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àà0 àÔ2ÔÔ3  Ô ÿÿ?AGMSYaioIndent0I.A.1.a.(1)(a)i)a)< Œ 9p`(&Times New Roman&Pxr8Mac DefaultMac DefaultÓ ` °šX°œXÓ(92`$¡¡Ý ƒ xrÿÝÓ ` °šX°œXÓÝ  Ý(ÈhH  Z 6Times New Roman Regular  U U E U Ubb¼F<&3|x(ÈhH  Z 6Times New Roman Regular Ñ „ ÑPtPtPHHÚ(ÿáÿâùFP(üPHHÚ(d'd"rþ\Styl{WP}01’ÃÃÃÃÃÃÃÃÃÃÃÃÃÃÃÃÃÃà Ãà Ãà Ãà Ãà ÃÃÃÃÃÃÃÃÃÃÃÐ ÐÐHHÐÐ  ÐÐ2ÐÐÿÿ¸æ$ÿÐÐHHÐÐÐÐÐÐÐÐ  ÐÐ ÐÐ ÐÑÑÑGenevaÑÑ ÑÑ € ÑÑ<Px–ÈÑÒÒÒ443!#4ÒÒ$ *$ÒÒ$*$ÒÒ ÿKK ÒÒ  Geneva ÒÒ  Geneva ÒÓ.,ÓÓÓÓ6ÓÓ ÓßßßßßßßßßßßßßßßßßßÑTimesÑÑ ÑÒ sc:Sys Times ÒÒ sc:Sys Times Ò Ñ ° ÑÝ ƒ!`!ÝÓ ` °šX°œXÓÝ  ÝÓ ` °—X` °šXÓÔ€&±(&&&ÔÔ€ô^Ãô&&±(Ôò òÔ‡'ôˆ+ ôôô^ÃÔññÑ€(¿[ÑññññÑ€+Oa ÑññFax„On„DemandÐ ° ÐFax€Number:€(202)€401„0527ÌItem:€6060Ô€'XÍäX ô'ôˆ+Ôó ó€Ô#†XTpXX'XÍä˜#ÔÔ€X>ÙXXXTpÔÐ @ ÐÌÓ  Óò òÔ€#XÍäXXX>ÙÔTHE€AGENCYððS€RESPONSES€TO€PUBLIC€COMMENTS€ON€THE€DRAFT€FQPAÐ øH ÐSCIENCE€POLICY€DOCUMENT:ó ó€Ð è8 ÐÌòòGuidance€for€Identifying€Pesticide€Chemicals€That€Have€a€Common€Mechanism€of€ToxicityóóÐ È  ÐÔ€#&<&X#XÍäÔ(Announced€August€8,€1998;€63€FR€42031,€FRL„5797„7.)Ô€#XÍäX&#&<ÔÐ ¸  ÐÌ(ññ€ññJanuary€ññ29,€1999ññññ€ññññ)ñññ ñÌñ ñÌÓ  ÓÌà  àThe€Agency€reviewed€all€comments€pertaining€to€this€document€that€were€submittedÏspecifically€under€this€docket€(OPP„00542)€or€in€relation€to€the€Tolerance€ReassessmentÏAdvisory€Committee€(TRAC).€€A€listing€of€the€names€and€affiliations€of€the€individualsÏsubmitting€comments€is€provided€at€the€end€of€this€document.€€The€Agency€would€like€to€thankÏthese€organizations€for€critically€reviewing€the€document,€and€for€providing€recommendations€toÏimprove€the€document.€€All€comments€were€extensively€reviewed€and€considered€by€the€Agency.€ÏMany€of€the€recommendations€made€by€the€commentors€were€incorporated€into€the€revisedÏdocument.€€Most€of€the€comments€were€similar€in€content,€and€pertained€to€general€issuesÏdealing€with€grouping€of€chemicals€for€purposes€of€cumulative€risk€assessment,€or€specificÏsections€within€the€draft€document.€€To€facilitate€review€and€consideration€of€the€comments€forÏpurposes€of€revising€the€document,€the€Agency€grouped€the€comments€in€accordance€to€nature€ofÏthe€comment,€or€issue€or€section€of€the€document€with€which€they€addressed.€€Following€is€aÏlisting€and€description€of€the€more€significant€comments,€along€with€EPAððs€general€responses.€€ÏThe€numbers€used€in€the€summary€below€correspond€to€specific€commentors€(listed€at€the€end€ofÏthis€document).ÌÌòòA.€Purpose€and€Introduction€of€the€Document.óóÐ R¢ ÐÌà  àOne€commentor€[11]€stated€that€the€document€lacks€a€clear€statement€of€purpose.à Ð àÐ 2!‚ ÐSeveral€other€commentors€[2„6,€9,13]€appear€to€have€misunderstood€the€purpose€of€theÏdocument.€€These€commentors€were€of€the€impression€that€the€primary€purpose€of€the€documentÏis€to€describe€the€approach€EPA€will€use€to€assess€cumulative€toxicity€and€risk€from€pesticidesÏthat€have€a€common€mechanism€of€toxicity.€€The€purpose€of€the€document€is€stated€on€page€2:Ïð ðThe€primary€purpose€of€the€document€is€to€describe€the€approach€that€EPA€will€use€forÏidentifying€and€categorizing€pesticide€chemical€substances€that€have€a€common€mechanism€ofÏtoxicity.ðð€€€This€statement€is€retained€in€the€revised€version,€and€has€been€modified€to€includeÏother€substances€(i.e.,€non„pesticidal€substances).ÌÌà  àSome€commentors€[1,€2,€3,€9,€11,€15]€stated€that€the€opening€paragraphs€of€the€documentÏimply€that€the€issue€of€considering€cumulative€effects€is€new,€when€in€fact€it€has€been€a€legalÏrequirement€under€FIFRA€and€FFDCA€for€many€years,€and€promulgation€of€FQPA€has€not€madeÏcumulative€risk€assessments€a€new€requirement.€€The€Agency€agrees€that€FIFRA€and€FFDCAÐ b-²(, Ðmandated€prior€to€FQPA€that€in€registering€pesticides€and€setting€pesticide€tolerances€EPA€mustÏgive€appropriate€consideration€to€ways€in€which€consumers€may€be€affected€by€the€sameÏpesticide€chemical€or€by€other€ð ðrelatedðð€substances€that€are€ð ðpoisonous€or€deleterious.ðð€€TheÏAgency€has€always€given,€and€continues€to€give,€such€consideration€during€its€risk€assessmentsÏof€pesticides.