Aluminum-Induced Entropy in Biological Systems ...people.csail.mit.edu/seneff/Shaw_et_al_JOT_2014.pdf · ReviewArticle Aluminum-Induced Entropy in Biological Systems: Implications

Review ArticleAluminum-Induced Entropy in Biological SystemsImplications for Neurological Disease

Christopher A Shaw123 Stephanie Seneff4 Stephen D Kette5 Lucija Tomljenovic1

John W Oller Jr6 and Robert M Davidson7

1 Neural Dynamics Research Group Department of Ophthalmology and Visual Sciences 828 W 10th Avenue VancouverBritish Columbia Canada V5Z 1L8

2 Program Experimental Medicine University of British Columbia Vancouver Canada V5Z 1L83 Program in Neurosciences University of British Columbia Vancouver Canada V5Z 1L84MIT Computer Science and Artificial Intelligence Laboratory 32 Vassar Street Cambridge MA 02139 USA5Hudson FL 34667 USA6Department of Communicative Disorders University of Louisiana Lafayette LA 70504-3170 USA7 Internal Medicine Group Practice PhyNet Inc 4002 Technology Center Longview TX 75605 USA

Correspondence should be addressed to Christopher A Shaw cashawlabgmailcom

Received 9 June 2014 Accepted 28 July 2014 Published 2 October 2014

Academic Editor William Valentine

Copyright copy 2014 Christopher A Shaw et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Over the last 200 years mining smelting and refining of aluminum (Al) in various forms have increasingly exposed living speciesto this naturally abundant metal Because of its prevalence in the earthrsquos crust prior to its recent uses it was regarded as inertand therefore harmless However Al is invariably toxic to living systems and has no known beneficial role in any biologicalsystems Humans are increasingly exposed to Al from food water medicinals vaccines and cosmetics as well as from industrialoccupational exposure Al disrupts biological self-ordering energy transduction and signaling systems thus increasing biosemioticentropy Beginning with the biophysics of water disruption progresses through the macromolecules that are crucial to livingprocesses (DNAs RNAs proteoglycans and proteins) It injures cells circuits and subsystems and can cause catastrophic failuresending in death Al forms toxic complexes with other elements such as fluorine and interacts negatively with mercury lead andglyphosate Al negatively impacts the central nervous system in all species that have been studied including humans Because ofthe global impacts of Al on water dynamics and biosemiotic systems CNS disorders in humans are sensitive indicators of the Altoxicants to which we are being exposed

1 Introduction

Aluminum (Al) is the most common metal and the thirdmost abundant element in the earthrsquos crust [1ndash3] Howeverit seems to have no beneficial role in the biochemistry ofany biota [1] Until the 1820s when the industrial extractionof Al primarily from bauxite ore [4] made it possible tobring Al into food processing manufacturing medicinescosmetics vaccines and other applications Al was almostcompletely absent from the biosphere [5] Concerns about the

toxicity of ingesting Al were expressed over 100 years ago [6]Today biologically ingested or injected forms include salts ofAl in processed foods [7] and medicinal products [8] suchas antacids glossy coatings for pills and vaccine adjuvantsThe last use which portrays Al compounds as ldquohelpersrdquomdashthe English translation of the Latin root of adjuvantsmdashis supposed to shock the recipientrsquos immune defenses intoaction ostensibly to enhance the immunogenicity of thepathogen(s) in the vaccine(s) [9] Al salts are also found indyes [10] cosmetics [5] antiperspirants [11ndash14] sunscreens

Hindawi Publishing CorporationJournal of ToxicologyVolume 2014 Article ID 491316 27 pageshttpdxdoiorg1011552014491316

2 Journal of Toxicology

[15 16] and thousands of material products including foilsfood containers and utensils

In this paper we will show that Al is harmful to the CNSacting in a number of deleterious ways and across multiplelevels to induce biosemiotic entropy [17] A countervailingview exists [18ndash20] but the assertions of safety are invariablybased onweak epidemiological designs ones that overwhelmsignificant negative signals with irrelevant noise factorsSuch studies that fail to detect significant negative outcomesneither stand up to rigorous scrutiny nor outweigh betterdesigned research in a vast and growing literature showingsignificant negative impacts sustaining the central hypothesisof this paper Irrefutable research evidence shows that Alexposure is harmful Further results discussed in this papershow that it is counterfactual for researchers to argue that Alis universally safe or beneficial even in trace amounts

Al is used extensively in food processing for examplein Al-mordanted dye lakes for food coloring in coatings forpharmaceutical tablets and vitamin capsules for emulsifyingas a rising agent to thicken gravies and in meat-bindersstabilizing agents and texturizers [18] Even drinking wateris a source of Al exposure although the amount containedin drinking water is typically far below concentrations incommon antacids [21] However there is concern that theAl in drinking water may be more easily absorbed than atmealtime due to the fact that an empty stomach promotesabsorption [21] Alum (Al sulfate or Al potassium sulfate) iscommonly used in water treatment plants as a coagulant toallow negatively charged colloidal particles to clump togetherfor easy removal Epidemiological studies have shown thatpeople living in districts with higher Al burden in drinkingwater are more likely to be diagnosed with Alzheimerrsquosdisease [22]

Because tea plants contain a higher concentration ofAl than many other plants and because tea beverages areconsumed in large quantities worldwide a high incidenceof Al exposure comes through drinking tea [23] Al contentin tea ranges from 2 to 6mgL [24] Tea infusions havebeen analyzed for the speciation of Al content and it hasbeen determined that it is typically bound to large organicmolecules such as polyphenols or to citrate [24 25] Teatypically contains much more Al than water and so teabecomes a significant source of Al for heavy tea drinkersAn experiment to estimate oral Al bioavailability from teainvolving 8 rats was conducted by injecting Al citrate intotea leaves delivering approximately the same amount of Alas is inherently found in tea leaves (05 to 1mggm) [26] Thebrewed tea was administered through intragastric infusionFollowing infusion peak serum levels of Al were up to 1500-fold above mean pretreatment values

In a substantial and recent review of research Walton[27] concludes that Alzheimerrsquos disease is a manifestation ofchronic Al neurotoxicity in humans Because Al is similarto iron it gains access to iron-dependent cells involved inmemory As it accumulates over time in such cells it causesmicrotubule depletion and disables neuronal afferents andefferents resulting in themultiregion atrophy characteristic ofAlzheimerrsquos pathology [27] Table 1 highlights some of the Alcompounds to which humans are commonly exposed which

are known to have deleterious effects on the central nervoussystems (CNS) of both animals and humans [28] whereasTables 2 and 3 respectively present Al intake data and itsphysical properties compared to other metals Table 1 alsoshows dosage and known effects of each source on animalsandor humans

Al in all of the forms studied as Table 1 shows producesharmful effects in living organisms it especially harms theCNS In studies involving in vitro cultures of neuronal-glialcells the ROS-generating capabilities of several physiolog-ically relevant neurotoxic factors were compared [29 30]It was found that Al-sulfate was the most potent singlemetal sulfate inducer of ROS as well as the most potentcombinatorial inducer in conjunction with Fe Nanomolarconcentrations of Al were sufficient to induce ROS and proin-flammatory gene expression Nanomolar concentrations ofAl-sulfate upregulated the expression of several genes impli-cated in Alzheimerrsquos disease including proinflammatory andproapoptotic gene expression [30]

Given the fact that there are no known biochemical reac-tions that require Al should it be surprising that introducingit into living organisms commonly leads to pathologicaloutcomes [31ndash46] Because of its +3 charge Al attractsnegatively charged ions and electrons but because it cannottransition to other oxidation states besides +3 it is not a com-ponent in any redox reactions Oxygen carbon hydrogennitrogen calcium andphosphorous constitute 99of humanbody mass with the remaining 1 consisting of potassiumsulfur sodium chlorine and magnesium as well as traceelements such as fluorine selenium and zinc and xenobiotic(biologically foreign and usually toxic) elements such astitaniummercury and lead [47]ThusAl can endup inmanybiochemical contexts in theory but in fact some atoms andmolecules are far more likely to react with Al compounds[48] Among the most vulnerable molecules are those mostdirectly involved in self-ordering self-assembling systems ofbiosemiotics that work like multilayered interrelated lan-guages The best known macromolecules that are susceptibleto minute but often disabling injuries by Al compounds areDNA molecules that must be translated via the assistance ofa growing multitude of RNA molecules into proteins Thelatter in turn are essential to the structure and functions ofthe whole society of cells [49] tissues and organ systemsFormerly it was thought following the Crick dogma [50]that communications were essentially a one-way street fromDNA to RNA to protein but it has more recently beenargued [17 51 52] that communications involve more com-plex bidirectional interactions among thosemacromoleculessuch that the genome is informed concerning what is goingon in the environment The dynamical matrix of negativecharge densities in heparan sulfate proteoglycans (HSPGs) asmodulated in time and space by interfacial water exchangingbetween the first few solvation layers and bulk might proveto be the supramolecular physical basis for informing thegenome over distance [53]

There are estimated to be 20000ndash25000 protein codinggenes in the human genome [54] and even more variantproteins possible through posttranslational modificationsestimated to be upwards of 100000 Thus there are many

Journal of Toxicology 3

Table1Com

mon

sourceso

fAlcom

poun

dsandtheirimmun

oneurotoxicologicaleffectsinhu

mansa

ndanim

als

Aluminum

sourcecom

poun

dDoseamp

duratio

nRo

ute

Species

Adversee

ffects

Standard

infant

feedingsolutio

nsim20120583gkgday

gt10

days

Intravenou

s(parenteral)

Hum

anpremature

infants

Redu

ceddevelopm

entalatta

inmentatthe

correctedpo

st-term

ageo

f18

mon

thsas

evidencedby

significantly

lower

Bayley

Mental

Develo

pmentInd

ex(BMDI)scores

(meanlossof

onep

oint

onthe

BMDId

ayof

fullintravenou

sfeeding

afte

radjustm

entfor

potentially

confou

ndingfactors)comparedto

infantsfed

with

Al-d

epleted

solutio

ns[31]

Al-c

ontainingdialysis

fluid

(derived

from

Al-sulfatetre

ated

tap

water)

1ppm

chron

ic(2ndash5

years)

Intravenou

s

Hum

andialysis

patie

nts

(15ndash61

yearso

ldatthe

starto

fthe

dialysis

treatment)

Speech

impairm

ents(stutte

ringdysarthriadyspraxiaand

motor

aphasia

)movem

entd

isorders(twitchestre

morsmyoclo

nicjerks

seizuresand

motor

apraxia)cognitiv

eimpairm

entsandbehaviou

ral

changes(progressived

ementia

paranoiaconfusion

andpsycho

sis)

anddeath[32]

Al-c

ontaining

antacids

Chronic

Oral

Hum

aninfants

Craniosyno

stosis

(prematureo

ssificatio

nof

thes

kullandob

literation

ofthes

utures)[33]

Vario

usdietary

Chronic

Oral

Elderly

human

subjects

Impaire

dvisuom

otor

coordinatio

npo

orlong

-term

mem

oryand

increasedsensitivityto

flicker

(correlated

with

high

Al-serum

levels)

[34]

Alsulfate

(present

asflo

cculant

inpo

tablew

ater

supp

liesaccidentally

released

inhigh

amou

nts)

500ndash

3000

xthe

acceptablelim

itun

der

European

Union

Legisla

tion

(0200

mgL)chron

ic(15years)

Oral

Hum

anadult(female44

yearso

ld)

Sporadicearly

-onset120573am

yloidangiop

athy

(Alzh

eimerrsquos-related

disease)diffi

culty

infin

ding

wordsprogressiv

edem

entia

visu

alhallu

cinatio

nsheadacheanxietycerebralisc

hemiaand

death[35]

Al-c

ontainingfood

pellets

05ndash17

mgkgday

(typicalhum

an)

chronic(22ndash32

mon

ths)

Oral

Rats

6mon

thso

ldatthe

startof

treatment

Cognitiv

edeterioratio

nandim

paire

dperfo

rmance

inlearning

tasks

impaire

dconcentration

andbehavioralchangesincluding

confusion

andrepetitiveb

ehaviour

[36]

Allactate

500ndash

1000

ppm

chronic(du

ring

gesta

tionand

lactation)

Oral

Miced

ams

Hindlim

bparalysis

seizuresanddeath(dam

s)low

erneurob

ehaviorald

evelo

pmentand

alteredperfo

rmance

ona

neurob

ehavioraltestb

attery

inpu

ps(fo

otsplayforelim

bandhind

limbgrip

strengths

redu

ced)

[37]


Table1Con

tinued

Aluminum

sourcecom

poun

dDoseamp

duratio

nRo

ute

Species

Adversee

ffects

Alhydroxide

asa

vaccinea

djuvant

1ndash17

doseso

fAl-c

ontaining

vaccines

(hepatitisB

hepatitisAand

tetanu

stoxoid)

inthe

perio

dof

10years

priortodisease

diagno

sis

Intram

uscular

injection

Hum

anadult

macroph

agic

myofasciitis(M

MF)

synd

romep

atients

(meanage4

5years)

MMFtypicalclin

icalmanifestationsm

yalgiaarthralgiachronic

fatig

ue(disa

blingfatig

uegt6mon

ths)m

uscle

weakn

essa

ndcogn

itive

dysfu

nctio

n(overtcogn

itive

alteratio

nsaffectin

gmem

oryand

attentionmanifeste

din

51of

cases)[38ndash41]

Typicalh

istop

atho

logypresenceo

fgranu

lomatou

smyopathological

lesio

ncomprise

dof

Al-h

ydroxide-lo

aded

macroph

ages

atthes

iteof

vaccineinjectio

n(usuallydelto

idmuscle

)persistence

ofAl

long

-term

upto

8ndash10

yearsinpo

stinjectionmice[383942]

15ndash20

MMFpatie

ntsc

oncurrently

developan

autoim

mun

edise

ase

mostfrequ

ently

beingmultip

lesclerosis

-like

demyelin

atingdisorders

Hashimotorsquos

thyroiditisand

diffu

sedysim

mun

eneuromuscular

diseases

(ie

derm

atom

yositis

necrotizingautoim

mun

emyopathy

myastheniag

ravisandinclu

sionbo

dymyositis)evenin

thea

bsence

ofovertautoimmun

edise

aselowtitreso

fautoantibod

iesincreased

inflammatorybiom

arkersand

abno

rmaliro

nsta

tusc

ommon

lydetected

inexpo

sedmice[3839]

Alhydroxide

asa

vaccinea

djuvant

14injections

over

a6-mon

thperio

dSubcutaneous

Sheepmale3

mon

thold

lambs

ldquoSheep

adjuvant

synd

romerdquofirstidentifi

edfollo

wing

mass-vaccinationforb

lueton

gueexperim

entally

reprod

uced

byrepetitiveinjectio

nwith

Al-c

ontainingvaccines

[14]ob

served

inacuteform

(affecting25of

expo

sedflo

cks05

anim

alsw

ithin

aflo

ck)a

ndchronicp

hase

form

(affecting50ndash70

ofallexp

osed

flocks

andup

to100

ofanim

alsw

ithin

agiven

flock)

Acutep

hase

symptom

slethargyrelu

ctance

tomovebrux

ism(te

eth

grinding

)transie

ntblindn

essnystagmus

(rapid

abno

rmaleye

movem

ents)

stupo

rabno

rmalbehaviordiso

rientation

andalow

respon

seto

externalstim

uliseizuresand

occasio

nally

death

histo

pathologicallesio

nsmainlyconsistingof

acute

meningoenceph

alitis(sim

ilartothoseo

bservedin

humans

postv

accinatio

n)anddemyelin

atingfoci

Chronicp

hase

symptom

ssevere

neurob

ehavioraloutcomes

inclu

ding

restlessnesscom

pulsive

woo

lbiting

generalized

weakn

ess

muscle

tremorslossof

respon

seto

stimuliataxiatetraplegia

(paralysisof

allfou

rlim

bs)stu

porcomaanddeathInflammatory

lesio

ns(m

ultifocalneuron

alnecrosisandneuron

lossin

both

dorsal

andventralcolum

nof

theg

raymatter)andpresence

ofAlinCN

Stissues

[43]


Table1Con

tinued

Aluminum

sourcecom

poun

dDoseamp

duratio

nRo

ute

Species

Adversee

ffects

Alhydroxide

asa

vaccinea

djuvant

2injections

2weeks

apart

Subcutaneous

injection(behindthe

neck)

Mice3mon

thso

ldCD

-1male

Motor

neuron

degeneratio

nandapop

tosism

otor

functio

ndeficits

decrease

instreng

thcognitiv

edeficits

anddecreasedperfo

rmance

inlearning

tasksdecrem

entsin

spatialm

emoryactiv

ationof

microglia

[4445]

Aloxide

fumes

occupatio

nal

expo

sure

013ndash195m

gm

3 chronic

Inhalatio

nHum

anadu

lts(m

eanage3

9years)

Headacheem

otionalirritabilityconcentrationdifficultyinsom

nia

moo

dlability[46]


macromolecules with which Al3+ species can interact eitherdirectly or indirectly Eukaryotic proteins are polymers ofvarious combinations and lengths consisting of an array of23 amino acids joined by peptide bonds Each of the 23amino acids has a unique side chain consisting of variousorganic substituents Al can interact with the side chains[55] some of whichmdashserine threonine and tyrosinemdashare phosphorylated enabling phosphoregulation of enzymeactivity and binding with other proteins Al can disrupt allof these side chains and the processes dependent on them[56] Cysteine methionine homocysteine and glutathionecontain sulfur and they are intermediaries instrumental inmethylation and transsulfuration pathways as well as inheavy metal detoxification These processes can be disruptedby Al [57] because of the strong binding affinity of Al withsulfur oxyanions Glutamic and aspartic acids have negativelycharged carboxylate side chains Al has a much strongerbinding affinity to these side chains for instance than thenontoxic cation magnesium [58]

Therefore Al is ineffective in redox reactions though its+3 charge makes it likely to adsorb to suspended colloids(eg complex proteinaceous polymeric molecular structuresor clusters suspended in fluid) in nonliving systems resultingin its kosmotropic character (see Table 4) which enables thesalting-out known as ldquoflocculationrdquoThis useful tendency forexample in public water systems can however be catas-trophic in the blood and fluids of living organisms wherebuilding blocks of necessary proteins are apt to be turnedinto useless debris linked to Al salts [59 p 1410] and [60]According to its Lewis acidity classification [61] Al3+ belongsin Class A a small (hard) metal ion with low polarizability(deformability) preferentially forming ionic complexes withsimilar nonpolarizable ligands particularly oxygen donorssuch as oxyanions of carbon phosphorus and sulfurmdashallof which are plentiful in living organismsmdashgiving Al thepotential to wreak havoc in living systems For these reasonsAl is certainly not ldquoinertrdquo nor is it biologically harmless [29ndash48] As Table 1 shows Al is causally linked to disorders inplants animals and humans [9 28 57] especially in the CNSof animals and humans

Among the CNS problems in humans attributed toAl are dialysis associated encephalopathy (DAE) [32 62]autism spectrum disorders [9 63 64] Alzheimerrsquos diseaseParkinsonrsquos disease and related dementias [28 36] includingthose typical in Down syndrome [18] Experimental andclinical data show the CNS as the most sensitive organsystem negatively impacted by Al Toxic effects manifestin impaired psychomotor control altered behavior (ieconfusion anxiety repetitive behaviors sleep disturbancesdeficits of speech concentration learning andmemory) andin potentially fatal seizures [18 28 38] Al has been identifiedas the efficient cause of a whole class of immune dysfunctionsdirectly involving the CNS and known as ldquoautoimmune-inflammatory syndrome induced by adjuvantsrdquo (ASIA) [65ndash68] As will be seen in this paper the disorders with which Alhas been associated as a causal factor are pervasive becausethey begin with the disruption of fluid structures involvingwater Also although Al negatively affects every layer ofthe bodyrsquos biosemiotic systems on which health depends

the symptoms of Al poisoning are often noticed when theyinevitably reach and impact the CNS

11 Aluminum in the Nervous System As Table 2 showshumans get about 95 of their Al burden from food [69]though estimates vary between 2 and 25mg per day amount-ing to 14ndash175mg per week [70ndash73] In urban societies theintake can exceed 100 mg per day between 4 and 50 timesthe averages shown in Table 2 Because of increasing con-sumption of Al-containing convenience foods [74] in 2006the Food and Agriculture World Health Organization JointExpert Committee on Food Additives (FAOWHO-JECFA)amended their provisional tolerable weekly intake (PTWI)for Al from 7mg per kilogram of body weight (amountingto 490mg per week for an average 70 kg human) to 17of that amount The Committee concluded that ldquoaluminumcompounds have the potential to affect the reproductivesystem and developing nervous system at doses lower thanthoserdquo previously supposed [74] Interpreting the averages inTable 2 using the estimated intake in urban settings as thehigher end of the actual range referring to the supposedlytolerable weekly intake based on the post-2006 numbersaverage consumers weighing 70 kilograms are consumingbetween 2 to 100 times the provisionally estimated safeamounts of Al

Given that severe toxic effects of Al occur in animalmodels at a concentration of 15 to 5mgkg of wet weightindependent of the mode of administration [75] it may beinferred that lethal poisoning of humans can occur at about3ndash10 times the average amounts estimated to be absorbedby adult consumers studied This leaves a narrow marginbetween the estimated average uptake and the lethal thresh-old of Al in the human CNS Experiments on cats involvedinjecting Al into the brain and monitoring the response bothbehaviorally and physiologically [76] Measured tissue levelsof Al averaging 14 microgramsgram were associated withextensive neurofibrillary tangles which are a common featureof AD This level is only marginally higher than the 9ndash11microgramsgram that have been detected in some regionsof AD brains postmortem This physiological effect wasassociated with observed impairment in short-term memoryand acquisition of a conditioned avoidance response [77]Al also causes a condensation of brain chromatin disruptingDNA transcription [78] Animal models of neurologicaldisease plainly suggest that the ubiquitous presence of Al inhuman beings implicates Al toxicants as causally involvedin Lou Gehrigrsquos disease (ALS) [44 45] Alzheimerrsquos disease[20 21 28] and autism spectrum disorders [9 63]

12 The Toxic Effects of Aluminum as a Vaccine AdjuvantAl salts (hydroxide and phosphate) are the most commonlyused vaccine adjuvants and until recently the only adjuvantslicensed for use in the USA [79ndash89] In the absence of Alaccording to their manufacturers antigenic components ofmost vaccines (with the exception of live attenuated vaccines)fail to elicit the desired level of immune response [66 80]Although Al is neurotoxic it is claimed by proponents thatthe concentrations at which Al is used in the vaccines do not


Table 2 Estimates of daily and weekly intakes of Al in humans [28 74]

Major sources of Alexposure in humans Daily Al intake (mgday) Weekly Al

intake (mgday)

dividePTWIdagger (1mgkgbw foran average 70 kg human

PTWI = 70mg)

Amount delivered dailyinto systemic circulation (at

025 absorption rate)Natural food 1ndash10 [2 8 23ndash26] 7ndash70 01ndash1 25ndash25 120583g

Food with Al additives 1ndash20 (individual intake canexceed 100) [3 5 18]

7ndash140(700)

01ndash2(10)

25ndash50 120583g(250 120583g)

