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!5!:`ªªUUïÿ”ÿ‹ ­O¨(dÐÿS*ñ22”ÿ‹ ßÿùÿÿhª‚ÒR¢)Ƭ°húØ+ÿhÔA€< Œ 9p`(GenevaAÔÔ€XXXÔá áááÓ  ÓÔS€M< Œ 9p`(&Times New RomanSÔÔ€MôôôÔò ò€Ô€MÔif€mechanism€has€not€been€previouslyÌ€determined,€proceed€to€step€3bÔ€MôôôÔ4€¥«÷ÿ Ûâÿþp£µ0.¸ùMƸù%Æ !ÿÿÿÿÿÿÿÿ5!<५÷ÿ Ûâÿþp£µ0.2Ƹù%HÀ¸ù%¸ùË !5!4€¬÷ÿ²"ôÿÙ éÉh=¸ùMƸù_Æ !ÿÿÿÿÿÿÿÿ5!<à¬÷ÿ²"ôÿÙ éÉh=lƸù_HÀ¸ù_¸ùË !5!:`ªªUUïÿq©süÿÿÆøT(dÐÿS »22q©süÿÿø¨:ùÿÿhª‚ÒR¢)Õª, húØ+ÿhÔA€< Œ 9p`(GenevaAÔÔ€XXXÔá áááÓ  ÓÔS€M< Œ 9p`(&Times New RomanSÔÔ€MôôôÔò ò€Ô€MÔif€mechanism€has€been€Ì€€previously€determined,€Ì€€proceed€to€step€4Ô€MôôôÔ:પUUïÿXª÷ÿÿÿBøŒdÐÿSqÿ’22Xª÷ÿÿÿt¨rßÿÿhª‚ÒR¢)O <húØ+ÿÜÔA€< Œ 9p`(GenevaAÔÔ€XXXÔá áááÓ  ÓÔS€M< Œ 9p`(&Times New RomanSÔÔ€MôôôÔò òó ó€€Ô€MÔStep€4Ô€MôôôÔò ò.Ô€MÔ€€Compare€the€mechanism€of€toxicity€of€each€substance€(from€step€3)€within€aÌ€€€€€€€€€€€€€€common€toxic€effect€grouping.Ô€MôôôÔ:પUUïÿîÿÁO0 dÉÿˆéÿÈ22îÿÁCÿÛÿÿhª‚àý.&û§ÀhúØ+ÿ|ÔA€< Œ 9p`(GenevaAÔÔ€XXXÔá áááÓ  ÓÔS€M< Œ 9p`(&Times New RomanSÔÔ€MôôôÔó óóóóóóóÔ€MÔ€€Step€5ò 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°šXÓÔ€MX7\XXXÔÔ€Mô¦ÕôXMX7\ÔFax„On„DemandÐ ° ÐFax€Number:€(202)€401„0527ÌItem:€6055Ô€MX7\XôMô¦ÕÔ€Ô€M&ï&XMX7\ÔÐ @ ÐÌÌÓ  ÓÔ€M ¿  &M&ïÔGÔ€MŠ‹Î Š M ¿ ÔUIDANCE€FORÔ€M¼ŸZ ¼ ŠMŠ‹ÎÔ€Ô€M ¿   ¼M¼ŸZÔIÔ€MŠ‹Î Š M ¿ ÔDENTIFYING€Ô€M ¿   ŠMŠ‹ÎÔPÔ€MŠ‹Î Š M ¿ ÔESTICIDE€Ô€M ¿   ŠMŠ‹ÎÔCÔ€MŠ‹Î Š M ¿ ÔHEMICALS€AND€Ô€M ¿   ŠMŠ‹ÎÔOÔ€MŠ‹Î Š M ¿ ÔTHER€€Ð ä4 ÐÔ€M ¿   ŠMŠ‹ÎÔSÔ€MŠ‹Î Š M ¿ ÔUBSTANCES€Ô€M ¿   ŠMŠ‹ÎÔTÔ€MŠ‹Î Š M ¿ ÔHAT€Ô€M ¿   ŠMŠ‹ÎÔHÔ€MŠ‹Î Š M ¿ ÔAVE€A€Ô€M ¿   ŠMŠ‹ÎÔCÔ€MŠ‹Î Š M ¿ ÔOMMON€Ô€M ¿   ŠMŠ‹ÎÔMÔ€MŠ‹Î Š M ¿ ÔECHANISM€OF€Ô€M ¿   ŠMŠ‹ÎÔTÔ€MŠ‹Î Š M ¿ ÔOXICITYññÐ $ t Ðññ€ÌñŒñÓ  ÓñŒññŒñÓ  ÓÓ  ÓñŒñ€ñŠññ†ñ(ñ†ññŠññ‹ññ‹ññŽñÔ‡MX7\X ŠMŠ‹ÎÔñŽññ‹ñ(€ñ‹ññ‡ññ†ñJanuaryñ†ññ‡ññ‡ñJanuaryñ‡ññ†ñ€ñ†ññˆñ29,€1999ñˆññ‰ñ€ñ‰ññˆñ)ñˆññŽñÔ#†MŠ‹Î ŠXMX7\j#ÔñŽñÐ h ¸ ÐñŒñÓ4ÓñŒññ…ñÌÌñ…ñÌÔ€M¼ŸZ ¼ ŠMŠ‹ÎÔEÔ€M&ï& ¼M¼ŸZÔXECUTIVE€Ô€M¼ŸZ ¼&M&ïÔSÔ€M&ï& ¼M¼ŸZÔUMMARYÔ€MX7\X&M&ïÔÐ xÈ  ÐÔ€M&ï&XMX7\Ôó óÌÓ  ÓÔ€M¼ŸZ ¼&M&ïÔà  àTÔ€M&ï& ¼M¼ŸZÔhe€Food€Quality€Protection€Act€(FQPA)€of€1996€requires€the€United€States€EnvironmentalÐ h¸  ÐProtection€Agency€(EPA)€to€assess€the€cumulative€risks€to€human€health€that€can€result€from€exposure€toÏpesticides€and€other€substances€that€are€toxic€by€a€common€mechanism.€€The€Agency€is€currently€developingÏa€process€for€performing€cumulative€risk€assessments€of€this€type.€€Such€assessments€will€play€anÏincreasingly€important€role€in€the€evaluation€of€risks€posed€by€pesticides,€and€will€improve€the€AgencyððsÏability€to€make€regulatory€decisions€that€fully€protect€public€health€and€sensitive€subpopulations,€includingÏinfants€and€children.€€ÌÌà  àThe€identification€of€pesticides€and€other€substances€that€cause€a€common€toxic€effect€by€a€commonÏmechanism€is€the€first€step€of€the€cumulative€risk€assessment€process.€This€document€describes€the€approachÏthat€EPA€will€use€for€identifying€pesticides€and€other€substances€that€cause€common€toxic€effects€byÏcommon€mechanisms€of€toxicity.€€€Specifically,€this€document€describes:€EPAððs€interpretation€of€commonÏmechanism€of€toxicity€with€respect€to€making€a€determination€of€safety;€the€specific€steps€that€will€be€takenÏfor€identifying€mechanisms€of€toxicity€of€pesticides€and€other€substances€that€cause€a€common€toxic€effect;Ïthe€types€of€data€and€their€sources€that€are€needed;€how€these€data€are€to€be€used€in€reaching€conclusionsÏregarding€commonality€of€mechanisms€of€toxicity;€and€criteria€the€Agency€will€use€for€categorizingÏpesticides€and€other€substances€for€purposes€of€cumulative€risk€assessments.€€Details€on€the€other€aspectsÏof€the€cumulative€risk€assessment€process€will€be€discussed€in€a€separate€document.ÌÌà  àThis€document€was€developed€from€a€draft€version€entitled€òòGuidance€for€Identifying€PesticideÐ Ò""! ÐChemicals€that€Have€a€Common€Mechanism€of€Toxicity,€for€Use€in€Assessing€the€Cumulative€Toxic€EffectsÏof€Pesticides,€óóthat€was€released€for€public€comment€in€August€of€1998€(FR€63€42031,€FRL„5797„7).€€TheÐ †$Ö# ÐAgency€received€comments€from€various€organizations.€€Each€of€the€commentors€offered€recommendationsÏfor€improving€the€science€policy.€€All€comments€were€extensively€evaluated€and€considered€by€the€Agency.€ÏThis€revised€version€embodies€many€of€the€sentiments€and€recommendations€of€the€commentors.€The€publicÏcomments,€as€well€as€a€detailed€summary€of€the€Agencyððs€response€to€the€comments€are€being€madeÏavailable€in€the€Federal€Register.€€€€€€€€€ÌÌÐ  |*Ì%* ÐÑ7€R’4RôôdÈXXdÈ7Ñò òÔ€M¼ŸZ ¼&M&ïÔI.€€IÔ€M&ï& ¼M¼ŸZÔNTRODUCTIONó óÐ @ ÐÌÔ€M¼ŸZ ¼&M&ïÔà  àTÔ€M&ï& ¼M¼ŸZÔhe€Food€Quality€Protection€Act€(FQPA)€of€1996€stipulates,€among€other€things,׃K×Ý ƒ=#ÃÝòòÚ  Ú1Ú  ÚóóÝ  Ý×  ×€that€whenÐ 0ð Ðdetermining€the€safety€of€a€pesticide€chemical€EPA€shall€base€its€assessment€of€the€risk€posed€by€theÏpesticide€chemical€on:€aggregate€(i.e.,€total€dietary,€residential,€and€other€non„occupational)€exposure€to€theÏpesticide€and€available€information€concerning€the€cumulative€effects€to€human€health€that€may€result€fromÏdietary,€residential,€or€other€non„occupational€exposure€to€other€substances׃L˜×Ý ƒ=#ÃÝòòÚ  Ú2Ú  ÚóóÝ  Ý×  ×€that€have€a€common€mechanismÐ Ô ” Ðof€toxicity.€€The€Act€specifically€mandates€the€Agency€to€consider€the€special€susceptibility€of€infants€andÏchildren€to€the€toxic€effects€caused€by€pesticides.€€The€Agency€must€also€base€its€risk€assessment€on€availableÏinformation€concerning€the€òòcumulativeóó€effects€on€infants€and€children€to€the€pesticide€and€other€substancesÐ b"  Ðthat€have€a€òòcommon€mechanism€of€toxicityóó.€€The€reason€for€consideration€of€these€factors€is€due€to€theÐ <ü  Ðpossibility€that€low„level€exposures€to€multiple€substances€that€cause€a€common€toxic€effect€by€a€commonÏmechanism€could€lead€to€the€same€adverse€health€effect€as€would€a€higher€level€of€exposure€to€any€of€theÏchemicals€individually.€€A€person€exposed€to€a€pesticide€at€a€level€that€is€considered€safe€may€in€factÏexperience€harm€if€that€person€is€also€exposed€to€other€substances€that€cause€a€common€toxic€effect€by€aÏmechanism€common€with€that€of€the€subject€pesticide,€even€if€the€individual€exposure€levels€to€the€otherÏsubstances€are€also€considered€safe.