review article toxicant exposure and bioaccumulation: a...

Review ArticleToxicant Exposure and BioaccumulationA Common and Potentially Reversible Cause ofCognitive Dysfunction and Dementia

Stephen J Genuis1 and Kasie L Kelln2

1Faculty of Medicine at the University of Calgary Calgary AB Canada T2N 4N12Faculty of Medicine at the University of Saskatchewan Saskatoon SK Canada S7N 5E5

Correspondence should be addressed to Stephen J Genuis sgenuisualbertaca

Received 25 November 2014 Revised 31 December 2014 Accepted 31 December 2014

Academic Editor Gianfranco Spalletta

Copyright copy 2015 S J Genuis and K L Kelln 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

Juxtaposed alongside the ongoing rise in the incidence and prevalence of dementia is the surge of recent research confirmingwidespread exposure and bioaccumulation of chemical toxicants Evidence from sources such as the Centers for Disease Controlreveals that most people have accrued varying degrees of assorted toxic pollutants including heavy metals flame retardants andpesticide residues within their bodies It has been well established that many of these toxicants have neurodegenerative as wellas neurodevelopmental impact as a result of various pathophysiologic mechanisms including neuronal mitochondrial toxicity anddisruption of neurotransmitter regulation Elimination of stockpiled toxicants from the bodymay diminish adverse toxicant impacton human biology and allow restoration of normal physiological function Incorporating a review of medical literature on toxicantexposure and dementia with a case history of a lead-exposed individual diagnosed with dementia this paper will discuss a muchoverlooked and potentially widespread cause of declining brain function and dementia

1 Introduction

The rising incidence and prevalence of dementia has becomean enormous public health challenge At the 2009 Inter-national Conference on Alzheimerrsquos disease in Vienna DrWilliam Thies Chief Medical and Scientific Officer for theAlzheimerrsquos Association summarized the challenge with hiscomment ldquoThe number of people affected by Alzheimerrsquosand dementia is growing at an epidemic pace and theskyrocketing financial and personal costs will devastate theworldrsquos economies and health care systems and far too manyfamiliesrdquo [1]

A diagnosis of dementia has profound personal and socialimplications for patients and their loved ones The mostcommon type of dementia Alzheimerrsquos disease (AD) occursin about one in every nine people aged 65 and over with acontinued rise in incidence anticipated in the coming years[2] Dementia is associated with high rates of morbidityand mortality and is accompanied by enormous personal

suffering for patients as well as challenging managementproblems for families physicians and health care systems[3] It appears that efforts at prevention and treatment ofdementia for the last two decades have had little effect onthe rising prevalence of this health problem or the qualityof life for many patients suffering with this disorder [3]By integrating information from the medical and scientificliterature with clinical outcomes from a case history of anindividual diagnosed with dementia this paper will discusstoxicant exposure and bioaccumulation a much overlookedand potentially modifiable cause of declining brain functionand dementia

2 Sources of Information

This review was prepared by assessing medical and sci-entific literature from MEDLINEPubMed several booksand toxicology journals conference proceedings govern-ment publications and environmental health periodicals

Hindawi Publishing CorporationBehavioural NeurologyVolume 2015 Article ID 620143 10 pageshttpdxdoiorg1011552015620143

2 Behavioural Neurology

References cited in identified publications were examined foradditional relevant writings Searching techniques includedkeyword searches with terms related to chemical exposureand dementia toxicants and AD (Alzheimerrsquos disease) pol-lutants and neurodegenerative disease environmental healthsciences and the elderly neurotoxicity with poisoning anddetoxification

A primary observation was that limited scientific litera-ture exists on the link between neurodegenerative processesand toxicant bioaccumulation on the pathogenesis involvedas well as the management of degenerative states associ-ated with toxicant accrual The first authorrsquos professionalobservations and published research as an environmentalhealth physicianwere also incorporated into the discussion ofmanagement strategies The format of an integrated clinicalreview was chosen as such reviews play a pivotal role inscientific research and professional practice in emergingmedical issues with limited primary study and unchartedclinical territory [4]

3 Background

Recent evidence has emerged linking the development ofdementia with various inorganic and organic toxicants in ourenvironment [5ndash9] For example a recent report from JAMANeurology found that elevated serum levels of the toxicantDDE (dichlorodiphenyldichloroethylene) a direct reflectionof brain DDE levels [10] are associated with increased sus-ceptibility for developing Alzheimerrsquos disease [10] DDE is apersistent metabolite of the organochlorine compound DDT(dichlorodiphenyltrichloroethane) a pesticide widely usedfollowing World War II DDT was banned in most countriesin the early 1970rsquos because of persistence within the humanorganism and the environment and the consequent adversehealth effects associated with exposure and bioaccumulation[11] Metabolic byproducts of DDT such as DDE continueto be found in serum samples of 75ndash80 of the populationdue to its long half life and continued exposure Peopleremain at risk of exposure by consuming imported foodsfrom countries where DDT is still used as well as frompollution in soil and water sources [11 12]

A growing body of evidence has recently implicatedmany other exposures to organic chemicals as potentialdeterminants in the development of dementia (Table 1)Formaldehyde a common indoor air pollutant off-gassingfrom wood products and various other sources within thehome has been linked to dementia [13ndash15] Exposure tomethanol a potential contaminant of ambient air and somefoodstuffs has also been associated with neurodegenerationin animals [16 17] Some common pharmaceutical exposuresincluding ongoing use of benzodiazepines have been linkedto an increased risk of Alzheimerrsquos disease [18] Variouscommon components of air pollution a widespread problemin many areas of the world have also been implicated in theescalating pandemic of dementia [19]

Many other classes of common bioaccumulative organiccompounds have also been recognized to have neurotoxiceffects including brominated flame retardants (PBDEs) [20]solvents [21] ldquononstickrdquo perfluorinated compounds [22]

Table 1 Exposures potentially associated with neurodegenerativedisease

Metals

Lead [6ndash9 25ndash27 29 35 37 38 47 4863 83 84 87 90 92 104]Mercury [8 25ndash27]Aluminum [7 8 28]Zinc overload [7]Manganese [8 29 47]Arsenic [8 27 29]Tin [8]Copper [30ndash33]

Pesticides

Dichlorodiphenyldichloroethylene [10](DDE)Aldrin [29]Chlordane [29]Heptachlor [29]Rotenone [5 7]Dieldrin [5]Methyl parathion [26]Organophosphates [5 7 26 46 48]Maneb [5 29]Paraquat [5 7 29 46]Pyrethroids [5]

Flame retardantsHexabromocyclododecane [20]Tetrabromobisphenol-A [20]

Brominated [93] Decabromodiphenyl ether [20]6-Hydroxy-221015840441015840-tetrabromodiphenylether [105]

Chlorinated 221015840441015840-tetrachlorobiphenyl [105]Trichloroethylene [7]Carbon disulfide [26 29]

Solvents [48] Toluene [26]Perchloroethylene (PERC) [106]

Pharmaceuticals Anesthetic agents [107]Benzodiazepines [18]

Air pollution [6 47]

Particulate matter [19]Ozone [19]Nitrogen dioxide [19]Second hand smoke [27]Carbon monoxide [8 48]

Plasticizers Phthalate esters [59 93]Bisphenol A [59 93]

