Atrazine Re-Evaluation:Scientific Considerations in PotentialSensitivityof Infants & ChildrenPresentation to Scientific Advisory PanelJuly 26-29, 2011Eli b thMé dPh DElizabethndez,..Health Effects DivisionUSEPA Office of Pesticide ProgramsUSEPAOfficeofPesticideProgramsFQPA 10X Safety FactorAnalysisThe FFDCA, as amended by the FQPA (1996), requires theA t i i l tt ti t th t ti l i k t i f tAgencyto give specialattentiontothe potentialrisktoinfantsand children. Specifically, FQPA instructs EPA, in making its“reasonable certainty of no harm” finding, that in “the case ofth h ld ff tdditi l t f ld i f f tfthresholdeffects,an additionaltenfoldmargin ofsafetyorthe pesticide chemical residue and other sources of exposureshall be applied for infants and children to take into accounti ldl ii d l fpotentapre- anpost-nataltoxicity andcompleteness ofdata with respect to exposure and toxicity to infants andchildren.” Section 408 (b)(2)(C) further states that “theAdministrator may use a different margin of safety for thepesticide chemical residue onlyif, on the basis of reliabledata, such margin will be safe for infants and children.” This2additional margin of safety is referred to as the “FQPA SafetyFactor.”FQPA 10X Safety FactorAnalysisH d C id ti•HazardConsiderations• Important Issue: available data to assess criticallifestages• Consider all the relevant information•Mode of actionModeofaction• Animal database of toxicology studies• Dose-response relationships• Human relevance of animal findings• Epidemiology findings3FQPA 10X Safety FactorAnalysis•Hazard Considerations (cont’d)• Consider all relevant information• Neuroendocrine MOA relevant for reproductive anddevelopmental effects•Epidemiology findings discussed during SeptemberEpidemiologyfindingsdiscussedduringSeptemberSAP meetingQualitative information on human relevance of animal findingsNot sufficiently robust to establish causal associations4FQPA 10X Safety FactorAnalysis•Hazard Considerations (cont’d)• Experimental toxicitystudiesy• Core guideline toxicity studies (multigenerationreproduction and developmental toxicity studies)St di ifilif t( t tii tl•Studies on specificestagesgestation, pernatal,peripubertal, and reproductive age)•None of the available studies provide endpoints lowerNoneoftheavailablestudiesprovideendpointslower(i.e., more sensitive) than studies on LH attenuation5FQPA 10X Safety FactorAnalysisAUTHOR(YR)EXPOSURENOAEL/LOAEL/k /dEFFECT( )mg/kg/dayGestational Exposure(2008) GD14-parturition 10/50 Delayed PPSR t l (2005)GD 1319NA/100Delay in mammaryRayner etal.(2005)GD13-19NA/100Delayinmammarygland developmentRayner et al. (2005) GD 17-19 NA/100Delay in mammarygland developmentR t l (2007)GD 1519NA/100P t titiRayner etal.(2007)-ProstatitisFraites et al.(2011)GD 14-21 20/100Decreased pup weightand pup viability (PND1-4)†Davis et al.(2011)GD 14-21 20/100Decreased pup weightand pup viability (PND0-4). Delay in VO6†Decreased maternal body weight was alsoobserved at the 100 mg/kg/day dose levelFQPA 10X Safety FactorAnalysisAUTHOR (YR) EXPOSURENOAEL/LOAELmg/kg/dayEFFECTPerinatal ExposurePND1412 5/25ProstatitisStoker 1999-412.5/25ProstatitisPND 6-9 NA/25Non-stat sigprostatitis7FQPA 10X Safety FactorAnalysisNOAEL/LOAELAUTHOR (YR) EXPOSUREmg/kg/dayEFFECTPeripubertal ExposureStoker et al ., 2001 PND 23 to 53 6.25/12.5 Delayed PPSTrentacoste et al .,2001PND 22 to 47 50 lowest dose/100 Delayed PPSStoker et al ., 2001 PND 23 to 53 25/50 Decreased VP and SVTrentacoste et al .,2001PND 22 to 47 50 lowest dose/100 Decreased VP and SVStoker et al ., 2001 PND 23 to 53 ND/200Decreased intra-testicular T on PND 45Trentacoste et al .,2001PND 22 to 47 ND/50Decreased T on PND47Friedmann, 2002 PND 22 to 47 ND/50Decreased test. andserum T on PND 47Pogrimic et al ., 2009 PND 23 to 50 50/200Decreased T/DHT onPND 50Laws (2000)PND 224125/50Delayed VO8Laws(2000)PND22-4125/50DelayedVO‡Lowest dose testedFQPA 10X Safety FactorAnalysisMultiLifestagestudy•-Lifestage• Exposure encompassing prenatal, postnatal,peripubertal, and adult lifestagesp• Evaluated female offspring only• No effects on LH at≤50 mg/kg/day (highest dosetested)• Inconsistent with preponderance of peer reviewed literature(e.g.,Foradori et al. 2009, Cooper et al. 2007, 2010 andMorseth et al. 1996).