nt J Biol Sci 2009; 5:438-443 Review How Subchronic and Chronic Health E ect! can be "e#lected or $%&!' (e!ticide!

or Che)ical! $ille!-Eric S*ralini+'2 ' ,o-l S.irou/ de 0end1)oi!2' 2o)ini3ue Cellier2'3' Charle! Sultan2'4' %arcello 4uiatti2'5' 5ou $alla#her6' %ichael 7ntoniou8' 9ri!hna R: 2rona)ra;u8 +: <niver!it= o Caen' >n!titute o 4iolo#=' 4ioche)i!tr=' E!.lanade de la (ai/ +4032 Caen Cede/ ?rance: 2: CR>>$E"' 40 rue %onceau' 85008 (ari! ?rance 3: <niver!it= o Rouen' 5>@>S E7 4+08' 8682+ %ont Saint-7i#nan' ?rance 4: <niver!it= o %ont.ellier' School o %edicine' >$H' C"RS' ?rance 5: <niver!it= o ?irenAe' >tal= 6: >n!titute or Environ)ental Science and Re!earch' 5td' Crown Re!earch >n!titute' (orirua' "ew Bealand 8: 9in#C! Colle#e 5ondon School o %edicine' 2e.t: %edical and %olecular $enetic!' 5ondon' <nited 9in#do) 8: ?oundation or $enetic Re!earch' Hou!ton' <S7 How to cite this article: S*ralini $E' de 0end1)oi! ,S' Cellier 2' Sultan C' 4uiatti %' $alla#her 5' 7ntoniou %' 2rona)ra;u 9R: How Subchronic and Chronic Health E ect! can be "e#lected or $%&!' (e!ticide! or Che)ical!: Int J Biol Sci 2009; 5:438-443: 7vailable ro) htt.:DDwww:biol!ci:or#Dv05.0438:ht) 7b!tract Chronic health e ect! are increa!in# in the world !uch a! cancer!' hor)onal' re.roductive' nervou!' or i))une di!ea!e!' even in =oun# .eo.le: 2urin# re#ulator= to/icolo#ical !ubchronic te!t! to .revent the!e on )a))alian health' .rior co))ercialiAation o che)ical!' includin# .e!ticide! and dru#!' or $%&!' !o)e !tati!ticall= !i#ni icant indin#! )a= be revealed: @hi! di!cu!!ion i! about the need to inve!ti#ate the relevant criteria to con!ider tho!e a! biolo#icall= !i#ni icant: @he !e/ di erence! and the non linear do!e or ti)e related e ect! !hould be con!idered in contra!t to the clai)! o a %on!anto-!u..orted e/.ert .anel about a $%&' the %&" 863 4t )aiAe' but al!o or .e!ticide! or dru#!' in .articular to reveal hor)onede.endent di!ea!e! and ir!t !i#n! o to/icitie!: Keywords: (e!ticide!' $%&' %&" 863' !ide e ect!' to/icolo#ical te!t!:

Introduction
So)e conta)ination! or .ollution! b= .e!ticide! E+F and other che)ical re!idue! E2-4F a ect hu)an and ani)al health' to#ether with biodiver!it=: @hu! it i! i).ortant to !tud= .otential )id and lon#-ter) to/icolo#ical e ect! durin# re#ulator= te!t! .rior to

co))ercialiAation o che)ical!' and not to te!t onl= !hort-ter) or !ubchronic e ect!: @hi! 3ue!tion ha! al!o been rai!ed or $%&! E5F' e!.eciall= tho!e containin# .e!ticide!' either becau!e the= tolerate G!uch a! Roundu. Read= !o=aH or .roduce G!uch a! 4t )aiAeH the!e )olecule! G99 I o co))erciall= cultivated $%&!H: @hi! !ub;ect ha! been reviewed recentl= b= 2rona)ra;u E6F:

Objectives
Here we !hall di!cu!! )ore .articularl= the e/i!tin# data on .o!!ible to/ic e ect! o a $%& on )a))al!' with .utative relevance to hu)an!' and with the ai) o co))entin# on current .rocedure! and e/.eri)ental .rotocol! in )a))alian eedin# e/.eri)ent! G?i#: +H: 2oull et al. E8F indicated their #eneral criteria needed to cla!!i = a! biolo#icall= relevant the ob!erved !i#ni icant e ect! durin# 90d to/icolo#ical te!t! on )a))al!: @he e/a).le taJen wa! or a $%&' a 4t )aiAe called %&" 863' .roducin# in it! cell! a new Jind o )odi ied in!ecticide Cr=34b+' Jnown a! a to/in or coleo.teran!: 4ut the!e author! clai) to a..l= the !a)e criteria to other .roduct! !uch a! .e!ticide! and dru#!: @he hi!tor= o the debate on the bio!a et= o thi! $%& i! .aradi#)atic' and it rai!e! a !erie! o #eneral 3ue!tion! on ri!J a!!e!!)ent o co))ercial tran!#enic cro.! and o .e!ticide! or che)ical!: @he!e con!ideration! are crucial' !ince .ublic health i! concerned and their di!cu!!ion )a= criticall= in luence the deci!ion to relea!e in .articular !o)e a#ricultural $%&! or not' and al!o to another e/tent the econo)ic ea!ibilit= o thi! Jind o .ro;ect: Figure 1 Co).ari!on o re#ulator= to/icit= te!t! #enerall= .er or)ed in vivo on )a))al!' or in!tance with rat!' the )o!t u!ed )odel' be ore co))ercialiAation o variou! .roduct!: @he!e are $%&! u!ed or ood or eed' .e!ticide!' dru#!' or the be!t te!ted che)ical!: @he choice o how to a..l= !tandard! i! )ade b= !cienti ic co))i!!ion! o re#ulator= in!tance!: @hi! i#ure doe! not include re.roductive' develo.)ental or tran!#enerational te!t! that are not re3ue!ted or co))ercialiAed $%&! or ood or eed: "utritional te!t! are not re.re!ented either becau!e the= do not re3uire blood anal=!e!' which are ver= in or)ative on health !econdar= e ect!: So)e )a))alian nutritional te!t! are .er or)ed with .i#! or cow!' or in!tance or $%&!' and )a= la!t lon#er with ewer ani)al!: Subchronic to/icit= te!t! are in the la!t ca!e .er or)ed' i an=' onl= with rat! or )o!t $%&!: @hen it i! onl= with +0 ani)al! ull= a!!e!!ed on 20 or each o two do!e!' and .er !e/: @here are 3 )a))alian !.ecie! u!ed or other .roduct!: @hi! i! to )ea!ure !hort-ter) e ect!: @he !o-called chronic te!t! Gla!tin# )ore than 3 )onth!H #ive )ore chance! to reveal )etabolic' nervou!' i))une' hor)onal or cancer di!ea!e!: @he= are widel= .er or)ed or .e!ticide! and dru#! and or !o)e che)ical! over a certain .roduction' but not or actual co))ercialiAed $%&! relea!ed in the environ)ent G+995-2009H: @hi! i! a )atter o debate' !ince 99:9I o tho!e are #eneticall= )odi ied to contain new .e!ticide re!idue! that the= tolerate Ge/: Roundu. Read= !o=aH or that the= .roduce Ge/: in!ecticide! 4t in )aiAe' that are newl= )odi ied .roteic to/in!H: Gd: da=; ): )onth; =: =earH:

GClicJ on the i)a#e to enlar#e:H

The protocol used to test GMOs in regulatory in vivo tests with a

als

Recentl=' 2oull et al. E8F o ered a new contradictor= anal=!i! o S*ralini et al: E5F: >t wa! about the inter.retation o the onl= crude data available ro) the lon#e!t to/icit= te!t G90 da=!H on a )a))al that had been ed with %&" 863: @he ori#inal eedin# e/.eri)ent wa! .er or)ed b= Covance and %on!anto E8F' with a #reat e/.erience o thi! Jind o te!t! alwa=! de!i#ned in a !i)ilar )anner: @he= )ea!ured the e ect o eed containin# onl= two do!e! G++ and 33I $% in the e3uilibrated dietH and or onl= two .eriod! o e/.o!ure G5 and +4 weeJ!H: @he #oal i! a debate on !tandard! to be !et to inter.ret ad)itted !i#ni icant e ect! E8F between treated #rou.! ver!u! control! a! biolo#icall= relevant or not in to/icolo#ical te!t! in #eneral: @here are !everal .reli)inar= un!olved 3ue!tion! at !taJe to be an!wered !uch a! whether to .rolon# te!t! be ore co))ercial relea!e' or in!tance u. to two =ear! or $%&!' a! i! done or !o)e .e!ticide! or dru#!' in order to a!!e!! chronic e ect! not vi!ible in !hort .eriod!: @here are al!o 3ue!tion! re#ardin# the a..ro.riate nu)ber o concentration! o the .utative to/ic a#ent to be te!ted etc:' and critical e/.eri)ental criteria !uch a! nu)ber o ani)al! to be u!ed .er do!e or concentration to increa!e their re!olution .ower to obtain ho)o#eneou! and reliable !i#ni icance level! in outco)e )ea!ure)ent data: However' the crude data on %&" 863 were obtained b= %on!anto or onl= one )a))alian !.ecie! Gin!tead o the three u!ed or evaluation! o .e!ticide! or dru#!H and ir!t cla!!i ied a! con idential b= the Co).an= which obtained it G2002H: @he data wa! then u!ed to obtain co))ercial relea!e a#ree)ent! all over the world: 7 ter heated di!cu!!ion! in Euro.e concernin# the .o!!ible .h=!iolo#ical e ect! .rovoJed b= thi! $%&' a deci!ion in the $er)an 7..eal Court allowed .ublic acce!! to the crude data G2005H: %on!anto then .ubli!hed it! own inter.retation o the data E8F in which it wa! concluded that the %&" 863 wa! !a e to eat: 7 ter care ul anal=!i! o the crude data' S*ralini et al. E5F a..lied a..ro.riate !tati!tical )ethodolo#= to te!t the e ect! o the 4t )aiAe on )a))alian health: ?ir!t' $% ed rat! were co).ared to their clo!e!t i!o#enic control!' and then to the !i/ re erence #rou.! who were ed variou! other )aiAe-ba!ed diet! that %on!anto added in the !tud=: 2ata were co).iled b= or#an' do!e and ti)in# o dietar= e/.o!ure: >n addition' the e ect! on the rat )etaboli!) o the diet co).o!ition without $% )aiAe wa! !tudied' co).arin# onl= control and re erence #rou.! between the) to avoid !=!te)aticall= linJin# the!e e ect! to the $% diet: >n the ir!t in!tance %on!anto did not do !uch a !tati!tical !tud= GE8F and in co))ercial re3ue!t ileH but onl= tooJ into account e ect! between the $%

ed rat! at the hi#he!t do!e and all other #rou.!: >t i! i).ortant to note that in order to i!olate the e ect o the $% tran! or)ation .roce!! ro) other variable! it i! onl= valid to co).are the $%& Gin thi! ca!e %&" 863H with it! i!o#enic non-$% e3uivalent: @here ore' the inclu!ion in the anal=!i! o unrelated eedin# #rou.! !erve! to con u!e rather than clari = the e ect o the %&" 863 event: @he #oal o the !tati!tical anal=!i! i! to decide whether the con!u).tion o $%&! can be con!idered to have no e ect Gnull h=.othe!i! H0 trueH or to have an e ect GH0 al!eH on the health o the rat!: @hi! anal=!i! cannot be reduced in the co).utation o a collection o .-value!: Stati!tical re;ection o the null h=.othe!i! H0 doe! not i).l= that the e ect i! biolo#icall= !i#ni icant: >n the !a)e wa=' ailure to re;ect H0 doe! not )ean that it i! true: @here ore' the .ower o the h=.othe!i! te!t )u!t be a!!e!!ed: @he .ower o a !tati!tical te!t de.end! on the !a).le !iAe Gand there ore the e/.eri)ental de!i#nH' the !i#ni icance level o the te!t and the e ect !iAe Gwhich can be con!idered a! biolo#icall= !i#ni icantH: @hi! )o!t i).ortant i!!ue i! totall= overlooJed in the e/.eri)ental de!i#n and the !tati!tical re.ort )ade b= %on!anto on %&" 863: %oreover' an= h=.othe!i! which i! not !tati!ticall= !i#ni icant with their reductive )ethod i! alwa=! e/cluded: @hi! di!turbin# over!i#ht run! al!e ne#ative re!ult! and a ri!J o health con!e3uence! or )illion! o .eo.le and ani)al!:

!e"#related and non#linear signs o$ to"icity

>n the %&" 863 !tud=' S*ralini et al. E5F were al!o concerned b= al!e .o!itive re!ult!' but concluded that there were enou#h !i#n! o to/icit= to .rolon# the eedin# e/.eri)ent!: @hi! i! )o!tl= becau!e !i#ni icant e ect! were concentrated in liver! and Jidne=! a! )ain deto/i ication or#an! reactin# in ca!e! o ood D che)ical conta)ination; there were at the!e level! !o)e worr=in# .h=!iolo#ical .ro ile!: %oreover' the e ect! o the %&" 863 in!ecticide to/in it!el are not e/.eri)entall= docu)ented on )a))alian cell!: ?urther)ore' it re)ain! a .o!!ibilit= that there would be !ide e ect! due to in!ertional )uta#ene!i! durin# the $% tran! or)ation: ?or in!tance' the S*ralini et al. E5F anal=!i! !howed evidence o a !i#ni icant increa!e in blood #luco!e o +0I in $%- ed e)ale!' in tri#l=ceride! o 24-40I' overwei#ht liver! and enhanced liverDbrain ratio! G8IH' !)all but !i#ni icant bod= wei#ht #ain G3:8IH' and di!turbed Jidne= .ara)eter!: Khen co).arin# e)ale! eatin# $%&! to their clo!e!t control! eatin# the i!o#enic line' there were !i#n! o a .o!!ible .re-diabetic .ro ile: >n both !e/e! and .eriod! the .ro ile! were di erent but it concerned liver and Jidne= .ara)eter!: ?ro) that' 2oull et al. E6F concluded that an= e ect! with no clear do!e-re!.on!e relation!hi. Gwhich !hould increa!e with do!eH or with ti)e are unrelated to the $% diet: Ke con!ider that ir!t o all' to a !cienti ic .oint o view' choo!in# a priori 2 do!e! and 2 .eriod! doe! not allow the a!!e!!)ent o a linear do!e- or .eriod-related e ect E9++F: &ur h=.othe!i! wa! to 3ue!tion the .o!!ibilit= o !ubchronic or chronic health e ect! that were not or onl= .artiall= revealed b= !hort-ter) te!t!: Several hor)onal di!ru.tin# e ect! do not linearl= increa!e with ti)e or do!e' but .re!ent non-linear .eaJ! in the !ha.e o < or , curve! E+2-+4F at !o)e .eriod! or !o)e ran#e! o do!e!' de.endin# on the a#e and e/.o!ure .eriod o the te!t ani)al! E+5-+8F: Secondl=' a clear

hi!to.atholo#ical !tud= !hould be .ubli!hed and !tudied in .arallel to the bioche)ical e ect! ound b= %on!anto or the %on!anto-!u..orted e/.ert .anel E8F: >t i! .o!!ible that )etabolic chan#e! .recede' within 90 da=!' hi!to.atholo#ical le!ion! that could a..ear a terward!: @hi! i! another rea!on to .rolon# the e/.eri)ent! and )a= al!o !olve the .roble) o re.roducibilit=: Si)ultaneou!l=' the occurrence o !i)ilar e ect! in both !e/e! i! an i).ortant criterion o to/icit= or 2oull et al. E8F' which i! not or u!: Se/de.endent di erence! in chronic di!ea!e! re!ultin# ro) che)ical into/ication are well e!tabli!hed E+8' +9F: @he liver i! it!el a !e/-di erentiated or#an; or e/a).le che)ical !en!itivit= i! di erent in )ale! and e)ale! E20F: >n %on!antoC! data or the!e 3 )onth rat te!t! with 4t )aiAe %&" 863' or all rat! includin# the !i/ ti)e! bi##er #rou. o nor)al control and re erence ani)al! eatin# non $% diet!' there were con ir)ed !e/di erentiated e ect! in liver and Jidne=! .ara)eter! G?i#:27 and 4H: 2oull et al. E8F al!o con!idered a nor)al ran#e o variation! in unde ined hi!torical data' or co).iled the clo!e!t i!o#enic control with other re erence #rou.! that have diet! di erent in !alt or !u#ar!: @hi! i! not !cienti icall= .reci!e: Figure % &' (rinci.al Co).onent 7nal=!i! or liver .ara)eter! in all rat! o the %&" 863 e/.eri)ent: >t wa! .er or)ed accordin# to Hotellin# E29F in order to !tud= the !catterin# o the di erent actor!: @he !che)e obtained or .ara)eter! at weeJ +4 e/.lain! 42:42I o the total data variabilit= GinertiaH e/.re!!ed on 2 a/e! G32:0+I or actor +; +0:4+I or actor 2H' !cale dL2: @hi! de)on!trate! the clear !e.aration o .ara)eter! value! accordin# to !e/: (' (rinci.al Co).onent 7nal=!i! or Jidne= .ara)eter! in all rat! o the %&" 863 e/.eri)ent: @he !che)e obtained or .ara)eter! at weeJ +4 e/.lain! 48:83I o the total data variabilit= GinertiaH e/.re!!ed on 2 a/e! G26:95I or actor +; 20:88I or actor 2H' !cale dL5: @hi! de)on!trate! the clear !e.aration o .ara)eter! value! accordin# to !e/:

)onclusion
Ke a!!u)e that S*ralini et al. E5F )ethodolo#= can di!cri)inate .otential al!e .o!itive and $%-linJed e ect!' avoidin# to !o)e e/tent al!e ne#ative one!' in the be!t wa= we can do or thi! di!cu!!ed and too li)ited .rotocol alread= in u!e or co))ercialiAed $%&!: @he!e $%-linJed e ect! are then con!idered a! !i#n! o to/icit= in the 90 da=!' not .roo ! o to/icit=: @he biolo#ical .lau!ibilit= o a !ubchronic or chronic !ide e ect o the $% diet' linJed to the new to/in in the )a))alian re#i)en' or due to the )uta#ene!i! e ect o the #enetic )odi ication it!el ' i! thu! non ne#li#ible: ?inall= it !hould be !tre!!ed that !tati!ticall= !i#ni icant e ect! o $% diet!' or o re!idue! o .e!ticide! that are contained b= $%&!' have al!o been ob!erved in other in!tance! E2+25F' but not in all !tudie! E26' 28F enli#htenin# the nece!!it= o a ca!e-b=-ca!e a..roach' and that the real to/icolo#ical !tudie! are 3uite li)ited u. to date or that E28F: 7ll the!e ob!ervation! taJen to#ether in our o.inion! do not allow a clear !tate)ent o to/ic e ect!' but to !u##e!t the) a! !uch' becau!e the= are clearl= undeniable: "ow' to an= #ood re!earcher !i)ilar re!ult! would )ean that there i! )uch to be i).roved in the .lannin# o e/.eri)ental de!i#n; and thu! to increa!e their re!olution .ower to obtain une3uivocal !tate)ent!' or in!tance increa!in# the duration andDor the nu)ber o rat! te!ted: $enerall= !.eaJin# it !ee)! to u! unbelievable that a ri!J a!!e!!)ent carried out onl= on ort= rat! o each !e/ receivin# $% rich diet! or 90 da=! G=ieldin# re!ult! o ten

at the li)it! o !i#ni icanceH have not been re.eated and .rolon#ed inde.endentl=: Ke !hould overall taJe into account the act that the anal=!ed $% .roduct could be ed lon#-ter) to .eo.le and ani)al! o variou! a#e! and !e/e!' and with variou! .atholo#ie!: Ke call or )ore !eriou! !tandardiAed te!t! !uch a! tho!e u!ed or .e!ticide! or dru#!' on at lea!t three )a))alian !.ecie! te!ted or at lea!t three )onth! e).lo=in# lar#er !a).le !iAe!' and u. to one and two =ear! be ore co))ercialiAation' or $% ood or eed !.eci icall= )odi ied to contain .e!ticide re!idue!: Ke al!o call or a !eriou! !cienti ic debate about the criteria or te!tin# !i#ni icant adver!e health e ect! or .e!ticide! or che)ical!' but overall or $% ood or eed .roduct!' !uch a! %&" 863:

&c*nowledge ents
Ke thanJ ?ranMoi! Roullier or ?i#: 2 and !tati!tical !tudie!:

)on$lict o$ Interest
@he author! have declared that no con lict o intere!t e/i!t!:

+e$erences
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&uthor contact
Corre!.ondence to: (ro : $ille!-Eric S*ralini' (h2' >n!titute o 4iolo#= and CR>>$E"' <niver!it= o Caen' E!.lanade de la (ai/' +4032 Caen Cede/' ?rance: @el P33 2 3+ 56 56 84; ?a/ P33 2 56 53 20; E)ail: crii#en unicaen: r:

Received 2009-2-26 7cce.ted 2009-6-+6 (ubli!hed 2009-6-+8