Others

Perfluorooctanesulfonic acid (PFOS) [93]Perfluoroctanoic acid (PFOA) [93]Organochlorine compounds [7]Acrylamide [29]Dioxins [25 27]Formaldehyde [13ndash15]Methanol [16 17]

polychlorinated biphenyls (PCBs) [23] and various typesof pesticides [7 24] With further research it remains tobe seen which organic pollutants alone or in combinationwill be significant determinants of the growing epidemic ofdementia

As well as organic compounds the scientific literaturehighlights the myriad adverse effects of various inorganic

Behavioural Neurology 3

toxic elements such as mercury [25ndash27] aluminum [7 828] arsenic [8 27 29] copper [30ndash33] and particularlylead [7 34] Elevated levels of lead have been implicatedin hypertension and linked to vascular causes of memoryimpairment and dementia [35 36] The acquisition storageand retrieval of verbal information also appears to be affectedby cumulative exposure to lead [37] After years of researchon the effects of lead Stewart and Schwartz suggest thefollowing ldquoa significant proportion of what is considered tobe normal age-related cognitive decline may in fact be dueto past exposure to neurotoxicants such as leadrdquo [38] Whilelead is an established neurotoxicant that is associated withneurodevelopmental deficits in children recent evidencesuggests that even low levels of ambient lead exposure inthe air also appears to increase the risk of neurodegenerativedisease [6]

(i) Toxicant Exposure and Bioaccumulation The problem oftoxicant exposure and bioaccumulation in the populationappears to be rising rapidly yet this escalating health threatremains insufficiently recognized bymanywithin themedicalcommunity A recent study by the Centers for DiseaseControl reveals that most American adults and children ofboth genders have bioaccumulated numerous toxic pollu-tants in their body [39] A similar epidemiological studyin Canada also reveals a widespread accrual of assortedtoxicants [40] Furthermore a recent cord-blood study oninfants revealed that at birth most neonates have alreadyaccumulated assorted toxicants reflecting maternal exposure[41] The neurodevelopmental sequelae of such exposurescan be observed in the swelling pandemic of autism [42]and other neurodevelopmental disorders [43 44] Yet whilemost people are aware of the risks associated with toxicantexposure and accrual from pollutants such as nicotine andcadmium found in cigarettes many are not yet apprised ofthe adverse outcomes of exposures to various other chemicalagents that are at least as harmful as what is found in tobacco

Groups such as the Pediatric Academic Societies havebegun to speak out regarding pediatric toxicant exposureannouncing that ldquolow level exposure to environmental toxic-ity may be impacting the functioning of the current genera-tionrdquo [45] However there has been little appreciation withinthe medical community of neurodegenerative toxicants andtheir potential impact on the maturing adult segment ofthe population As well as dementia research continues toelucidate the relationship between environmental toxicantexposure and the development of other neurodegenerativediseases including Parkinsonrsquos Disease Multiple Sclerosisand Amyotrophic Lateral Sclerosis [7 28 30 46ndash48] Table1 provides an overview of some of the chemical toxicants thathave been directly associatedwith neurodegenerative disease

Many assume that in the absence of ongoing exposuretoxicants are eliminated efficiently It has recently beenrecognized however thatmany toxicants including some sol-vents pesticides petrochemicals mycotoxins and assortedsynthetic chemical agents are persistent pollutants with half-lives that can last for many years or even decades [49ndash51] Accordingly the problem of neural decline may be theresult of exposures that occurred long ago With stockpiled

toxicants persistently disrupting normal human processesand physiology it is understandable that the resulting patho-physiology may induce chronic disease

Some challenge the idea that apparently miniscule dosesof toxicant exposures can have such a profound impact onphysiological function there are two important consider-ations in response to this misguided claim First toxicantexposures donot usually occur as single isolated eventsManypeople through occupation or habitat environments arerepeatedly exposed to chemical toxicants and are thereforeaccruing persistent pollutants on an ongoing basis some ofwhich will remain in tissues for decades This is of particularnote with the potential degree of exposure via polluted airas the average adult inhales about 10 thousand liters of airper day Whereas single exposures may be less problematicand perhaps harmless depending on the particular toxicagent and the dose the repeated exposure to toxic agentspresents an accumulated burden or total load to the intricatephysiological functioning of the body [50]

Second it is noteworthy that standard biochemicalswithin our inherent physiology as well as prescribed pharma-ceutical agents are bioactive at levels of parts per billion (ppb)and some at parts per trillion (ppt) For example ethinylestradiol in the birth control pill maintains contraceptive effi-cacy at serum levels below62 to 83 ppt (parts per trillion) [52]It is hardly surprising therefore that serum concentrations ofvarious toxicant chemicals often measured in ppb (one thou-sand times higher than ppt) or parts per million (an orderof magnitude one million times higher than ppt) might havebiological impact on the human organism In review varioustoxicants can have extremely potent physiological impact atseemingly miniscule doses [53] with incremental impact forsome pollutants at increasing levels of accrual [54 55]

(ii) Toxicant Mechanisms of Harm Environmental pollutantsmay disrupt biological function through various destructivepathways Pathophysiological mechanisms of harm includemitochondrial damage [56] oxidative stress [57] cell death[58] neurotransmitter dysregulation [56] endocrine dis-ruption [59] and epigenetic modification [60] Toxicantinduced mitochondrial dysfunction appears to be a primarymechanism of harm in neurodegenerative diseases such asAD [7] Oxidative stress is also an early contributor toneurodegeneration as markers of oxidative stress have beenfound in neurons of AD patients as well as those with mildcognitive impairment [7] Toxicant induced cell death viaapoptosis autophagy and necrosis may initiate or exacerbatethe neurodegenerative process [61] Cell death for exampleis a known consequence of accrual of PBDEs [20]

As plaques formed by deposition of the beta-amyloidpeptide within the brain have been routinely observed inpostmortem assessments of AD patients [62] it has beenhypothesized that Alzheimerrsquosrsquo dementia may be the resultof amyloid plaque buildup around neurons often resultingin cell apoptosis It has been recently recognized howeverthat development of such peptide plaques is often the resultof exposure and bioaccumulation of toxicants such as PBDEs[20] As the brain contains considerable amounts of fatty tis-sue this organ accrues lipophilic compounds such as PBDEs


which are among the most common toxicant exposures sincePBDEs have been used extensively to reduce flammability ineveryday consumer products such asmattresses and furniture(which then off-gas and contaminate individuals)

There is emerging evidence that lead in particularimpairs cell-to-cell communication with neurotransmitterssuch as acetylcholine and glutamate by blocking neuronalcalciumandpotassiumchannels [26] Ratmodels have shownthat lead exposure specifically affects the hippocampus bydecreasing potassium stimulation and release of glutamateand GABA [63] Lead has also been shown to increase thepermeability of the blood brain barrier leaving the brainvulnerable to a variety of other insults [26] Alterations inthe blood brain barrier have been implicated in neurodegen-erative diseases including Parkinsonrsquos Disease AmyotrophicLateral Sclerosis and Alzheimerrsquos Dementia [7]

