grandjean_developmental_2006.doc | Neurobiology | Nervous System\nspeicherngrandjean_developmental_2006.doc für später speichern\nFrom: Bryan, Rose (ELS) To: Subje !: 0"ART#$0$% Messa&e 'a!\ne: "#2#2006 08:02\nTuesday - May 2, 2006 8:02 AM\nFrom: Bryan, Rose (ELS) (Rose)Bryan*+an e!) om, To: -.&rand*/s./)/ar0ard)edu- (.&rand*/s./)/ar0ard)edu, 'ear 1ro2essor 3randjean, 4 am de+5&/!ed !o be ab+e !o &50e you !/e ne6s !/a! your .a.er on 'e0e+o.men!a+ !o75 5!y o2 5ndus!r5a+ /em5 a+s /as no6 been a e.!ed 2or .ub+5 a!5on 5n T/e Lan e! as a Re05e6) T/e ne7! s!e. 5s !/a! you 65++ re e50e .roo2s 2rom one o2 my Ass5s!an! Ed5!or o++ea&ues) 1+ease no!e !/a! 6e do subs!an!5a++y subed5! manus r5.!s !o 5m.ro0e +ar5!y and !o our /ouse s!y+e) Many !/an8s 2or a++ your /ard 6or8 on !/5s Re05e6) Re&ards) Rose Bryan sen! on be/a+2 o2 'r As!r5d 9ames 'e.u!y Ed5!or - T/e Lan e! Te+: 020 :%2% %$2; Fa7: 020 :%2% %$;2\nManus r5.! subm5!!ed !o T/e Lan e! (a e.!ed 2or .ub+5 a!5on, 2 May 2006)\nDevelopmental neurotoxicity of industrial chemicals A silent pandemic\n1 3randjean, 19 Landr5&an\n4ns!5!u!e o2 1ub+5 <ea+!/, =n50ers5!y o2 Sou!/ern 'enmar8, "000 >dense, 'enmar8, and 'e.ar!men! o2 En05ronmen!a+ <ea+!/, <ar0ard S /oo+ o2 1ub+5 <ea+!/, Bos!on, MA, =SA (1ro2 1 3randjean M' 'MS ) 'e.ar!men!s o2 ?ommun5!y Med5 5ne and 1ed5a!r5 s, Moun! S5na5 S /oo+ o2 Med5 5ne, @e6 Aor8, @A, =SA (1ro2 19 Landr5&an M' M1<)\n?orres.onden e !o: 'r 1/5+5..e 3randjean, 'e.ar!men! o2 En05ronmen!a+ <ea+!/, <ar0ard S /oo+ o2 1ub+5 <ea+!/, Landmar8 ?en!er BE-;;0, %0; 1ar8 'r50e, Bos!on, MA 022;", =SA) Te+e./one: C;-6;:-B8%8$0:) Fa7: C;-6;:-B8%-8$$%) E-ma5+: .&rand*/s./)/ar0ard)edu\nAbstract @eurode0e+o.men!a+ d5sorders (@''s), su / as men!a+ re!arda!5on, a!!en!5on de25 5! d5sorder, erebra+ .a+sy, and au!5sm are ommon, os!+y and an ause +52e+on& d5sab5+5!y) T/e5r ae!5o+o&y 5s mos!+y un8no6n) A sma++ number o2 5ndus!r5a+ /em5 a+s D +ead, me!/y+mer ury, .o+y /+or5na!ed b5./eny+s, arsen5 , and !o+uene D are re o&n5sed auses o2 @''s and o2 sub +5n5 a+ bra5n dys2un !5on) E7.osures !o !/ese /em5 a+s dur5n& ear+y de0e+o.men! an ause bra5n 5njury a! dose +e0e+s mu / +o6er !/an !/ose a22e !5n& adu+! bra5n 2un !5on) Re o&n5!5on o2 !/ese r5s8s +ed !o e05den e-based .ro&rams o2 .re0en!5on, su / as e+5m5na!5n& +ead add5!50es 5n .e!ro+) A+!/ou&/ a+ready /5&/+y su ess2u+, !/ese .re0en!5on am.a5&ns 6ere 5n5!5a!ed on+y a2!er subs!an!5a+ de+ays) T6o /undred add5!5ona+ /em5 a+s are 8no6n !o ause +5n5 a+ neuro!o75 5!y 5n adu+!s) 'es.5!e a +a 8 o2 sys!ema!5 !es!5n&, many more are 8no6n !o be neuro!o75 5n +abora!ory mode+s) T/e5r !o75 5!y !o !/e de0e+o.5n& /uman bra5n 5s no! 8no6n and !/ey are no! re&u+a!ed !o .ro!e ! /5+dren) T/e !6o major 5m.ed5men!s !o .re0en!5n& neurode0e+o.men!a+ de25 5!s o2 /em5 a+ or5&5n are !/e &rea! &a.s 5n !es!5n& /em5 a+s 2or de0e+o.men!a+ neuro!o75 5!yE and !/e /5&/ +e0e+ o2 .roo2 reFu5red 2or re&u+a!5on) @e6, .re au!5onary a..roa /es are reFu5red 2or /em5 a+ !es!5n& and on!ro+ !/a! re o&n5se !/e un5Fue 0u+nerab5+5!y o2 !/e de0e+o.5n& bra5n)\nSearch strategy Ge 5den!525ed 5ndus!r5a+ /em5 a+s !/a! /a0e aused neuro!o75 e22e !s 5n /umans 2rom !/e <aHardous Subs!an es 'a!a Ban8 o2 !/e @a!5ona+ L5brary o2 Med5 5ne, as su..+emen!ed by 2a ! s/ee!s a! !/e (=S) A&en y 2or To75 Subs!an es and '5sease Re&5s!ry, and !/e 4n!e&ra!ed R5s8 4n2orma!5on Sys!em o2 !/e =S En05ronmen!a+ 1ro!e !5on A&en y) Ge used Ineuro!o75 J, Ineuro+o&5 J, and Ineuro-J as sear / !erms) For ea / neuro!o75 subs!an e 5den!525ed, 6e !/en used synonyms, ommer 5a+ names and ?AS numbers !o sear / 1ubMed, T>K@ET, and T>KL4@E !o 5den!52y +5!era!ure on de0e+o.men!a+ neuro!o75 5!y) T/e .r5mary sear / !erms 6ere I1rena!a+ E7.osure 'e+ayed E22e !sJLMeS<M and I@euro!o75 5!y SyndromesJLMeS<M) Se ondary sear /es used omb5na!5ons o2 Ima!erna+ e7.osureJ and Ima!erna+ 2e!a+ e7 /an&eJ 65!/ Ide0e+o.men!a+ d5sab5+5!5es# /em5 a++y 5ndu edJ and Ineuro!o75nsJ, a++ o2 !/em 65!/ !/e +5m5!ers IA++ ?/5+d: 0-;8 years, mos! re en! ;0 Aears, En&+5s/, <umanJ) Ge a+so used re2eren es 5!ed 5n !/e .ub+5 a!5ons re!r5e0ed)\n>ne ou! o2 e0ery s57 /5+dren /as a de0e+o.men!a+ d5sab5+5!y, and 5n mos! ases !/ese d5sab5+5!5es 5n0o+0e !/e ner0ous sys!em); T/e mos! ommon neurode0e+o.men!a+ d5sorders (@''s) 5n +ude +earn5n& d5sab5+5!5es, sensory de25 5!s, de0e+o.men!a+ de+ays, and erebra+ .a+sy); Some obser0ers re.or! !/a! .re0a+en e o2 er!a5n @''s D a!!en!5on de25 5!#/y.era !505!y d5sorder and au!5sm, 5n .ar!5 u+ar D may be 5n reas5n&, bu! da!a !o sus!a5n !/a! .os5!5on are +5m5!ed)2 T/e !rea!men! o2 !/ese d5sorders 5s d5225 u+!, and !/e d5sab5+5!5es !/ey ause an be .ermanen!)B T/ey are 0ery os!+y !o 2am5+5es and !o so 5e!y)%-6 E05den e /as been a umu+a!5n& o0er se0era+ de ades !/a! 5ndus!r5a+ /em5 a+s an ause @''s, and !/a! sub +5n5 a+ s!a&es o2 !/ese ond5!5ons may be ommon) T/e sus.5 5on o2 a +5n8 be!6een /em5 a+s and 65des.read neurobe/a05oura+ dama&e 6as 25rs! ra5sed by resear / demons!ra!5n& !/a! +ead 5s !o75 !o !/e de0e+o.5n& bra5n a ross a 65de ran&e o2 e7.osures):-;0 4! 6as bu!!ressed by re.or!s 5nd5 a!5n& !/a! o!/er en05ronmen!a+ .o++u!an!s are a+so !o75 !o ear+y bra5n de0e+o.men!);; A re.or! 2rom !/e =S @a!5ona+ Resear / ?oun 5+ on +uded !/a! BN o2 de0e+o.men!a+ d5sab5+5!5es are !/e d5re ! onseFuen e o2 neuro!o75 en05ronmen!a+ e7.osures, and !/a! ano!/er 2"N ar5se !/rou&/ 5n!er.