Docstoc

Possible Connection of Heavy Metal Toxicity and Autism Mercury Toxicity and Autism

Document Sample
Possible Connection of Heavy Metal Toxicity and Autism Mercury Toxicity and Autism Powered By Docstoc
					Mercury Toxicity and Autism

    Prof. James B. Adams, Ph.D.
 Chemical and Materials Engineering
      Arizona State University
               Collaborators
•   Jeff Bradstreet, MD – ICDRC
•   Charles E. Holloway - ASU
•   Michael Margolis, D.D.S.
•   Frank George, D.O.
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)
      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
     Background - Lead Toxicity
• Lead- most widespread case of heavy metal poisoning
• 1991-1994: 4.4% of US children ages 1-5 “affected”
  (blood levels >10 ug/dL)
• loss of 4-7 IQ points per 10 ug
• even levels below 10 ug may affect children
• can affect every organ
• correlates with lower class rank, absenteeism, slower
  reaction times, worse coordination
• effects often life-long
• exposure of parents can affect their child 30 years later
  (greater risk of learning disabilities)
Children more susceptible than Adults

–   more exposure (crawling, playing in dirt, licking hands)
–   less excretion (adults retain only 1%, children retain 33%)
–   brain still developing
–   lead crosses placenta, no blood/brain barrier in fetuses
–   low calcium in mothers results in lead stored in bone being
    released
             Major Sources of Lead
•   Leaded Gasoline:
     – major source of lead, permanently contaminating soil near roads
     – introduction of unleaded gasoline in 1980’s has greatly reduced emissions
        (95 million kg in 1979 to only 2 million kg in 1989); average blood lead
        levels now much lower than 20 years ago
•   Old paint:
     – up to 1955, most household paint 50% lead
     – 1955-1971: voluntary limit of 1% lead
     – 1971: 1% lead required
     – 1977: “lead-free” paint limited to 0.06% lead
     – note that remodeling an old home (especially sanding) is very hazardous
•   Lead Pipes:
     – still used in many homes
     – replaced with copper, but used lead solder until 1991
     – brass faucets contain up to 8% lead
     – most filters useless; only reverse osmosis removes lead
  Prevention and Treatment for Lead Poisoning
• Most states require check of blood lead level in school-age
  children (but often too late)
• Reduce children’s exposure lead (remediation of environment
  by removing paint chips, dust, dirt)
• increasing calcium intake (to reduce lead intake)
• chelation if high blood lead level (> 40 ug/dL);
• for blood lead level of 20-40 ug/dL, large study of 780
  children found that chelation with DMSA for 1 month did
  temporarily lower blood lead levels, but rapidly returned and
  no long-term benefit (however, could longer-term treatment
  help?)
• The only “accepted” current treatment is prevention

Lead poisoning taken seriously now in US, but took decades;
  Mercury poisoning largely ignored
Mercury Exposure: Major Sources