Many toxicants are known endocrine disruptors someof the most notable disruptors are pesticides such as DDE[64] and plasticizers such as Bisphenol A and phthalates[59] These latter toxicants have also been implicated inneurotoxicity as a result of their hormonal impact on neu-rological function [59] Moreover it has been suggested thatepigenetic alterations resulting from histone modificationfrom exposure to these plasticizers may be a causative mech-anism in toxicant induced neurodegeneration [46] Further-more toxicant induced epigenetic modification has recentlybeen recognized to have transgenerational effects that mayimpact future generations [60] In review through assortedpathophysiological mechanisms toxicants have become aubiquitous but poorly recognized cause of ill-health in the21st century [65]

(iii) Potential Treatments With recent recognition that vari-ous pollutants are neurotoxicants there is emerging consid-eration of outcomes that might be achieved if measures aretaken to eliminate the toxicant burden [66] Recent researchhas highlighted assorted interventions that can be used toeliminate accrued persistent pollutants [67ndash74] Evidence ofneuropsychiatric improvement has been observed with indi-viduals receiving treatment to facilitate toxicant eliminationof retained pollutants such as lead [70] and mercury [75]Preliminary evidence also suggests significant ameliorationof morbidity following interventions to clear toxicants inautistic children contaminated with inorganic pollutants [7677] Assorted other medical states have improved followingtreatment to eliminate persistent toxicants from the body[67 68] Bredesen reports on the reversal of cognitive declinethrough a personalized therapeutic program which incorpo-rates the exclusion of heavy metal toxicity in patients withAD [78] Lowering serum free copper with zinc therapy hasbeen shown to protect against memory impairment in olderadults [31] and Squitti et al further advocate that using low-copper diets may help prevent neurodegenerative memoryimpairment associated with Alzheimerrsquos disease [32 33]

These findings have enormous clinical significance forpatients suffering with dementia As the development ofdementia may follow environmental exposure to and accrualof chemical toxicants a potential approach for patientswith dementia might involve assessing for and eliminating

stockpiled toxicantsThe following case history demonstrateshow investigating for and then addressing the underlyingtoxicant burden improved the quality of life and cognitivefunction of a patient with dementia

4 Case History

A 69-year-old married retired male with complaints ofdiminishing cognitive function severe memory impairmentand profound fatiguewas brought to an environmental healthphysician by his wife and daughter (a nurse) The patient hadseen a neurologist and following the clinical assessment anMRI and a CT scan a diagnosis of dementia was givenTherewas no history of brain injury seizures stroke or substanceabuse

The family indicated that the patient moved to Canadafrom Europe in excellent health in his midtwenties and tooka job in a glass shop making stained-glass windows Soonafter commencing this work which involved the heating ofmetal rims in a confined space with inadequate ventilationthe patient began experiencing progressive mental healthproblems and was diagnosed with bipolar disorder Althoughhe left his job making stained-glass windows he continuedto suffer with recurrent episodes of depression and manicepisodes for the next 35 years Under the care of a psychiatristhe had been treated with lithium for 25 years as well as withantidepressants and mood stabilizers for the bipolar illness

Over the last five years however the patient displayedincreasing cognitive decline with escalatingmemory impair-ment and social isolation He had become increasinglydependent on his family for care and support By the timehe presented to the environmental health clinic he barelyspoke and was not attentive to discussions about his healthWith a diagnosis of irreversible dementia discussion ensuedbetween family and caregivers about potential placement inan extended care facility for the remainder of his life Hismedications at the time of presentation included Quetiapineand Divalproex

Other than signs of profound cognitive decline physicalexamination did not reveal any objective findings except achronic fungal infection of the patientrsquos toenails Variousinvestigations were undertaken as part of the assessmentat the environmental health facility Noteworthy laboratoryresults after provocation testing revealed a significant burdenof the toxic metal lead most likely from exposure while heat-ing lead-containing metal rims in an inadequately ventilatedroom as part of the process of making stained-glass windowsin his previous employment His tests also revealed elevatedferritin immunoglobulin E C-reactive protein and positiveantinuclear antibody all common findings in patients withtoxicant bioaccumulation Aswell his creatininewas elevatedand glomerular filtration rate was decreased likely the resultof years of lithium use

The family was intrigued by the evidence for lead accu-mulation They presented the information to the psychiatristwho refused to believe there was evidence of lead accrualDisparaging in his comments he suggested that this wasnonsense and indicated he would prove this by testing Hedid a blood and urine level for lead and confirmed minimal


amounts of lead on such testing The family presented thisinformation to the environmental health physician prior tocommencing any treatment As was explained to the familyin detail the body has different compartments It is wellrecognized that lead and many other toxicants sequester inlocations such as bone brain and adipose tissue and do nottypically remain in the blood [25] That is there may be anabsence of lead in blood or urine testing with considerableretained stores in tissues Testing for lead accumulationwithin tissues requires provocation testing where stores arefirst mobilized and agents such as DMSA or EDTA are thenused to bind the lead and release it into urine and stool[79 80]

With evidence of lead bioaccumulation therapies todiminish the body burden of this toxic metal were com-menced Various toxicant elimination interventions includ-ing skin depuration [70] oral DMSA [81] and EDTA [82] byrectal suppository were used to get the lead out Nutritionalsupplementation was provided to prevent mineral deficiencya potential occurrence with treatments to eliminate toxicelements The patient and his spouse were educated to makechanges in their lives to preclude ongoing exposure to variouspotential toxicants

Within six months the patient noticed considerableimprovement in memory and mood Within one year oftreatment friends and family concluded he had made adramatic recovery and observed a restoration of his distinc-tive sense of humor The chronic fungal infection in thepatientrsquos toenails resolved spontaneously within 18 monthsof treatment Repeated follow-up provocative metal testingrevealed that excretion of lead had diminished considerablylikely reflecting a decline in the total body burden Lab valuesof ferritin and immunoglobulin E subsequently returned tonormal range within two years The patient and his familywere happy with the results but when the patient felt well andwas able to function he became less compliant and eventuallydiscontinued further treatment to eliminate the total burdenof lead Six years after his initial visit for environmental healthassessment the patient continues to feel well now livingindependently with his spouse and enjoying a good qualityof life

5 Discussion

Cognitive decline associated with lead exposure has beenrecognized for centuries The earliest known descriptionsof lead poisoning in literature originate from the Greekphysician and poet Nikander of Colophon circa 200 BC withdescriptions of health damage due to occupational exposureto this toxicmetal [83] Recent discussion has also consideredthe impact of lead exposure on some historical events It hasbeen hypothesized by some historians for example that thefall of the Roman Empire may have been influenced by anepidemic of lead exposure among Roman aristocracy due tothe presence of this toxic element in pottery utensils waterpiping and drinking vessels for wine [84] Renowned artistVincent Van Gogh was believed to have suffered lead toxicityfrom eating chips of lead-based paint while creating his well-known works of art [85] and after researchers discovered

lead deposited in his hair and bones [86] lead toxicitymay have been a major determinant in the mental healthand auditory afflictions suffered by the celebrated composerLudwig van Beethoven

