• J. B. Adams and F. George
• 2) Nine doses over 3 days, 10 mg/kg
• Found 3x higher excretion of mercury in children
  with autism (n221) vs. controls (n18), p lt
  0.0002
• Bradstreet J, Geier DA, Kartzinel JJ, Adams JB,
  Geier MR. Journal of American Physicians and
  Surgeons 8 (3) Summer 2003 76-79.

35
Current study

• Phase 1 9 doses of DMSA over 3 days, 10 mg/kg
  collect urine for baseline, after 1st dose, and
  after 9th dose
• Phase 2 3 month, double-blind,
  placebo-controlled treatment study
• 3 days on DMSA, 11 days off repeat 6x
• 65 of 80 children enrolled 13 completed phase 1

36
Preliminary Results

• Baseline urine (autism28, controls 15
  includes 1st DMSA group)
• Average mercury excretion (ug / g creat.) lower
  in autism but not statistically significant
• Autism avg 0.51 median 0.40
• Controls avg 0.98 median 0.70
• Average thallium excretion higher in autism,
  p0.06
• Autism avg 0.19 med 0.10
• Controls avg 0.09 med 0.10
• No other significant differences in excretion of
  toxic metals at baseline

37
Toxic Metal Excretion after DMSA
DMSA mostly increased excretion of lead, mercury,
and tin. At 9th dose, only lead has greatly
increased excretion.
38
Excretion of Essential Minerals after DMSA
(autism only, n12)
Increased excretion of potassium, copper,
manganese.
39
Excretion of Essential Minerals after DMSA
(cont.)autism only, n12
Increased initial excretion of chromium and
vanadium
40
Amount of extra loss of essential minerals

• How to estimate? Children produce approximately
  20 mg/kg-bodyweight-day of creatinine, so a 45 lb
  child (24 kg) produces about 500 mg (0.5 g) of
  creatinine
• So, if report is per gram of creatinine, divide
  result by 2
• K 1500 mg significant, but only 350 on 9th
  dose
• Zn 0.06 mg very little
• Cu 0.01 mg very little
• Mn 0.0005 mg very little
• Cr 0.03 mg very little
• V 0.01 mg significant, but much less on 9th
  dose

41
Preliminary conclusions

• Baseline excretion of Hg may be low in autism
• DMSA increases excretion of lead, mercury, tin
• DMSA has little effect on arsenic or cadmium
• DMSA increases excretion of copper, and some
  initial excretion of potassium, chromium,
  vanadium. However, total excretion of most
  essential elements (except potassium, vanadium)
  is small.
• Of greater concern is loss of cysteine, since 90
  of DMSA is excreted bound to 1-2 cysteine.