• Seafood: larger fish have most mercury, due to eating
  smaller fish
• Vaccines: many childhood vaccines used to contain 12.5-
  25 ug of thimerosal, so that a fully-vaccinated child could
  receive up to 237.5 ug of thimerosal injected into them
• Dental amalgams: usually emit 1-10 ug/day; amount of
  mercury in brain strongly correlated with number of dental
  fillings; could release much more when first placed or
  removed
      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
           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
  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
 Prevalence of Mercury Toxicity
• In 2004, large EPA study of 1709 women find many have
  hazardous levels of mercury in their blood; eating fish
  2x/week results in 7x level of mercury vs. non-seafood
  eaters.
• EPA estimates that 300,000-600,000 of 4 million babies
  born in US each year are exposed to “unacceptable” levels
  of mercury
• Who are they? Mostly not diagnosed, since mercury only
  briefly stays in blood, and limited physician
  knowledge/experience for diagnosing
• Are some children with mercury/heavy metal toxicity
  diagnosed with a behavioral label of autism, Asperger’s,
  ADD/ADHD, or learning disabilities?
    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.”
Bernard et. al. “Autism: A Novel Type of Mercury Poisoning”
                       Medical Hypothesis 56(4) 462-471 (2001)
  They discuss the many similarities between autism and mercury toxicity, including:
  Psychiatric Disturbances: social withdrawal; repetitive behaviors; anxiety; irritability; poor
    eye contact
  Speech/Language Deficits: loss of speech or delayed speech; speech comprehension deficits
  Sensory Abnormalities: oral, touch, light and sound sensitivities
  Motor Disorders: flapping motions; poor coordination; abnormal gait
  Cognitive Impairments: low intelligence; poor memory; difficulty with abstract ideas
  Unusual Behaviors: self-injurious; sleep difficulties; ADHD
  Physical Disturbances: gastrointestinal disorders
  Biochemistry: reduced glutathione; decreased detoxification ability of liver; disrupted purine
    metabolism;
  Immune System: increased likelihood of auto-immune response, allergies, and asthma
  CNS Structure: mercury accumulates in amygdala, hippocampus, basal ganglia, and cerebral
    cortex, which are damaged in autism; mercury also damages Purkinje and granule cells (seen
    in autism); disruption of neuronal organization
  Neurochemistry: decreased serotonin synthesis; elevated norepinephrine and epinephrine;
    demyelination
  Neurophysiology: abnormal EEGs; abnormal vestibular nystagmus response
  Gender bias: higher sensitivity/occurrence in males vs. females
Combined Toxicity of Lead and Mercury

• Since lead, mercury, and other heavy metals are excreted
  by the same mechanism, then a combined dose is more
  dangerous
• A study of rats found that the LD1 of lead and the LD1 of
  mercury resulted in LD100 (all the rats died). Schubert et
  al, J. Toxicology and Env. Health V4, 763-776, 1978.
• Note that humans are usually exposed to many toxic metals
  simultaneously, but most toxicology tests done on
  individual metals
                  Present Study
Participants
• 53 children with ASD ages 3-15 years, chosen
  from Phoenix ASA mailing list
• 48 typical children chosen from their
  friends/neighbors (unrelated), same age and sex
Methodology
• heavy metal exposure questionnaire
• hair analysis
• dental exam
          Results of Heavy Metal Questionnaire

Caveat: mostly based on mother’s memory

Seafood: 58% of ASD mothers consumed more than 2
  servings/month during pregnancy/breastfeeding, compared
  to 33% of controls;
  yields a 2.7x relative risk of ASD (p<0.02);
  presumably mercury in the seafood is the major problem
        Results of Heavy Metal Questionnaire (cont.)

Ear Infections: during first three years of life:
  ASD: 11x            controls: 4x
   p<0.001 highly statistically significant

  Symptom or cause?
  1) could be an indication of weakened immune system
  2) In a study of rats given high doses of oral antibiotics
  (Rowland, Archives of Environmental Health 1984: 39(6); 401-408),
       half-life for excretion of mercury increased from 10
  days to >100 days; if also on milk diet, >300 days
  (possibly due to yeast/bacterial overgrowth, which can last
  for years in children with autism)
          Results of Heavy Metal Questionnaire (cont.)


• Chronic GI Severity: scale of none/mild/moderate/severe
     ASD:           60% moderate or severe
     Controls:      2% moderate
                    p<0.0000001
     consistent with a major gut dysbiosis

• Sleep Problems:
      ASD:          60% moderate or severe
      Controls:     2% moderate
      p<0.00000001
      Sleep and GI correlated (correlation coefficient = 0.3)
     Results of Heavy Metal Questionnaire

• Pica: 30% of ASD vs 0% of the controls
   – a major source of heavy metals
   – symptom and/or cause?
    Results of Heavy Metal Questionnaire (cont.)


