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Vaccines and Childhood Illnesses: Beyond Thimerosal. disclosure: no financial conflicts. David Ayoub, MD Springfield, Illinois August 5th, 2009 [email protected]. Aluminum MSDS. - PowerPoint PPT Presentation
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Vaccines and Childhood Illnesses: Beyond Thimerosal
David Ayoub, MDSpringfield, IllinoisAugust 5th, 2009
disclosure: no financial conflicts
Aluminum MSDSIngestion: Chronic ingestion of aluminum may cause Aluminum Related Bone Disease or aluminum-induced Osteomalacia with fracturing Osteodystrophy, microcytic anemia, weakness, fatigue, visual and auditory hallucinations, memory loss, speech and language impairment (dysarthria, stuttering, stammering, anomia, hypofluency, aphasia and eventually, mutism), epileptic seizures (focal or grand mal), motor disturbance (tremors, myoclonic jerks, ataxia, convulsions, asterixis, motor apraxia, muscle fatigue), and dementia (personality changes, altered mood, depression, diminished alertness, lethargy, 'clouding of the sensorium', intellectual deterioration, obtundation, coma), and altered EEG.
http://www.sciencelab.com/xMSDS-Aluminum-9922844
“Now the presentations we heard yesterday clearly demonstrate that there are huge gaps in our information about what we know about the toxicology of aluminum. I would like to just reiterate what Neal Halsey said, the differences between adults and infants, there appears to be practically no[t] even animal data never mind human data.”
May 11th - 12th, 2000
What is aluminum?
• 3rd most abundant element
• food, water, air, soil, medicine
• ~8% of earth’s crust
• no biological role
• a poison
published1928
Dr Charles T Betts
“All salts of aluminum are poisonous when injected subcutaneously or intravenously”
Dr. Victor Vaughn, Toxicologist, University of Michigan before US Federal Trade Commission Hearings on aluminum, 1927
Adjuvant
“agents that act nonspecifically to increase the specific immune response to an antigen”
Dictionary of Immunology
(How) do aluminium adjuvants work?Brewer JM. Immunol Lett. 2006 15;102(1):10-5.
The aluminium compounds, originally identified as adjuvants over 70 years ago, remain unique in their widespread application to human vaccines. Given this history, it is surprising that the physicochemical interactions between aluminium compounds and antigens are relatively poorly understood. This has clearly been a contributing factor to vaccine failures, for example, through inappropriate selection of aluminium species or buffers. Similarly, the mechanism(s) of action of aluminium adjuvants are relatively unstudied, although it appears that these agents fail to fit within the current principles underlying activation of the immune response. This review aims to examine recent developments in our understanding of the physicochemical and biological aspects of research into aluminium adjuvants
Aluminum Salts Adjuvants
aluminum hydroxide
aluminum phosphate
aluminum sulfate
aluminum hydroxyphosphate sulfate
mercury-containing shots
aluminum-containing shots
Number of administered vaccines containing aluminum increased after
Thimerosal reduced (by 18 months age)
source: David Ayoub, MD, Prairie Collaborative, Inc
• DTaP Infanrix 625 micrograms
• Hep B Engerix 250 micrograms
• HiB PedVax 225 micrograms
• Pediarix 850 micrograms
• Prevnar 125 micrograms
• DTaP Daptacel 330 micrograms
• DTaP Tripedia 170 micrograms
• HepB HiB Comvax 225 micrograms
• HepB Recombivax 500 micrograms
• Hep A Havrix 250 micrograms
• HepA-B Twinrix 450 micrograms
Aluminum content of some vaccines
Aluminum Exposure Safety Limits
TITLE 21--FOOD AND DRUGSCHAPTER I--FOOD AND DRUG ADMINISTRATION
DEPARTMENT OF HEALTH AND HUMAN SERVICESSUBCHAPTER F--BIOLOGICS
PART 610 -- GENERAL BIOLOGICAL PRODUCTS STANDARDSSec. 610.15 Constituent materials.
(a) Ingredients, preservatives, diluents, adjuvants. An adjuvant shall not be introduced into a product unless there is satisfactory evidence that it does not affect adversely the safety or potency of the product. The amount of aluminum in the recommended individual dose of a biological product shall not exceed:
(1) 0.85 milligrams if determined by assay;
(2) 1.14 milligrams if determined by calculation on the basis of the amount of aluminum compound added; or
(3) 1.25 milligrams determined by assay provided that data demonstrating that the amount of aluminum used is safe and necessary to produce the intended effect are submitted to and approved by the Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research (see mailing addresses in 600.2 of this chapter).