Water 008ndash0224 [2 8 21] 056ndash156 0008ndash002 02ndash056 120583gPharmaceuticals (antacidsbuffered analgesicsantiulceratives andantidiarrheal drugs)

126ndash5000 [1 2 8] 882ndash35000 126ndash500 315ndash12500 120583g

Vaccines (HepB Hib TdDTP) 051ndash456 [9] NA NA 510-4560 120583gDagger

Cosmetics skin-careproducts andantiperspirantssect

70 [1 9] 490 NA 84 120583g (at 0012absorption rate) [10 11]

Cooking utensils and foodpackaging 0ndash2 [2] 0ndash14 0ndash02 0ndash5 120583gdaggerPTWI (provisional tolerable weekly intake) is based on orally ingested Al generally only 01ndash04 of Al is absorbed from the GI tract however Al may formcomplexes with citrate fluoride carbohydrates phosphates and dietary acids (malic oxalic tartaric succinic aspartic and glutamic) which may increase itsGI absorption (05ndash5 [70 82]) Coexposure to acidic beverages (lemon juice tomato juice and coffee) also increases Al absorption as well as conditions ofCa2+ Mg2+ Cu2+ and Zn2+ deficiency [70 83ndash85]DaggerA single dose of vaccine delivers the equivalent of 204ndash1284mg orally ingested Al (051minus556 mg) all of which is absorbed into systemic circulation [86 91]Al hydroxide a common vaccine adjuvant has been linked to a host of neurodegenerative diseases it also induces hyperphosphorylation of MAP tau in vivo[44 45 87]sectThe risk of antiperspirants is both fromdermal exposure and inhalation of acrosols Al is absorbed from the nasal epithelia into olfactory nerves and distributeddirectly into the brain [88 91]

Table 3 A comparison of the physical properties of metallic Al with those of its common competitors in biological systems [89] Crystalionic radius source [92] Magnetic susceptibilities source [47 pp 4-131 to 4-136] Viscosity 119861 coefficient source [93] Standard molarelectrostriction volume source [94]

Mg Al Ca Mn Fe Co ZnAtomic number 12 13 20 24 25 27 30Electron configuration [Ne]3s2 [Ne]3s23p1 [Ar]4s2 [Ar]4s23d5 [Ar]4s23d6 [Ar]4s23d7 [Ar]4s23d10

Ionization energies(kJmol)

737714507[7732]

57751816727448[11577]

589811454[49124]

71731509[3248]

762615619[2957]

76041648[3232]

906417333[3833]

Crystal ionic radius(pm) 86 675 114 97 92 135 88

Electron affinity(kJmol) 0 425 237 0 157 637 0

Electronegativity (eV) 131 161 10 155 183 188 165Magnetic susceptibility(11988311989810minus6 cm3 molminus1) +131 +165 +40 +511 Ferro-

magneticFerro

magnetic minus915

Charge density(coulombssdotmmminus1) 1201 3726 516 1437 981 1549 1121

Viscosity 119861 Coefficient(dm3 molminus1 29815 K) 0385 075 0289 0390 042 0376 0361

Standard molarelectrostriction volume(minusΔ elstr119881119894)(cm

3 molminus1)525 593 385 307 mdash 385 mdash


Table 4 Summary comparisons of chaotropic versus kosmotropic ions

Chaotropes (water-structure breakers) Kosmotropes (water-structure makers)Typically larger radius singly charged ions with lowcharge density

Typically small radius often multiply charged ions withhigh charge density

Interact more weakly with waters than water moleculesinteract with each other

Interact more strongly with waters than watermolecules interact with each other

Interfere little with hydrogen bonds of the surroundingwaters

Capable of weakening and breaking hydrogen bonds ofthe surrounding waters

Decrease surface tension Increase surface tensionReduce viscosity Increase viscosityIncrease nonpolar solubility Decrease nonpolar solubilityUnfold proteins Stabilize proteinsDestabilize hydrophobic aggregates Stabilize hydrophobic aggregates and bondingIncrease solubility of hydrophobic solutes Reduce solubility of hydrophobic solutesSalt in proteins Salt out proteinsNet positive entropy of ion solvation Net negative entropy of ion solvation

represent a health hazard [19] For that reason vaccine trialsoften treat an Al adjuvant-containing injection as a harmlessldquoplacebordquo (a comparison benchmark or control treatment)or they use another Al-containing vaccine to treat a ldquocontrolgrouprdquo despite evidence thatAl in vaccine-relevant exposuresis universally toxic to humans and animals [9 90 91] Itsuse in a supposed ldquoplacebordquo or in any ldquocontrolrdquo treatment invaccine trials is indefensible [95] It is precisely analogous tocomparing fire A against fire B to make the argument thatsince A is no hotter than B A is therefore not a fire

During the last decade studies on animal models andhumans have shown that Al adjuvants by themselves causeautoimmune and inflammatory conditions [19 79ndash81 90 95ndash103] The animal models show that subcutaneous injectionsof Al hydroxide induced apoptotic neuronal death anddecreased motor function in mice [2 37ndash39] and sheep[43] In newborn mice they were associated with weightincreases behavioral changes and increased anxiety [2] Allthese findings plausibly implicate Al adjuvants in pediatricvaccines as causal factors contributing to increased ratesof autism spectrum disorders in countries where multipledoses are almost universally administered [9] Also as shownby Goldman and Miller in studies published in 2011 and2012 strong correlations between infant mortality rates andthe number of doses of vaccines administered also suggestdeleterious impact ofmultiple exposures to their components[104 105]

Follow-up experiments focusing on Al adjuvants in miceby Khan et al [106] have shown that the adjuvants donot stay localized in the muscle tissue upon intramuscularinjection The particles can travel to the spleen and brainwhere they can be detected up to a year after the injectionSuch findings refute the notion that adjuvant nanoparticlesremain localized and act through a ldquodepot effectrdquo On thecontrary the Al from vaccine adjuvants does cross the blood-brain and blood-cerebrospinal fluid barriers and incitesdeleterious immunoinflammatory responses in neural tissues[1ndash3 9] Tracking experiments in mice reveal that some Al

hydroxide nanoparticles escape the injected muscle insideimmune system cells such as macrophages which travel toregional draining lymph nodes where it can exit to thebloodstream gaining access to all organ systems includingthe brain As Khan et al [106] have warned repeated dosesof Al hydroxide are ldquoinsidiously unsaferdquo especially in closelyspaced challenges presented to an infant or a person withdamaged or immature blood brain or cerebrospinal fluidbarriers [2] Given macrophages acting as highly mobileldquoTrojan horsesrdquo [107] the Khan et al warning suggeststhat cumulative Al from repeated doses in vaccines canproduce the cognitive deficits associated with long-termencephalopathies and degenerative dementias in humans [4099]

The latest research by Lujan et al [43] described a severeneurodegenerative syndrome in commercial sheep linkedto the repetitive inoculation of Al-containing vaccines Inparticular the ldquosheep adjuvant syndromerdquo mimics in manyaspects human neurological diseases linked to Al adjuvantsMoreover the outcomes in sheep were first identified fol-lowing a mass-vaccination campaign against blue tongue andhave now been successfully reproduced under experimentalconditions following administration of Al-containing vac-cines Notably the adverse chronic phase of this syndromeaffects 50ndash70 of the treated flocks and up to 100 of theanimals within a given flock The disorder is made worseby cold weather conditions suggesting synergy with otherstress producing factors The disorder is characterized bysevere neurobehavioral outcomesmdashrestlessness compulsivewool biting generalized weakness muscle tremors loss ofresponse to stimuli ataxia tetraplegia stupor inflammatorylesions in the brain and the presence of Al in the CNStissues coma and death [43] These findings confirm andextend those of Khan et al [106] who demonstrated theability of Al adjuvants to cross the BBB and they show thatAl in the brain can trigger severe long-term neurologicaldamage The findings by Lujan et al [43] and Khan et al[106] also show how and why reported adverse reactions


following vaccinations are most commonly neurological andneuropsychiatric [6 7]

13 Aluminum Disrupts Biosemiosis The nervous systemutterly depends on coherent signaling from the genomeupward to psychological and social behaviors and is suitedto induce entropy at these and the levels in between themThe long-term consequences involve many minute injuriesleading to inflammation disorders diseases and the ultimatedeath of certain neuronal elements and possibly of thewhole organism As documented by Gryder et al [108] inreference to cancer disruptions in gene signaling andorRNA transcriptionmechanisms induce a range of deleteriousoutcomes on protein formation In turn altered proteinsimpact cellular function As Al moves in the body and CNAit can create dysfunctional cells that foul signaling systemsand neural circuits leading to additional dysfunctions andeven behavioral aberrations Immediately and cumulativelyAl-induced injuries tend to be expressed as abnormalities inthe CNS trending toward ultimate fatality [109]

2 Biophysics of Aluminum Toxicity andImpact on Cellular Processes

The concepts of kosmotropic and chaotropic solutes (waterstructure makers and breakers) introduced by Collins andWashabaugh in 1985 have been used extensively by the bio-chemical and biophysical communities [110] These conceptsare highly relevant to this section The reader is referred toTable 4 (above) for a summary of the concepts Accordingto Marcus (2012) when ldquothe structural entropy accordingto [Barthel and] Krestov (1991) was compared by Collins(1997) to the entropy of pure waterfor the alkali metal andhalide ions and Δ119878 = Δ struc119878 minus 119878

lowast (H2O) Those with

Δ119878 lt 0 have large surface charge densities and are calledkosmotropes (water structure making) whereas those withΔ119878 gt 0 have small surface charge densities and are chaotropes(water structure breaking)rdquo [111ndash113]

21 Al3+ Disrupts Water Dynamics of Biological ExclusionZones Al is a reactive element existing abundantly in naturebut almost exclusively bound as mineral salts Al salts arerelatively insoluble except under acidic conditions whichare created by organic acids in vivo and adjacent to theexclusion zones (EZs) of biomembranes [114] ConcerningEZs as argued by Ling [115] (also see his references) ldquounderan ideal condition an idealized checkerboard of alternatinglypositively and negatively charged sites of the correct sizeand distribution could polarize and orient deep layers ofwater molecules ad infinitum Based on the quantitative datathus obtained and a relevant simple statistical mechanicallaw the new theory predicts that a thin layer of water heldbetween two juxtaposed ideals or near-ideal nanoprotoplasm(NP) surfaces will not freeze at any (attainable) temperatureOn the other hand water polarized and oriented by anideal or near-ideal NP-NP system may also not evaporateat temperature hundreds of degrees higher than the normalboiling temperature of waterrdquo (p 91) However as Ling

has also shown Al has the power to alter these crucialEZs disrupting their unique biophysical properties [116]Or as argued more recently by Davidson and colleaguestoxicants such as Al are invariably disposed to contribute toexogenous interfacial water stress (EIWS) in the critical EZsprecipitating in vast numbers of minute toxic injuries andleading to disorders diseases and sometimes catastrophicchanges ending in fatalities [57 59 68 117ndash119] Concerningthe many ways that toxicants in both their near and distanteffects can increase biosemiotic entropy also (see argumentsdeveloped by Oller [17 51] Gryder et al [108] and Ho[52]) Shaw et al (2013) have also presented data showingthat biological water dynamics crucially enable quantumcoherence across all biosemiotic systems [68]

22 Al3+ Speciation Solubility and Adsorption Are pH-Dependent Conventional beliefs about Al safety [19] arerooted in the knowledge that in the absence of citrateinsoluble Al compounds are poorly absorbed even if ingested[91] However the fact that Al hydroxide and phosphatesolutions remain nearly saturated at neutral pH and standardtemperature in pure water suggests that their poor solubilitydoes not make them benign in living systems Many otherligands besides water molecules can interact with Al whenit is inhaled ingested topically absorbed or parenterallyinjected Acidic beverages such as soft drinks have a pH lt3 most fruit drinks have a pH lt 4 Al in drinking waterin concert with chemical agents that literally pull it outlike clawsmdashas suggested by the term chelationmdashcan increasegastrointestinal absorption [107] and thus the biosemioticentropy-inducing tendency of Al Moreover precipitates ofAl need not be soluble to be toxic especially in low pHcompartments in vivo which favor more mobile hydratedAl3+ aqua ion [Al(H

2O)6]3+ as opposed to inner sphere

contact ion pairs According to Martin the octahedralhexahydrate [Al(H

2O)6]3+ dominates at pH lt 5 and the

tetrahedral [Al(OH)4]minus at pH gt 62 while there is a mixture

of species from 5 lt pH lt 62 [120 p 12] Adsorption anddesorption of Al3+ species have long been known to demon-strate pH dependence [121 122] The aluminum aqua ion[Al(H

2O)6]3+ is well characterized in solution and the solid

state [123] In 1994 Marcus provided data indicating thatwhile [Al(H

2O)6]3+ behaved like a typical strong kosmotrope

with a negative structural entropy value and enhancement ofthe H-bond structure of water [Al(OH)

4]minus demonstrated the

properties of a chaotrope with a positive structural entropyvalue and lessening of the H-bond structure of water [93]Thus it is clear from these data that pH has a major influencein determining the speciation solubility adsorption andHofmeister behavior [58 59] of Al in vivo

23 GlyphosatemdashA Ubiquitous Al3+ Chelating Agent Being amodified form of glycine with both phosphonyl and carbonylgroups glyphosate is already known to chelate metal cations[124]Moreover Al caged by glyphosate dimers and trimmers[125] bears a certain resemblance to chelation complexesof Al citrate Given its biocidal effects on gut biota [126127] leading to inflammatory intestinal disorders commonly


treated by Al-containing antacids [128] Al interacting withglyphosate is likely to increase its crossing of the endogenousintestinal biofilm barrier into the blood stream [129 130]Such Al-induced leaking of the endogenous biofilms of thegut and blood brain barrier could increase Al accumulationin the CNS Glyphosate impairs the bioavailability of bothtryptophan and methionine [126] and significantly reducedplasma concentrations of these amino acids have been foundin Alzheimerrsquos disease patients [131 132]

Given the escalating use of glyphosate worldwide andthe increasing incidence of inflammatory bowel disease [133]and gastroesophageal reflux disease [134] studieswith animalmodels [135] are needed to assess the potential of glyphosateto specifically chelate and distribute Al compounds in vivoHigh precision adsorption calorimetrymay prove to be usefulmeans of studying the thermodynamics of Al biosequestra-tion generally and glyphosate Al chelation complexation invitro [136ndash138] specifically as suggested in Figure 2 fromGuoand Friedman [139] which shows how Gadolinium (Gd3+)serves in biological cation sequestration CNS delivery isknown to occur at least in part via adsorptive transcytosisof cationized proteins and peptides [140] This empiricobservation therefore begs the questions does glyphosatepromote adsorptive transcytosis of Al and vice versa doesAl promote adsorptive transcytosis of glyphosate across theprotective biofilms of the gut and blood brain barrier

24 Al3+ Induces Oxidative Genotoxic and Interfacial WaterStressmdashA Triple Threat A well-recognized effect of Al3+is the induction of oxidative stress [141] and though ithas prooxidant [142] effects through its impact on waterdynamics as Ling has shown [143ndash145] it disrupts enzymesinvolved in the methylation pathway increasing EIWS [59]As a consequence Al impacts epigenetic interactions andeverything dependent upon them As early as 1968 Riddickshowed that Al3+ generally promotes agglomeration andprecipitation even of anionic colloidal finely ground silica(minusil) [146] Evidently it does so in the same way thatin living organisms Al3+ disrupts interfacial hydrogen bond(H-bond) cooperativity and the quantum coherence of wateressential for cellular homeostasis

25 Al3+ Disrupts H-Bond Cooperativity of Biological WaterThe disruption induced by Al3+can be seen as a ldquored shiftrdquoof the stretching bands in the absorption spectra of waterto longer wavelengthsmdashthus a ldquobathochromicrdquo shiftmdashonboth infrared and Raman spectroscopy In 1985 Newtonand Friedman employed a neutron diffraction method [147]to show that the dominant isotope effect of +3 ions isassociated with the OndashH stretch of the water The shift tolower frequencies is proportional to the square of the ioniccharge 119911 in Na+ Mg2+ Al3+ (or resp 1 4 and 9) whilethe oscillatory motionmdashthe ldquolibrationrdquo frequencymdashincreaseslinearly with z in the same series (or resp 1 2 and 3) Morerecent confirmation of this expectation has been produced ina series of papers by Probst and Hermansson (1992) Desirajuand Steiner (2001) Joseph and Jemmis (2007) and Jemmisand Parameswaran (2007) [148ndash151]

Light and electron microscopy also show that cell mor-phology is sensitive to EIWS [152] Tielrooij et al (2010)[153] employed both terahertz and femtosecond infraredspectroscopy showing that the effects of ions and counterionson water can be strongly interdependent and nonadditiveand in certain cases extend well beyond the first solvationshell of water molecules directly surrounding the ion [153]They also found that ldquoif strongly hydrated cations and anionsare combined the dynamics of water molecules are affectedwherein the hydrogen bond network is locked in multipledirections (italics ours)rdquo as shown in Figure 1

26 Al3+Disrupts the CriticalMetastable State of NeurolemmalMembranes Al3+ dangerously shifts the intracellular balancethat normally keeps macromolecules of DNA RNA andproteins from breaking up and disintegrating into an inco-herent disordered chaotropic mixture This can lead to thedisintegration of blood cells for example in hemolysis orwith equal harm bioactive molecules combining in biolog-ically useless ways into kosmotropic precipitates formingdysfunctional molecular debris deposited on the walls ofblood vessels (as in atherosclerosis eg) or disabling neurons(as seen in the beta amyloid andor hyperphosphorylated taudeposits characteristic of Alzheimerrsquos plaques and tangles)To the extent that the membranous (plasmalemmal) materialof all cells along with the material linings of mitochondrianeurons and neurofibrils can be depolarized by Al3+ theloss of cytoskeletal conduction much like an electrical circuitthat ldquoshorts-outrdquo and burns is certain to be injurious tomacromolecules and to cells

Some molecular damage can result in the orderly andusually safe disassembly of cells by apoptosis [154] orwith Al3+ toxicity the disorderly disintegration which mayrelease formerly contained pathogens andor additional toxicdebris leading to necrosis and disease-enabling conditionsThe noted effects of Al3+ can graduate from destroyingmacromolecules plasmalemmal membranes and whole cellsto the destruction of tissues organs and even the death ofthe whole organism [155] Studies on plant seedlings haveshown an immediate effect on the cytoskeleton in which Al3+causes a calcium channel blockade by its depolarization ofmembrane potential [156] In both plants and animals Al3+blocks voltage-gated calcium channels and interferes withnormalmetabolism [157ndash162] It also disrupts the stable waterclusters found in highly structured multilayered EZs thatserve as vehicles for storing incident radiant energy as Chaiet al have shown [161]

Platt et al (1993) demonstrated that extracellular pHmodulates the Al blockade of mammalian voltage-activatedcalcium channel currents [163] at concentration rangelt200120583M Platt and Busselberg (1994) then investigatedthe extracellular and intracellular effects of Al on voltage-activated calcium channel currents (VACCCs) in rat dor-sal root ganglion neurons [164] and found that (a) Alapplied extracellularly reduces VACCCs in a concentration-dependent manner (b) the effect of Al was highly pHdependent in the investigated range (pH 64 to 78) and (c)there was evidence of intracellular as well as extracellular


120583

p

+

(a)

minus

120583

p

(b)

+

minus

(c)

Figure 1 Semirigid hydration and cooperativity ((a) and (b)) a watermolecule in the solvation shell of a cation (a) and an anion (b) Dielectricrelaxation measurements probe the reorientation of the permanent dipole vector p Femtosecond infrared spectroscopy is sensitive to thereorientation of the OD-stretch transition dipole moment 120583 The dotted arrows indicate reorientation in a cone in the case of semirigidhydration (c) Proposed geometry in which the water dynamics are locked in two directions because of the cooperative interaction withthe cation and the anion Figure 1 is reproduced here from (Tielrooij et al 2010) [153] with permission of the American Association for theAdvancement of Science

Gd3+

Xminus

R+

Figure 2 Depiction of how Gadolinium (Gd3+) vibronic side band luminescence spectroscopy (GVSBLS) acts as a probe of the coordinationof biologically-relevant sites of cation sequestration The figure is reproduced here from (Guo and Friedman 2009) [139] with permission ofthe American Chemical Society Copyright 2009 American Chemical Society

bindingThey concluded that irreversibility use dependenceand pH dependence as well as binding sites for Al insidecells contribute to its neurotoxicity Platt and Busselberg alsoexamined the combined actions of Pb2+ Zn2+ and Al3+ onVACCCs [164] showing that each of these metals reducedVACCCs for all possible combinations independent of theorder of applicationThe impactswere additive and consistentwith twometals acting at the same site as well as independentactions at different locations of the ion channel Trombley(1998) demonstrated selective disruption of class A gamma-aminobutyric acid the ligand gated ion channels (GABAA)receptors by Al occurred with a minuscule concentration oflt100 120583M in a culture of rat olfactory bulb neurons [165]

At the same time and for some of the same reasonsultrafast electron crystallography of rsquo interfacial water byPal and Zewail (2004) as followed by Oliveira et al (2010)showed that recognition at the macromolecular levels ofDNA RNA and protein is dependent on biological waterdynamics in the 20ndash40 picosecond range [159 160] Basedon the biosemiotic functions of such macromolecules loss of

such recognitionwould invariably lead tomolecularmimicryimmune dysfunction and the onset of autoimmune diseaseNeuropathological states involving immune disorders canthus be conceptualized to arise from the breakdown of ordeviation from the metastable critical state of biologicalwater dynamics at the interphase of neuronal membranesSimilarly with respect to neurological damage Al has beenshown to induce neuronal apoptosis in vivo as well as in vitro[166]

Sadiq et al (2012) found that metal ions such as Al3+tend invariably to target signaling pathways and may interactwith various targets simultaneously The long-range conse-quences show that ions interacting with any given moleculartarget can disrupt all of the processes dependent on it[162] With respect to developmental neurological and othercommunication disorders Oller and colleagues (2010a 2014)have described this phenomenon as a domino or cascadingeffect [167ndash169] and Seneff et al produced the same sort ofargument for the biophysical level [57] Likewise Shaw et al(2013) showhowminimally stable states of interphasewater at


neurolemmal membranes can be upset by ldquonoiserdquo from Al3+producing a ldquodominordquo effect [68] inducing long-wavelengthperturbations leading to a cascade of energy dissipation onall scales [170]

