Review of Atrazine CancerEpidemiologyCarol H. Christensen, Ph.D., MPHEpidemiologistHealth Effects Division, OPP1Previous Reviews•Previous FIFRA SAP ReviewsJ 2000B tO i P tt•une2000:Breast,Ovarian,Prostate, nonHodgkin lymphoma (NHL)•July 2003: Prostate CancerJuly2003:ProstateCancer• Triazine Manufacturing Plant Worker Studies•EPA Preliminary Conclusion October 2003 (IRED)• “The Agency does not find anyresults among the availablestudies that would lead us toconclude that potential cancerrisk is likely from exposure to atrazine...”• Re-visit when additional studies available, particularlyAgricultural Health Study (AHS)•Current Evaluation Updates and Extends• Emphasis publications since 20032Use of Epidemiologyin Risk AssessmentUse of Epidemiologyin Risk Assessmentssess e t•OPP “Framework” utilized to review atrazine cancerepidemiology literature:epidemiologyliterature• Identified studies evaluating atrazine risk•Described methodology (Appendix B 2)Describedmethodology(AppendixB.2)• Evaluated strengths and limitations (Appendices B.3-B.5)A li ti i l i / l i it i•Applicationinclusion/exclusion criteria• Method of exposure, outcome, and confoundermeasurement•Potential systematic error (bias)Potentialsystematicerror(bias)• Statistical Analysis and study power• Informative sensitivity analysesGenerali abilit3•GeneralizabilityUse of Epidemiologyin Risk AssessmentUse of Epidemiologyin Risk Assessmentssess e t•Results of cancer epidemiology studiessynthesizedandintegratedwith experimental database• Use of“Framework”document, considering postulated MOA,key events as well as:keyeventsaswellas:• Exposure-response• Temporality•Strength of associationStrengthofassociation• Consistency• Biological plausibility•Scientific JudgmentScientificJudgment•Formulateoverall conclusionoverallconclusion4Literature Review Methodology•Performed comprehensive review, broad range•Searched major biomedical databasesSearchedmajorbiomedicaldatabases(PubMed/Web of Science)• Aid of reference librarian (search string)• No date restriction, hand-search reference lists• Broad criteria: atrazine/triazine, cancer•Excluded: no full text available or exposure-only orExcluded:nofulltextavailable,orexposureonly,oreditorial/review articles• Multiple raters qualitatively adjudicated relevance/quality•40 studies in current cancer epidemiology review•Mid-1980’through May 2011sthroughMay20115Atrazine CancerEpidemiologyDatabaseAtrazine CancerEpidemiologyDatabasede o ogy atabase•Endocrine/ReproductiveSystem•Other AnatomicalCancer Sites• Prostate, Breast,Ovarian, ThyroidCancerSites• Brain/glioma,pediatric cancers•LymphohematopoieticTumors•Other AHS RiskEstimates (2003+)• Multiple Myeloma,Non-HodgkinEstimates(2003+)• Oral, colorectal,esophageal, pancreas,l bl dd lglymphoma (NHL),other sub-typeslung,bladder, melanoma,kidney, larynx, liver• 2 Cohort• 6 Nested Case-Control6Prostate Cancer•Triazine manufacturingplant studies•AHS Studiesplantstudies• Initial SIR elevated• 300 (110-652)•Bias partial explanation•1) Nested Case Control• OR 0.94(95% CI 0.78,•Biaspartialexplanation• Individual exposuremeasures, no associationamong PSA tested(1.14)•2) Cohort (2004)•OR Q5 v Q1: OR 0 88•Cancer Registry (CA)and Pesticide Use Data•Ecologic study•ORQ5v.Q1:OR0.88,(95% CI 0.63, 1.23), nolinear trend3) C h t (2011)•Ecologicstudy• Black males (ρ=0.67)• Nested case control(UFW)•Simazine OR 1 5 (95% CI•3)Cohort(2011)• OR Q4 v. Q1: OR 1.04(95% CI 0.89, 1.22), no•SimazineOR1.5(95%CI1.0, 2.3) [groupedexposure]linear trend7Prostate Cancer•Summary:•Among available studies those with stronger design andAmongavailablestudies,thosewithstrongerdesignandmethods do not suggest a positive association in populationsstudiedSt th f St di•Strengths ofStudies:• Consistent across study design, populations• Case-control, cohort; and,manufacturing, application• AHS evaluations performed with sufficient statistical power•Limitations of Studies:•Relatively