Negative immediate reaction to vaccines:
                    Moderate      Severe
     ASD            12%           18%
     Controls       4%            2%
                    p=0.001 - highly significant;
Since mercury has a latency period of several months, this
is probably due to other components of the vaccine.
         ASD Reports of Adverse Vaccine Reactions - Severe
•   MMR, DTaP, varicella (12 mo)         respiratory arrest led to hospitalization for 5
    days, and then autistic symptoms began
•   DTaP (18 mo) high fever the next day, which lasted for 10 days; hospitalized on
    day 6 for 3 days; very lethargic; major regression started 4 months later
•   MMR (15 mo) high fever, very listless/passive for 5 days with no eating or
    drinking, then began regression into autistic behavior
•   DTaP, IPV, MMR, HIB, Varicella (14 mo) began wheezing within a few days,
    developed asthma within 2 weeks
•   Petusssis (8 mo) severe diarrhea for 3 months, continued to some extent for 27
    months
•   DTaP (2 mo): 105 fever for 1 week
     – MMR (12 mo): high fever; didn’t eat for 3 months
•   DTaP (6 mo): screamed loudly for six hours, and then began long-term regression
    resulting in autism
•   MMR (13 mo) high fever, very sick for 1 week, then ear infection and little sleep;
    slow development before, and slower afterwards – possible regression
•   MMR - within 1 week started seizures (none prior)
•   HepB (21 mo) fever; cough; after several weeks developed ITP (severe blood
    disorder) and bruised head to toe for 9 months
 ASD: Moderate Reactions
    •   HepB: high fever for 2 days
    •   DTaP: greatly swollen thigh for 1 day
    •   DTP/MMT: very high fever, screaming, hives for 2 days
    •   Most vaccinations caused high fever for 1-2 days


Controls: Moderate and Severe Reactions
   •Varicella (12 mo): lethargic for 2 weeks, rested in bed
   •MMR: 104 fever for 2 days; several seizures lasting 1-2 minutes
   for 2 days; then okay
   •MMR/DTP/Polio: 103 fever for 3 days; rash; lethargic

Over $1 billion paid to children injured/killed by vaccines in US
       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
                 Tylenol
• Tylenol frequently given before and after
  vaccinations
• Tylenol decreases glutathione, which is an
  important defense against mercury
              Dental Amalgams
• Mothers of children with autism had an average of 9.9
  dental amalgam surfaces, vs 8.2 for mothers of typical
  children: not statistically significant
• However, for placement of fillings during pregnancy:
   – ASD: 6 mothers          Controls: 1 mothers   p=0.09 (trend)
• Our recent study found that a new dental amalgam releases
  approximately 450 mcg/day (about 500x what an old
  amalgam emits), so new amalgams should be avoided in
  women who are planning to conceive, pregnant, or
  nursing
• Future epidemiological studies should focus on placement
  of amalgams during pregnancy/nursing, not the total number
  of amalgams
                HAIR MERCURY OF
            AUTISTIC VS. CONTROL
             20
Hair Hg level
(ppm)        18
                     GROUPS                     Female

                                                Male

                16
                14
                12
                10
                8
                6
                4
                2
                0
                     Non-autistic    Autistic
                     Mean=3.79      Mean=0.47
                        n=34          n=94
            HAIR MERCURY BY
           SEVERITY OF AUTISM
            1.4
Hair Hg level
(ppm)                                        Female
            1.2                              Male


                1

            0.8

            0.6

            0.4

            0.2

                0
                      Mild      Moderate     Severe
                    Mean=0.71   Mean=0.46   Mean=0.21
                      n=27        n=43        n=24
“Tooth Fairy” Study:

Measure amount of mercury, lead, and zinc in baby
 teeth in children with autism vs. controls

Rationale: crown of tooth forms during pregnancy,
  but continues to grow until age 4 years; thus,
  provides a measure of cumulative exposure during
  early childhood

Criteria:
   Arizona Residents
   Born 1988-1999
   full vaccination records
    Initial Results of Baby Tooth Study
            (15 autism, 11 controls)