€Ì€€Ìà  àHence,€in€assessing€the€risks€posed€by€a€given€pesticide€chemical,€EPA€must€assess€the€cumulativeÏrisks€to€human€health€that€can€result€from€exposure€to€the€pesticide,€as€well€as€from€other€pesticide€chemicalsÏand€other€substances€that€are€toxic€by€a€common€mechanism.€€€The€goal€of€a€cumulative€risk€assessment,€inÏregard€to€implementing€FFDCA€as€amended€by€FQPA,€is€to€characterize€the€potential€for€a€cumulative€toxicÏeffect€and€the€magnitude€of€the€effect€in€individuals€exposed€to€pesticides€and€other€substances€that€causeÏa€common€toxic€effect€by€a€common€mechanism.€€In€order€to€assess€these€cumulative€toxic€effects,€theÏAgency€needs€to€first€identify€and€categorize€those€pesticides€and€other€substances€that€cause€a€commonÏtoxic€effect€by€a€common€mechanism.€€ò òThe€purpose€of€this€document€is€to€describe€the€approach€thatÐ Â ÐEPA€will€use€for€identifying€and€categorizing€pesticides€and€other€substances€that€cause€common€toxicÏeffects€from€common€mechanisms€of€toxicity.ó ó€€Specifically,€this€document€describes:Ð ¶v ÐÌÌÒŒ °ÒÓ XÓÓ  ÓÔ€M¼ŸZ ¼&M&ïÔà ` àððÔ€M&ï& ¼M¼ŸZÔ€à ¸ àEPAððs€interpretation€of€common€mechanism€of€toxicity€Ð D  Ðà  àà ` àà ¸ àwith€respect€to€à h àmaking€a€determination€of€safety€under€Ð Z! Ðà  àà ` àà ¸ àFFDCA€as€amended€by€FQPA;ÌÒä °ÒÒ°Œ ÒÓ  ÓÌÒ°ä ÒÒŒ °ÒÓ  ÓÔ€M¼ŸZ ¼&M&ïÔà ` àððÔ€M&ï& ¼M¼ŸZÔ€à ¸ àThe€specific€steps€that€need€to€be€taken€for€identifying€à  àÐ è#¨" Ðà  àà ` àà ¸ àmechanisms€of€toxicity€of€pesticides€and€other€substances€¼à  àà ` àà ¸ àthat€cause€a€common€toxic€effect;ÌÓ  ÓÐ ²&r % ÐÓ  ÓÔ€M¼ŸZ ¼&M&ïÔà ` àððÔ€M&ï& ¼M¼ŸZÔ€à ¸ àThe€types€of€data€(and€their€sources)€that€are€needed€for€Ð @ Ðà  àà ` àà ¸ àdoing€so;ÌÓ  ÓÌÓ  ÓÔ€M¼ŸZ ¼&M&ïÔà ` àððÔ€M&ï& ¼M¼ŸZÔ€à ¸ àHow€these€data€are€to€be€used€in€reaching€conclusions€à  àÐ  Ê Ðà  àà ` àà ¸ àregarding€commonality€of€mechanisms€of€toxicity;ÌÓ  ÓÌÓ  ÓÔ€M¼ŸZ ¼&M&ïÔà ` àððÔ€M&ï& ¼M¼ŸZÔ€à ¸ àCriteria€the€Agency€will€use€for€categorizing€pesticides€à  àÐ Ô ” Ðà  àà ` àà ¸ àand€other€substances€for€purposes€of€cumulative€risk€à  àÐ ê ª Ðà  àà ` àà ¸ àassessments.€ÌÌÌÓ  ÓÓ XÓÝ‚ gÿÝÒ°ÒÒ°Œ ÒÓ ÓÝ  ÝÝ‚ gÿ}%ƒ<ÝÒ°ÒÒŒ °ÒÓ ÓÝ  ÝÝ‚ gÿÝÒ°ÒÒ°Œ ÒÓ ÓÝ  ÝÝ‚ gÿ&ƒ<ÝÒ°ÒÒŒ °ÒÓ ÓÝ  ÝÝ‚ gÿÝÒ°ÒÒ°Œ ÒÓ ÓÝ  ÝÝ‚ gÿ¡&ƒ<ÝÒ°ÒÒŒ °ÒÓ ÓÝ  ÝÝ‚ gÿÝÒ°ÒÒ°Œ ÒÓ ÓÝ  ÝñŽñÒ°ÒñŽñÝ‚ gÿ3'ƒ<ÝÒ°ÒÒŒ °ÒÓ ÓÝ  ÝÝ‚ gÿÝÒ°ÒÒ°Œ ÒÓ ÓÝ  ÝÝ‚ gÿÝ'ƒ<ÝÒ°ÒÒŒ °ÒÓ ÓÝ  ÝÝ‚ gÿÝÒ°ÒÒ°Œ ÒÓ ÓÝ  ÝÝ‚ gÿo(ƒ<ÝÒ°ÒÒŒ °ÒÓ ÓÝ  ÝÝ‚ gÿÝÒ°ÒÒ°Œ ÒÓ ÓÝ  ÝÝ‚ gÿ)ƒ<ÝÒ°ÒÒŒ °ÒÓ ÓÝ  ÝÝ‚ gÿÝÒ°ÒÒ°Œ ÒÓ ÓÝ  ÝÒ°ÒThis€document€does€not€address€how€EPA€will€assess€cumulative€toxicity€when€making€determinations€ofÏsafety.€€This€topic€will€be€discussed€in€a€forthcoming€Agency€science€policy€document.ÌÌÔ€M¼ŸZ ¼&M&ïÔÌѰ+Ñò òÔ€MŠ‹Î Š ¼M¼ŸZÔII.Ô€M&ï& ŠMŠ‹ÎÔ€€Ô€MŠ‹Î Š&M&ïÔDÔ€M&ï& ŠMŠ‹ÎÔEFINITIONS€OF€Ô€MŠ‹Î Š&M&ïÔTÔ€M&ï& ŠMŠ‹ÎÔERMS€ó óÐ ö¶  ÐÌà  àThis€document€uses€a€number€of€terms€that€are€necessary€for€discussions€of€toxic€effects,€mechanismÏof€toxicity,€and€the€identification€of€substances€that€cause€a€common€toxic€effect€by€a€common€mechanism.€ÏThese€terms€are€not€defined€(some€are€not€mentioned)€in€FQPA.€€The€definitions€presented€here€representÏEPA's€interpretation€of€the€terms€for€purposes€of€implementing€the€requirements€of€FQPA.ÌÌà  àò òAnalog(s).€€ó óAnalog€is€a€generic€term€used€to€describe€substances€that€are€chemically€closely€related.€Ð Ö ÐStructural€analogs€are€substances€that€have€similar€or€nearly€identical€molecular€structures.€€StructuralÏanalogs€may€or€may€not€have€similar€or€identical€biological€properties.€Ì€€Ìò òà  àToxic€Effect.ó ó€€A€toxic€effect€is€an€effect€known€(or€can€reasonably€be€expected)€to€occur€in€humans,Ð ~> Ðthat€results€from€exposure€to€a€chemical€substance€and€that€will€or€can€reasonably€be€expected€to€endangerÏor€adversely€affect€quality€of€life.€€Some€examples€of€toxic€effects€are€acute€lethality,€loss€of€hearing,€renalÏtubule€necrosis€and€cardiomyopathy,€to€name€just€a€few.׃N×Ý ƒ=#ÃÝòòÚ  Ú3Ú  ÚóóÝ  Ý×  ׀Р Ì ÐÌà  àò òSite€of€a€Toxic€Effect.€€ó óThe€site€of€a€toxic€effect€is€the€specific€anatomical€or€physiological€site€orÐ À!€ Ðlocus€(e.g.,€organ€or€tissue)€at€which€the€effect€occurs.ÌÌà  àò òCommon€Toxic€Effect.ó ó€€A€pesticide€and€another€substance€that€are€known€to€cause€the€same€toxicÐ N$" Ðeffect€in€or€at€the€same€anatomical€or€physiological€site€or€locus€(e.g.,€same€organ€or€tissue)€are€said€to€causeÏa€common€toxic€effect.€€Thus,€a€toxic€effect€observed€in€studies€involving€animals€or€humans€exposed€to€aÏpesticide€chemical€is€considered€common€with€a€toxic€effect€caused€by€another€chemical€if€there€isÏconcordance€with€both€site€and€nature€of€the€effect.ÌÐ (P"' Ðò òà  àCumulative€Toxic€Effect.€€ó ó€A€cumulative€toxic€effect€is€the€net€change€in€magnitude€of€a€commonÐ @ Ðtoxic€effect€resulting€from€exposure€to€two€or€more€substances€that€cause€the€common€toxic€effect€by€aÏcommon€mechanism,€relative€to€the€magnitude€of€the€common€toxic€effect€caused€by€exposure€to€any€of€theÏsubstances€individually.€€€€€ò òÐ ÎŽ Ðó óÌò òà  àToxophore.ó ó€€Substances€that€are€capable€of€causing€a€toxic€effect€contain€a€structural€feature€orÐ ‚ B Ðmoiety€that€bestows€the€toxic€property.€€This€structural€feature€or€moiety€is€referred€to€generically€as€theÏtoxophore,€or€toxophoric€moiety׃O×Ý ƒ=#ÃÝòòÚ  Ú4Ú  ÚóóÝ  Ý×  ×.€€A€toxic€substance€elicits€its€toxicity€through€interaction€of€its€toxophoreÐ 6 ö Ðwith€a€biomolecular€site€(e.g.,€receptor)׃Pf×Ý ƒ=#ÃÝòòÚ  Ú5Ú  ÚóóÝ  Ý×  ×€in€cells€of€tissue€or€organs€to€cause€changes€or€alterations€in€normalÐ  Ð Ðcellular€biochemistry.€These€biochemical€changes€or€alterations€lead€to€€disruption€of€the€physiologicalÏprocess(es)€the€tissue€or€organs€perform€and,€ultimately,€the€toxic€effect.€€The€toxicity€of€many€substances,Ïhowever,€is€not€due€to€a€direct€interaction€with€a€biomolecular€site.€€Rather,€the€toxicity€results€fromÏmetabolism€of€a€structural€substituent€to€a€toxophore,€which€then€causes€the€toxicity.€€Metabolic€pathwaysÏthat€lead€to€toxicity€are€often€called€ò òbioactivation€pathways.ó óÐ R  Ðò òÌà  àMechanism€of€Toxicity.׃Q¨ ×Ý ƒ=#ÃÝòòÚ  Ú6Ú  ÚóóÝ  Ý×  ×€€ó óMechanism€of€toxicity€is€defined€as€the€major€steps€leading€to€a€toxicÐ Æ  Ðeffect€following€interaction€of€a€pesticide€with€biological€targets.