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12 Merritt Lecture 2 Lead Toxicity PDF
12 Merritt Lecture 2 Lead Toxicity PDF
HISTORY Lecture 2
Cases and Calculations EDTA
Atherosclerosis: Mechanisms
TACT
Metal: Mechanisms
TRIAL
VASCULO
TOXIC
CASES METALS
EDTA
I HAVE NO CONFLICTS OF INTEREST OR
Treatment
FINANCIAL CONFLICTS - DFM MD
Disclosure of Financial Relationships:
None
Off-Label Usage
Yes, The nature of the unapproved or investigative
use is:
EDTA and heart disease
1) Review ideal set up of infusion suite
2) Recall use of hood
3) Explain
new laws and regulations
coming/enforcement varies state to state
COCKCROFT-GAULT FORMULA
Comment: His age would make me cut it by 50% until I saw stable creatinine after
5-6 treatments and I would check creatinine every other time and I would make
treatments every other week initially
What if Case 1 was a female
LBW formula would use 45.5 instead of 50 mg/kg= 84.5kg
Creatinine Clearance formula would be reduced by .85
Comment: LBW calculation is more than her actual weight: Use actual Kg
Pts with liver disease have renal insufficiency starting at .8 creatinine
.85 dose reduction in dose due to being female and I would suggest
further reduction in dose due to hepatic status and creatinine until
stable creatinine status proven
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• Healthy: NO adjustment
• Stage‐1: Multiply full dose by 0.75
• Stage‐2: Multiply full dose by 0.66
• Stage‐3: Multiply full dose by 0.50
• Stage‐4: Multiply full dose by 0.25
IF Chelation benefits outweigh risks
• Stage 5: Chelation contraindicated
Calculation Example:
65 Kg 35 YO Male, healthy and “normal” eGFR
• EDTA Dose: 50 mg X 65 Kg = 3250 mg
• Max dose adjustment: 3000 mg
• eGFR adjustment: NONE
• Form of EDTA: Na2EDTA
• DMPS Dose: 2 mg X 65 Kg = 130 mg
• Max dose adjustment: NONE
• eGFR adjustment: NONE
• Other adjustment considerations:
• NONE
Final Dose, Admin. Rate, Test / First Dose, Remin. Frequency:
EDTA Dose: 3000mg DMPS Dose: 130mg Admin Rate: Na2EDTA 1000mg/hr – DMPS
25 mg/min. Test / First Dose: Na2EDTA 2000 mg / DMPS 75 mg Remin. Freq.: 1:3
Calculation Example:
75 Kg 65 YO Female (frail appearing) with Stage‐3 CKD
• EDTA Dose: 50 mg X 75 Kg = 3750 mg
• Max dose adjustment: 3000 mg
• eGFR adjustment: (X 0.50) 1500 mg Merritt’s comments
• Form of EDTA: CaNa2EDTA EDTA 1000/hr max for Ca or
• DMPS Dose: 2 mg X Kg = 150 mg Na EDTA by published
• Max dose adjustment: NONE standards. However, faster
• eGFR adjustment: (x 0.50) 75 mg rates appear to be tolerated
• Other adjustment considerations:
• Frail:
Final Dose, Admin. Rate, Test / First Dose, Remin. Frequency: EDTA
Dose: 1500mg DMPS Dose: 75 mg Admin Rate: EDTA 2000 mg/hr
Test / First Dose: EDTA 500 mg / DMPS 50 mg Remin. Freq.: 1:2
Calculation Example:
Healthy 90 Kg 32 YO Male, excellent health (In addition to Pb, Cd, Hg
elevations he has very high Al).