• Lead: slightly higher in autistic children
   – Autism:         0.36 +/- 0.13 mcg/g
   – Controls:       0.29 +/- 0.14
• Zinc: almost identical between two groups
   – Autism:         93 +/- 10
   – Controls:       96 +/- 9
• Mercury: 3x higher in autism
   – Autism:        0.14 +/- 0.11
   – Controls:      0.05 +/- 0.05
   – p=0.05 statistically significant, but more samples
     needed
              DMSA Challenge
Bradstreet used a 3-day, 9-dose, 10 mg/kg-dose DMSA
  treatment in roughly 200 children with autism and 19
  controls. He found that children with ASD excreted 6x as
  much mercury as the controls.

Our trial of a single dose of 10 mg/kg-day of DMSA
  increased excretion of several heavy metals in both autism
  and controls (little difference); so, 9-dose challenge is
  better

Together, our data suggests ASD children have inhibited
  ability to excrete heavy metals
                  Epidemiology
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
Study by CDC found 2.5x relative risk of autism at
  highest level of thimerosal, based on analysis of 2
  HMO’s
However, study redone by Verstratten after hired by
  pharmaceutical company, and now finds no link
Danish study: authors find no link, but reanalysis
  finds 2x risk from thimerosal-containing vaccines
    Limitation of DMSA, DMPS
Recent study by Dr. Aposhian of chelation of rats found:
• DMSA and DMPS both effective in totally removing
  mercury from kidney
• DMSA, DMPS have ZERO effect on removing mercury
  from brain (cannot cross blood-brain barrier)
• Vitamin C, glutathione, and alpha lipoic acid have NO
  EFFECT on mercury levels in kidney or brain
• Vitamin C, glutathione, and alpha lipoic acid have NO
  EFFECT on mercury in brain when used with DMSA or
  DMPS

• Currently, we do NOT know how to chelate mercury from
  the brain
    Cu, Zn and Metallothionein
• Pfeiffer Labs found high Cu:Zn ratio in autism
  (1.7 vs 1.1 in controls, n= 503 and 20, p<0.001)
• 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
                       Sulfate
• Waring has reported that children with autism:
   – Excrete 2x normal amount of sulfate in urine
   – Have 1/5 normal amount of sulfate in blood
• Lack of sulfate would decrease ability to excrete
  heavy metals, and have many other effects
• Case Study: 10-yr old girl with 1/10 normal
  plasma sulfate, 2x normal urinary excretion;
  Epsom Salt baths ineffective; 1300 mg MSM
  raised plasma sulfate to half normal levels, and
  symptoms improved
                        Conclusions

Seafood consumption > 2 servings/month yields 2.7x risk
Ear infections > 8x (first 3 years) yields 8x risk ; antibiotics
   greatly reduce mercury excretion
Placement of dental fillings during pregnancy suspicious
Pica is common in ASD (major source of heavy metals)
Vaccine reactions are more common in ASD
Hair data suggests an impairment in mercury excretion in
   infants
Baby teeth show 3x higher mercury in children with autism
DMSA results show 6x more excreted from children with ASD

Children with autism cannot excrete mercury easily, so it
  builds up to high levels in their body.
Recommendations for Prevention
• Larger, more controlled study is needed to confirm
  results
• However, if the results are correct, then many cases
  of autism might be prevented by:
   – limiting maternal seafood consumption (warning labels on
     fish)
   – reduced use of oral antibiotics (especially many repeated
     uses)
   – removal of thimerosal from vaccines
   – No mercury fillings (especially none placed during
     pregnancy)
          Testing and Treatment
           Recommendations