27 Biological Water Modulates Biosemiotic Entropy at Mul-tiple Levels Concurrently Underlying all of the foregoingevidence there is sound theory and a growing body ofresearch (partially summed up in Figure 1) showing thatwater rather than being a passivemedium inwhich biologicalreactions take place is an active participant [59 60 171]With that in mind it is plain that Al3+ must disrupt long-range dynamical interfacial H-bond cooperativity and thatit must interfere with the quantum coherence of water bothof which are essential for cellular homeostasis The geometryproposed by Tielrooij et al (Figure 1) in which the waterdynamics are locked in two directions shows how the cationand anion produce the polarized-oriented multilayer (PML)confirming the theory of Ling (2003) [115] the exclusionzones (EZs) of water reported by Zheng and Pollack (2003)[114 172 173] and the H-bond cooperativity implicit inthe EIWS theory [59] Because of their chemical propertiesand affinities Al3+ species tend to disrupt the hydrophobicsurfaces of water based biofilms of all kinds Al3+ disruptssuch films by breaking down the complex hydrophobic forcesbinding the liquid This kind of breakdown can be seen in itsimpact on the liquid films containing the peculiar colloidsknown as ldquocoacervatesrdquo studied for the last 150 years byLillie [174] Oparin and Synge [175] and numerous othersthe recounting of which is found in Lingrsquos work as cited Italso has the same disintegrative effect on the neurolemmalmembranes throughout the body showing how protoplasmicpoisoning is invariably induced at many levels by the Al3+species The barriers between the blood and the brain andblood and the spinal cord as well as the barriers protectingthe blood and the rest of the bodyrsquos tissues from the contentsof the gut can be thought of as analogous to ldquoexclusion zonesrdquoor differentiated ldquocoherence domainsrdquo [172 176] consistingin part or in whole of polarized-oriented multilayers ofbiological water as described by Ling [115] (and see hisreferences)

Because of stretching and reorientation of HndashO bondsgeneralized from the dynamics illustrated in Figure 1 thelocal ldquounwettingrdquo ldquostretchingrdquo and hydrophobic ldquocollapserdquo ofinterfacial water can also disrupt signaling systems leading toimmune dysfunctions and autoimmune diseases all begin-ning with EIWS [59 68] Also for reasons already partiallyexplained the CNS is particularly susceptible to Al toxicdamage especially considering the critical role of biosulfatesboth the HSPGs and especially the sulfoglycolipids such assulfatide [57 117 118 177] in the CNS The latter are cruciallyinvolved in the formation of myelin which is essential forhealthy neural tissue and functions of the CNS and peripheralsystems Myelin in turn depends on HSPGs which areessential in generating current and separating charge Butbecause myelin lipids and proteins demonstrate surfacefractality over many scales [170 178] toxic impact from Aland its compounds can do far-reaching harm Also it is

known that Al3+ F1minus Hg2+ and Pb2+ are synergistically toxicand particularly so because of their affinity for biosulfatessuch as the HSPGs

The anion in Figure 2 may be generalized conceptuallyto include the biosulfates ROSO

3

1minus or SO4

2minus fluoride (1minus)carboxylates oxyanions of nitrogen and the biophosphatesThe cation in this figuremay also be generalized conceptuallyto include high charge density polycationic metals suchas Al3+ Hg2+ and Pb2+ as well as oxycations If vectors(arrows with direction and magnitude) are employed asin Figure 1 [153] the dynamical reorientation of the OD-stretch transition dipole moment vectors and permanentdipole vectors will result in polarization and orientation ofmultiple layers of water along the lines explained by Ling in2003 [115]

28 Protoplasmic Poisoning via Cooperative Adsorption ofPolycationic Metal Toxicants In 2008 Harrison et al foundthat certain heavy metal cations exert synergistic bactericidaland antibiofilm activity against Pseudomonas aeruginosa[179] In May 28 2008 Harrison et al filed patent (US20080118573 A1) for use of heavy metals in the treatmentof biofilms including metal cations such as Mn2+ Co2+Ni2+ Cu2+ Zn2+ Al3+ Ag+ Hg2+ Pb2+ Cd2+ Sn4+ andmetalloid oxyanions In 2010 Renslow et al employedpulsed-field gradient nuclear magnetic resonance to studyin situ effective diffusion coefficient (D

119903119904) profiles in live

biofilms [180] and observed distinctive spatial and temporalvariation in D

119903119904for various locations in the biofilm In

2013 Davidson et al reviewed literature showing that inseveral neurodegenerative and neuroimmune diseases loss ofanisotropy loss of curvature increase in diffusionmagnitudeand loss of stiffness (softening) may be directly attributedto destructuring of interfacial water which precedes overtsigns and symptoms of oncologic neurologic and infectiousdisease [119 pp 3851-3852]

Ling (1991) has argued as follows

In autocooperative adsorption the adsorptionof an 119894th solute favors the adsorption of moreith solute in a heterocooperative adsorption theadsorption of an 119894th solute favors the adsorptionof the alternative 119895th solute Autocooperativebehaviors like those of a school of swimmingfish and the sentinels guarding the Great Wallof China tend to be all-or-none autocoop-erative adsorption is the backbone of coherentbehavior in living cells including the mainte-nance of the living state [181 pp 135ndash58]

Heterocooperative adsorption of Hg2+ solute would favorthe adsorption of an alternative solute such as Al3+ and viceversa in a manner which tends to be all-or-none Cumula-tive heterocooperative adsorption of cationic neurotoxicantmetals for example Hg2+ Al3+ and Pb2+ explains theirneurotoxic synergy and biosequestration

29 EIWS Promotes Both Structural and Biosemiotic EntropyThe fact that Al3+ species are potent exogenous interfacial


water stressors per the EIWS theory was elaborated byDavidson et al [57 59 68 117 119 177] Marcus (2013) foundin his study of the incremental surface tensions of variouselements that Al3+ has one of the largest individual ionicsurface tension increments (second only to La3+) [94] Thisfinding explains why Al3+ along with Hg2+ and Pb2+ aswell as various cationic and nonionic surfactants are potentfactors in producing EIWS Such observed facts explain howaluminumphosphate and aluminumsulfate species eitheras the Al3+ aqua ion form at low pH or the inner spherecontact ion pairs at higher pH by exceeding the incrementalsurface tension threshold of exclusion zones can disrupt H-bond cooperativity [123] In doing so they must augmentbiosemiotic entropy in vivo tending toward dehydration asdescribed by Sharma and Debenedetti (2012) [182]

In 1966 and 1967 Selye had already provided a compre-hensive exposition of the toxicity of polyvalent metal ionsalts [183 184] particularly those with high charge densityleading to serial sensitization resulting in both local andsystemic thrombohemorrhagic phenomena with microvas-cular ischemic and immune sequelae in a highly stereotypedpluricausal manner The earliest events in the toxicity of Al3+are biophysicalmediated bywater throughdisrupted interfa-cial H-bond cooperativity and quantum coherence [185ndash190]Consistent with the red shift in Raman vibrational absorptionfrequencies discussed earlier and demonstrating it in partFalk (1984) had already found that a lowering of the bendingfrequency of water is associated with increasing cation chargeand decreasing cation size [191] Much more recently Imotoet al (2013) studied the origin of the difference in the HndashOndashH bend of the infrared spectra between liquid water and ice[192] Furthermore as suggested by Exley (2004) [142] andMujika et al (2011) [193] Al3+ may be predisposed to reactin vivo with toxic impact on endogenous reactive oxygenspecies such as the superoxide radical anion to form an Al-superoxide semireduced radical cation complex [AlO∙

2]2+

210 Distinctive Physical Properties of Al Species DetermineTheir Toxicity Another unique property of Al ions is theirhigh charge density Ionic charge densities are reportedin Table 3 using the methodology described by Rayner-Canham and Overton (2010) [194] Also reported in thetable are the crystal atomic radii as published by Shan-non (1976) for the various ions [92] The charge densityof Al3+ is 3726 Csdotmmminus1 as compared to that of Gd3+(915 Csdotmmminus1) F1minus (162 Csdotmmminus1) Na+ (245 Csdotmmminus1) andCa2+ (516 Csdotmmminus1)

The high charge density of Al is a consequence of itsrelatively small radius and its fixed 3+ charge These factorsimpact the solubility of the individual Al salts and their incre-mental impact on the surface tension of water [94 195 196]With respect to biological impact the vast array of enzymesand signaling proteins inhibited by Al species shows that Altoxicity is not limited merely to diffusion The interaction ofthe various Al species with long-range dynamical H-bondnetworks and the coherence domains of interfacial watersuggests the involvement of nonthermal magnetic [47] andquantum effects that are no doubt generalizable to many

Table 5 Selected hydration enthalpies of common biologicallyrelevant ions [89]

Symbol Δ119867hydr (kJmolminus1) SourceNO3minus

minus312 [198]K+

minus321 [197]NH4+

minus329 [198]HSO4

minusminus368 [198]

Clminus minus371 [197]HCO3

minusminus384 [198]

Na+ minus413 [197]OHminus minus520 [198]H2PO4

minusminus522 [198]

SO42minus

minus1035 [198]H+

minus1100 [197]Ca2+ minus1650 [197]Mg2+ minus1920 [197]Mg2+ minus1949 [198]Al3+ minus4690 [197]

toxicants particularly those with polycationic surfactants ofhigh charge density (see Table 3)

Inorganic ions can be ranked on a chaotropic (disinte-grative) to kosmotropic (colloid forming) gradient accordingto their enthalpy of hydration [197 198] presented in Table 5(above) The more negative the enthalpy of hydration themore kosmotropic the solute The opposite would indicate achaotropic tendency A formula that aids in understandingthe relationship between charge density radius and enthalpyof hydration is given as follows

119867 = minus

119885119890

2

2119903

(1 minus

1

)

(1)

where 119867 = Hydration enthalpy 119885119890 = Charge of the ion r =Ionic radius and = Dielectric constant of the solvent

A smaller atomic radius and higher charge corre-late with a more negative hydration enthalpy and greaterkosmotropismmdashdefined biologically as the tendency to causemacromolecular complexes in bodily fluids to form uselesscolloidal precipitates that are effectively sequestered fromthe water in organelles cells blood lymph protoplasmor any bodily fluid In biological systems protein foldingand unfolding (DNA also) depend on a delicate balance ofchaotropic and kosmotropic forces on water [199] Solutessorted according to a chaotropic to kosmotropic gradientdefine the Hofmeister series [59] In agreement with hydra-tion enthalpies found in Table 5 Al3+ normally acting as apowerful kosmotrope plays havocwith the biological balanceIn particular the more kosmotropic a substance is the morecapable it is of salting-out proteins from an aqueousmediumTable 4 presents a comparison of the properties of chaotropicand kosmotropic ions

The oxyphilic behavior of Al acting as a kosmotrope isshown in its avid binding to oxyanions of carbon sulfurand phosphorus [120] Its lipophilicity dose-dependencetime-dependence and glial versus neuronal specificity have


been studied by Campbell et al (2001) [200] and as early as1996 Bondy and Kirstein had already shown how Al speciescan promote iron-induced generation of harmful reactiveoxygen species [201] Cations such as Al can bind to 120587electrons within biomolecules [202] in vivo inciting lipidperoxidation DNA damage and disruption of essentiallyall the biosemiotic systems deploying molecules containingcalciumand sulfur [203] A prima facie indicator of its toxicityis inflammation shown in cerebralmarkers elicited by chronicexposure to Al in drinking water [204] Kiss (2013) hasreviewed the coordination chemistry of Al3+ with small andlarge biomolecules including serum components and alsothe role of time in the distribution of this ldquosluggishrdquo metalion in a biological environment [205] The results agreedwith the computer model of Beardmore and Exley (2008)showing that Al has kosmotropic effects at a greater distanceand more quickly than the ldquodepotrdquo theories could possiblyexplain [206]

The magnitude of the kosmotropic property of Al3+ canbe seen in bold relief by comparing the degree of H-bondstrengthening required to cause Al3+ to behave as a chaotrope[207] If the H-bond energy of water increases then variouskosmotropic ions behave as chaotropes and vice versa Therequired change in strength of H-bonds to cause Na+ tobehave as a chaotrope is 11 strengthening and for K+ tobehave as a kosmotrope is 11 weakening The gradientbetween Na+ and K+ is almost two orders of magnitudesmaller in comparison with the hydration enthalpy of Al3+(minus4690 kJmolminus1) in theory the amount of energy released(as heat) when a mole of Al3+ dissolves into an infinitelydiluted solutionThe change of H-bond strength required forAl3+ a kosmotrope to behave as a chaotrope is 126075 H-bond strengthening The required H-bond strengthening iscalculated by dividing the hydration enthalpy of the solute bythe estimated isotropic point (minus372 kJmolminus1) Table 5 showsselected hydration enthalpies of several common biologicallyrelevant ions

211 Molecular and Cellular Biosemiotic Disruption by Al3+ IsConcomitant The foregoing facts and findings in this sectionhelp to show why and how Al3+ interacts synergistically withcertain other toxic molecules and how it acts in producingor augmenting auto- and neuroimmune diseases Kamalov etal (2011) demonstrated the cytotoxicity on immune cells ofenvironmentally common concentrations of Al (10ndash40 120583M)in murine thymocytes and lymphocytes [208] Nearly allthymocytes showed evidence of damage at 30120583MAlCl

3after

only 5 minutes of incubation A 60-minute exposure to10 120583MAlCl

3caused damage of about 5 of thymocytes while

50 were injured after 10 minutes at 20 120583M In lymphocytesinjury was observed at 15 120583MAlCl3 and less than 50 ofcells were injured after a 60-minute exposure to 20120583MInjury only rarely proceeded to rapid cell death and wasassociated with cell swelling These results demonstrateda rapid dose-dependent injury in murine thymocytes andlymphocytes resulting from exposure to Al as indicated byan increase in the entry into the cell of the DNA-bindingdye propidium iodideThe data suggest direct damage to the

plasma membrane manifested as an increase in membranepermeability consistent with the EIWS theory

Likewise with respect to the synergistic interaction ofAl3+ with Hg2+ species Kern et al (2013) examined theaction of low levels le1000 nM of thimerosal (4955 Hg2+by weight) on immortalized B-cells taken respectively fromautism spectrum disorder subjects their fraternal twins asibling and an agesex matched control Observed contrastsshowed impaired sulfation chemistry owed to the thimerosalexposure [209 210] In 2009 Pogue et al presented datawhich underscores the potential of nanomolar concentra-tions of Al to drive genotoxic mechanisms characteristic ofneurodegenerative disease processes [211 212] These datacombined with results reported earlier by Haley (2005)suggest toxic synergy between 120583M Al3+ levels and nMthimerosal levels in vivo [213]

While Al3+ can undoubtedly form complexes with pro-teins nucleotides nucleosides RNAs and DNAs so too canstable nanoclusters of water some of which are helical [214]The presence of Al3+ could only create difficulties in suchdelicately balanced systems [215] Also given the growingbody of empirical data suggesting that both gene structureand protein structure are dependent in part on interfacialwater dynamics it follows that the best known biologicalmacromolecules depend in part on supramolecular systems[216 217]

3 Corrupted Processes and Pathways Inducedby Aluminum

31 Effect of Al on Iron Toxicity and Interference with BH4 andCalmodulin Function Al is primarily transported in serumby transferrins [218] Al may interact with transferrins atmultiple candidate binding sites including the transferrinreceptors thus influencing iron metabolism and transportThe fastest subunit of transferrins to react with iron is thetyrosinate complex [219] Other amino acid residues withwhich Al may interact are aspartic acid glutamic acid andglutamine [220] Al readily binds to apo-transferrin bindingsites but does not compete with iron for binding withhalo-transferrins Al causes small conformational changes intransferrins without significant structural consequence [221]thus enabling transferrin receptors to actively transport Alacross the blood brain barrier as if it were iron [222] Once inthe brain displacement of iron from transferrins by Al resultsin iron toxicity and overproduction of reactive oxygen speciesby Fenton reactions [203 223]

Six interactive cycles within the methylation pathwayinclude (1) the urea cycle (2) the tetrahydrobiopterin (BH4)cycle (3) the folate cycle (4) the methionine cycle (5) theS-Adenosyl methionine (SAM) cycle and (6) the transsul-furation pathway Dihydrobiopterin reductase (DHPR) is acritically important enzyme in the BH4 cycle that is inhibitedbyAl and calmodulin (CaM) is critically inhibited in the ureacycle

DHPR inhibition is implicated in Al inducedencephalopathy [224] Many accounts of Al toxicity arereported in the context of renal insufficiency Al intoxication


associated with pediatric renal insufficiency causesprogressive encephalopathy in children [225] FurthermoreAl intoxication by any cause such as occupational exposureswill have the same inhibitory effect on DHPR [226]BH4BH2 ratios are decreased as a result of DHPRinactivation BH4BH2 ratios are reported to be decreased inAlzheimerrsquos disease [28] and in autism [227] About 60 ofchildren on the autism spectrum are reported to experienceclinical improvement after BH4 replacement therapy [228]

The folate cycle [229] enables components of urea BH4and methionine cycles to adapt to varying oxidative con-ditions The dihydrofolate reductase (DHFR) system is ameans of BH4 supply in cases of dysfunctional or inactiveDHPR [230] In this process DHPR becomes more active inrecycling BH4 from BH2 instead of acting on dihydrofolateto synthesize tetrahydrofolate when DHPR is functionalCongenital DHPR deficiency such as in phenylketonuria(PKU) is associated with folate depletion [231] and treatmentfor PKU includes dietary folate replacement [232]

In addition BH4 is cofactor for production of dopaminefrom tyrosine Dopamine cyanocobalamin and 5-methyltetrahydrofolate are required for synthesis of methioninefrom homocysteine [233 234] In Al toxicity as in autism[63] dopamine becomes depleted because BH4 is depletedfurther limiting remethylation of DNAs RNAs lipids andproteins [235] Furthermore methionine is required tomethylate DNA The brain malformations seen in autopsiesof autistic subjects [236] suggest failure of DNA methylationduring brain development and growth

In the urea cycle BH4 is a cofactor with arginine inthe synthesis of nitric oxide (NO) under endothelial nitricoxide synthase (eNOS) Not only does Al inhibit DHPR andproduction of BH4 but it also out-competes calcium forbinding sites on calmodulin (CaM) causing conformationalchanges [237] Properly bound with calcium CaM is anessential cofactor in coupled eNOS mediated production ofcitrulline and NO from arginine If BH4 is depleted or Albinds to calmodulin eNOS follows an uncoupled pathwaythat favors production of peroxynitrite and superoxide NOlevels are paradoxically high in BH4 depletion because itcontinues to be produced by alternate pathways and itsrelease from endothelial cells is inhibited by the high level ofaccumulated homocysteine [238]

High NO levels are associated with increased vascularpermeability NO stimulates mast cells and macrophages torelease proinflammatory cytokines including IL-1 IL-6 tumornecrosis factor (TNF) and vascular endothelial growth factor(VEGF) [239] This is the inflammatory profile found inautistic encephalopathy [240] Accumulation of both reactiveoxygen and nitrogen species results in severe oxidative andnitrosative stress [241ndash243]

32 Effects of Distinct Formulations of Aluminum AdjuvantsA Role for the Zeta Potential As already noted Al adjuvantsare predominant modulators used in vaccines althoughrelatively little is known about how they work [244] Itwas formerly claimed that Al adjuvants directly stimulateantigen-presenting cells by forming an antigen depot at the

Table 6 Three different formulations of the DTaP vaccine and thenumber of reported adverse reactions available from VAERS foreach one

Formulation Adjuvant Adversereactions

Tripedia Aluminum potassiumsulfate 11178

Daptacel Aluminum phosphate 8786Infanrix Aluminum hydroxide 13238

injection site [245] Given the evidence that Al species usedin adjuvants are readily transported throughout the body thedepot theory must be rejected Others have proposed that Alstimulates dendritic cells activates the immune complementsystem and induces the release of chemokines [246] Itis generally agreed that Al hydroxide induces a Th2 typeimmune response [247 248] whereas Al phosphate has beenshown to induce aTh1 type response [249]

However based on data from the CDCrsquos Vaccine AdverseEvent Reporting System (VAERS) database it is possible tocompare the three distinct Al adjuvants used in the DTaPvaccine in particular (seeTable 6) they consist of a hydroxidea potassium sulfate and a phosphate The fact that all areused in the same multivalent vaccine minimizes the degreeto which other factors including the several antigens in thevaccine might be influencing adverse reactions Assumingonly that all other factors excepting the Al adjuvants areheld constant an experimentally orthogonal comparison ispossible among the three adjuvants The method of compar-ison was a standard ratio of an expected value to the oneobtained in each instance as susceptible to a standard chi-square distribution (the log-likelihood ratio) as described in[250]

The statistic in question expresses the likelihood that agiven ratio of expected adverse reactions to actually observedadverse reactions could be attributed to chance The criticalprobability for our tests was conservatively set at 119901 lt005 The VAERS database for DTaP adverse reactions forthe several formulations were compared with subsamplesmatched for age and number of cases The comparisonenabled the testing of experimental predictions concerningthe relative mobility of charged particles in an electric fieldbased on the Zeta potential (ZP) of the various Al adjuvantsat issue In bloodmdashthe most abundant fluid involved intransporting adjuvants from an injection sitemdashthe ZP reflectsthe negative charge of molecules attached to the membranesof suspended particles such as red blood cells (RBCs) or lipidparticles which the Al3+ compound in any given case wouldbe likely to link up with A less negative ZP is associated withan increased tendency for RBCs to aggregate [251] that is toform clots whereas an even more negative ZP reduces thattendency

The three DTaP formulations (Table 6) differ chemicallyonly in their Al adjuvant component as detailed by Caulfieldet al [244] and to that extent the vaccines differ in zetapotential (ZP) As those researchers found ZP measuredat pH 70 closely matching the value for blood yielded a


Table 7 Adverse reactions reported in VAERS for sulfate versushydroxide in age-matched samples and the likelihood that thecontrasts observed in these distributions could have occurred bychance (p lt 005)

Condition Sulfate Hydroxide p valueSwelling 2210 2665 00066Cellulitis 445 617 0020Pain 622 815 0020Fever 2032 2296 0034Injection site reaction 393 520 0038Injection site swelling 7 33 0045

Table 8 Counts of various adverse reactions reported in VAERSfor sulfate versus phosphate in age-matched equal subsets of thesample space and the likelihood that the contrasts observed inthese distributions could have occurred by chance according to alog likelihood ratio test Included are all the reactions for whichphosphate was more common with a p value under 005

Condition Sulfate Phosphate p valueHospitalization 177 363 00044Seizures 186 333 0011Rotavirus 3 47 0013Abdominal pain 6 53 0014Nausea 203 338 0015Diarrhea 95 174 0028Pneumonia 13 50 0032Dehydration 12 48 0032Throat irritation 81 147 0036

ZP value for hydroxide at +30mV for sulfate at 0mV andfor phosphate at minus20mV the sulfate formulation thereforeshould have the least impact Using its ZP value at 0mV as thebaseline it provided a reasonable estimate of the ldquoexpectedvaluerdquo for the ratio comparisons with the other two adjuvantsto assess the impact of ZP on the adverse reactions reportedResults shown in Tables 7 and 8 show the outcomes forphosphate and hydroxide adjuvants Compared to phosphatelocal adverse events are reported more often for hydroxidewhich as expected shouldmigrate less from the injection siteowing to a higher positive ZP while phosphate should showthe opposite effect owing to its negatively displaced ZP value

The negative charge induces mobility owing to theelectrical field induced by the voltage difference betweenarteries and veins [99 100] while the positive charge tendsto prevent mobility through the bloodThe voltage differenceis partly because the veins have a lower pH because CO

2

is more acidic than O2 The lymphatic system of course

as noted by Gherardi and colleagues [98ndash100] affords abypass route that white blood cells (eg immune cells) cantake (having penetrated the endothelial wall into the tissues)[252 253] However this pathway also has the same voltagedrop that would propel movement of negatively chargedparticles as the lymph system returns to the venous systemat the subclavian vein On the other hand positively charged

particles would be stalled in the tissues as shown byDavidsonand Seneff [59]