€€The€historical€statements€in€the€opening€paragraphs€are€correct,€however,€in€thatÏmost€determinations€of€safety€made€to€date€by€the€Agency€for€pesticides€have€been€based€largelyÏon€the€potential€for€each€individual€pesticide€to€cause€a€particular€toxic€effect€rather€than€anÏassessment€of€cumulative€effects€of€more€than€one€pesticide€chemical€or€other€substance.€€It€wasÏthe€Agencyððs€intention€to€use€the€opening€paragraphs€to€inform€the€reader€that,€in€addition€to€theÏpre„exisiting€statutory€mandates,€FQPA€explicitly€mandates€the€Agency€to€consider€whenÏdetermining€the€safety€of€a€pesticide€the€possibility€of€cumulative€toxicity€to€human€health€thatÏmay€be€caused€by€exposure€to€other€pesticides€that€have€a€common€mechanism€of€toxicity.€€TheÏpurpose€of€the€guidance€document€is€to€describe€the€approach€that€EPA€will€use€for€identifyingÏpesticides€and€other€substances€that€have€a€common€mechanism€of€toxicity,€for€purposes€ofÏassessing€the€cumulative€toxicity€of€such€pesticides€and€other€substances.€€€Ìò òòòÌó óB.€Exposure€Issues.óóÐ ° ÐÔåÔÌà  àÔåÔEPA€received€a€number€of€comments€concerning€exposure.€€One€commentor€[1]€statedÏthat€grouping€of€chemicals€should€be€based€only€on€causing€a€common€toxic€effect€by€a€commonÏmechanism,€excluding€exposure€as€a€criterion€for€grouping.€€Other€commentors€[9,€11,€15]Ïsuggested€that€to€conserve€resources€and€fulfill€the€FQPA€mandates€more€accordingly,€EPAÏshould€do€an€exposure€assessment€first€and€use€exposure€as€a€basis€for€grouping.€€Hence,€groupÏonly€those€chemicals€which:€1)€have€overlapping€exposures,€2)€cause€a€common€toxic€effect,€andÏ3)€have€a€common€mechanism€of€toxicity.€€Some€commentors€[2,€5,€6]€stated€that€EPA€shouldÏnot€restrict€cumulative€risk€assessments€to€only€those€pesticides€within€a€common€mechanismÏgroup€for€which€there€is€concomitant€(i.e.,€simultaneous)€exposure€(as€stated€in€the€draft€version),Ïwhereas€other€commentors€[9,€15]€stated€that€the€Agency€should€restrict€cumulative€riskÏassessments€to€only€those€pesticides€within€a€group€for€which€there€is€concomitant€exposure.ÔåÔ€ÔåÔTheÏAgency€will€not€use€concomitant€exposure€as€a€criterion€for€grouping€chemicals€that€cause€aÏcommon€toxic€effect€by€a€common€mechanism,€because€it€has€no€bearing€on€whether€or€notÏsubstances€can€cause€common€toxic€effects€by€common€mechanisms.€€The€Agency€agrees€thatÏcumulative€toxicity€may€result€from€exposures€that€are€not€concomitant,€and€cumulative€riskÏassessments€performed€by€the€Agency€on€pesticides€and€other€substances€within€a€commonÏmechanism€group€should€not€be€restricted€to€only€those€for€which€there€is€concomitant€exposure.€ÏIn€revising€the€guidance€document,€previous€statements€that€concomitant€exposure€is€aÏprerequisite€for€conducting€cumulative€risk€assessments€have€been€removed.€€The€Agency€isÏcurrently€preparing€a€document€(see€next€paragraph)€that€will€describe€the€approach€EPA€will€useÏto€conduct€cumulative€risk€assessments€on€pesticides€and€other€substances€that€have€a€commonÏmechanism€of€toxicity.€€That€document€will€discuss€in€more€detail€all€the€factors€that€will€beÏconsidered€by€the€Agency€to€assess€cumulative€toxicity€that€may€be€caused€by€such€substances.ÌÌà  àSeveral€commentors€[1,€8,€9,€11,€15]€stated€that€there€is€a€lack€of€detail€or€discussion€onÏhow€the€Agency€plans€to€assess€exposure€when€conducting€cumulative€risk€assessments€onÏchemicals€that€have€been€grouped€by€common€mechanism€of€toxicity.€€Some€commentors€[4,€6,Ð ð-@), Ð9,€11,€15]€stated€that€the€document€needs€to€be€expanded€to€include€more€detail€on€how€theÏAgency€will€conduct€cumulative€risk€assessments€on€pesticides€that€have€a€common€mechanismÏof€toxicity.€€Two€commentors€[9,€16]€suggested€that€the€guidance€document€should€be€revised€toÏinclude€examples€on€how€the€Agency€will€apply€the€common€mechanism€guidelines,€assessÏcumulative€toxicity,€and€conduct€cumulative€risk€assessments.€€The€€Agencyððs€response€to€theseÏcomments€is€as€follows.€€First,€the€Agency€plans€to€make€available€within€the€next€six€to€twelveÏmonths€(at€public€forums€such€as€national€conferences,€FIFRA€Scientific€Advisory€PanelÏmeetings,€etc.)