• EDTA Dose: 50 mg X 90 Kg = 4500 mg
• Max dose adjustment: 3000 mg
• eGFR adjustment: NONE
• Form of EDTA: CaNa2EDTA
• DMPS Dose: 2 mg X 90 Kg 180 mg
• Max dose adjustment: NONE
• eGFR adjustment: NONE
• Other adjustment considerations: ALUMINUM
Final Dose, Admin. Rate, Test / First Dose, Remin. Frequency:
EDTA Dose: 3000 mg DMPS Dose: 200 mg Admin Rate: EDTA 2000 mg/hr First
Dose: both at 50% Remin. 1:3 AND: add Magnesium Malate 850 mg PO BID
A Workbook For The
Administration Of IV EDTA In An
Outpatient Setting
Mixing alternatives, osmolarity,
dose calculations, example cases
OSMOLARITY WORKSHEET FOR EDTA CHELATION AND VARIOUS IVS
KEEP mOsm/l less than 1000 and greater than 330 for best results
Medication mOSM/cc Amount(cc) Total mOsm
additives cc 65.5
mOsm additives with 7gms Vit C 188.05
mOsm additives with 2gms Vit C 118.45
Total IV mOsm/l
IV Sizes Tot IVcc mOsm/l 7gm C 2 gm C
1 Sterile water 500cc 0 500 565.5 0 332 209
2 NS 250cc 0.602 250 315.5 150.5 1072 852
3 NS 500cc 0.602 500 565.5 301 978 741
4 1/2NS 250cc 0.465 250 315.5 116.25 964 743
5 1/2 NS 500cc 0.465 500 565.5 232.5 744 621
6 RL 500cc 0.569 500 565.5 284.5 945 712
7 D5W 250cc 0.569 250 315.5 142.25 1047 826
8 D5W 500cc 0.569 500 565.5 284.5 835 712
Other Meds
Keep mOsm under 1000 and above 330
Remove all but 2gms Vit C if needing to reduce osmolarity due to IV shortages
NUTRITIONAL SUPPORT TO SUPPORT LEAD TOXICITY
MY OFFICE SET UP
MY OFFICE SET UP
To‐Go balls Trochar for Vit C
W.A. Shrader, Jr., MD
Santa Fe Center for Allergy
& Environmental Medicine
EQUIPMENT NEEDED
Safety Catheter Needle
Tourniquet
Alcohol Swab
Gloves
Gauze
IV Tubing
Paper Tape
IV Bag and IV Pole
AirClean Hood
Laminate and use one of the tact trial slides that compares
EDTA to usual medical treatment and put on your exam room
walls or display areas
Use the lead slides to show 18% of people who die per year
die of lead (NHANES 2018) or 412K people in US; Emphasize
the fact that US CV death rate dropped 32% in the decade
after lead taken out of cars but its still in their bones
Draw BLL in all people yearly after age 50
Prevent bone turnover now
Set up an account with a national lab such as Genova, Doctors
Data or similar lab for urine metal testing
Set up an account a 501B compounding lab for iv materials
Set up account to get your IV s and to go balls
Buy a hood
Find out your state requirements for compounding and
enforcement
Find out your labs lower limit of lead: quest 3, Lab corp 1
Print off the HnP and consent forms‐very important
HISTORY
Atherosclerosis
TACT
TRIAL
EDTA
ATHEROSCLEROSIS
VASCULO
TOXIC
METALS
CASES
EDTA
I HAVE NO CONFLICTS OF INTEREST OR
Treatment
FINANCIAL CONFLICTS - DFM MD
Atherosclerosis Learning Objectives
#1 cause of mortality in world is CV
low level lead exposure in 1988 causes
412,000 deaths/year now (NHANES 2018)
ATHERO‐ Reduction of exposure to Pb and Cd has
reduced CV mortality by 32% from late 80’s
SCLEROSIS to late 90’s. Total reduced CV mortality was
43% from reduction of exposures to metals
EDTA reverses many pathways in the
formation of atherogenic plaque and
removes lead and other heavy metal ions
ATHEROSCLEROSIS 2018
Source: NHLBI.
AT WHAT AGE SHOULD WE SCREEN AND TREAT TO
PREVENT MORBIDITY AND MORTALITY?
40 36.7
Percent of Population
35
30 25.1
25 22.7
20 16.6
15
10 7.0 7.0
5 0.7 0.7
0
20-39 40-59 60-79 80+
Men Women
Lead Ozone
Arsenic Aldehydes
Mercury Carbon Monoxide
Cadmium Particulate matter
Metals: lead, cadmium, mercury, arsenic, Long‐term exposure to fine particulate matter
cobalt, thallium, tungsten. less than 2∙5 μm in diameter (PM2∙5) and traffic‐
related air pollutant concentrations are
Air pollutants: DEP (diesel exhaust particles),
associated with CV risk
ozone, particulate matter (PM <2.5), solvents
For each 5 μg PM 2∙5/m(3) increase, coronary
Women’s Health Initiative: 76% increase in risk
calcium progressed by 4∙1 Agatston units per
with each increase of 10 μg per cubic meter in
year (95% CI 1∙4‐6∙8) and for each 40 ppb NOX
long‐term PM 2.5 exposure — accounting for
coronary calcium progressed by 4∙8 Agatston
subjects in approximately the 10th to 90th
units per year (0∙9‐8∙7)
percentiles for exposure.
