| Possible Connection of Heavy Metal Toxicity and Autism Prof. James B. Adams, Ph.D. Chemical and Materials Engineering Arizona State University Collaborators Charles E. Holloway - ASU Brittany Done, ASU Mary Kerr Michael Margolis, D.D.S. Frank George, D.O. Karen Medville, D.Sc. Woody McGinnis, M.D. Xianchen Liu, M.D., Ph.D. Hypothesis Do mercury and other heavy metals contribute to the causes and/or symptoms of autism in some cases? 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 truly effective current treatment is prevention Mercury Exposure: Sources Coal-burning Power Plants: emit 52 tons of Hg/year into air (unregulated); most ends up in water, and then in fish Seafood: larger fish have most mercury, due to eating smaller fish Water: limited to 2 ppb (regulated) Fungicides/Pesticides: some contain mercury (decreasing) 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 Thimerosal Toxicity Previous studies of thimerosal had two major limitations: only tested thimerosal in adult animals only followed animals for 14-45 days, even though lethal doses in humans may not produce any symptoms for 3 months Thus, actual lethal dose may be much lower than believed. Comparison of thimerosal toxicity Humans: immediately lethal at 10,000-30,000 mcg/kg Lower doses lethal after several months 3000 mcg/kg? Infants more vulnerable 1000 mcg/kg? Vulnerable population (1 in 250) 100 mcg/kg? Neurological damage instead of death 10 mcg/kg? Oral antibiotics prevent excretion 1 mcg/kg? exposure to other heavy metals 0.1 mcg/kg? Note: the EPA safe limit for mercury exposure is 0.1 mcg/kg Thimerosal in vaccines: up to 237 mcg total; in 2-month children, about 60 mcg/5 kg, or 12 mcg/kg in one day Conclusion: amount of thimerosal in vaccines could have harmed children, especially those on oral antibiotics or genetically vulnerable Thimerosal Settling Thimerosal molecule is far denser than other molecules in vaccine, due to heavy mercury atom So, thimerosal may settle to bottom of 10-dose vial, so that some unlucky children could have received up to 10x the dose of thimerosal Rather than replacing thimerosal with other preservatives, single- dose vials would be safer at modest cost 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 National Academy of Sciences estimates 60,000 children/yr in US suffer neurological damage due to mercury poisoning. 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? Mercury Toxicity 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 55 children with ASD ages 3-24 years (mostly 3-10), chosen from Phoenix ASA mailing list 50 typical children chosen from their friends/neighbors (unrelated), same age and sex Methodology heavy metal exposure questionnaire hair analysis dental exam psychological testing (Gilliam Autism Rating Scale) urine test of sulfate (results pending) Preliminary Results of Heavy Metal Questionnaire Caveat: mostly based on mother’s memory Seafood: 60% of ASD mothers consumed more than 2 servings/month during pregnancy/breastfeeding, compared to 30% of controls; yields a 3.4x relative risk of ASD (p<0.02); presumably mercury in the seafood is the major problem Preliminary Results of Heavy Metal Questionnaire (cont.) Ear Infections: during first three years of life: ASD: 10x controls: 2x yields an 8x relative risk of ASD if > 8 infections; p<0.001 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) Preliminary Results of Heavy Metal Questionnaire (cont.) Chronic GI Severity: ASD: 1.8 controls: 0.1 (scale of 0-3) p<0.0000001 consistent with a major gut dysbiosis Pica: 30% of ASD vs 0% of the controls a major source of heavy metals symptom and/or cause? Pesticides: 2x higher use of pesticides in autism homes (p<0.02) note that Edelson found elevated levels of a wide variety of toxic chemicals in blood of children with autism could indicate a general problem with detoxification Preliminary Results of Heavy Metal Questionnaire (cont.) Negative immediate reaction to vaccines: None. Mild Moderate Severe ASD 53% 27% 12% 18% Controls 72% 21% 7% 0% p=0.01 - highly significant; Since mercury has a latency period of several months, this is probably due to other components of the vaccine. Still analyzing vaccination records for long-term effects of vaccines. Preliminary Hair Data Children: ASD cntrl p value lead 0.40 0.54 0.10 mercury 0.14 0.17 0.67 Mothers: mercury 0.39 0.17 0.34 There is a trend that children with autism excrete slightly less lead and mercury than typical children. Surprising, since 30% exhibit pica (those children excrete more than controls). Mothers of autistic children seem to excrete roughly 2x mercury than typical mothers, presumably due to higher seafood consumption. Need more data to be conclusive (still collecting) 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, 