few studies available (n=10)Relativelyfewstudiesavailable(n=10)• Aggregate exposure assessment method used in several• Stronger studies, primarily white, male applicators (AHS)C l ti bl k l t d (Mill 1998)•Correlation amongblackmales reported(Mills1998)8Breast Cancer•Ecologic Studies•Significant 10-20%•Case Control Study(WI)Significant10-20%increased risk, notreplicated in follow-up•Significant association in(WI)• OR Q5/Q1: OR 1.2 (95%CI 0.3, 5.8), adjusted•Drinking water robustSignificantassociationin1 of 2 geographic studysites•Cancer Registry (CA)•Drinkingwater,robustmethods, range (0.15 -3.0 ppb)AHS St di•CancerRegistry(CA)and Pesticide Use Data• No association observedCA L i•AHSStudies• Indirect (spouses):(n=309 cases) OR 1.1(95% CI 0 7 1 6)amongCALatinas• Ecologic-type exposureassessment(95%CI0.7,1.6)• Direct (applicators):(n=36 cases) OR 1.1(95% CI 0 5 2 5)(95%CI0.5,2.5)• Ever-use atrazine9Breast Cancer•Summary:•Although available epidemiology database is limited dataAlthoughavailableepidemiologydatabaseislimited,dataindicate strong positive associations unlikely•Strengths:• Consistent across available analytic studies among highlyexposed populations (high use area, ag workers, applicator)• Breast cancer risk factors measured in studies• Exposure measurement: sophisticated methods (drinkingwater), direct and indirect exposures measured, lifetime•Limitations:• Limited exposure range or ever/never metric, ecologicexposure measures used in 4 of 7 studiesSmall number exposed/highly exposed cases•Smallnumberexposed/highlyexposedcases10Ovarian Cancer•Ecologic Studies (2)•Inverse; no association•Cancer Registry (CA)and Pesticide Use DataInverse;noassociation•Population Based CaseControl (Italy, 1989)andPesticideUseData• OR triazine: 1.3 (95% CI0.8, 2.3)(n=20 exposed cases)•OR atrazine: 0 76 (95%• Cancer Registry,pesticide usequestionnaire, interviewORatrazine:0.76(95%CI 0.2, 3.6) (n=2 exposedcases)• <10% triazine exposed,• Triazine OR 2.7 (95% CI1.0, 6.9)• Lack adjustment other10%triazineexposed,questionnaire data,response rate•AHS Cohortpesticides• Relatively small sampleAHSCohort• Ever-Atrazine: OR 2.91(95% CI 0.6, 13.6)A iili9•proranayss;9cases• 4 atrazine exposed11Ovarian Cancer•Summary:•Although available epidemiological database is limitedAlthoughavailableepidemiologicaldatabaseislimited,positive associations observed, however alternativeexplanations may exist•Strengths:• Positive, suggestive associations observed in analyticstudies, including prospective study (AHS)• Hypothesis testing studies, based upona prioriknowledge• Highly exposed agricultural populations (worker, applicator)•Limitations:os• Small number exposed cases, imprecise estimates• Lack exposure-response, adjustment other pesticides12Thyroid Cancer•Prospective, large sample,lifetime exposure measure,ExposureDays(PPE)#CasesOR 95% CIother confounder information• Male applicators only(n=29 cases)(PPE)0-<20 3 1.0≥2056124 551 27 16 24• Adjusted BMI, otherpesticides• All thyroid cancers,≥20-56124.551.27,16.2456-178.5 3 1.16 0.23, 5.89y ,grouped•Test linear trend significantatp<0.10,non-monotonic≥178.5 11 4.84 1.31, 17.93Trend(p-value)0.08p ,•n<5 cases in specificexposure categories(pvalue)Beane-Freeman et al. 201113Thyroid Cancer•Summary:•Based upon only one epidemiologic study positiveBasedupononlyoneepidemiologicstudy,positiveassociations observed, and replication required•Strengths:• Strong association observed in study lack significant sourcesbias• Exposure-response evaluated•Limitations:• One study only•Grouped thyroid cancer sub-typesGroupedthyroidcancersub• No link hypothyroidism in other AHS investigation• Biologic mechanism not determined14LymphohematopoieticCancersMultiple Myeloma (MM),LeukemiaNon-Hodgkin Lymphoma(NHL)•Case control (Midwest)• No association: MM,Leukemia•Case control (Midwest)• Non-significant, positiveassociations earlystudies,• Strong design, lowpotential