€specific€examples€of€how€it€will€apply€its€guidance€for€identifying€pesticideÏchemicals€that€have€a€common€mechanism€of€toxicity.€€Secondly,€the€primary€purpose€of€theÏdraft€document€is€to€describe€the€approach€that€EPA€will€use€to€identify€pesticides€and€otherÏsubstances€that€have€a€common€mechanism€of€toxicity.€€It€is€not€intended€to€describe€how€theÏAgency€will€assess€exposure€to€such€substances€and€the€cumulative€risks€that€they€may€pose.€€ÏThe€Agency€is€currently€preparing€a€separate€document€that€will€describe€the€approach€it€will€useÏto€conduct€cumulative€risk€assessments.€That€document€will€include€at€least€one€example€of€howÏthe€Agency€will€apply€the€guidance€described€in€the€draft€document.€€The€document€will€alsoÏcontain€discussions€on€how€the€Agency€will€evaluate€exposures€to€pesticides€that€have€a€commonÏmechanism€of€toxicity,€and€provide€examples€of€how€the€Agency€will€assess€cumulative€risksÏposed€by€such€pesticides.€€The€document€will€be€made€available€for€public€comment€in€June€ofÏ1999.€Ì€€€ÌòòC.€Consideration€of€Substances€other€than€Pesticides.óó€Ð pÀ ÐÌà  àOne€commentor€[4]€recommended€that€the€guidance€document€needs€to€be€expanded€toÏinclude€guidance€on€how€the€Agency€will€conduct€cumulative€risk€assessments€on€pesticidesÏ[and€other€substances]€that€are€not€toxic€via€a€common€mechanism€of€toxicity.€€The€Agency€didÏnot€include€such€guidance€because€it€is€beyond€the€scope€of€the€document.€€Some€commentors€[4,Ï5,€6]€pointed€out€that€the€focus€of€the€guidance€document€is€only€on€identifying€òòpesticidesóó€thatÐ ` Ðhave€a€common€mechanism€of€toxicity,€and€not€on€identifying€òòotheróó€òòsubstancesóó€(i.e.,€non„Ð P Ðpesticide€chemicals)€that€have€a€mechanism€of€toxicity€common€with€that€of€a€given€pesticide€orÏpesticides.€These€commentors€are€concerned€that€forthcoming€pesticide€cumulative€riskÏassessments€performed€by€the€Agency€will€exclude€non„pesticide€chemicals€that€are€toxic€by€aÏmechanism€common€with€that€of€a€given€pesticide€or€group€of€pesticides.€€The€Agency€agreesÏthat€the€focus€of€the€draft€document€is€on€identifying€and€grouping€pesticide€substances€that€haveÏa€common€mechanism€of€toxicity.€€Although€the€Agency€intends€to€use€the€approach€described€inÏthe€document€to€identify€pesticide€substances€and€other€substances€(e.g.,€drug€products,Ïchemicals€used€in€industry,€as€well€other€substances€used€in€commerce)€that€cause€a€commonÏtoxic€effect€by€a€common€mechanism,€this€intent€was€not€made€clear€in€the€draft€version.€€TheÏAgency€has€changed€the€title€of€the€document€and€has€made€other€editorial€changes€throughoutÏthe€document€that€broaden€its€scope€to€include€substances€not€used€as€pesticides.€€The€AgencyÏwishes€to€make€clear€that€it€will€include€other€substances€that€are€toxic€from€a€mechanismÏcommon€with€that€of€a€given€pesticide€or€pesticides€in€a€cumulative€risk€assessment.Ìñ ñÌñ ññ ññ ñÌÌñ ñÐ ð-@), Ðñ ñòòD.€Definitions€of€Certain€Terms.óóÐ ,`'* ÐÌà  àA€number€of€commentors€questioned€the€Agencyððs€definitions€of€certain€terms€used€inÐ ð-@), Ðthe€document.€€Several€commentors€questioned€the€Agencyððs€definition€of€ð ðcommon€mechanismÏof€toxicity.ðð€€Some€commentors€[1,€2,€3,€9,€11,€12,€15]€believe€that€the€Agencyððs€definition€isÏeither€too€broad,€unclear€or€needs€to€be€made€more€simple€and€rigorous.€€Other€commentors€[4,Ï5,€6]€believe€that€the€Agencyððs€definition€is€too€narrow€in€that€it€encompases€toxic€effects€that€areÏthe€same€in€nature€and€site,€but€doesnððt€encompass€toxic€effects€that€are€the€same€but€occur€atÏdifferent€sites.€€Commentors€4,€5€and€6€also€believe€that€the€Agencyððs€definition€departs€from€aÏdefinition€proposed€by€a€working€group€of€€the€International€Life€Sciences€Institute€(ILSI).€ÏAnother€commentor€[7]€believes€that€the€Agencyððs€definition€is€clear€and€appropriate,€andÏconsistent€with€the€definition€proposed€by€the€ILSI€working€group.€€One€commentor€[13]Ïbelieves€the€Agency€should€interpret€ð ðcommon€mechanism€of€toxicityðð€as€used€in€FQPA€to€meanÏð ðcommon€mechanism€of€actionðð,€because€the€latter€phrase,€in€the€opinion€of€the€commentor,€isÏless€descriptive€for€defining€or€describing€a€mechanism€of€toxicity.