Chemistry Reference
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development,orlifespanofthetargetorganismdistinguishablefromnormal(control)organismsof
thesamespeciesandstrainunderthesamedeinedconditionsofexposure.”
AsanalternativetothetraditionalNOAELapproach,thebenchmarkdose(BMD)concepthas
been proposed for use in the quantitative assessment of the dose-response relationship (Crump
1984;Barnesetal.1995).TheBMDisthedoseofasubstancethatisexpectedtoresultinapre-
speciiedlevelofeffect(SetzerandKimmel2003).TheBMDapproachwasnotappliedinthesafety
evaluation of sweeteners authorized for food use up to date. However, a recent opinion from the
EFSAScientiicCommitteenowadvocatestheuseoftheBMDapproachinfutureriskassessments
ofchemicalsinfood(EFSA2009c).
Fornongenotoxicchemicals,itisgenerallyacceptedthatthereisathresholdfortoxicityand
exposure below the threshold is safe. Based on the type of critical effect in a pivotal study, the
dose-responserelationshipofacriticaleffect,andtheoverallqualityofthescientiicdatabase,an
uncertaintyfactorisselected.Thisfactortakesintoaccountspeciesdifferencesbetweenthetest
animalandthehuman,andvariationwithinhumans(Renwick1993;RenwickandLazarus1998;
IPCS1994;WHO2009).Whenthedatabaseisconsideredadequate,anuncertaintyfactorof100
isusedbydefault,butitmaybemodiiedwhenadequatehumandataareavailable.TheNOAEL
identiiedforthetestcompoundisthendividedbytheselecteduncertaintyfactortoestablishan
acceptabledailyintake(ADI)forhumans.
TheADIisameasurefortheinnocuousnessofasubstance.Itistheamountofafoodadditive,
expressedonamilligramperkilogrambodyweight(bw)basis,thatcanbeingesteddailyoveralife-
timewithoutincurringanyappreciablehealthrisk(WHO1987).Allintensesweetenerspermittedfor
thefooduseintheEU,exceptforthaumatin,havebeenallocatedanumericalADI(Table14.1).
Whenthedatabaseisnotoptimalbuttherearenoindicationsofanyshort-termhealthproblems
from the anticipated use of a food additive, a temporary ADI may be established using a larger
uncertaintyfactor(200bydefault),requestingadditionalstudieswithinagiventimeframe.
When,onthebasisoftheavailabletoxicological,biochemical,andclinicaldata,thetotaldaily
intakeofthesubstance,arisingfromitsnaturaloccurrenceand/oritspresentuse(s)infoodatthe
level necessary to achieve the desired technological effect, will not represent a hazard to health,
the establishment of a numerical ADI is not considered necessary. Instead, terms such as “ADI
acceptable” (SCF 1985) or “ADI not speciied” are used (WHO 1987). Both terms do not mean,
however,thatanyamountofthesubstanceistoxicologicallyacceptable.Suchanadditivemustbe
used according to good manufacturing practice; that is, it should be technologically eficacious,
shouldbeusedatthelowestlevelnecessarytoachievethetechnologicaleffect,shouldnotconceal
inferiorfoodqualityoradulteration,andshouldnotcreatenutritionalimbalance.Allbulksweeten-
ersauthorizedforfooduseintheEUhavebeenallocatedanADIacceptable(Table14.1).
TheADIdoesnotapplytoneonatesandinfantsbeforetheageof12weeks.Thesusceptibility
ofinfantsandchildrentofoodadditiveshasbeenanimportantsubjectinthediscussionoffood
chemicalsafety(LarsenandPascal1998).Foodadditivestobeusedininfantformulasrequirea
specialevaluation.
Itisabasicrulethatasubstancethatisgenotoxicandcausescancerinanimalstudiesbydirectly
damagingthegenesisnotacceptedasafoodadditive.
14.5.3 exposure assessment
Exposureassessmentisbasedoninformationonthelevelsofacompoundintendedforuseas
afoodadditiveindifferentfoodcategoriesanddataontheintakeoftherelevantfooditemsinthe
countryorregioninquestion.Informationonfoodconsumptionmaybederivedfromfoodsupply
data,householdsurveys,individualdietarysurveys,totaldietstudies,and/ortheuseofbiomark-
ers.Theestimatesofexposureshouldincludeaverage,medium,andmaximumintakeiguresfrom
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