€€All€steps€leading€to€an€effect€do€not€needÏto€be€specifically€understood.€€Rather,€it€is€the€identification€of€the€crucial€events€following€chemicalÏinteraction€that€are€required€in€order€to€describe€a€mechanism€of€toxicity.€€Generally,€the€more€that€isÏunderstood€about€the€various€steps€in€the€pathway€leading€to€an€adverse€effect,€the€more€confident€one€isÏabout€the€mechanism€of€toxicity.€€For€instance,€a€mechanism€of€toxicity€may€be€described€by€knowing€theÏcascade€of€effects€such€as€the€following:€€a€chemical€binds€to€a€given€biological€target€òòin€vitro,óó€and€causesÐ "â Ðthe€receptor„related€molecular€response;€òòin€vivoóó€it€also€leads€to€the€molecular€response€and€causes€a€numberÐ ü¼ Ðof€intervening€biological€and€morphological€steps€that€result€in€an€adverse€effect.€€Other€processes€mayÏdescribe€a€mechanism€of€toxicity€in€other€cases.ÌÌò òà  àCommon€Mechanism€of€Toxicity.ó ó€€Common€mechanism€of€toxicity€pertains€to€two€or€moreÐ d$ Ðpesticide€chemicals€or€other€substances€that€cause€a€common€toxic€effect€to€human€health€by€the€same,€orÏessentially€the€same,€sequence€of€major€biochemical€events.€€Hence,€the€underlying€basis€of€the€toxicity€isÏthe€same,€or€essentially€the€same,€for€each€chemical.Ì€€Ð ÌŒ Ðà  àò òToxic€Action.€ó óToxic€action€of€a€given€substance€is€its€interaction€with€biological€targets,€to€lead€toÐ @ Ða€toxic€effect.Ìà  àÌà  àò òSite€of€Toxic€Action.ó ó€€The€site€of€toxic€action€of€a€given€substance€is€the€anatomical€or€physiologicalÐ ÎŽ Ðsite(s),€locus,€or€loci€€at€which€takes€place€the€interaction€of€the€substance€with€its€biological€targets,€to€leadÏto€a€toxic€effect.ò òÐ ‚ B Ѐó óà  àÐ \  Ðò òà  àStructure„Activity€Relationships.ó ó€€€Substances€that€contain€or€are€bioactivated€to€the€sameÐ 6 ö Ðtoxophore€may€cause€a€common€toxic€effect€by€a€common€mechanism.€€The€relative€toxic€efficacy€andÏpotency׃S×Ý ƒ=#ÃÝòòÚ  Ú7Ú  ÚóóÝ  Ý×  ×€among€the€substances€in€their€ability€to€cause€the€toxic€effect€may€vary.€€Differences€in€potency€orÐ ê ª  Ðefficacy€are€directly€related€to:€the€specific€or€incremental€structural€differences€between€the€substances;€theÏinfluence€these€differences€have€on€the€ability€of€the€toxophore€to€reach€and€interact€with€its€biomolecularÏsite€of€action;€and€on€the€intrinsic€abilities€of€each€of€the€substances€to€cause€the€effect.€€The€ability€of€twoÏor€more€structurally„related€substances€to€cause€a€common€toxic€effect€and€the€influence€that€their€structuralÏdifferences€have€on€toxic€efficacy€and€potency€are€referred€to€as€structure„activity׃T€×Ý ƒ=#ÃÝòòÚ  Ú8Ú  ÚóóÝ  Ý×  ×€relationships.€Ð ,ì  ÐÌà  àò òWeight„of„Evidence.ó ó€€Weight„of„evidence€refers€to€a€qualitative€scientific€evaluation€of€a€chemicalÐ à   Ðsubstance€for€a€specific€purpose.€€€A€weight„of„evidence€evaluation€involves€a€detailed€analysis€of€severalÏor€more€data€elements,€such€as€data€from€different€toxicity€tests,€pharmacokinetic€data,€and€chemistry€data,Ïfollowed€by€a€conclusion€in€which€a€hypothesis€is€developed,€or€selected€from€previous€hypotheses.€€€€€€€€€€Ï€€€€€€€€€€€€€ò òÐ H Ðó óà  à€Ð "â ÐÌò òÔ€MŠë† Š&M&¿RÔÌIII.Ô€MXgX ŠMŠë†Ô€Ô€M¼ ¼XMXgÔPÔ€M&¿R& ¼M¼ÔROCESS€FOR€Ô€M¼ ¼&M&¿RÔIÔ€M&¿R& ¼M¼ÔDENTIFYING€Ô€M¼ ¼&M&¿RÔPÔ€M&¿R& ¼M¼ÔESTICIDEÔ€M¼ ¼&M&¿RÔ€CÔ€M&¿R& ¼M¼ÔHEMICALS€AND€Ô€M¼ ¼&M&¿RÔOÔ€M&¿R& ¼M¼ÔTHER€Ô€M¼ ¼&M&¿RÔSÔ€M&¿R& ¼M¼ÔUBSTANCESÐ Úš ÐTHAT€€Ô€M¼ ¼&M&¿RÔHÔ€M&¿R& ¼M¼ÔAVE€AÔ€M¼ ¼&M&¿RÔ€CÔ€M&¿R& ¼M¼ÔOMMONÔ€M¼ ¼&M&¿RÔ€MÔ€M&¿R& ¼M¼ÔECHANISM€OF€Ô€M¼ ¼&M&¿RÔTÔ€M&¿R& ¼M¼ÔOXICITY.€ó óÐ ð° ÐÌà  àTo€assess€the€cumulative€toxicity€of€pesticides€and€other€substances€that€cause€common€toxic€effectsÏby€common€mechanisms,€EPA€will€first€need€to€identify€those€pesticides€and€other€substances€that€causeÏcommon€toxic€effects€by€common€mechanisms,€and€then€group€them€in€accordance€with€commonality€ofÏtoxic€effect€and€toxic€mechanism.€€Once€grouped,€combined€risk€assessments€can€be€performed€and€theÏpotential€for€cumulative€toxicity€that€may€result€from€exposure€to€substances€within€a€group€can€beÏcharacterized.Ì€€Ð ü"¼! Ðà  àThe€conceptual€framework€of€the€process€that€EPA€will€use€to€identify€pesticide€chemicals€and€otherÏsubstances€that€cause€a€common€toxic€effect€by€a€common€mechanism€is€illustrated€in€Figure€1.€€This€processÏis€designed€to€enable€EPA€to€make€accurate€identification€and€categorization€of€pesticides€and€otherÏsubstances€that€are€toxic€from€a€common€mechanism,€in€both€a€timely€and€resource„effective€manner.€Ï(Specific€examples€of€the€application€of€this€process€are€in€preparation,€and€will€be€made€available€at€a€futureÏdate.)€€To€implement€the€process,€the€Agency€has€convened€a€multidisciplinary€team€of€EPA€scientists€whoÏare€experts€in€chemistry,€biology,€pharmacology,€toxicology€and€pharmacokinetics.€€It€is€the€responsibilityÏof€this€team€to€identify€and€analyze€data€and€information€pertaining€to€toxic€mechanisms,€and€to€make€expertÏjudgements€regarding€mechanisms€of€toxicity€of€pesticides€and€other€substances.€€The€following€policies€andÏpractices€will€be€used€by€the€Agency€for€identifying€chemicals€that€have€a€common€mechanism€of€toxicity:Ìñ|ñÒ°isÒñ|ñÒ¸ °ÒÌÌÌÌÓ*` „°` ‰X(#‹X` °—X*ÓÔ€M¼ ¼&M&¿RÔÝ‚ gÿx(€of€ÝÒ°°ÒÒŒ ¸ ÒÓ ÓÝ  ÝÒ` °Òñ|ñÒŒ isÒñ|ñððà ¸ àÔ€M&¿R& ¼M¼ÔA€thorough€identification€and€analysis€of€all€relevant€à  àÐ ,ì  Ðññà ¸ àññinformation€will€be€undertaken€for€each€pesticide€ñ}ñà È àñ}ñchemical€andÏñ€ñà ¸ àñ€ñother€substances€under€consideration.€This€ñ~ñà  àñ~ñwill€provide€theÏñ‚ñà ¸ àñ‚ñbasis€for€identifying€underlying€ññà  àññmechanisms€of€toxicity;€ÌÒ` Òñ|ñÒŒ isÒñ|ñÓ9` ܸ †XLxX` „°` ‰X(#‹X9ÓÔ€M¼ ¼&M&¿RÔÌÓ  ÓÓ9` ܈XLxŒX` ܸ †XLxX9Óà ` àððÔ€M&¿R& ¼M¼Ôà ¸ àA€ð ðweight„of„evidenceðð€approach€will€be€used€to€support€Ð æ¦ Ðà ` àà ¸ àthe€development€of€hypotheses€pertaining€to€mechanisms€¼à ` àà ¸ àof€toxicity.€€Generally,€no€single€piece€ñ„ñà p àñƒñ\ñƒññ„ñof€information€will€¼à ` àà ¸ àsuffice€to€support€the€characterization€of€a€specific€or€¼à ` àà ¸ àcommon€mechanism€of€toxicity;€this€finding€will€be€¼à ` àà ¸ àsupported€by€the€analysis€and€inter„relationships€of€¼à ` àà ¸ àavailable€pieces€of€information;ÌÓ  ÓÌÒ` Òñ|ñÒŒ isÒñ|ñÓ  ÓÔ€M¼ ¼&M&¿RÔððÔ€M&¿R& ¼M¼Ôà ¸ àExternal€review€of€EPAððs€decisions€concerning:€utilization€Ð ò² Ðà ¸ àof€established€à h àtoxic€mechanisms;€determination€of€toxic€Ð È Ðà ¸ àmechanisms€for€specific€substances;€and€grouping€of€¼à ¸ àsubstances€by€mechanism€of€toxicity€will€be€solicited€as€¼à ¸ àneeded€.