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Human Health Impacts of Exposure to Pesticides Contractref:011005,WWFAustraliaMerielWatts,PhDMerielWattsResearchandConsultingPOBox296,Ostend,WaihekeIsland,Auckland,NewZealandmerielwatts@xtra.co.nzNovember2012________________________________________________________________________ Contents Executivesummary1. Introduction2. Objectivesandmethodology3. Keychronichealthimpacts Cancer Neurodevelopmentproblems,children’sIQ,behaviouraldisorders Otherneurologicaldamage Birthdefects,birthoutcomes Respiratoryproblems Metabolicdisorders–obesity,diabetes,metabolicdisease4. Keysystemicimpacts Endocrinedisruption Immuneeffects5. Childrenatgreatestrisk Greaterexposure Greatervulnerability Futuregenerations–epigeneticeffects6. Keyscientificconsiderations Thedifferencebetweenacuteandchronicexposures Theaddedtoxicityofinertingredients Laboratoryversusepidemiologicalevidence Bioaccumulation7. Internationalconcernsandapproaches Endocrinedisruptingchemicals Lowdoseexposures Chemicalmixtures Hazardversusriskassessmentinpesticideregulation Precaution Substitution Minimumharm8. ConclusionReferences

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Executive Summary Theobjectivesof thispaperare toprovidea summaryscientific reviewofpeer‐reviewedliteratureonthehumanhealthimpactsofexposuretopesticides,especiallythosethatmaybeimpactingAustralia’sGreatBarrierReef;andtobrieflyreviewkeyinternationalconcernsandemergingapproachestopesticideissues.Evidenceisprovidedoftheincreasedriskofsomeadversehealtheffectsfromexposuretopesticides.ThereisevidencethatanumberofthepesticidesfoundintheGreatBarrierReefwatersand inwaterwaysdischarging into theareamaycausecancer(e.g.atrazine,2,4‐D,diuron, simazine), neurological conditions (chlorpyrifos), birth defects (atrazine, 2,4‐D,diuron, endosulfan, MCPA), reduced foetal growth (atrazine, chlorpyrifos, 2,4‐D,metolachlor),andmetabolicproblemsleadingtoobesityanddiabetes(chlorpyrifos).Foetal and early childhood exposures to pesticides are a key concern, with considerableevidence of links between such exposures to awide variety of pesticides and a range ofchildhoodcancers,especiallybraincancerandleukaemia.Prenatalexposure,particularlytoorganophosphate insecticides, is strongly linkedwith a rangeofdevelopmental, cognitiveandbehaviourdeficits,thatcanresultinlastingadverseeffectsonthebrainandleadingtowhathasbeendescribedasa “silentpandemic”ofdevelopmentalneurotoxicity. Prenatalexposureisalsostronglylinkedwitharangeofbirthdefects.Key systemic effects underlying many of these conditions involve the endocrine andimmune systems.Exposures to endocrinedisrupting chemicals (EDCs)during these earlylife stages can have permanent and irreversible effects,with severe health consequencesthroughoutchildhoodandintoadulthood,andevenforsubsequentgenerations,theeffectscontinuinglongaftertheexposuretotheendocrinedisruptingchemicalhasceased.‘Inert’ ingredients are added to pesticide formulations for a number of reasons includinghelpingtheproductsticktothesurfaceofleavesandsoil,spreadoversurfaces,ordissolveinwater.Theycanbemoretoxicthantheactivepesticidalingredienttohumans,nontargetplants, animals and microorganisms. For example the ‘inert’ ingredients in glyphosateincrease its aquatic toxicity. Generally there is no requirement to identify the inertingredients on pesticide labels or publically available registration information, andpesticideproprietorsclaimtheidentityof‘inerts’asconfidentialbusinessinformation.Thismakes it impossible for the general public or researchers to know what is in theformulationsbeingused.Areas of pesticide toxicology and policy of key international concern include endocrinedisrupting chemicals, low dose exposures, chemical mixtures, hazard versus riskassessmentinpesticideregulation,precaution,substitution,andcausingminimumharmtohumans and the environment through pestmanagement techniques. Increasingly hazardassessmentiscomingtoreplaceriskassessmentasitisrealisedthatthecurrentregulatoryprocessofassessingtheriskofasinglepesticideatatimefailstoaccountfortherealityofhumanexposuretoongoinglowdosesofmixturesofpesticides.Currentlynocountryhasanadequateregulatoryprocessforassessingtheseeffects,orthoseofendocrinedisruptingpesticides. Nor do they adequately implement the precautionary principle, or thesubstitution of hazardous pesticides with less hazardous pesticides and nonchemicalmethods.Noneatallworkonthebasisoftheprincipleofminimumharm,askingthefirst

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question:howdowecontrolpest,weedsanddiseasesinthemannerthatisleastharmfultopeopleandtheenvironment?1. Introduction Pesticidesarechemicalsusedforkillingorcontrollingunwantedinsects,diseasesonplants,weeds,slugsandsnails,birds,andvertebratemammalsregardedaspestssuchasrodents.Theyareusedforcontrollingphysiologicalfunctionsinplantssuchasregulatingflowering,thinning fruit, preventing fruit drop, defoliating crops before harvest. Pesticide is thegeneric term that includes insecticides, miticides, nematicides, fungicides, herbicides,algaecides, fumigants, vertebrate poisons, etc. The term pesticide commonly refers tosyntheticchemicalsusedforthesepurposesbutcanalsoincludebiopesticides–pesticidesbasedonmicroorganismsornaturalproducts.The main classes of insecticides are organochlorines (e.g. DDT), organophosphates(chlorpyrifos), carbamates (carbaryl), synthetic pyrethroids (permethrin), andneonicotinoids(imidacloprid).Themainclassesofherbicidesarephenoxyherbicides(2,4‐D),andtriazines(atrazine),althoughthemostcommonlyusedherbicide,glyphosate,isnotinoneofthemainfamilies.Pesticides are used in a multitude of situations including in crops, orchards, forestry,ornamental plantings, sports turf, homes, gardens, parks, industrial premises, shops,restaurants,schools,hospitals,airports,railwaylines,roadsides,transmissionlines,drains,waterways,onanimals,andevenonpeopleforpestssuchasscabiesandheadlice.Theyaresprayed in open spaces and city streets for disease vector control. They can be added toproductssuchaspaints,textile,clothingandbednets.Peopleareexposedtopesticidesthroughdirectcontact(skin,inhalation)whenusingthem,direct skin contact after someone else has used them, spray drift from neighbouringapplications, household fly sprays and insect coils, in food, water and drinks, andapplicationsonpets.Peopleareexposedtoresidualinsecticidesusedtotreattheinsidesofsomeairplanesorsprayedasaerosolsinotherairplanes.Childrenareexposedbeforetheyareborn,aspesticidesabsorbedbytheirmotherscrosstheplacentaandaretakenupbythefoetus. The first faeces of newborn infants have been found to contain a number ofpesticides. Infants are then exposed againwhen they are breast fed, for awide range ofpesticidesarecommonlyfoundinbreastmilk.AWorldBank (2008) report estimates that355,000peopleworldwidedie eachyear fromunintentional pesticide poisoning. An older, but authoritative study (Jeyaratnam 1990)estimates that there are possibly one million cases of serious unintentional pesticidepoisoningseachyear.Theauthorofthisstudynotesthatthisfigurereflectsonlyafractionof the real problem and estimates that there couldbe asmany as 25million agriculturalworkers in thedevelopingworld suffering some formofoccupationalpesticidepoisoningeachyear, thoughmost incidentsarenotrecordedandmostpatientsdonotseekmedicalattention.Oneoftheconclusionsthisauthorreachesisthatacutepesticidepoisoningmay

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in somedeveloping countriesbe as serious apublichealth concern as are communicablediseases.Although those figures relatemainly to developing countries where acute exposures aremore evident than in countries such as Australia, they do not tell the story of chronicexposures either in the developing world or in developed countries. Chronic effects forwhichthereissubstantialevidenceofassociationwithpesticideexposuresincludecancer,neurodevelopmental and behaviour effects, other neurological effects includingneurodegenerative diseases, birth defects and other adverse birth outcomes, andrespiratory diseases. More recently evidence has begun to emerge of associations withobesity,type2diabetesandmetabolicdisease.Someeffectslastawholelifetime;somearepassedon to future generations. Concern continues tomount about the reality of humanexposure to ongoing low doses of mixtures of pesticides, especially those that causeendocrinedisruptionordamagethedevelopingbrainoftheunbornfoetus.Becauseofthedifficultyinestablishinglinksbetweenspecificexposureincidentsandthedevelopmentofchroniceffects,whichmay takedecades todevelop, it is impossible toestablish theexactextentofthechroniceffectsofpesticideexposureinanycountry,letalonethecoststothehealth system, the economy, or people’s wellbeing and happiness. But there is sufficientevidencetoproposethatsuchcostswillbefarinexcessofthoseofacuteexposure.Theuncertaintyabouttheextentandcostofthesechroniceffectshasbeenusedfordecadestodelayactioninremovingtheworstoffendersandinshiftingagriculturalproductionawayfrom the current chemical input approach and towards an ecosystem approach inwhichpriority is given to creating a healthy agroecosystem in which natural enemies andbiologicalcontrolsflourish,andinwhichpesticidesareusedonlyasalastresort.Thisshiftinfocusofagricultureisnowespousedatthehighestinternationallevel,suchasFoodandAgricultureOrganisationoftheUnitedNations(FAO),UNSpecialRapporteurontheRighttoFood,andtheInternationalCodeofConductontheDistributionanduseofPesticides.

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2. Objectives and methodology Theobjectiveof this report is toestablish that thescientificbasisofWWF’s campaignonpesticidesissound,byprovidingasummaryscientificreviewofpeer‐reviewedliteratureonthe chronic human health impacts of exposure to pesticides, as well as key scientificconcepts, emerging concerns and international approaches, as described in the terms ofreference.Giventhevastscaleofthepeerreviewedliteratureavailableontheadversehumanhealtheffects of pesticides, and the constraints of time and resources, recent appropriatemeta‐analysesofscientificpaperswereusedwherepossible,togetherwithotherrelevantpapers.Itwasnotpossibletoreviewallpublishedpapersonanyoneaspectofthisreport.Ratheranindicativeoverviewisgiven.EmphasiswasplacedoncurrentusepesticidesratherthanlegacypesticidessuchasDDT.Inaddition,somedatawasprovidedonpesticidesthathavebeenfoundcontaminatingtheGreatBarrierReefarea,andthewaterwaysthatemptyintotheReefarea,althoughthisreport shouldnotbe inanywayregardedasprovidingall theinformationavailableontheeffectsofthesepesticides.Pesticides found in the inshorewaters surrounding the reef are the herbicides ametryn,atrazine,diuron,hexazinone,simazine,andtebuthiuron(QueenslandGovernment2011).PesticidesdetectedinthewaterwaysdischargingtotheGreatBarrierReefareaincludetheherbicides ametryn, atrazine (and degradation products), bromacil, 2,4‐D, diuron,hexazinone, MCPA, metolachlor, simazine, tebuthiuron; and the insecticides endosulfan,imidacloprid,andmalathion–underliningindicatingthosethatarefoundfrequentlyandatrelativelyhighconcentrations(Lewisetal2009).Other pesticides in wide use in the Great Barrier Reef catchment include chlorpyrifos,paraquat,andglyphosate(Kingetal2012).Anoteabouttheterminologyused:itisseldompossibletostatewithabsolutecertaintythatapesticidecausesaparticulareffectinhumans,becausethelevelofproofrequiredtosupportsuchanassertionisdifficulttoobtaininthefaceofmanyvariables.Insteadtheterms‘associatedwith’,‘linkedwith’,or‘increasedrisk’aregenerallyusedtodescribeascientificallysupportedlevelofevidencethatsuchaneffectmaybecausedbythepesticide.