systematic error,small number casesy ,adjustment attenuated(range OR: 1.1, 2.2)• Pooled OR(n=650 cases)•Hospital based studies(France)(leukemias/lymphomas)El d i k f( )• 1.5 (95% CI 1.0, 2.5)• t(14:18) positive•OR 1 7 (95% CI 1 0 2 8)•Elevatedrisks,fewstatistically significant(HCL), notedF dOR1.7(95%CI1.0,2.8)•AHS Cohort• Initial, suggestive 2-foldi NHL MM t•Few exposedcases, noadjustment other pesticidesincreaseNHL,MMnotreplicated in extendedfollow-up (n=152 cases)15LymphohematopoieticCancersLymphohematopoieticCanrsce s•Summary•Among all available studies those with stronger design andAmongallavailablestudies,thosewithstrongerdesignandmethods do not suggest a positive association in populationsstudied•Strengths:• Recent studies prospective, large sample, evaluateexposure response and sub-types of cancer, exposurepp(reliable/valid)• Control for use of other pesticides•Limitations:• Small number cases for some LHP sub-types• Possible effect modification by t(14:18), not replicated• Primarily white, male target population16Other Cancer Sites•Brain/Glioma•Case-Control High-usePediatric AcuteLymphocytic LeukemiaCase-Control,High-usearea• Atrazine OR 1.1 (95% CI0 7 1 8)LymphocyticLeukemia(ALL)•Case control (CA)M t l id0.7,1.8)• No association amongmen, women•Case ascertainment•Maternalresidence,proxy pesticide exposure• OR triazines 4.1, (95% CI1 5 11 1) ti id•Caseascertainmentissues, other limitations1.5,11.1), pesticideadjusted, mid-rangegroupTi i t i•Triazines: atrazine,cyanazine, prometryn,pymetrozine, and simzineO l t d il bl•Only study available17Other AHS Cancer Sites•Other AHS Point Estimates• Based upon preliminary research• 2 Cohort Studies (2004, 2011)• 6 Nested Case Control Studies (2003+)• No evidence association:• Oral, colorectal, esophageal, pancreas, lung,bladder, melanoma, kidney, larynx, liver18Other Cancer Sites•Summary•Available preliminary studies do not strongly suggestAvailablepreliminarystudiesdonotstronglysuggestpossible associations•Strengths:• Several hypothesis generating reports, several amongstudies with strong design and methods (AHS)•Limitations:• Fewa priorihypotheses• Pediatric ALL: one study available, data are inconclusive•Lack biological plausibility at this timeLackbiologicalplausibilityatthistime19Synthesis of Epidemiology DataAnatomicalCancer SitesSynthesis ofEpidemiologic DataCurrentDatabase LimitationsLymphoma/Stronger studies(design Relativelyfew studiespLeukemia, Prostateg (gand methods) do notsuggest a positiveassociation inpopulations studiedyavailable each site; studypopulations primarilywhite, malespopulationsstudiedBreast, Thyroid, Ovarian Although availableepidemiological databaseis limited, somepositiveRelatively few studiesavailable each site, smallnumber exposed cases,islimited,somepositiveassociations observed,however alternativeexplanations may existnumberexposedcases,lack exposure-response(except thyroid)Oral, colorectal,esophageal, pancreas,lung, bladder, melanoma,kidney larynx liverAvailable hypothesisgenerating epidemiologystudies do not stronglysuggest a positiveSmall number cases insome instances, subtypes; lack biologicplausibilitya priorikidney,larynx,liver,brain/glioma, pediatriccancers)suggestapositiveassociation inpopulations studiedplausibility,apriorihypotheses20Weight of Evidence“Framework” AnalysisWeight of Evidence“Framework” Analysise o a ys s•Cancer Mode of Action (MOA): Mammary glandtumors in rats due to HPG axis disruptiontumorsinratsduetoHPGaxisdisruption• Mechanism not operative in humans• Current Cancer classification: Not likely• No other tumors identified in experimental toxicitydataW i ht f id d t t t i it•Weightofevidencedoes notsupportgenotoxicity,mutagenicity of atrazine•Experimental evidence does not indicate a role forExperimentalevidencedoesnotindicatearoleforatrazine in carcinogenic process in humans21Weight of Evidence:Prostate Cancer• Experimental toxicology