€€Several€commentors€alsoÏquestioned€the€Agencyððs€definition€of€ð ðmechanism€of€toxicity.ðð€€These€commentors€[2,€9,€11,€15]Ïbelieve€that€the€Agencyððs€definition€of€this€term€is€too€vague€or€general,€whereas€anotherÏcommentor€[7]€believes€that€the€Agencyððs€definition€is€appropriate.€€The€Agency€re„evaluated€itsÏdefinitions€of€these€terms.€€The€Agency€believes€that€its€definitions€of€the€terms€ð ðmechanism€ofÏtoxicityðð€and€ð ðcommon€mechanism€of€toxicityðð€are€sufficiently€clear,€and€consistent€with€that€ofÏthe€ILSI€working€group€and€the€intent€of€FQPA.€€However,€the€Agency€has€included€additionalÏdiscussion€(Section€III€of€the€revised€document)€that€adds€further€clarification€to€these€terms.€€ItÏalso€is€important€to€make€clear€here€that€the€Agency€develops€it€own€science€policies:€otherÏorganizations€do€not€develop€Agency€policies.€€While€the€Agency€may€utilize€the€expertise€ofÏscientists€from€sources€(e.g.,€ILSI)€outside€of€the€Agency,€and€consider€the€recommendationsÏmade€by€such€individuals€or€organizations€for€purposes€of€establishing€Agency€science€policiesÏor€practices,€the€Agency€does€not€have€to€accept€or€implement€any€recommendations€made€fromÏoutside€sources.€€Hence,€the€Agencyððs€definitions€of€terms€used€in€its€policy€documents€do€notÏhave€to€be€consistent€with€the€definitions€developed€or€recommended€by€individuals€orÏorganizations€outside€of€the€Agency.€€€ÌÌà  àSeveral€commentors€[9,€11,€15]€questioned€the€Agencyððs€definitions€of€ð ðtoxic€effectðð€orÏð ðcommon€toxic€effect,ðð€and€stated€that€the€Agency€needs€to€define€these€terms€more€clearly€or€beÏmore€specific.€€The€Agency€believes€that€its€definitions€of€ð ðtoxic€effectðð€and€ð ðcommon€toxicÏeffectðð€are€sufficiently€clear,€and€consistent€with€the€intent€of€FQPA.€€However€the€Agency€hasÏadded€some€additional€text€to€the€definition€of€ð ðcommon€toxic€effectðð,€and€has€added€additionalÏtext€in€Section€III€of€the€revised€document€that€adds€further€clarification€to€the€meaning€of€theseÏterms,€and€how€they€will€be€applied.€€€One€commentor€[16]€disagreed€with€the€AgencyððsÏdefinition€of€ð ðcumulative€toxic€effect.ðð€€This€commentor€stated€that€there€does€not€need€to€be€anÏoverall€increase€in€toxicity€to€be€cumulative,€and€suggested€that€the€Agency€remove€the€part€ofÏits€definition€that€states€there€is€an€overall€increase€in€toxicity.€€The€Agency€agrees€that€theÏcumulative€toxicity€following€exposure€to€two€or€more€chemicals€does€not€necessarily€have€toÏresult€in€an€overall€increase€in€toxicity€relative€to€exposure€to€any€of€the€chemicals€alone.€€TheÏAgency€has€clarified€its€original€definition€of€ð ðcumulative€toxic€effectðð€in€the€revised€version€ofÏthe€document.€€ÌÌòòñ ñÌÐ ð-@), Ðñ ñE.€Assessing€Cumulative€Toxicity.óóÐ ° ÐÌà  àSome€of€the€commentors€had€comments€pertaining€to€Section€IV€of€the€document:€ÏòòPolicies€for€Assessing€the€Cumulative€Toxic€Effects€Posed€by€Two€or€More€Pesticides€that€areÐ €Ð ÐToxic€By€a€Common€Mechanismóó.€€One€commentor€[9]€wants€the€Agency€to€clarify€this€section,Ð pÀ Ðby€providing€more€details.€€The€other€commentors€[11,€12,€15,€16]€who€commented€on€thisÏsection€questioned€the€example€that€poses€a€hypothetical€pharmacokinetic€interaction€betweenÏtwo€substances€and€describes€how€EPA€will€consider€such€an€interaction€in€its€evaluation€ofÏcumulative€toxicity.€€The€primary€purpose€of€the€document€is€to€describe€the€approach€that€EPAÏwill€use€to€identify€the€mechanism(s)€of€toxicity€of€individual€pesticides€and€other€substancesÏand€group€those€pesticides€and€other€substances€that€have€common€mechanisms€of€toxicity.€ÏWhile€a€description€of€how€the€Agency€will€proceed€with€assessing€the€cumulative€toxicity€ofÏsubstances€within€a€common€mechanism€group€is€beyond€the€scope€of€the€document,€the€AgencyÏbelieved€it€would€be€helpful€to€the€reader€to€mention€some€of€the€practicies€and€policies€that€theÏAgency€intends€to€use€when€assessing€the€cumulative€toxicity€of€pesticides€that€are€toxic€by€aÏcommon€mechanism.