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3.   Key chronic health impacts The impacts of pesticides on human health are wide‐ranging, affecting every part of thebody but only the major chronic impacts are considered here. Others include acutepoisoning, cardiovascular, skin andeye effects, liver andkidneydamage, reduced fertilityandfecundity,earlyonsetpuberty,endometriosis,andmultiplechemicalsensitivity.3.1  Cancer Thereisaconsiderablebodyofepidemiologicalevidencelinkingpesticidestocancer,andinparticulartochildcancerresultingfrombothparentalanddirectchildhoodexposures.ChildcancerThe evidence is strongest for leukaemia and brain cancer (Infante‐Rivard &Weichenthal 2007;Lyons&Watterson2010;VanMaele‐Fabryetal2010),butthereisevidencealsoforassociationswithnon‐Hodgkin’s lymphoma, neuroblastoma (a tumour innerve tissue), Ewing’s sarcoma (atumourofbonetissue),andWilm’stumour(kidney).Otherchildcancerslinkedtopesticideexposures include soft‐tissue sarcoma, colorectal cancer, germ cell cancer, Hodgkin’sdisease, eye cancer, renal and liver tumours, thyroid cancer, andmelanoma (Zahm &Ward1998, Infante‐Rivard&Weichenthal 2007;Carozza et al 2008; Thompsonet al 2008; Ferrís I Tortajada et al2008).Maternal exposures, but also paternal exposures preconception, including bothoccupational and household exposures, are associated with leukaemia and brain cancer(Infante‐Rivard & Weichenthal 2007; Lyons & Watterson 2010; Van Maele‐Fabry et al 2010). A largeinternational study across seven countries identified an association between childhoodbraintumoursandmaternalfarmexposuretopesticidesduringthefiveyearsprecedingthediagnosis (Efird et al 2003). A high rate of brain cancer was found in children playing inorchardsinKashmir,India(Bhatetal2010).AdultonsetcancerTherearealsoanumberofadultcancersassociatedwithexposuretopesticidesincludingbreast, lung, multiple myeloma, non‐Hodgkin’s lymphoma, leukaemia, ovary, pancreas,prostate,kidneybladder,stomach,colon,rectal,lip,connectivetissue,brain,andtesticular.Ofthese,atleastbreast,prostate,andtesticularcancerarethoughttohaveoriginsinearlydevelopmentalexposurestoenvironmentalhormonedisruptors(Bassiletal2007;Waggoneretal 2011; Cooper et al 2011; Alavanja & Bonner 2012). Swedish research has concluded that adultcancerriskislargelyestablishedduringthefirst20yearsoflife(Czeneetal2002;Hemminki&Li2002).One large epidemiological study in the US states of Iowa and North Carolina, theAgriculturalHealthStudywhichinvolvedacohortof89,656pesticideapplicatorsandtheirspouses,foundadecreaseinoverallcancermortalityrate,butanincreaseinmortalityratesfor specific cancers: lymphohaematopoietic cancers, melanoma, and digestive system,prostate, kidney, and brain cancers amongst applicators; and among spouses,lymphohaematopoieticcancersandmalignanciesofthedigestivesystem,brain,breast,andovary(Waggoneretal2011).Pesticidesimplicated

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Epidemiological studies have associated an array of cancerswith all themain functionalclassesofpesticides–herbicides,insecticides,fungicides,fumigants–andchemicalclassesincluding organochlorine (OC), organophosphate (OP), and carbamate insecticides, andphenoxyacidandtriazineherbicides(Alavanja&Bonner2012).TheAgriculturalHealthStudyreferred to above produced evidence of increased risk of cancer associated with 12pesticides: alachlor, aldicarb, carbaryl, chlorpyrifos, diazinon, dicamba, S‐ethyl‐N,N‐dipropylthiocarbamate (EPTC), imazethapyr,metolachlor,pendimethalin,permethrin,andtrifluralin (Weichenthal et al 2010). The authors noted that animal toxicity data supports thefindingsforalachlor,carbaryl,metolachlor,pendimethalin,permethrin,andtrifluralin.Alavanja & Bonner (2012) also reviewed other studies and among the associations theynotedwere:

simazinewithprostatecancer aldicarbwithcoloncancer butylatewithprostatecancer carbarylwithmelanoma chlorpyrifoswithlungandrectalcancers diazinonwithlungcancerandleukaemia dicambawithcoloncancer fonophoswithprostatecancer EPTCwithcolonandpancreaticcancers imazethapyrwithcolonandbladdercancers lindanewithnon‐Hodgkin’slymphoma manebandmancozebwithmelanoma parathionwithmelanoma pendimethalinwithrectalcancer trifluralinwithcoloncancer

Someotherexamplesofparticularpesticide/cancerassociationsinepidemiologicalstudiesinclude:

atrazine–bonecancer,leukaemia(Thorpe&Shirmohammadi2005;Rulletal2009) carbaryl–brain(Zahm&Ward1998) endosulfan–leukaemia(Rauetal2012) metolachlor – bone cancer, leukaemia (Thorpe & Shirmohammadi 2005); lung cancer

(Weichenthaletal2010) pyrethroidheadliceshampoo–leukaemia(Menegauxetal2006) simazine–prostatecancer(Mills&Yang2003;Bandetal2011) glyphosate – Mink et al (2012) in their review of case control and cohort studies

concludedthattherewas“noconsistentpatternofapositiveassociationindicatinga casual relationship” with cancer; but the studies reviewed showed a strikingtendency of increased risk of non‐Hodgkin’s lymphoma. Other cancers showingincreased risk ratios included multiple myeloma, breast, rectal, and brain. Theauthors dismissed the studies for reasons including their being not statisticallysignificant on further analysis, confidence limits too large, or inconsistent results.However this leaves cause for concern about glyphosate and cancer, especially inlightoflaboratorystudies.

2,4‐D– non‐Hodgkin’s lymphoma (Miligi et al 2006), prostate cancer (Band et al 2011),mesothelioma(Burnsetal2011).

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malathion–prostatecancer(Bandetal2011);breastcancer(Mills&Yang2005).TheWWFlistofAustralia’sMostDangerousPesticides(Immig2010)contains17pesticidesregisteredinAustraliathatareknown,likelyorprobablecarcinogens(indicatedby*),andanother42thatarepossibleorsuspectedcarcinogens,accordingtoregulatoryinformationintheUSA,andtoassessmentbytheInternationalAgencyforResearchonCancer.

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Theseare:acephateacrifluorfenalpha‐cypermethrinamitrazbifenthrinbioallethrinbromoxynilcarbaryl*carbendazimchlorfenapyrchlorthalchlorothalonil*cyanazinecypermethrindichlorvos

diclofop*dicofoldifenoconazoledimethipindimethenamiddimethoatediuron*dithianonethyleneoxide*fenoxycarb*fluometuronhaloxyfop*hexaconazoleimazalil*iprodione*lindane

linuronmalathionmancozeb*mecopropmercuricchloridemetaldehydemethidathionmolinateoxadixylpendimethalinpermethrin*phosmetpiperonylbutoxidepirimicarb*prochloraz

propachlor*propanilpropiconazolepropoxur*tebuconazoletetraconazole*thiacloprid*thiodicarb*triademefontriadimenoltrichlorfonzetacypermethrinziram

Laboratorystudies indicatingthatparticularpesticidescancausecancer,oraregenotoxicor mutagenic are too numerous to review here. Some of them confirm epidemiologicalfindings,somedonot.Diuronisanexampleofapesticideforwhichthelaboratorystudiesclearly indicate carcinogenicity, but forwhich carcinogenic associationswith cancer havenot shown up in epidemiological studies so far. The APVMA (2011) review reported thatdiuron increased incidences of malignant carcinoma in the urinary bladder of males;malignanttransitionalcarcinomasintheurinarybladderepitheliumofmalesandfemales;and malignant neoplasias in the uterus, and adenocarcinoma in the mammary gland infemalerats.3.2  Neurodevelopment problems, children’s IQ, behavioural disorders Epidemiological studies have shown that prenatal exposure to pesticides, especiallyorganophosphate insecticides such as chlorpyrifos, is associated with pervasivedevelopmentaldisorders,delayedor reducedcognitivedevelopment, learningdisabilities,poorer short‐termmemory andmotor skills, longer reaction time, behavioural disorderssuch as AttentionDeficit Hyperactivity Disorder (ADHD), and autism spectrum disorders(Guillette et al 1998; Eskenazi et al 2007, 2008; Roberts et al 2007; Gilbert 2008; Jurewicz & Hanke 2008;Searles Nielsen et al 2010; London et al 2012). Prenatal exposure to pesticides can have lastingadverseeffectson thebrain leading towhathasbeendescribedasa “silentpandemic”ofdevelopmentalneurotoxicity(Hararietal2010).

Children from agricultural communities in the US showed poorer response speedandslower learning inneurobehavioural tests thanchildren fromnon‐agriculturalcommunities(Rohlmanetal2005).

A study of Hispanic children living in an agricultural community in Arizona, USAshowedthatshort‐termOPexposurereducedchildren'scognitiveandbehaviouralfunctioning, including speed of attention, sequencing, mental flexibility, visualsearch,conceptformation,andconceptualflexibility(Lizardietal2008).

Garry et al (2002) found an association between children borne to pesticideapplicators exposed to glyphosate and neurobehavioural deficits; and between

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those exposed to the grain fumigant phosphine and neurological andneurobehavioural deficits, including ADHD and autism. Forty‐three percent ofchildrenwithADHDhadfatherswhousedglyphosate.

Each10‐fold increase inurine levelsofOPmetabolites in childrenwasassociatedwitha55to72percentincreaseinthelikelihoodofADHDinchildrenagedeightto15years,inaUSstudy(Kuehnetal2010).

Each 10‐fold increase in a pregnant mother's urinary concentration of OPmetabolites ledtoa500percent increasedriskthatherchildwouldbediagnosedwithADHDbyagefive(Marksetal2010).

Eskenazi et al (2007) found a 230% increased risk of Pervasive DevelopmentalDisorders, which include autism, for each 10 nanomole/litre increase in urinarymetabolitesofOPs.