and epidemiology dataconsistent, supportive of the conclusion of no association• Experimental toxicology•No evidence of prostate hyperplasia or tumorigenesis in ratNoevidenceofprostatehyperplasiaortumorigenesisinratRodent bioassay poor predictor of human prostate cancer• Observational Epidemiology• Among available studies, those with stronger design andmethods do not suggest a positive association in populationsstudied•Available data do not support association betweenatrazine exposure and prostate canceratrazineexposureandprostatecancer22Weight of Evidence:Breast CancerBreastCancer• Experimental toxicology and available epidemiologydata consistentdataconsistent• Experimental toxicology• Mammary gland tumors in female (SD) rats, not mice• MOA not relevant in humans• Observational Epidemiology•Although epidemiology database is limited available dataAlthoughepidemiologydatabaseislimited,availabledataindicate strong positive associations unlikely•Available data do not support associationbetween atrazine exposure and breast cancer23Weight of Evidence:OvarianCancerWeight of Evidence:OvarianCancera a Ca ce• Some inconsistencies between experimentaltoxicology and epidemiology datatoxicologyandepidemiologydata• Experimental Toxicology• No evidence ovarian pathology or tumorigenesis• Tumors may result from an altered endocrine environment,MOA supports reduced risk ovarian cancer“incessant ovulation” hypothesis• Observational Epidemiology• Although available epidemiological database is limited,positive associations observed however alternativepositiveassociationsobserved,howeveralternativeexplanations may existAvailable data do not support association•Availabledatadonotsupportassociationbetween atrazine exposure and ovarian cancer24Weight of Evidence:ThyroidCancerWeight of Evidence:ThyroidCancero d Ca ce•Experimental toxicology and only availableepidemiology study inconsistentepidemiologystudyinconsistent•Experimental Toxicology• No evidence thyroid hyperplasia or tumor formation, noralteration of thyroid hormones in rodents• Rat sensitive to thyroid (follicular cell) carcinogenesis (T-P)•Observational Epidemiology• Based upon only one epidemiologic study, positiveassociations observed, and replication required•Available data do not support associationbetween atrazine exposure and thyroid cancers25Weight of Evidence:LymphohematopoieticCancersWeight of Evidence:LymphohematopoieticCancersp o e atopo et c Ca ce s•Experimental toxicology and epidemiologicalevidence consistentevidenceconsistent•Experimental Toxicology• No evidence increase in LHP tumor formation• No evidence HPG, hormonal component to LHP cancers•Observational Epidemiology•Among available studies those with stronger design andAmongavailablestudies,thosewithstrongerdesignandmethods do not suggest a positive association in populationsstudied•Available data do not support associationbetween atrazine exposure andlymphohematopoietic cancers26Weight of Evidence:OtherSitesWeight of Evidence:OtherSitese S tes•Experimental and observational databases consistent•Experimental ToxicologyExperimentalToxicology• No evidence of tumor formation in rodent bioassays•Observational epidemiologygy• Available preliminary epidemiology studies do not stronglysuggest possible associations•Available data do not support associationbetween atrazine exposure and these othercancers27EPA Conclusion•“While some epidemiology studies are weaklysuggestive of an associationbetween atrazinesuggestiveofanassociationbetweenatrazineexposure and cancer incidence in the humanpopulation, the preponderance of the different lines ofidi l di b th i t l devence–includingbothexperimentalandepidemiology studies – does not strongly suggest arole of atrazineon human carcinogenesis. Thus, theweight of the evidence, at this time, supports thatatrazine is not likely to be carcinogenicin the humanpopulation”.28Questions for Clarification•Thank You29