While the effects of high levels of lead exposure arewell understood a growing body of literature has raisedconcern with very low levels of lead bioaccumulation as well[87 88] Manifestations of lead stockpiling may be silentfor many years and it is now known that even blood levelsbelow 10 ugdL can result in renal dysfunction hypertensionand essential tremor [87] Such low levels of lead werepreviously considered acceptable and safe new evidencehighlighting the adverse effects of very low levels of lead onhuman health has resulted in a significant shift downwardin what is considered to be acceptable levels of exposure[83] This recognition has recently been affirmed with thefinding that even ambient lead exposure from air pollutionhas been associated with developing Alzheimerrsquos disease asdemonstrated by MRI imaging showing hippocampal andentorhinal cortex atrophy [89]

Althoughmany public health initiatives have been under-taken to decrease toxic element exposure in the populationthe bioaccumulation of lead and resulting health problemsare still surprisingly prevalent and patients continue to beexposed from a variety of sources [87] In fact a recentstudy done by the CDC found that 13 of pregnant womenhad blood lead levels above acceptable limits [90] possiblyrelated in some cases to exposure fromcontaminated prenatalsupplements [91]With a prolonged half-life leadmay persistin the body for many years even after absence of continuedexposure [92]

Neurodegenerative Disease and Toxicant Exposure As toxi-cants have the potential to greatly affect neurological function[7] the increasing rates of neurodegenerative diseases inthe population may not be solely due to people survivinglonger but also due to the increasing toxicity from chemicalsin our environment [29] Air pollutants particularly ozoneparticulate matter and nitrogen dioxide have been linked tocognitive decline in older adults living in Los Angeles [19]Although not yet fully understood it has been proposed thatair pollutionmay contribute to brain inflammationmicrogliaactivation and white matter abnormalities [47] While expo-sure to endocrine disrupting chemicals like brominatedflame retardants perfluorinated compounds phthalates andphenols during gestation or early life has been correlatedwith neurotoxic effects in children [93] active research isnow exploring the impact of these toxicants on physiologicneurogenesis in older populations and the associated risk forneurodegeneration [59]

Given that the prevalence of dementia is expected toincrease by 40 percent over the next decade it may beclinically indicated to assess for toxicant bioaccumulation inpatients presenting with cognitive decline One of the mainchallenges with assessments for toxicant accrual with thecentral nervous system however is that serummeasurementsand even adipose tissue biopsies may underestimate andnot be reflective of the burden of pollutants within othertissues such as brain [73 94 95] Accordingly techniques


for mobilization of tissue-based toxicants such as caloricrestriction [96] thermal therapy and exercise may need tobe incorporated into toxicant panel biomonitoring [42]

If toxicant bioaccumulation is evident interventionsshould be undertaken to eliminate the toxicant burden Thismay not only ameliorate symptoms of dementia and cognitivedecline but also may have a positive impact on a variety ofother body systems and help prevent further neurodegenera-tion Such interventions have the potential to greatly impactquality of life for both patients and their families Since ratesof hospitalization for patients with dementia are three timeshigher per year as compared to other older patients withoutdementia [2] the potential benefits to the health care systemare also evident

Medical Education As recent evidence suggests that 70ndash90 of chronic disease is likely related to environmentaldeterminants [97] ample understanding of environmentalhealth science is required for the practice of contemporaryhealth care [98] Although high dose acute poisoning maybe easy to recognize and the effects of such exposures arewell known more subtle low dose and cumulative chronicexposures can be challenging to identify and clinical carerequires knowledge and skills about environmental sourcesof toxicants [99] While a call to incorporate environmentalmedicine into the medical curricula has been in the literaturefor some time [100] such education remains largely absentfrom medical school programs [99] Many physicians arethus ill-equipped to provide environmental health servicesincluding toxicant assessment and elimination to patientspresenting with diverse complaints including neurodegener-ative illness [100]

Formalizing basic environmental medicine education aspart of medical school curricula specialty training andcontinuing medical education for practitioners would helpequip physicians with the knowledge and skills necessary tocorrectly identify varying toxicant exposures in patients Suchtraining would also allow health providers to incorporateevidence-based interventions to facilitate elimination of tox-icants Furthermore this knowledge would allow physiciansto identify patients at risk and provide education regardingprevention of exposure

6 Conclusion

Exposure to and bioaccumulation of various chemical pol-lutants is increasingly being established as a widespreaddeterminant in the development of neurodegenerative ill-ness such as Alzheimerrsquos Disease Despite this recognitionchemical toxicant accrual as an etiological and potentialreversible cause of illness has generally been overlooked inmedicine neurology public health and psychiatry [48 101]While most people recognize that high-dose exposure tovarious chemical agents can alter brain function there isnot yet widespread recognition (other than with cigarettes)that ongoing exposure to low levels of toxic pollutantsand chronic bioaccumulationcan of these agents can causesustained disruption of physiologic function including brainbiology In keeping with recent evidence that the majority of

chronic illness is not primarily genetic but environmental inorigin [97] a lack of etiology-centeredmedicine is sometimesallowing the underlying causes of disease to go unnoticedwhile clinicians focus on symptomatic management [102]

Exposure to toxic substances has historically been rec-ognized as one of the five fundamental etiologies of chronicillness [103] Identification and eradication of underlyingtoxicant burdens can be life-changing for patients and theirfamilies [9] Prior to his treatment and recovery the patientdiscussed in the case history presented in this paperwas beingconsidered for transfer to a long-term care facility in orderto meet his increasing needs for assistance His remarkablerecovery is now allowing him to live independently with hiswife and to enjoy a productive life

Despite expanding attention in major public health andtoxicology journals to the field of toxicant exposures as deter-minants of chronic illness there continues to be a constantstream of new potential pollutants being introduced intothe environment With inadequate scrutiny and regulationprior to release there is often insufficient knowledge of theimplications that such toxicants may have on individual andpublic health [29] Increasing exploration of the potentialimpact of environmental toxicants on current and futuregenerations must be a priority [26]

Our culture has increasingly equated advanced age withsickness and disability If we continue to neglect the impactof a lifetime of environmental pollutants on aging popula-tions we may forego a future of healthy and capable olderadults as is evidenced by the expanding contemporary chal-lenge of neurodegenerative illness Taking a precautionaryapproach and having strategies for prevention of exposureis of paramount importance [26] Furthermore integratingtoxicant etiology-centered approaches to illness may revealthe true underlying cause of the illness [103] and allowphysicians to effectively treat or even reverse disease Thepotential to limit or reverse a condition such as dementiamight have considerable impact on individuals families andpopulation groups

Comprised of about sixty percent fat a concentrationhigher than is found in any organ in healthy individuals thehuman brain is amagnet for lipophilic persistent toxicants Inan age of unprecedented and ubiquitous chemical exposureand bioaccumulation as confirmed bymedical organizationssuch as the Centers for Disease Control [39] and governmentagencies such as Health Canada [40] it is recommended thatall patients with inexplicable cognitive decline and dementiabe investigated for evidence of accrued pollutants and treatedwhen diagnosed to considerably diminish their toxicantburden [73]

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Authorsrsquo Contribution

Stephen J Genuis and Kasie L Kelln have contributed to thepreparation of this paper


References

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[2] 2014 Alzheimerrsquos Disease Facts and Figures Alzheimerrsquos Associ-ation 2014

[3] J Weuve L E Hebert P A Scherr and D A Evans ldquoDeathsin the United States among persons with Alzheimerrsquos disease(2010ndash2050)rdquo Alzheimerrsquos amp Dementia vol 10 no 2 pp e40ndashe46 2014