After reviewing published data Dr David Bellinger (2012), of the USA’s ChildrenHospitalBoston,concludedthatOPswereresponsibleforloweringthecountry’sIQlevel by 17 million points, not much less than the 23 million points lost to leadpoisoning,awidelyrecognisedcauseofcognitivelossinchildren.

Three recent studies in theUS confirmed thatprenatal exposure toOPs results inlower IQs, and reducedmemory andperceptual reasoning in children. Engel et al(2011)showedelevatedlevelsofOPmetabolitesinawoman’surineduringthethirdtrimesterofpregnancyresultedinreducedcognitivedevelopmentinherchildat12months of age, particularly perceptual reasoning. Bouchard et al (2011) correlatedelevatedlevelsofOPmetabolitesinpregnantwomenwithsignificantlyreducedIQintheirchildrenattheageof7,byasmuchas7points,aswellasreducedworkingmemory,processingspeed,verbalcomprehension,andperceptualreasoning.Rauhet al (2011) found that as little as 4.6 picograms of chlorpyrifos per gram of cordblood during gestation resulted in a drop of 1.4 percent of a child’s IQ and 2.8percentofher/hisworkingmemory.

This is a small selection of epidemiological studies illustrating neurodevelopmentalproblemsresultingfromfoetalandearlychildhoodexposuretopesticides.Therearemanymore such studies. Additionally there are numerous laboratory studies on animalsdemonstratingsimilareffectsandconfirmingthebiologicalplausibilityof,andmechanismsinvolvedin,theseoutcomes,especiallyfororganophosphateinsecticides(Slotkin2004;Colborn2006;Slotkinetal2006;Flaskos2012).Thepotentialsocietaleffectsofthesefindingscannotbeoverstated.Ratesofmentalillnessand suicide are higher in children suffering developmental, learning and behaviouraldisabilities,with increased likelihoodof substanceabuseandcriminalactivity later in life(Szpir 2006).Attentiondeficitat theageof10hasbeenassociatedwith loweremploymentrates, worse jobs, lower earnings if employed, and lower expected earnings overall, in astudyof38‐year‐oldsintheUK(Knappetal2011).InCanadatheestimatedcosttothecountryofthelossof5IQpointsis29billionAustraliandollarsperyear(Muir&Zegarac2001)–andrecentstudiesintheUShavefoundprenatalexposuretoOPsreducingchildren’sIQbyasmuchas7points.3.3  Other neurological damage 

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Manypesticidescanactthroughneurotoxicmechanismsthatarerelevanttohumanhealth,including organophosphates (OPs), organochlorines (OCs), carbamates and pyrethroids(London et al 2012). The effects can range frommild cognitive dysfunction (Bosma et al 2000)through,impairedperipheralnervoussystemfunction(Starksetal2012),delayedneuropathy(Jokanovicetal2011),mooddisorders(Meyeretal2010),andpsychologicaldistress(Wesselingetal2010),tosuicidesandneurodegenerativediseases(Londonetal2012;Maleketal2012).Highlevelsofexposure,suchaswithoccupationalexposuresandpoisonings,mayresultinincreased risk of neuropsychiatric outcomes including increased anxiety, depression andsuicide;andincreasedagriculturalinjuryasaresultofthedepression(Stallones&Beseler2002;London et al2012).Arecentcohortstudyofgrain farmers inCanadahas linkedexposuretophenoxy herbicides (2,4‐D and MCPA) with physician diagnosed mental ill‐health,particularlyforhospitaladmissionsamongstthosewhohadbeenexposedfor35yearsformore(Cherryetal2012).The effects of OP exposures during adolescence can manifest as mental and emotionaldisturbances (Jurewicz & Hanke 2008). A relatively consistent pattern of neurobehaviouraldeficits, including increased neuroses, have been observed in studies of pesticideapplicators, greenhouse workers, agricultural workers and farm residents exposedrepeatedlyovermonthsoryearstolowlevelsofOPs(AbdelRasouletal2008;Londonetal2012).Pesticideexposurescanalso influencesleep:onecase–control study foundanassociationbetweenpreviousoccupational exposureand idiopathicREMsleepbehaviourdisorder (acommonprediagnosticsignofparkinsonismanddementia)(Posthumaetal2012).There is evidence of an association between chronic exposure to pesticides withneurodegenerative disease including dementia, Alzheimer’s disease, Parkinson’s disease,amyotrophic lateral sclerosis (a form of motor neuron disease) and multiple sclerosis(Parrón et al 2011; Malek et al 2012). A systematic meta‐analysis of occupational exposure topesticidesbyVanMaele‐Fabryetal(2012)concludedthatthereisastatisticallysignificantincreased risk of Parkinson’s disease with occupational exposure, especially amongstbanana,sugarcaneandpineappleplantationworkers.Asecondmeta‐analysis,of46studies,concludedthatthereisapositiveassociationbetweenParkinson’sdiseaseandexposuretoherbicides and insecticides, but not fungicides (van der Mark et al 2012). A third reviewassociated increased risk of Parkinson’s diseasewith exposure to chlorpyrifos, paraquat,andmaneb(Freire&Koifman2012).13.4  Birth defects, birth outcomes BirthdefectsAnimal studies have identified a number of pesticides that cause birth defects. Theseincludediuron(delayedossificationofvertebraeandsternumandotherskeletalalterationsinrats–APVMA2011),atrazine(feminisationofmalefrogs–Hayesetal2006a),ametaboliteofmetolachlor (2‐ethyl‐6‐methyaniline, teratogenic in frogs – Osanao et al 2002), and 2,4‐D(urinarytactmalformation,extraribs–USEPA2007).

1 Sincethepublicationofthethirdmeta‐analysis(Freire&Koifman2012),theworkbyresearcherMonaThiruchelvamhasbeendiscredited.Thisstudycitessomeofherworkbuttheconclusionsarenotdependentonit,asotherstudiescitedhaveimplicatedthesamepesticides.

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Numerous epidemiological studies have been carried out to try to determine whetherpesticides do cause birth defects in humans, and if so which pesticides are implicated.Studiesvaryinquality,andinthequestionstheyaddress.Somehavenotfoundapositivelink with pesticides, but many have. A recent review of studies by Sanborn et al (2012)concluded that “all of thehigh‐qualitybirthdefect studies reportedpositiveassociations”with hypospadias,2 neural tube defects, and congenital diaphragmatic hernia. Other birthdefectspositivelyassociatedwithpesticideexposureincludecryptorchidism3(Kristensenetal1997; Carbone et al 2006; Rocheleau et al 2009) and micropenis (Gaspari et al 2011); missing orreduced limbs (Schwartz & LoGerfo 1986, 1988); anencephaly4 (Lacasana et al 2006); spina bifida(Brenderetal2010);andcongenitalheartdisease(Yuetal2008).Associationbetweenpesticidesandbirthdefectshavebeenfoundforanumberofdifferentexposurescenarios:familiesofpesticideapplicators(Garryetal1996);familieslivinginruralareas(Schreinemachers2003);andmaternalexposure(Blatteretal1996;Shawetal1999;Engeletal2000;Medina‐Carriloetal2002;Rojasetal2000;Calvertetal2007;Rocheleauetal2009;Brenderetal2010;Dugasetal2010;Gabeletal2011),especiallyinfloriculture(Restrepoetal1990a,1990b;Idrovo&Sanín2007),gardening(Weidneretal1998),inorchards,greenhousesorgrainfarming(Kristensenetal1997;Andersenetal2008),anduseinthehome(Brenderetal2010).Associationshave also beenmade between exposure to pesticides duringparticular timeperiodsandcertainbirthdefects:forexamplematernalexposurepreconceptionwithspinabifida (White et al 1988); maternal exposure during the period from the month beforeconception and the first trimester with multiple anomalies including nervous systemdefectsandoralclefts(Nurminenetal1995;Garciaetal1998);useofinsectrepellentsduringthefirst trimester with hypospadias (Dugas et al 2010); and paternal exposure in greenhousesproducing vegetables and flowers during the 3 months prior to conception withhypospadias(Brouwersetal2007)andcryptorchidism(Pieriketal2004).Inanumberofstudies,specificpesticideshavebeenlinkedwithbirthdefects:

atrazine: one study found a relationship between gastroschisis5 and exposure toatrazine, inparticular inwomenwho resided<25km froma site of highatrazineconcentration (Waller 2010). An earlier study had found a correlation betweenhigher incidence of abdominal wall defects (including gastroschisis andomphalocele) and surfacewater contaminationwithatrazine in theUS (Mattix et al2007);

herbicides: 2,4‐D,MCPA, atrazine, and trifluralin are associatedwith anomalies ofthecentralnervoussystem,circulatory,respiratory,urogenital,andmusculoskeletalsystems,particularlyinmalechildren(Garryetal1996,2002;Schreinemachers2003);

2,4‐D and 2,4,5‐T: paternal exposure to Agent Orange (2,4,5‐T and 2,4‐D) isassociatedwithspinabifida(Ngoetal2010);

2 Hypospadiasistheabnormallyplacedurinaryopeningonthepenis. 3Cryptorchidismistheabsenceofoneorbothtestes.4Anencephalyistheabsenceofamajorpartofthebrainandskull,causedbyfailureoftheneuraltubetoclose,usuallybetweenthe23rdand26thdaysofpregnancy.Itmayalsoinvolvefacialdistortionsandheartdefects. 5 Gastroschisisisabirthdefectinwhichthebaby’sintestinesprotrudethroughaholeintheabdominalwall.

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endosulfan: parental exposure to endosulfan is linked to avarietyof birthdefectsandcongenitalconditionsinIndia(NIOH2002);

diclofop‐methyl: maternal exposure to diclofop‐methyl during pregnancy isassociatedwithincreasedriskofhypospadias(Meyeretal2006);

cyanazine and dicamba: parental exposure to both cyanazine and dicamba isassociatedwithcongenitalabnormalities(Weselaketal2008);

oxydemeton‐methyl: maternal exposure to oxydemeton‐methyl at 4 weeks ofpregnancyisassociatedwithcongenitaldefectsofheart,eye,faceandbrain(Romeroetal1989).