• Slight delay in VO (1.4 – 2.3 days) at 50 mg/kg/day ifexposure startedin uterobutnotif it startedpostnatallyy9FQPA 10X Safety FactorAnalysisMulti-Lifestage Study10FQPA 10X Safety FactorAnalysis•Summary•Data available spanninglifestagesDataavailablespanninglifestagesfrom conception to adulthoodf• No evidence oa unique quantitativesusceptibility in the developingorganism11FQPA 10X Safety FactorAnalysis•Summary (Cont’d)• Reproductive/developmental effectsconsistent with perturbations of the HPG axisD i LH ti l k t•DecreasesinLHserve as sentinelkey eventin atrazine’s neuroendocrine MOA that leadsto adverse outcomes in rats(delays inpubertyyp yonset, ovarian cyclicity disruption, inhibition ofsuckling-induced prolactin release/prostatitis)•No effects at doses lower than those eliciting the LHNoeffectsatdoseslowerthanthoseelicitingtheLHsurge attenuation in adult female rats (BMDL1 std. dev=2.56 mg/kg/day).1213FQPA 10X Safety FactorAnalysisAUTHOR (YR) EXPOSURE NOAEL/LOAEL mg/kg/day EFFECTCooper (2007) 4days adult cycling♀NA/25↓GnRH releaseCooper (2000) 1 day adult cycling♀NA/300 mg/kg↓LH surge, estrous cyclicity disruption3 day adult cycling♀NA/50↓LH surgeCooper 2000 & 20104-dayadult cycling♀1.56/3.12↓LH surgeygMorseth (1996) 26 week 1.8/3.65↓LH surge, estrous cyclicity disruptionCooper (1996) 21 days NA/75 estrous cyclicity disruptionStokeret al., 2000 PND 23 to 53 NA/12.5Delayed PPSTrentacosteet al., 2001 PND 22 to 47 50 lowest dose/100 Delayed PPSStokeret al., 2001 PND 23 to 53 25/50Decreased VP and SVTrentacosteet al., 2001 PND 22 to 47 50 lowest dose/100 Decreased VP and SVStokeret al., 2001 PND 23 to 53 150/200Decreased intra-testicular T on PND 45Trentacosteet al., 2001 PND 22 to 47 ND/50Decreased T on PND 47Friedmann, 2002 PND 22 to 47 ND/50Decreased test. and serum T on PND 47Pogrimicet al., 2009 PND 23 to 50 50/200Decreased T/DHT onPND 50Lawset al.,2009 (2010) 15 minutes -♂rats 5./50 mg/kg↑ACTH. CORT, progesteroneFraiteset al.,2009 15 minutes – cycling♀N.A./75 mg/kg atrazine60.2 mg/kg DIA↑ACTH. CORT, progesteronePruettet al20091 hour–adult♀miceN A /200 mg/kg atrazineN A /200 mg/kg atrazine.,N.A./200mg/kgatrazineN.A./200mg/kgatrazinePruettet al.,2003 6 hours– adult♀mice N.A./100 mg/kg atrazineN.A./100 mg/kg atrazineFraiteset al.,2009 4 days – cycling♀N.A./12.5 mg/kg/day atrazine or 10 mg/kg/day DIA↑ACTH. CORT, progesteroneMcMullin (2004) 5 days – OVXD♀NA/30↓LH surgeForadori (2009) 4 days – adult♀NA/50↓LH surge50/100↓GnRH immunoreactive cellsZorrilla (2010)Ex vivo1/10μM↓GnRH releasePND 22-4125/50Delayed VOLaws (2000)PND224125/50DelayedVOPND 42-149 50/100Disrupted cyclicityShibayama (2009)2 or 4 weeks – start treating 5 wk old♀30/300Disrupted cyclicity,↓ovarian and uterine weights, ovarian, uterine histopath2 weeks pre-mating to GD 7 300/NANo effect in fertilityRosenberg (2008) GD14-parturition 10/50Delayed PPS14Rayner 2007 GD 15-19 NA/100Delayed PPS, prostatitisStoker 1999PND1-4 6.25/12.5ProstatitisPND 6-9 NA/25Non-stat sig prostatitisFQPA 10X Safety FactorAnalysisLife StageLH HormoneApical EndpointLifeStageLHHormone(NOAEL/LOAEL)ApicalEndpointNOAEL/LOAELPre-Natal (Fetus)•10/70 mg/kg/day; Delays inossification•10/50 mg/kg/day; DelayedPPS10/50mg/kg/day;Delayed•20/100 mg/kg/day; decreasedpup weight, viability, delayedVOPerinatal (Lactational)•12.5/25 mg/kg/day; increasedt titiprosasPeripubertal•6.25/12.5 mg/kg/day; increasedprostatitis, delayed PPS•25/50 mg/kg/day; delays invaginal openingpg•50/100 mg/kg/day; Delays invaginal opening, decreasedtestosteroneAdult2.56/4.92 mg/kg/day *(4 dayexposure)•50/100 mg/kg/day; disruptedcyclicity15*BMDL/BMD @ 1 standard deviation