€ÌÓ  ÓÌÌñ|ñÒ` isÒñ|ñÒ°Œ ÒÌÒ°` Òñ|ñÒ°isÒñ|ñà Ü àà  àWhen€identifying€toxic€effects,€common€toxic€effects,€mechanisms€of€toxicity,€and€commonÏmechanisms€of€toxicity€for€purposes€of€grouping€substances€that€cause€a€common€toxic€effect€by€a€commonÏmechanism€of€toxicity,€care€must€be€taken€not€to€confuse€ð ðmechanism€of€toxicityðð€with€ð ðsite€of€toxic€action,ððÏor€ð ðsite€of€toxic€actionðð€with€ð ðtoxic€effectðð€or€ð ðsite€of€toxic€effect.ðð€(These€terms€are€defined€near€theÏbeginning€of€this€document.)€€With€many€substances,€the€site€of€a€toxic€effect€is€the€same€as€the€site€of€toxicÏaction.€€It€is€also€true,€however,€that€with€many€other€substances€the€site€of€a€toxic€effect€may€be€differentÏthan€site€of€toxic€action.€€For€example,€a€substance€inhibits€the€catalytic€activity€of€the€peroxidase€enzymeÏwithin€the€thyroid€gland.€€Inhibition€of€this€enzyme€prevents€the€synthesis€of€thyroxine€and€triiodothyronine,Ïand€ultimately€leads€to€hypothyroidism,€the€toxic€effect.€€In€this€case,€the€site€of€the€toxic€effect€is€the€sameÏas€the€site€of€toxic€action:€the€thyroid€gland.€€Another€substance€known€to€cause€hypothyroidism€does€so€byÏpreventing€the€synthesis€of€thyroid„stimulating€hormone€within€the€anterior€pituitary€gland.€€Here€the€siteÐ ‚-B'- Ðof€the€toxic€effect€is€the€thyroid€gland,€but€the€site€of€toxic€action€is€the€anterior€pituitary€gland.€€AlthoughÏthese€two€substances€cause€a€common€toxic€effect,€they€would€not€be€considered€for€cumulative€riskÏassessment€because€they€have€different€mechanisms€of€toxicity.ÌÌà Ü àà  à€Many€substances€can€cause€more€than€one€toxic€effect,€depending€upon€level€of€exposure,€and€doÏso€by€different€mechanisms€of€toxicity€that€take€place€at€different€sites€of€toxic€action.€€However,€a€chemicalÏmay€also€cause€multiple€toxic€effects€at€multiple€sites€from€a€single€mechanism€of€toxicity€taking€place€atÏa€single€site€of€toxic€action,€provided€that€the€function€initially€altered€at€the€site€of€toxic€action€normallyÏcontrols€other€functions€at€distant€sites.€€For€example,€a€substance€that€prevents€the€conversion€of€cholesterolÏto€corticosteroid€hormones€in€the€adrenal€cortex€would€ultimately€cause€many€effects€throughout€the€bodyÏthat€would€differ€in€site€and€nature.€€The€Agency€will€group€substances€that€cause€multiple€toxic€effects€byÏa€common€mechanism€from€a€common€site€of€toxic€action€(e.g.,€the€multiple€effects€caused€by€certainÏendocrine€disruptors)€for€purposes€of€cumulative€risk€assessment,€provided€at€least€one€of€the€toxic€effectsÏis€common€among€the€substances.ÌÌÌò òÓ?` „ƒ,¸ …Xô x(#ŠX` ܈XLxŒX?Óà Ü àStep€1.€€Identify€a€Candidate€Set€of€Substances€That€Might€Cause€a€Common€Toxic€Effect€by€aÐ à   ÐCommon€Mechanism€of€Toxicity.€€ó óThe€process€of€identifying€pesticides€and€other€substances€that€have€aÐ ºz Ðcommon€mechanism€of€toxicity€begins€with€a€preliminary€grouping€of€chemicals€that€might€cause€a€commonÏtoxic€effect€by€a€common€mechanism€of€toxicity€(step€1,€Figure€1).€€Substances€that€are€related€structurally,Ïor€have€a€similar€mechanism€of€pesticidal€action,€or€share€a€general€mechanism€of€mammalian€toxicity€orÏcause€what€could€be€a€common€toxic€effect€in€humans€or€experimental€animals€are€those€that€could€causeÏa€common€toxic€effect€by€a€common€mechanism.€€Hence,€the€initial,€preliminary€grouping€of€substances€willÏbe€based€upon€at€least€one€of€the€following€criteria:€ÌÓN%` „°Œ ¸ …Xô x(#ŠX` „ƒ,¸ …Xô x(#ŠXNÓÌÝ‚ gÿÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÓT%` „°ƒXä „Xô x(#‰X` „°Œ ¸ …Xô x(#ŠXTÓÝ‚ gÿÎfgicaÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿ´ggicaÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿFhgicaÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿØhgicaÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿjigicaÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿüigicaÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿŽjgicaÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿÝÒ°ÒÒ°°ÒÓ ÓÝ  Ýñ„ñÒioÒÒX°Òñ„ñÝ‚ gÿ kgicaÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿØkgicaÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿjlgicaÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿülgicaÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿŽmgicaÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿ ngicaÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿ²ngicaÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿDogicaÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿÝÒ°ÒÒ°°ÒÓ ÓÝ  Ýñ„ñÒioÒñ„ñÒX°Òà ` àà ¸ àà ä àÔ€M¼ ¼&M&¿RÔððÔ€M&¿R& ¼M¼Ôà  àstructural€similarity;Ð ŠJ Ðà ` àà ¸ àà ä àÔ€M¼ ¼&M&¿RÔððÔ€M&¿R& ¼M¼Ôà  àmechanism€of€pesticidal€action;Ð  ` Ðà ` àà ¸ àà ä àÔ€M¼ ¼&M&¿RÔððÔ€M&¿R& ¼M¼Ôà  àgeneral€mechanism€of€mammalian€toxicity;€Ð ¶v Ðà ` àà ¸ àà ä àÔ€M¼ ¼&M&¿RÔððÔ€M&¿R& ¼M¼Ôà  àa€particular€toxic€effect.Ð ÌŒ ÐÌÝ‚ gÿÖogicaÝÒ°ÒÒ°XÒÓ ÓÝ  ÝÓ5€¼ |5ÓÌà  àUse€of€structural€similarity€as€a€starting€point€for€grouping€chemicals€relies€on€the€assumption€thatÏsubstances€that€are€structurally€analogous€could€contain€a€common€toxophore€(or€may€yield€a€commonÏtoxophore€upon€metabolism)€and€may€interact€analogously€with€cellular€biomolecular€sites€to€cause€aÏcommon€toxic€effect.€€To€identify€pesticides€and€other€substances€that€are€structurally€similar,€the€AgencyÏwill€perform€substructure€searches€in€databases€containing:€registered€pesticides;€pesticides€for€which€thereÏare€import€tolerances;€and€other€substances€(e.g.,€pharmaceuticals,€industrial€chemicals)€that€are€used€inÏcommerce€in€the€United€States.€€Search€queries€for€identification€of€structurally€similar€substances€mayÏinclude,€for€example:€toxophore€(if€known)€or€metabolic€precursor€of€the€toxophore;€base€structure;€andÏaccompanying€functional€groups€or€other€substituents€that€may€impact€on€the€propensity€of€a€substance€toÏproduce€a€toxicological€response€common€with€those€of€structurally„related€chemicals.