Thus with the Al hydroxide adjuvant we expect and findrelatively more edema (swelling) at the injection site accom-panied by ldquoinjection site reactionrdquo and cellulitis because bothplasma and lymphatic transit are stalled Al phosphate incontrast with higher mobility and easier migration throughthe lymphatic system into the venous system is more likely toreach distant areas including the brain resulting as observedin a greater likelihood of systemic responses such as throatirritation nausea diarrhea abdominal pain and seizures Asexpected Al potassium sulfate did not produce any reactionswith a 119901 value under 005 when compared against either ofthe other formulations

Observed syndromes associated with Al hydroxideinclude ldquomacrophagic myofasciitisrdquo (MMF) characterized bydiffuse myalgia chronic fatigue and cognitive dysfunctiontermed ldquomild cognitive impairmentrdquo [38 40] In a relevantstudy of that disorder it was determined that theAl hydroxideadjuvant led to an accumulation of Al-loaded macrophagesat the site of a previous intramuscular immunization [39]Given the results reported in Table 7 it must be inferredthat macrophages lingering at the injection site on accountof the elevated ZP associated with the hydroxide formulationare responsible for this observed syndrome Likewise theautoimmune syndrome recently identified by Shoenfeld andcolleagues [65ndash67] is consistent with the generalized toxicityof the Al adjuvants

33 Aluminum Interactions with Fluorine Fluorine is themost chemically reactive nonmetal and the most electroneg-ative element [254] According to Martin (1996) [255] Al3+binds Fminus more strongly than 60 other metal ions testedEven with micromolar concentrations of Al3+ these twoatoms react to form AlF

4

minus a molecule whose shape andphysical properties closely resemble those of the phosphateanion PO

4

minus2 This feature has been exploited to helpresearchers understand phosphate-dependent reactions insignaling cascades [255ndash258] For example it has been shownby exploiting AlF

4

minus that melatoninrsquos widespread signalingeffects are mediated by G-proteins [259] However if AlF

4

minus

forms whenever these two elements are both present it isknown to interfere with regulatory GTP hydrolases whichplay an initiating role in phosphate-based signaling cascades[260 261] Should the AlF

4

minusmimetic which is not responsiveto the GTPase stick in the ldquoonrdquo position an overresponsivecascade of transcription motility and contractility as wellas apoptosis would proliferate If this were to happen suchinterference for which Al toxicity affords many alternativeroutes remaining to be explored is certain in all cases toaugment biosemiotic entropy

Strunecka and Patocka proposed that the toxic role ofAl in Alzheimerrsquos disease may be predominantly due to theformation of AlF

4

minus [262] The formation of that complexaccording to experimental evidence in quantities as little as1 ppm of fluoride contamination of water supplied to rats ledto greater uptake of Al into the kidney and brain along withthe formation of amyloid deposits like those in Alzheimerrsquos


eNOS

CaMGPCR

GDP

Activator minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

(a)

eNOS

Al

Al

Al

GPCRAl

GDPSignaling cascades

NO

NO

NO

NO

NO

NO

Activator

P

CaMAl

FminusFminusFminus

Fminus

(b)

Figure 3 Illustration of the devastating effects of Aluminum on a typical cell related to sulfate inactivation G-protein signaling andcalmodulin signaling (a) A healthy cell without Al contamination eNOS attached to the membrane at a caveola produces sulfate whichmaintains a healthy glycocalyx with sufficient negative charge (b) Al binds to the sulfates eliminating the negative charge which allowscytokines to penetrate through the glycocalyx activating G-protein coupled receptor signaling cascades AlF

4

minus disrupts the signal actingas a phosphate mimic and Al binds to CaM inducing eNOS detachment from the membrane Phosphorylation cascades activate eNOS toproduce abundant NO released into the cytoplasm instead of producing sulfate to enrich the glycocalyx

disease [263] As proteins RNAs and DNAs become dam-aged through oxidation [264ndash267] if they cannot be repairedfailure of the lysosomal and mitochondrial organelles willlead to apoptosis [268ndash270] or in worse cases to necrosisAl compounds can only contribute to such outcomes in anegative way

Prior research has also shown that insufficient sulfate inthe extracellular matrix of all the tissues particularly theendothelial wall plays a significant role in disorders and dis-ease conditions [59 117 177 199] Heparan sulfate populatesthe glycocalyx in the capillaries [118 271ndash273] and enables alow-resistance capillary wall permitting smooth blood flow[57 59 68 117 177 199] Sphingosine-1-phosphate-inducedRac activation chemotaxis and angiogenesis associated withendothelial cell migration are mediated by G-proteins [274]

With all of the above considered it may be notable thatpostmortem examination of Alzheimerrsquos brains reveals severedeficiency in sulfatide a myelin-specific sulfated sphin-golipid which normallymakes up 6 of the lipid content andis especially concentrated in themyelin sheath [275] Twenty-two subjects in the early stage of Alzheimerrsquos disease showed adepletion of 93 in graymatter and up to 58 inwhitematterin all brain regions examined Aside from an overabundanceof ceramide the precursor to sulfatide (ceramidewas elevatedthreefold inwhitematter) all other lipid parameters appearednormal This outcome was not associated with a defectin sulfatide synthesis so the pathology appears to involvebreakdown of sulfatide to provide sulfate to the vasculaturecritical for maintenance of an adequate supply of oxygen andnutrients to the brain

Seneff et al previously suggested that endothelial nitricoxide synthase (eNOS) an enzyme present in endothelial

cells RBCs and platelets among other cell types is aldquomoonlightingrdquo enzyme which synthesizes sulfate when it isattached to caveolin in the plasmamembrane and synthesizesNO (which is converted to nitrate within a few seconds) whenit is phosphorylated and bound by a calcium-CaM complexin the cytoplasm [118] These findings suggest that eNOSplays the dual-purpose of regulating the balance betweenkosmotropes and chaotropes in the cytoplasm of the cell andalso enabling the proper folding and functions of cellularproteins [199] as detailed in Figure 3

4 Discussion

Considering all the ways Al3+ is known to impact biologicalsystems negatively as summed up in Table 1 exposure tothat cation generally disrupts biosemiotic cascades Its effectslead to minute cumulative injuries to DNAs RNAs cellularproteins and lipids through glycation and oxidation damageas well as impaired lysosomal recycling of debris andultimately in some cases leads to cell death by necrosisDeath by apoptosis the preferred alternative may also followAl-induced injuries and changes in DNAs RNAs proteinsand any downstreammediators For example MMF has beenshown to manifest with Al retention at the injection site ofvaccines containing Al hydroxide [38 39] and far-reachingnegative effects on the bodyrsquos immune systems can be seenin ASIA owed to eventual migration of Al adjuvants awayfrom the injection site [65ndash67] Given its positive differentialimpact on ZP Al hydroxide has been shown to linger atthe injection site for many months although it eventually istransported into brain bymacrophages [77] In that particularcase the normal apoptosis of injured cells is disrupted by


the high electrostatic attraction of the Al3+ ion towards thenegatively charged sulfates in the glycocalyx actually forcingthe Al3+ cation to penetrate and traverse the viscous water ofthe exclusion zone The result is disruption of the structuredwater in the exclusion zone compromising the glycocalyxbarrier and allowing signaling molecules to gain access andlaunch a G-protein mediated cascade reaction

This cascade is intensified by the effects of AlF119909on G-

protein signaling and the subsequent disruption of cellu-lar metabolism follows When the cell becomes necrotichaving skipped over any possibility of normally regulatedand orderly apoptosis it virtually disintegrates releasingDNA and other cellular debris into the interstitial spaces todegenerate or to be carried away by the lymphatic system Inthe case of the other less confined Al adjuvants that can morereadily migrate away from the injection site the confusioninduced in biosemiotic systems is the predictable source of aconfused and self-destructive autoimmune response as seenin ASIAThe downstream result is an immune attack on cellstissues and organs throughout the body but especially in theCNS as seen in diseases such as multiple sclerosis and otherdemyelinating conditions

It is clear that Al3+ toxicity interacting synergisticallywith other toxicants such as solvated species of Hg2+ Pb2+Fminus AlF

119909(aluminofluoride) SiF

119909(silicofluoride) glyphosate

and including chelation complexes must directly increasebiosemiotic entropy on multiple levels simultaneously bydisrupting long-range dynamical interfacial hydrogen bondcooperativity and the quantum coherence of water Theoutcome is widespread (systemic) and involves virtuallysimultaneous inhibition of many different enzyme systemsIt is therefore unsurprising that Al3+ is associated withanaphylaxis and sudden death [59]The data from the studiesreviewed here show that the complex coacervate protoplasmstudied now for about 150 years [145 174 175] is susceptibleto poisoning by high charge density polyvalent cations forexample Al3+ Hg2+ and Pb2+ Empirical studies [93 94] ofion solvation suggest that local order induction can resultin loss of long-range systemic coherence and cooperativity[185] On a supramolecular biosemiotic level EIWS inducedby Al3+ disrupts interfacial hydrogen bond cooperativityand quantum coherence of biointerfacial water At a criticalthreshold the self-ordered criticality of biointerfacial watercollapses The most notable effects of this sort occur in theCNS [68 276]

In the larger context however Al toxicants can them-selves or by synergistically interacting with other toxicantsdestroy cells in any organ system although none are morevulnerable than the CNS and the peripheral systems attachedto it While significant everywhere in the body the impactof biosemiotic entropy in the CNS is critical because ofthe nested and highly interdependent systems connected toit For example the loss of neural cells (neurons or glia)in the CNS tends to disrupt circuits that depend on suchcells In turn groups of neurons in functional nuclei canbe rendered dysfunctional through the loss of individualneuronal elements In the same way the loss of functionalnuclei can lead to catastrophic stress on the CNS itself andor

on dependent organ systems Fatality may be preceded bya cascading series of failures resembling the collapse ofcomplex interdependent networks [277]

An additional factor that makes the nervous systemuniquely vulnerable is the highly specified differentiationof neuronal activities due to sequenced developmental pro-grams These programs acting in response to both geneticand environmental instructions ensure that the loss of func-tional circuits cannot be easily replaced since the very milieuinto which they might be integrated (eg stem cells) differsfrom one stage of development to the next during whichsome window or ldquocritical periodrdquo for neuroplasticity mayhave passedWhile it is true that critical periods vary betweenneuronal regions (human association versus primary cortexeg) younger nervous systems appear to have a greatercapacity for recovery following injuries to organ systemsprovided stem cells remain intact However damage to theDNA of stem cells is apt to be irreparable even in early stagesof development and Al3+ can cause both injuries to organsand DNA damage directly impacting stem cells

A third reason for the notable toxicity of Al3+ is thatneurogenesismdashthat is the birth of new neuronsmdashis relativelyrare in the adult CNS in most regions Compared to theability of other organs to regenerate for example the skin orliver the CNS has limited capacity to do so which renders itmore vulnerable to irreversible damage at fairly early stages ofdevelopment Thus Al and its compounds have remarkablepower to harm neurons and to produce systemic damageThe observed impact may in some instances be suddenas in anaphylaxis and sudden death syndrome but in otherinstances it may build slowly to a crisis level through chronicdoses leading to systemic autoimmune responses as in thevaccine-induced disorders The variable range of toxic effectsin ASIA for example can best be explained in terms ofthe biodistribution and pharmacokinetics of the particularAl adjuvant used Some of the observed differences dependpredictably on ZP and its impact on interfacial water tension

Figure 4 is a two-dimensional schematic showing some ofthe ways Al and its compounds can impact the biosemioticsystems encompassed by the CNS The summary suggestsa nested biosemiotic hierarchy of ranked systems commu-nicating within and across levels In ascending order theyrange from molecules to genes proteins cells circuits CNSsubsystems and the CNS itself Impacts at any level caninduce changes in those above and below them For exampleAl actions at a cellular level will necessarily perturb proteinstructures and DNA (the levels below) and alter cell-to-cell communication at the circuit level (above) AlthoughFigure 4 focuses on the deleterious effects of Al on the ner-vous system it should be clear that its impacts are systemic

5 Conclusions

Aluminum induces entropy in living organisms by disruptingall levels of structure from water molecules through allbiosemiotic systems Entropy-inducing cascades feedbackloops (positive and negative) within and across levels candamage DNAs RNAs proteins cells tissues and whole


MolecularDisturbs water structure and dynamics

Changes zeta potential and interfacial tension Interacts with other elements (eg S O C F P)

GenomeAlters DNA chromatin RNA structure

Linked to viral DNA contaminants in HPV vaccine

ProteinAl binds to proteins impairs protein function

Associated with abnormal tauAlters enzyme function

Inhibits antioxidant enzyme actionIncreases oxidant stress

CellInterferes with synaptic transmission

ion channelsreceptors second messengersDisrupts mitochondria and organelles

Lipid peroxidation cellular apoptosis and death

SystemInduces autoimmune interactions

Loaded into macrophagesIncreases BBB permeability

Induces macrophagic myofasciitis in muscle

Central Nervous SystemImpaired cognitive and motor function

Impaired sensory development andsystems interaction

Linked to cognitive impairment AlzheimerrsquosALS dialysis encephalopathy and seizure disorders

CircuitBlocks neuronal signaling

Interrupts cell-cell communicationCorrupts neuronal-glial interactions

MolecularGenome

Protein

CellCircuitSystem

CNS

Figure 4 Schematic of the biosemiotic levels at which Al can impact the body and CNS

organ systems As a result of cellular damage caused by anAl compound injured and dying cells will release proteasesexcitatory amino acids and ions (eg potassium calcium)disrupting biosemiosis at many levels Toxic effects of Al andits compounds thus tend to proliferate Interactive resultsinvolving immune functions for instance make the impactworse than if only one system were involved Of course thedose-response of Al and its compounds must be consideredbut even at low doses especially with repeated exposures Alcan have cumulative deleterious effects that can be extremeand even fatal For that reason a repeated low dose exposuremay prove more damaging than a single larger dose Aland its compounds can cross biosemiotic levels damaginggenetic systems proteins cells and all systems up throughthe CNS While higher doses may rapidly affect multiplelevels as in dialysis-associated encephalopathy (DAE) lowdoses over time for example from vaccines can degrademetabolism and disrupt repair and defense systems and canspiral out of control as in ASIA Al adjuvants in vaccines mayhyperdrive the immune functions of the body but they alsodirectly disrupt biosemiotic systems Sound theory empiricalresearch and reasonable inferences from sources cited hereshow that Al and its compounds damage biological systemsSuch conclusions warrant considerations at a policy level tolimit human exposure to Al and its compounds

Highlights

(i) Aluminum (Al3+) suspected as a toxicant for 100years injures the CNS and immune systems individ-ually and synergistically

(ii) Al3+ disrupts biological water dynamics and macro-molecules DNAs RNAs proteoglycans and proteins

(iii) Al3+ disrupts H-bond cooperativity interfering withthe quantum coherence of living systems

(iv) Al3+ interferes with biological signalingmdashbiosemio-sismdashfrom the very lowest to the highest levels in thenervous system

(v) The effects are synergistic with other toxicantsincluding mercury lead fluoride and glyphosate

Disclosure

Christopher A Shaw Stephanie Seneff Stephen D KetteLucija Tomljenovic John W Oller Jr and Robert M David-son are equal first authors

Conflict of Interests

The authors declare that there is no conflict of interests

Acknowledgments

This work was supported in part by the Dwoskin FamilyFoundation theKatlyn Fox Foundation and the LutherAllynShouds Dean estate (to CAS) and by Quanta ComputersTaiwan under the auspices of the Qmulus projectThis paperis dedicated to thememory of Prof PeterHillman formerly ofthe Hebrew University and graduate supervisor and mentorof CAS Peter was a physicist and neurobiologist whosecuriosity was boundless The authors think he would haveappreciated this paper


References

[1] C Exley ldquoThe coordination chemistry of aluminium in neu-rodegenerative diseaserdquo Coordination Chemistry Reviews vol256 no 19-20 pp 2142ndash2146 2012

[2] C A Shaw Y Li and L Tomljenovic ldquoAdministration ofaluminium to neonatal mice in vaccine-relevant amounts isassociated with adverse long term neurological outcomesrdquoJournal of Inorganic Biochemistry vol 128 pp 237ndash244 2013

[3] C Exley ldquoDarwin natural selection and the biological essen-tiality of aluminiumand siliconrdquoTrends in Biochemical Sciencesvol 34 no 12 pp 589ndash593 2009

[4] G Power J S C Loh and C Vernon ldquoOrganic compounds inthe processing of lateritic bauxites to alumina part 2 effects oforganics in theBayer processrdquoHydrometallurgy vol 127-128 pp125ndash149 2012

[5] R A Yokel ldquoAluminium toxicokinetics an updated minire-viewrdquo Pharmacology and Toxicology vol 88 no 4 pp 159ndash1672001

[6] W J Gies ldquoSome objections to the use of alum baking-powderrdquoThe Journal of the American Medical Association vol 57 no 10pp 816ndash821 1911

[7] J F Struve ldquoTaking Aluminum out of the Dietrdquo httphomeearthlinknetsimjoannefstruve wsnpage2html

[8] ldquoAvoid aluminummdashLocate the unexpected sources ofaluminum in productsrdquo httpwwwnaturalnewscom033431aluminum personal care productshtml

[9] L Tomljenovic and C A Shaw ldquoAluminum vaccine adjuvantsare they saferdquo Current Medicinal Chemistry vol 18 no 17 pp2630ndash2637 2011

[10] R W Dapson ldquoThe history chemistry and modes of action ofcarmine and related dyesrdquo Biotechnic amp Histochemistry vol 82no 4-5 pp 173ndash187 2007

[11] P D Darbre ldquoUnderarm cosmetics are a cause of breast cancerrdquoEuropean Journal of Cancer Prevention vol 10 no 5 pp 389ndash393 2001

[12] P D Darbre ldquoAluminium antiperspirants and breast cancerrdquoJournal of Inorganic Biochemistry vol 99 no 9 pp 1912ndash19192005

[13] P D Darbre D Pugazhendhi and F Mannello ldquoAluminiumand human breast diseasesrdquo Journal of Inorganic Biochemistryvol 105 no 11 pp 1484ndash1488 2011

[14] A-P Sappino R Buser L Lesne et al ldquoAluminium chloridepromotes anchorage-independent growth in human mammaryepithelial cellsrdquo Journal of Applied Toxicology vol 32 no 3 pp233ndash243 2012

[15] ldquoScience News Aluminum Found in Sunscreen Could It CauseSkin Cancerrdquo httpwwwsciencedailycomreleases200708070812084458htm

[16] S Nicholson and C Exley ldquoAluminum a potential pro-oxidantin sunscreenssunblocksrdquo Free Radical Biology and Medicinevol 43 no 8 pp 1216ndash1217 2007

[17] J W Oller ldquoBiosemiotic entropy concluding the seriesrdquoEntropy vol 16 pp 4060ndash4087 2014

[18] R J Mitkus D B King M A Hess R A Forshee and M OWalderhaug ldquoUpdated aluminum pharmacokinetics followinginfant exposures through diet and vaccinationrdquoVaccine vol 29no 51 pp 9538ndash9543 2011

[19] P A Offit and R K Jew ldquoAddressing parentsrsquo concerns dovaccines contain harmful preservatives adjuvants additives orresidualsrdquo Pediatrics vol 112 no 6 pp 1394ndash1397 2003

[20] J R J Sorenson I R Campbell L B Tepper and R DLingg ldquoAluminum in the environment and human healthrdquoEnvironmental Health Perspectives vol 8 pp 3ndash95 1974

[21] T P Flaten ldquoAluminium as a risk factor in Alzheimerrsquos diseasewith emphasis on drinking waterrdquo Brain Research Bulletin vol55 no 2 pp 187ndash196 2001

[22] D Krewski R A Yokel E Nieboer et al ldquoHuman health riskassessment for aluminium aluminium oxide and aluminiumhydroxiderdquo Journal of Toxicology and Environmental Health BCritical Reviews vol 10 no 1 pp 1ndash269 2007

[23] Z-L Xie D-M Dong G-Z Bao S-T Wang Y-G Du and L-M Qiu ldquoAluminum content of tea leaves and factors affectingthe uptake of aluminum from soil into tea leavesrdquo ChineseGeographical Science vol 11 no 1 pp 87ndash91 2001

[24] T P Flaten and M Oslashdegard ldquoTea aluminium and Alzheimerrsquosdiseaserdquo Food and Chemical Toxicology vol 26 no 11-12 pp959ndash960 1988

[25] A-K Flaten andW Lund ldquoSpeciation of aluminium in tea infu-sions studied by size exclusion chromatography with detectionby post-column reactionrdquo Science of the Total Environment vol207 no 1 pp 21ndash28 1997

[26] R A Yokel and R L Florence ldquoAluminum bioavailability fromtea infusionrdquo Food and Chemical Toxicology vol 46 no 12 pp3659ndash3663 2008

[27] J R Walton ldquoChronic aluminum intake causes Alzheimerrsquosdisease applying Sir Austin Bradford Hillrsquos causality criteriardquoJournal of Alzheimerrsquos Disease vol 40 pp 765ndash838 2014

[28] L Tomljenovic ldquoAluminum and Alzheimerrsquos disease after acentury of controversy is there a plausible linkrdquo Journal ofAlzheimerrsquos Disease vol 23 no 4 pp 567ndash598 2011

[29] W J Lukiw S Bjattacharjee Y Zhao A I Pogue and ME Percy ldquoGeneration of reactive oxygen species (ROS) andpro-inflammatory signaling in human brain cells in primaryculturerdquo Journal of Alzheimerrsquos Disease amp Parkinsonism supple-ment 2 article 001 2012

[30] W J LukiwM E Percy andT P Kruck ldquoNanomolar aluminuminduces pro-inflammatory and pro-apoptotic gene expressionin human brain cells in primary culturerdquo Journal of InorganicBiochemistry vol 99 no 9 pp 1895ndash1898 2005

[31] N J Bishop RMorley B Chir J PhilipDay andA Lucas ldquoAlu-minum neurotoxicity in preterm infants receiving intravenous-feeding solutionsrdquo The New England Journal of Medicine vol336 no 22 pp 1557ndash1561 1997

[32] J A Flendrig H Kruis and H A Das ldquoAluminium intox-ication the cause of dialysis dementiardquo Proceedings of theEuropean Dialysis and Transplant Association vol 13 pp 355ndash368 1976

[33] E K Pivnick N C Kerr R A Kaufman D P Jones and R WChesney ldquoRickets secondary to phosphate depletion a sequelaof antacid use in infancyrdquo Clinical Pediatrics vol 34 no 2 pp73ndash78 1995

[34] N C Bowdler D S Beasley E C Fritze et al ldquoBehavioraleffects of aluminum ingestion on animal and human subjectsrdquoPharmacology Biochemistry and Behavior vol 10 no 4 pp505ndash512 1979

[35] C Exley andMM Esiri ldquoSevere cerebral congophilic angiopa-thy coincident with increased brain aluminium in a resident ofCamelford Cornwall UKrdquo Journal of Neurology Neurosurgeryand Psychiatry vol 77 no 7 pp 877ndash879 2006

[36] J RWalton andM-XWang ldquoAPP expression distribution andaccumulation are altered by aluminum in a rodent model for


Alzheimerrsquos diseaserdquo Journal of Inorganic Biochemistry vol 103no 11 pp 1548ndash1554 2009

