Toxins in Autism: Mercury to PCB’s

Woody R. McGinnis M.D.

Anaheim, June 28, 2003

Irene (Vicky) Colquhoun

1920-2000

Parent Pioneers

Bernard Rimland Ellen Bolte

Brenda O’ReillyVictoria BeckRik Rollens

The Mercury Team

Autism and ADHD are Symptoms

Multiple underlying problems

Variation and commonality

Gut and nutrition paramount

Cornerstones

Suboptimal Nutrition

Food Intolerances

Microbial Overgrowths

Toxins

Gut Disease Predominates

Esophagitis 69%Gastritis 42%

Duodenitis 67% Colitis 88%

Autistic Gut Symptoms•

Abdominal pain 69% Chronic diarrhea 58% Constipation 35% Night-awakening 42%

Gut Status

Poor digestion and absorption

Leaky gut: proteins out, toxins

and antigens in

Microbial overgrowths

Poor enzyme production

Altered signaling to CNS

Gut Dysfunction

Microbes Nutrients Peps, Ags,

Overgrow Low Toxins In

Laboratory Indices of Vitamin and Mineral Deficiency in Autism

Defeat Autism Now27 October 2002

San Diego

Tapan Audhya Ph.D.

Emar Vogelaar Ph.D.

Low Nutrient Levels in Autism(187 Autistic, 11-16 y.o vs. 10-17 y.o. controls)

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% C

hil

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rmal

Lev

el

Vit A Carotene Vit C Vit D Vit E

Before supplements After supplements

Low Nutrient Levels in Autism187 Autistics (11-16 y.o.) v. Controls (10-17 y.o.)

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% C

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rmal

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B1 B2 B3 B5

Before supplements After supplements

Low Nutrient Levels in Autism

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% C

hil

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n <

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rmal

Lev

el

B6 B12 Folate Biotin Inositol

Before supplements After supplements

Substrate Requirement for Maximal Activity of P5P Dependent Enzymes

010203040

506070

KM

Pyridoxal kinase Glutamatetransaminase

Glutamatedecarboxylase

Controls (n=16) v. Autistics (n=8-17)

Controls Autistics

Substrate Requirement for Maximal Activity of P5P Dependent Enzymes

0100200300400500600700800900

1000

DOPAdecarboxylase

Histidinedecarboxylase

5-HTPdecarboxylase

Controls Autistics

Low Minerals in Autism

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% C

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RBC Zinc RBC Magnesium RBC Selenium

(132 Autistics, 42 Controls)

Membrane Fatty Acids

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Low EPA Low GLA High AA High Tran

Nutrient Blockade

Absorption

Transport

Breakdown

Excretion

Inhibition

Blocked Absorption

Heavy metals: direct mucosal injury

Oral contraceptives block managnese

Insecticides: lipase inhibition

Poor acid production from microbial toxins and peptides means poor absorption of magnesium, zinc, B6 and amino acids

Blocked Transport

PCB’s block RBP, so low stored

and circulating Vitamin A

Cadmium displaces Zinc

Toxin-lowered [Magnesium]: poor P5P entry

Caramel coloring blocks P5P entry

Increased Breakdown

Ubiquitous toxins, including polyhalogenated hydrocarbons

(PCB’s, PCDD’s, PCDF’s) cause:

Vitamin A destruction

Increased Excretion

ETOH and Gentamycin: Vitamin B

Theophylline: Magnesium

Mercury: Magnesium and Calcium

Sulfa and Indocin: Folate

Tartrazine: Zinc

Nutrient Inhibition Insecticides and theophylline bind B6-

dependent enzymes

Sulfa drugs antagonize Folate

Lead competes for Calcium binding sites

Benzene binds Pyridoxine (B6)

Hydrazines (jets, corrosion inhibiter) and Hydrazides (“Alar” on fruits, cigarettes and

especially potato chips): B6 look-a-likes

Environmental Toxins in Autism?

Some Clues:

D-glucaric acid increased in 78%

Plasma glutathione low in 46%

Lower glutathione peroxidase (GSHPx)

Organic Toxins in Autism

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% C

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rmal

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evel

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Benzene Iso Acetone Pentane Hexane

Elevated Plasma Levels

Organic Toxins in Autism

0

5

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25

30

35

% C

hil

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n>

No

rmal

Lev

el

Aroclors(PCB) Perchlorethylene Xylene

Elevated Plasma Levels

Elevated Toxins in Autism(41 autistics, 24 controls)

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5

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35

% C

hild

ren

>N

orm

al

Le

ve

ls

Aluminum Arsenic Cadmium Lead

Red Blood Cell Levels

Toxins in Autism

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Total mercury Organic mercury Inorganic mercury

Elevated Red Blood Cell Levels

Metals in autism?

• Clinical Pediatrics, 1988; 23(1):41-44

Temporal association lead and autism

• Am J Dis Chld, 1976;130:47-48

Higher blood lead levels and response

to EDTA chelation.