[4] M P J M Dijkers ldquoThe value of lsquotraditionalrsquo reviews in theera of systematic reviewingrdquo The American Journal of PhysicalMedicine and Rehabilitation vol 88 no 5 pp 423ndash430 2009

[5] M T Baltazar R J Dinis-Oliveira M D L Bastos A MTsatsakis J A Duarte and F Carvalho ldquoPesticides exposure asetiological factors of Parkinsonrsquos disease and other neurodegen-erative diseasesmdasha mechanistic approachrdquo Toxicology Lettersvol 230 pp 85ndash103 2014

[6] L Mah ldquoEfficacy and safety of the anti-PD-1 monoclonalantibodyMK-3475 in 411 patients (pts) withmelanoma (MEL)rdquoJournal of Clinical Oncology vol 32 no 5 supplement 20142014 ASCO Annual Meeting Abstract no LBA9000

[7] J R Cannon and J T Greenamyre ldquoThe role of environmentalexposures in neurodegeneration and neurodegenerative dis-easesrdquo Toxicological Sciences vol 124 no 2 pp 225ndash250 2011

[8] P Schofield ldquoDementia associated with toxic causes andautoimmune diseaserdquo International Psychogeriatrics vol 17 no1 pp S129ndashS147 2005

[9] R Visvanathan ldquoIs it truly dementiardquoThe Lancet vol 357 no9257 article 684 2001

[10] J Richardson A Roy S Shalat et al ldquoElevated serum pesticidelevels and risk for Alzheimer diseaserdquo Journal of AmericanMedical Association Neurology vol 71 pp E1ndashE7 2014

[11] Dichlorodiphenyltrichloroethane (DDT) Centers for DiseaseControl and Prevention 2009

[12] Pesticide Monitoring ProgrammdashFY 2008 Food and DrugAdministration 2008

[13] J Lu J Miao T Su Y Liu and R He ldquoFormaldehyde induceshyperphosphorylation and polymerization of Tau protein bothin vitro and in vivordquo Biochimica et Biophysica Acta (BBA)mdashGeneral Subjects vol 1830 no 8 pp 4102ndash4116 2013

[14] Y Lu H J He J Zhou et al ldquoHyperphosphorylation resultsin tau dysfunction in DNA folding and protectionrdquo Journal ofAlzheimerrsquos Disease vol 37 no 3 pp 551ndash563 2013

[15] J D Rizak Y Ma and X Hu ldquoIs formaldehyde the missing linkin AD pathology The differential aggregation of amyloid-betawith APOE isoforms in vitrordquo Current Alzheimer Research vol11 no 5 pp 461ndash468 2014

[16] M Yang J Lu J Miao et al ldquoAlzheimerrsquos disease and methanoltoxicity (part 1) chronic methanol feeding led to memoryimpairments and tau hyperphosphorylation inmicerdquo Journal ofAlzheimerrsquos disease vol 41 no 4 pp 1117ndash1129 2014

[17] M Yang J Miao J Rizak et al ldquoAlzheimerrsquos disease andmethanol toxicity (part 2) lessons from four rhesus maca-ques (Macaca mulatta) chronically fed methanolrdquo Journal ofAlzheimerrsquos Disease vol 41 no 4 pp 1131ndash1147 2014

[18] S Billioti de Gage B Begaud F Bazin et al ldquoBenzodiazepineuse and risk of dementia prospective population based studyrdquoBritish Medical Journal vol 349 Article ID e6231 2014

[19] N M Gatto VW Henderson H N Hodis et al ldquoComponentsof air pollution and cognitive function inmiddle-aged and olderadults in Los Angelesrdquo NeuroToxicology vol 40 pp 1ndash7 2014

[20] F Al-Mousa and F Michelangeli ldquoSome commonly used bro-minated flame retardants cause Ca2+-atpase inhibition beta-amyloid peptide release and apoptosis in SH-SY5Y neuronalcellsrdquo PLoS ONE vol 7 no 4 Article ID e33059 2012

[21] C F Jin M Haut and A Ducatman ldquoIndustrial solvents andpsychological effectsrdquo Clinics in Occupational and Environmen-tal Medicine vol 4 no 4 pp 597ndash620 2004

[22] E Mariussen ldquoNeurotoxic effects of perfluoroalkylated com-pounds mechanisms of action and environmental relevancerdquoArchives of Toxicology vol 86 no 9 pp 1349ndash1367 2012

[23] H A Tilson P Rao and S Kodavanti ldquoThe neurotoxicity ofpolychlorinated biphenylsrdquoNeuroToxicology vol 19 no 4-5 pp517ndash525 1998

[24] H-A Rother ldquoCommunicating pesticide neurotoxicityresearch findings and risks to decision-makers and the publicrdquoNeuroToxicology vol 45 pp 327ndash337 2014

[25] K-S Liu J-H Hao Y Zeng F-C Dai and P-Q Gu ldquoNeu-rotoxicity and biomarkers of lead exposure a reviewrdquo ChineseMedical Sciences Journal vol 28 no 3 pp 178ndash188 2013

[26] B Walker Jr ldquoNeurotoxicity in human beingsrdquo Journal ofLaboratory and Clinical Medicine vol 136 no 3 pp 168ndash1802000

[27] D O Carpenter and R Nevin ldquoEnvironmental causes ofviolencerdquo Physiology amp Behavior vol 99 no 2 pp 260ndash2682010

[28] S C Bondy ldquoProlonged exposure to low levels of aluminumleads to changes associated with brain aging and neurodegen-erationrdquo Toxicology vol 315 no 1 pp 1ndash7 2014

[29] R Lucchini andNZimmerman ldquoLifetime cumulative exposureas a threat for neurodegeneration need for prevention strategieson a global scalerdquoNeuroToxicology vol 30 no 6 pp 1144ndash11482009

[30] K J Barnham and A I Bush ldquoBiological metals and metal-targeting compounds in major neurodegenerative diseasesrdquoChemical Society Reviews vol 43 no 19 pp 6727ndash6749 2014

[31] G J Brewer ldquoAlzheimerrsquos disease causation by copper toxicityand treatment with zincrdquo Frontiers in Aging Neuroscience vol6 article 92 2014

[32] R Squitti ldquoCopper subtype of Alzheimerrsquos disease (AD)meta-analyses genetic studies and predictive value of non-ceruloplasmim copper in mild cognitive impairment conver-sion to full ADrdquo Journal of Trace Elements in Medicine andBiology vol 28 no 4 pp 482ndash485 2014

[33] R Squitti M Siotto and R Polimanti ldquoLow-copper diet asa preventive strategy for Alzheimerrsquos diseaserdquo Neurobiology ofAging vol 35 supplement 2 pp S40ndashS50 2014

[34] C Exley and T Vickers ldquoElevated brain aluminium andearly onset Alzheimerrsquos disease in an individual occupationallyexposed to aluminium a case reportrdquo Journal of Medical CaseReports vol 8 no 1 article 41 2014

[35] E van Wijngaarden J R Campbell and D A Cory-SlechtaldquoBone lead levels are associated with measures of memoryimpairment in older adultsrdquoNeuroToxicology vol 30 no 4 pp572ndash580 2009