[37] M S Golub M E Gershwin J M Donald S Negri andC L Keen ldquoMaternal and developmental toxicity of chronicaluminum exposure in micerdquo Toxicological Sciences vol 8 no3 pp 346ndash357 1987

[38] R K Gherardi M Coquet P Cherin et al ldquoMacrophagicmyofasciitis an emerging entityrdquoThe Lancet vol 352 no 9125pp 347ndash352 1998

[39] R K Gherardi and F J Authier ldquoMacrophagic myofasciitischaracterization and pathophysiologyrdquo Lupus vol 21 no 2 pp184ndash189 2012

[40] E Passeri C Villa M Couette et al ldquoLong-term follow-up ofcognitive dysfunction in patients with aluminum hydroxide-inducedmacrophagicmyofasciitis (MMF)rdquo Journal of InorganicBiochemistry vol 105 no 11 pp 1457ndash1463 2011

[41] M Couette M F Boisse P Maison et al ldquoLong-term per-sistence of vaccine-derived aluminum hydroxide is associatedwith chronic cognitive dysfunctionrdquo Journal of Inorganic Bio-chemistry vol 103 no 11 pp 1571ndash1578 2009

[42] AM Ryan N BerminghamH J Harrington and C KeohaneldquoAtypical presentation ofmacrophagicmyofasciitis 10 years postvaccinationrdquo Neuromuscular Disorders vol 16 no 12 pp 867ndash869 2006

[43] L Lujan M Perez E Salazar et al ldquoAutoimmuneautoinflam-matory syndrome induced by adjuvants (ASIA syndrome) incommercial sheeprdquo Immunologic Research vol 56 no 2-3 pp317ndash324 2013

[44] M S Petrik M C Wong R C Tabata R F Garry and C AShaw ldquoAluminum adjuvant linked to Gulf War illness inducesmotor neuron death in micerdquo NeuroMolecular Medicine vol 9no 1 pp 83ndash100 2007

[45] C A Shaw and M S Petrik ldquoAluminum hydroxide injectionslead to motor deficits and motor neuron degenerationrdquo Journalof Inorganic Biochemistry vol 103 no 11 pp 1555ndash1562 2009

[46] H Sinczuk-WalczakM Szymczak G RazniewskaWMatczakand W Szymczak ldquoEffects of occupational exposure to alu-minumonnervous system clinical and electroencephalograph-ic findingsrdquo International Journal of Occupational Medicine andEnvironmental Health vol 16 no 4 pp 301ndash310 2003

[47] CRC CRC Handbook of Chemistry and Physics 2012-2013 CRCPress New York NY USA 2012

[48] C Exley ldquoHuman exposure to aluminiumrdquo EnvironmentalScience Processes amp Impacts vol 15 pp 1807ndash1816 2013

[49] C Sonnenschein and A M Soto The Society of Cells BiosScientific Oxford UK 1999

[50] F Crick ldquoCentral dogma of molecular biologyrdquoNature vol 227no 5258 pp 561ndash563 1970

[51] JWOller Jr ldquoThe antithesis of entropy biosemiotic communi-cation from genetics to human language with special emphasison the immune systemsrdquo Entropy vol 12 no 4 pp 631ndash7052010

[52] M-W Ho ldquoThe new genetics and natural versus artificialgenetic modificationrdquo Entropy vol 15 no 11 pp 4748ndash47812013

[53] D Grant W F Long and F B Williamson ldquoHeparin-polypeptide interaction Near-ir spectroscopy in an anhydrousdispersant allows the involvement of polymer-associated waterto be assessedrdquo Biochemical Journal vol 277 no 2 pp 569ndash5711991

[54] InternationalHumanGenomeSequencingConsortium ldquoInitialsequencing and analysis of the human genomerdquoNature vol 431pp 931ndash945 2004

[55] D Bohrer P C Do Nascimento J K A Mendonca V G Polliand L M de Carvalho ldquoInteraction of aluminium ions withsome amino acids present in human bloodrdquo Amino Acids vol27 no 1 pp 75ndash83 2004

[56] P J Brothers and C E Ruggerio ldquoCoordination and solutionchemistry of themetals biological medical and environmentalrelevancerdquo inTheGroup 13Metals Aluminium Gallium Indiumand Thallium Chemical Patterns and Peculiarities S Aldridgeand A J Downs Eds p 584 John Wiley amp Sons ChichesterUK 2011

[57] S Seneff R M Davidson and J Liu ldquoEmpirical data confirmautism symptoms related to aluminum and acetaminophenexposurerdquo Entropy vol 14 no 11 pp 2227ndash2253 2012

[58] J M Mercero J E Fowler and J M Ugalde ldquoAluminum(III)interactions with the acidic amino acid chainsrdquo Journal ofPhysical Chemistry A vol 102 no 35 pp 7006ndash7012 1998

[59] R M Davidson and S Seneff ldquoThe initial common pathway ofinflammation disease and sudden deathrdquo Entropy vol 14 no8 pp 1399ndash1442 2012

[60] V Gatta D Drago K Fincati et al ldquoMicroarray analysison human neuroblastoma cells exposed to aluminum 1205731-42-amyloid or the 1205731-42-amyloid aluminum complexrdquo PLoS Onevol 6 no 1 Article ID e15965 2011

[61] J H Duffus ldquolsquoHeavy metalsrsquo a meaningless termrdquo Pure andApplied Chemistry vol 74 no 5 pp 793ndash807 2002

[62] J C K Lai and J P Blass ldquoInhibition of brain glycolysis byaluminumrdquo Journal of Neurochemistry vol 42 no 2 pp 438ndash446 1984

[63] L Tomljenovic and C A Shaw ldquoDo aluminum vaccine adju-vants contribute to the rising prevalence of autismrdquo Journal ofInorganic Biochemistry vol 105 no 11 pp 1489ndash1499 2011

[64] J Lemire and V D Appanna ldquoAluminum toxicity and astrocytedysfunction ametabolic link to neurological disordersrdquo Journalof Inorganic Biochemistry vol 105 no 11 pp 1513ndash1517 2011

[65] Y Shoenfeld and N Agmon-Levin ldquoldquoASIArdquomdashautoimmunein-flammatory syndrome induced by adjuvantsrdquo Journal ofAutoimmunity vol 36 no 1 pp 4ndash8 2011

[66] E Israeli N Agmon-Levin M Blank and Y ShoenfeldldquoAdjuvants and autoimmunityrdquo Lupus vol 18 no 13 pp 1217ndash1225 2009

[67] N Agmon-Levin G Hughes and Y Shoenfeld ldquoThe spec-trum of ASIA lsquoAutoimmune (Auto-inflammatory) Syndromeinduced by Adjuvantsrsquordquo Lupus vol 21 no 2 pp 118ndash120 2012

[68] C A Shaw S D Kette R M Davidson and S SeneffldquoAluminumrsquos role in CNS-immune system interactions leadingto neurological disordersrdquo Immunome Research vol 9 article 12013

[69] R A Yokel C L Hicks and R L Florence ldquoAluminumbioavailability from basic sodium aluminum phosphate anapproved food additive emulsifying agent incorporated incheeserdquo Food and Chemical Toxicology vol 46 no 6 pp 2261ndash2266 2008

[70] Agency for Toxic Substances Disease Registry (ATSDR)Toxicological Profile for Aluminum Agency for Toxic Sub-stances Disease Registry (ATSDR) Atlanta Ga USA 2013httpwwwatsdrcdcgovtoxprofilestp22pdf

[71] SM Saiyed andR A Yokel ldquoAluminium content of some foodsand food products in the USA with aluminium food additivesrdquo


Food Additives amp Contaminants vol 22 no 3 pp 234ndash2442005

[72] J A T Pennington and S A Schoen ldquoEstimates of dietaryexposure to aluminiumrdquo Food Additives and Contaminants vol12 no 1 pp 119ndash128 1995

[73] J L Greger ldquoAluminum metabolismrdquo Annual Review of Nutri-tion vol 13 pp 43ndash63 1993

[74] FAOWHO ldquoSummary and conclusionsrdquo in Proceedings of the67th Meeting of the Joint FAOWHO Expert Committee on FoodAdditives (JECFA rsquo06) Rome Italy June 2006

[75] P O Ganrot ldquoMetabolism and possible health effects of alu-minumrdquo Environmental Health Perspectives vol 65 pp 363ndash441 1986

[76] D RCrapper S S Krishnan andA JDalton ldquoBrain aluminumdistribution in Alzheimers disease and experimental neurofib-rillary degenerationrdquo Science vol 180 no 4085 pp 511ndash5131973

[77] D R Crapper and A J Dalton ldquoAlterations in short termretention conditioned avoidance response acquisition andmotivation following aluminum induced neurofibrillary degen-erationrdquo Physiology and Behavior vol 10 no 5 pp 925ndash9331973

[78] W J Lukiw B Krishnan L Wong T P A Kruck C Bergeronand D R Crapper McLachlan ldquoNuclear compartmentalizationof aluminum in Alzheimerrsquos disease (AD)rdquo Neurobiology ofAging vol 13 no 1 pp 115ndash121 1992

[79] N W Baylor W Egan and P Richman ldquoAluminum salts invaccinesmdashUS perspectiverdquo Vaccine vol 20 supplement 3 ppS18ndashS23 2002

[80] JM Brewer ldquo(How) do aluminiumadjuvantsworkrdquo Immunol-ogy Letters vol 102 no 1 pp 10ndash15 2006

[81] T C Eickhoff and M Myers ldquoWorkshop summary aluminumin vaccinesrdquo Vaccine vol 20 supplement 3 pp S1ndashS4 2002

[82] B L Carson Aluminum Compounds Review of Toxicolog-ical Literature Abridged Final Report 84 pages IntegratedLaboratory Systems Research Triangle Park North Carolina2000 httpntpniehsnihgovntphtdocschem backgroundexsumpdfaluminum 508pdfsearch=aluminum compounds

[83] M R Wills and J Savory ldquoWater content of aluminumdialysis dementia and osteomalaciardquo Environmental HealthPerspectives vol 63 pp 141ndash147 1985

[84] G L Wenk and K L Stemmer ldquoThe influence of ingestedaluminum upon norepinephrine and dopamine levels in the ratbrainrdquo NeuroToxicology vol 2 no 2 pp 347ndash353 1981

[85] T Moos and E H Morgan ldquoTransferrin and transferrin recep-tor function in brain barrier systemsrdquo Cellular and MolecularNeurobiology vol 20 no 1 pp 77ndash95 2000

[86] R E Flarend S L Hem J LWhite et al ldquoIn vivo absorption ofaluminium-containing vaccine adjuvants using 26Alrdquo Vaccinevol 15 no 12-13 pp 1314ndash1318 1997

[87] E Autret-Leca L Bensouda-Grimaldi A P Jonville-Bera andF Beau-Salinas ldquoPharmacovigilance of vaccinesrdquo Archives dePediatrie vol 13 no 2 pp 175ndash180 2006

[88] R Flarend T Bin D Elmore and S L Hem ldquoA preliminarystudy of the dermal absorption of aluminium from antiperspi-rants using aluminium-26rdquo Food and Chemical Toxicology vol39 no 2 pp 163ndash168 2001

[89] MDayah ldquoDynamic Periodic Tablerdquo October 1997 httpwwwptablecom

[90] C A Shaw and L Tomljenovic ldquoAluminum in the centralnervous system (CNS) toxicity in humans and animals vaccine

adjuvants and autoimmunityrdquo Immunologic Research vol 56no 2-3 pp 304ndash316 2013

[91] R A Yokel and P J McNamara ldquoAluminium toxicokinetics anupdated minireviewrdquo Pharmacology and Toxicology vol 88 no4 pp 159ndash167 2001

[92] R D Shannon ldquoRevised effective ionic radii and systematicstudies of interatomic distances in halides and chalcogenidesrdquoActa Crystallographica A vol 32 pp 751ndash767 1976

[93] Y Marcus ldquoViscosity B-coefficients structural entropies andheat capacities and the effects of ions on the structure of waterrdquoJournal of Solution Chemistry vol 23 no 7 pp 831ndash848 1994

[94] Y Marcus ldquoIndividual ionic surface tension increments inaqueous solutionsrdquo Langmuir vol 29 no 9 pp 2881ndash2888 2013

[95] C Exley ldquoAluminium-based adjuvants should not be used asplacebos in clinical trialsrdquo Vaccine vol 29 no 50 9289 pages2011

[96] I Zivkovic V Petrusic M Stojanovic A Inic -Kanada IStojicevic and L Dimitrijevic ldquoInduction of decreased fecun-dity by tetanus toxoid hyper-immunization in C57BL6 micedepends on the applied adjuvantrdquo Innate Immunity vol 18 no2 pp 333ndash342 2012

[97] X-B Li H Zheng Z-R Zhang et al ldquoGlia activation inducedby peripheral administration of aluminum oxide nanoparticlesin rat brainsrdquo Nanomedicine Nanotechnology Biology andMedicine vol 5 no 4 pp 473ndash479 2009

[98] M Couette M-F Boisse P Maison et al ldquoLong-term per-sistence of vaccine-derived aluminum hydroxide is associatedwith chronic cognitive dysfunctionrdquo Journal of Inorganic Bio-chemistry vol 103 no 11 pp 1571ndash1578 2009

[99] R K Gherardi M Coquet P Cherin et al ldquoMacrophagicmyofasciitis lesions assess long-term persistence of vaccine-derived aluminium hydroxide in musclerdquo Brain vol 124 no 9pp 1821ndash1831 2001

[100] R K Gherardi and F-J Authier ldquoAluminum inclusionmacrophagic myofasciitis a recently identified conditionrdquoImmunology and Allergy Clinics of North America vol 23 no4 pp 699ndash712 2003

[101] Y Shoenfeld and N Agmon-Levin ldquorsquoASIArsquo - Autoimmunein-flammatory syndrome induced by adjuvantsrdquo Journal ofAutoimmunity vol 36 no 1 pp 4ndash8 2011

[102] P L Meroni ldquoAutoimmune or auto-inflammatory syndromeinduced by adjuvants (ASIA) old truths and a new syndromerdquoJournal of Autoimmunity vol 36 no 1 pp 1ndash3 2011

[103] Y Zafrir N Agmon-Levin Z Paz T Shilton and Y ShoenfeldldquoAutoimmunity following Hepatitis B vaccine as part of thespectrum of ldquoAutoimmune (Auto-inflammatory) Syndromeinduced by Adjuvantsrdquo (ASIA) analysis of 93 casesrdquo Lupus vol21 no 2 pp 146ndash152 2012

[104] G S Goldman and N Z Miller ldquoRelative trends in hospital-izations and mortality among infants by the number of vaccinedoses and age based on the Vaccine Adverse Event ReportingSystem (VAERS) 1990ndash2010rdquo Human and Experimental Toxi-cology vol 31 no 10 pp 1012ndash1021 2012

[105] N Z Miller and G S Goldman ldquoInfant mortality ratesregressed against number of vaccine doses routinely givenis there a biochemical or synergistic toxicityrdquo Human ampExperimental Toxicology vol 30 no 9 pp 1420ndash1428 2011

[106] Z Khan C Combadiere F-J Authier et al ldquoSlow CCL2-dependent translocation of biopersistent particles from muscleto brainrdquo BMCMedicine vol 11 article 99 2013


[107] E Nieboer B L Gibson A D Oxman and J R KramerldquoHealth effects of aluminum a critical review with emphasis onaluminum in drinkingwaterrdquoEnvironmental Reviews vol 3 no1 pp 29ndash81 1995

[108] B E Gryder C W Nelson and S Shepard ldquoBiosemioticentropy of the genome mutations and epigenetic imbalancesresulting in cancerrdquo Entropy vol 15 no 1 pp 234ndash261 2013

[109] T M Maynard L Sikich J A Lieberman and A-S LaMantialdquoNeural development cell-cell signaling and the ldquotwo-hitrdquohypothesis of schizophreniardquo Schizophrenia Bulletin vol 27 no3 pp 457ndash476 2001

[110] K D Collins and M W Washabaugh ldquoThe Hofmeister effectand the behaviour of water at interfacesrdquo Quarterly Reviews ofBiophysics vol 18 no 4 pp 323ndash422 1985

[111] Y Marcus Ions in Water and Biophysical Implications FromChaos to Cosmos Springer Dordrecht The Netherlands 2012

[112] J Barthel and G A Krestov Thermodynamics of SolvationSolution and Dissolution Ions and Solvents Structure andEnergetics Ellis Horwood Series in Physical Chemistry EllisHorwood New York NY USA 1991

[113] K D Collins ldquoCharge density-dependent strength of hydrationand biological structurerdquo Biophysical Journal vol 72 no 1 pp65ndash76 1997

[114] G H PollackThe Fourth Phase of Water Beyond Solid Liquidand Vapor Ebner amp Sons Seattle Wash USA 2013

[115] G N Ling ldquoA new theoretical foundation for the polarized-oriented multilayer theory of cell water and for inanimate sys-tems demonstrating long-range dynamic structuring of watermoleculesrdquo Physiological Chemistry and Physics and MedicalNMR vol 35 no 2 pp 91ndash130 2003

[116] G N Ling ldquoAn updated and further developed theory andevidence for the close-contact one-on-one association of nearlyall cell K+ with 120573- and 120574-carboxyl groups of intracellularproteinsrdquo Physiological Chemistry and Physics and MedicalNMR vol 37 no 1 pp 1ndash63 2005

[117] S Seneff R Davidson and L Mascitelli ldquoMight cholesterolsulfate deficiency contribute to the development of autisticspectrum disorderrdquoMedical Hypotheses vol 78 no 2 pp 213ndash217 2012

[118] S Seneff A Lauritzen R Davidson and L Lentz-MarinoldquoIs endothelial nitric oxide synthase a moonlighting proteinwhose day job is cholesterol sulfate synthesis Implicationsfor cholesterol transport diabetes and cardiovascular diseaserdquoEntropy vol 14 no 12 pp 2492ndash2530 2012

[119] R M Davidson A Lauritzen and S Seneff ldquoBiological waterdynamics and entropy a biophysical origin of cancer and otherdiseasesrdquo Entropy vol 15 no 9 pp 3822ndash3876 2013

[120] H Sigel and A Sigel EdsMetal Ions in Biological Systems vol24 of Aluminum and Its Role in Biology Marcel Dekker NewYork NY USA 1988

[121] DW Piper and B Fenton ldquoThe adsorption of pepsinrdquoDigestiveDiseases and Sciences vol 6 no 2 pp 134ndash141 1961

[122] R J Sepelyak J R Feldkamp T E Moody J L White andS L Hem ldquoAdsorption of pepsin by aluminum hydroxide Iadsorptionmechanismrdquo Journal of Pharmaceutical Sciences vol73 no 11 pp 1514ndash1517 1984

[123] ldquoMetal ions in aqueous solutionrdquo 2013 httpenwikipediaorgwikiMetal ions in aqueous solution

[124] S O Duke K C Vaughn and R D Wauchope ldquoEffects ofglyphosate on uptake translocation and intracellular local-ization of metal cations in soybean (Glycine max) seedlingsrdquo

Pesticide Biochemistry and Physiology vol 24 no 3 pp 384ndash394 1985

[125] M Purgel Z Takacs C M Jonsson et al ldquoGlyphosate com-plexation to aluminium(III) An equilibrium and structuralstudy in solution using potentiometry multinuclear NMRATR-FTIR ESI-MS and DFT calculationsrdquo Journal of InorganicBiochemistry vol 103 no 11 pp 1426ndash1438 2009

[126] A Samsel and S Seneff ldquoGlyphosatersquos suppression of cyto-chrome P450 enzymes and amino acid biosynthesis by the gutmicrobiome pathways tomodern diseasesrdquo Entropy vol 15 pp1416ndash1463 2013

[127] J A Carman H R Vlieger L J Ver Steeg et al ldquoA long-termtoxicology study on pigs fed a combined genetically modified(GM) soy and GM maize dietrdquo Journal of Organic Systems vol8 no 1 pp 38ndash54 2013

[128] D D Ulmer ldquoToxicity from aluminium antacidsrdquo The NewEngland Journal of Medicine vol 294 no 4 pp 218ndash219 1976

[129] J W Coburn M GMischel W G Goodman and I B SaluskyldquoCalcium citrate markedly enhances aluminum absorptionfrom aluminum hydroxiderdquo The American Journal of KidneyDiseases vol 17 no 6 pp 708ndash711 1991

[130] B B Kirschbaum and A C Schoolwerth ldquoAcute aluminumtoxicity associated with oral citrate and aluminum-containingantacidsrdquoTheAmerican Journal of theMedical Sciences vol 297no 1 pp 9ndash11 1989

[131] V Solfrizzi A M Colacicco A DrsquoIntrono et al ldquoMacronu-trients aluminium from drinking water and foods and othermetals in cognitive decline anddementiardquo Journal of AlzheimerrsquosDisease vol 10 no 2-3 pp 303ndash330 2006

[132] D Fekkes T J M van der Cammen C P M van Loon et alldquoAbnormal amino acid metabolism in patients with early stageAlzheimer dementiardquo Journal of Neural Transmission vol 105no 2-3 pp 287ndash294 1998

[133] J K Hou J R Kramer P Richardson M Mei and HB El-Serag ldquoThe incidence and prevalence of inflammatorybowel disease among US veterans a national cohort studyrdquoInflammatory Bowel Diseases vol 19 no 5 pp 1059ndash1064 2013

[134] H B El-Serag ldquoTime trends of gastroesophageal reflux diseasea systematic reviewrdquo Clinical Gastroenterology and Hepatologyvol 5 no 1 pp 17ndash26 2007

[135] J C Hoffmann N N Pawlowski A A Kuhl W Hohne andM Zeitz ldquoAnimal models of inflammatory bowel disease anoverviewrdquo Pathobiology vol 70 no 3 pp 121ndash130 2003

[136] S Keller C Vargas H Zhao G Piszczek C A Brautigamand P Schuck ldquoHigh-precision isothermal titration calorimetrywith automated peak-shape analysisrdquoAnalytical Chemistry vol84 no 11 pp 5066ndash5073 2012

[137] J C Martinez J Murciano-Calles E S Cobos M Iglesias-Bexiga I Luque and J Ruiz-Sanz ldquoIsothermal titrationcalorimetry thermodynamic analysis of the binding ther-mograms of molecular recognition events by using equi-librium modelsrdquo in Applications of Calorimetry in a WideContextmdashDifferential Scanning Calorimetry Isothermal Titra-tion Calorimetry and Microcalorimetry A A Elkordy Edchapter 4 InTech 2013

[138] C Zhou Y Gao and G Li ldquoTechnology of recovery effectivecomponents in wastewater from glyphosate production bydynamic adsorption methodrdquo CIESC Journal vol 64 no 4 pp1453ndash1458 2013 (Chinese)

[139] F Guo and J M Friedman ldquoCharge density-dependent modifi-cations of hydration shell waters by hofmeister ionsrdquo Journal of


the American Chemical Society vol 131 no 31 pp 11010ndash110182009

[140] F Herve N Ghinea and J-M Scherrmann ldquoCNS delivery viaadsorptive transcytosisrdquo AAPS Journal vol 10 no 3 pp 455ndash472 2008