Parental body burden of organochlorine pesticides such as DDT, DDE, HCH, HCB andendosulfan are also associated with a range of congenital defects including neural tubedefects,undescendedtesticles,cryptorchidism,extranippleinmales,andcretinism(Hosieetal2000;Longneckeretal2002;Damgaardetal2006;Ngayamaetal2007;Brucker‐Davisetal2008;Renetal2011).FoetalgrowthMeasures of foetal growth commonly include birth weight, head circumference, andintrauterine growth restriction. Again studies show mixed results, especially fororganochlorine pesticides, and in part this may be because of the notorious difficulty inproperlyidentifyingpesticideexposures,aproblemcommontoallepidemiologicalstudies.Neverthelessthestudies thatdoshowpositiveassociationsshouldbetakenseriouslyandnotdismissedsimplybecausenotallstudiesconfirmtheirfindings.ThereviewbySanbornetal (2012) foundthatmoststudiesshowedapositiveassociationbetweennon‐organochlorinepesticideexposureandfoetalgrowthoutcomes,especiallylowbirthweight.Theyregardthisasapublichealthprioritybecauselowbirthweightincreasestheriskofdeath,diseaseanddisabilityininfancyandchildhood,andoflong‐termadversehealthoutcomesinadulthood,suchascardiovasculardisease,type2diabetes,osteoporosis,depressive disorders, and some cancers (Perera & Herbstman 2011; Sanborn et al 2012).Intrauterine growth influences adultmetabolic disorders such as high blood cholesterol,fatty liver and obesity, and non‐metabolic disorders like chronic lung disease (Perera &Herbstman2011).Decreased head circumference, also found in some studies, is associated with lowercognitiveabilityinolderchildrenandadults(Sanbornetal2012).Anumberofpesticideshavebeenfoundtoaffectfoetalgrowth,including:

atrazine: decreased head circumference (Chevier et al 2011), intrauterine growthrestriction(Colborn&Carroll2007);

chlorpyrifos: significant reduction in head circumference (Berkowitz et al 2004),decreasedbirthweightandlength(Pereraetal2003;Whyattetal2004);

2,4‐D:pre‐termbirths(Colborn&Carroll2007); metolachlor: intrauterine growth restriction (Colborn & Carroll 2007), and decreased

birthweight(Barretal2010b).Pre‐term births have been associated, in epidemiological studies, with use of herbicidesespecially atrazine, 2,4‐D and OPs (Colborn & Carroll 2007), andmaternal exposure to DDT,endosulfanorHCH(Wigleetal2008;Pathaketal2010).

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Foetalloss:Resultsofstudiesaremixedbutsomepositiveassociationsbetweenpesticideexposureandfoetal losshavebeen found.Bothpaternal andmaternalexposure topesticides, includingoccupational andhomeuse, hasbeen linked to still births (Goulet & Thériault 1991; Rupa et al1991;Taha&Gray1993;Nurminenetal1995;Pastoreetal1997;Medina‐Carriloetal2002),withonestudylinking itparticularlytoexposureduringthesecondtrimester(Whiteetal1988),andonetopaternal exposure to DDT (Cocco et al 2005). Foetal death has been found to be higherfollowingmaternaloccupationalexposuretopesticidesroundthetimeofconception(Rondaet al2005).Sanbornetal (2012)reviewed fiveotherstudies thatall reportedanassociationbetween foetal loss andworking in greenhouses or horticulture as a proxy for pesticideexposure.Colborn&Carroll(2007)reportonstudiesthathaveassociatedexposuretoatrazine,2,4‐D,andglyphosatewithfoetalloss.

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3.5  Respiratory problems The review of pesticides and health issues by the Ontario College of Family Physicians(Sanbornetal2012)concludedthat:“Overall, there is evidence that exposure to pesticides, and to organophosphate orcarbamate insecticides in particular, is associatedwith the development of respiratorysymptomsandaspectrumofobstructiveandrestrictivelungdiseases.Studiesofasthmainchildren reported an association between maternal exposure to organophosphate andorganochlorine insecticides,while respiratory tract infections in infants were linked tomaternalexposuretoorganochlorineinsecticidesintwoofthreereviewedstudies.”

The association with asthma was found for occupational, domestic and environmentalexposuresespecially toparathionandcoumaphos. Inall12studies theauthorsreviewed,there was a consistent positive association between pesticide exposure and asthma –specificallyformaternalorganochlorine,organophosphate,biocideandfungicideexposure.Inuteroandpost‐natal(tooneyear)exposureswereassociatedwithasthmaandwheezeuptosixyearsofage(Sanbornetal2012).There is evidence too of an association between exposure to pesticides and chronicbronchitis,althoughtheassociationisnotasrobustasforasthma,withanoddsratioof<2.The strongest relationship was for paraquat, with OC, OP, carbamate and pyrethroidinsecticidesallshowinganassociation(Sanbornetal2012).Occupationalexposuressuchasinfarming,pesticidemanufacturing,andpesticidesprayingall showed a “subtle but persistent association between decreased lung function andexposure to a broad range of herbicides and insecticides”. Most striking was a strongassociation between chlorpyrifos and wheeze, chronic cough and shortness of breath inmanystudies.Carbamate,organophosphate,andneonicotinoidinsecticidesingeneralwereassociatedwithrestrictedlungfunction.Sarcoidosisandfarmer’slungwerebothassociatedwithoccupationalexposuretoinsecticides(Sanbornetal2012).3.6  Metabolic disorders – obesity, diabetes, metabolic disease Inrecentyearsscientificattentionhasbeguntofocusonenvironmentalfactorsimplicatedinescalatingratesofobesity,diabetesandmetabolicdisorder,aconditioninwhichobesityis associated with hypertension, type 2 diabetes and cardiovascular disease. As a resultthere are now a number of peer reviewed studies linking pesticide exposurewith theseconditions(Leeetal2006,2007;Rignell‐Hydbometal2007;Jonesetal2008;Montgomeryetal2008).Particular attention is being paid to prenatal and early childhood exposures, especiallythose causing what is known as foetal programming, in which in utero exposures causeepigeneticchangesthat leadtooverweight,obesity,anddiabetes,with theseeffectsbeingpassedontosubsequentgenerations(Newboldetal2007;Valvietal2012).Pesticides, especially organochlorines, are thought to cause weight gain are throughinterferencewiththemechanismsinvolvedinweightcontrol.Thepesticidesarethoughttodisruptweight‐controllinghormonessuchascatecholamines,thyroidhormones,estrogens,testosterone, corticosteroids, insulin, growth hormone, and leptin; alter the levels of and

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sensitivitytotheneurotransmittersdopamine,noradrenaline,andserotonin;interferewithmetabolicprocesses;anddamagenerveandmuscletissues(Baillie‐Hamilton2002).A number of epidemiological studies have linked exposure to largely obsoleteorganochlorine insecticides,suchasDDT,with increasedbodymass index (e.g.Verhulst et al2009;LaMerrill&Birnbaum2011;Mendezetal2011;Valvietal2012).However,currentlyusedpesticidesarealsoimplicated:aDanishstudyfoundthatchildrenexposed prenatally to currently use pesticides – their mothers worked in greenhousesduringearlypregnancy–werenotonlybornwithlowerbirthweightbutbytheagesof6to11yearshadsignificantlyhigherbodymassindexandbodyfatpercentage,thelaterbeingnearlyone thirdhigher (Wohlfahrt‐Veje et al 2011).Laboratory studies supportsuch findings,with chlorpyrifos, parathion and diazinon found to have effects on rats that includeexcessiveweightgain,signsofapre‐diabeticstate,metabolicpatternsthatresemblesadultrisk factors for atherosclerosis and type 2 diabetes, and appetite disorders in adulthood(Aldridgeetal2004;Slotkinetal2005;Lassiter&Brimijoin2008;Lassiteretal2008;Adigunetal2010).Sulfonylurea herbicides and imidazole fungicides have also been identified as potentiallyimplicated in obesity and diabetes, because of their effects on weight gain, blood sugarlevels,orthepancreas(Thayeretal2012).In reporting on a workshop of scientists gathered to discuss the role of environmentalchemicalsindiabetesandobesity,Thayeretal(2012)commentedthat“thegeneralfindingsare that early‐life exposures to otherwise sub‐toxic levels of OPs results in pre‐diabetes,abnormalities of lipid metabolism, and promotion of obesity in response to increaseddietaryfat”.

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4. Key systemic impacts   4.1  Endocrine disruption  TheEndocrineSociety,anorganisationof15,000scientistsinmorethan100countries,hasrecently defined an endocrine disrupting chemical (EDC) simply as “a chemical thatinterfereswithanyaspectofhormonalaction”(Zoelleretal2012).Theendocrine,orhormonalsystem,isadelicatelybalancedsystemofglandsandhormonesthatmaintainhomeostasisinthebody,regulatingmetabolism,growth,responsestostress,the function of the digestive, cardiovascular, renal and immune systems, sexualdevelopment and reproduction, and neurobehavioural processes including intelligence(Birnbaum 2010). The mechanisms involved are complex and include binding to hormonereceptors where they exert agonist or antagonist effects, binding to allosteric sites6 andproducing unexpected effects, and interfering with hormone synthesis, metabolism,transportordegradation(Zoelleretal2012).Normalhormonalactionchangesoverthelifetimeofanindividual.Themostcriticalaspectof an endocrine disruptor is when exposure occurs, rather than the level of exposure.Becausetheendocrinesystemoperatesontinyamountsofhormones,endocrinedisruptionoccursatlevelsofexposurefarlowerthanthosenormallyconsideredtoxic.TherearetimeswhenthereisnonormalendogenoushormoneexposureandevenverylowdoseexposurestoEDCsatthesetimescanhavepotentandirreversibleeffects.Additionally,hormonesandhormonallyactivechemicalscancausedifferenteffectsatdifferentlevelsofexposure,andlowdoseexposurecommonlyexperiencedbyhumanscanhaveprofoundlyseriouseffectsevenwhenthehighdoseexposuresnormallytestedonratsinlaboratoriesmaynothaveaneffect. So EDCs cannot be regarded as if they are general toxins butmust be seen in thecontext of endocrine function under both normal and pathological conditions. In fact thedose response curve, normally assumed for general toxins to be positive and linear(monotonic), is never linear with hormones and EDCs but tends to be sigmoidal7 exceptwhen it isnon‐monotonic8.Additionally, there isnothreshold forEDCeffects.Thismeansthat the data normally used to register pesticides utterly fails to reflect the reality ofexposure to low levels of endocrine disrupting pesticides, especiallywhen that exposureoccursduringthecriticalstagesofdevelopmentinuteroandinearlychildhood.(Myersetal2009;Birnbaum2010;Zoelleretal2012)Exposures to EDCs during these early life stages can have permanent and irreversibleeffects, with severe health consequences throughout childhood and into adulthood, andevenforsubsequentgenerations,theeffectscontinuinglongaftertheexposuretotheEDChasceased.Someoftheeffectsdonotmanifestuntiladulthood.Mostofthehealthimpactsdescribedintheprecedingchaptercanbeprecipitatedbyendocrinedisruptioninthefoetaland early childhood stages – birth defects, cognitive development and behaviouralproblems; breast, prostate, testicular and cancers; diabetes, obesity, and cardiovascular

6Bindingtositesotherthanthereceptorsite.7S‐shapedcurve,inwhichthelowestdosesgivethegreatestresponses(Zoelleretal2012).8Notlinear;mostcommonnon‐monotonicdosecurveforEDCsistheinvertedU‐shapedinwhichintermediatedosesgivegreatestresponses(Zoelleretal2012).

