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# Re-Evaluation of Human Health Effects of Atrazine: Review of Experimental Animal and In vitro Studies and Drinking Water Monitoring FrequencyElizabeth Méndez, Ph.D.Senior Scientist, Health Effects DivisionOffice of Pesticides Programmendez.elizabeth@epa.gov2



# OutlinezIntroductionzPeer Review Historyz2003 Human Health Risk AssessmentMode of Action (MOA) & Points of Departure(PODs)zCurrent reevaluationMammalian toxicity and 

# in vitrostudiesDrinking water sampling frequency3



# IntroductionzAtrazine widely used in the U.S.Approximately 70 million pounds a.i. per yearUsed primarily on cornzInterim Reregistration Eligibility Decision(IRED) finalized in 2003zRED finalized in 20064 

# Peer Review Historyz1988 SAP: Evaluation of rat mammary gland tumorsz2000 SAP: Evaluation of MOAMammary gland tumors, reproductive anddevelopmental findings in ratsHuman relevancez2003 SAP: Evaluation of prostate cancerEpidemiology study on relationship between atrazineexposure and prostate cancer in workers at atrazinemanufacturing plantz2009 SAP: Re-opening Atrazine Human Health EffectsEvaluationzFeb. 2010 SAP: Draft framework for incorporatingepidemiology and human incident datain risk assessment5 

# 2003 Human Health Risk Assessment6 

# Mode of Action (1)zMode of Action: Perturbation of hypothalamicpituitary-gonadal (HPG) axisz2003 Key events:Hypothalamic effects resulting in changes incatecholamine function and regulation of the pulsatilerelease of GnRHAttenuation of the LH surgeCessation of ovulation with the ensuing persistentrelease of estrogenIncreased prolactin release by the pituitary as asecondary consequence resulting from the elevatedestrogen levelsProlactin and estrogen-induced proliferative processesin the mammary gland leading to tumorigenesis7 

# Mode of Action (2)zHPG axis perturbationAttenuation of LH surgeMammary gland tumorigenesisDelayed puberty onsetzNot relevant for mammary tumordevelopment in humanszRelevant to assess potential non-canceradverse reproductive effects in humans8 

# Non-cancer EffectszAcute exposures: Delayed ossification in ratfetuses and decreased body weight gain in dams(NOAEL/LOAEL of 10/70 mg/kg/day)zShort exposures: Delayed puberty onset in males(NOAEL/LOAEL of 6.25/12.5 mg/kg/day)zIntermediate and long-term exposures:attenuation of Luteinizing Hormone (LH) surge9 

# Current Analysis10



# ObjectivezConduct objective and thorough review of new datazIntegrate new information with existing data to reevaluate hazard identification and dose-responserelationshipszDetermine the extent to which new science indicatesa need for the Agency to develop a new humanhealth risk assessmentzRe-consider, as appropriate, the frequency ofdrinking water monitoring conducted by Syngenta,the atrazine registrant11 

# Scope of Current AnalysiszMammalian toxicity and 

# in vitrostudiesThree databases searched (EMBASE, PubMed, Medline)Approximately 100 studies since 2003Additional information on atrazine’s MOAVarious types of toxicities reported in the literature:reproductive/developmental, immunotoxicity, neurotoxicity,genotoxicity, carcinogenicity as well as MOAzDrinking water sampling frequencyTwo approaches for monitoring drinking waterIntegrates the temporal aspects of the toxicity profile intothe sampling frequency12



# PresentationszMode of Action Analysis: Dr. Ralph CooperzImmunotoxicity Analysis: Dr. Robert LuebkezNeurotoxicity Analysis: Dr. John LiccionezSummary of Mammalian Toxicity: Dr. Elizabeth MendezNext stepszApproaches to Evaluating Water Sampling Strategies andFrequency of Monitoring: Dr. Nelson ThurmanzEvaluating the Performance of Sampling Strategies:Dr. Mary FrankenberryzArtificial Neural Network Modeling: Dr. Michael Messner13