The Autism-Mercury Connection and Preliminary Results of a DMSA Treatment Study

Embedded Scribd iPaper - Requires Javascript and Flash Player
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
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 • Nutritional deficiencies
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.
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.
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.”
• •
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 25100x the safe limits until 2001, when the FDA recommended removing it from childhood vaccines.
Mercury in Seafood - highest level
SPECIES Tilefish *Swordfish *Shark King Mackerel MEAN (PPM) 1.45 1.00 0.96 0.73 RANGE (PPM) 0.65-3.73 0.10-3.22 0.05-4.54 0.30-1.67 0.05-1.35 NO. OF SAMPLES 60 598 324 213 64
Grouper (Mycteroperca) 0.43 * commonly consumed
data from US-Food and Drug Administration, 2001
Mercury in Seafood - Lower Levels
SPECIES MEAN (PPM) 0.32 RANGE (PPM) ND-1.30 191 0.05-1.31 88 NO. OF SAMPLES Tuna (fresh or frozen) *Halibut 0.23 *Sablefish *Pollock 0.20 *Tuna (canned) *Crab Blue *Scallop 0.05 *Catfish 0.07 *Salmon ND *Oysters ND *Shrimp ND *Lobster Northern (American) 0.31 0.02-0.63 29 0.22 0.17 0.17 ND-0.70 102 ND-0.75 248 0.02-0.50 94 0.02-0.48 50 ND-0.78 107
*Crab Dungeness 0.18
ND-0.22 66 ND-0.31 22 ND-0.18 52 ND-0.25 33 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
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
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
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
Children with autism have a limited ability to excrete mercury.
• Glutathione is the body’s 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 (p<0.0001), 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.
Hair Hg level (ppm)
HAIR MERCURY OF AUTISTIC VS. CONTROL GROUPS
20 18 16 14 12 10 8 6 4 2 0
Female Male
Non-autistic Mean=3.79 n=34
Autistic Mean=0.47 n=94
HAIR MERCURY BY SEVERITY OF AUTISM
Hair Hg level (ppm)
1.4 1.2 1 0.8 0.6 0.4 0.2 0
Female Male
Mild Mean=0.71 n=27
Moderate Mean=0.46 n=43
Severe Mean=0.21 n=24
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; p<0.01
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, p=0.05 • Lead levels only slightly elevated, zinc levels were normal.
T. Audhya: Toxic Metals in Red Cells of Children (ng/ml)
(n =29) Control (n=46) Autistic %High
Aluminum 1-140 (55) Arsenic 3-14 (8) Cadmium 0.4-1.9 (1.0) Lead 40-122 (74) Mercury (total) 11-34 (20) Mercury (org.) 5-16 (9) Mercury (inorg.) 8-22 (12)
56-280 (170) 11-48 (32) 1.5-4.6(3.4) 66-380 (230) 26-103 (68) 8-56 (35) 4-94 (59)
14.3 32.1 16.3 29.3 17.3 21.2 28.5
Toxic Chemical in Red Cells of Children (ng/ml)
Control (n 29) Aroclors 1-4 (2) Benzene 65-140 (98) Methyl Benzene 25-84 (51) Isopro. Acetone 90-194 (138) Pentane 30-110 (67) Perchloroethylene 30-50 (36) Diflurobexzamide none Methylated DFB none Hexane (mg/ml) 2.8-7.9 (5) Xylene (mg/ml) 1.0-2.9 (1.8) Autistic (n 46) 50-84 (70) 240-540 (400) 50-230 (150) 140-890 (505) 60-688 (384) 70-200 (142) trace trace 5-14 (10) 3.6-8.4 (6.5) % High 19.4 41.3 32.4 48.6 56 34
67.3 21.3
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 Geier’s 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
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
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; p=0.0002 Lead, cadmium levels were similar Bradstreet, Geier, Kartzinel, Adams, Geier., J. Am Phys. Surg 8(3) 2003 76-79.
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%
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”
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.”
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.”
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.”
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.
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)
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
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
Preliminary Results of 3 DMSA Study
rd
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
Two previous studies of DMSA treatment for children with autism
1) Single dose, 10 mg/kg:
Found higher excretion of toxic metals in children with autism (n=16) vs. controls (n=15), 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 (n=221) vs. controls (n=18), p < 0.0002 Bradstreet J, Geier DA, Kartzinel JJ, Adams JB, Geier MR. Journal of American Physicians and Surgeons 8 (3) Summer 2003 76-79.
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
Preliminary Results
Baseline urine (autism=28, 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, p=0.06 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
Toxic Metal Excretion after DMSA
Al Sb As Cd Pb Hg Ni Tl Sn W controls autism -12% 88% 290% 49% 19% -6% 0% 6% 478% 373% 90% 202% -2% 4% 124% 82% -9% 109% 10% 45% 9th dose (n=12) -48% 7% 0% -26% 877% 12% 34% 94% 52% -26%
DMSA mostly increased excretion of lead, mercury, and tin. At 9th dose, only lead has greatly increased excretion.
Excretion of Essential Minerals after DMSA (autism only, n=12)
Na K P Ca Mg Zn Cu S Mn Mo 1st dose 9th dose 51% -7% 181% 38% -16% -18% 10% 5% 4% 33% 16% 29% 94% 147% 15% 3% 112% 17% 4% -20%
Increased excretion of potassium, copper, manganese.
Excretion of Essential Minerals after DMSA (cont.) autism only, n=12
Increased initial excretion of chromium and vanadium
B
Amount of extra loss of essential minerals
How to estimate? Children produce approximately 20 mg/kgbodyweight-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
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.