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disease; allergies and asthma; and reproductive disorders including those of fertility andfecundity,precociouspuberty,andendometriosis(Myersetal2009;Birnbaum2010).In their 2011 reviewMnif et al (2011) stated there are “about” 105 endocrine‐disruptingpesticides, 46% ofwhich are insecticides, 21% herbicides, and 31% fungicides, althoughadditionalpesticidesare identified inotherstudies.McKinlayetal (2008)put the figureat127 pesticides; and PAN International’s list of HHPs (PAN Germany 2011), based on EUclassification for endocrine disruption (according to EU Regulation 1272/2008/EC) putsthefigureat98.Thetablebelowbrieflysummarisessomeoftheendocrineeffectsofthepesticidesofinteresthere.Table1:Somemammalianendocrinedisruptingeffectscausedbythepesticidesofinterest 

Pesticide Effect Biomonitoring Referenceatrazine Inhibitsandrogens,weakoestrogeniceffect.

Disruptshypothalamiccontrolofluteinisinghormonesandprolactinlevels.Inducesaromataseactivity,increasesoestrogenproduction.Damagesadrenalglandsandreducessteroidhormonemetabolism.

urine,semen,humanserum

Mnifetal2011

chlorpyrifos Androgenantagonist. urine,serum,maternalserum,umbilicalcord,hair

2,4‐D Synergisticandrogeniceffectwhencombinedwithtestosterone.

urine,semen Mnifetal2011

diuron Inhibitsactionofandrogens. Mnifetal2011

glyphosate Disruptionofaromataseactivity,preventionofproductionofoestrogens;causesproliferationofoestrogen‐dependenthumanbreastcancercells.

urine Lin&Gary2000;Mnifetal2011

imidacloprid Alterslevelsofluteinizinghormone,follicle‐stimulatinghormoneandprogesterone,decreasedtestosteroneandgrowthstimulatinghormone.

Kapooretal2011;Baletal2012

malathion Inhibitscatecholaminesecretion;bindstothyroidhormonereceptors.

urine,meconium,hair,semen

Mnifetal2011

MCPA ActivatespregnaneXcellularreceptor. urine,serum,semen,maternalserum,umbilicalcord

Mnifetal2011

paraquat Decreasestestosterone,follicle‐stimulatinghormone,luteinizinghormoneandprolactininmalerats.

Zain2007

simazine Inducesaromataseactivity,increasesoestrogenproduction.

Mnifetal2011

 Endocrinedisruptionbyexogenouschemicalsisnowfirmlyrecognisedasasignificantissueinenvironmentalhealth.TheStateoftheArtreportonendocrinedisruptorspreparedfortheEuropeanCommissionbyProfessorAndreasKortenkampandcolleagues(Kortenkampetal

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2011), describes them as “substances of concern equivalent to carcinogens,mutagens andreproductivetoxins,aswellaspersistentandbioaccumulativetoxicchemicals”.

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4.2  Immune system dysfunction The immunotoxicity of awide range of pesticideshasbeen established in laboratory andepidemiological studies, but few meta‐analyses are available, compared with endocrinedisruptors. However impacts on the immune system are important and can have far‐reaching results, especially for exposures that occur whilst immune function is stilldeveloping– fromconceptionuntilaroundage18when the thymusglandgainsmaturity(Corsinietal2008).Exposure to pesticides may result in decreased immunocompetence which can result inmore severe and prolonged infections, and the development of cancer; or immuno‐stimulation which can lead to immune‐mediated diseases, hypersensitivity reactions,inflammatoryresponses,asthma,allergiesandautoimmunediseases(Corsinietal2008;Hertz‐Picciotto et al 2008). Additionally it seems that there is a strong connection between thedevelopment of the immune system and that of the central nervous system, such thatdisruptiontocriticaleventsinthedevelopmentoftheimmunesystemmayresultinneuro‐behaviouralandpsychiatricdisorders(Hertz‐Picciottoetal2008).Evidence suggests that the outcome of exposure to pesticides depends on thewindowofimmunedevelopmentwhen the exposure occurs, and so the developmental status of theimmune system is a key factor in determining the resulting effects on health (WHO 2006).Foetal exposure to immunotoxic chemicals that cross the placenta may permanentlydamage the development of the immune system leading to deficient immunity andconsequent conditions such as asthma, type 1 diabetes, recurrent otitismedia, paediatriccoeliacdisease,decreasedresistance to infectiousdisease,reducedability to fightviruses,bacteria, parasites, tumour cells, autoimmune disease, hypersensitivity reactions, andchronicdiseaseslaterinlife(Peden2000;Milleretal2002;Dietert2011;Winansetal2011).Table2:SomeimmuneeffectscausedbythepesticidesofinterestPesticide Immuneeffect Referenceametryn Suppressionofhumoralimmuneresponse. Wiltroutetal1978atrazine DecreasedNKcellactivity(invitro‐human);

developmentalexposure(rats)causedalteredproliferativeresponsesinBandTlymphocytes.

Corsinietal2008;Winansetal2011

chlorpyrifos Increasedatopyandantibioticsensitivity (occupationalexposure);increasedCD26cells,autoantibodiesandautoimmunity;decreasedCD5cellsandproliferativeresponsetomitogens(environmentalexposure).

Corsinietal2008

diuron Inhibitedcytokineproduction(invitro‐human). Hoogheetal20002,4‐D Inhibitedcytokineproduction(invitro‐human);

respiratoryallergen;elevatedallergiesandhayfever(inutero‐humans).Exposureofadolescentandadultworkersassociatedwithproliferationoflymphocytesandanti‐nuclearantibodies.

Fukuyamaetal2009;Koojimanetal2010;USEPA2007;Weselaketal2008

glyphosate Autoimmuneblisteringofskinandmucousmembranesafterinhalingfumesofburningglyphosate(human).

Fisheretal2008

imidacloprid Increasedleucocytes,andimmunoglobulins,especiallyIgG;decreasedphagocyticactivity,chemokinesisandchemotaxis(human).

Mohanyetal2011

malathion Allergiccontactdermatitis(occupationalexposure). Corsinietal2008

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paraquat Decreaseinmacrophagecells;suppressionofTlymphocytes;increasedreleaseofhistaminefrommastcells(rats).InhibitedproliferationofTandB‐cells(mice).

Caroleoetal1996;Satoetal1998;Repetto&Baliga1996;Hassunehetal2012

simazine Inhibitedcytokineproduction(invitro‐human);decreasedTlymphocytes,inducedspleenimmunecellapoptosis(mice).

Hoogheetal2000;Kimetal2003;Renetal2012

5.   Groups at greatest risk People with compromised immune systems, with compromised livers that cannotadequately detoxify chemicals, and thosewith specific genetic variations thatmake themmoresusceptibletoforexamplebreastcancer,orwhichdecreasetheirabilitytometaboliseorganophosphateinsecticides,areallatgreaterriskthantheso‐calledaverageperson.But the group at greatest risk from exposure to pesticides are children. This is in partbecause their exposures are relatively greater than those of other non‐occupationallyexposedpeople,andinpartbecauseoftheirgreatervulnerabilitytotheeffectsofpesticides.5.1  Greater exposure Children eat and drink more than adults in relation to their body weight and so take in relatively more residues. Additionally, their diets tend to include greater amounts of the foods most commonly containing residues, i.e. fruits and vegetables (Landrigan et al 1999). Children eating organic diets in Seattle, USA, were found to have six times lower levels of metabolites of organophosphates in their urine compared with children eating a conventional diet (Curl et al 2003). And when the children changed to organic fruit and vegetables, their urinary levels of chlorpyrifos and malathion metabolites fell to undetectable almost immediately (Lu et al 2006, 2008). Children also inhale relatively more air than adults, making them more vulnerable to the effects of spray drift and household insecticides. A breathing rate approximately double that of adults, in the first 12 years of life (Miller et al 2002), together with relatively greater lung surface area means the amount of airborne residues reaching the lung surface in a 3-month old child is likely to be about 3-4 times that in adults (WHO 2006). Childrenliveclosertozonesofpotentialcontaminationsuchashousedustonthefloorandcontaminated soil outside. They put into their mouths various objects that may becontaminated,suchastoysafterhouseholdinsecticideuse,anddirtinthegarden.Levelsofhousehold pesticides in indoor air are higher in the infant breathing zone than the adultsittingzone(Fenskeetal1990).Notsurprisingly,significantlyhigherlevelsofthemetabolitesof pyrethroid insecticides, commonly used in households, were found in the urine ofchildrenthaninthatofadolescentsoradults,inaUSAstudy(Barretal2010a). There are two other routes of exposure to pesticides that are unique to children, and which unfortunately coincide with their most vulnerable stages of development: in the womb and at the breast. Children’s exposure to pesticides begins before they are born. Many pesticides can bereadilytransferredfromthemotheracrosstheplacentatothedevelopingfoetus(Dastonetal2004), and children are now frequently born carrying a significant load of pesticides,

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includingOCsandOPs(Whyatt&Barr2001;Barretal2010b).OnestudyinNewYorkfound29pesticides in the umbilical cord blood of newborn infants, themost common ones beingdicloran and chlorpyrifos (Whyatt et al 2003). Others included atrazine, metolachlor andmalathion. Residues are also found in meconium, the first faeces of newborns, whichprovides a kind of cumulative catalogue of what they have been exposed to in utero.Chlorpyrifosandmalathionhavebothbeenfoundinmeconium,alongwithatleastanother12pesticides(Ostreaetal2006;Barretal2007;Ostreaetal2009).Infants are then exposed to an additional load of contaminants through breastfeeding. Alargenumberofstudieshaveshownthatbreastmilkcommonlycarries loadsofpesticideresidues: at least 33 have beenmeasured including atrazine, chlorpyrifos andmalathion(Sanghietal2003;Pathak&Dikshit2011;Srivastavaetal2011). 5.2 Greater vulnerability Childrenaremorevulnerabletotheeffectsofpesticidesthanadultsbecauseof:5.2.1GreatertissuepermeabilityChildren’s skin is more permeable to pesticides; and the blood‐brain barrier, whichprovides someprotection to theadultbrainandnervoussystembypreventingchemicalsbeingabsorbedbythebrain,isnotfullydevelopeduntilabout6monthsofage(WHO2006).5.2.2ImmaturemetabolicpathwaysThe liver and kidney are still developing, so a child’s ability tometabolise, detoxify, andexcretechemicalsisalsostilldeveloping.Thiscanleadtogreaterconcentrationsandlongerhalf‐livesinthebodiesofchildrencomparedwithadults(Suketal2003;Daston2004).Newbornchildrencanbe65to164timesmorevulnerablethanadultstotheOPinsecticidessuchaschlorpyrifos (Furlong et al 2006) because the enzyme responsible for detoxifying them,Paraoxonase1(PON1)ispresentatverylowlevelsinchildrenundertheageoftwo(Furlongetal2005),three‐to‐fourfoldlowerthanthoseoftheirmothers(Hollandetal2006).5.2.3CriticalwindowsofdevelopmentalvulnerabilityChildrenundergo rapidgrowthanddevelopment throughout the firstyearsof their lives,especially whilst still in the womb, and the complex delicate processes involved areextremely vulnerable to derailment by pesticides and other toxic chemicals. Criticalwindows for such damage to occur stretch from the point of conception until aroundadolescence,dependingontheorgansystem.Forexample,thebrainisstilldevelopinguntiltheageof12,butchlorpyrifoshasitsgreatestimpactonneuralcellreplicationandneuralsignallingwith exposures before birth, and its greatest effect on the development of gliacells in the neonatal stage (Slotkin et al 2004). The brain, unlike some other organ systemscannot repaircells thathavebeendamaged,andexposure toevenvery small amountsofneurotoxins during criticalwindowsof earlydevelopment can change the architectureofthebrainforever(Selevanetal2000).Other organ systems are also vulnerable to early exposures to pesticides: fullimmunocompetenceisnotachieveduntilabout18yearsofage,andexposuresbeforethatcanresult inimmunosuppression,alteredresistancetoinfectiousandcarcinogenicagents,autoimmunity,hypersensitivity,orcarcinogenicity(WHO2006).Foetalexposureinparticularcan result in deficient immunity and consequent conditions such as asthma, decreasedresistance to infectious disease, reduced ability to fight tumours, autoimmune disease,