• DAN 2001 case report: normal 4 y.o. regresses severely to ASD post-amalgams

HEAVY METALS

AC / DCDANGER DANGER

EROTIC LIQUID CULTUREJEREMY & THE SUICIDES

MEGA DEATHMETALLICA

MOTORHEADNEAR LIFE EXPERIENCE

NEUROTICANEW AMERICAN SHAME

PSYCHOTICAVITAMIN F

Toxic Metals

Mercury Nickel

Lead Tin

Cadmium Free Copper

Arsenic Free Iron

Metals: Toxic Mechanisms

Membrane damage

Protein distortion

Calcium channel block

Nutrient depletion

Immune suppression

Detoxifier depletion

Oxidative stress

Sensitivity to Metals

Chemical form

Amount and duration

Age, gender, genetics

Nutrition and immunity

Other toxins

Autism / Mercury Clues

Acidosis Cholinergic block

Low sulphate Autoimmunity

TH2 shift Demyelination

Seizures Visual

Depressed NK Purkinje / granule

Se depletion B6 depletion

Pink Disease

From 1890, often lethal

Often pink cheeks, nose and painful hands (‘acrodynia’)

Calomel teething powder

Typically latent onset

Only 1 in 500 exposed

Pink Disease

Apathy Repetitive rockingLost play Repetitive handsSound / light Poor muscle toneTouch averse SeizuresHead-banging Infections, insomnia

Autism / Mercury Traits

Social deficit Toe-walkingSpeech loss Head-bangingEcholalia Touch-averseRepetitive Sound sensitiveLateral gaze Poor eye-handFlapping RashesCircling Poor sleepAbnormal G.I. ADHD

Case study – C.M.

EPA maximum is 0.1 mcg Hg / kg / day

First Hep-B 12.5 mcg, so X 30 that day

[Presumed] 25 mcg in each DPT and

H-flu. By 6 mos, total Hg 187.5 mcg,

or X 2 EPA (total exposure)

CASE STUDY - C.M.

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FIRST SECOND THIRD FOURTH

Thimerosal Aliases

Ethyl mercury

Elcide

Ethylmercurithiosalicylate

Mercurothiolate

Merfamin

Merthiolate

Ethylmercuric thiosalicylate

Timerasol, Thimerosal, Thiomerosal..

Mercury Injections

No safety studies

Organic forms of Hg most toxic

Faroes Islands bolus lesson

Infants poor excretors

Vaccines open BBB

Thimerosal and Autism

• CDC: initial suggestion of association, prior to revision of study results

• IOM: thimerosal / autism link “plausible”

• First published epidemiological report: incidence of autism X 6 if received DPT with Hg [Geier M and Geier D, 2003]

Metals-Detox NutrientsVitamin C 250-2000 mg b.i.d ups GSH

Vitamin E 150-400 IU daily helps Se combat Hg and Cd

Selenium 1-4 mg/kg/day

Melatonin up to 0.1 mg/kg

Lipoic Acid 1-10 mg/kg

Support MET pathway

Taurine 200-1000mg/d

Glutathione

Calcium and Heavy Metals

Mercury increases calcium loss

Calcium aids lead excretion

Cadmium decreases calcium

absorption

DMSA Perspectives

Thousands of autistics

No irreversible side effects

Nutritional and gut prep first

Stay up on the zinc

Many excellent responses

Some talk only on DMSA days

Heavy Metals and the Gut Mercury and cadmium avidly bind intestine and are highly caustic

Mercury blocks vitamin B6 and DPPIV

in the gut

Antibiotic-altered flora may recirculate mercury

DMSA Mechanisms?

Reduction of Hg and other heavy metals

Reduction of Cu burdens

Clear sensitive muscarinic cerebral-

dilating receptors.

Definition

Free-radicals are highly-reactive molecules which damage cells by oxidizing lipids,

proteins and nucleic acids.

Some free-radicals are a natural by-product of energy metabolism. Environmental

toxins are either free-radicals themselves, or lead to the generation of free-radicals in the body (as do infections and allergies).

Increase Free-Radicals

Smoking, pollution, ozone, metals Inflammatory cytokines

Infections, allergies Oxidized foods, food additives

Dirty foods (insecticide, herbicide) Unbound Copper and Iron

Depleted anti-oxidant defense

Protect from Free-Radicals Vitamin C Urate

Vitamin E Glutathione (GSH)

Vitamin A Metallothionein (MT)

Vitamin B6 GSHPx Vanilla

Zinc Catalase Phenothiazines

Carnosine SOD Estrogen

Niacinamide Melatonin EPA

Folate CoQ10

Definition

Oxidative Stress is cellular impairment resulting from free-radicals in excess of

available anti-oxidant defense.

The interplay of genes, nutrients and toxins determines the level of oxidative stress.

Metals Increase Oxidative Stress

• Metals with high-affinity for SH-groups (Hg,Pb,Cd,As,) deplete GSH and MT

• Metals with fluctuating valency (Cu, Fe, Mn) generate free radicals directly

• Metals which mimic calcium (Pb,Sn) over-excite the cell via increased intracellular calcium, which generates free radicals.

