LETTERSTOTHEEDITOR 309
References
1.PosarA, ViscontiP.Autism in2016: theneed for answers.J
Pediatr(RioJ).2017;93:111---9.
2.FlueggeKR,FlueggeKR.GlyphosateusepredictsADHD
hospi-taldischarges intheHealthcareCost and UtilizationProject
Net(HCUPnet): a two-wayfixed-effects analysis. PLoS One.
2015;10:e0133525.
3.FlueggeK.Doesenvironmentalexposuretothegreenhousegas,
N2O,contributeto etiologicalfactorsinneurodevelopmental
disorders? A mini-review of the evidence. Environ Toxicol
Pharmacol.2016;47:6---18.
4.TianH, ChenG, LuC,Xu X, RenW, Zhang B,et al. Global
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PJ,etal.Trendsandseasonalcyclesintheisotopiccomposition
ofnitrousoxidesince1940.NatGeosci.2012;5:261---5.
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7.LundströmS,ReichenbergA,AnckarsäterH,LichtensteinP,
Gill-bergC.AutismphenotypeversusregistereddiagnosisinSwedish
children:prevalencetrendsover10yearsingeneralpopulation
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9.TaylorB,JickH,MaclaughlinD.Prevalenceandincidencerates
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10.CommitteetoEvaluatetheSupplementalSecurityIncome Dis-abilityProgramfor ChildrenwithMentalDisorders;Boardon the Health of Select Populations;Board on Children, Youth, andFamilies;InstituteofMedicine;DivisionofBehavioraland SocialSciencesandEducation;TheNationalAcademiesof Sci-ences,Engineering,andMedicine;BoatTF,WuJT,eds.Mental disordersand disabilitiesamong low-income children. Wash-ington(DC):NationalAcademiesPress(US).14,Prevalenceof autismspectrumdisorder.[cited4July2016].Availablefrom:
http://www.ncbi.nlm.nih.gov/books/NBK332896/.
KeithFluegge
InstituteofHealthandEnvironmentalResearch, Cleveland,UnitedStates
E-mail:keithfluegge@gmail.com
http://dx.doi.org/10.1016/j.jped.2016.12.001
0021-7557/
©2016SociedadeBrasileiradePediatria.PublishedbyElsevier EditoraLtda.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Authors’
reply:
‘‘Autism
in
2016:
additional
discovery’’
夽Resposta
do
autor:
‘‘Autismo
em
2016:
descoberta
adicional’’
DearEditor,
Flueggeinhisletter1commentedonourreviewaboutautism
spectrumdisorder(ASD)etiopathogenesis,underscoringthe possibleroleofoneairpollutantandgreenhousegas,nitrous oxide(N2O),wellknownasthelaughinggasusedinsurgery
foritsanalgesicandanestheticproperties.2In2006Cohen
consideredthehypothesisofaninvolvementofN2OinASD
etiopathogenesis, observing that high amounts of N2O in
the blood could explain the uncontrollable laughter and high painthresholddetected in some subjectswith ASD.2
Forsomeyearsthishypothesiswaspassedover insilence, while,especiallyin theUnitedStates(USA),manystudies have been performed toinvestigate the possible associa-tion between various air pollutants and an increasedrisk ofASD.Datafromthesestudiessuggesttheinvolvementof early exposure to several air pollutants (includingozone,
DOIofreferstoarticle:
http://dx.doi.org/10.1016/j.jped.2016.12.001
夽 Please cite this article as: Posar A, Visconti P. Authors’
reply:‘‘Autismin2016:additionaldiscovery’’. JPediatr (RioJ). 2017;93:309---10.