ÌÌà  àPreliminary€grouping€of€pesticides€based€on€mechanism€of€pesticidal€action€is€justifiable€becauseÏthe€mechanisms€by€which€a€number€of€pesticides€are€toxic€to€humans€are€fundamentally€similar€or,€in€someÏcases,€identical€to€their€mechanisms€of€intended€toxicity€to€pests.€€With€such€pesticides€the€portion€of€theÏmolecule€that€is€responsible€for€pesticidal€action€is€also€responsible€for€human€toxicity€(i.e.,€the€portion€ofÐ ‚-B'- Ðthe€molecule€that€bestows€pesticidal€activity€is€also€the€human€toxophore).€The€pesticidal€action€and€humanÏtoxicity€of€these€pesticides€are€often€due€to€analogous€interactions€of€their€toxophores€with€specificÏbiomolecular€sites€that€are€common€to€pests€and€humans,€respectively.ÌÌà  àPreliminary€grouping€of€pesticides€and€other€substances€that€share€a€general€mechanism€ofÏmammalian€toxicity€is€based€on€the€possibility€that€such€substances€may€cause€a€common€toxic€effect.€ÏExamples€of€general€mechanism€of€toxicity€include,€for€example,€substances€that€uncouple€oxidativeÏphosphorylation,€or€substances€that€are€known€to€undergo€the€same€or€similar€bioactivation€pathways,€or€thatÏare€metabolized€to€the€same€or€analogous€metabolites€that€are€toxic.€€òòÐ  Ð ÐÌà  àóóPreliminary€grouping€of€pesticides€and€other€substances€that€cause€a€particular€toxic€effect€knownÐ Ä„  Ðto€occur€in€experimental€animals€or€humans€is€based€on€the€possibilty€that€the€effect€could€be€common€(i.e.,Ïconcordant€in€both€site€and€nature),€and€that€commonality€in€toxicity€among€two€or€more€substances€couldÏbe€due€to€a€common€mechanism.€€Since€this€type€of€grouping€is€functionally„based,€not€structure„based,€itÏenables€the€identification€of€structurally€unrelated€substances€that€cause€a€common€toxic€effect€from€aÏcommon€mechanism€that€otherwise€may€not€be€identifiable€from€groupings€based€on€structural€similarityÏor€mode€of€pesticidal€action€alone.€€€ÌÌà  àNot€all€toxic€effects€can€be€used€as€a€preliminary€basis€for€grouping€substances.€€Toxic€effects€whichÏhave€many€possible€unrelated€causes,€or€which€could€be€defined€as€nonspecific€in€origin€are€not€appropriateÏas€the€primary€basis€for€initial€grouping€of€chemicals.€€These€effects,€such€as€body€weight€changes€or€death,Ïcan€result€from€many€unrelated€factors€and€are€usually€of€limited€value€in€understanding€mechanism€ofÏtoxicity.€€Therefore,€such€generalized€effects,€which€could€have€many€different€causes,€ordinarily€will€notÏbe€used€as€a€basis€for€initial€grouping€of€pesticides.€€An€exception,€however,€is€genetic€alterations.€€WhileÏgenetic€alterations€can€result€from€a€variety€of€causes,€knowledge€of€the€mechanism€by€which€a€chemicalÏsubstance€causes€genetic€alterations€can€provide€insight€into€the€mechanism€by€which€it€causes€adverseÏhuman€health€effects.€Therefore,€data€for€chemicals€with€common€mutagenic€effects€may€serve€as€a€basisÏfor€initial€grouping€of€such€chemicals.ÌÌà  àFollowing€preliminary€grouping€of€substances€using€any€of€the€criteria€described€above,€otherÏsubstances€that€are€mammalian€metabolic€precursors€to€the€substances€identified€under€step€1€will€be€addedÏto€the€initial€grouping.€€The€basis€for€including€a€metabolic€precursor€to€a€substance€identified€under€step€1Ïis€that€since€it€is€metabolized€to€the€substance,€it€may€cause€a€common€toxic€effect€by€a€mechanism€commonÏwith€that€of€the€substance.€ÌÌà  àIt€is€important€to€emphasize€and€to€make€clear€that€the€purpose€of€step€1€is€for€òòpreliminary€groupingÐ $Î# Ðonlyóó,€and€that€substances€(including€any€metabolic€precursors)€identified€under€this€step€will€not€be€includedÐ è$¨$ Ðin€a€cumulative€risk€assessment€if€it€is€determined€that€they€do€not€cause€a€common€toxic€effect€by€a€commonÏmechanism.€€€For€example,€while€some€substances€that€contain€the€same€toxophore,€or€that€are€otherwiseÏstructurally€analogous,€may€cause€a€common€toxic€effect€by€a€common€mechanism,€others€may€not.€€€€It€isÏalso€possible€for€substances€to€cause€a€particular€toxic€effect€in€which€the€nature€of€the€toxic€effect€causedÏby€each€substance€is€the€same,€but€the€organ€or€specific€location€in€the€body€where€the€effect€occurs€differs€Ïamong€the€substances.€€It€is€also€possible€for€two€substances,€even€those€that€are€structurally€analogous,€toÏcause€entirely€different€toxic€effects.€€Such€differences€between€location€or€nature€of€a€toxic€effect€can€beÏascribed€to€the€specific€structural€and€physicochemical€differences€between€the€substances,€and€the€effect€Ï€these€differences€have€on€their€respective€pharmacokinetics€(i.e.,€absorption,€distribution,€metabolism,€andÏexcretion€of€each€substance)€or€pharmacodynamics€(i.e.,€the€interaction€of€the€toxophore€with€biomolecular€Ð l-,'. Ðsites).€€In€these€instances€the€policy€of€the€Agency€is€òònotóó€to€group€such€substances€for€cumulative€riskÐ @ Ðassessment€purposes,€because€the€toxic€effects€are€not€common,€as€defined€earlier.€€It€is€also€possible€withÏsubstances€that€cause€a€common€toxic€effect€to€cause€the€effect€by€different€mechanisms€of€toxicity.€ÏConversely,€substances€that€share€a€general€mechanism€of€toxicity€may€not€necessarily€cause€a€commonÏtoxic€effect(s).€Furthermore,€substances€that€have€a€common€mechanism€of€pesticidal€action€may€notÏnecessarily€have€a€common€mechanism€of€toxicity€in€mammals.€€Again,€in€these€instances€the€policy€of€theÏAgency€is€not€to€group€such€substances€for€cumulative€risk€assessment€purposes€because€they€are€notÏconsistent€with€the€definition€of€common€mechanism€of€toxicity.Ì€€€Ìà  àIt€must€also€be€stressed€that€step€1€(like€step€2€discussed€below)€is€a€very€inclusive€and€necessaryÏscreening€step€to€identify€preliminary€groupings€of€substances€for€a€rigorous€assessment.€€In€particular,€theÏcriteria€used€in€step€1€are€very€broad,€and€thus€there€is€a€real€possibility€that€a€substantial€portion€of€theÏpesticide€chemicals€and€other€substances€which€are€included€in€a€preliminary€grouping€may€not€have€aÏcommon€mechanism€of€toxicity,€and€many€will€be€dropped€from€a€group€in€subsequent€steps.€€Accordingly,ÏEPA€does€not€regard€information€which€shows€substances€meet€the€step€1€(and€step€2)€criteria€for€groupingÏas€reliable€by€itself€to€conclude€that€such€substances€have€a€common€mechanism€of€toxicity.