Pollutant exposures were not associated with
intima‐media thickness change
J Med Toxicol. 2012 Jun;8(2):166‐75./J Thorac Dis. 2016
Jan; 8(1): E8–E19./N Engl J Med 2007; 356:447‐458
Kaufman JD, et al. Lancet. 2016.
Lead in soil
The review identified 37 unique studies comprising 348 259
non‐overlapping participants, with 13 033 coronary heart
disease, 4205 stroke, and 15 274 cardiovascular disease
outcomes in aggregate
Exposure to arsenic, lead, cadmium, and copper is associated
with an increased risk of cardiovascular disease and coronary
heart disease. Mercury is not associated with cardiovascular
risk.
NHANES surveys document a marked reduction in population
exposure to lead and cadmium largely reflecting large scale
public health policies on the control of tobacco, reduction of
air pollution, remediation of hazardous waste, renovation of
drinking water infrastructures, and banning of lead in gasoline
Concomitant with these reductions, cardiovascular mortality
rates in the US decreased by 43% from 1988‐94 to 1999‐
2004. An analysis that accounted for traditional
cardiovascular disease risk factors, showed that 32% of this
reduction in cardiovascular mortality could be explained by
the decline in lead and cadmium exposures.
BMJ 2018;362:k3310
Int J Epidemiol. 2017 Dec 1;46(6):1903-1912
CORONARY RISK FACTORS
Aspirin: 25% (Anti‐platelet Trialists’ Collaboration. BMJ 1994;308:81‐106 Level A) (NNT 25‐50 2 years)
Beta‐Blocker: 23% (Capricorn Investigators Lancet 2001 Level A) (NNT 42 2 years)
Statin: 21% 4S Trial Level A (NNT 33‐65 2 years)
ACE‐ Inhibitor: 19% SAVE trial Level A (NNT 28 ‐> 200)
Chelation/Vitamins: 26% trial level A
EDTA in Diabetics‐ 41% (ALL), 51% (MI), 43% (Death) Level A
Number RR Death p value
IV EDTA+ Vits in Post MI
Beta blocker during MI 28,970 .87 (.77-.98) 0.02
• 26% reduction in endpoints NNT 12
Beta blocker post MI 24,298 .77 (.70-.84) <0.001
ACEI during MI 100,963 .94 (.89-.98) 0.006
ACEI post MI if LV dysfxn 5,986 .78 (.70-.86) <0.001 IV EDTA IN DIABETICS POST MI
Nitrates during MI 81,908 .94 (.90-.99) 0.03 • 43% reduction in death NNT 7
Ca++ blockers 20,342 1.04 (.95-1.14) 0.41 • 41% reduction in cv endpoint NNT 12
Magnesium 61,860 1.02 (.96-1.08) >0.05
Lidocaine 9,155 1.38 (.98-1.95) >0.05 IV EDTA IN DIABETICS POST MI with high dose vitamins
Class I Antiarrhythmics 6,300 1.21 (1.01-1.44) 0.04 • Primary endpoint reduction NNT 6
PLAQUE RUPTURE AUTONOMOUS IMMUNE TSUNAMI
“Tsunami” of Inflammation, thrombosis,
and vasoconstriction effects after the
“Earthquake”(rupture)
Endothelial lining thins, retracts, allows migration
of LDL, foam cells exposed
Macrophage foam cells interact with platelets
Fibrous lesion results
Grows to mature atherosclerotic lesion
Plaque with fibrous cap
“Vulnerable” plaque ruptures leading to
thrombosis
68% of MI: < 50% Stenosis
14% of MI: < Significant Stenosis
62% of men – 1st symptom of CHD is MI
46% of women – 1st symptom of CHD is MI
STATIN REGRESSION DATA
22 of 26 cardiometabolic risk biomarkers
showed statistical improvement in the
“treatment” group compared to 0/26 in the
usual care group at one year
Cardiovascular Diabetology2018 17:56 Bhanpuri et al
INTEREST IN THE KETOGENIC DIET GROWS FOR
WEIGHT LOSS AND TYPE 2 DIABETES
The ketogenic diet was introduced in 19241 after two years of
clinical trial. Wilder,2 in 1921, on the basis of Geyelin's3 results
with starvation, suggested that diets in which the proportion of
carbohydrate and protein was sufficiently restricted might offer a
method of treatment of epilepsy. JAMA 1928;90(18):1427‐29
JAMA. 2018;319(3):215‐217. doi:10.1001/jama.2017.20639
ROBERT FURCHGOTT, LOUIS IGNARRO AND FERID MURAD
SHARED NOBEL PRIZE IN MEDICINE IN 1998 FOR DISCOVERIES PROVING
NITRIC OXIDE AS A SIGNALING MOLECULE IN THE CV SYSTEMS
Defects in endothelial NO function associated with all
major CV risk factors & has predictive value for disease
progression
(Schachinger, Britten et al. 2000; Halcox, Schenke et al. 2002; Bugiardini,
Manfrini et al. 2004; Lerman and Zeiher 2005 )
NITRIC OXIDE MECHANISMS AND LEAD
We found a negative correlation
between plasma nitrite and B‐Pb
concentrations suggesting increased
inhibition of NO formation with
increasing B‐Pb or P‐Pb
concentrations.