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hypersensitivityreactions,andchronicdiseaseslaterinlife(Peden2000;Milleretal2002;Winansetal2011).However, it is theendocrinesystemthat is themostvulnerableto insultsbypesticides intheearlystagesofachild’slife,andwiththemostprofoundoutcomes.Thissystemgovernsvirtually every organ and every process in the human body (Birnbaum et al 2010), andexposure to endocrine disrupting chemicals in utero can result in effects felt throughoutchildhood, into adulthood and even for successive generations if epigenetic effects result(WHO 2006). All of the effects described in the previous chapter can be precipitated byendocrine disruption in the foetal and early childhood stages, including birth defects,behavioural problems, cancer, diabetes, obesity, cardiovascular disease, immune effectsincludingallergiesandasthma;andreproductivedisordersincludinginfertility,precociouspuberty,andendometriosis,andevenosteoporosis(WHO2006;Myersetal2009;Birnbaum2010).5.2.4MoretimetodevelopchronicdiseasesLogically, childrengenerallyhavemoreof their life still aheadof them thando adults, sotheyhavealongertimeperiodoverwhichdiseasesandconditionsprecipitatedbyexposuretopesticidescandevelop.Thisisparticularlyrelevantfordiseasessuchascancerthathavealonglatencyperiod,i.e.thatrequireyearsorevendecadestoevolvefromtheinitiationofthediseasetoitsactualmanifestation(Suketal2003).Thereisincreasingscientificevidenceforwhatistermed‘thedevelopmentaloriginsofadultdisease’:manydiseasesaretriggeredbyfoetalandneonatalexposuretoenvironmentalchemicalsthatwouldnotnormallycausesuchdiseasewithexposureslaterinlife(Newboldetal2007;Gillmanetal2007).Earlyexposuretoneurotoxicpesticidesmayincreaseriskofadult‐onsetchronicneurologicdiseasessuchasdementia,Parkinson'sdisease,andamyotrophiclateralsclerosis(Landriganetal1999;Suketal2003);andtoobesityanddiabetes(Lassiteretal2008).5.3. Future generations – epigenetic effects Exposure to toxic chemicals during embryonic and foetal development can result inpermanent re‐programming of heritable traits, with the effects lasting over a number ofgenerations. The chemical causes modification of the operation of the genes, or geneexpression,butdoesnotdamagetheDNAitself.Conditionsthatmaybepassedonthroughepigenetic effects of chemicals include cancer, reproductive abnormalities and diabetes(Grandjeanetal2008).Oneexampleisthatofthefungicidevinclozolin:exposureduringcriticalwindowsofdevelopmentforratembryosresultedinbreasttumourdevelopmentinatleastfoursubsequentgenerations(Anwayetal2006).

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6.   Key Scientific considerations 6.1 The difference between acute and chronic exposures Acuteeffectsarethosesignsandsymptomsexperienced,usually,afteramoderatetohighlevel of exposure, although for some people acute effects can occur at low levels ofexposure.Theycanrangefrommildskinsensationstodeath.Thetablebelowliststhemorecommonsymptomsofacuteexposuretopesticides.Table3:Someacutesymptomsofpesticidepoisoningnumblips,tonguesorethroatblurredvisionlacrimationheadachesalivationnosebleedswellingchestpain,tightness,wheezingsuffocation,difficultbreathingsweatingburningskinitchingblistersdiscolouredirregularnailsnausea,vomitingabdominalcrampsdiarrhoeauncontrolledurination

weakness,fatigue,lethargydizzinessdisorientation,confusionagitationinarticulatespeechdepressionmemorylossdifficultyinwalkinganxiety,restlessnessinvoluntarytwitchinghypotension,hypertensionrapidpulsemuscularpain,stiffnessmuscleweaknessbackpainseizuresparalysiscomadeath

Source:Watts2010Some acute effects, such as vomiting, headaches, respiratory problems, eye and skinirritation,andstomachtroubles,areoftenconfusedwithcommonillnesses(Watts2010).Chronic effects, such as cancer,neurodegenerativediseases, and reproductiveeffects, canarisefromongoingexposuretoapesticide,orasalong‐termsequelofanacuteexposure.Forexample,OPinsecticides,wellknownforbeingacutelyverytoxic,canalsocauselong‐term damage to the nervous system and undermine the immune system. Visible acuteeffects may represent the tip of the iceberg, with chronic effects going unrecognised.Chroniceffectsarecomplexanddifficulttolinkbacktopesticideexposureand,especially,toprove.6.2 The added toxicity of ‘inert’ ingredients Pesticidesareappliedasformulatedproductsthatcontaintheactiveingredient,whichhasthe killing power, and other ingredients usually called inert ingredients, or inerts,whichhaveavarietyoffunctionssuchas(NPIC 2011):

preventingcakingorfoaming;

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extendingproductshelf‐life; helpingtheproductsticktothesurfaceofleavesandsoil,spreadoversurfaces,or

dissolveinwater; allowingherbicidestopenetrateplants; preventingcloggingduringapplication;or makingingredientscompatible.

Inthiscontextinertdoesnotmeannon‐toxic,itonlymeansthatitisnotthekillingagentintheformulation(USEPA2012).Infactinertingredientsusedinpesticidesmayhavebiologicalactivityandsomecanbehighlytoxic(NPIC2011).Theycanincreasedevelopmentaltoxicity,genotoxicityanddisruptionofhormonefunction,andenhancetoxicitytothecardiovascularsystem and mitochondria. They can also increase dermal absorption and decrease theprotectiveness of clothing. Glyphosate formulations have been found to cause greatergenotoxicity,toxicitytoplacentalcells,inhibitionofprogesteroneproduction,andreducedactivity of the enzyme aromatase than the active ingredient alone. Formulations of 2,4‐Dcausedhumanbreastcancercellstoproliferatewhereastheactiveingredientdidnot.OneformulationofatrazineincreasedDNAdamageinhumanlymphocytesbuttheactivealonedidnot.(Cox&Surgan2006)Inerts can also increase the ecotoxicity of pesticides to nontarget plants, animals andmicroorganisms.2,4‐Dformulationshavebeenfoundtobemoregenotoxictopoultrythantheactive ingredientsalone.Oneglyphosate formulation isup to100timesmore toxic tofishthattheactivealone.Someglyphosateformulationsarealsomoretoxictotadpolesandciliatedprotozoa.(Cox&Surgan2006)Inerts can also affect the distribution of pesticides in the environment, sometimesenhancing runoff, leaching and volatilisation. Run off from turf treated with a granularformulationofimidaclopridwastwiceashighasthattreatedwithawettablepowder(Cox&Surgan2006).The enhanced effects experienced with the presence of some inert ingredients informulationsmaybe a result of direct toxic effect of the inert, or an interactionwith theactive(Cox&Surgan2006).Generally there is no requirement to identify the inert ingredients on pesticide labels orpublicallyavailableregistrationinformation,andpesticideproprietorsclaimtheir identityas confidential business information (Cox & Surgan 2006). This makes it impossible for thegeneralpublicorresearcherstoknowwhatisintheformulationsbeingused.Additionallybiomonitoringandenvironmentalmonitoringseldomincludesinertsingredients.6.3 Laboratory versus epidemiological evidence Therearetwobroadcategoriesofscientificresearchusedtostudytheeffects,andpotentialeffects,ofpesticidesonpeople:epidemiologicalstudiesandlaboratorystudies.6.3.1LaboratorystudiesLaboratorystudiesareusedtoidentifypotentialandlikelyeffectsofexposuresonhumans.Theycanbefurtherdividedintoinvivo,andinvitrostudies.Invivostudiesinvolvetesting

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pesticidesonliveanimalsandobservingtheeffectsonbehaviour,weightchangesandothervisible parameters, taking blood samples, and eventually sacrificing the animals to studyeffectsontissuesandorgans.Invitrostudiesinvolveusingonlyacomponentoftheanimal,or human, isolated from its usual biological surrounding, such as cell cultures or tissuecultures, sub‐cellular components such asmitochondria or ribosomes, or cellular or sub‐cellularextractssuchasproteins,DNAorRNA.Specificcelllinesareoftendevelopedtotestparticular reactions – for example the human breast cancer cell line MCF‐7 has beendevelopedtotesttheeffectsofchemicalsthatmayhaveoestrogenicproperties.Whilstregulatoryproceduresstillemphasisinvivostudies,manyscientistsprefertouseinvitrostudies,partlytoavoidunnecessarysufferingofanimals,andpartlybecausemoderninvitro techniquesallowforbetterelucidationofmechanismsofactionandsubtleeffectsofchemicals not evidentwhen intact animals are fed low,medium or high dose levels of achemical. Some scientists argue that in vivo studies better reflect the exposures humansmayexperienceandthatreactionsobservedininvitrostudiesmaynotberelevantinintactanimals.Othersarguethatstudiesonanimalsdonotnecessarilypredicteffectsinhumans.Laboratory generated data suffers from a number of flaws; for example with regard tomammarycarcinogensthefollowingflawswereidentifiedbyRudeletal(2007):

Atypicalcancerbioassayprogramusingsmallnumbersofanimalsandhighdosesinordertodetecteffectsisdesignedtodetectgenotoxiceffectsbutisunlikelytodetectnon‐genotoxiccarcinogens,suchas thosethataffectmammaryglanddevelopmentoract aspromoters,orhave transgenerationalepigeneticeffects (i.e. causebreastcancerinthesubsequentgeneration).

It cannot be assumed that all chemicals that are carcinogenic in rodents are alsocarcinogenicinhumansandviceversa;animaltestsmayfalselyidentifychemicalsasmammarycarcinogens forhumans,or conversely fail to identify chemicals thatareinfactmammarycarcinogensinhumans.

Typically the testsare carriedoutonpubertal animals andarenot carriedoutonyoungerdevelopinganimalswhichcanbeverymuchmoresensitivetotheeffectsofchemicals.