"The amount of 15 mg of alum or 0.85 mg aluminum per dose was selected empirically from data that demonstrated that this amount of aluminum enhanced the antigenicity and effectiveness of the vaccine (Joan May, FDA/CBER, personal communication)."
from NW Baylor, W Egan and Paul Richman,
FDA, CBER; VACCINE; 20 (2002), S18-23
FDA limits NOT based upon safety data!
50 - 250 µg/kg
2 methods:
acute toxicity:1) maximum blood levels
chronic toxicity:2) weight adjusted total exposures
250 -1225 µg
Aluminum Exposure Defined
blood volume
aluminum in shot
Aluminum blood levels
K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Children With Chronic Kidney Disease
12.2.b Baseline levels of serum aluminum should be <20 µg/L. (OPINION)
12.2.c If levels of serum aluminum are between 20-60 µg/L, a search for and elimination of all sources of aluminum should be performed. (OPINION)
12.3 A deferoxamine (DFO) test should be performed if there are elevated serum aluminum levels (60-200 µg/L) or clinical signs and symptoms of aluminum toxicity
newborn: 250 μg/ 250ml blood = 1,000 μg/L
2 month infant*:1225 μg/ 340ml blood = 3,603 μg/L
adult:1225 μg/ 5L blood = 245 μg/L
potential aluminum blood levels post vaccine
*70cc/kg blood volume
weight adjusted exposure
“Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.”
from: http://www.fda.gov/cder/foi/appletter/2004/19626scs019ltr.pdf
“....I5 and 30 mcg/kg/day of aluminum from TPN solutions. This amount resulted in tissue loading with aluminum but not in clearly associated disease. Thus, this rate of aluminum administration could be defined as unsafe. Finally,.....60 mcg/kg/d of aluminum (32). This rate could be considered toxic.”
Gordon Klein, et al 1991
Al-containing vaccine
03.30 kg
2mo4.86 kg
4mo6.54 kg
6mo7.80 kg
12 mo10.1 kg
15 mo10.9 kg
18 mo11.5 kg
HepBEnergix
250 250 - 250 250 -
DTaPInfanrix
- 625 625 625 625 625
HiBPedvax
- 225 225 225 225 225
PCVPrevnar
- 125 125 125 125 125
HepAHavrix
- - - - 250 250
Max dose
(μg)250 1225 975 1225 850 975 875
Max weight adjusted dose
μg/kg/day
75.8 252 149 157 84.1 89.4 76.1
Finally,.....60 mcg/kg/d of aluminum (32). This rate could be considered toxic.”
Gordon Klein, et al 1991
23-55 kg (50-120 lbs)225 µg/shot x 3 shots= 675 µg total
*blood volume (70 cc/kg)
1.6-3.9 L blood volume*
58-140 µg/L potential blood aluminum
4-10 µg/kg per shot (12-30 µg/kg total)
Calculating the dose of aluminum exposure
9-11 y/o:
Calculating the potential peak blood level
9-11 y/o:
Al-containing
vaccine
content(micrograms)
HepBEnergix
250
DTaPInfanrix
625
HepAHavrix
250
PCVPrevnar 125
HPV 225
total 1475 27-64 µg/kg on day of vaccines
> 800 µg/L blood level
vaccine
note: This is a smaller dose than children now receive
breast milk
formula
MRL
MRL violation with just 2 vaccines!
syringe
interstitialfluid
blood/lymph
dissolved by alpha-hydroxycarboxylic acids
citratemalatelactate
urine
excretion
tissue
retention
transferrin
ferritinbrainbone
spleen/livermyocardium
endocrine
Solubilization of aluminum-containing adjuvants by constituents of interstitial fluid. Seeber SJ, White JL, Hem SL. J Parenter Sci Technol. 1991 May-Jun;45(3):156-9.
Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, Indiania.
The solubilization of three commercially available aluminum-containing adjuvants by citrate anion was studied. Amorphous aluminum hydroxyphosphate and boehmite were both solubilized, however, amorphous aluminum hydroxyphosphate dissolved significantly faster than boehmite. The results suggest that citrate and other alpha-hydroxy carboxylate anions in the interstitial fluid are able to solubilize and thereby facilitate the excretion of aluminum from aluminum-containing adjuvants which are administered by intramuscular injection. The results also suggest that the release of antigen following administration may be significantly more rapid from an amorphous aluminum hydroxyphosphate-adjuvanted vaccine in comparison to a boehmite-adjuvanted vaccine.
Gardasil’s aluminum adjuvant may be solubilized faster and thus peak serum
aluminum levels may appear higher and sooner than with other adjuvants
toxic
n=17
blood levels of aluminum after Hep B vaccine in adults on dialysis: significant blood levels achieved with inter-individual variability
baseline
so where is the rest of the aluminum? 78-95% retained in 1 month!