€€€€However,€the€Agency€is€currently€developing€a€separate€document€thatÏwill€describe€in€detail€the€policies,€practices€and€factors€the€Agency€will€use€or€consider€in€theÏassessment€of€cumulative€toxicity€(risks)€of€pesticides€and€other€substances€that€are€toxic€by€aÏcommon€mechanism,€and€will€be€made€available€for€public€comment€in€June€of€1999.€€TheÏAgency€no€longer€believes€that€discussion€of€assessing€cumulative€toxicity€is€necessary€in€theÏpresent€document.€€Hence,€the€Agency€has€made€extensive€revisions€to€section€IV€of€theÏdocument.€€The€Agency€agrees€that€the€hypothetical€pharmacokinetic€example€is€inappropriate.€ÏAccordingly,€the€Agency€has€removed€the€example€and€will€address€the€issue€of€pharmacokineticÏinteractions€in€the€cumulative€risk€assessment€document.€ÌÌòòF.€Use€of€Assumptions€or€Hypotheses.ó󀀀Р p ÐÌà  àSeveral€commentors€[1,€9,€10,€11,€14,€15]€expressed€concern€that€the€Agency€plans€to€useÏmany€assumptions€€and€hypotheses€when€elucidating€or€inferring€mechanisms€of€toxicity€ofÏindividual€pesticides,€and€grouping€pesticides,€or€recommended€that€the€Agency€not€use€defaultÏassumptions.€Many€of€these€commentors€questioned,€for€example,€the€Agencyððs€basis€forÏassuming€additivity€of€a€toxic€effect€when€assessing€cumulative€toxicity,€or€the€use€of€structure„¼activity€relationships€as€part€of€the€weight€of€the€evidence€approach€for€determining€mechanismsÏof€toxicity.€€ÌÌà  àHistorically,€the€Agency€has€used€and€continues€to€use€certain€key€assumptions€andÏhypotheses€during€essentially€all€phases€of€assessing€the€risks€posed€by€substances,€includingÏsubstances€that€are€(or€intended€to€be)€used€as€pesticides.€€It€is€a€necessary€aspect€of€riskÏassessment€for€the€Agency€to€make€reasonable€assumptions€and€use€appropriate€hypotheses€as€aÏpractical€means€of€filling€gaps€or€science€questions€that€may€be€too€difficult,€costly,€time„¼consuming€or,€in€some€instances,€impossible€to€fill€otherwise.€€The€Agency€believes€that€the€draftÏdocument€does€not€imply€that€the€Agency€will€use€an€unusually€large€amount€of€assumptions€orÏhypotheses,€or€use€them€inappropriately.€€Determinations€of€mechanisms€of€toxicity€will€beÏbased€largely€on€a€weight€of€scientific€evidence,€and€not€on€many€assumptions€or€hypotheses.ÏThe€Agency€anticipates,€however,€that€in€the€process€of€identifying€pesticides€and€otherÐ ð-@), Ðsubstances€that€have€a€common€mechanism€of€toxicity,€assumptions€and€hypotheses€may€need€toÏbe€made€and€used€on€occasion.€€As€alluded€to€in€the€draft€guidance€document,€assumptions€andÏhypotheses€will€be€used€when€they€are€scientifically€defensible.€€Comments€pertaining€to€the€useÏof€structure„activity€relationships€or€the€assumption€of€additivity€are€addressed€separately€below.Ìò òòòÌó óG.€Use€of€the€Phrase€ð ðMechanism€of€Toxicity.ððóóÐ ` ° ÐÌà  àTwo€commentors€[13€and€16]€suggested€that€the€EPA€should€abandon€the€phraseÏð ðmechanism€of€action€€[or€toxicity],ðð€and€replace€it€with€ð ðmode€of€action€[toxicity].ðð€€TheseÏcommentors€believe€that€the€latter€phrase€is€more€appropriate€because€it€is€less€descriptive.€ÏFQPA€specifically€mandates€that€EPA€assess€the€cumulative€toxic€effects€of€pesticides€that€haveÏa€common€mechanism€of€toxicity.€€Therefore,€the€Agency€will€continue€to€use€the€phraseÏð ðmechanism€of€toxicityðð,€for€purposes€of€clarity€and€consistency€with€FQPA.ÌÌòòH.€€Use€of€Genetic€Alterations€as€a€Basis€for€Preliminary€GroupingóóÔåÔ.Ð Ð  ÐÌà  àÔåÔOne€commentor€[16]€stated€that€demonstration€of€chemically€induced,€genetic€alterationsÏis€by€itself€an€inadequate€basis€for€assuming€pesticides€or€other€substances€are€toxic€by€aÏcommon€mechanism€and€grouping€chemicals.€€The€Agency€agrees€with€the€commentor.€ÏHowever,€the€Agency€believes€that€this€commentor€misunderstood€the€Agencyððs€intended€use€ofÏinformation€pertaining€to€genetic€alterations.€€€The€Agency€stated€that€it€will€use€data€pertainingÏto€genetic€alterations€for€preliminary€grouping€only€(Figure€1,€step€1).€The€Agency€did€not€stateÏit€will€use€chemically€induced€genetic€alterations€as€a€basis€for€grouping€chemicals€for€purposesÏof€cumulative€risk€assessment.€The€Agency€will€use€genetic€alterations€as€a€basis€for€initialÏgrouping€only,€and€not€as€a€basis€for€conducting€a€cumulative€risk€assessment.