+ay be!6een en05ronmen!a+ 2a !ors ( /em5 a+ and o!/er) and 5nd505dua+ &ene!5 sus e.!5b5+5!y)B T/ese es!5ma!es 6ere based on !/e +5m5!ed neuro!o75 5!y 5n2orma!5on a0a5+ab+e and may !/ere2ore underes!5ma!e !/e !rue .re0a+en e o2 /em5 a++y-5ndu ed abnorma+5!5es) @eurobe/a05oura+ dama&e aused by 5ndus!r5a+ /em5 a+s 5s, 5n !/eory, .re0en!ab+e) An essen!5a+ .rereFu5s5!e !o .re0en!5on 5s re o&n5!5on o2 a /em5 a+Os ab5+5!y !o /arm !/e de0e+o.5n& bra5n) Pno65n& !/a! a /em5 a+ 5s neuro!o75 an !r5&&er e22or!s !o res!r5 ! 5!s use and on!ro+ e7.osures) 1re05ous e05den e-based .ro&rams o2 e7.osure .re0en!5on, su / as !/ose d5re !ed a&a5ns! /5+drenOs e7.osure !o +ead, /a0e u+!5ma!e+y been /5&/+y su ess2u+, a+!/ou&/ !/ey 6ere 5n5!5a!ed on+y a2!er subs!an!5a+ de+ay) T/e .ur.ose o2 !/5s re05e6 5s !o /ara !er5se !/e 0u+nerab5+5!y o2 !/e de0e+o.5n& ner0ous sys!em !o /em5 a+ !o75 5!yE !o !abu+a!e .ub+5 +y a0a5+ab+e da!a on /uman neuro!o75 5!y o2 5ndus!r5a+ /em5 a+sE !o e7am5ne !/e .oss5b+e e7!en! o2 a de0e+o.men!a+ neuro!o75 5!y .andem5 E !o des r5be !/e 8no6n onseFuen es o2 de0e+o.men!a+ neuro!o75 5!y a! 5nd505dua+ and so 5e!a+ +e0e+sE !o e7am5ne !/e 5m.+5 a!5ons 2or /uman /ea+!/ o2 !/e urren! +a 8 o2 !o75 o+o&5 a+ 5n2orma!5onE and !o ons5der .ros.e !s 2or .re0en!5on)\nVulnerability of the developing brain T/e de0e+o.5n& /uman bra5n 5s 5n/eren!+y mu / more sus e.!5b+e !o 5njury aused by !o75 a&en!s !/an !/e bra5n o2 an adu+!);2 T/5s sus e.!5b5+5!y re2+e !s !/e 2a ! !/a! 5n !/e n5ne mon!/s o2 .rena!a+ +52e !/e /uman bra5n mus! e0o+0e 2rom a s!r5. o2 e++s a+on& !/e dorsa+ e !oderm 5n!o a om.+e7 or&an om.r5sed o2 b5++5ons o2 .re 5se+y +o a!ed, /5&/+y 5n!er onne !ed and s.e 5a+5sed e++s) >.!5ma+ bra5n de0e+o.men! reFu5res !/a! neurons mo0e a+on& .re 5se .a!/6ays 2rom !/e5r .o5n!s o2 or5&5n !o !/e5r ass5&ned +o a!5ons, !/a! !/ey es!ab+5s/ onne !5ons 65!/ o!/er e++s near and d5s!an!, and !/a! !/ey +earn !o 5n!er ommun5 a!e);2-;% A++ o2 !/ese .ro esses mus! !a8e .+a e 65!/5n a !5&/!+y on!ro++ed !5me 2rame, 5n 6/5 / ea / de0e+o.men!a+ s!a&e mus! be rea /ed on s /edu+e and 5n !/e orre ! seFuen e) Be ause o2 !/e e7!raord5nary om.+e75!y o2 /uman bra5n de0e+o.men!, 65ndo6s o2 un5Fue sus e.!5b5+5!y !o !o75 5n!er2eren e o ur !/a! /a0e no oun!er.ar! 5n !/e ma!ure bra5n, or 5n any o!/er or&an) 42 a de0e+o.men!a+ .ro ess 5n !/e bra5n 5s /a+!ed or 5n/5b5!ed, !/ere 5s +5!!+e .o!en!5a+ 2or +a!er re.a5r, and !/e onseFuen es may !/en be .ermanen!);2,;% 'ur5n& 2oe!a+ de0e+o.men!, !/e .+a en!a o22ers some .ro!e !5on a&a5ns! un6an!ed /em5 a+ e7.osures, bu! 5! 5s no! an e22e !50e barr5er a&a5ns! en05ronmen!a+ neuro!o75 an!s);" For e7am.+e, many me!a+s eas5+y ross !/e .+a en!a, and !/e mer ury on en!ra!5on 5n ord b+ood 5s ons5derab+y /5&/er !/an 5n ma!erna+ b+ood);6 T/e b+ood-bra5n barr5er, 6/5 / .ro!e !s !/e adu+! bra5n 2rom many !o75 a&en!s, 5s no! om.+e!e+y 2ormed un!5+ abou! 6 mon!/s a2!er b5r!/);: 1os!na!a++y, !/e /uman bra5n on!5nues !o de0e+o., and !/e .er5od o2 /e5&/!ened 0u+nerab5+5!y !/ere2ore e7!ends o0er many mon!/s !/rou&/ 5n2an y and 5n!o ear+y /5+d/ood) G/5+e mos! neurons /a0e been 2ormed by !/e !5me o2 b5r!/, &ro6!/ o2 &+5a+ e++s and mye+5n5sa!5on o2 a7ons on!5nue 2or se0era+ years);B,;% T/e sus e.!5b5+5!y o2 5n2an!s and /5+dren !o 5ndus!r5a+ /em5 a+s 5s 2ur!/er am.+525ed by !/e5r 5n reased e7.osures, au&men!ed absor.!5on ra!es, and d5m5n5s/ed ab5+5!y !o de!o752y many e7o&enous om.ounds re+a!50e !o adu+!s ;8, ;$ 1ers5s!en! +5.o./5+5 subs!an es, 5n +ud5n& er!a5n .es!5 5des and /a+o&ena!ed 5ndus!r5a+ om.ounds, su / as .o+y /+or5na!ed b5./eny+s, a umu+a!e 5n ma!erna+ ad5.ose !5ssue and are .assed on !o !/e 5n2an! 05a /uman m5+8, !/ereby resu+!5n& 5n e7.osures !o !/e 5n2an! !/a! e7 eed !/e mo!/erOs o6n d5e!ary e7.osure by ;00-2o+d on a body 6e5&/! bas5s)20 Recognition of developmental and subclinical neurotoxicity of chemicals 4n5!5a+ +5n5 a+ re o&n5!5on o2 de0e+o.men!a+ neuro!o75 5!y 5n /5+dren e7.osed !o 5ndus!r5a+ /em5 a+s /as !y.5 a++y 5n0o+0ed ob05ous 2un !5ona+ abnorma+5!5es 5n /5&/-dose s enar5os !/a! aused ob05ous .o5son5n&) SubseFuen!, more so./5s!5 a!ed resear / /as do umen!ed !/e .resen e o2 +ess s!r585n&, bu! none!/e+ess ser5ous ad0erse e22e !s a! +o6er +e0e+s o2 e7.osure (25&ure ;)) T/5s seFuen e o2 d5s o0ery +ed !o !/e re o&n5!5on !/a! en05ronmen!a+ !o75 an!s e7er! a ran&e o2 ad0erse e22e !s D some are +5n5 a++y e05den!, bu! o!/ers an be d5s erned on+y !/rou&/ s.e 5a+ !es!5n& and are no! e05den! on !/e s!andard e7am5na!5on, /en e !/e !erm Isub +5n5 a+ !o75 5!y)J T/e under+y5n& on e.! 5s !/a! !/ere e75s!s a dose-de.enden! on!5nuum o2 !o75 e22e !s, 5n 6/5 / +5n5 a++y ob05ous e22e !s /a0e !/e5r sub +5n5 a+ oun!er.ar!s)2; A .andem5 o2 sub +5n5 a+ neuro!o75 5!y 5s !/ere2ore +58e+y !o be Is5+en!J, 5)e) no! a..aren! 2rom s!andard /ea+!/ s!a!5s!5 s) T/e on e.! o2 sub +5n5 a+ !o75 5!y !ra es 5!s or5&5ns !o .5oneer5n& s!ud5es o2 +ead !o75 5!y 5n +5n5 a++y asym.!oma!5 /5+dren under!a8en by Landr5&an and o++ea&ues: and by @eed+eman and o++ea&ues,8 6/o s/o6ed !/a! /5+drenOs e7.osure !o +ead ou+d ause de reases 5n 5n!e++5&en e and a+!era!5on o2 be/a05our e0en 5n !/e absen e o2 +5n5 a++y 05s5b+e sym.!oms o2 +ead !o75 5!y) T/e sub +5n5 a+ !o75 5!y o2 +ead 5n /5+dren /as subseFuen!+y been on25rmed 5n .ros.e !50e e.5dem5o+o&5 s!ud5es)22,2B\n1ara++e+ 25nd5n&s /a0e been re.or!ed on some o!/er 5ndus!r5a+ /em5 a+s, bu! !