[36] C Patterson J W Feightner A Garcia G-Y R Hsiung CMacKnight and A D Sadovnick ldquoDiagnosis and treatmentof dementia 1 Risk assessment and primary prevention ofAlzheimer diseaserdquo Canadian Medical Association Journal vol178 no 5 pp 548ndash556 2008


[37] M L Bleecker D P Ford K N Lindgren V M HoeseK S Walsh and C G Vaughan ldquoDifferential affects of leadexposure on components of verbal memoryrdquo Occupational andEnvironmental Medicine vol 62 no 3 pp 181ndash187 2005

[38] W F Stewart and B S Schwartz ldquoEffects of lead on the adultbrain a 15-year explorationrdquoTheAmerican Journal of IndustrialMedicine vol 50 no 10 pp 729ndash739 2007

[39] Centers for Disease Control and Prevention Departmentof Health and Human Services Fourth National Report onHuman Exposure to Environmental Chemicals Updated TablesCenters for Disease Control and Prevention Department ofHealth and Human Services Atlanta Ga USA 2013 httpwwwcdcgovexposurereportpdfFourthReport UpdatedTablesMar2013pdf

[40] Health Canada ldquoSecond report on human biomonitoring ofenvironmental chemicals in Canadardquo 2013 httpoccupa-tionalcancercawp-contentuploads2013052ndHumanBio-monitoringReportpdf

[41] Environmental Working Group ldquoToxic Chemicals Found InMinority Cord Bloodrdquo 2009 httpwwwewgorgnewsnews-releases20091202toxic-chemicals-found-minority-cord-blood

[42] D A Rossignol S J Genuis and R E Frye ldquoEnvironmentaltoxicants and autism spectrum disorders a systematic reviewrdquoTranslational Psychiatry vol 4 articel e360 2014

[43] P Grandjean and P Landrigan ldquoDevelopmental neurotoxicityof industrial chemicalsrdquoTheLancet vol 368 no 9553 pp 2167ndash2178 2006

[44] P Grandjean and P J Landrigan ldquoNeurobehavioural effects ofdevelopmental toxicityrdquoThe Lancet Neurology vol 13 no 3 pp330ndash338 2014

[45] D Coury ldquoPediatric Academic societies annual meeting April28-May 1 2001 BaltimoreMaryland USA AbstractsrdquoPediatricResearch vol 49 no 4 part 2 supplement 2001

[46] A Kanthasamy H Jin V Anantharam et al ldquoEmerging neuro-toxic mechanisms in environmental factors-induced neurode-generationrdquo NeuroToxicology vol 33 no 4 pp 833ndash837 2012

[47] M L Block A Elder R L Auten et al ldquoThe outdoor airpollution and brain health workshoprdquoNeuroToxicology vol 33no 5 pp 972ndash984 2012

[48] J Reis and G C Roman ldquoEnvironmental neurology a promis-ing new field of practice and researchrdquo Journal of the Neurolog-ical Sciences vol 262 no 1-2 pp 3ndash6 2007

[49] E L Sabbath L-A Gutierrez C A Okechukwu et al ldquoTimemay not fully attenuate solvent-associated cognitive deficits inhighly exposed workersrdquo Neurology vol 82 no 19 pp 1716ndash1723 2014

[50] S J GenuisM E Sears G Schwalfenberg JHope andR Bern-hoft ldquoClinical detoxification elimination of persistent toxi-cants from the human bodyrdquo The Scientific World Journal vol2013 Article ID 238347 3 pages 2013

[51] J Hope ldquoA review of the mechanism of injury and treat-ment approaches for illness resulting from exposure to water-damaged buildingsmold andmycotoxinsrdquoTheScientificWorldJournal vol 2013 Article ID 767482 20 pages 2013

[52] Drugscom ldquoLevonorgestrel and ethinyl estradiol TABLE IMean (SD) Pharmacokinetic parameters of Levonorgestrel andEthinyl Estradiol tablets over a 21-day dosing periodrdquo 2014httpwwwdrugscomprolevonorgestrel-and-ethinyl-estra-diolhtml

[53] W V Welshons K A Thayer B M Judy J A Taylor EM Curran and F S vom Saal ldquoLarge effects from small

exposures I Mechanisms for endocrine-disrupting chemicalswith estrogenic activityrdquo Environmental Health Perspectives vol111 no 8 pp 994ndash1006 2003

[54] K Steenland S Tinker A Shankar and A Ducatman ldquoAsso-ciation of perfluorooctanoic acid (PFOA) and perfluorooctanesulfonate (PFOS) with uric acid among adults with elevatedcommunity exposure to PFOArdquo Environmental Health Perspec-tives vol 118 no 2 pp 229ndash233 2010

[55] S J Frisbee A Shankar S S Knox et al ldquoPerfluorooctanoicacid perfluorooctanesulfonate and serum lipids in childrenand adolescents results from the C8 health projectrdquo Archives ofPediatrics and Adolescent Medicine vol 164 no 9 pp 860ndash8692010

[56] E A Belyaeva T V Sokolova L V Emelyanova and I OZakharova ldquoMitochondrial electron transport chain in heavymetal-induced neurotoxicity effects of cadmium mercury andcopperrdquo The Scientific World Journal vol 2012 Article ID136063 14 pages 2012

[57] Y W Chen C F Huang C Y Yang C C Yen K S Tsai andS H Liu ldquoInorganic mercury causes pancreatic 120573-cell death viathe oxidative stress-induced apoptotic and necrotic pathwaysrdquoToxicology and Applied Pharmacology vol 243 no 3 pp 323ndash331 2010

[58] Q Huang J Zhang F L Martin et al ldquoPerfluorooctanoic acidinduces apoptosis through the p53-dependent mitochondrialpathway in human hepatic cells a proteomic studyrdquo ToxicologyLetters vol 223 no 2 pp 211ndash220 2013

[59] B Weiss ldquoThe intersection of neurotoxicology and endocrinedisruptionrdquo NeuroToxicology vol 33 no 6 pp 1410ndash1419 2012

[60] C Guerrero-Bosagna and M K Skinner ldquoEnvironmentallyinduced epigenetic transgenerational inheritance of phenotypeand diseaserdquoMolecular and Cellular Endocrinology vol 354 no1-2 pp 3ndash8 2012

[61] S Orrenius P Nicotera and B Zhivotovsky ldquoCell deathmechanisms and their implications in toxicologyrdquo ToxicologicalSciences vol 119 no 1 pp 3ndash19 2011

[62] G S Bloom ldquoAmyloid-120573 and tau the trigger and bullet inAlzheimer disease pathogenesisrdquo JAMA Neurology vol 71 no4 pp 505ndash508 2014

[63] SM Lasley andM E Gilbert ldquoRat hippocampal glutamate andGABA release exhibit biphasic effects as a function of chroniclead exposure levelrdquo Toxicological Sciences vol 66 no 1 pp139ndash147 2002

[64] L S Kjeldsen M Ghisari and E C Bonefeld-Joslashrgensen ldquoCur-rently used pesticides and their mixtures affect the functionof sex hormone receptors and aromatase enzyme activityrdquoToxicology and Applied Pharmacology vol 272 no 2 pp 453ndash464 2013

[65] S J Genuis ldquoThe chemical erosion of human health adverseenvironmental exposure and in-utero pollutionmdashdeterminantsof congenital disorders and chronic diseaserdquo Journal of PerinatalMedicine vol 34 no 3 pp 185ndash195 2006