€€ChemicalsÏinitially€grouped€by€genetic€alterations€will€undergo€further€evaluation,€as€with€any€otherÏchemical,€in€order€to€determine€their€mechanisms€of€toxicity€and€which€ones,€if€any,€have€aÏcommon€mechanism€of€toxicity.€€€€€ò òÐ P ÐÌó óòòI.€€Use€of€the€Terms€ð ðSimilarðð€or€ð ðAnalogous,ðð€and€Distinctions€between€ð ðMechanism€ofÐ à0 ÐToxicityðð€and€ð ðToxic€Effect.ððò òóóÐ Ð  Ðó óÌà  àSeveral€commentors€[€3,€9,€11]€objected€to€the€Agencyððs€use€of€the€terms€ð ðsimilarðð€orÏð ðanalogousðð€in€the€discussions€pertaining€to€comparing€toxic€effects,€toxic€mechanisms€orÏgrouping€of€compounds€by€toxic€mechanism.€€These€commentors€believed€that€these€terms€areÏnot€sufficiently€clear.€€Some€commentors€[9,€11]€asked€the€Agency€to€distinguish€or€define€theÏrelationship€between€ð ðmechanism€of€toxicityðð€and€ð ðtoxic€effect.ðð€€As€a€result,€the€Agency€hasÏincorporated€in€Section€III€of€the€revised€document€additional€statements€and€examples€thatÏmake€further€distinctions€between€ð ðmechanism€of€toxicityðð€and€ð ðtoxic€effect.ðð€€In€addition,€theÏAgency€has€added€the€terms€ð ðsite€of€toxic€actionðð€and€ð ðsite€of€a€toxic€effectðð,€and€includedÏdefinitions€of€these€terms.€€These€terms€provide€additional€additional€clarification€on€regardingÏthe€terms€ð ðmechanism€of€toxicityðð€and€ð ðtoxic€effectðð.€€€The€Agency€believes€that€the€termsÏð ðsimilarðð€and€ð ðanalogousðð,€as€used€in€the€document,€€are€sufficiently€clear€and€appropriate.€ÏHowever,€some€additional€clarification€of€the€meaning€of€these€terms€is€provided€here€in€theÏform€of€a€hypothetical€example.€€The€mechanism€of€toxicity€of€a€particular€commercial€substanceÐ ð-@), Ðthat€contains€a€primary€alcohol€moiety€(„CHòò2óóOH)€is€known€to€involve€metabolism€of€the€alcoholÐ ° Ðmoiety€to€a€carboxylic€acid€moiety€(„COOH),€and€that€it€is€the€carboxylic€acid€metabolite€thatÏcauses€a€particular€toxic€effect.€€Letððs€say€that€the€carboxylic€acid€metabolite€is€also€usedÏcommercially€as€a€separate€chemical€product.€€Test€data€show€that€it€causes€the€same€toxic€effectÏ(i.e.,€concordant€in€both€site€and€nature)€as€does€its€metabolic€precursor.€€Hence,€the€toxic€effectÏcaused€by€the€two€substances€is€common.€€Strictly€speaking,€some€may€feel€that€the€mechanismsÏof€toxicity€of€each€commercial€substance€are€not€entirely€identical€because€the€first€commercialÏsubstance€requires€metabolic€oxidation€whereas€the€second€does€not.€€However,€the€AgencyÏbelieves€these€mechanisms€are€ð ðsimilarðð€(or€ð ðanalogousðð)€in€causing€the€common€toxic€effect,Ïand€that€they€meet€the€Agencyððs€definition€of€common€mechanism€of€toxicity.€€ÌÌà  àThe€Agency€is€using€the€revised€guidance€to€identify€chemicals€that€cause€common€toxicÏeffects€by€common€mechanisms.€€The€results€from€these€investigations€will€be€made€available,Ïand€the€Agency€believes€the€results€will€further€demonstrate€how€the€meanings€of€the€termsÏð ðsimilarðð€and€ð ðanalogousðð€will€be€applied€by€the€Agency€when€identifying€mechanisms€ofÏtoxicity€and€grouping€(or€not€grouping)€chemicals.€€These€groupings€will€also€demonstrate€theÏrelationship€between€toxic€effects€and€mechanisms€of€toxicity.€Ìò òòòÌó óJ.€€Requests€for€Specific€Examples€of€Common€Toxic€Effects€and€Toxic€Effects,€and€of€SubstancesÐ à Ðthat€Cause€Cumulative€Toxic€Effects.ÌóóÌà  àSome€of€the€commentors€[9,€11]€asked€the€Agency€to€give€specific€examples€of€ð ðcommonÏtoxic€effectsðð€and€ð ðtoxic€effectsðð€that€could€be€used€for€either€initial€grouping€of€pesticides€thatÏmay€have€a€common€mechanism€of€toxicity€or€regulatory€purposes.€€The€Agency€provides€suchÏexamples€in€Section€II€and€Section€III€of€the€draft€guidance€document.€€The€revised€documentÏcontains€additional€examples€in€the€same€sections.€€Many€more€examples€are€available€in€theÏReregistration€Eligibility€Decision€(RED)€pesticide€documents€that€are€issued€by€the€EPAððsÏOffice€of€Pesticide€Programs.ÌÌà  àSome€of€the€commentors€[9,€11,€13]€requested€that€the€Agency€provide€specific€examplesÏof€substances€that€exhibit€cumulative€toxic€effects€through€a€common€mechanism€of€toxicity.