• Limit exposure to heavy metals (avoid seafood, especially
  those with high mercury; no mercury fillings; limit pica;
  wash hands)
• check mercury in baby hair and baby teeth (if available)
• DMSA challenge test of heavy metals
• consider DMSA chelation (esp. younger children)
• Caveat: unclear if damage caused by heavy metals can be
  reversed, especially in older children/adults
         Physician reports
• Many physicians (Cave, Holmes,
  Bradstreet, McCandless, others) have
  reported on high levels of toxic metals after
  chelation challenge, and reduction in
  autistic symptoms due to chelation,
  especially in younger children (under 6 yr).
            DMSA Challenge
• Don’t do if mercury fillings or consuming seafood
• Give DMSA at dosage of 10 mg/kg, 3 doses/day, for
  3 days (single dose is misleading!)
• On last day, just before last dosage, empty bladder,
  and then collect urine for 10 hours
• Note: Reference ranges in urine are for non-
  chelated level, so only be concerned at very high
  levels (above 90%)
              DMSA Treatment
• First, prepare with nutritional supplements, heal gut
• DMSA: 3 days on, 11 days off;
   – 3-6x/day
   – I recommend initial dose of 10 mg/kg per day, split into 3-6
      doses; then, gradually increase up to 30 mg/kg/day) over
      several weeks when metal levels are lower
   – Repeat until metal levels low in urine (10 hr test)
• Note: DMSA increases excretion of zinc, so supplement with
  zinc in-between
• Rectal suppository of DMSA may be better (less chance of
  exacerbating bacterial/yeast overgrowth)
• This regimen is generally viewed as very safe by DAN!
  Doctors, but modest risk of GI overgrowth; needs occasional
  tests of kidney/liver function
               Other Chelators
• DMPS: similar to DMSA, but better at removing
  mercury; slightly higher risk of adverse effects;
  not FDA-approved, but physician can have it
  compounded; oral form preferred over intra-
  venous, because can give same dose over longer
  time (less chance of side-effects)
• Alpha Lipoic Acid: controversial
   – some DAN! Physicians report using it after many
     rounds of DMSA, and then giving with DMSA to
     increase excretion; anecdotal reports of higher excretion
     in stool
   – Problem: high chance of developing GI overgrowth
   – Problem: Study by Aposhian shows it does not affect
     excretion of mercury from rats
            Other Chelators (cont.)
• TTFD: a form of vitamin B1;
   – Pilot study by Lonsdale with 10 autistic children found
     good improvement in ATEC scores in half patients
     after 8 weeks
   – Weak evidence of increased arsenic excretion
• Glutathione: helps protect against initial exposure to
  mercury, but study by Aposhian shows zero effect on
  mercury levels after exposure
• MT Promoter: unclear if it increases MT levels; no
  evidence of chelation ability
• Beware unknown chelators (Metal Free, PCA-RX) –
  ingredients unclear, no data, suspicious
         Chelation Conclusion
• Mercury and possibly other toxic metals present at
  high levels in autistic children
• Every child with autism should do a DMSA
  challenge
• For treatment, I only recommend oral DMSA or
  oral DMPS, under guidance of experienced
  physician, with regular urine testing and
  kidney/liver function testing (every 3 months)
• TTFD may have some modest chelation benefit,
  but recommend trying only after DMSA
• Children under 6 will benefit most, children under
  12 may benefit, older children/adults have small
  chance of modest benefit
    Current and Future Studies

• Baby hair study with NIH and MIT (to
  replicate Holmes’ study)
• Baby tooth study with Un. Texas
• TTFD study
• DMSA treatment study
Recruiting for Autism-Baby Hair Study
Goal: Measure level of mercury and other toxic and essential
  minerals in baby hair of autism vs. controls
Criteria: born 1988-1999; autism (not PDD/NOS or
  Asperger’s); vaccination records with manufacturers lot
  number (just call your pediatrician).
Controls needed - please help!

Contact Jane Romdalvik: jromdalvik@aol.com
  623 376-0758 (email preferred)

Funded by Autism Research Institute and NIEHS
        Acknowledgements
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

				
DOCUMENT INFO