Especially Sensitive to Oxidative Stress

Gut: extreme sensitivity of

mucosa to free-radicals

Brain: high lipid, low GSH,

low metallothionein levels

Oxidative Stress in Autism?Extensive GI inflammation

Opiod binding blocked by GSH

DPPIV active in reducing conditions

Muscarinic targets

Stim-relieving effect of GSH

DMSO a hydroxyl scavenger

Increased PLA2

Response to DMSA

Autoimmunity

Oxidative Stress in Autism?Poor anti-oxidant nutrient status

Lower GSH and GSHPx

Extreme copper intolerance

Phenolic intolerance

Breathe ethane in ADHD

ApoE4 genotypes

Vitamin C / carnosine trials

B6 blockade in autism

50% high-Mauve

PHF LEVELS

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ADD ADHD AUT

AVERAGE

MEDIAN

High-PHF Rats

Exceedingly high biomarkers for oxidative stress in these SHR.

Oxidative stress and symptoms in these animals relieved by

vitamin C or MET.

Zinc is Free-Radical Protection

Blocks lipid peroxidation

Protects protein structure by coordination with SH-groups, blocking Cu and Fe.

Essential for maintenance of Vit A level

Supplementation increases GSH

Co-factor for MET pathway

Key constituent for SOD

Deficiency increases SO4 loss

Glutathione (GSH)Ubiquitous FR-quencher, lst-line gut defense

Protects receptor and enzyme function

Key partner to MT

Substrate for GSHPx and Phospholipid Hydroperoxide GSHPx

Excellent responses to I.V. GSH

Significant oral absorption, intact

Excellent responses to oral 10-50mg/kg/d

Oxidative Stress Measurement (“Biomarkers”)

Anti-oxidant nutrient levelsEndogenous anti-oxidant compounds

Oxidized lipids, including breatheOxidized proteins

Oxidized nucleic acidsIsoprostanes, Isolevuglandin adducts

Apoptosis

The Mauve Factor

Excellent response to anti-oxidants across multiple diagnoses

Zinc and B6 deficits, which vary individually and which fluctuate

Putative metric for oxidative stress

“Mauve Factor” Means Pyrroles

• Measurable as “Kryptopyrrole”

• A core test in the the management of all behavioral disorders

• 1-800-494-7785

Urinary Pyrrole: The Mauve Factor

Useful, economical, may be pivotal.

Elevation makes zinc,Vitamin B6

and anti-oxidants top priorities

Careful handling: highly labile

Autistic Urinary Pyrrole Levels and B6 (10mg/kg/day) + Zn (25mg) + Mg (400mg)

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Months of Treatment

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Mauve Factor Inhibits Heme

Heme Inhibition associated with decreased Zn, increased Fe.

Heme-dependent anti-oxidant enzymes include: catalase,

peroxidase, cystathionine synthase, heme-hemopexin for MT synthesis,

p450, cytochromes for energy production.

Diketone Neurofilament Injury

ConclusionOxidative stress may be the primary,

shared pathological mechanism for diverse factors contributing to autism,

and its reversal may significantly affect the course of the disease.

Biomarker studies underway.

Potential for objective criteria to guide therapy, enhance focus for gene and

tissue studies.

Goal: Lessen Oxidative Stress

Minimize toxins, infections, allergens

Give plenty of anti-oxidants

Support detoxification metabolism:

Vitamins B6, B12, (Folate)

Magnesium, Zn, Selenium (folic acid)

(Methionine)

METHIONINE

HC

GSHMT

CYS

ATP, Mg

B6 (Mg, Zn)

TAU DETOXBILE

SO4SO4

Detoxification Organic foods, pure water Clean living environment

No additives or flavor enhancers Regular bowel movements: fiber, mag-

citrate, vitamin C, bethanecol Plug nutritional holes and suppress

overgrowths DMSA / Lipoic Acid metals protocol

Basic Lab List

Stool studies Mauve Factor RBC minerals Organic acids Serum IgG / IgE

food allergy Vitamins (esp A)

RBC fatty acids Peptides PCR for mycopl.

and chlamydia

Immune profile Toxins Amino acids

Treatment

Supplements

Food avoidance

Suppress overgrowths

Detoxify

Really Key Nutrients

Zinc Magnesium Calcium Vitamin B6 Fatty Acids

Vitamin A Vitamin C Vitamin E Vitamin B12 Biotin GSH

Supplementation

History, physical, lab, empirical

Don’t be deceived: use sensitive measurements

Keep re-checking to confirm

Changing needs and variability

General Approach

Introduce interventions individually

Smaller doses may be necessary at first

Continue interventions unless reason to stop

If combination nutritional formulations are not well-tolerated, add one-at-a-time

Adding Nutrients Individually

Build sequentially Zinc, then P5P/Magnesium Glycinate,

Calcium, Selenium, C, E, Multi-Vit without Copper, Biotin, B12, Cod liver oil (for Vitamin A)

Really assure zinc Away from food, minerals and P5P

Zinc/Manganese about 3:1

Fatty-Acid Basics

Pre-treat with anti-oxidants

Treat low-normal GLA, DGLA and EPA lab values

Dry hair or skin, allergy: usually need fish oil EPA

Infections, leaky gut: usually need evening primrose GLA