€€Nor€does€suchÏinformation€create€a€sufficient€presumption€of€the€existence€of€a€common€mechanism€of€toxicity€that€itÏcompels€EPA€to€complete€the€remaining€steps€described€below€before€making€its€safety€determination.ÌÌà  àHence,€only€those€substances€€that€EPA€determines,€through€the€in„depth€review€described€below,Ïcause€a€common€toxic€effect€by€a€common€mechanism€will€be€considered€for€cumulative€risk€assessment.€ÏAs€shown€in€the€Figure,€this€examination€will€involve:€a€thorough€evaluation€of€toxicity€data€to€determineÏwhich€substances€identified€under€step€1€cause€a€common€toxic€effect;€determination€of€the€mechanism€ofÏtoxicity€by€which€each€substance€causes€the€common€toxic€effect;€and€subsequent€comparison€of€eachÏmechanism€to€confirm€or€rule„out€commonality.€€€It€is€likely€that€EPA€will€conclude€a€substantial€portionÏof€the€substances€identified€in€step€1€should€not€be€included€in€a€cumulative€risk€assessment.€€Ð  ŠJ ÐÔ€&ï»&&M&¿RÔÔ€XÞûX&&ï»Ôßh€WY4$ ` \óç* `À©,E°@ó (ÒO (°@ó (hßÔ€&ï»&XXÞûÔÔ€M&¿R&&&ï»ÔÐ  @ Ðßh€W[4$ ` \î”* `ÀóË,E°@î (b) (°@î (hßÐ  @ Ðò òÓW(` „ƒ,` ¸ ‚,hƒXô x(#ˆX` „°ƒXä „Xô x(#‰XWÓà Ü àStep€2.€€Definitively€Identify€Those€Substances€from€Step€1€That€Cause€a€Common€Effect.€ó ó€€TheÐ @ Ðprimary€purpose€of€step€2€is€to€further€refine€the€preliminary€grouping€created€at€step€1€by€screening€outÏsubstances€that€obviously€do€not€cause€a€òòcommon€toxic€effect.óó€€Following€the€preliminary€grouping€ofÐ ô´ Ðsubstances€(step€1,€Figure€1)€a€detailed€evaluation€of€available€toxicology€data€for€each€substance€will€beÏundertaken€to€identify€and€characterize€the€toxic€effects€caused€by€each€substance,€and€to€determine€whichÏof€the€substances€cause€toxic€effects€that€are€common€with€other€substances€(i.e.,€toxic€effects€that€areÏconcordant€in€both€site€and€nature).€€A€primary€data€set€to€be€used€by€EPA€will€be€toxicity€data€generatedÏin€support€of€regulatory€activities€as€outlined€in€40€CFR€158.€€The€Agency€may€also€use€toxicity€dataÏobtained€from€other€studies,€such€as€those€described€in€government€reports,€or€the€published€literature.€TheÏevaluation€of€toxicology€data€for€purposes€of€identifying€and€characterizing€toxic€effects€will€be€conductedÏin€a€manner€similar€to€that€used€by€EPA€in€its€pesticide€registration€and€re„registration€programs.€€ÌÌà Ü àà  àMost€substances,€depending€upon€level€of€exposure,€can€elicit€more€than€one€toxic€effect€(albeit€oneÏtoxic€effect€is€generally€more€readily€elicitable€than€the€others).€€All€toxic€effects€caused€by€each€substance,Ïregardless€of€the€exposure€levels€required€to€induce€the€effects,€will€be€evaluated€and€compared€to€the€toxicÏeffects€caused€by€the€other€substances.€€Only€those€substances€that€cause€a€common€toxic€effect€will€remainÏgrouped.€Thus,€for€those€substances€initially€grouped€(step€1)€using€the€ð ðparticular€toxic€effectðð€criterionÏ(step€1),€a€determination€as€to€which€substances€the€toxic€effect€is€in€fact€common€will€need€to€be€made.€€TheÏtoxicity€data€for€substances€initially€grouped€using€any€of€the€other€criteria€in€step€1€will€also€be€evaluatedÏto€determine€which€of€these€substances€cause€a€common€toxic€effect.€€Substances€may€be€placed€in€more€thanÏone€group€in€instances€where€substances€cause€more€than€one€common€toxic€effect.€€€Pesticide€chemicalsÏthat€do€not€cause€a€toxic€effect€that€is€common€with€at€least€one€other€substance€identified€under€step€1€willÏbe€eliminated€from€the€group€and,€thus,€will€not€undergo€further€cumulative€risk€consideration.ÌÌà Ü àò òStep€3.€€Determine€the€Toxic€Mechanism(s)€by€Which€Each€Substance€Causes€a€Common€ToxicÐ °p ÐEffect.€€ó óThe€next€phase€of€the€review€process€(step€3,€Figure€1)€is€to€determine€the€mechanisms€by€whichÐ ŠJ Ðthe€substances€cause€the€common€toxic€effect(s)€identified€under€step€2€(Figure€1).€€Generally,€the€more€thatÏis€understood€about€the€various€biochemical€events€that€lead€to€a€toxic€effect,€the€more€apparent€andÏscientifically€acceptable€is€the€mechanism€of€toxicity.€€While€desirable,€all€of€the€specific€biochemical€eventsÏinvolving€a€substance€in€the€causation€of€its€toxicity€do€not€need€to€be€known€or€completely€characterizedÏin€order€to€describe€its€mechanism€of€toxicity.€€What€is€needed,€as€a€minimum,€is€an€understanding€of€thoseÏbiochemical€events€that€are€most€crucial€in€causing€the€toxicity.€€Once€the€critical€biochemical€eventsÏpertaining€to€toxicity€are€understood€for€each€substance,€they€can€be€compared€and€identification€of€thoseÏsubstances€that€are€toxic€from€a€common€mechanism€can€be€made.€€Hence,€the€goal€of€step€3€is€to€determine,Ïto€the€extent€possible€for€each€substance€identified€under€step€2€as€causing€a€common€toxic€effect,€thoseÏbiochemical€events€that€are€most€critical€in€causing€the€effect.€ÌÌà Ü àà  àThe€toxic€mechanisms€of€some€classes€of€substances€in€causing€a€given€toxic€effect€have€beenÏcharacterized,€and€are€described€in€various€literature€sources€(e.g.,€textbooks,€journals,€etc.).€€€TheseÏmechanisms€were€elucidated€from€the€development€and€comprehensive€analysis€of€data€€pertaining€to€theÏstructure,€pharmacokinetics€and€toxicity€of€the€substances€and€their€analogs.€€The€toxophoric€moieties€andÏstructure„activity€relationships€of€many€of€these€chemical€classes€were€similarly€characterized.€The€toxicÏmechanisms,€toxophores€and€structure„activity€relationships€of€other€pesticides,€however,€have€not€been€fullyÏcharacterized,€either€because€of€insufficient€data,€or€because€available€data€have€not€yet€been€fully€analyzed.ÌÌà Ü àà  àRather€than€reexamining€òòde€novoóó€all€of€the€relevant€data,€EPA€will€assume€that€a€substance€is€toxicÐ ’,R&- Ðby€the€mechanism€that€has€been€previously€determined€provided€that€the€mechanism€is€consistent€withÐ l-,'. Ðcurrent€toxicological€theory€and€deemed€scientifically€plausible€by€the€Agency€for€these€purposes.€€Thus,Ïidentification€of€toxic€mechanisms€will€involve€an€initial€search€of€Agency€databases€and€the€literature€(stepÏ3a,€Figure€1)€for€assessments€or€studies€that€describe€mechanisms€of€toxicity€for€any€of€the€pesticidesÏgrouped€in€step€2.