/e5r number 5s om.ara!50e+y sma++) A..ro75ma!e+y 80,000 /em5 a+s are re&5s!ered 2or ommer 5a+ use 65!/ !/e =S En05ronmen!a+ 1ro!e !5on A&en y, and 62,000 6ere 5n use 6/en !/e To75 Subs!an es ?on!ro+ A ! 6as ena !ed 5n !/e =SA ;$::)2% T/e s5!ua!5on 5s .ara++e+ 5n !/e E=, 6/ere ;00,000 /em5 a+s 6ere re&5s!ered 5n ;$8;)2" T/e 2u++ e7!en! !o 6/5 / !/ese /em5 a+s on!r5bu!e !o ausa!5on o2 @''s and sub +5n5 a+ neuro!o75 5!y 5s s!5++ 05r!ua++y un8no6n) Identification of neurotoxic chemicals S!ud5es 5n e7.er5men!a+ an5ma+s su..or! !/e no!5on !/a! a 65de ran&e o2 5ndus!r5a+ /em5 a+s may ause de0e+o.men!a+ neuro!o75 5!y a! +o6 doses !/a! are no! /arm2u+ !o adu+!s)26,2: Su / 5njury a..ears !o resu+! 5n .ermanen! /an&es 5n bra5n 2un !5on !/a! may be ome de!e !ab+e on+y 6/en !/e an5ma+ rea /es ma!ur5!y and !/e .ar!5 u+ar 2un !5on 5s e7.ressed) Be ause de0e+o.men!a+ neuro!o75 5!y may no! be a..aren! 2rom rou!5ne !o75 o+o&y !es!s,28 5den!525 a!5on o2 neuro!o75 /em5 a+s o2!en res!s on +5n5 a+ and e.5dem5o+o&5 a+ da!a) To 5den!52y en05ronmen!a+ /em5 a+s !/a! are !o75 !o !/e /uman bra5n, 6e sear /ed !/e <aHardous Subs!an es 'a!a Ban8 o2 !/e @a!5ona+ L5brary o2 Med5 5ne, 6/ere subs!an e 5den!5!5es are +5n8ed !o ad0erse e22e !s 5n /umans) Ge /e 8ed !/e om.+e!eness o2 !/5s +5s! a&a5ns! o!/er da!a sour es and 65!/ a .re05ous assessmen! o2 !/e .ub+5s/ed +5!era!ure on +5n5 a+ !o75 5!y)2$ Tab+e ; +5s!s !/e do umen!ed /uman neuro!o75 an!s a ord5n& !o major +asses o2 5ndus!r5a+ /em5 a+s) Ge /a0e e7 +uded dru&s, 2ood add5!50es, m5 rob5a+ !o75ns, or sna8e 0enoms and s5m5+ar b5o&en5 subs!an es) T/5s +5s! does no! 5n +ude /em5 a+s !/a! /a0e been 2ound !o be neuro!o75 so+e+y 5n +abora!ory an5ma+s, 2or 6/5 / no sys!ema!5 +5s!5n& e75s!s) Tab+e ; .r5mar5+y 5n +udes a u!e !o75 an!s !/a! /a0e aused ser5ous a 5den!s or /a0e been used 5n su5 5de a!!em.!s, and neuro!o75 an!s ma5n+y aus5n& /ron5 or de+ayed d5sease are +58e+y !o be underre.resen!ed)2$ T/e +ar&es! &rou.s o2 5den!525ed om.ounds are me!a+s, so+0en!s, and .es!5 5des, 6/5+e o!/er &rou.s o2 /em5 a+s are underre.resen!ed) Tab+e ; s/ou+d !/ere2ore no! be re&arded as a om.re/ens50e +5s! o2 a++ !/e 5ndus!r5a+ /em5 a+s !/a! may be neuro!o75 5n /umans) T/e subs!an e names +5s!ed 5n Tab+e ; 6ere used 2or sear /es o2 .ub+5s/ed +5!era!ure on de0e+o.men!a+ neuro!o75 5!y) Based on our r5!5 a+ e0a+ua!5on, !/e /uman de0e+o.men!a+ neuro!o75 an!s are /5&/+5&/!ed 5n Tab+e ;) T/e5r number 5s +ear+y 0ery sma++) Many add5!5ona+ /em5 a+s !/a! 6e /a0e no! +5s!ed are 8no6n !o be de0e+o.men!a+ neuro!o75 an!s 5n +abora!ory an5ma+s,2: bu! no .ub+5s/ed 5n2orma!5on 5s a0a5+ab+e on !/e5r .o!en!5a+ !o75 5!y !o /uman bra5n de0e+o.men!) Ge !/ere2ore under!oo8 a re05e6 o2 ea / o2 !/e do umen!ed /uman de0e+o.men!a+ neuro!o75 an!s !o de!erm5ne /o6 !/e5r !o75 5!y /ad been 25rs! re o&n5sed and !o +earn /o6 re o&n5!5on o2 /aHard de0e+o.ed and +ed !o on!ro+ o2 e7.osure) Lead T/e neuro!o75 5!y o2 +ead !o adu+!s 6as 8no6n a+ready 5n Roman !5mes, bu! a re.or! 2rom Aus!ra+5a .ub+5s/ed ;00 years a&o 6as !/e 25rs! des r5.!5on o2 e.5dem5 +ead .o5son5n& 5n youn& /5+drenE !/e sour e o2 !/e ou!brea8 6as !ra ed !o 5n&es!5on o2 +ead-based .a5n! by /5+dren .+ay5n& on 0erandas 65!/ .ee+5n& .a5n!)B0 Fur!/er re.or!s o2 /5+d/ood +ead .o5son5n& 2rom !/e =SA and Euro.e 2o++o6ed) Lead .o5son5n& 6as a! !/a! !5me ons5dered an a u!e 5++ness, 2rom 6/5 / a /5+d e5!/er re o0ered or d5ed) Lon&-!erm seFue+ae 6ere 25rs! do umen!ed 5n !/e;$%0s, 6/en ;$ o2 20 sur050ors o2 a u!e .o5son5n& 6ere 2ound !o /a0e se0ere +earn5n& and be/a05oura+ .rob+ems)B; 'es.5!e !/ose ear+y .aed5a!r5 6arn5n&s, !/e +ar&e+y un /e 8ed use o2 +ead 5n .e!ro+, .a5n!s, eram5 &+aHes, and many o!/er .rodu !s !/rou&/ mu / o2 !/e !6en!5e!/ en!ury on!5nued !o ause r5s8s o2 +ead .o5son5n&) 'ur5n& !/e ;$:0s, 65des.read sub +5n5 a+ neurobe/a05oura+ de25 5!s, 5n +ud5n& .rob+ems 5n on en!ra!5on, memory, o&n5!5on, and be/a05our, 6ere\ndo umen!ed 5n asym.!oma!5 /5+dren 65!/ e+e0a!ed b+ood-+ead on en!ra!5ons):,8 S.urred by re ommenda!5ons 5ssued by !/e Euro.ean Re&5ona+ >225 e o2 !/e Gor+d <ea+!/ >r&an5Ha!5on, s!ud5es 6ere 5n5!5a!ed 5n many oun!r5esE !/e resu+!s orrobora!ed !/e .re05ous on +us5ons)B2 As a resu+! o2 !/e a umu+a!5n& e05den e, many sour es o2 +ead e7.osure ame !o be on!ro++ed, !/ou&/ no! a++ sour es, and no! 5n a++ oun!r5es) A $0N redu !5on 5n /5+d/ood b+ood +ead +e0e+s 2o++o6ed !/e !erm5na!5on o2 +ead add5!50es 5n .e!ro+)BB ?urren! resear / on +ead neuro!o75 5!y 2o uses on !/e s/a.e o2 !/e dose-res.onse ur0e a! 0ery +o6 e7.osure +e0e+s !/a! a..ear !o ause sur.r5s5n&+y +ar&e 2un !5ona+ de remen!s)22 As on05n 5n& e05den e be ame re o&n5sed, /ea+!/ a&en 5es /a0e ser5a++y redu ed !/e .erm5ss5b+e on en!ra!5on o2 +ead 5n /5+drenOs b+ood) <o6e0er, !/e mos! re en! resear /22 su&&es!s !/a! !/e urren! 5m.a ! o2 +ead e7.osure on /uman bra5n de0e+o.men! may be e0en &rea!er !/an .re05ous+y !/ou&/!) Methylmercury Me!/y+mer ury, !oo, 6as 25rs! es!ab+5s/ed as a neuro!o75 an! 5n men e7.osed o u.a!5ona++y)B% T/e de0e+o.men!a+ !o75 5!y o2 !/5s or&an5 mer ury om.ound be ame e05den! 5n !/e ;$60s 5n M5nama!a, 9a.an, 6/ere an e.5dem5 o2 s.as!5 5!y, b+5ndness and .ro2ound men!a+ re!arda!5on /ad o urred amon& 5n2an!s born !o mo!/ers 6/o onsumed on!am5na!ed 25s/) A2!er many years o2 +5n5 a+ and e7.er5men!a+ s!ud5es, !/e sour e 6as 2ound !o be mer ury om.ounds re+eased 5n!o M5nama!a Bay by a .