nitric oxide, nitrogen dioxide, carbon monoxide, sulfur dioxide,diesel particulates,some heavymetals, aromatic solvents)inASDetiopathogenesis.Recently,Flueggehas fre-quently mentioned the theory that the early exposure to N2Omayincreasetheriskforneurodevelopmentaldisorders,
includingASDs,andinonereviewhedescribedindetail sev-eralpossible etiopathogenetic mechanisms throughwhich N2Omayleadtoneurodevelopmentaldisorders,including:
dopaminergicdysregulation; N-methyl-D-aspartate(NMDA) receptorantagonism; kappa-opioidreceptor (KOR) activa-tion;and␣7cholinergicinhibition.3
We believe that any effort to better understand the etiopathogenesisof ASDs, and in particular the causes of theirdramaticallyincreasingprevalenceobservedinrecent decades at least in the USA,4 is commendable. However,
at present there is no study, neither retrospective nor prospective, involving human individuals to suggest an association between early exposure to N2O pollution and
increasedASDrisk.Forthisreason,inourreviewwehavenot mentionedN2OamongthepollutantsimplicatedintheASD
310 LETTERSTOTHEEDITOR
rather pollutant mixtures are involved in ASD etiopatho-genesis,duetosynergisticeffects.5However,basedonthe
observationsbyFluegge,weconsideritrecommendableto includeN2O amongthe pollutants tobe monitoredin the
futureepidemiologicalstudiesconcerningASDriskfactors. Inouropinion,theotherconsiderationsbyFlueggeabout the hypothetical differential dynamics in ASD prevalence between the USA and Europe1 are more questionable. As
reportedby Boilsonetal., in Europesystematic and reli-able data concerning the ASD prevalence are lacking,6
unlike in the USA where the Autism and Developmental Disabilities Monitoring Network system periodically pro-vides estimates of the ASD prevalence among children.4
Therefore,nowadays a real comparison between the ASD prevalencedynamicsintheUSAandEuropeduringthelast decadesseemstobeinfeasible.
Wefeeltheneedtomakeonelastremark:inhisletter,1
Fluegge cites one of his own articles7 that, nonetheless,
hasbeen retracted.8 We believethat it is notan optimal
choicetocite aretractedpaper,although itreflects what thatauthorthinks.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
Acknowledgments
TheauthorswouldliketothankCeciliaBaronciniforEnglish revision.
References
1.FlueggeK.Autismin2016:additionaldiscovery.JPediatr(RioJ).
2017;93:308---9.
2.Cohen BI. Ammonia (NH3), nitric oxide (NO) and nitrous
oxide (N2O) --- the connection with infantile autism. Autism.
2006;10:221---3.
3.FlueggeK.Doesenvironmentalexposuretothegreenhousegas,
N2O, contribute to etiological factors in neurodevelopmental
disorders?Amini-reviewoftheevidence.EnvironToxicol
Pharma-col.2016;47:6---18.
4.ChristensenDL,BaioJ,VanNaardenBraunK,BilderD,Charles
J, Constantino JN, et al. Prevalence and characteristics of
autism spectrum disorder among children aged 8 years
---Autismand Developmental DisabilitiesMonitoringNetwork,11
Sites, United States, 2012. MMWR Surveill Summ. 2016;65:
1---23.
5.vonEhrensteinOS,AralisH,CockburnM,RitzB.Inuteroexposure
totoxicairpollutantsandriskofchildhoodautism.Epidemiology.
2014;25:851---8.
6.BoilsonAM,StainesA,RamirezA,PosadaM,SweeneyMR.
Oper-ationalisationoftheEuropean Protocolfor Autism Prevalence
(EPAP)forautismspectrumdisorderprevalencemeasurementin
Ireland.JAutismDevDisord.2016;46:3054---67.
7.FlueggeKR, Fluegge KR.Glyphosate usepredicts ADHD
hospi-taldischarges in the Healthcare Cost and Utilization Project
Net (HCUPnet): a two-way fixed-effects analysis. PLoS One.
2015;10:e0133525.
8.PLOSONEStaff.Retraction:GlyphosateusepredictsADHD
hos-pitaldischargesintheHealthcareCostandUtilizationProject
Net (HCUPnet): a two-way fixed-effects analysis. PLoS One.
2015;10:e0137489.
AnnioPosara,b,∗,PaolaViscontia
aIRCCSInstituteofNeurologicalSciencesofBologna,Child
NeurologyandPsychiatryUnit,Bologna,Italy
bUniversityofBologna,DepartmentofBiomedicaland
NeuromotorSciences,Bologna,Italy
∗Correspondingauthor.
E-mail:annio.posar@unibo.it(A.Posar).
http://dx.doi.org/10.1016/j.jped.2016.12.002
0021-7557/