[141] S Han J Lemire V P Appanna C Auger Z Castonguay andVDAppanna ldquoHowaluminum an intracellular ROSgeneratorpromotes hepatic and neurological diseases themetabolic talerdquoCell Biology and Toxicology vol 29 no 2 pp 75ndash84 2013

[142] C Exley ldquoThe pro-oxidant activity of aluminumrdquo Free RadicalBiology amp Medicine vol 36 no 3 pp 380ndash387 2004

[143] G N Ling ldquoAn updated and further developed theory andevidence for the close-contact one-on-one association of nearlyall cell K+ with 120573- and 120574-carboxyl groups of intracellularproteinsrdquo Physiological Chemistry and Physics and Medical vol37 no 1 pp 1ndash63 2005

[144] G Ling ldquoNano-protoplasm the ultimate unit of liferdquo Physiolog-ical Chemistry and Physics and Medical NMR vol 39 no 2 pp111ndash234 2007

[145] G N Ling Life At the Cell and below Cell Pacific Press NewYork NY USA 2001

[146] TM RiddickControl of Colloid Stability through Zeta PotentialWith a Closing Chapter on Its Relationship to CardiovascularDisease Livingston Wynnewood Pa USA 1968

[147] MDNewton andH L Friedman ldquoAproposedneutrondiffrac-tion experiment to measure hydrogen isotope fractionation insolutionrdquo The Journal of Chemical Physics vol 83 no 10 pp5210ndash5218 1985

[148] M M Probst and K Hermansson ldquoOn frequency shifts inOH stretching vibrations of hydrated cationsrdquo The Journal ofChemical Physics vol 96 no 12 pp 8995ndash9004 1992

[149] G G R Desiraju and T Steiner ldquoThe weak hydrogen bondrdquoin Structural Chemistry and Biology p 507 Oxford UniversityPress Oxford UK 2001

[150] J Joseph and E D Jemmis ldquoRed- blue- or no-shift in hydrogenbonds a unified explanationrdquo Journal of the American ChemicalSociety vol 129 no 15 pp 4620ndash4632 2007

[151] E D Jemmis and P Parameswaran ldquoStructure and bonding incyclic isomers of BAl2Hnm (n = 3 minus 6 m =minus2 to +1) preferencefor planar tetracoordination pyramidal tricoordination anddivalencyrdquo Chemistry vol 13 pp 2622ndash2631 2007

[152] D Gallez and W T Coakley ldquoInterfacial instability at cellmembranesrdquo Progress in Biophysics and Molecular Biology vol48 no 3 pp 155ndash199 1986

[153] K J Tielrooij N Garcia-Araez M Bonn and H J BakkerldquoCooperativity in ion hydrationrdquo Science vol 328 no 5981 pp1006ndash1009 2010

[154] S L Budd L Tenneti T Lishnak and S A Lipton ldquoMitochon-drial and extramitochondrial apoptotic signaling pathways incerebrocortical neuronsrdquo Proceedings of the National Academyof Sciences of the United States of America vol 97 no 11 pp6161ndash6166 2000

[155] J J Lemasters and V K Ramshesh ldquoImaging of mitochondrialpolarization and depolarization with cationic fluorophoresrdquoMethods in Cell Biology vol 80 pp 283ndash295 2007

[156] M Sivaguru S PikeWGassmann andT I Baskin ldquoAluminumrapidly depolymerizes cortical microtubules and depolarizesthe plasma membrane evidence that these responses are medi-ated by a glutamate receptorrdquo Plant and Cell Physiology vol 44no 7 pp 667ndash675 2003

[157] D Busselberg B Platt D Michael D O Carpenter and H LHaas ldquoMammalian voltage-activated calcium channel currentsare blocked byPb2+ Zn2+ andAl3+rdquo Journal ofNeurophysiologyvol 71 no 4 pp 1491ndash1497 1994

[158] D Julka and K D Gill ldquoAltered calcium homeostasis a possiblemechanism of aluminium-induced neurotoxicityrdquo Biochimicaet Biophysica ActamdashMolecular Basis of Disease vol 1315 no 1pp 47ndash54 1996

[159] S K Pal and A H Zewail ldquoDynamics of water in biologicalrecognitionrdquo Chemical Reviews vol 104 pp 2099ndash2123 2004

[160] R G Oliveira E Schneck S S Funari M Tanaka and BMaggio ldquoEquivalent aqueous phase modulation of domain seg-regation in myelin monolayers and bilayer vesiclesrdquo BiophysicalJournal vol 99 no 5 pp 1500ndash1509 2010

[161] B Chai H Yoo and G H Pollack ldquoEffect of radiant energy onnear-surface waterrdquo Journal of Physical Chemistry B vol 113 no42 pp 13953ndash13958 2009

[162] S Sadiq Z Ghazala A Chowdhury and D Busselberg ldquoMetaltoxicity at the synapse presynaptic postsynaptic and long-termeffectsrdquo Journal of Toxicology vol 2012 Article ID 132671 42pages 2012

[163] B Platt H Haas and D Busselberg ldquoExtracellular pH mod-ulates aluminium-blockade of mammalian voltage-activatedcalcium channel currentsrdquo NeuroReport vol 4 no 11 pp 1251ndash1254 1993

[164] B Platt and D Busselberg ldquoActions of aluminum on voltage-activated calcium channels currentsrdquo Cellular and MolecularNeurobiology vol 14 pp 819ndash829 1994

[165] P Q Trombley ldquoSelectivemodulation of GABA(A) receptors byaluminumrdquo Journal of Neurophysiology vol 80 no 2 pp 755ndash761 1998

[166] M Kawahara ldquoEffects of aluminum on the nervous system andits possible link with neurodegenerative diseasesrdquo Journal ofAlzheimerrsquos Disease vol 8 no 2 pp 171ndash182 2005

[167] J W Oller Jr S D Oller and L C Badon Cases IntroducingCommunication Disorders Across the Life Span Plural Publish-ing San Diego Calif USA 2010

[168] J W Oller Jr and S D Oller Autism The Diagnosis Treatmentand Etiology of the Undeniable Autism Epidemic Jones andBartlett Boston Mass USA 2010

[169] J W Oller Jr S D Oller and S N Oller Milestones NormalSpeech and Language Development across the Span PluralPublishing San Diego Calif USA 2nd edition 2014

[170] B Johansson and S Sukhotskaya ldquoAllometric scalingbehaviormdasha quantum dissipative state implies a reductionin thermal infrared emission and fractal ordering in distilledcoherent waterrdquoWater vol 3 pp 100ndash121 2012

[171] P Ball ldquoWater as an active constituent in cell biologyrdquo ChemicalReviews vol 108 no 1 pp 74ndash108 2008

[172] J Zheng and G H Pollack ldquoLong-range forces extending frompolymer-gel surfacesrdquo Physical Review E Statistical Nonlinearand Soft Matter Physics vol 68 Article ID 031408 2003

[173] D T Nhan and G H Pollack ldquoEffect of particle diameter onexclusion-zone sizerdquo International Journal of Design and Natureand Ecodynamics vol 6 no 2 pp 139ndash144 2011

[174] R S Lillie Protoplasmic Action and Nervous Action Universityof Chicago Press 1923

[175] A I Oparin and A SyngeThe Origin of Life on the Earth Aca-demic Press New York NY USA 3rd edition 1957 translatedby A Synge


[176] E G del Giudice P R Spinetti and A Tedeschi ldquoWaterdynamics at the root of metamorphosis in living organismsrdquoWater vol 2 pp 566ndash586 2010

[177] S Hartzell and S Seneff ldquoImpaired sulfate metabolism andepigenetics is there a link in autismrdquo Entropy vol 14 pp 1953ndash1977 2012

[178] R G Oliveira M Tanaka and B Maggio ldquoMany length scalessurface fractality inmonomolecular films ofwholemyelin lipidsand proteinsrdquo Journal of Structural Biology vol 149 no 2 pp158ndash169 2005

[179] J J Harrison R J Turner D A Joo et al ldquoCopper andquaternary ammonium cations exert synergistic bactericidaland antibiofilm activity against Pseudomonas aeruginosardquoAntimicrobial Agents andChemotherapy vol 52 no 8 pp 2870ndash2881 2008

[180] R S Renslow P D Majors J S McLean J K Fredrickson BAhmed and H Beyenal ldquoIn situ effective diffusion coefficientprofiles in live biofilms using pulsed-field gradient nuclearmagnetic resonancerdquo Biotechnology and Bioengineering vol106 no 6 pp 928ndash937 2010

[181] G N Ling ldquoCoherent behavior and control mechanismsrdquo inA Revolution in the Physiology of the Living Cell pp 135ndash158Krieger Malabar Fla USA 1991

[182] S Sharma and P G Debenedetti ldquoEvaporation rate of waterin hydrophobic confinementrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 109 no12 pp 4365ndash4370 2012

[183] H SelyeThrombohemorrhagic Phenomena Charles CThomasSpringfield Ill USA 1966

[184] H Selye InVivoTheCase for Supramolecular Biology LiverightNew York NY USA 1967

[185] E D Giudice A Tedeschi G Vitiello and V Voeikov ldquoCoher-ent structures in liquid water close to hydrophilic surfacesrdquoJournal of Physics Conference Series vol 442 no 1 Article ID012028 2013

[186] I Prigogine Thermodynamics of Irreversible Processes JohnWiley amp Sons New York NY USA 1955

[187] F Gunther Self- organisation in systems far from thermodynamicequilibrium some clues to the structure and function of biologicalsystems [PhD thesis] Department of Systems Ecology Stock-holm University Stockholm Sweden 1994

[188] C N R Rao P C Dwivedi H Ratajczak and W J Orville-Thomas ldquoRelation between O-H stretching frequency andhydrogen bond energy Re-examination of the Badger-Bauerrulerdquo Journal of the Chemical Society Faraday Transactions 2Molecular and Chemical Physics vol 71 pp 955ndash966 1975

[189] S Melandri ldquolsquoUnion is strengthrsquo how weak hydrogen bondsbecome strongerrdquo Physical Chemistry Chemical Physics vol 13no 31 pp 13901ndash13911 2011

[190] G Gilli and P Gilli ldquoTowards an unified hydrogen-bondtheoryrdquo Journal ofMolecular Structure vol 552 no 1ndash3 pp 1ndash152000

[191] M Falk ldquoThe frequency of the HOH bending fundamentalin solids and liquidsrdquo Spectrochimica Acta A Molecular Spec-troscopy vol 40 no 1 pp 43ndash48 1984

[192] S Imoto S S Xantheas and S Saito ldquoMolecular origin of thedifference in the HOH bend of the IR spectra between liquidwater and icerdquo Journal of Chemical Physics vol 138 no 5 ArticleID 054506 2013

[193] J I Mujika F Ruiperez I Infante J M Ugalde C Exleyand X Lopez ldquoPro-oxidant activity of aluminum stabilization

of the aluminum superoxide radical ionrdquo Journal of PhysicalChemistry A vol 115 no 24 pp 6717ndash6723 2011

[194] G Rayner-Canham and T Overton ldquoPolorization and cova-lencyrdquo in Descriptive Inorganic Chemistry pp 96ndash97 W HFreeman New York NY USA 2010

[195] Y Marcus Supercritical Water John Wiley amp Sons HobokenNJ USA 2012

[196] B Hribar N T Southall V Vlachy and K A Dill ldquoHow ionsaffect the structure of waterrdquo Journal of the American ChemicalSociety vol 124 no 41 pp 12302ndash12311 2002

[197] J E House ldquoInorganic chemistryrdquo in Inorganic Chemistry pp229ndash237 Academic Press Burlington Mass USA 2008

[198] Y Marcus Ion Properties Marcel Dekker New York NY USA1997

[199] D Russo ldquoThe impact of kosmotropes and chaotropes onbulk and hydration shell water dynamics in a model peptidesolutionrdquo Chemical Physics vol 345 no 2-3 pp 200ndash211 2008

[200] A Campbell D Hamai and S C Bondy ldquoDifferential toxicityof aluminum salts in human cell lines of neural origin impli-cations for neurodegenerationrdquo NeuroToxicology vol 22 no 1pp 63ndash71 2001

[201] S C Bondy and S Kirstein ldquoThe promotion of iron-inducedgeneration of reactive oxygen species in nerve tissue by alu-minumrdquo Molecular and Chemical Neuropathology vol 27 no2 pp 185ndash194 1996

[202] A S Mahadevi and G N Sastry ldquoCation-120587 interaction itsrole and relevance in chemistry biology and material sciencerdquoChemical Reviews vol 113 pp 2100ndash2138 2013

[203] S J Stohs and D Bagchi ldquoOxidative mechanisms in the toxicityof metal ionsrdquo Free Radical Biology and Medicine vol 18 no 2pp 321ndash336 1995

[204] A Campbell A Becaria D K Lahiri K Sharman and SC Bondy ldquoChronic exposure to aluminum in drinking waterincreases inflammatory parameters selectively in the brainrdquoJournal of Neuroscience Research vol 75 no 4 pp 565ndash5722004

[205] J T Kiss ldquoFrom coordination chemistry to biological chemistryof aluminiumrdquo Journal of Inorganic Biochemistry vol 128 pp156ndash163 2013

[206] J Beardmore and C Exley ldquoTowards a model of non-equilibriumbinding ofmetal ions in biological systemsrdquo Journalof Inorganic Biochemistry vol 103 no 2 pp 205ndash209 2009

[207] M F Chaplin ldquoWaters hydrogen bond strengthrdquo in Waterand Life The Unique Properties of H

2O R M Lynden-Bell S

ConwayMorris J D Barrow J L Finney andC LHarper Edspp 69ndash86 CRC Press Boca Raton Fla USA 2010

[208] J Kamalov D O Carpenter and I Birman ldquoCytotoxicityof environmentally relevant concentrations of aluminum inmurine thymocytes and lymphocytesrdquo Journal of Toxicologyvol 2011 Article ID 796719 7 pages 2011

[209] J Kern B Haley D Geier L Sykes P King and M GeierldquoThimerosal exposure and the role of sulfation chemistry andthiol availability in autismrdquo International Journal of Environ-mental Research and Public Health vol 10 no 8 pp 3771ndash38002013

[210] S J James S Rose SMelnyk et al ldquoCellular andmitochondrialglutathione redox imbalance in lymphoblastoid cells derivedfrom children with autismrdquo The FASEB Journal vol 23 no 8pp 2374ndash2383 2009

[211] A I Pogue Y Y Li J G Cui et al ldquoCharacterization of anNF-120581B-regulated miRNA-146a-mediated down-regulation of


complement factor H (CFH) in metal-sulfate-stressed humanbrain cellsrdquo Journal of Inorganic Biochemistry vol 103 no 11pp 1591ndash1595 2009

[212] A I Pogue B M Jones S Bhattacharjee M E Percy Y Zhaoand W J Lukiw ldquoMetal-sulfate induced generation of ROSin human brain cells detection using an isomeric mixture of5- and 6-carboxy-2101584071015840-dichlorofluorescein diacetate (carboxy-DCFDA) as a cell permeant tracerrdquo International Journal ofMolecular Sciences vol 13 no 8 pp 9615ndash9626 2012

[213] B E Haley ldquoMercury toxicity genetic susceptibility and syner-gistic effectsrdquoMedical Veritas vol 2 pp 535ndash542 2005

[214] S Acosta-Gutierrez J Hernandez-Rojas J Breton J M GLlorente and D J Wales ldquoPhysical properties of small waterclusters in low and moderate electric fieldsrdquo The Journal ofChemical Physics vol 135 no 12 Article ID 124303 2011

[215] S Sabella R P Carney V Brunetti et al ldquoA general mechanismfor intracellular toxicity of metal-containing nanoparticlesrdquoNanoscale vol 6 pp 7052ndash7061 2014

[216] H Frauenfelder G Chen J Berendzen et al ldquoA unified modelof protein dynamicsrdquo Proceedings of the National Academy ofSciences of theUnited States of America vol 106 no 13 pp 5129ndash5134 2009

[217] S H Chen M Lagi X Q Chu et al ldquoDynamics of a globularprotein and its hydration water studied by neutron scatteringand MD simulationsrdquo Spectroscopy vol 24 no 1-2 pp 1ndash242010

[218] W R Harris Z Wang and Y Z Hamada ldquoCompetitionbetween transferrin and the serum ligands citrate and phos-phate for the binding of aluminumrdquo Inorganic Chemistry vol42 no 10 pp 3262ndash3273 2003

[219] G S Waldo and E C Theil ldquoFormation of iron(III)-tyrosinateis the fastest reaction observed in ferritinrdquo Biochemistry vol 32no 48 pp 13262ndash13269 1993

[220] X Liu and E C Theil ldquoFerritins dynamic management ofbiological iron and oxygen chemistryrdquo Accounts of ChemicalResearch vol 38 no 3 pp 167ndash175 2005

[221] S Tang R MacColl and P J Parsons ldquoSpectroscopic studyof the interaction of aluminum ions with human transferrinrdquoJournal of Inorganic Biochemistry vol 60 no 3 pp 175ndash1851995

[222] R A Yokel ldquoBlood-brain barrier flux of aluminummanganeseiron and other metals suspected to contribute to metal-inducedneurodegenerationrdquo Journal of Alzheimerrsquos Disease vol 10 no2-3 pp 223ndash253 2006

[223] H J H Fenton ldquoLXXIIImdashOxidation of tartaric acid in pres-ence of ironrdquo Journal of the Chemical Society Transactions vol65 pp 899ndash910 1894

[224] I Bone and M Thomas ldquoDialysis dementia aluminium andtetrahydrobiopterin metabolismrdquoThe Lancet vol 313 no 8119p 782 1979

[225] A Rotundo T E Nevins M Lipton L A Lockman S MMauer and A F Michael ldquoProgressive encephalopathy inchildren with chronic renal insufficiency in infancyrdquo KidneyInternational vol 21 no 3 pp 486ndash491 1982

[226] Z Z Altindag T Baydar A B Engin and G Sahin ldquoEffects ofthemetals on dihydropteridine reductase activityrdquoToxicology inVitro vol 17 no 5-6 pp 533ndash537 2003

[227] Y Tani E Fernell Y Watanabe T Kanai and B LangstromldquoDecrease in GR-5678-tetrahydrobiopterin content in cere-brospinal fluid of autistic patientsrdquoNeuroscience Letters vol 181no 1-2 pp 169ndash172 1994

[228] R E Frye L C Huffman and G R Elliott ldquoTetrahydro-biopterin as a novel therapeutic intervention for autismrdquo Neu-rotherapeutics vol 7 no 3 pp 241ndash249 2010

[229] H F Nijhout M C Reed P Budu and C M Ulrich ldquoAmathematical model of the folate cycle new insights into folatehomeostasisrdquo The Journal of Biological Chemistry vol 279 no53 pp 55008ndash55016 2004

[230] M J Crabtree A L Tatham Y Al-Wakeel et al ldquoQuanti-tative regulation of intracellular endothelial nitric-oxide syn-thase (eNOS) coupling by both tetrahydrobiopterin-eNOSstoichiometry and biopterin redox status insights from cellswith TET-regulated GTP cyclohydrolasei expressionrdquo Journalof Biological Chemistry vol 284 no 2 pp 1136ndash1144 2009

[231] A PonzoneM Spada S Ferraris I Dianzani andLDe SanctisldquoDihydropteridine reductase deficiency in man From biologyto treatmentrdquoMedicinal Research Reviews vol 24 no 2 pp 127ndash150 2004

[232] I Smith K Hyland and B Kendall ldquoClinical role of pteridinetherapy in tetrahydrobiopterin deficiencyrdquo Journal of InheritedMetabolic Disease vol 8 no 1 pp 39ndash45 1985

[233] M Waly H Olteanu R Banerjee et al ldquoActivation of methio-nine synthase by insulin-like growth factor-1 and dopamine atarget for neurodevelopmental toxins and thimerosalrdquoMolecu-lar Psychiatry vol 9 no 4 pp 358ndash370 2004

[234] R Carmel S Melnyk and S J James ldquoCobalamin deficiencywith and without neurologic abnormalities differences inhomocysteine and methionine metabolismrdquo Blood vol 101 no8 pp 3302ndash3308 2003

[235] H G Yang B L Lee Y X Liang Y X Zheng and C N OngldquoThe effects of exposure to aluminium on neurobehaviouralfunction and dopaminergic metabolismrdquo International Journalof Environmental Health Research vol 8 no 2 pp 101ndash110 1998

[236] J Wegiel I Kuchna K Nowicki et al ldquoThe neuropathology ofautism defects of neurogenesis and neuronal migration anddysplastic changesrdquo Acta Neuropathologica vol 119 no 6 pp755ndash770 2010

[237] N Siegel andAHaug ldquoAluminum interactionwith calmodulinEvidence for altered structure and function from optical andenzymatic studiesrdquo Biochimica et Biophysica Acta vol 744 no1 pp 36ndash45 1983

[238] G Topal A Brunet E Millanvoye et al ldquoHomocysteineinduces oxidative stress by uncoupling of no synthase activitythrough reduction of tetrahydrobiopterinrdquo Free Radical Biologyand Medicine vol 36 no 12 pp 1532ndash1541 2004

[239] T J Guzik R Korbut and T Adamek-Guzik ldquoNitric oxide andsuperoxide in inflammation and immune regulationrdquo Journal ofPhysiology and Pharmacology vol 54 no 4 pp 469ndash487 2003

[240] X Li A Chauhan A M Sheikh et al ldquoElevated immuneresponse in the brain of autistic patientsrdquo Journal of Neuroim-munology vol 207 no 1-2 pp 111ndash116 2009

[241] S Y Lo X Geng and D Gann ldquoEvidence for the existenceof stable-water-clusters at room temperature and normal pres-surerdquo Physics Letters A General Atomic and Solid State Physicsvol 373 no 42 pp 3872ndash3876 2009

[242] S Y Lo and B Bonavida ldquoPhysical chemical and biologicalproperties of stable water IE clustersrdquo in Procedings of the 1stInternational Symposium on Physical Chemical and BiologicalProperties of Stable Water (IE) Clusters p 212 World ScientificSingapore 1998

[243] J K Kern and A M Jones ldquoEvidence of toxicity oxidativestress and neuronal insult in autismrdquo Journal of Toxicology andEnvironmental Health B vol 9 no 6 pp 485ndash499 2006


[244] M J Caulfield L Shi S Wang et al ldquoEffect of alternativealuminum adjuvants on the absorption and immunogenicity ofHPV16 L1 VLPs inmicerdquoHumanVaccines vol 3 no 4 pp 139ndash145 2007

[245] E B Lindblad ldquoAluminium adjuvantsmdashin retrospect andprospectrdquo Vaccine vol 22 no 27-28 pp 3658ndash3668 2004

[246] H HogenEsch ldquoMechanisms of stimulation of the immuneresponse by aluminum adjuvantsrdquo Vaccine vol 20 no 3 ppS34ndashS39 2002

[247] J M Brewer and J Alexander ldquoCytokines and the mechanismsof action of vaccine adjuvantsrdquo Cytokines Cellular amp MolecularTherapy vol 3 no 4 pp 233ndash246 1997

[248] J M Brewer M Conacher C A Hunter M Mohrs FBrombacher and J Alexander ldquoAluminium hydroxide adjuvantinitiates strong antigen-specificTh2 responses in the absence ofIL-4- or IL-13-mediated signalingrdquo Journal of Immunology vol163 no 12 pp 6448ndash6454 1999