Clinical evidence for lead‐induced inhibition of nitric oxide
formation, Fernando Barbosa, Jonas T. C. Sertorio, Raquel
F. Gerlach and Jose E. Tanus‐Santos, Arch Toxicol (2006)
80:811‐816
CA EDTA PROTECTS VIA NO PATHWAY
Oxidative stress
Nitric Oxide inactivation
Changes in B receptor
density
Endocrine Disruption
Renal impairment-Prox
Tubular dysfx
Lipid Peroxidation
↑ produc on of ROS
Endothelial injury
Chemokines Vascular remodeling Vasoconstriction
Monocyte adhesion Platelet activation Na retention
LDL oxidation ↓ TPAI Adrenergic activity
Foam cell formation
Hypertension
Atherosclerosis
Thrombosis
Am J Physiol Hrt Circ Physiol(2008)295:H454‐H465
NITRIC OXIDE‐SUMMARY
Lead and other heavy metals reduce NO
EDTA independent of removing lead, increased NO,
and eNOS and has other anti‐inflammatory, anti‐
atherogenic properties
DMSA increases GFR in high via NO and low dose lead
exposed rats, but does not fix pathological lesions in
kidney
Farhad Khalil‐Manesh, Harvey C. Gonick, Arthur Cohen, Enrico Bergamaschi, Antonio Mutti Experimental model of lead nephropathy: II. Effect of removal from
lead exposure and chelation treatment with dimercaptosuccinic acid (DMSA) Environmental Research Volume 58, Issues 1–2, Pages 35‐54 (June–August 1992)
NITRIC OXIDE
NOS III
NO
Inhibition of
- -
- -
Oxidation of Smooth muscle Expression of Endothelin
LDL-cholesterol proliferation adhesion molecules production
Increased Glutathione Peroxidase (GSH-Px) lowers BP, reduces MI, LVH and CHF.
GSH-Px confers more cell, tissue and organ protection than SOD or catalase, or the
combination of both.
Circulation 2004; 109:544-549/ NEJM 2003; 349:1605-13./Coronary Artery Disease 2003; 14:149-153).
GSH STATUS AND OXIDATIVE STRESS
59 YO WM, heavy smoker‐ hypertension, and elevated
levels of blood lead and cadmium
8‐OH‐dG*
*(8‐hydroxy‐2’‐deoxyguanosine)
* First AM urine collection
Dorothy Merritt, MD
LEAD
Vasculotoxic Metals 1
ARSENIC
GADOLINIUM
VASCULO
TOXIC
MERCURY
IRON
METALS
CADMIUM
PLATINUM
• 231 adults living in a small industrial Swiss town near a major highway were
followed for 18 years (1959-1976)
• 59 adults received 10+ IV Calcium EDTA in starting in late1958
• 1/59 EDTA patients 1.7% died of cancer during the 18 years
• 30/172 control patients(17.4%) died of cancer during the 18 years
The two groups did not differ in smokers, age, exposure to highway, male/female
ratio or income
• “Low‐level exposures are associated with long‐term effects
not previously recognized” (NIEHS)
• Knowledge of adverse effects are based primarily on independent studies
of a single toxicant (C.D.C)
• Metals can elicit independent, additive or synergistic toxic
effects (C.D.C.)
• MRLs for exposures have not considered that humans bioaccumulate
metals (C.D.C.)
Lead and Cadmium are Synergistic
1+1>2
• Environmental cadmium and lead exposures are widespread, and both metals are
nephrotoxic at high exposure levels
• 14,778 adults with mean blood Cd levels of 0.41 microg/L and lead levels of 1.58
microg/dL in study
• RESULTS : the odds ratios for albuminuria, reduced GFR, and both albuminuria and reduced eGFR were
1.92 , 1.32 and 2.91 respectively, comparing the highest with the lowest blood cadmium quartiles.