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 Preliminary DMSA results Much higher levels of Al, Hg, Sn, and U in autistics vs. controls Somewhat higher levels of Sb, As, Pb, W in autistics vs controls Need more numbers for differences to be statistically significant DMSA results (continued) Child 16: excess Sn (60x normal) Child 50: excess Al (700x), Sb(13x), Bi(5x), Cd(6x), Pb(5x), Ni(5x), W (5x), U(200x) - most severe case Child 53: excess Sb (8x) Child 2: excess Sb (7x), As(10x), Hg(150x) Child 51: nothing unusual Child 35: excess Hg (6x) Child 36: excess Al(35x), U(60x) DMSA results Bradstreet used a 3-day, 30 mg/kg-day DMSA treatment in roughly 200 children with autism and 19 controls. He found that children with ASD excreted 5x as much mercury as the controls. Together, our data suggests ASD children have inhibited ability to excrete heavy metals Conclusions Seafood consumption > 2 servings/month yields 3.4x risk Ear infections > 8x (first 3 years) yields 8x risk ; antibiotics greatly reduce mercury excretion Pica is common in ASD (major source of heavy metals) Home pesticide use is important Vaccine reactions are more common in ASD Hair data intriguing but not yet conclusive DMSA results strongly suggest children with autism cannot excrete heavy metals; need more data and pre-test data Overall, mercury and other metals appear to be a major risk factor for ASD Edelson/Cantor Studies S. Edelson and D. Cantor, Toxicology and Industrial Health (2000) 16 1-9. Evaluated 39 children with autism blood test of 20 toxic chemical solvents by Accu-Chem; compared against labs reference range for “maximum acceptable for adult� 3-methylpentane (n=24, 3.7x adult max) N-Hexene (n=17, 9.5x adult max) 2-methylpentane (n=13, 9.2x adult max) toluene (n=13, 6.1x adult max) tetracholorethylene (n=10, 8.5x adult max) 13 other chemicals: n=1-6, levels = 1.8-21.5x adult max) 89% of children had 1 or more excess levels of toxic chemicals Consistent with their earlier study of 20 children with autism. (Toxicology and Indus. Health, 1998, V.14, 799-811) Edelson/Cantor Studies - continued Liver Detoxification Test: challenge with caffeine, Tylenol, aspirin (Great Smokies) Measure % of abnormal results (n=36) - compared to adults? phase 1 value 81 plasma cysteine 8 plasma sulfate 25 glutathione conjugation 22 glycine conjugation 31 sulfation 19 glucoronidation 19 phase 1/sulfation 42 phase 1/gluconation 81 phase 1/glucuronidation 81 plasma cysteine/sulfate 14 Phase I overactive compared to phase II: 86% Functional Phase I, but impaired phase II: 14% 100% of children with autism had abnormal liver detoxification (compared to adults?) Revised Hypothesis Liver detoxification problems in autism could lead to impaired ability to excrete heavy metals and chemical toxins, as well as waste products from body’s metabolism 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 Testing and Treatment Recommendations DMSA challenge test of heavy metals check levels of toxic chemicals (Accu-Chem labs) check mercury in baby hair (if available) Limit exposure to heavy metals (check drinking water and paint; avoid seafood, especially those with high mercury; limit pica; wash hands) support liver detoxification consider DMSA chelation consider sauna other? still a lot to learn Caveat: unclear if damage caused by heavy metals can be reversed, especially in older children/adults Case Study: Adult recovery from mercury toxicity April 1999: Airline pilot (Gulf War Veteran) suffered from abnormal weight loss (40 pounds), elevated liver enzymes, elevated blood pressure, esophagitis, gastritis, duodenitis, anxiety, depression, insomnia, muscle joint pain, and short term memory loss. Voluntarily removed himself from active flight status 8/1999: Carl Hayden VA Hospital evaluates patient at 66% intellectual ability. Diagnosis of Severe Depression, Adjustment Disorder and Post Traumatic Stress Disorder, with variable to poor short-term memory, and Acalculus Cholecystitis. 11/1999 - Gulf War veteran found to have high level of mercury in hair (14.2 ppm, >5 ppm indicative of mercury toxicity) 2/2000 - Chelation challenge with 250 mg DMPS found 74 ug/g- creatinine in urine, compared with pre-challenge level of 3.3 ug/g- creatinine 11/2000 - after removing dental amalgams and 9 months of chelation therapy, complete symptom relief; urine level after DMPS reduced from 74 -> 10; hair level reduced from 14.2 -> 1.2; VA Hospital evaluates intellectual function at 93%, no diagnosis; returned to active flying status Current and Future Studies More DMSA testing Expanded epidemiological study baby hair collection (duplicate Holmes’ results) protein/gene abnormalities chelation treatment study? Acknowledgements Funded by Arizona State University, Greater Phoenix Chapter of ASA, and Pima County Chapter of ASA www.eas.asu.edu/~autism |