+as!5 s .+an!)B" Me!/y+mer ury a umu+a!ed and rea /ed /5&/ +e0e+s 5n +o a++y au&/! 25s/) E7.osed adu+!s, 5n +ud5n& mo!/ers o2 .o5soned /5+dren, 6ere +ess ser5ous+y a22e !ed, 52 a! a++)B6 S5m5+ar ou!brea8s o2 .ro2ound @''s 5n !/e 5n2an!s o2 05r!ua++y una22e !ed mo!/ers /a0e o urred 2o++o65n& ma!erna+ onsum.!5on dur5n& .re&nan y o2 seed &ra5n !rea!ed 65!/ me!/y+mer ury 2un&5 5des)B:,B8 S!ud5es o2 a ser5ous .o5son5n& 5n 5den! 5n 4raF es!ab+5s/ed a rude dose-res.onse re+a!5ons/5. be!6een ma!erna+ /a5r-mer ury on en!ra!5ons and r5s8 o2 neuro+o&5 a+ abnorma+5!5es 5n !/e5r /5+dren)B$ Re en! s!ud5es /a0e 2o used on .rena!a+ e7.osures !o +o6er +e0e+s o2 me!/y+mer ury) T/ey /a0e e7am5ned .o.u+a!5ons 65!/ a /5&/ 5n!a8e o2 sea2ood and 2res/6a!er 25s/ 65!/ 0ar5ous de&rees o2 me!/y+mer ury on!am5na!5on) 1ros.e !50e e7am5na!5on o2 a @e6 Qea+and o/or! 2ound a !/ree-.o5n! de remen! 5n 4R as 6e++ as a+!era!5ons 5n a22e ! amon& /5+dren born !o 6omen 65!/ /a5r mer ury +e0e+s abo0e 6 S&#&)%0 A +ar&e .ros.e !50e s!udy 5n !/e Faroe 4s+ands 2ound e05den e 2or dose-re+a!ed 5m.a5rmen!s 5n memory, a!!en!5on, +an&ua&e and 05suos.a!5a+ .er e.!5on)%; A !/5rd .ros.e !50e o/or! s!udy 5n !/e Sey /e++es .ro05ded on+y +5m5!ed su..or! 2or .rena!a+ neuro!o75 5!y a2!er adjus!men! 2or .os!na!a+ e7.osures)%2 Se0era+ ross-se !5ona+ s!ud5es 2ound s5&n525 an! asso 5a!5ons be!6een me!/y+mer ury e7.osure and neurobe/a05ora+ 5m.a5rmen! 5n youn& /5+dren)%B T/e =S @a!5ona+ A ademy o2 S 5en es re05e6ed !/ese s!ud5es and on +uded !/a! s!ron& e05den e e75s!s 2or !/e 2oe!a+ neuro!o75 5!y o2 me!/y+mer ury, e0en a! +o6 e7.osure +e0e+s)%% T/ese 25nd5n&s /a0e +ed 2ood sa2e!y au!/or5!5es !o 5ssue d5e!ary ad05sor5es, and na!5ona+ and 5n!erna!5ona+ a&en 5es (65!/ oord5na!5on 2rom !/e =n5!ed @a!5ons En05ronmen! 1ro&ramme) no6 see8 !o on!ro+ and +5m5! mer ury re+eases !o !/e en05ronmen!) Subs!an!5a+ redu !5ons /a0e a+ready been a /5e0ed 5n mer ury use and re+ease 2rom /os.5!a+s and 5n 5nera!ors)%" A re+a!ed subs!an e, e!/y+mer ury, /as been 65de+y used as .ar! o2 .reser0a!50es o2 0a 5nes, bu! a neuro!o75 r5s8 /as no! been do umen!ed)%6 Arsenic 4n&es!5on o2 arsen5 - on!am5na!ed dr5n85n&-6a!er /as +on& been re o&n5sed !o ause .er5./era+ neuro.a!/y 5n adu+!s)%: 'rama!5 do umen!a!5on o2 de0e+o.men!a+ neuro!o75 5!y due !o arsen5 6as re.or!ed 5n ;$"" 2rom 9a.an, 6/ere onsum.!5on o2 .o6dered m5+8 on!am5na!ed 65!/ arsen5 +ed !o o0er ;2,000 .o5son5n& ases and ;B; dea!/s)%8 A 2o++o6-u. s!udy o2 !/ree &rou.s o2 ado+es en!s born dur5n& !/e !5me o2 !/e m5+8 on!am5na!5on 5n +uded one &rou. !/a! 6as 2u++y\nbreas!2ed, one !/a! 6as e7.osed !o !/e !a5n!ed m5+8 .rodu !, and one !/a! re e50ed o!/er su..+emen!s, bu! no !a5n!ed 2ormu+a)%$ S5&n525 an!+y more men!a++y-re!arded 5nd505dua+s 6ere 2ound 5n !/e e7.osed &rou.) 1oor s /oo+ re ords, emo!5ona+ d5s!urban es and abnorma+ or border+5ne EE3 25nd5n&s 6ere a+so more ommon 5n !/e e7.osed &rou.) Be ause !/ese 25nd5n&s 6ere 5n5!5a++y .ub+5s/ed 5n 9a.anese journa+s no! eas5+y a0a5+ab+e e+se6/ere,%8,%$ !/ey /a0e been o0er+oo8ed, e0en 5n !/e mos! !/orou&/ r5s8 assessmen!s o2 en05ronmen!a+ arsen5 e7.osure)"0,"; Arsen5 o urs 5n &round 6a!er 6or+d65de, and 5ndus!r5a+ .o++u!5on 5s 65des.read) ?rossse !5ona+ s!ud5es o2 /5+dren a! s /oo+ a&e s/o6ed o&n5!50e de25 5!s asso 5a!ed 65!/ dr5n85n& 6a!er on!am5na!5on +e0e+s"2 and 5n reased ur5nary arsen5 on en!ra!5ons)"B S5m5+ar resu+!s 6ere ob!a5ned 5n /5+dren 65!/ arsen5 e7.osure 2rom a sme+!er)"% A .oss5b+e jo5n! ad0erse e22e ! on 4R aused by arsen5 and man&anese e7.osures 6as su&&es!ed by /a5r me!a+s on en!ra!5ons 5n /5+dren +505n& near a /aHardous 6as!e s5!e)"" A+!/ou&/ !/e re en! e05den e 2or sub +5n5 a+ neurode0e+o.men!a+ neuro!o75 5!y o2 arsen5 5s +ess 6e++ de0e+o.ed !/an 2or +ead and me!/y+mer ury, !/e da!a are 5n!erna++y ons5s!en! and 25! 65!/ !/e /5&/-e7.osure 25nd5n&s 2rom 9a.an) S!5++, re&u+a!ory a !5on does no! em./as5se !/e need !o .ro!e ! !/e de0e+o.5n& bra5n a&a5ns! !/5s neuro!o75 an!)"0,"; Polychlorinated biphenyls 1o+y /+or5na!ed b5./eny+s (1?Bs) 6ere 65de+y used 5n e+e !r5 a+ eFu5.men! as 5nsu+a!ors) <uman !o75 5!y 6as 25rs! des r5bed 2rom 5ndus!r5a+ e7.osures,"6 bu! neuro+o&5 a+ e22e !s a..eared !o be o2 +5m5!ed on ern) 'e0e+o.men!a+ !o75 5!y o2 1?Bs 6as 25rs! obser0ed 5n /5+dren e7.osed !o /5&/ +e0e+s 5n !6o .o5son5n& e0en!s 5n As5a, 6/ere oo85n& o5+ /ad been on!am5na!ed by 1?Bs and re+a!ed subs!an es dur5n& manu2a !ur5n&) 1rena!a+ e7.osure 5n !/e Ta56an 5n 5den! 6as asso 5a!ed 65!/ +o6 b5r!/ 6e5&/!, de+ayed de0e+o.men!a+ m5+es!ones, and +o6er 4Rs 5n om.ar5son 65!/ une7.osed s5b+5n&s)": E7.osed boys (bu! no! &5r+s) s/o6ed de25 5!s 5n s.a!5a+ reason5n&) Fo++o6u. s!udy s/o6ed &ro6!/ 5m.a5rmen!, s+o6 de0e+o.men!, +a 8 o2 enduran e, +umsy mo0emen!, and 0ery +o6 4Rs)"8 4n a s5m5+ar 5n 5den! 5n 9a.an, neuro+o&5 a+ dama&e a..eared +ess .rom5nen!)"$ Be ause o2 !/e m57ed e7.osures, !/e s.e 525 on!r5bu!5on by 1?B !o !/ese ad0erse e22e !s anno! be de+5nea!ed) E.5dem5o+o&5 a+ s!ud5es o2 asym.!oma!5 .o.u+a!5ons .rena!a++y e7.osed !o 1?Bs and re+a!ed on!am5nan!s !/rou&/ ma!erna+ d5e! 6ere 25rs! ondu !ed 5n !/e =SA) Sub +5n5 a+ de0e+o.men!a+ de25 5!s 6ere demons!ra!ed 5n !/e mos! /5&/+y e7.osed o2 !/ese /5+dren60,6; and 6ere asso 5a!ed, a! a&e ;; years, 65!/ an a0era&e 4R s ore 6)2 .o5n!s be+o6 !/a! o2 /5+dren 65!