[66] S J Genuis M E Sears G Schwalfenberg J Hope andR Bernhoft ldquoClinical detoxification elimination of persistenttoxicants from the human bodyrdquo The Scientific World Journalvol 2013 Article ID 238347 3 pages 2013

[67] T G Redgrave PWallace R J Jandacek and P Tso ldquoTreatmentwith a dietary fat substitute decreased Arochlor 1254 contam-ination in an obese diabetic malerdquo The Journal of NutritionalBiochemistry vol 16 no 6 pp 383ndash384 2005

[68] G H Ross and M C Sternquist ldquoMethamphetamine exposureand chronic illness in police officers significant improvement


with sauna-based detoxification therapyrdquo Toxicology and Indus-trial Health vol 28 no 8 pp 758ndash768 2012

[69] R J Jandacek J E Heubi D D Buckley et al ldquoReduction ofthe body burden of PCBs and DDE by dietary intervention ina randomized trialrdquo Journal of Nutritional Biochemistry vol 25no 4 pp 483ndash488 2014

[70] S J Genuis D Birkholz I Rodushkin and S Beesoon ldquoBloodurine and sweat (BUS) study monitoring and eliminationof bioaccumulated toxic elementsrdquo Archives of EnvironmentalContamination amp Toxicology vol 61 no 2 pp 344ndash357 2011

[71] R J Jandacek and S J Genuis ldquoAn assessment of the intestinallumen as a site for intervention in reducing body burdens oforganochlorine compoundsrdquo The Scientific World Journal vol2013 Article ID 205621 10 pages 2013

[72] P A Egner J G Chen A T Zarth et al ldquoRapid and sustainabledetoxication of airborne pollutants by broccoli sprout beverageresults of a randomized clinical trial in Chinardquo Cancer Preven-tion Research vol 7 no 8 pp 813ndash823 2014

[73] S J Genuis ldquoElimination of persistent toxicants from thehuman bodyrdquoHuman and Experimental Toxicology vol 30 no1 pp 3ndash18 2011

[74] S J Genuis Y Liu Q I T Genuis J W Martin and T KandaldquoPhlebotomy treatment for elimination of perfluoroalkyl acidsin a highly exposed family a retrospective case-seriesrdquo PLoSONE vol 9 no 12 Article ID e114295 2014

[75] S J Genuis ldquoToxic causes of mental illness are overlookedrdquoNeuroToxicology vol 29 no 6 pp 1147ndash1149 2008

[76] J B Adams M Baral E Geis et al ldquoSafety and efficacy of oralDMSA therapy for children with autism spectrum disorderspart Amdashmedical resultsrdquo BMC Clinical Pharmacology vol 9article 16 2009

[77] J B Adams M Baral E Geis et al ldquoSafety and efficacy of oralDMSA therapy for children with autism spectrum disorderspart Bmdashbehavioral resultsrdquo BMC Clinical Pharmacology vol 9article 1472 2009

[78] D E Bredesen ldquoReversal of cognitive decline a novel therapeu-tic programrdquo Aging vol 6 no 9 pp 707ndash717 2014

[79] S Porru and L Alessio ldquoThe use of chelating agents in occu-pational lead poisoningrdquo Occupational Medicine vol 46 no 1pp 41ndash48 1996

[80] S Bradberry T Sheehan and A Vale ldquoUse of oral dimercap-tosuccinic acid (succimer) in adult patients with inorganic leadpoisoningrdquoQJM An International Journal of Medicine vol 102no 10 pp 721ndash732 2009

[81] S Bradberry and A Vale ldquoDimercaptosuccinic acid (succimerDMSA) in inorganic lead poisoningrdquo Clinical Toxicology vol47 no 7 pp 617ndash631 2009

[82] M E Sears ldquoChelation harnessing and enhancing heavy metaldetoxificationmdasha reviewrdquoTheScientificWorld Journal vol 2013Article ID 219840 13 pages 2013

[83] R P Wedeen ldquoLead poisoning the evolving definitionrdquo Inter-national Journal of Occupational and Environmental Medicinevol 2 no 1 pp 1ndash3 2011

[84] S Hernberg ldquoLead poisoning in a historical perspectiverdquoAmerican Journal of Industrial Medicine vol 38 no 3 pp 244ndash254 2000

[85] W N Arnold ldquoThe illness of Vincent van Goghrdquo Journal of theHistory of the Neurosciences vol 13 no 1 pp 22ndash43 2004

[86] R J Shamberger ldquoValidity of hair mineral testingrdquo BiologicalTrace Element Research vol 87 no 1ndash3 pp 1ndash28 2002

[87] Centers for Disease Control and Prevention (CDC) ldquoVeryhigh blood lead levels among adultsmdashUnited States 2002ndash2011rdquoMorbidity amp Mortality Weekly Report vol 62 no 47 pp 967ndash971 2002

[88] J Liu and G Lewis ldquoEnvironmental toxicity and poor cognitiveoutcomes in children and adultsrdquo Journal of EnvironmentalHealth vol 76 no 6 pp 130ndash138 2014

[89] L Mah M Kohli and G Chan ldquoAmbient lead exposureis associated with greater risk of conversion to Alzheimerrsquosdisease and hippocampal atrophy in individuals with amnesticmild cognitive impairmentrdquo The American Journal of GeriatricPsychiatry vol 22 no 3 pp S117ndashS118 2014

[90] Centers for Disease Control and Prevention (CDC) ldquoLeadexposure among females of childbearing agemdashUnited States2004rdquoMorbidity amp Mortality Weekly Report vol 56 no 16 pp397ndash400 2007

[91] S J Genuis G Schwalfenberg A-K J Siy and I RodushkinldquoToxic element contamination of natural health products andpharmaceutical preparationsrdquo PLoS ONE vol 7 no 11 ArticleID e49676 2012

[92] HNeedleman ldquoLow level lead exposure history anddiscoveryrdquoAnnals of Epidemiology vol 19 no 4 pp 235ndash238 2009

[93] M Casas C Chevrier E D Hond et al ldquoExposure to bromi-nated flame retardants perfluorinated compounds phthalatesand phenols in European birth cohorts ENRIECO evaluationfirst human biomonitoring results and recommendationsrdquoInternational Journal of Hygiene and Environmental Health vol216 no 3 pp 230ndash242 2013

[94] S L Archibeque-Engle J D Tessari D T Winn T J KeefeT M Nett and T Zheng ldquoComparison of organochlorinepesticide and polychlorinated biphenyl residues in humanbreast adipose tissue and serumrdquo Journal of Toxicology andEnvironmental Health vol 52 no 4 pp 285ndash293 1997

[95] G W Yu J Laseter and C Mylander ldquoPersistent organic pollu-tants in serum and several different fat compartments inhumansrdquo Journal of Environmental and Public Health vol 2011Article ID 417980 8 pages 2011

[96] R J Jandacek N Anderson M Liu S Zheng Q Yang andP Tso ldquoEffects of yo-yo diet caloric restriction and olestra ontissue distribution of hexachlorobenzenerdquo American Journal ofPhysiologymdashGastrointestinal and Liver Physiology vol 288 no2 pp G292ndashG299 2005