Typically thedurationof the studies–usually twoyears– is too short to identifymammarycarcinogenswithalongerlatencyperiod.

Thetests fail to identifytheeffectsofchemical interactionsbecausethey testonlyonechemicalatatime.

6.3.2 EpidemiologicalstudiesGood epidemiological studies are seen as the gold standard in proof of actual effects onpeople.Howevertheyarenotoriouslydifficulttocarryoutandespeciallytoestablishwithanacceptabledegreeofcertaintywhatlevelsofexposurehaveoccurred.There are a number of different types of epidemiological studies. Cohort studies selectsubjects based on exposures, and then follow them through time to assess their healthoutcomes– forexample theAgriculturalHealthStudy in theUS,whichhas followedover89,000pesticideapplicatorsandtheirspousessince1993(AHSundated).Case‐controlstudiesselectparticipantsbasedontheirdiseasestatusandcomparethosewithapositivediseasestatuswith thoseofanegativediseasestatus, lookingatpotentialexposures; forexamplethe case‐control studyofnon‐Hodgkin’s lymphomaandatrazine exposure in theUS (HoarZahmet al1993).Ecologicalstudies lookatpopulationsratherthan individuals; forexample

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the study by Van Leeuwen et al (1999) looked at the association between incidence ofstomachcanceranddrinkingwatercontaminationwithatrazineandnitrates.The validity of results of epidemiology studies can be severely compromised byconfounding factors, such as lifestyle factors, genetic andother environmental influences,and by the difficulty of establishing what exposures to pesticides occurred, especially atcritical periods of development such as in utero. Exposure tomixtures of chemicals andsynergismbetweenchemicalsisregularlyoverlooked.Brodyetal(2005)warnthatthereisalwaysastronglikelihoodofgenerating“inconclusivenegativefindings,whicharecommonincase‐controlstudiesofhard‐to‐assessexposurestopollutantsinthegeneralpopulation”;and the resultsof studies that fail to showanassociation contribute littlebecause “studydesignlimitationsmeanwecannotconcludefromnullresultsthatnoassociationexists”.6.4 Bioconcentration and bioaccumulation of pesticides Bioaccumulation refers to the accumulation of pesticides, or other chemicals within anorganism, usually the fatty tissues; and it occurs when the organism is absorbing thechemical at a greater rate than it is expelling ormetabolising it. Bioaccumulation occurswithpersistentsubstances,althoughnotallpersistentsubstancesarebioaccumulative.Bioconcentration refers to the increase in concentration of a chemical from theenvironment to the first organism in the food chain. Bioconcentration usually refers touptake fromwater,whereasbioaccumulationrefers touptake fromothersourcessuchassediment and food.Theconcentrationsof the substance continue to increaseup the foodchain (biomagnification), and can result in toxic accumulations and consequent healtheffects(Katagi2010).International criteria for bioconcentration and bioaccumulation are provided within theStockholm Convention on Persistent Organic pollutants. Annex D 1(c) of the StockholmConventionstates:

(i) Evidencethatthebioconcentrationfactororbioaccumulationfactorinaquaticspeciesforthechemicalisgreaterthan5,000or,intheabsenceofsuchdata,thatthelogKowisgreaterthan5;

(ii) Evidencethatachemicalpresentsotherreasonsforconcern,suchashighbio‐accumulationinotherspecies,hightoxicityorecotoxicity;or

(iii) MonitoringdatainbiotaindicatingthatthebioaccumulationpotentialofthechemicalissufficienttojustifyitsconsiderationwithinthescopeofthisConvention.

TheEuropeanUnionregulatoryprocesshasmorestringentcriteria(Rorijeetal2011):a)forsubstancesthatarebioaccumulativeinaquaticorganisms (i) BCF>2000 (ii) logKow>4.5b)forsubstancesthatareverybioaccumulativeinaquaticorganisms (i) BCF>5000 (ii) logKow>4.5

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7.   International concerns and approaches 7.1 Endocrine disruptors Endocrinedisruptionhasbeendescribedindetail insection5.1,anditshealtheffectswillnotberevisitedhere.ThereisawealthofscientificknowledgeoftheimportanceofEDCsonhumanandenvironmentalhealth,yetregulatoryprocesseshavebeenveryslowtocatchupwith the science and regulators have been dismissive of potential effects. There has notevenbeenglobalconsensusontheimportanceofendocrinedisruption–untilveryrecently.In September 2012, the 3rd International Conference of Chemical Management (ICCM3),which implements the voluntary global agreement, Strategic Approach to InternationalChemicalManagement(SAICM),agreedunanimouslytoincludeendocrinedisruptorsasanemerging issue within SAICM, recognizing (by consensus) “potential adverse effects ofendocrine disruptors on human health and the environment” and “the need to protecthumans,andecosystemsandtheirconstituentpartsthatareespeciallyvulnerable” (ICCM32012). ICCM3 also agreed the need for international cooperation to build awareness anddisseminateinformationonendocrinedisruptingchemicals,aswellasbuildingcapacitytoreducerisksfromthem,signallingthatactionneedstobetakenattheregulatorylevel.Meanwhile,no country, includingAustralia andNewZealand,hasanadequate regulatoryprocessforEDCs.Kortenkampetal(2011)providedaStateoftheArtreportonEDCsfortheEuropeanCommission inDecember2011, including recommendations forEU regulationsforEDCs.EUchemicalregulationsdolaydowntestingrequirementsforEDCsbutthey“donot capture the whole range of endocrine disrupting effects that can be measured withinternationally agreed and validated test results”. The EU has recognised at least 98pesticidesasendocrinedisruptorsplacingthemin2categoriesdependingonthestrengthofevidence(EURegulation1272/2008/EC).In2010,theUSEPAreleaseditsdraftguidancefor its firststageofscreeningEDCs,Tier1.Only67chemicalshavebeenselected,despitethe evidence showing there aremanymore pesticides alone, than this (Schmidt 2012). TheguidelinesarecriticisedbytheEndocrineSocietyfortestingonlyalimitedsetofendpointsthat do not reflect understanding of endocrinology principle’s, and of testing at doses sohightheywillmisslowdosenon‐monotoniceffects(Zoelleretal2012).7.2 Low dose exposures For some decades now environmental health scientists have been concerned about lowdoseexposures–inparticularlythetheorythatlowdosesofchemicalscanhaveeffectsthatarenotpredictedfromhighdoseexposures(Birnbaum2012).Laboratory studies on animals, the key toxicological studies that are used for registeringpesticides,aretypicallycarriedoutatthreedoseranges: ‘low’,mediumandhigh,withtheexpectationofapositivedoseresponse:thehigherdosescausegreatereffectthanthelowerdoses.ThesestudiesareusedtodetermineNoObservedAdverseEffectsLevels(NOAELS)andLowestObservedAdverseEffectsLevels(LOAELS);fromthesearederived ‘reference’doses,whichareassumedtobesafeforhumans(Birnbaum2012).However,asexplainedinthesectiononendocrinedisruptors,suchassumptionscannotbemade,especially inthecaseofendocrinedisruptorswherea lowerdosemaycauseworse

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effectsthanahigherdose.Endocrinedisruptionoccursatlevelsofexposurefarlowerthanthose normally considered toxic (Birnbaum 2010). Low dose exposures, commonlyexperienced by humans, can have profoundly serious effects even when the high doseexposuresnormally tested on rats in laboratoriesmaynothavean effect (Myers et al 2009;Birnbaum 2010). Effects have been observed on animals at very low doses in laboratories(Melnick et al 2002; Bulayeva & Watson 2004; Wozniak et al 2005), and on fish at or below thedetectionlimits(EC2004).Humansexperienceenvironmentalexposureto thousandsofsyntheticchemicalsat levelsthoughttobesafefromariskassessmentperspective,butwhichcannolongerbeassumedtobesafe.Lowinternaldosesofendocrinedisruptorsfoundinhumanpopulationsarenowlinked with obesity, infertility, neurobehavioural disorders, and immune dysfunction(Birnbaum2012).7.3 Chemical mixtures Inpesticideregulatoryprocesses,risksareestimatedforasinglepesticideatatime;butthereality of human experience is that people are constantly exposed to complex chemicalmixtures, with some of the chemicals having additive effects and others synergisticinteractionstomagnifythedamagingeffectsorevencausenewkindsofharm(Schettleretal2000).In 2009 Kortenkamp et al, in their State of the Art Report on Mixture Toxicity for theEuropean Commission, concluded that there is good evidence chemicals with commonspecificmodes of action, and chemicalswith differentmodes of action,work together toproducecombinationeffectsthatarelargerthantheeffectsofeachmixturecomponentbyitself. Additivity is most commonwith chemicals of commonmode of action. Hence anyconcentration of a pesticide needs to be considered, regardless of whether or not it ispresent at levels above or below its effect threshold, because it adds to the mixtureconcentration. This phenomenon, termed ‘something from nothing’ has been repeatedlydemonstrated forabroadrangeofchemicalmixtures in toxicologicalandecotoxicologicalstudies.Kortenkampetalreiteratedthisview,withrespecttoendocrinedisruptors,in2011:“Thereis good evidence that several EDCs can work together to produce combined effects.Especially when exposure is to multiple chemicals simultaneously that are capable ofaffecting the sameendpoint, combination effects canoccuratdoseswhere each chemicalindividuallyiswithoutdetectableeffects”(Kortenkampetal2011).AdditivityistheusualmodeforcombinationeffectsofEDCs(Kortenkampetal2009).Synergisticeffectshavebeennotedwithcarcinogens thatact togetheron thesame targetorganor tissue, and there is “overwhelming evidence” that carcinogenswork together toexert tumour‐promoting effects after sequential or simultaneous exposures.There is alsoevidence that genotoxic and mutagenic chemicals can work together at very lowconcentrationstoproducemixtureeffects(Kortenkampetal2009).Hayesetal(2006b)examinedtheeffectsoffourherbicides(alachlor,atrazine,metolachlor,nicosulfuron), three insecticides (cyfluthrin, cyhalothrin, tebupirimphos), and twofungicides(metalaxylandpropiconazole)aloneorincombinations,onmetamorphosis,time

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tometamorphosis,andgonadaldifferentiation innorthern leopard frogs.They foundthatthemixtureshadmuchgreatereffectsthanindividualpesticidesininhibitinglarvalgrowthanddevelopment.Dimethoate,glyphosateandzineb,exhibitedmixturetoxicitywhentestedonrats,withthecombinationcausinggreateroxidativestressintheplasma,liverandtestes,anddecreaseinhormonelevels,thanwhenadministeredalone(Astizetal2009).In2012Hernándezetal,inareviewoftoxicologicalinteractionsatmolecularlevels,drewattention to the ability of organophosphate insecticides to potentiate (i.e. enhance) thetoxicity of pyrethroids, carbaryl, and triazine herbicides. Additionally, mixtures of 5organophosphates (chlorpyrifos, diazinon, dimethoate, acephate and malathion) haveproducedgreaterthanadditiveeffects(i.e.synergisticeffects)onlaboratoryanimals.Kortenkampetal(2009)concludedthatitispossibletopredictthetoxicityofchemicalmixtures,especiallywheredoseadditionoccurs,withreasonableaccuracyandprecision,butthisapproachisnotsofarbeingimplementedinanyregulatoryregimeforpesticides.Theyalso stated: “There is scientific consensus in the fieldofmixture toxicology that thecustomarychemical‐by‐chemicalapproachtoriskassessmentmightbetoosimplistic.It isin danger of underestimating the risk of chemicals to human health and to theenvironment.”7.4  Precaution 

