JPediatr(RioJ).2017;93(3):308---310
www.jped.com.br
LETTERS
TO
THE
EDITOR
Autism
in
2016:
additional
discovery
夽Autismo
em
2016:
descoberta
adicional
TotheEditor,
Posar and Visconti1 have recently published their
narra-tivebiomedicalreviewonthedevelopmentsinthefieldof autismresearchin2016,withaparticularfocusonthe hypo-thetical role of environmental factors, like air pollution. Theauthorssearchedtheavailablerecent literatureusing PubMed (United States National Library of Medicine) for interestinghypothesespublishedbetweenJanuary1,2013 andAugust20,2016 andrelevant literature(case---control studiesinvolvinghumanparticipantswerepreferred)using avarietyofselectedkeywords.Althoughtheauthors iden-tified a search strategy, their review did not consider a recentlypublishedmini-review identifying theroleof the specific agricultural air pollutant, nitrous oxide (N2O), in
autismetiopathogenesisandneurodevelopmentaldisorders morebroadly.
Fluegge2hassuggestedrepeatedlythatexposureto
envi-ronmental N2O may increase susceptibility to a range of
neurodevelopmental disorders,including autism spectrum disorders (ASD) and attention deficit hyperactivity disor-der(ADHD).Aninitialepidemiologicalanalysisrevealedan association between the use of the pesticide glyphosate andADHD, but subsequentsensitivity analyses found that the association was likely dependent upon the level of land urbanization and glyphosate’s strong county-specific association with nitrogen-based fertilizers and presum-able emissions of N2O.2 These findings were replicated
in an analysis of ASD hospitalizations (personal communi-cation). Hypothesized mechanisms of interest underlying these associations included known pharmacological tar-getsof low level N2O exposure, including NMDA receptor
antagonism(N-methyl-d-aspartatereceptor),stimulationof
centralopioid peptiderelease, andsuppressionof cholin-ergic activity.3 The review is particularly notable since
environmentalN2OhasnotbeenconsideredbyeitherPosar
andVisconti1 or the studies thatcomprise their narrative
review as an air pollutant capable of inducing adverse
夽 Pleasecitethisarticleas:FlueggeK.Autismin2016:additional
discovery.JPediatr(RioJ).2017;93:308---9.
humanhealthconsequencesandautism,inparticular.Itis, therefore, interesting to read the authors’ suggestion to investigatewhether thereis adifferenceinautism preva-lence among nations exposed to low vs. high levels of pollution.
Tian et al.4 recently reported on the annual rates of
changeforamultitudeofenvironmentalfactorsfor differ-entcontinents,havingfoundsignificantincreasesinnitrogen fertilizeruseinNorthAmericafrom1981to2010and signifi-cantdecreasesinnitrogenfertilizeruseinEuropeduringthe sameperiod.Astheuseofanthropogenicnitrogensources isthemostdirectlytiedenvironmentalcontributortoN2O
emissions,5 this continental difference in nitrogen
fertil-izer use going back decades is particularly revealing and suggests higherU.S. emissions of N2O derived from
nitro-genfertilizerscomparedtoEurope,afactconfirmedbythe IntergovernmentalPanelonClimateChange(IPCC,2015).6
Thisgeographicaldistinctioncouldexplainthedifferential dynamicsinASDprevalence.
Epidemiologic, population-based studies from Europe indicate that much of the increase in ASD prevalence between 1980 and2003 can beaccounted for by changes in administrative and reporting practices,7,8 while ASD
prevalence in the subsequent years in the UK may have plateaued.9 These data argue for the possibility that the
increaseintheregisteredprevalenceofASDmaybedriven more by administrative changes. However, the marked increase in ASDprevalence in the United States between 2000and2012,inparticular,couldnotbereadilyaccounted for by any evolution in diagnostic criteria since no for-malchangeswereintroducedoradopted duringthistime, althoughitcannotbediscountedthattheincreasing preva-lence of ASD during this time might be attributable to lingeringdiagnosticsubstitutionortheaccrualofpractices startedinthepriordecades.10This,therefore,leavesopen
thepossibilitythatsecularenvironmentalcontributors,like environmentalN2O,mayplayaroleinASD
etiopathogene-sisinacontinentallydistinctway.Inlightofthisresearch, Posarand Visconti1 maywishtoexpandtheir viewonthe
role of air pollution as a risk factor in ASD. Considering that N2O is not regarded as a human health pollutant in
the literature or by governmentofficials, a call for a re-evaluationofthisparticularenvironmentalpollutantseems necessary.
Conflicts
of
interest
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 methaneandnitrousoxideemissionsfromterrestrial ecosys-temsduetomultipleenvironmental changes.EcosystHealth Sustain.2015;1:1---20.
5.ParkS,CroteauP,BoeringKA,EtheridgeDM,FerrettiD,Fraser PJ,etal.Trendsandseasonalcyclesintheisotopiccomposition ofnitrousoxidesince1940.NatGeosci.2012;5:261---5. 6.Intergovernmental Panel on ClimateChange (IPCC). Climate
Change2001: Mitigation [cited4 July2016].Available from: http://www.ipcc.ch/ipccreports/tar/wg3/index.php?idp=11. 7.LundströmS,ReichenbergA,AnckarsäterH,LichtensteinP,
Gill-bergC.AutismphenotypeversusregistereddiagnosisinSwedish children:prevalencetrendsover10yearsingeneralpopulation samples.BMJ.2015;350:h1961.
8.HansenSN,SchendelDE,ParnerET.Explainingtheincreasein theprevalenceofautismspectrumdisorders:theproportion
attributabletochangesinreportingpractices. JAMAPediatr. 2015;169:56---62.
9.TaylorB,JickH,MaclaughlinD.Prevalenceandincidencerates ofautismintheUK:timetrendfrom2004---2010inchildrenaged 8years.BMJOpen.2013;3:e003219.
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