• The odds ratios comparing participants in the highest with the lowest quartiles of both cadmium and lead were
2.34, 1.98 and 4.10 for both outcomes.
Pb,Hg,As,Cd,Co,Cr6 glyphosate, 0 antigen on P aero and K pneu GSTP1 33% have SNP Extracellular: Eczema, asthma, sinusitis IBS
inhibit metabolism and increase toxicity of xenobiotic or drug
GSTM1 9% have SNP Intracellular: Cancer
PHASE II NAT 2 Enzyme inhibition Regenerates MB12 for MTR-50% have SNP mutation MTHF, MB12, MET
Bottomline: Metals further inhibit metabolic enzymes that are already at risk due to SNPs in the population
7+ 7+ 7+
Heavy metal pollution still represents a primary concern regarding human health.
Recently, it become evident that the contribution of heavy metals extends far
beyond their accepted role in allergic diseases, and that they may play a more
extensive role in a variety of other diseases. Several lines of evidence indicate that
heavy metals have a key role in the induction or exacerbation of several
autoimmune diseases (AD).
Moreover, the association between exposure to heavy metals and the signs of
autoimmunity are supported by some studies. The mechanisms by which heavy
metals induce the development of AD are not yet fully understood. Our objective
here is to highlight the association of exposure to some heavy metals and AD. In
addition, we present recent results showing the possible alterations in Th1/Th2
reactivity by some heavy metals, which may constitute the trigger for the
incidence of autoimmunity in susceptible individuals.
Initial Nuclear stress test POSITIVE
Final Nuclear stress test NEGATIVE
PERSONAL CASE FROM MY PRACTICE
Results of Serial Urine Lead
(result x urine concentration of cr x volume and move
decimal point back 5 spaces)
Jan 6, 2016 AMI EKG
Post STEMI‐ 100% compliant with lifestyle and Rxs
s/p 2 EDTA per week post MI, BLL <1
In 1 month, essentially normal parameters.EKG
almost back to normal, BLL<1
What Environmental Factors Could be Involved
• Lives in one of the top 10 cities for poor AQI : aldehydes, ozone, PM<2.5 high
• Extreme emotional stress due to employment changes; hostile work environment for
over a year prior to change
• Grew up in a high lead period and has high lead bone by exposure hx
What Environmental Factors Increase Viscosity
Abnormal Plasma Volume Without Compensation
There are at least four conditions in which hyperviscosity is caused by hemoconcentration: primary
hypertension, secondary hypertension caused by alcoholism, cigarette smoking,4 and dehydration. In these
conditions, hematocrit is elevated because of normal or increased red cell mass and decreased plasma
volume. In primary hypertension, plasma volume is appropriately decreased, but red cell mass is not
proportionately decreased for unknown reasons. Hence, hematocrit and blood viscosity are increased, resulting
in hypertension. Ethanol reduces secretion of antidiuretic hormone, resulting in water loss and contraction of
plasma volume. Conditions which are associated with hypertension, such as cigarette smoking, obesity,
diabetes mellitus, and metabolic syndrome are also associated with hyperviscosity and activate the
homeostatic pathway to control blood viscosity. In those who are predisposed to partial failure of this
pathway, the result is hypertension.
8/9/13 right carotid bulb stenosis 55% left carotic bulb 75% stenosis
3/28/17 right carotid bulb stenosis 40% , left 50‐60% stenosis
3/22/18 right carotid bulb <15%, left carotid bulb <15% stenosis
7/26/18 Calcium scoring heart: LAD 65.57
4/19/17 Came in for EDTA consult. BLL 4 hx cataracts, osteopenia Had been using
RRY, Nattokinase and homeopathic treatments A1c 5.8 Chol 211, ldl 116, ldl
particle 1500, hdl 73, crp 2, T3 elevated(on armour) 13/30 pos on lead HnP ROS ,
43ug/lead on 24 hour challenged urine, and elevated Cadmium too.
Changed to Levothyroid and Cytomel to avoid high T3
associated with Pork thyroid
Started on weekly IV Ca EDTA
BLL < 1 after 20 treatments
3/22/18 right carotid bulb <15%, left carotid bulb <15%
stenosis
7/26/18 Calcium scoring heart: LAD 65.57
Patient electing to continue monthly treatments for
maintenence