€€The€types€of€literature€sources€that€will€be€searched€and€used€include€standard€referenceÏand€text€books,€€peer„reviewed€journals,€government€reports,€and€study€reports€submitted€to€the€Agency.€ÏThis€will€allow€segregation€of€the€substances€into€two€sub„groups:€those€for€which€mechanism(s)€of€causingÏa€common€toxic€effect€have€been€determined;€and€those€for€which€their€mechanism(s)€have€not€beenÏdetermined.€€When€deemed€necessary,€more€comprehensive€literature€or€Agency€database€searches€will€needÏto€be€conducted€to€identify€data€that€support€or€invalidate€previously€determined€mechanisms€of€toxicity€forÏwhich€uncertainty€exists.ÌÌ€à Ü àà  àEPA€will€attempt€to€determine€the€mechanisms€of€toxicity€of€those€substances€whose€toxicÐ ž^  Ðmechanisms€are€not€known€or€not€well€understood,€or€for€which€there€is€an€absence€of€direct€mechanisticÏdata.€€The€determination€of€a€toxic€mechanism€will€be€based€upon€an€evaluation€of€various€data€elements.€ÏThe€types€of€data€and€information€that€the€Agency€will€use€to€develop€a€scientifically€defensibleÏdetermination€of€a€given€pesticideððs€toxic€mechanism€are€structural€data,€pharmacokinetic€data,€and€toxicityÏdata.€€In€situations€in€which€such€data€are€not€available€or€are€insufficient€for€a€pesticide,€the€Agency€willÏreview€and€may€use€mechanistic,€structural,€pharmacokinetic€or€toxicity€data€pertaining€to€one€or€moreÏanalogs€of€the€pesticide€(or€other€substance)€as€a€basis€for€determining€the€toxic€mechanism€of€the€pesticide.€Ï€Identifying€and€obtaining€pesticide€or€analog€data€will€involve€a€comprehensive€search€of€the€literature€andÏAgency€databases.€€A€primary€source€of€these€data€and€information€will€be€studies€that€have€been€submittedÏto€the€Agency€in€support€of€registration€and€reregistration€decisions.€€Other€sources€of€data€will€include€peer„¼reviewed€journals,€text€books€and€government€reports.€ÌÌà Ü àà  àThe€Agency€will€analyze€these€data€and,€using€a€weight„of„evidence€approach,€will€attempt€toÏdetermine€the€major€biochemical€events€involving€a€pesticide€(or€other€substance)€that€are€most€critical€inÏcausing€its€toxicity€(step€3b).€€From€an€analysis€of€a€substanceððs€structure,€for€example,€the€recognition€ofÏmoieties€that€are€known€or€expected€to€react€with€biological€macromolecules,€or€are€known€or€expected€toÏbe€metabolized€to€reactive€(e.g.,€radical,€electrophilic)€intermediates,€or€are€otherwise€known€or€expectedÏto€bestow€toxicity€may€allow€one€to€infer€one€or€more€biochemical€events€that€are€responsible€for€theÏsubstanceððs€toxicity.€€Data€that€define€the€metabolism,€distribution€and€excretion€of€a€pesticide€in€the€bodyÏare€also€very€useful€for€determining€its€mechanism€of€toxicity.€€Metabolism€data€that€show€the€formation€ofÏtoxic€metabolites€òòin€vivo€óóare€especially€useful€for€characterizing€metabolic€pathways€which€may€be€operativeÐ €!@  Ðin€causing€toxic€effects.€€Distribution€and€excretion€data€show€the€partitioning€patterns€of€a€substance€in€theÏbody,€and€may€in€some€cases€be€used€to€infer€the€types€of€metabolic€transformations€that€are€most€likely€toÏoccur€and€where€they€are€most€likely€to€take€place.€€These€data,€in€conjunction€with€structural€and€toxicityÏdata,€may€also€provide€explanations€for€differences€in€toxicity€of€structurally€similar€substances.€€ToxicityÏdata€can€be€helpful€in€the€determination€of€a€toxic€mechanism€in€many€ways.€€Genetic€alterations,€forÏexample,€are€important€in€the€causation€of€cancers€and€developmental€effects.€Tests€for€genetic€alterationsÏthat€show€that€a€substance€(or€a€metabolite€thereof)€forms€a€covalent€adduct€with€DNA€may€be€useful€to€inferÏor€support€a€mechanism€by€which€a€pesticide€known€to€cause€cancer€or€developmental€toxicity€causes€eitherÏof€these€effects.€€ÌÌà Ü àà  àData€pertaining€to€analogs€of€a€pesticide€or€other€substance€will€be€reviewed€and€may€be€used€inÏsituations€in€which€mechanism„related€data€are€not€available€for€the€pesticide.€€An€established€mechanismÏof€toxicity€of€a€pesticideððs€analog(s),€for€example,€may€serve€as€a€basis€for€determining€the€toxic€mechanismÏof€the€pesticide.€€Conclusions€based€on€the€toxic€mechanisms€of€an€analog€or€analogs€will€only€be€madeÐ l-,'. Ðwhen:€there€is€evidence€that€shows€that€the€toxicological€effects€caused€by€the€pesticide€and€the€analogs€areÏcommon;€there€is€sufficient€evidence€that€supports€the€toxic€mechanism€of€the€analog(s);€and€there€isÏsufficient€evidence€for€the€Agency€to€conclude€that€the€mechanism€of€toxicity€of€the€pesticide€is€commonÏwith€the€mechanism€of€toxicity€of€the€analog(s).€€Pharmacokinetic,€toxicity€and€structure„activity€relationshipÏdata€that€are€available€for€analogs€of€a€pesticide€will€also€be€used€as€a€basis€for€determining€the€toxicÏmechanism€of€the€pesticide€(step€3b,€Figure€1).€€For€example,€it€is€stated€above€that€test€data€pertaining€toÏgenetic€alterations€may€be€useful€to€infer€or€support€a€mechanism€of€a€pesticide€known€to€cause€cancer€orÏdevelopmental€toxicity.€€Genetic€alterations€data€available€for€analogs€of€a€pesticide€known€to€cause€cancerÏor€developmental€toxicity€may€be€useful€for€inferring€the€mechanism€by€which€the€pesticide€causes€theseÏeffects.€€ò ò€ó óGenetic€alterations€that€are€similar€among€a€pesticide€and€its€analogs€are€also€useful€in€a€weight„of„Ð ê ª  Ðevidence€confirmation€of€the€validity€of€such€inferences,€particularly€when€mechanistic€data€are€availableÏfor€the€analog€but€not€for€the€subject€pesticide.ÌÌà Ü àà  àRelationships€between€structure€and€toxicity€within€a€given€series€of€structurally„similar€substancesÏor€of€a€single€given€substance€are€often€discernable€from€an€analysis€of:€the€general€structure;€the€chemicalÏproperties€of€the€substance(s);€information€pertaining€to€the€pharmacokinetics€and€toxicity€of€theÏsubstance(s);€and€the€structural€differences€within€the€series€and€their€corresponding€affect€on€toxic€efficacyÏand€potency.€€While€knowledge€of€the€mechanism€of€toxicity€is€usually€not€necessary€in€order€to€discern€aÏcausal€relationship€between€structure€and€activity€(toxicity),€the€relationship€becomes€more€apparent€andÏmore€useful€when€the€mechanism€of€toxicity€is€known.