Since1982therehasbeenwidespreadadoptionoftheprecautionaryprincipleinanumberof international treaties and conventions, a number of them addressing pesticide issues,includingtheStockholm Convention on Persistent Organic Pollutants (POPs) and the Strategic Approach to International Chemicals Management (SAICM). It is variously expressed in these documents but one of the most widely accepted versions is known as the 1998 Wingspread Statement on the Precautionary Principle (SEHN 1998): When an activity raises threats of harm to human health or the environment, precautionary measures should be taken even if some cause and effect relationships are not fully established scientifically. The precautionary principle was designed to deal with situations exactly such as thoseinvolving ongoing low dose exposures to multiple pesticides. It provides a framework,procedures, and policy tools for situations of scientific complexity, uncertainty andignorance,where there is a need to act before there is strong proof of harm in order toavoid,orreduce,potentiallyseriousorirreversiblethreatstohealthortheenvironment.Itacknowledges that pesticides are inherently hazardous and should be presumed harmfuluntilprovenotherwise,andacceptstherealitythatthelong‐termimpactsoftoxicchemicalsaredifficulttopredictandoftenimpossibletoprove.7.5   Hazard versus risk assessment in pesticide regulation Most current pesticide regulatory processes are the exact antithesis of the precautionaryprinciple: theyarebasedonariskassessmentmodelwith itsunderlyingassumption that

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thereisa‘safe’levelbelowwhichatoxicpesticideisnottoxic(Antoniouetal2011).Howeverthere are numerousways inwhich this approach fails to take into account the effects ofpesticidesexperiencedineverydaylife,asalreadydescribedinthisdocument:

Risks are estimated for a single chemical at a time when in reality people areexposedtocomplexchemicalmixtures,withsomeofthechemicalshavingadditiveeffectsandothershavingsynergisticinteractions.

Existing body burdens of chemicals and cumulative effects are ignored indeterminingsafeexposures(Antoniouetal2011).

The positive‐dose response requirement fails to take into account endocrinedisruptionthatcanbestrongeratverylowdosesthanathighdoses.

There is a concomitant assumption of a threshold below which there is nosignificant toxicity, but any exposure level can be significant if mixture toxicityoccurs.

Thehighdoseprotocolsfailtoconsiderexposuresthatareenvironmentallyrelevantespeciallytotheunbornandnewborn,atcriticalstagesofdevelopmentfromfoetallifethroughtoadulthood.

Early life exposures, i.e. during critical windows of foetal development, are notgenerallyincludedinthetestsrequiredforregulatorypurposes(Makris2011).

Thesearejustsomeofthereasonsthatbestscientificthinking,andinternationalpractice,isnow moving away from risk assessment as the preferred methodology for regulatingchemicals,andreplacingitwithahazard‐basedapproach.TheEuropeanCommissionisthefirsttoenshrinesuchanapproachinmodernlaw,completewithcut‐offcriteriaforcertainhazardous qualities, such as carcinogenicity, mutagenicity, developmental neurotoxicity,developmental immunotoxicity, and endocrine disruption. Unlike the old risk assessmentmodelthisapproachdoesnotassumethatwhenahazardexiststheriskcanbemanaged.Insteaditisbasedontheviewthatifaparticularhazardexists,alesshazardousalternativeshouldbeused.GovernmentssuchastheU.S.,Australia,andNewZealand,andthepesticideindustry,areallstillstronglyopposedtothisapproachandarefightinghardtoretainariskassessment approach. However, at the global level there is progress: a conference roompaper at ICCM3 calling for “theprogressivebanofHighlyHazardousPesticides and theirsubstitutionwith safer alternatives”, although blocked by several developednations,wassupportedby65countries.TheCounciloftheFoodandAgricultureOrganisation(FAO)ofthe United Nations in 2006 decided on a new policy approach that would include “theprogressivebanofhighlyhazardouspesticides”(FAO2006).Europehasinstitutedsuchasystem,toalimitedextent,althoughthehazardcut‐offcriteriaarestillinsufficienttoprotectchildren.Industryisfightingtoothandnailtopreventhazardassessmentgaininggroundagainstriskassessment(Antoniouetal2011),butitisvitalthattheoldindustry‐protectiveregimebereplacedwithanewonesupportiveofpublichealthandparticularlychildren’shealth.7.6   Substitution Thesubstitutionprinciplebroadlyrequiresthereplacementofhazardouspesticidesbylesshazardousalternativeswhileattemptingto(i) reducethehazardasmuchaspossible, (ii)retainorincreasefunctionalityoftheoriginalsubstanceasmuchaspossible,and(iii)keep

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costsaslowaspossible(Hanssonetal2011).Thepriorityaccordedeachofthesepointswillbedetermineddifferentlyindifferentsettingsdependingonthevaluesofthoseinvolved.Thesubstitutionprinciplehasbeen inuse since the1985,when itwas first incorporatedintoSwedishpesticidepolicy:

“According to the Swedish Act on Chemical properties (SFS 1985, p 426) section 5‘anyonehandlingor importingachemicalproductmusttakesuchstepsandotherwiseobservesuchprecautionsasareneededtopreventorminimizeharmtohumanbeingsortotheenvironment.This includesavoidingchemicalproducts forwhich lesshazardoussubstitutesareavailable’.” Bergkvistetal1996

The substitution principle can be applied at two levels: the first involving onlyconsideration of less hazardous pesticides, the second involving consideration of non‐chemical methods of pest, weed, and disease management (the latter approach issometimes called informed substitution – Hansson et al 2011). The first approach, that issimplechemicalsubstitution,ismorecommonlyused,forexampleintheREACHlegislationoftheEU.HoweverSweden’sNationalBoardofAgriculturedidtakethesecondapproach:

“If equally effective, non‐chemicalmethods are available for a certaincontrolapesticidewillbebannedforthatcontrol.”

Liden1989The StockholmConventiononPersistentOrganicPollutants also embodies both chemicalandnonchemicalsubstitutesasreplacementsforchemicalslistedundertheConventionforglobalphaseout.AccordingtoHanssonetal(2011)substitutionshouldbeseennotasasingledecisionbutasacontinuousdevelopmenttowardssaferprocesses.Hanssonetal(2011)alsoprovidethefollowinglistofmethodstopromotesubstitution:

i) increasingtheavailabilityoftoxicitydataii) increasingtheavailabilityofdataonthechemicalcompositionofmaterials(e.g.

ofinertsinpesticides)iii) increasingtheavailabilityofinformationabouttechnicalfunctionalityiv) developinggreenchemistryv) helpdeskfunctionsvi) listofunwantedsubstancesvii) positivelistsviii) banofdangeroussubstancesix) requiredsubstitutionplansx) economicincentives

7.7  Minimum Harm There is one further principle that needs to be considered here briefly, and that is theprinciple of minimum harm. This principle essentially extends the substitution principleand turns the question ‘what is a safer alternative’, on its head, to ask ‘what is the leastharmfulwayofcontrollingtherelevantpest,weedordisease’(Watts2000).Ifimplementeditwouldmeanthatapesticidewouldonlyberegistered if there isno lessharmfuleffective

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wayofmanagingtheparticularpest,weedordisease,includingbynon‐chemicalmethods.The principle has been given expression formany years, e.g. inRespect ofNature (Taylor1986),andevenacknowledgedbytheWorldBankwhichstatedthat“tobeethicaltheprojectwith the least environmental impacts should be selected” (Montague 1996), but is not yetenshrinedinpesticidelegislation.

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8.   Conclusion Peopleareexposedtopesticidesthroughmanyroutes,includingspraydrift,skincontactevenfornon‐users,andinfoodanddrinkingwater.Childrenarebornpre‐pollutedwithpesticides,andreceiveadditionaldoseswhenbreast‐fed.There is sufficient evidence that many pesticides, including some of those found in thewatersaroundGreatBarrierReef,maybecausingarangeofadversehumanhealtheffects,suchascancer,neurodevelopmentalproblems,andbirthdefects,forallpeopleinvolvedinthemanagementofpestsandpesticides to takeaprecautionaryapproach,andsubstitutethemwith less hazardous alternatives including nonchemicalmethods. In fact, all peopleinvolved, from government policy makers and regulators to users should be asking theprimary question first: how tomanage pests effectively by themethods least harmful tohumansandtheenvironment.Children are especially vulnerable to the effects of pesticides, particularly those causingendocrine disruption and immune effects. Endocrine disruption, still not regulatedsufficientlybyanycountry,hasbeenrecognisedatthehighestinternationallevel,theUN’sInternational Conference on Chemical Management, as an emerging issue of concern,signallingthatactionneedstobetakenattheregulatorylevel.Actionalsoneedstobetakenataregulatoryleveltorecognisetheproblemsofongoinglowdoseexposuretomixturesofpesticides, the effects of which are not adequately addressed by the standard riskassessment of individual pesticides. For this reason there is amove internationally awayfromriskassessmentandtowardsregulatingonthebasisofhazard.References AbdelRasoulGM,AbouSalemME,MechaelAA,HendyOM,RohlmanDS,IsmailAA.2008.Effectsofoccupationalpesticideexposureonchildrenapplyingpesticides.Neurotoxicology29(5):833‐8.Adigun AA, Wrench N, Seidler FJ, Slotkin TA. 2010. Neonatal organophosphorus pesticide exposure alters the developmental trajectory of cell-signaling cascades controlling metabolism: differential effects of diazinon and parathion. Environ Health Perspect 118:210-5. AHS. Undated. Welcome to the Agricultural Health Study. National Institutes of Health. http://aghealth.nci.nih.gov/study.html. AlavanjaMCR,BonnerMR.2012.Occupationalpesticideexposuresandcancerrisk:areview.JToxicolEnvironHealthBCritRev15(4):238‐63. Alridge JE, Seidler F, Slotkin TA. 2004. Developmental exposure to chlorpyrifos elicits sex-selective alterations of serotonergic synaptic function in adulthood: critical periods and regional selectivity for effects on the serotonin transporter, receptor subtypes, and cell signalling. Environ Health Perspect 112(2):148-55. AndersenHR,SchmidtIM,GrandjeanP,JensenTK,Budtz‐JørgensenE,KjaerstadMB,BælumJ,NielsenJB,SkakkebækNE,MainKM.2008.Impairedreproductivedevelopmentinsonsofwomenoccupationallyexposedtopesticidesduringpregnancy.EnvironHealthPerspect116(4):566‐72.

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