[249] S Wang X Liu K Fisher et al ldquoEnhanced type I immuneresponse to a hepatitis B DNA vaccine by formulation withcalcium- or aluminum phosphaterdquo Vaccine vol 18 no 13 pp1227ndash1235 2000

[250] T Dunning ldquoAccurate methods for the statistics of surprise andcoincidencerdquo Computational Linguistics vol 19 p 6174 1993

[251] K M Jan and S Chien ldquoRole of surface electric charge in redblood cell interactionsrdquo Journal of General Physiology vol 61no 5 pp 638ndash654 1973

[252] GOliver andMDetmar ldquoThe rediscovery of the lymphatic sys-tem old and new insights into the development and biologicalfunction of the lymphatic vasculaturerdquoGenes and Developmentvol 16 no 7 pp 773ndash783 2002

[253] MW Peterson P Stone andDM Shasby ldquoCationic neutrophilproteins increase transendothelial albuminmovementrdquo Journalof Applied Physiology vol 62 no 4 pp 1521ndash1530 1987

[254] G F Liptrot Modern Inorganic Chemistry Mills amp BoonsLondon UK 1974

[255] R B Martin ldquoTernary complexes of Al3+ and Fminus with a thirdligandrdquo Coordination Chemistry Reviews vol 149 pp 23ndash321996

[256] A Strunecka and J Patocka ldquoAluminofluoride complexes auseful tool in laboratory investigations but a hidden dangerfor living organismsrdquo in Group 13 Chemistry FundamentalResearch Material Science and Catalysis P Shapiro and DAtwood Eds vol 822 of ACS Symposium Series chapter 192002

[257] A Strunecka R Blaylock and J Patocka ldquoAluminofluoridecomplexes phosphate analogues and a hidden hazard for livingorganismsrdquo Current Inorganic Chemistry vol 2 pp 8ndash18 2012

[258] A Strunecka and J Patocka ldquoChapter 19rdquo in Group 13 Chem-istry Fundamental Research Material Science and Catalysis PShapiro andD Atwood Eds ACS Symposium Series 822 2002

[259] M Bubis ldquoFacilitation and inhibition of G-protein regulatedprotein secretion by melatoninrdquo Neurochemistry Internationalvol 27 no 2 pp 177ndash183 1995

[260] H E Hamm ldquoThe many faces of G protein signalingrdquo TheJournal of Biological Chemistry vol 273 no 2 pp 669ndash6721998

[261] N Wettschureck and S Offermanns ldquoMammalian G proteinsand their cell type specific functionsrdquo Physiological Reviews vol85 no 4 pp 1159ndash1204 2005

[262] A Strunecka and J Patocka ldquoAluminofluoride complexes in theetiology of Alzheimerrsquos diseaserdquo Structure and Bonding vol 104pp 139ndash180 2003

[263] J A Varner K F Jensen W Horvath and R L IsaacsonldquoChronic administration of aluminum-fluoride or sodium-fluoride to rats in drinking water alterations in neuronal andcerebrovascular integrityrdquo Brain Research vol 784 no 1-2 pp284ndash298 1998

[264] SMacNeil T Lakey and S Tomlinson ldquoCalmodulin regulationof adenylate cyclase activityrdquo Cell Calcium vol 6 no 3 pp 213ndash226 1985

[265] L Lyras N J Cairns A Jenner P Jenner and B HalliwellldquoAn assessment of oxidative damage to proteins lipids andDNA in brain from patients with Alzheimerrsquos diseaserdquo Journalof Neurochemistry vol 68 no 5 pp 2061ndash2069 1997

[266] D A Butterfield J Drake C Pocernich and A Castegna ldquoEvi-dence of oxidative damage in Alzheimerrsquos disease brain centralrole for amyloid 120573-peptiderdquo Trends in Molecular Medicine vol7 no 12 pp 548ndash554 2001

[267] PMecocci UMacGarvey andM F Beal ldquoOxidative damage tomitochondrial DNA is increased inAlzheimerrsquos diseaserdquoAnnalsof Neurology vol 36 no 5 pp 747ndash751 1994

[268] T Kurz A Terman B Gustafsson andU T Brunk ldquoLysosomesand oxidative stress in aging and apoptosisrdquo Biochimica etBiophysica ActamdashGeneral Subjects vol 1780 no 11 pp 1291ndash1303 2008

[269] R Castellani K Hirai G Aliev et al ldquoRole of mitochondrialdysfunction in Alzheimerrsquos diseaserdquo Journal of NeuroscienceResearch vol 70 no 3 pp 357ndash360 2002

[270] P I Moreira C Carvalho X Zhu M A Smith and G PerryldquoMitochondrial dysfunction is a trigger of Alzheimerrsquos diseasepathophysiologyrdquo Biochimica et Biophysica Acta MolecularBasis of Disease vol 1802 no 1 pp 2ndash10 2010

[271] S Reitsma D W Slaaf H Vink M A M J Van Zandvoortand M G A Oude Egbrink ldquoThe endothelial glycocalyxcomposition functions and visualizationrdquo Pflugers ArchivEuropean Journal of Physiology vol 454 no 3 pp 345ndash3592007

[272] M Nieuwdorp M C Meuwese H L Mooij et al ldquoMeasuringendothelial glycocalyx dimensions in humans a potential noveltool to monitor vascular vulnerabilityrdquo Journal of AppliedPhysiology vol 104 no 3 pp 845ndash852 2008

[273] R D Rosenberg N W Shworak J Liu J J Schwartz and LZhang ldquoHeparan sulfate proteoglycans of the cardiovascularsystem specific structures emerge but how is synthesis regu-latedrdquo The Journal of Clinical Investigation vol 100 no 11 ppS67ndashS75 1997

[274] M J Lee SThangada J H Paik et al ldquoAkt-mediated phospho-rylation of the G protein-coupled receptor EDG-1 is requiredfor endothelial cell chemotaxisrdquoMolecular Cell vol 8 no 3 pp693ndash704 2001

[275] X Han D M Holtzman D W McKeel Jr J Kelley andJ C Morris ldquoSubstantial sulfatide deficiency and ceramideelevation in very early Alzheimerrsquos disease potential role indisease pathogenesisrdquo Journal of Neurochemistry vol 82 no 4pp 809ndash818 2002

[276] T J Taylor C Hartley P Simon I Z Kiss and L BerthouzeldquoIdentification of criticality in neuronal avalanches I A theo-retical investigation of the non-driven caserdquo Journal of Mathe-matical Neuroscience vol 3 article 5 2013

[277] S V Buldyrev R Parshani G Paul H E Stanley and S HavlinldquoCatastrophic cascade of failures in interdependent networksrdquoNature vol 464 no 7291 pp 1025ndash1028 2010

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of


StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of



Advances in Pharmacological Sciences

Tropical MedicineJournal of


Medicinal ChemistryInternational Journal of


AddictionJournal of



BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Autoimmune Diseases


Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of


Pharmaceutics


MEDIATORSINFLAMMATION

of


[15 16] and thousands of material products including foilsfood containers and utensils

In this paper we will show that Al is harmful to the CNSacting in a number of deleterious ways and across multiplelevels to induce biosemiotic entropy [17] A countervailingview exists [18ndash20] but the assertions of safety are invariablybased onweak epidemiological designs ones that overwhelmsignificant negative signals with irrelevant noise factorsSuch studies that fail to detect significant negative outcomesneither stand up to rigorous scrutiny nor outweigh betterdesigned research in a vast and growing literature showingsignificant negative impacts sustaining the central hypothesisof this paper Irrefutable research evidence shows that Alexposure is harmful Further results discussed in this papershow that it is counterfactual for researchers to argue that Alis universally safe or beneficial even in trace amounts

Al is used extensively in food processing for examplein Al-mordanted dye lakes for food coloring in coatings forpharmaceutical tablets and vitamin capsules for emulsifyingas a rising agent to thicken gravies and in meat-bindersstabilizing agents and texturizers [18] Even drinking wateris a source of Al exposure although the amount containedin drinking water is typically far below concentrations incommon antacids [21] However there is concern that theAl in drinking water may be more easily absorbed than atmealtime due to the fact that an empty stomach promotesabsorption [21] Alum (Al sulfate or Al potassium sulfate) iscommonly used in water treatment plants as a coagulant toallow negatively charged colloidal particles to clump togetherfor easy removal Epidemiological studies have shown thatpeople living in districts with higher Al burden in drinkingwater are more likely to be diagnosed with Alzheimerrsquosdisease [22]

Because tea plants contain a higher concentration ofAl than many other plants and because tea beverages areconsumed in large quantities worldwide a high incidenceof Al exposure comes through drinking tea [23] Al contentin tea ranges from 2 to 6mgL [24] Tea infusions havebeen analyzed for the speciation of Al content and it hasbeen determined that it is typically bound to large organicmolecules such as polyphenols or to citrate [24 25] Teatypically contains much more Al than water and so teabecomes a significant source of Al for heavy tea drinkersAn experiment to estimate oral Al bioavailability from teainvolving 8 rats was conducted by injecting Al citrate intotea leaves delivering approximately the same amount of Alas is inherently found in tea leaves (05 to 1mggm) [26] Thebrewed tea was administered through intragastric infusionFollowing infusion peak serum levels of Al were up to 1500-fold above mean pretreatment values

In a substantial and recent review of research Walton[27] concludes that Alzheimerrsquos disease is a manifestation ofchronic Al neurotoxicity in humans Because Al is similarto iron it gains access to iron-dependent cells involved inmemory As it accumulates over time in such cells it causesmicrotubule depletion and disables neuronal afferents andefferents resulting in themultiregion atrophy characteristic ofAlzheimerrsquos pathology [27] Table 1 highlights some of the Alcompounds to which humans are commonly exposed which

are known to have deleterious effects on the central nervoussystems (CNS) of both animals and humans [28] whereasTables 2 and 3 respectively present Al intake data and itsphysical properties compared to other metals Table 1 alsoshows dosage and known effects of each source on animalsandor humans

Al in all of the forms studied as Table 1 shows producesharmful effects in living organisms it especially harms theCNS In studies involving in vitro cultures of neuronal-glialcells the ROS-generating capabilities of several physiolog-ically relevant neurotoxic factors were compared [29 30]It was found that Al-sulfate was the most potent singlemetal sulfate inducer of ROS as well as the most potentcombinatorial inducer in conjunction with Fe Nanomolarconcentrations of Al were sufficient to induce ROS and proin-flammatory gene expression Nanomolar concentrations ofAl-sulfate upregulated the expression of several genes impli-cated in Alzheimerrsquos disease including proinflammatory andproapoptotic gene expression [30]

Given the fact that there are no known biochemical reac-tions that require Al should it be surprising that introducingit into living organisms commonly leads to pathologicaloutcomes [31ndash46] Because of its +3 charge Al attractsnegatively charged ions and electrons but because it cannottransition to other oxidation states besides +3 it is not a com-ponent in any redox reactions Oxygen carbon hydrogennitrogen calcium andphosphorous constitute 99of humanbody mass with the remaining 1 consisting of potassiumsulfur sodium chlorine and magnesium as well as traceelements such as fluorine selenium and zinc and xenobiotic(biologically foreign and usually toxic) elements such astitaniummercury and lead [47]ThusAl can endup inmanybiochemical contexts in theory but in fact some atoms andmolecules are far more likely to react with Al compounds[48] Among the most vulnerable molecules are those mostdirectly involved in self-ordering self-assembling systems ofbiosemiotics that work like multilayered interrelated lan-guages The best known macromolecules that are susceptibleto minute but often disabling injuries by Al compounds areDNA molecules that must be translated via the assistance ofa growing multitude of RNA molecules into proteins Thelatter in turn are essential to the structure and functions ofthe whole society of cells [49] tissues and organ systemsFormerly it was thought following the Crick dogma [50]that communications were essentially a one-way street fromDNA to RNA to protein but it has more recently beenargued [17 51 52] that communications involve more com-plex bidirectional interactions among thosemacromoleculessuch that the genome is informed concerning what is goingon in the environment The dynamical matrix of negativecharge densities in heparan sulfate proteoglycans (HSPGs) asmodulated in time and space by interfacial water exchangingbetween the first few solvation layers and bulk might proveto be the supramolecular physical basis for informing thegenome over distance [53]

There are estimated to be 20000ndash25000 protein codinggenes in the human genome [54] and even more variantproteins possible through posttranslational modificationsestimated to be upwards of 100000 Thus there are many


Table1Com

mon

sourceso

fAlcom

poun

dsandtheirimmun


mansa

ndanim

als

Aluminum

sourcecom

poun

dDoseamp

duratio

nRo

ute

Species

Adversee

ffects

Standard

infant

feedingsolutio

nsim20120583gkgday

gt10

days

Intravenou

s(parenteral)

Hum

anpremature

infants

Redu

ceddevelopm

entalatta

inmentatthe

correctedpo

st-term

ageo

f18

mon

thsas

evidencedby

significantly

lower

Bayley

Mental

Develo

pmentInd

ex(BMDI)scores

(meanlossof

onep

oint

onthe

BMDId

ayof

fullintravenou

sfeeding

afte

radjustm

entfor

potentially

confou


infantsfed

with

Al-d

epleted

solutio

ns[31]

Al-c

ontainingdialysis

fluid

(derived

from

Al-sulfatetre

ated

tap

water)

1ppm

chron

ic(2ndash5

years)

Intravenou

s

Hum

andialysis

patie

nts

(15ndash61

yearso

ldatthe

starto

fthe

dialysis

treatment)

Speech

impairm

ents(stutte


motor

aphasia

)movem

entd


morsmyoclo

nicjerks

seizuresand

motor

apraxia)cognitiv

eimpairm

entsandbehaviou

ral


ementia

paranoiaconfusion

andpsycho

sis)

anddeath[32]

Al-c

ontaining

antacids

Chronic

Oral

Hum

aninfants

Craniosyno

stosis

(prematureo

ssificatio

nof

thes

kullandob

literation

ofthes

utures)[33]

Vario

usdietary

Chronic

Oral

Elderly

human

subjects

Impaire

dvisuom

otor

coordinatio

npo

orlong

-term

mem

oryand


flicker

(correlated

with

high

Al-serum

levels)

[34]

Alsulfate

(present

asflo

cculant

inpo

tablew

ater

supp

liesaccidentally

released

inhigh

amou

nts)

500ndash

3000

xthe

acceptablelim

itun

der

European

Union

Legisla

tion

(0200

mgL)chron

ic(15years)

Oral

Hum

anadult(female44

yearso

ld)

Sporadicearly

-onset120573am

yloidangiop

athy

(Alzh

eimerrsquos-related

disease)diffi

culty

infin

ding

wordsprogressiv

edem

entia

visu

alhallu

cinatio


hemiaand

death[35]

Al-c

ontainingfood

pellets

05ndash17

mgkgday

(typicalhum

an)

chronic(22ndash32

mon

ths)

Oral

Rats

6mon

thso

ldatthe

startof

treatment

Cognitiv

edeterioratio

nandim

paire

dperfo

rmance

inlearning

tasks

impaire

dconcentration


confusion

andrepetitiveb

ehaviour

[36]

Allactate

500ndash

1000

ppm

chronic(du

ring

gesta

tionand

lactation)

Oral

Miced

ams

Hindlim

bparalysis


s)low

erneurob

ehaviorald

evelo

pmentand

alteredperfo

rmance

ona

neurob

ehavioraltestb

attery

inpu

ps(fo

otsplayforelim

bandhind

limbgrip

strengths

redu

ced)

[37]


Table1Con

tinued

Aluminum

sourcecom

poun

dDoseamp

duratio

nRo

ute

Species

Adversee

ffects

Alhydroxide

asa

vaccinea

djuvant

1ndash17

doseso

fAl-c

ontaining

vaccines

(hepatitisB

hepatitisAand

tetanu

stoxoid)

inthe

perio

dof

10years

priortodisease

diagno

sis

Intram

uscular

injection

Hum

anadult

macroph

agic

myofasciitis(M

MF)

synd

romep

atients

(meanage4

5years)

MMFtypicalclin

icalmanifestationsm


fatig

ue(disa

blingfatig

uegt6mon

ths)m

uscle

weakn

essa

ndcogn

itive

dysfu

nctio

n(overtcogn

itive

alteratio

nsaffectin

gmem

oryand

attentionmanifeste

din

51of

cases)[38ndash41]

Typicalh

istop

atho

logypresenceo

fgranu

lomatou

smyopathological

lesio

ncomprise

dof

Al-h

ydroxide-lo

aded

macroph

ages

atthes

iteof

vaccineinjectio

n(usuallydelto

idmuscle

)persistence

ofAl

long

-term

upto

8ndash10

yearsinpo


15ndash20

MMFpatie

ntsc

oncurrently

developan

autoim

mun

edise

ase

mostfrequ

ently

beingmultip

lesclerosis

-like

demyelin

atingdisorders

Hashimotorsquos

thyroiditisand

diffu

sedysim

mun

eneuromuscular

diseases

(ie

derm

atom

yositis

necrotizingautoim

mun

emyopathy

myastheniag

ravisandinclu

sionbo

dymyositis)evenin

thea

bsence

ofovertautoimmun

edise

aselowtitreso

fautoantibod

iesincreased

inflammatorybiom

arkersand

abno

rmaliro

nsta

tusc

ommon

lydetected

inexpo

sedmice[3839]

Alhydroxide

asa

vaccinea

djuvant

14injections

over

a6-mon

thperio

dSubcutaneous

Sheepmale3

mon

thold

lambs

ldquoSheep

adjuvant

synd


edfollo

wing


lueton

gueexperim

entally

reprod

uced


nwith

Al-c

ontainingvaccines

[14]ob

served

inacuteform

(affecting25of

expo

sedflo

cks05

anim

alsw

ithin

aflo

ck)a

ndchronicp

hase

form

(affecting50ndash70

ofallexp

osed

flocks

andup

to100

ofanim

alsw

ithin

agiven

flock)

Acutep

hase

symptom

slethargyrelu

ctance

tomovebrux

ism(te

eth

grinding

)transie

ntblindn

essnystagmus

(rapid

abno

rmaleye

movem

ents)

stupo

rabno

rmalbehaviordiso

rientation

andalow

respon

seto

externalstim

uliseizuresand

occasio

nally

death

histo

pathologicallesio


acute

meningoenceph

alitis(sim

ilartothoseo

bservedin

humans

postv

accinatio

n)anddemyelin

atingfoci

Chronicp

hase

symptom

ssevere

neurob

ehavioraloutcomes

inclu

ding

restlessnesscom

pulsive

woo

lbiting

generalized

weakn

ess

muscle

tremorslossof

respon

seto


(paralysisof

allfou

rlim

bs)stu


lesio

ns(m

ultifocalneuron

alnecrosisandneuron

lossin

both

dorsal

andventralcolum

nof

theg


ofAlinCN

Stissues

[43]


Table1Con

tinued

Aluminum

sourcecom

poun

dDoseamp

duratio

nRo

ute

Species

Adversee

ffects

Alhydroxide

asa

vaccinea

djuvant

2injections

2weeks

apart

Subcutaneous

injection(behindthe

neck)

Mice3mon

thso

ldCD

-1male

Motor

neuron

degeneratio

nandapop

tosism

otor

functio

ndeficits

decrease

instreng

thcognitiv

edeficits

anddecreasedperfo

rmance

inlearning

tasksdecrem

entsin

spatialm

emoryactiv

ationof

microglia

[4445]

Aloxide

fumes

occupatio

nal

expo

sure

013ndash195m

gm

3 chronic

Inhalatio

nHum

anadu

lts(m

eanage3

9years)

Headacheem


nia

moo

dlability[46]












intake (mgday)


PTWI = 70mg)




7ndash140(700)

01ndash2(10)

25ndash50 120583g(250 120583g)










737714507[7732]

57751816727448[11577]

589811454[49124]

71731509[3248]

762615619[2957]

76041648[3232]

906417333[3833]




magneticFerro

magnetic minus915



















































120583

p

+

(a)

minus

120583

p

(b)

+

minus

(c)


Gd3+

Xminus

R+












3

1minus or SO4














2]2+





minus312 [198]K+

minus321 [197]NH4+

minus329 [198]HSO4

minusminus368 [198]


minusminus384 [198]


minusminus522 [198]

SO42minus

minus1035 [198]H+




119867 = minus

119885119890

2

2119903

(1 minus

1

)

(1)








3after

































2







4


4


4


4

minus


4



4



eNOS

CaMGPCR

GDP

Activator minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

(a)

eNOS

Al

Al

Al

GPCRAl


NO

NO

NO

NO

NO

NO

Activator

P

CaMAl

FminusFminusFminus

Fminus

(b)


4







4 Discussion















5 Conclusions





















MolecularGenome

Protein

CellCircuitSystem

CNS



Highlights






Disclosure




Acknowledgments



References










































































































































































































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


Table1Com

mon

sourceso

fAlcom

poun

dsandtheirimmun


mansa

ndanim

als

Aluminum

sourcecom

poun

dDoseamp

duratio

nRo

ute

Species

Adversee

ffects

Standard

infant

feedingsolutio

nsim20120583gkgday

gt10

days

Intravenou

s(parenteral)

Hum

anpremature

infants

Redu

ceddevelopm

entalatta

inmentatthe

correctedpo

st-term

ageo

f18

mon

thsas

evidencedby

significantly

lower

Bayley

Mental

Develo

pmentInd

ex(BMDI)scores

(meanlossof

onep

oint

onthe

BMDId

ayof

fullintravenou

sfeeding

afte

radjustm

entfor

potentially

confou


infantsfed

with

Al-d

epleted

solutio

ns[31]

Al-c

ontainingdialysis

fluid

(derived

from

Al-sulfatetre

ated

tap

water)

1ppm

chron

ic(2ndash5

years)

Intravenou

s

Hum

andialysis

patie

nts

(15ndash61

yearso

ldatthe

starto

fthe

dialysis

treatment)

Speech

impairm

ents(stutte


motor

aphasia

)movem

entd


morsmyoclo

nicjerks

seizuresand

motor

apraxia)cognitiv

eimpairm

entsandbehaviou

ral


ementia

paranoiaconfusion

andpsycho

sis)

anddeath[32]

Al-c

ontaining

antacids

Chronic

Oral

Hum

aninfants

Craniosyno

stosis

(prematureo

ssificatio

nof

thes

kullandob

literation

ofthes

utures)[33]

Vario

usdietary

Chronic

Oral

Elderly

human

subjects

Impaire

dvisuom

otor

coordinatio

npo

orlong

-term

mem

oryand


flicker

(correlated

with

high

Al-serum

levels)

[34]

Alsulfate

(present

asflo

cculant

inpo

tablew

ater

supp

liesaccidentally

released

inhigh

amou

nts)

500ndash

3000

xthe

acceptablelim

itun

der

European

Union

Legisla

tion

(0200

mgL)chron

ic(15years)

Oral

Hum

anadult(female44

yearso

ld)

Sporadicearly

-onset120573am

yloidangiop

athy

(Alzh

eimerrsquos-related

disease)diffi

culty

infin

ding

wordsprogressiv

edem

entia

visu

alhallu

cinatio


hemiaand

death[35]

Al-c

ontainingfood

pellets

05ndash17

mgkgday

(typicalhum

an)

chronic(22ndash32

mon

ths)