[97] S M Rappaport and M T Smith ldquoEnvironment and diseaserisksrdquo Science vol 330 no 6003 pp 460ndash461 2010

[98] S J Genuis ldquoMedical practice and community health care inthe 21st century a time of changerdquo Public Health vol 122 no 7pp 671ndash680 2008

[99] J R Roberts and J R Reigart ldquoEnvironmental health educationin the medical school curriculumrdquo Ambulatory Pediatrics vol1 no 2 pp 108ndash111 2001

[100] K S Gehle J L Crawford andM T Hatcher ldquoIntegrating envi-ronmental health into medical educationrdquo American Journal ofPreventive Medicine vol 41 no 4 pp S296ndashS301 2011

[101] K H Kilburn ldquoWhy is chemical brain injury ignored Ponder-ing causes and risksrdquo Archives of Environmental Health vol 58no 3 pp 132ndash134 2003

[102] S J Genuis ldquoBack to the future of healthcare aetiology-centredmedicinerdquo The New Zealand Medical Journal vol 118 no 1215Article ID U1467 2005

[103] S J Genuis ldquoWhatrsquos out there making us sickrdquo Journal ofEnvironmental and Public Health vol 2012 Article ID 60513710 pages 2012


[104] D Rhodes A Spiro III A Aro and H Hu ldquoRelationship ofbone and blood lead levels to psychiatric symptoms the nor-mative aging studyrdquo Journal of Occupational and EnvironmentalMedicine vol 45 no 11 pp 1144ndash1151 2003

[105] H S Hendriks E C Antunes Fernandes A Bergman Mvan den Berg and R H S Westerink ldquoPCB-47 PBDE-47 and6-OH-PBDE-47 differentially modulate human GABAA andalpha4beta2 nicotinic acetylcholine receptorsrdquo ToxicologicalSciences vol 118 no 2 pp 635ndash642 2010

[106] S M Goldman P J Quinlan G W Ross et al ldquoSolvent expo-sures and Parkinson disease risk in twinsrdquo Annals of Neurologyvol 71 no 6 pp 776ndash784 2012

[107] V Jevtovic-Todorovic A R Absalom K Blomgren et alldquoAnaesthetic neurotoxicity and neuroplasticity an expert groupreport and statement based on the BJA Salzburg SeminarrdquoBritish Journal of Anaesthesia vol 111 no 2 pp 143ndash151 2013

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


References cited in identified publications were examined foradditional relevant writings Searching techniques includedkeyword searches with terms related to chemical exposureand dementia toxicants and AD (Alzheimerrsquos disease) pol-lutants and neurodegenerative disease environmental healthsciences and the elderly neurotoxicity with poisoning anddetoxification

A primary observation was that limited scientific litera-ture exists on the link between neurodegenerative processesand toxicant bioaccumulation on the pathogenesis involvedas well as the management of degenerative states associ-ated with toxicant accrual The first authorrsquos professionalobservations and published research as an environmentalhealth physicianwere also incorporated into the discussion ofmanagement strategies The format of an integrated clinicalreview was chosen as such reviews play a pivotal role inscientific research and professional practice in emergingmedical issues with limited primary study and unchartedclinical territory [4]

3 Background

Recent evidence has emerged linking the development ofdementia with various inorganic and organic toxicants in ourenvironment [5ndash9] For example a recent report from JAMANeurology found that elevated serum levels of the toxicantDDE (dichlorodiphenyldichloroethylene) a direct reflectionof brain DDE levels [10] are associated with increased sus-ceptibility for developing Alzheimerrsquos disease [10] DDE is apersistent metabolite of the organochlorine compound DDT(dichlorodiphenyltrichloroethane) a pesticide widely usedfollowing World War II DDT was banned in most countriesin the early 1970rsquos because of persistence within the humanorganism and the environment and the consequent adversehealth effects associated with exposure and bioaccumulation[11] Metabolic byproducts of DDT such as DDE continueto be found in serum samples of 75ndash80 of the populationdue to its long half life and continued exposure Peopleremain at risk of exposure by consuming imported foodsfrom countries where DDT is still used as well as frompollution in soil and water sources [11 12]

A growing body of evidence has recently implicatedmany other exposures to organic chemicals as potentialdeterminants in the development of dementia (Table 1)Formaldehyde a common indoor air pollutant off-gassingfrom wood products and various other sources within thehome has been linked to dementia [13ndash15] Exposure tomethanol a potential contaminant of ambient air and somefoodstuffs has also been associated with neurodegenerationin animals [16 17] Some common pharmaceutical exposuresincluding ongoing use of benzodiazepines have been linkedto an increased risk of Alzheimerrsquos disease [18] Variouscommon components of air pollution a widespread problemin many areas of the world have also been implicated in theescalating pandemic of dementia [19]

Many other classes of common bioaccumulative organiccompounds have also been recognized to have neurotoxiceffects including brominated flame retardants (PBDEs) [20]solvents [21] ldquononstickrdquo perfluorinated compounds [22]

Table 1 Exposures potentially associated with neurodegenerativedisease

Metals

Lead [6ndash9 25ndash27 29 35 37 38 47 4863 83 84 87 90 92 104]Mercury [8 25ndash27]Aluminum [7 8 28]Zinc overload [7]Manganese [8 29 47]Arsenic [8 27 29]Tin [8]Copper [30ndash33]

Pesticides

Dichlorodiphenyldichloroethylene [10](DDE)Aldrin [29]Chlordane [29]Heptachlor [29]Rotenone [5 7]Dieldrin [5]Methyl parathion [26]Organophosphates [5 7 26 46 48]Maneb [5 29]Paraquat [5 7 29 46]Pyrethroids [5]

Flame retardantsHexabromocyclododecane [20]Tetrabromobisphenol-A [20]

Brominated [93] Decabromodiphenyl ether [20]6-Hydroxy-221015840441015840-tetrabromodiphenylether [105]

Chlorinated 221015840441015840-tetrachlorobiphenyl [105]Trichloroethylene [7]Carbon disulfide [26 29]

Solvents [48] Toluene [26]Perchloroethylene (PERC) [106]

Pharmaceuticals Anesthetic agents [107]Benzodiazepines [18]

Air pollution [6 47]

Particulate matter [19]Ozone [19]Nitrogen dioxide [19]Second hand smoke [27]Carbon monoxide [8 48]

Plasticizers Phthalate esters [59 93]Bisphenol A [59 93]

Others

Perfluorooctanesulfonic acid (PFOS) [93]Perfluoroctanoic acid (PFOA) [93]Organochlorine compounds [7]Acrylamide [29]Dioxins [25 27]Formaldehyde [13ndash15]Methanol [16 17]

polychlorinated biphenyls (PCBs) [23] and various typesof pesticides [7 24] With further research it remains tobe seen which organic pollutants alone or in combinationwill be significant determinants of the growing epidemic ofdementia

As well as organic compounds the scientific literaturehighlights the myriad adverse effects of various inorganic


















4 Case History










5 Discussion












6 Conclusion












References






















































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

































4 Case History










5 Discussion












6 Conclusion












References






















































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




















5 Discussion












6 Conclusion












References






















































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















6 Conclusion












References






















































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















References






















































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















review article toxicant exposure and bioaccumulation: a...

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