In viva absorption of aluminium-containing vaccine adjuvants using 26AlRE Flarend SL Hem, JL White. et al. Vaccine 1997:15(12-13);1314-18.
less than vaccine exposureaverage 78% of aluminum still retained in 5 infants exposed for at least 2 weeks (range 60-95%)
Premies
Evidence of aluminum loading in infants receiving intravenous therapy. Sedman AB, Klein GL, Merritt RJ, Miller NL, Weber KO, Gill WL, Anand H, Alfrey AC.N Engl J Med. 1985 May 23;312(21):1337-43.
• aluminum hydroxide in young adult
mice
• 50 μg/kg per dose x 2 shots
• 100 μg/kg fully vaccinated
infants: 50-250 μg/kgGardasil: 27-64μg/kg
• Behavioral effects of aluminum
• 50% reduction in strength/endurance (wire-mesh
hanging)
• 138% increase in anxiety(open-field testing)
• increase memory errors (water maze; ns)
• 20% hair loss at injection site
histopathology
• spinal cord:
• 255% increase in apoptosis in spinal cord neurons
• 35% reduction in motor neurons in cord
• 350% increase astrocytes
• motor cortex neurons
• 192% increase in apoptosis
Morin stain for aluminum
myelin
mitochondria
microsomes
synapses
Are their similarities between aluminum toxicity and neurodevelopmental
disorders?
renal insufficiency•oral phosphate binders•contaminated dialysate•oral antacids•TPN•infant formula
normal renal function•aluminum containing vaccines and MMF•antacids/TPN/formula
..............................................47 cases
.............34 cases................................................4 cases
85 cases
interval to presentation 0-156 mo
developmental delay 95%
small head (<-2 sd) 75%
EEG abnormal 94%
seizures 65%
hypotonia 65%
dyskinesia 55%corticol atrophy/ventriculomegaly 47%
chorea 20%
gait/ataxia 20%
myoclonus 15%
lethargy/dec LOC 15%
weakness 10%
Progressive encephalopathy in children with chronic renal insufficiency in infancy. Rotundo A, Nevins TE, Lipton M, Lockman LA, Mauer SM, Michael AF. Kidney Int. 1982 Mar;21(3):486-91.
n=20
ASD and Aluminum Toxicity
•seizures•myoclonus•hypotonia•motor development •autonomic/cholinergic dysfunction•mitochondrial dysfunction•oxidative stress•ADD/ADHD•iron deficiency and anemia•calcium homeostasis•bone metabolism/microcephaly•melatonin, seratonin and sleep disorders•neuropathology•immune dysfunction•systemic infections/ bacterial binding/immunity
A Random Case SurveyAluminum in Autism Spectrum Disorders
David Ayoub, MDAnju Usman, MD
October 10, 2007Fall DAN! Think Tank
n-38
76.3%
upper limits normal
mean 12.9 µg/g
Aluminum in Hair
• Iron: 10.5% above upper limits
• Manganese: 13.2% above upper limits
Urinary Provocative Challenge
IV Ca-EDTA
• n-34, profile with the highest metals recorded if multiple done
post IV Ca EDTAchallenge
measuring urinary metals
Aluminum in Urinerandom vs EDTA vs other agents*
n-4 n-10
410
18
0-210-31
177.0
n-4 n-10 n-34
13.9 10.0
mean
* DMSA, DMPS, glutathione
mean
97%
Urinary Porphyrins
•First 2 intermediates analyzed-Uroporphyrin III (UP)-66% elevated
-Hepatocarboxy porphyrin (7cxP)-50% elevated
•Levels expressed as ratio with “upper limits” value
Aluminum Aluminum
Toxic Metals in Red Cells of Children (ng/ml)
modified from Adams, 2006
unpublished data from Dr T. Audhya:
n-46 n-21
Numerous studies show glutathione depletion in autistics
Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. James SJ, Cutler P, Melnyk S, Jernigan S, Janak L, Gaylor DW, Neubrander JA. Am J Clin Nutr. 2004 Dec;80(6):1611-7.
Al(maltol)3
Maltate control
Maltate control
High cell death
Al(maltol)3
low glutathione
High cell death
oral Al chloride (100mg/kg)8 weeks
Brain weight
Control
al(Cl)3
adults
1.676 +/- 0.07
1.679 +/- 0.21
pups
1.742 +/- 0.007
1.4939 =/- 0.08
- 17.4%p <0.001
mercury-containing shots
aluminum-containing shots
Number of administered vaccines containing aluminum increased after
Thimerosal reduced (by 18 months age)
source: David Ayoub, MD, Prairie Collaborative, Inc
Treatment