€ÏThe€Agency€is€currently€developing€documents€that€will€describe€in€detail€and€provide€examplesÏof€how€the€Agency€will€accumulate€toxicity€and€assess€the€cumulative€risks€posed€by€pesticidesÏthat€are€toxic€from€common€mechanisms.€€The€documents€will€also€provide€specific€examples€ofÏsubstances€that€exhibit€cumulative€toxic€effects€from€a€common€mechanism€of€toxicity.€€Some€ofÏthese€documents€will€be€made€available€by€June,€1999.€€The€other€documents€will€becomeÏavailable€between€June€and€December€of€1999.Ìò òòòÌó óK.€The€Agencyððs€Policy€of€Assuming€Additivity.Ð P( #& ÐóóÌ€€à  àSeveral€commentors€[9,€11,€13,€15]€questioned€the€Agencyððs€policy€for€assumingÐ 0*€%( Ðadditivity€when€accumulating€toxicity€of€chemicals€that€have€a€common€mechanism€of€toxicity.€ÏAs€stated€in€the€document,€the€Agency€recognizes€that€the€magnitude€of€accumulation€of€a€givenÏcommon€toxic€effect€following€exposures€to€two€or€more€chemicals€within€a€given€group€ofÏpesticides€that€cause€the€effect€by€a€common€mechanism€may€be€equal€to€(i.e.€additive),€greaterÐ ð-@), Ðthan€(i.e.,€synergistic,€potentiated),€or€less€than€that€expected€by€addition€of€the€toxic€effect€asÏcaused€by€each€substance€individually.€€€The€Agency€anticipates,€however,€that€in€manyÏsituations€there€may€not€be€sufficient€experimental€data€to€determine€whether€the€magnitude€ofÏthe€accumulation€is€equal€to,€greater€than,€or€less€than€that€expected€by€addition€of€the€toxicÏeffect.€€€In€such€instances€the€Agency€will€assume€that€the€accumulation€is€additive.€€TheÏassumption€of€additivity€in€assessing€the€cumulative€toxicity€of€pesticides€that€cause€a€commonÏtoxic€effect€from€a€common€mechanism€was€presented€by€the€Agency€to€the€FIFRA€ScientificÏAdvisory€Panel€in€March€of€1997.€€The€Panel€concurred€with€the€Agencyððs€intended€use€of€thisÏassumption.€€In€addition,€it€is€the€general€practice€of€the€Agency€to€assume€additivity€in€assessingÏthe€health€risks€posed€by€two€or€more€chemical€substances.€€For€example,€the€AgencyððsÏdocument€entitled€ð ðGuidance€for€Conducting€Health€Risk€Assessment€of€Chemical€MixturesððÏ(USEPA/ORD€document€NCEA„C„0148,€June,€1998)€states€that€the€Agency€will€assumeÏadditivity€unless€data€to€the€contrary€are€available.€€à  àÐ ð@  Ðò òòòÌó óL.€€Use€of€Structure„Activity€Relationships.óóÐ Ð  ÐÌà  àSeveral€commentors€[1,€8,€9,€12,€15,€16]€raised€concern€about€the€Agencyððs€use€ofÏstructure„activity€relationships€for€purposes€of€identifying€mechanisms€of€toxicity.€€OneÏcommentor€expressed€concern€that€the€Agency€will€use€structure„activity€relationships€as€a€toolÏto€deliberately€impose€unnecessary€regulations€on€certain€pesticides.€€Other€commentors€believeÏthat€the€Agency€should€not€use€structure„activity€relationships€at€all€or,€if€they€must€be€used,€useÏthem€with€great€caution.€€The€Agency€is€well€experienced€with€using€structure„activityÏrelationships.€€The€Agency€will€use€structure„activity€relationship€data,€along€with€other€types€ofÏdata,€as€part€of€the€weight€of€the€evidence€in€determinations€of€mechanisms€of€toxicity€andÏjudgements€regarding€whether€to€group€or€not€to€group€chemicals.€€€The€use€of€structure„activityÏrelationships€for€such€purposes€was€presented€to€the€FIFRA€Scientific€Advisory€Panel€in€MarchÏof€1997.€€The€Panel€concurred€with€the€Agencyððs€intended€use€of€structure„activity€relationshipsÏfor€these€purposes.€€The€Agency€will€not€use€structure„activity€relationships€for€imposingÏð ðunnecessary€regulationsðð€on€pesticides.€ÌÌòòM.€€Burden€of€Proof.€óóÐ Ð  ÐÌà  àSeveral€commentors€raised€concern€regarding€burden€of€proof.€€These€commentors€[4,€5,Ï6]€believe€that€the€document€implies€that€the€burden€is€on€EPA€to€prove€that€compounds€have€aÏcommon€mechanism€of€toxicity.€€Under€FIFRA€and€FFDCA,€the€ultimate€burden€of€provingÏsafety€of€a€given€pesticide€rests€on€the€proponent€of€registration€(or€reregistration)€of€theÏpesticide.€The€FFDCA€also€requires€that€EPA€consider€the€possibility€of€cumulative€toxic€effectsÏresulting€from€exposure€to€the€pesticide€and€other€substances€that€are€toxic€from€a€commonÏmechanism€when€determining€the€safety€of€a€given€pesticide.