/ +o6er e7.osures)62 A 'u! / o/or! 5n +uded %;8 /ea+!/y 5n2an!s and 2ound sub +5n5 a+ de remen!s on !/e neona!a+ neuro+o&5 a+ e7am5na!5on and 5n subseFuen! de0e+o.men!a+ !es!s re+a!ed !o 5n reased 1?B e7.osures)6B ?on!5nued 2o++o6-u. o2 !/5s o/or! su&&es!ed !/a! !/e e22e !s may be mod525ed or mas8ed 65!/ a&e, bu! e22e !s 6ere s!5++ de!e !ab+e a! a&e $ years)6% Resu+!s 2rom a 3erman o/or! su..or!ed !/ese 25nd5n&s and a+so su&&es!ed !/a! .os!na!a+ 1?B e7.osure 2rom breas!-2eed5n& on!r5bu!es !o o&n5!50e de25 5!s)6" A .oss5b+e me /an5sm !/rou&/ 6/5 / 1?Bs 5njure !/e de0e+o.5n& bra5n 5s 5n!er2eren e 65!/ ma!erna+ !/yro5d 2un !5on,;B,66 6/5 / may no! /arm adu+! bra5n 2un !5ons) A+!/ou&/ 1?B manu2a !ure /as been banned 5n mos! na!5ons, and e7.osures are de reas5n&, e7.osures a! +e0e+s urren!+y .re0a+en! may s!5++ ause de0e+o.men!a+ neuro!o75 5!y)6: Solvents So+0en! neuro!o75 5!y 5n adu+!s 5s 6e++ 8no6n 2rom a u!e .o5son5n& ases and 2rom o u.a!5ona+ s!ud5es)68 E!/ano+ 5s !/e .ro!o!y.5 a+ so+0en!) 4n!erm5!!en!, +o6-+e0e+ e7.osures .rodu e m5+d 5nebr5a!5n& e22e !s, bu! do no! +ead !o 5rre0ers5b+e dama&e) <ea0y, +on&-!erm e!/ano+ 5n!a8e 5n\nadu+!s an, /o6e0er, +ead !o ser5ous 5njury, 5n +ud5n& Gern5 8eOs syndrome) Be ause su / e7.osures are 0o+un!ary, e!/ano+ 5s no! 5n +uded 5n Tab+e ;) T/e 2oe!a+ a+ o/o+ syndrome 5s Fua+5!a!50e+y d522eren!) 4! 6as 25rs! des r5bed 5n 5n2an!s o2 mo!/ers 65!/ a ser5ous dr5n85n& /ab5!, and 5n0o+0es o&n5!50e and be/a05oura+ de25 5!s as 6e++ as a+!ered 2a 5a+ 2ea!ures) 1ermanen! neuro!o75 dama&e 5n !/e mo!/er 5s no! a .rereFu5s5!e 2or 5rre0ers5b+e e22e !s 5n !/e /5+d)6$ A! +o6er onsum.!5on +e0e+s, sub!+e, bu! .ermanen! neuro!o75 5!y, 5n +ud5n& de reased 4R s ores, /a0e been demons!ra!ed):0 E22e !s o2 a+ o/o+ on !/e 2oe!us may be en/an ed by er!a5n &ene!5 .o+ymor./5sms):; Less so+5d do umen!a!5on 5s a0a5+ab+e on o!/er so+0en!s more 65de+y used 5n 5ndus!ry) Be ause o2 5!s anaes!/e!5 e22e !s, !o+uene /as been used 2or sn5225n&, and ase re.or!s /a0e re.or!ed !/a! 5n2an!s o2 mo!/ers 6/o sn522ed !o+uene 5n .re&nan y /ad abnorma++y +o6 s ores on de0e+o.men!a+ !es!s and s/o6ed de+ayed de0e+o.men! o2 s.ee / and mo!or 2un !5on):2-:% Add5!5ona+ e05den e omes 2rom +5m5!ed s!ud5es o2 mo!/ers, 6/o re.or!ed o u.a!5ona+ e7.osure !o so+0en!s, 5n +ud5n& !o+uene, dur5n& .re&nan y):"-:: T/e 6omen 6ere a..aren!+y e7.osed 65!/5n .erm5ss5b+e 6or8.+a e +5m5!s a5med a! .re0en!5n& neuro!o75 5!y 5n !/e 6or8ers !/emse+0es) <o6e0er, !/ese s!ud5es do no! a++o6 any de25n5!e on +us5ons on !/e s.e 525 /aHard and !/e na!ure o2 dose-res.onse re+a!5ons/5.s 2or de0e+o.men!a+ neuro!o75 5!y) Pesticides >0er 600 re&5s!ered .es!5 5des 5n +ude 5nse !5 5des, 2un&5 5des, roden!5 5des, and 2um5&an!s) 4n !/e =SA a+one, o0er ; b5++5on .ounds are a..+5ed annua++y) A u!e .es!5 5de neuro!o75 5!y 5s 6e++ 8no6n 2rom o u.a!5ona+ e7.osure s!ud5es, .o5son5n& e0en!s and su5 5de da!a)2$ 4! 5s o2!en due !o /o+5nes!erase 5n/5b5!5on 2rom or&ano./os./a!e a&en!s) 'e0e+o.men!a+ neuro!o75 5 5!y 6as su&&es!ed by an an!/ro.o+o&5 a+ s!udy o2 !6o s5m5+ar &rou.s o2 asym.!oma!5 , %-" year-o+d AaFu5 /5+dren 5n Me75 o):8 T/ose /ea05+y e7.osed !o a m57 o2 .es!5 5des, 5n +ud5n& or&ano./os./a!es, /ad d5m5n5s/ed s/or!-!erm memory, eye-/and oord5na!5on and dra65n& ab5+5!y, 6/5+e une7.osed /5+dren o2 !/e same !r5be s/o6ed norma+ de0e+o.men!):8 L58e65se, .res /oo+ /5+dren 2rom a&r5 u+!ura+ ommun5!5es 5n !/e =SA s/o6ed .oorer .er2orman e on mo!or s.eed and +a!en y):$ E uadorean s /oo+ /5+dren, 6/ose mo!/ers dur5n& .re&nan y /ad been e7.osed !o or&ano./os./a!es and o!/er .es!5 5des 2rom 6or85n& 5n &reen/ouses, s/o6ed 05suos.a!5a+ de25 5!s om.ared !o !/e5r une7.osed .eers)80 4n on!ras!, urren! .es!5 5de e7.osure, as re2+e !ed by ur5nary e7 re!5on o2 or&ano./os./a!e me!abo+5!es, 6as asso 5a!ed 65!/ de+ays 5n !/e /5+drenOs s5m.+e rea !5on !5me)80 A u!e e7.osure o2 Amer5 an /5+dren !o !/e or&ano./os./a!e .es!5 5de, me!/y+ .ara!/5on, 6as asso 5a!ed 65!/ .ers5s!en! .rob+ems 5n s/or!-!erm memory and a!!en!5on s.an)8; 1ros.e !50e e.5dem5o+o&5 a+ s!ud5es o2 /uman 5n2an!s e7.osed in utero !o !/e or&ano./os./a!e, /+or.yr52os, 2ound s5&n525 an! de reases 5n /ead 5r um2eren e and body 6e5&/! a! b5r!/ as 6e++ as s+o65n& o2 re2+e7es)82-8% 'e reased /ead 5r um2eren e, a r5s8 2a !or 2or @''s, 6as seen on+y 5n !/ose e7.osed 5n2an!s 6/o 6ere born !o mo!/ers 65!/ +o6 e7.ress5on +e0e+s o2 PO !, an es!erase 5n0o+0ed 5n or&ano./os./a!e de!o7525 a!5on)8B T/e e22e ! o2 /+or.yr52os on body 6e5&/! d5sa..eared a2!er 5m.os5!5on o2 a ban on res5den!5a+ use o2 !/e om.ound)8% A+!/ou&/ or&ano./os./a!es an undoub!ed+y ause de0e+o.men!a+ neuro!o75 5!y, !/e da!a are ye! 5nsu225 5en! !o de!erm5ne !/e .o!en!5a+ /aHard !o !/e de0e+o.5n& bra5n .osed by 5nd505dua+ om.ounds amon& !/e doHens o2 or&ano./os./a!es s!5++ 5n use 6or+d65de) "merging neurotoxic substances 'o umen!a!5on o2 de0e+o.men!a+ e22e !s 5n /umans 2or !/e rema5n5n& om.ounds +5s!ed 5n Tab+e ; 5s m5n5ma+) <o6e0er, !/ree ob05ous and5da!e subs!an es deser0e .ar!5 u+ar a!!en!5on, 5n +ud5n& !6o !/a! /a0e a..aren!+y no! aused neuro!o75 5!y 5n adu+!s)\nManganese neuro!o75 5!y 5n adu+!s /as been 6e++ do umen!ed 5n o u.a!5ona++y e7.osed .o.u+a!5onsE .ar85nson5sm 5s !/e +ass5 +5n5 a+ 2ea!ure, and sub +5n5 a+ neuro!o75 5!y 5s a+so re.or!ed)8" ?on ern abou! !/e de0e+o.men!a+ neuro!o75 5!y o2 man&anese /as emer&ed be ause !