nt J Biol Sci 2009; 5:438-443

Review
How Subchronic and Chronic Health Eect! 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 Cellier
2'3
' Charle!
Sultan
2'4
' %arcello 4uiatti
2'5
' 5ou $alla#her
6
' %ichael 7ntoniou
8
' 9ri!hna R:
2rona)ra;u
8
+: <niver!it= o Caen' >n!titute o 4iolo#=' 4ioche)i!tr=' E!.lanade de la (ai/ +4032
Caen Cede/ ?rance:
2: CR>>$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 Eect! 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 eect! 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#niicant 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#niicant: @he !e/
dierence! and the non linear do!e or ti)e related eect! !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)one-
de.endent di!ea!e! and ir!t !i#n! o to/icitie!:
Keywords: (e!ticide!' $%&' %&" 863' !ide eect!' 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
aect 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 eect! durin# re#ulator= te!t! .rior to
co))ercialiAation o che)ical!' and not to te!t onl= !hort-ter) or !ubchronic eect!:
@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 eect! 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#niicant eect! 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 )odiied 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!aet= 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= inluence 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= .eror)ed in vivo on )a))al!' or
in!tance with rat!' the )o!t u!ed )odel' beore 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= !cientiic 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= inor)ative on health !econdar= eect!: So)e )a))alian nutritional
te!t! are .eror)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 .eror)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) eect!: @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= .eror)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= )odiied 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= )odiied
.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 aals
Recentl=' 2oull et al. E8F oered 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! .eror)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 eect 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#niicant eect! 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! beore 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 eect! 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#niicance 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!!iied a! conidential 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: 7ter heated
di!cu!!ion! in Euro.e concernin# the .o!!ible .h=!iolo#ical eect! .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! !ae to eat:
7ter careul anal=!i! o the crude data' S*ralini et al. E5F a..lied a..ro.riate !tati!tical
)ethodolo#= to te!t the eect! 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/ reerence #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 eect! on
the rat )etaboli!) o the diet co).o!ition without $% )aiAe wa! !tudied' co).arin#
onl= control and reerence #rou.! between the) to avoid !=!te)aticall= linJin# the!e
eect! 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 eect! 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 eect 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:
@hereore' the inclu!ion in the anal=!i! o unrelated eedin# #rou.! !erve! to conu!e
rather than clari= the eect o the %&" 863 event:
@he #oal o the !tati!tical anal=!i! i! to decide whether the con!u).tion o $%&! can
be con!idered to have no eect Gnull h=.othe!i! H
0
trueH or to have an eect GH
0
al!eH
on the health o the rat!: @hi! anal=!i! cannot be reduced in the co).utation o a
collection o .-value!: Stati!tical re;ection o the null h=.othe!i! H
0
doe! not i).l= that
the eect i! biolo#icall= !i#niicant: >n the !a)e wa=' ailure to re;ect H
0
doe! not )ean
that it i! true: @hereore' the .ower o the h=.othe!i! te!t )u!t be a!!e!!ed: @he .ower
o a !tati!tical te!t de.end! on the !a).le !iAe Gand thereore the e/.eri)ental de!i#nH'
the !i#niicance level o the te!t and the eect !iAe Gwhich can be con!idered a!
biolo#icall= !i#niicantH: @hi! )o!t i).ortant i!!ue i! totall= overlooJed in the
e/.eri)ental de!i#n and the !tati!tical re.ort )ade b= %on!anto on %&" 863:
%oreover' an= h=.othe!i! which i! not !tati!ticall= !i#niicant with their reductive
)ethod i! alwa=! e/cluded: @hi! di!turbin# over!i#ht run! al!e ne#ative re!ult! and a
ri!J o health con!e3uence! or )illion! o .eo.le and ani)al!:
!e"#related and non#linear signs o$
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#niicant eect! were concentrated in liver! and
Jidne=! a! )ain deto/iication 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 .roile!:
%oreover' the eect! 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 eect! 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#niicant 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#niicant 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 .roile: >n
both !e/e! and .eriod! the .roile! were dierent but it concerned liver and Jidne=
.ara)eter!:
?ro) that' 2oull et al. E6F concluded that an= eect! 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 !cientiic .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 eect E9-
++F: &ur h=.othe!i! wa! to 3ue!tion the .o!!ibilit= o !ubchronic or chronic health
eect! that were not or onl= .artiall= revealed b= !hort-ter) te!t!: Several hor)onal
di!ru.tin# eect! 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
eect! 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 aterward!: @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 eect! 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 dierence! 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/-dierentiated or#an; or e/a).le che)ical
!en!itivit= i! dierent 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 reerence ani)al! eatin# non $% diet!' there were conir)ed !e/-
dierentiated eect! 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 undeined hi!torical data' or co).iled
the clo!e!t i!o#enic control with other reerence #rou.! that have diet! dierent in !alt
or !u#ar!: @hi! i! not !cientiicall= .reci!e:
Figure %
&' (rinci.al Co).onent 7nal=!i! or liver .ara)eter! in all rat! o the %&" 863
e/.eri)ent: >t wa! .eror)ed accordin# to Hotellin# E29F in order to !tud= the !catterin#
o the dierent 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 eect!' 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 eect! 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 eect
o the $% diet' linJed to the new to/in in the )a))alian re#i)en' or due to the
)uta#ene!i! eect o the #enetic )odiication it!el' i! thu! non ne#li#ible: ?inall= it
!hould be !tre!!ed that !tati!ticall= !i#niicant eect! 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
eect!' 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! oten
at the li)it! o !i#niicanceH 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! beore co))ercialiAation' or $% ood or
eed !.eciicall= )odiied to contain .e!ticide re!idue!: Ke al!o call or a !eriou!
!cientiic debate about the criteria or te!tin# !i#niicant adver!e health eect! or
.e!ticide! or che)ical!' but overall or $% ood or eed .roduct!' !uch a! %&" 863:
&c*nowledgeents
Ke thanJ ?ranMoi! Roullier or ?i#: 2 and !tati!tical !tudie!:
)on$lict o$ Interest
@he author! have declared that no conlict 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