Oral

Rats

6mon

thso

ldatthe

startof

treatment

Cognitiv

edeterioratio

nandim

paire

dperfo

rmance

inlearning

tasks

impaire

dconcentration


confusion

andrepetitiveb

ehaviour

[36]

Allactate

500ndash

1000

ppm

chronic(du

ring

gesta

tionand

lactation)

Oral

Miced

ams

Hindlim

bparalysis


s)low

erneurob

ehaviorald

evelo

pmentand

alteredperfo

rmance

ona

neurob

ehavioraltestb

attery

inpu

ps(fo

otsplayforelim

bandhind

limbgrip

strengths

redu

ced)

[37]


Table1Con

tinued

Aluminum

sourcecom

poun

dDoseamp

duratio

nRo

ute

Species

Adversee

ffects

Alhydroxide

asa

vaccinea

djuvant

1ndash17

doseso

fAl-c

ontaining

vaccines

(hepatitisB

hepatitisAand

tetanu

stoxoid)

inthe

perio

dof

10years

priortodisease

diagno

sis

Intram

uscular

injection

Hum

anadult

macroph

agic

myofasciitis(M

MF)

synd

romep

atients

(meanage4

5years)

MMFtypicalclin

icalmanifestationsm


fatig

ue(disa

blingfatig

uegt6mon

ths)m

uscle

weakn

essa

ndcogn

itive

dysfu

nctio

n(overtcogn

itive

alteratio

nsaffectin

gmem

oryand

attentionmanifeste

din

51of

cases)[38ndash41]

Typicalh

istop

atho

logypresenceo

fgranu

lomatou

smyopathological

lesio

ncomprise

dof

Al-h

ydroxide-lo

aded

macroph

ages

atthes

iteof

vaccineinjectio

n(usuallydelto

idmuscle

)persistence

ofAl

long

-term

upto

8ndash10

yearsinpo


15ndash20

MMFpatie

ntsc

oncurrently

developan

autoim

mun

edise

ase

mostfrequ

ently

beingmultip

lesclerosis

-like

demyelin

atingdisorders

Hashimotorsquos

thyroiditisand

diffu

sedysim

mun

eneuromuscular

diseases

(ie

derm

atom

yositis

necrotizingautoim

mun

emyopathy

myastheniag

ravisandinclu

sionbo

dymyositis)evenin

thea

bsence

ofovertautoimmun

edise

aselowtitreso

fautoantibod

iesincreased

inflammatorybiom

arkersand

abno

rmaliro

nsta

tusc

ommon

lydetected

inexpo

sedmice[3839]

Alhydroxide

asa

vaccinea

djuvant

14injections

over

a6-mon

thperio

dSubcutaneous

Sheepmale3

mon

thold

lambs

ldquoSheep

adjuvant

synd


edfollo

wing


lueton

gueexperim

entally

reprod

uced


nwith

Al-c

ontainingvaccines

[14]ob

served

inacuteform

(affecting25of

expo

sedflo

cks05

anim

alsw

ithin

aflo

ck)a

ndchronicp

hase

form

(affecting50ndash70

ofallexp

osed

flocks

andup

to100

ofanim

alsw

ithin

agiven

flock)

Acutep

hase

symptom

slethargyrelu

ctance

tomovebrux

ism(te

eth

grinding

)transie

ntblindn

essnystagmus

(rapid

abno

rmaleye

movem

ents)

stupo

rabno

rmalbehaviordiso

rientation

andalow

respon

seto

externalstim

uliseizuresand

occasio

nally

death

histo

pathologicallesio


acute

meningoenceph

alitis(sim

ilartothoseo

bservedin

humans

postv

accinatio

n)anddemyelin

atingfoci

Chronicp

hase

symptom

ssevere

neurob

ehavioraloutcomes

inclu

ding

restlessnesscom

pulsive

woo

lbiting

generalized

weakn

ess

muscle

tremorslossof

respon

seto


(paralysisof

allfou

rlim

bs)stu


lesio

ns(m

ultifocalneuron

alnecrosisandneuron

lossin

both

dorsal

andventralcolum

nof

theg


ofAlinCN

Stissues

[43]


Table1Con

tinued

Aluminum

sourcecom

poun

dDoseamp

duratio

nRo

ute

Species

Adversee

ffects

Alhydroxide

asa

vaccinea

djuvant

2injections

2weeks

apart

Subcutaneous

injection(behindthe

neck)

Mice3mon

thso

ldCD

-1male

Motor

neuron

degeneratio

nandapop

tosism

otor

functio

ndeficits

decrease

instreng

thcognitiv

edeficits

anddecreasedperfo

rmance

inlearning

tasksdecrem

entsin

spatialm

emoryactiv

ationof

microglia

[4445]

Aloxide

fumes

occupatio

nal

expo

sure

013ndash195m

gm

3 chronic

Inhalatio

nHum

anadu

lts(m

eanage3

9years)

Headacheem


nia

moo

dlability[46]












intake (mgday)


PTWI = 70mg)




7ndash140(700)

01ndash2(10)

25ndash50 120583g(250 120583g)










737714507[7732]

57751816727448[11577]

589811454[49124]

71731509[3248]

762615619[2957]

76041648[3232]

906417333[3833]




magneticFerro

magnetic minus915



















































120583

p

+

(a)

minus

120583

p

(b)

+

minus

(c)


Gd3+

Xminus

R+












3

1minus or SO4














2]2+





minus312 [198]K+

minus321 [197]NH4+

minus329 [198]HSO4

minusminus368 [198]


minusminus384 [198]


minusminus522 [198]

SO42minus

minus1035 [198]H+




119867 = minus

119885119890

2

2119903

(1 minus

1

)

(1)








3after

































2







4


4


4


4

minus


4



4



eNOS

CaMGPCR

GDP

Activator minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

(a)

eNOS

Al

Al

Al

GPCRAl


NO

NO

NO

NO

NO

NO

Activator

P

CaMAl

FminusFminusFminus

Fminus

(b)


4







4 Discussion















5 Conclusions





















MolecularGenome

Protein

CellCircuitSystem

CNS



Highlights






Disclosure




Acknowledgments



References










































































































































































































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


Table1Con

tinued

Aluminum

sourcecom

poun

dDoseamp

duratio

nRo

ute

Species

Adversee

ffects

Alhydroxide

asa

vaccinea

djuvant

1ndash17

doseso

fAl-c

ontaining

vaccines

(hepatitisB

hepatitisAand

tetanu

stoxoid)

inthe

perio

dof

10years

priortodisease

diagno

sis

Intram

uscular

injection

Hum

anadult

macroph

agic

myofasciitis(M

MF)

synd

romep

atients

(meanage4

5years)

MMFtypicalclin

icalmanifestationsm


fatig

ue(disa

blingfatig

uegt6mon

ths)m

uscle

weakn

essa

ndcogn

itive

dysfu

nctio

n(overtcogn

itive

alteratio

nsaffectin

gmem

oryand

attentionmanifeste

din

51of

cases)[38ndash41]

Typicalh

istop

atho

logypresenceo

fgranu

lomatou

smyopathological

lesio

ncomprise

dof

Al-h

ydroxide-lo

aded

macroph

ages

atthes

iteof

vaccineinjectio

n(usuallydelto

idmuscle

)persistence

ofAl

long

-term

upto

8ndash10

yearsinpo


15ndash20

MMFpatie

ntsc

oncurrently

developan

autoim

mun

edise

ase

mostfrequ

ently

beingmultip

lesclerosis

-like

demyelin

atingdisorders

Hashimotorsquos

thyroiditisand

diffu

sedysim

mun

eneuromuscular

diseases

(ie

derm

atom

yositis

necrotizingautoim

mun

emyopathy

myastheniag

ravisandinclu

sionbo

dymyositis)evenin

thea

bsence

ofovertautoimmun

edise

aselowtitreso

fautoantibod

iesincreased

inflammatorybiom

arkersand

abno

rmaliro

nsta

tusc

ommon

lydetected

inexpo

sedmice[3839]

Alhydroxide

asa

vaccinea

djuvant

14injections

over

a6-mon

thperio

dSubcutaneous

Sheepmale3

mon

thold

lambs

ldquoSheep

adjuvant

synd


edfollo

wing


lueton

gueexperim

entally

reprod

uced


nwith

Al-c

ontainingvaccines

[14]ob

served

inacuteform

(affecting25of

expo

sedflo

cks05

anim

alsw

ithin

aflo

ck)a

ndchronicp

hase

form

(affecting50ndash70

ofallexp

osed

flocks

andup

to100

ofanim

alsw

ithin

agiven

flock)

Acutep

hase

symptom

slethargyrelu

ctance

tomovebrux

ism(te

eth

grinding

)transie

ntblindn

essnystagmus

(rapid

abno

rmaleye

movem

ents)

stupo

rabno

rmalbehaviordiso

rientation

andalow

respon

seto

externalstim

uliseizuresand

occasio

nally

death

histo

pathologicallesio


acute

meningoenceph

alitis(sim

ilartothoseo

bservedin

humans

postv

accinatio

n)anddemyelin

atingfoci

Chronicp

hase

symptom

ssevere

neurob

ehavioraloutcomes

inclu

ding

restlessnesscom

pulsive

woo

lbiting

generalized

weakn

ess

muscle

tremorslossof

respon

seto


(paralysisof

allfou

rlim

bs)stu


lesio

ns(m

ultifocalneuron

alnecrosisandneuron

lossin

both

dorsal

andventralcolum

nof

theg


ofAlinCN

Stissues

[43]


Table1Con

tinued

Aluminum

sourcecom

poun

dDoseamp

duratio

nRo

ute

Species

Adversee

ffects

Alhydroxide

asa

vaccinea

djuvant

2injections

2weeks

apart

Subcutaneous

injection(behindthe

neck)

Mice3mon

thso

ldCD

-1male

Motor

neuron

degeneratio

nandapop

tosism

otor

functio

ndeficits

decrease

instreng

thcognitiv

edeficits

anddecreasedperfo

rmance

inlearning

tasksdecrem

entsin

spatialm

emoryactiv

ationof

microglia

[4445]

Aloxide

fumes

occupatio

nal

expo

sure

013ndash195m

gm

3 chronic

Inhalatio

nHum

anadu

lts(m

eanage3

9years)

Headacheem


nia

moo

dlability[46]












intake (mgday)


PTWI = 70mg)




7ndash140(700)

01ndash2(10)

25ndash50 120583g(250 120583g)










737714507[7732]

57751816727448[11577]

589811454[49124]

71731509[3248]

762615619[2957]

76041648[3232]

906417333[3833]




magneticFerro

magnetic minus915



















































120583

p

+

(a)

minus

120583

p

(b)

+

minus

(c)


Gd3+

Xminus

R+












3

1minus or SO4














2]2+





minus312 [198]K+

minus321 [197]NH4+

minus329 [198]HSO4

minusminus368 [198]


minusminus384 [198]


minusminus522 [198]

SO42minus

minus1035 [198]H+




119867 = minus

119885119890

2

2119903

(1 minus

1

)

(1)








3after

































2







4


4


4


4

minus


4



4



eNOS

CaMGPCR

GDP

Activator minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

(a)

eNOS

Al

Al

Al

GPCRAl


NO

NO

NO

NO

NO

NO

Activator

P

CaMAl

FminusFminusFminus

Fminus

(b)


4







4 Discussion















5 Conclusions





















MolecularGenome

Protein

CellCircuitSystem

CNS



Highlights






Disclosure




Acknowledgments



References










































































































































































































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


Table1Con

tinued

Aluminum

sourcecom

poun

dDoseamp

duratio

nRo

ute

Species

Adversee

ffects

Alhydroxide

asa

vaccinea

djuvant

2injections

2weeks

apart

Subcutaneous

injection(behindthe

neck)

Mice3mon

thso

ldCD

-1male

Motor

neuron

degeneratio

nandapop

tosism

otor

functio

ndeficits

decrease

instreng

thcognitiv

edeficits

anddecreasedperfo

rmance

inlearning

tasksdecrem

entsin

spatialm

emoryactiv

ationof

microglia

[4445]

Aloxide

fumes

occupatio

nal

expo

sure

013ndash195m

gm

3 chronic

Inhalatio

nHum

anadu

lts(m

eanage3

9years)

Headacheem


nia

moo

dlability[46]












intake (mgday)


PTWI = 70mg)




7ndash140(700)

01ndash2(10)

25ndash50 120583g(250 120583g)










737714507[7732]

57751816727448[11577]

589811454[49124]

71731509[3248]

762615619[2957]

76041648[3232]

906417333[3833]




magneticFerro

magnetic minus915



















































120583

p

+

(a)

minus

120583

p

(b)

+

minus

(c)


Gd3+

Xminus

R+












3

1minus or SO4














2]2+





minus312 [198]K+

minus321 [197]NH4+

minus329 [198]HSO4

minusminus368 [198]


minusminus384 [198]


minusminus522 [198]

SO42minus

minus1035 [198]H+




119867 = minus

119885119890

2

2119903

(1 minus

1

)

(1)








3after

































2







4


4


4


4

minus


4



4



eNOS

CaMGPCR

GDP

Activator minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

(a)

eNOS

Al

Al

Al

GPCRAl


NO

NO

NO

NO

NO

NO

Activator

P

CaMAl

FminusFminusFminus

Fminus

(b)


4







4 Discussion















5 Conclusions





















MolecularGenome

Protein

CellCircuitSystem

CNS



Highlights






Disclosure




Acknowledgments



References










































































































































































































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of












intake (mgday)


PTWI = 70mg)




7ndash140(700)

01ndash2(10)

25ndash50 120583g(250 120583g)










737714507[7732]

57751816727448[11577]

589811454[49124]

71731509[3248]

762615619[2957]

76041648[3232]

906417333[3833]




magneticFerro

magnetic minus915



















































120583

p

+

(a)

minus

120583

p

(b)

+

minus

(c)


Gd3+

Xminus

R+












3

1minus or SO4














2]2+





minus312 [198]K+

minus321 [197]NH4+

minus329 [198]HSO4

minusminus368 [198]


minusminus384 [198]


minusminus522 [198]

SO42minus

minus1035 [198]H+




119867 = minus

119885119890

2

2119903

(1 minus

1

)

(1)








3after

































2







4


4


4


4

minus


4



4



eNOS

CaMGPCR

GDP

Activator minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

(a)

eNOS

Al

Al

Al

GPCRAl


NO

NO

NO

NO

NO

NO

Activator

P

CaMAl

FminusFminusFminus

Fminus

(b)


4







4 Discussion















5 Conclusions





















MolecularGenome

Protein

CellCircuitSystem

CNS



Highlights






Disclosure




Acknowledgments



References










































































































































































































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of




intake (mgday)


PTWI = 70mg)




7ndash140(700)

01ndash2(10)

25ndash50 120583g(250 120583g)










737714507[7732]

57751816727448[11577]

589811454[49124]

71731509[3248]

762615619[2957]

76041648[3232]

906417333[3833]




magneticFerro

magnetic minus915



















































120583

p

+

(a)

minus

120583

p

(b)

+

minus

(c)


Gd3+

Xminus

R+












3

1minus or SO4














2]2+





minus312 [198]K+

minus321 [197]NH4+

minus329 [198]HSO4

minusminus368 [198]


minusminus384 [198]


minusminus522 [198]

SO42minus

minus1035 [198]H+




119867 = minus

119885119890

2

2119903

(1 minus

1

)

(1)








3after

































2







4


4


4


4

minus


4



4



eNOS

CaMGPCR

GDP

Activator minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

(a)

eNOS

Al

Al

Al

GPCRAl


NO

NO

NO

NO

NO

NO

Activator

P

CaMAl

FminusFminusFminus

Fminus

(b)


4







4 Discussion















5 Conclusions





















MolecularGenome

Protein

CellCircuitSystem

CNS



Highlights






Disclosure




Acknowledgments



References










































































































































































































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of















































120583

p

+

(a)

minus

120583

p

(b)

+

minus

(c)


Gd3+

Xminus

R+












3

1minus or SO4














2]2+





minus312 [198]K+

minus321 [197]NH4+

minus329 [198]HSO4

minusminus368 [198]


minusminus384 [198]


minusminus522 [198]

SO42minus

minus1035 [198]H+




119867 = minus

119885119890

2

2119903

(1 minus

1

)

(1)








3after

































2







4


4


4


4

minus


4



4



eNOS

CaMGPCR

GDP

Activator minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

(a)

eNOS

Al

Al

Al

GPCRAl


NO

NO

NO

NO

NO

NO

Activator

P

CaMAl

FminusFminusFminus

Fminus

(b)


4







4 Discussion















5 Conclusions





















MolecularGenome

Protein

CellCircuitSystem

CNS



Highlights






Disclosure




Acknowledgments



References










































































































































































































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of

































120583

p

+

(a)

minus

120583

p

(b)

+

minus

(c)


Gd3+

Xminus

R+












3

1minus or SO4














2]2+





minus312 [198]K+

minus321 [197]NH4+

minus329 [198]HSO4

minusminus368 [198]


minusminus384 [198]


minusminus522 [198]

SO42minus

minus1035 [198]H+




119867 = minus

119885119890

2

2119903

(1 minus

1

)

(1)








3after

































2







4


4


4


4

minus


4



4



eNOS

CaMGPCR

GDP

Activator minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

(a)

eNOS

Al

Al

Al

GPCRAl


NO

NO

NO

NO

NO

NO

Activator

P

CaMAl

FminusFminusFminus

Fminus

(b)


4







4 Discussion















5 Conclusions





















MolecularGenome

Protein

CellCircuitSystem

CNS



Highlights






Disclosure




Acknowledgments



References










































































































































































































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of











120583

p

+

(a)

minus

120583

p

(b)

+

minus

(c)


Gd3+

Xminus

R+












3

1minus or SO4














2]2+





minus312 [198]K+

minus321 [197]NH4+

minus329 [198]HSO4

minusminus368 [198]


minusminus384 [198]


minusminus522 [198]

SO42minus

minus1035 [198]H+




119867 = minus

119885119890

2

2119903

(1 minus

1

)

(1)








3after

































2







4


4


4


4

minus


4



4



eNOS

CaMGPCR

GDP

Activator minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

(a)

eNOS

Al

Al

Al

GPCRAl


NO

NO

NO

NO

NO

NO

Activator

P

CaMAl

FminusFminusFminus

Fminus

(b)


4







4 Discussion















5 Conclusions





















MolecularGenome

Protein

CellCircuitSystem

CNS



Highlights






Disclosure




Acknowledgments



References










































































































































































































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


120583

p

+

(a)

minus

120583

p

(b)

+

minus

(c)


Gd3+

Xminus

R+












3

1minus or SO4














2]2+





minus312 [198]K+

minus321 [197]NH4+

minus329 [198]HSO4

minusminus368 [198]


minusminus384 [198]


minusminus522 [198]

SO42minus

minus1035 [198]H+




119867 = minus

119885119890

2

2119903

(1 minus

1

)

(1)








3after

































2







4


4


4


4

minus


4



4



eNOS

CaMGPCR

GDP

Activator minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

(a)

eNOS

Al

Al

Al

GPCRAl


NO

NO

NO

NO

NO

NO

Activator

P

CaMAl

FminusFminusFminus

Fminus

(b)


4







4 Discussion















5 Conclusions





















MolecularGenome

Protein

CellCircuitSystem

CNS



Highlights






Disclosure




Acknowledgments



References










































































































































































































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of







3

1minus or SO4














2]2+





minus312 [198]K+

minus321 [197]NH4+

minus329 [198]HSO4

minusminus368 [198]


minusminus384 [198]


minusminus522 [198]

SO42minus

minus1035 [198]H+




119867 = minus

119885119890

2

2119903

(1 minus

1

)

(1)








3after

































2







4


4


4


4

minus


4



4



eNOS

CaMGPCR

GDP

Activator minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

(a)

eNOS

Al

Al

Al

GPCRAl


NO

NO

NO

NO

NO

NO

Activator

P

CaMAl

FminusFminusFminus

Fminus

(b)


4







4 Discussion















5 Conclusions





















MolecularGenome

Protein

CellCircuitSystem

CNS



Highlights






Disclosure




Acknowledgments



References










































































































































































































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of




2]2+





minus312 [198]K+

minus321 [197]NH4+

minus329 [198]HSO4

minusminus368 [198]


minusminus384 [198]


minusminus522 [198]

SO42minus

minus1035 [198]H+




119867 = minus

119885119890

2

2119903

(1 minus

1

)

(1)








3after

































2







4


4


4


4

minus


4



4



eNOS

CaMGPCR

GDP

Activator minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

(a)

eNOS

Al

Al

Al

GPCRAl


NO

NO

NO

NO

NO

NO

Activator

P

CaMAl

FminusFminusFminus

Fminus

(b)


4







4 Discussion















5 Conclusions





















MolecularGenome

Protein

CellCircuitSystem

CNS



Highlights






Disclosure




Acknowledgments



References










































































































































































































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of





3after

































2







4


4


4


4

minus


4



4



eNOS

CaMGPCR

GDP

Activator minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

(a)

eNOS

Al

Al

Al

GPCRAl


NO

NO

NO

NO

NO

NO

Activator

P

CaMAl

FminusFminusFminus

Fminus

(b)


4







4 Discussion















5 Conclusions





















MolecularGenome

Protein

CellCircuitSystem

CNS



Highlights






Disclosure




Acknowledgments



References










































































































































































































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of























2







4


4


4


4

minus


4



4



eNOS

CaMGPCR

GDP

Activator minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

(a)

eNOS

Al

Al

Al

GPCRAl


NO

NO

NO

NO

NO

NO

Activator

P

CaMAl

FminusFminusFminus

Fminus

(b)


4







4 Discussion















5 Conclusions





















MolecularGenome

Protein

CellCircuitSystem

CNS



Highlights






Disclosure




Acknowledgments



References










































































































































































































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of








2







4


4


4


4

minus


4



4



eNOS

CaMGPCR

GDP

Activator minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

(a)

eNOS

Al

Al

Al

GPCRAl


NO

NO

NO

NO

NO

NO

Activator

P

CaMAl

FminusFminusFminus

Fminus

(b)


4







4 Discussion















5 Conclusions





















MolecularGenome

Protein

CellCircuitSystem

CNS



Highlights






Disclosure




Acknowledgments



References










































































































































































































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


eNOS

CaMGPCR

GDP

Activator minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

minus2

(a)

eNOS

Al

Al

Al

GPCRAl


NO

NO

NO

NO

NO

NO

Activator

P

CaMAl

FminusFminusFminus

Fminus

(b)


4







4 Discussion















5 Conclusions





















MolecularGenome

Protein

CellCircuitSystem

CNS



Highlights






Disclosure




Acknowledgments



References










































































































































































































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of














5 Conclusions





















MolecularGenome

Protein

CellCircuitSystem

CNS



Highlights






Disclosure




Acknowledgments



References










































































































































































































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of




















MolecularGenome

Protein

CellCircuitSystem

CNS



Highlights






Disclosure




Acknowledgments



References










































































































































































































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


References










































































































































































































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of






































































































































































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of

































































































































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of



























































































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of
























































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


















































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of










































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of








































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of





Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of

Documents

Aluminum-Induced Entropy in Biological Systems ...people.csail.mit.edu/seneff/Shaw_et_al_JOT_2014.pdf · ReviewArticle Aluminum-Induced Entropy in Biological Systems: Implications