/e or&an5 man&anese om.ound, me!/y+ y +o.en!ad5eny+ man&anese !r5 arbony+ (MMT), /as been added as an an!5-8no 8 a&en! !o .e!ro+ 5n Aus!ra+5a and ?anada and may be used 5n !/e 2u!ure 5n !/e =S and e+se6/ere) Man&anese a+so an o ur 5n dr5n85n& 6a!er) 4n a .ros.e !50e s!udy o2 2%: b5r!/s 5n 1ar5s, Fran e, !/e man&anese on en!ra!5on 5n ord b+ood 6as asso 5a!ed 65!/ 5m.a5red neurobe/a05oura+ de0e+o.men!, es.e 5a++y on !/e Brune!-LeH5ne s a+es a! n5ne mon!/s and !/e M ?ar!/y s a+es a! B years)86 A! a&e 6, 6/ere no asso 5a!5on 6as seen, on+y ;00 /5+dren .ar!5 5.a!ed)86 ?ommun5!y e7.osures !o man&anese re+eased !o !/e en05ronmen! by ombus!5on o2 MMT,8: e7.osures 2rom a !o75 6as!e s5!e 5n !/e =SA"" and 2rom on!am5na!ed dr5n85n& 6a!er 5n Ban&+ades/88 /a0e been asso 5a!ed 65!/ sub +5n5 a+ neuro+o&5 a+ 5m.a5rmen! 5n /5+dren) #luoride may ause neuro!o75 5!y 5n e7.er5men!a+ an5ma+s,8$ bu! 5s no! +5s!ed 5n Tab+e ; as a do umen!ed /uman neuro!o75 an!) T/5s subs!an e o urs 5n dr5n85n& 6a!er as a na!ura+ on!am5nan!, bu! !/e on en!ra!5on de.ends on +o a+ &eo+o&5 a+ 5r ums!an es) 4n rura+ ommun5!5es 5n ?/5na, /5&/ 2+uor5de on en!ra!5ons 5n 6e++ 6a!er may &50e r5se !o s8e+e!a+ abnorma+5!5es) 4n one su / ommun5!y, 222 /5+dren a&ed 8-;B years s/o6ed s5&n525 an!+y 5n2er5or 4R +e0e+s om.ared !o 2$0 une7.osed on!ro+ /5+dren)$0 1ara++e+ resu+!s 6ere ob!a5ned 5n a sma++er s!udy o2 ;;8 /5+dren o2 s5m5+ar a&e)$; Ano!/er s!udy o2 %:: s /oo+ /5+dren 2rom 22 05++a&es su&&es!ed !/a! bo!/ 5n reased 6a!er 2+uor5de on en!ra!5ons and 0ery +o6 +e0e+s 6ere asso 5a!ed 65!/ 4R de25 5!s, as om.ared 65!/ /5+dren e7.osed !o Inorma+J on en!ra!5ons be+o6 ; m&#L)$2 T/e .ub+5s/ed re.or!s do no! a++o6 a !/orou&/ ons5dera!5on o2 .oss5b+e on2ound5n&, bu! do su&&es! !/a! 2ur!/er 5n-de.!/ s!ud5es be ondu !ed) Perchlorate 5s +58e65se no! 8no6n as a neuro!o75 an! 5n adu+!s) 4! 5s a 65des.read on!am5nan! o2 &round 6a!er 5n !/e =SA 2rom !/e use o2 ammon5um .er /+ora!e as a so+5d-2ue+ .ro.e++an! 2or ro 8e!s and m5ss5+es)$B T/e !/yro5d 5s !/e .r5mary !ar&e! o2 .er /+ora!e !o75 5!y, and .er /+ora!e b+o 8s 5od5ne u.!a8e by !/e !/yro5d) Abnorma+ bra5n de0e+o.men!, onseFuen! !o 5n/5b5!5on o2 ma!erna+ !/yro5d 2un !5on,;B,66 5s !/e major .o!en!5a+ e22e ! o2 .er /+ora!e e7.osure)$B Be ause !/e a0a5+ab+e e05den e 5s un5n2orma!50e as !o neurobe/a05ora+ !o75 5!y, dr5n85n& 6a!er s!andards 2or .er /+ora!e are se! a! +e0e+s !o .ro!e ! adu+!s and do no! 5n +ude /5+d-.ro!e !50e sa2e!y 2a !ors) $ealth and Societal Impacts of %evelopmental eurotoxicity T/e 250e subs!an es re o&n5Hed as auses o2 de0e+o.men!a+ neuro!o75 5!y s/o6 a .ara++e+ .a!!ern 5n !/e de0e+o.men! o2 s 5en!525 do umen!a!5on o2 !/e5r r5s8s) T/5s .a!!ern o2 d5s o0ery s!ar!ed 5n ea / 5ns!an e 65!/ re o&n5!5on o2 adu+! neuro!o75 5!y, !y.5 a++y 5n 6or8ers, and o2 a u!e, /5&/dose .o5son5n& e.5sodes 5n0o+05n& /5+dren) 4! !/en .ro&ressed !o !/e a umu+a!5on o2 e.5dem5o+o&5 a+ e05den e o2 neurobe/a05oura+ de25 5!s 5n /5+dren 65!/ de0e+o.men!a+ e7.osures a! +o6er +e0e+s !/a! are no! !o75 !o adu+!s (25&ure ;)) For +ead, me!/y+mer ury, and 1?Bs, 65des.read sub +5n5 a+ neuro!o75 5!y /as been do umen!ed 5n!erna!5ona++y, 6/5+e !/e 2u++ 5m.+5 a!5ons o2 e7.osures !o arsen5 and !o+uene are s!5++ un +ear) For mos! subs!an es +5s!ed 5n Tab+e ;, on+y neuro!o75 5!y 5n adu+!s /as been do umen!ed so 2ar) T/e omb5ned e05den e su&&es!s !/a! neurode0e+o.men!a+ !o75 5!y aused by 5ndus!r5a+ /em5 a+s /as rea!ed a s5+en! .andem5 5n modern so 5e!y) A+!/ou&/ !/ese /em5 a+s /a0e aused 5m.a5red bra5n de0e+o.men! 5n m5++5ons o2 /5+dren 6or+d65de, !/e .ro2ound e22e !s o2 !/5s .andem5 are no! a..aren! 2rom a0a5+ab+e /ea+!/ s!a!5s!5 s) 4n add5!5on, on+y a 2e6 /em5 a+ auses /a0e been re o&n5sed) Ge !/ere2ore .os!u+a!e !/a! !/e 2u++ 5m.a ! o2 !/5s .andem5 may be subs!an!5a++y &rea!er !/an urren!+y re o&n5Hed)\nAs 5s s/o6n by !/e e05den e on 5nor&an5 +ead, &+oba++y 5n reased e7.osures /a0e been res.ons5b+e 2or eros5on o2 o&n5!50e s85++s 65!/ sub +5n5 a+, bu! .ermanen! de reases 5n 4R) Add5!5ona++y, !/5s neuro!o75 an! /as .rodu ed +52e+on& a+!era!5ons o2 be/a05our 65!/ s/or!en5n& o2 a!!en!5on s.an, 5n reased 5m.u+s505!y, /e5&/!ened a&&ress50eness, s+o6ed mo!or oord5na!5on, and 5m.a5red memory and +an&ua&e s85++s) T/e onseFuen es are 5n reased +58e+5/ood o2 s /oo+ 2a5+ure, d5m5n5s/ed e onom5 .rodu !505!y, and .oss5b+y 5n reased r5s8 o2 an!5so 5a+ and r5m5na+ be/a05our)$% T/e mos! s!r585n& o2 !/ese e22e !s o ur a! !/e e7!remes o2 e7.osureE amon& /5&/+y e7.osed /5+dren, a+mos! none /ad su.er5or 2un !5on, 6/5+e !/e number 65!/ ob05ous de25 5!s 5n reased mar8ed+y)$" T/5s +a!!er &rou. 65++ +58e+y reFu5re s.e 5a+ edu a!5on and be +ess +58e+y !/an !/e5r .eers !o .ursue .rodu !50e areer o.!5ons) A s!udy o2 adu+!s 6/o /ad su22ered e7 ess +ead e7.osure as /5+dren re0ea+ed !/a! !/ey 6ere s5&n525 an!+y +ess su ess2u+ 5n +52e !/an an a +ess e7.osed om.ar5son &rou.)$6 T/e onseFuen es o2 !/5s .andem5 o2 de0e+o.men!a+ neuro!o75 5!y e7!end beyond !/e mea&re des r5.!50e da!a on !/e 5n 5den e and .re0a+en e o2 +5n5 a++y d5a&nosed @''s);,B 4n reased r5s8 o2 1ar85nsonOs d5sease$: and o!/er neurode&enera!50e d5sease$8 5s a 2ur!/er .o!en!5a+ onseFuen e o2 !/5s .andem5 ) T/us, ear+y sub +5n5 a+ /em5 a+ 5njury /as been /y.o!/es5sed !o 85++ s5+en!+y a 2ra !5on o2 !/e e++s reFu5red !o sus!a5n bra5n 2un !5on 5n +a!er +52e, 2or e7am.+e 5n !