€€€Once€deduced,€the€structure„activity€relationshipÏof€the€substance€or€the€series€can€be€useful€for€inferring€the€likelihood€of€an€analogous,€untested€chemicalÏto€cause€the€same€toxicological€effect,€and€for€estimating€its€toxic€potency.€€In€cases€where€the€mechanismÏof€toxicity€is€known€for€a€substance€or€a€group€of€substances,€structure„activity€relationships€are€useful€forÏinferring€the€mechanism€of€toxicity€of€an€analogous,€untested€substance€and€for€supporting€or€refutingÏproposed€mechanisms€of€toxicity€of€analogous€untested€substances.€ÌÌÌò òà Ü àSteps€4€and€5.€Comparison€of€Mechanisms€of€Toxicity€(Step€4)€and€Refined€Grouping€ofÐ >þ ÐSubstances€€(Step€5).€ó ó€€Once€the€mechanism€of€toxicity€of€each€substance€has€been€identified,€comparisonsÐ Ø Ðof€mechanisms€will€be€made€to€determine€which€substances€identified€under€step€2€as€causing€a€givenÏcommon€toxic€effect€do€so€by€a€common€mechanism.€€Determinations€that€two€or€more€substances€are€toxicÏby€a€common€mechanism€will€be€based€on€similarities€in€both€the€nature€and€sequence€of€the€majorÏbiochemical€events€that€cause€toxicity.€€Mechanistic€similarities€that€would€support€a€finding€of€a€commonÏtoxic€mechanism€include,€for€example,€analogous€interactions€of€the€pesticides€or€other€substances€withÏidentical€or€similar€biological€targets,€or€the€occurence€of€similar€metabolic€transformations€that€yieldÏcommon€or€structurally€analogous€metabolites€that€interact€with€similar€biological€targets,€or€that€areÏotherwise€involved€in€causing€toxicity.€€Substances€that€cause€a€common€toxic€effect€by€differentÏmechanisms€will€excluded€from€the€refined€grouping€(Step€5).€€Ìò òÌà Ü àà  àó óPeer€review€of€EPAððs€decisions€concerning:€utilization€of€established€toxic€mechanisms;Ð v'6!' Ðidentification€of€toxic€mechanisms€for€specific€substances;€and€grouping€(or€non„grouping)€of€substancesÏfor€purposes€of€cumulative€risk€assessment€will€be€solicited€in€situations€in€which€the€Agency€believesÏadditional€evaluation€is€needed€to€ensure€that€Agency€decisions€are€consistent,€well„reasoned€and€reflectÏcurrent€scientific€thinking.€ÌÌÌÐ l-,'. Ðò òÔ€MŠë† Š&M&¿RÔIV.€Ô€M¼ ¼ ŠMŠë†ÔAÔ€M&¿R& ¼M¼ÔSSESSING€THE€Ô€M¼ ¼&M&¿RÔCÔ€M&¿R& ¼M¼ÔUMULATIVE€Ô€M¼ ¼&M&¿RÔTÔ€M&¿R& ¼M¼ÔOXICITY€Ô€MŠë† Š&M&¿RÔPÔ€M&¿R& ŠMŠë†ÔOSED€€BY€Ô€M¼ ¼&M&¿RÔTÔ€M&¿R& ¼M¼ÔWO€OR€Ô€M¼ ¼&M&¿RÔMÔ€M&¿R& ¼M¼ÔORE€Ô€M¼ ¼&M&¿RÔSÔ€M&¿R& ¼M¼ÔUBSTANCESÐ @ ÐÔ€M¼ ¼&M&¿RÔTÔ€M&¿R& ¼M¼ÔHAT€Ô€M¼ ¼&M&¿RÔAÔ€M&¿R& ¼M¼ÔREÔ€MXgX&M&¿RÔ€Ô€M¼ ¼XMXgÔTÔ€M&¿R& ¼M¼ÔOXIC€BY€AÔ€MXgX&M&¿RÔ€Ô€M¼ ¼XMXgÔCÔ€M&¿R& ¼M¼ÔOMMONÔ€MŠë† Š&M&¿RÔ€Ô€M¼ ¼ ŠMŠë†ÔMÔ€M&¿R& ¼M¼ÔECHANISM.€ó óÐ V ÐÌà Ü àà  àCumulative€toxicity€represents€the€net€change€in€toxicity€resulting€from€exposure€to€two€or€moreÏchemical€substances,€relative€to€the€toxicity€caused€by€each€substance€alone.€€The€evaluation€of€cumulativeÏtoxicity€will€be€conducted€in€accordance€to€a€cumulative€risk€assessment€process€being€developed€by€theÏAgency.€€The€goal€of€the€cumulative€risk€assessment€process,€in€regard€to€implementing€FFDCA€as€amendedÏby€FQPA,€is€to€characterize€the€potential€for€a€cumulative€toxic€effect€and€the€magnitude€of€the€effect€inÏindividuals€following€known€or€anticipated€exposures€to€substances€that€cause€the€effect€by€a€commonÏmechanism.€€Pesticide€chemicals€and€other€substances€within€a€refined€common€mechanism€grouping€(stepÏ5,€Figure€1)€will€undergo€cumulative€risk€assessment€to€determine€the€potential€cumulative€toxicity€posedÏby€exposures€to€such€substances.€€This€will€involve€consideration€of€a€number€of€factors€that€pertain€to:Ïexposure;€the€pharmacokinetics€of€each€substance;€the€nature€of€the€common€toxic€effect;€theÏpharmacodynamics€of€each€substance€in€causing€the€effect;€pharmacokinetic€or€pharmacodynamicÏinteractions€that€may€take€place€between€the€substances;€subpopulations€for€which€exposures€are€anticipated;Ïand€susceptibility€and€sensitivity€of€exposed€individuals€or€subpopulations€to€the€common€toxic€effect.€€AÏdiscussion€of€how€these€factors€affect€cumulative€toxicity€is€beyond€the€scope€of€this€document.€€In€additionÏto€the€substances€wihitn€a€refined€grouping,€the€Agency€will€also€consider€the€potential€contribution€toÏcumulative€toxicity€from€other€substances€that€undergo€environmental€degradation€or€metabolism€in€plantsÏto€any€of€the€substances€within€the€refined€group.€€Substances€that€degrade€in€the€environment,€or€that€areÏmetabolized€in€plants€to€substances€in€the€refined€grouping€will€be€included€in€a€cumulative€risk€assessmentÏbecause€such€precursor€substances€may€represent€an€additional€source€of€exposure€to€the€substances€in€theÏrefined€grouping.€The€cumulative€risk€assessment€process€that€the€Agency€will€use€will€be€described€in€aÏforthcoming€Agency€science€policy€guidance€document.€€The€document€will€include€detailed€discussionsÏof€the€above€factors,€how€these€and€other€factors€will€be€considered€by€the€Agency€in€assessing€cumulativeÏtoxicity,€and€what€the€Agency€will€do€when€there€are€data€gaps€with€the€above€factors.€€ÌÌà Ü àà  à€ÌÌÓW%` „°ƒXä „Xô x(#‰X` „ƒ,` ¸ ‚,hƒXô x(#ˆXWÓÌÌ€€€€€€Ìà  àÌÌÌÌà  àÌÝ‚ gÿÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÓB` „°‰XxŒX` „°ƒXä „Xô x(#‰XBÓÝ‚ gÿ€Øhe€mÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿTÙhe€mÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿæÙhe€mÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿxÚhe€mÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿ Ûhe€mÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿœÛhe€mÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿ.Ühe€mÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÒeÒñ„ñÒ°neÒÒeneÒÒX°Òñ„ñÝ‚ gÿÀÜhe€mÝÒ°eÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿ”Ýhe€mÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿ&Þhe€mÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿ¸Þhe€mÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿJßhe€mÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿÜßhe€mÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿnàhe€mÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿáhe€mÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÝ‚ gÿÝÒ°ÒÒ°°ÒÓ ÓÝ  ÝÒeÒÒX°ÒÌÝ‚ gÿ’áhe€mÝÒ°eÒÒ°XÒÓ ÓÝ  ÝÒ°Òñ„ñÒ°neÒñ„ñÓ!` ` „°‰XxŒX!ÓÔ€MXgX&M&¿RÔ