€€The€science€guidance€documentÏexplains€the€approach€that€EPA€will€use€for€identifying€pesticide€chemicals€and€other€substancesÏthat€are€toxic€from€a€common€mechanism,€for€use€in€assessing€the€cumulative€toxicity€posed€byÏsuch€substances.€€The€document€is€not€intended,€in€any€way,€to€address,€much€less€alter,€theÏburden€of€proof€as€established€by€existing€statutes.€Ìñ ñÌñ ñÐ ð-@), ÐÑ(¿[ ÑÑ„°ÑÑ  ÑòòN.€€Criteria€that€will€be€Used€for€Preliminary€Grouping€of€Substances.ò òóó€€ó óÐ ° ÐÌà  àSeveral€commentors€[3,€9,€12„16]€raised€concern€regarding€EPAððs€use€of€structuralÏsimilarity,€mechanism€of€pesticidal€action€or€common€toxic€effect€as€a€basis€for€preliminaryÏgrouping€of€chemicals.€€These€commentors€feel€that€these€criteria,€alone€or€in€combination,€areÏnot€scientific€and€should€not€be€used€for€grouping€chemicals€cumulative€risk€assessment€becauseÏsubstances€that€meet€these€criteria€may€not€necessarily€cause€a€common€toxic€effect€by€aÏcommon€mechanism€of€toxicity.€€€The€Agency€agrees€with€these€commentors.€€However,€theÏAgency€believes€that€the€commentors€have€misunderstood€the€Agencyððs€purpose€of€using€eitherÏstructural€similarity,€mechanism€of€pesticidal€action,€or€common€toxic€effect€as€described€in€theÏdraft€version€of€the€guidance€document.€€As€stated€on€page€9€(Section€III)€of€the€draft€document,Ïthese€criteria,€either€alone€or€in€combination,€will€be€used€for€initial€grouping€only,€and€ò ònotó ó€finalÐ P  Ðgrouping€of€chemicals€for€purposes€of€cumulative€risk€assessment.€€The€scientific€basis€for€usingÏthese€criteria€for€initial€grouping€is€also€described€in€the€document.€€Substances€initially€groupedÏusing€any€of€these€criteria€will€undergo€subsequent€rigorous€evaluation€to€determine€whichÏsubstances€cause€a€common€toxic€effect€by€a€common€mechanism€of€toxicity€and€which€do€not.€ÏDetails€of€the€evaluation€are€given€in€the€draft€document.€€However,€the€revised€documentÏcontains€much€more€text€that€adds€further€clarification€to€how€these€criteria€and€other€criteria€willÏbe€applied€for€initial€grouping€only,€and€why€they€will€not€be€used€for€final€grouping.€€€ÔåÔ€€ÔåÔà Ð àÐ à ÐÌò òList€of€Public€Commentors€and€AffiliationsÔ€#ŠŠX#XÍäÔó óÐ pÀ ÐÔ€#XÍäXŠ#ŠÔÌòòòòI.D.€#óóà  àà ` àòòName€and€OrganizationóóÐ P  ÐÔ€#&<&X#XÍäÔóó1.à  àWilliam€Patrick€Cockrell,€Director€of€Agricultural€Policy,€Ð @ Ðà  àòòFlorida€Farm€Bureau€Federationóó.€Gainesville,€Florida.Ð j ÐÌ2.à  àDaniel€M.€Byrd,€President,€òòÐ Î Ðà  àConsultants€in€Toxicology,€Risk€Assessment€and€Product€Safety.óó€Washington,€D.C.Ð ¨ø ÐÌ3.à  àLouie€A.€Brown,€Jr.,€Director€of€Food€Safety,€Ð \¬ Ðà  àòòCalifornia€Farm€Bureau€Federation.óó€Sacremento,€California.Ð 6 † ÐÌ4.à  àJeannine€Kenny,€òòConsumers€Union.óó€Washington,€D.C.€Ð ê!:  ÐÌ5.à  àShelley€Davis,€Co„Executive€Director,€òòFarmworker€Justice€Fund,€Inc.óó€Washington,€D.C.Ð ž#î" ÐÌ6.à  àDavid€Wallinga,€Senior€Scientist,€òòNatural€Resources€Defense€Council€(NRDC).óó€à x àà Ð à€€Ð R%¢ $ Ðà  àWashington,€D.C.ÌÌ7.à  àMark€A.€Keating,€Policy€Analyst,€òòHenry€A.€Wallace€Institute€for€Alternative€Agriculture.ó󀀀Рà'0#' Ðà  àGreenbelt,€Maryland.ÌÌ8.à  àPriscilla€L.€Friedman,€òòDuPont€Agricultural€Products.óó€Wilmington,€Delaware.Ð n*¾%* ÐÌ9.à  àLouisiana€Farm€Bureau€Federation.Ð ",r', ÐÌ10.à  àLinda€M.€Johnson,€Director€of€Government€Relations,€òòWashington€State€Farm€Bureau.óó€à Ð à€€Ð Ö-&). Ðà  àWashington.Ð °.*/ ÐÑ+Oa ÑѰ„ÑÑ  ÑÌ11.à  àFQPA€Implementation€Working€Group€(IWG).Ð ŠÚ ÐÌ12.à  àCharles€B.€Breckenridge,€òòNovartis€Crop€Protection,€Norvartis.óó€Ð >Ž Ðà  àGreensboro,€North€Carolina.ÌÌ13.à  àSandra€L.€Tirey€and€C.T.€(ð ðKipðð)€Howlett,€Jr.€òòChemical€Manufacturers€Association.óó€à Ð à€€Ð Ì  Ðà  àArlington,€Virginia.ÌÌ14.à  àNancy€Erickson,€Director€of€National€and€Environmental€Resources,€Ð Z ª  Ðà  àòòIllinois€Farm€Bureau.óó€€Illinois.Ð 4 „  ÐÌ15.à  àAndy€G.€Kurtz,€Executive€Secretary€and€Chief€Administrative€Officer,€òòÐ è8  Ðà  àArizona€Fram€Bureau€Federation.óó€€Phoenix,€Arizona.Ð Â  ÐÌ16.à  àNancy€G.€Doerrer,€Vice€President€of€Scientific€and€Policy€Programs,€Ð vÆ  Ðà  àòòAmerican€Industrial€Health€Council€(AIHC).óó€€Washington,€D.C.Ô€#XÍäX&#&<ÔÐ P   Ð