/e subs!an!5a n5&ra) T/ese +a!en! 5m.a5rmen!s ause no sym.!oms 5n /5+d/ood, bu! may be unmas8ed dur5n& !/e neurona+ a!!r5!5on asso 5a!ed 65!/ a&5n&) G5!/ a&e-re+a!ed de +5nes 5n 2un !5ona+ reser0e a.a 5!y, d5sease ou+d !/en be ome man52es!)$$,;00 T/e 65de e7!en! o2 /uman e7.osure !o neuro!o75 an!s 5s no6 be om5n& 05s5b+e a2!er sys!ema!5 o++e !5on o2 da!a on !/e o urren e o2 !/ese subs!an es 5n !/e en05ronmen! and 5n /uman !5ssues);0; E0en !/en, re o&n5!5on o2 ausa+ asso 5a!5ons may be d5225 u+!, be ause e7.osures 0ary 65!/ !5me, more !/an one !o75 an! may be 5n0o+0ed, 5nd505dua+ 0u+nerab5+5!y 0ar5es, and o!/er 2a !ors !/a! an b5as e.5dem5o+o&5 a+ s!ud5es !o6ard !/e nu++ /y.o!/es5s, es.e 5a++y 6/en !/e ou! ome may be unre o&n5sed 2or se0era+ years, or e0en de ades);02 For 5ndus!r5a+ /em5 a+s 5n 65de use, !/e .o.u+a!5on a! r5s8 o2 sub +5n5 a+ neuro!o75 5!y an be 0ery +ar&e) T/us, 05r!ua++y a++ /5+dren born 5n 5ndus!r5a+ oun!r5es be!6een ;$60 and ;$80 6ere e7.osed !o subs!an!5a+ amoun!s o2 +ead 2rom .e!ro+ !/a! may /a0e redu ed !/e number o2 /5+dren 65!/ !ru+y su.er5or 5n!e++5&en e (4R s ores abo0e ;B0 .o5n!s) by o0er "0N and +58e65se 5n reased !/e number 65!/ 4R s ores be+o6 :0)$" 4n !/e =SA a+one, !/e a&&re&a!e .o.u+a!5on o2 /5+dren a! r5s8 o2 e7.osure !o a5rborne +ead a! !/e !5me 6as a..ro75ma!e+y ;00 m5++5on) 'ur5n& !/5s .er5od, !/e resu+!5n& e onom5 os!s are es!5ma!ed !o /a0e ran&ed 2rom T;;0 b5++5on !o TB;$ b5++5on 5n ea / annua+ b5r!/ o/or!);0B T/e major sour e o2 !/ese os!s 6as !/e d5m5n5s/ed e onom5 .rodu !505!y !/a! resu+!ed o0er !/e e7.osed /5+drenOs en!5re +52e!5mes 2rom 65de-s a+e redu !5ons 5n 5n!e++5&en e) Today !/e os!s o2 +ead .o5son5n& are es!5ma!ed s!5++ !o be T%B b5++5on 5n ea / b5r!/ o/or! 5n !/e =SA," 6/5+e !/e os!s o2 .rena!a+ me!/y+mer ury !o75 5!y are es!5ma!ed !o amoun! !o T8): b5++5on annua++y (ran&e, T2)2-%B)8 b5++5on))6 '5m5n5s/ed e onom5 .rodu !505!y rema5ns !/e .r5n 5.a+ sour e o2 !/ese os!s) 'ue !o !/e absen e o2 dose-res.onse re+a!5ons/5.s 2or o!/er neuro!o75 an!s, !/e e7!en! o2 !/e !o!a+ os!s 5s un8no6n) T/e 5m.a ! o2 /em5 a+ neuro!o75 5!y e7!ends beyond !/e 5ndus!r5a++y de0e+o.ed na!5ons) To75 /em5 a+s, su / as /5&/+y dan&erous .es!5 5des !/a! are banned 5n 5ndus!r5a+5sed oun!r5es, are e7.or!ed !o de0e+o.5n& so 5e!5es, 6/ere en05ronmen!a+ and o u.a!5ona+ s!andards are o2!en 6ea8 or a! 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S!5++, !/ese 5n5!5a!50es may !a8e de ades !o &enera!e !/e !y.e o2 de!a5+ed do umen!a!5on urren!+y needed 2or /em5 a+s re&u+a!5on) Amon& +e&a+ a..roa /es, !/e Food Rua+5!y 1ro!e !5on A ! 5n !/e =SA reFu5res !/a! .es!5 5de s!andards be se! a! +e0e+s !/a! 65++ .ro!e ! 5n2an!s a&a5ns! de0e+o.men!a+ !o75 5!y) G/en !es!5n& da!a are no! a0a5+ab+e, a /5+d-.ro!e !50e sa2e!y 2a !or mus! be used 5n s!andard se!!5n&) <o6e0er, a..+5 a!5on o2 !/5s sa2e!y 2a !or /as been une0en, and 2u!ure a..+5 a!5on needs !o re o&n5se a+so !/e 0u+nerab5+5!y o2 .rena!a+ bra5n de0e+o.men!) 1re0en!5on o2 @''s o2 /em5 a+ or5&5n 65++ reFu5re 2undamen!a++y ne6 a..roa /es !o on!ro+ o2 /em5 a+ e7.osures) T/e 0u+nerab5+5!y o2 !/e /uman ner0ous sys!em and 5!s s.e 5a+ sus e.!5b5+5!y dur5n& ear+y de0e+o.men! su&&es! !/a! .ro!e !5on o2 !/e youn& bra5n s/ou+d be a .aramoun! &oa+ o2 .ub+5 /ea+!/ .ro!e !5on) T/e reFu5remen! o2 a /5&/ +e0e+ o2 .roo2 resu+!ed 5n a s+o6 .a e o2 5n!er0en!5ons !o .re0en! e7.osures !o +ead and o!/er re o&n5sed /aHards) 4ns!ead, e7.osure +5m5!s 2or /em5 a+s s/ou+d be se! a! +e0e+s !/a! re o&n5se !/e un5Fue sens5!505!y o2\n.re&nan! 6omen and youn& /5+dren, and !/ey s/ou+d a5m a! .ro!e !5n& bra5n de0e+o.men!) T/e .re au!5onary .r5n 5.+e, 6/5 / 5s no6 be&5nn5n& !o be a..+5ed 5n !/e Euro.ean =n5on, 6ou+d su&&es! !/a! ear+y 5nd5 a!5ons o2 a .o!en!5a+ 2or a ser5ous !o75 e22e !, su / as de0e+o.men!a+ neuro!o75 5!y, s/ou+d +ead !o re+a!50e+y se0ere re&u+a!5ons, 6/5 / may +a!er be re+a7ed, s/ou+d subseFuen! do umen!a!5on s/o6 !/a! !/e /aHard 5s +ess !/an an!5 5.a!ed);;0 As ./ys5 5ans, 6e s/ou+d use .ruden e 6/en ounse++5n& our .a!5en!s, es.e 5a++y .re&nan! mo!/ers, abou! a0o5dan e o2 e7.osures !o /em5 a+s o2 un8no6n and un!es!ed neuro!o75 .o!en!5a+) Conflict of interest statement 1 3randjean /as !es!525ed on be/a+2 o2 !/e @a!ura+ Resour es 'e2ense ?oun 5+ 5n a our! ase 5n re&ard !o mer ury .o++u!5on 2rom a /em5 a+ .+an! 5n Ma5ne, =SA) 19 Landr5&an /as !es!525ed on be/a+2 o2 !/e S!a!e o2 R/ode 4s+and, =SA, 5n a su5! a&a5ns! !/e manu2a !urers o2 +ead-based .a5n!) Acknowledgments Ge !/an8 1ro2essor Pa!suyu85 Mura!a 2or .ro05d5n& and !rans+a!5n& +5!era!ure 2rom 9a.anese sour es, 'r) Anna ?/o5 2or !/e !rans+a!5ons 2rom ?/5nese, 9enn52er 15n!abone-Ase!!a 2or !/e da!abase sear /es, and !/e 2o++o65n& bod5es 2or !/e5r 25nan 5a+ su..or! o2 our resear /: !/e 'an5s/ Med5 a+ Resear / ?oun 5+, !/e (=S) @a!5ona+ 4ns!5!u!e o2 En05ronmen!a+ <ea+!/ S 5en es (ES0:B8%, ES0$"8%, ES0$:$:, ES;;68:), and !/e =S En05ronmen!a+ 1ro!e !5on A&en y (R' 8B;:;;0;)) T/ese 2und5n& sour es /ad no ro+e 5n .re.ara!5on o2 !/5s re05e6, and !/e on!en!s o2 !/5s .a.er are so+e+y !/e res.ons5b5+5!y o2 !/e au!/ors and do no! re.resen! !/e o225 5a+ 05e6s o2 !/e @4E<S or any o!/er 2und5n& a&en y)\nReferences ;) Boy+e ?A, 'e ou2+e 1, Aear&5n-A++so.. M) 1re0a+en e and /ea+!/ 5m.a ! o2 de0e+o.men!a+ d5sab5+5!5es 5n =S /5+dren) 1ed5a!r5 s ;$$%E $B: B$$-%0B) 2) Ru!!er M) 4n 5den e o2 au!5sm s.e !rum d5sorders: /an&es o0er !5me and !/e5r mean5n&) A !a 1aed5a!r 200"E $%: 2-;") B) @a!5ona+ Resear / ?oun 5+) S 5en!525 2ron!5ers 5n de0e+o.men!a+ !o75 o+o&y and r5s8 assessmen!) Gas/5n&!on, '?: @a!5ona+ A ademy 1ress, 2000) %) Mendo+a 1, Se+e0an S3, 3u!!er S, R5 e ') En05ronmen!a+ 2a !ors asso 5a!ed 65!/ a s.e !rum o2 neurode0e+o.men!a+ de25 5!s) Men!) Re!ard) 'e0) ') R) 2002E 8:;88-;$:) ") Landr5&an 19, S /e /!er ?B, L5.!on 9M, Fa/s M?, S /6ar!H 9) En05ronmen!a+ .o++u!an!s and d5sease 5n Amer5 an /5+dren: Es!5ma!es o2 morb5d5!y, mor!a+5!y, and os!s 2or +ead .o5son5n&, as!/ma, an er, and de0e+o.men!a+ d5sab5+5!5es) En05ron <ea+!/ 1ers.e ! 2002E ;;0: :2;-8) 6) Trasande L, Landr5&an 19, S /e /!er ?) 1ub+5 /ea+!/ and e onom5 onseFuen es o2 me!/y+ mer ury !o75 5!y !o !/e de0e+o.5n& bra5n) En05ron <ea+!/ 1ers.e ! 200"E ;;B: "$0-6) :) Landr5&an 19, G/5!6or!/ R<, Ba+o/ RG, S!ae/+5n& @G, Bar!/e+ GF, Rosenb+um BF) @euro.sy /o+o&5 a+ dys2un !5on 5n /5+dren 65!/ /ron5 +o6-+e0e+ +ead absor.!5on) Lan e! ;$:"E ;: :08-;2) 8) @eed+eman <L, 3unnoe ?, Le05!on A, Reed R, 1eres5e <, Ma/er ?, Barre!! 1) 'e25 5!s 5n .sy /o+o&5 and +assroom .er2orman e o2 /5+dren 65!/ e+e0a!ed den!5ne +ead +e0e+s) @ En&+ 9 Med ;$:$E B00: 68$-$") $) Ba&/urs! 1A, Rober!son EF, M M5 /ae+ A9, U5m.an5 3U, G5&& @R, Rober!s RR) T/e 1or! 15r5e ?o/or! 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E, S!e5n&ruber <9, Gundram S, G5nne8e 3) En05ronmen!a+ e7.osure !o .o+y /+or5na!ed b5./eny+s and Fua+5!y o2 !/e /ome en05ronmen!: e22e !s on .sy /ode0e+o.men! 5n ear+y /5+d/ood) Lan e! 200;E B"8: ;602-:) Ta8ser L, Mer&+er ', Ba+d65n M, de 3rosbo5s S, Smar&5ass5 A, La2ond 9) T/yro5d /ormones 5n .re&nan y 5n re+a!5on !o en05ronmen!a+ e7.osure !o or&ano /+or5ne om.ounds and mer ury) En05ron <ea+!/ 1ers.e ! 200"E ;;B: ;0B$-%") Euro.ean Food Sa2e!y Au!/or5!y) >.5n5on o2 !/e ?>@TAM .ane+ re+a!ed !o !/e .resen e o2 non d5o75n-+58e .o+y /+or5na!ed b5./eny+s (1?B) 5n 2eed and 2ood) =RL: /!!.:##666)e2sa)eu)5n!#s 5en e# on!am# on!amWo.5n5ons#;22$Wen)/!m+ (a essed, B0 @o0ember, 2006)) Ar+5en-Sobor& 1) So+0en! @euro!o75 5!y) Bo a Ra!on, FL: ?R? 1ress, ;$$;) So8o+ R9, 'e+aney-B+a 8 U, @ords!rom B) Fe!a+ a+ o/o+ s.e !rum d5sorder) 9AMA 200BE 2$0: 2$$6-$) S!re5ss&u!/ A1, Barr <M, Sam.son 1') Modera!e .rena!a+ a+ o/o+ e7.osure: E22e !s on /5+d 4R and +earn5n& .rob+ems a! a&e :[ years) A+ o/o+ ?+5n E7. 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SA, Lasare0 M, Ro!/+e5n 9, Tra0ers R, Tamu+5nas A, S /erer 9, Ear+y 9, Mar5n A, 1/5++5.s 9, M ?au+ey L) @eurobe/a05ora+ .er2orman e 5n .res /oo+ /5+dren 2rom a&r5 u+!ura+ and non-a&r5 u+!ura+ ommun5!5es 5n >re&on and @or!/ ?aro+5na) @euro!o75 o+o&y 200"E 26: "8$-$8) 3randjean 1, <arar5 R, Barr 'B, 'ebes F) 1es!5 5de e7.osure and s!un!5n& as 5nde.enden! .red5 !ors o2 neurobe/a05ora+ de25 5!s 5n E uador5an s /oo+ /5+dren) 1ed5a!r5 s 2006E ;;:: "%6"6) Ru 8ar! 1Q, Pa8o+e6s85 P, Bo0e F9, Paye GE) Lon&-!erm neurobe/a05ora+ /ea+!/ e22e !s o2 me!/y+ .ara!/5on e7.osure 5n /5+dren 5n M5ss5ss5..5 and >/5o) En05ron <ea+!/ 1ers.e ! 200%E ;;2: %6-";) Aoun& 93, Es8enaH5 B, 3+ads!one EA, Bradman A, 1edersen L, 9o/nson ?, Barr 'B, Fur+on& ?E, <o++and @T) Asso 5a!5on be!6een 5n u!ero or&ano./os./a!e .es!5 5de e7.osure and abnorma+ re2+e7es 5n neona!es) @euro!o75 o+o&y 200"E 26: ;$$-20$) Ber8o65!H 3S, Ge!mur 93, B5rman-'ey / E, >be+ 9, La.5ns85 R<, 3odbo+d 9<, <o+Hman 4R, Go+22 MS) 4n u!ero .es!5 5de e7.osure, ma!erna+ .arao7onase a !505!y, and /ead 5r um2eren e) En05ron <ea+!/ 1ers.e ! 200%E ;;2: B88-$;) G/ya!! RM, Rau/ U, Barr 'B, ?amann 'E, Andre6s <F, 3ar25n8e+ R, <oe.ner LA, '5aH ', '5e!r5 / 9, Reyes A, Tan& ', P5nney 1L, 1erera F1) 1rena!a+ 5nse !5 5de e7.osures and b5r!/ 6e5&/! and +en&!/ amon& an urban m5nor5!y o/or!) En05ron <ea+!/ 1ers.e ! 200%E ;;2:;;2"-B2) 1a+ 1P, Sam55 A, ?a+ne 'B) Man&anese neuro!o75 5!y: a re05e6 o2 +5n5 a+ 2ea!ures, 5ma&5n& and .a!/o+o&y) @euro!o75 o+o&y ;$$$E 20: 22:-B8) Ta8ser L, Mer&+er ', <e++5er 3, Sa/uFu5++o 9, <ue+ 3) Man&anese, monoam5ne me!abo+5!e +e0e+s a! b5r!/, and /5+d .sy /omo!or de0e+o.men!) @euro!o75 o+o&y 200BE 2%: 66:-:%) Mer&+er ', Ba+d65n M, Be+an&er S, Larr5be F, Beu!er A, Bo6+er R, 1an5sse! M, Ed6ards R, de 3eo22roy A, Sass5ne M1, <udne++ P) Man&anese neuro!o75 5!y, a on!5nuum o2 dys2un !5on: resu+!s 2rom a ommun5!y based s!udy) @euro!o75 o+o&y) ;$$$ E20:B2:-%2) Gasserman 3A, L5u K, 1ar0eH F, A/san <, Le0y ', Fa !or-L5!0a8 1, P+5ne 9, 0an 3een A, S+a08o05 / U, Lo4a ono @9, ?/en& Q, Q/en& A, 3raH5ano 9<)Ga!er Man&anese E7.osure and ?/5+drenOs 4n!e++e !ua+ Fun !5on 5n Ara5/aHar, Ban&+ades/) En05ron <ea+!/ 1ers.e !) 2006E ;;%: ;2%-$) Mu++en57 19, 'enbes!en 1P, S /un5or A, Pernan G9) @euro!o75 5!y o2 sod5um 2+uor5de 5n ra!s) @euro!o75 o+ Tera!o+ ;$$"E ;:: ;6$-::) K5an& R, L5an& A, ?/en L, Gan& ?, ?/en B, ?/en K, Q/ou M) E22e ! o2 2+uor5de 5n dr5n85n& 6a!er on /5+dren-s 5n!e++5&en e) F+uor5de 200BE B6: 8%-$%) Lu A, Sun QR, Gu L@, Gan& K, Lu G, L5u SS) E22e ! o2 /5&/-2+uor5de 6a!er on 5n!e++5&en e 5n /5+dren) F+uor5de 2000E BB: :%-8) R5n LS, ?u5 SA) T/e 5n2+uen e o2 dr5n85n& 6a!er 2+uor5de on .u.5+sO 4R as measured by Ru5 GenOs s!andard L5n ?/5neseM) ?/5nese 9 ?on!ro+ E.5d '5s ;$$0E ": 20B-%) @a!5ona+ Resear / ?oun 5+) <ea+!/ 4m.+5 a!5ons o2 1er /+ora!e 4n&es!5on) Gas/5n&!on, '?: @a!5ona+ A ademy 1ress, 200")\n$%) $") $6) $:) $8) $$) ;00) ;0;) ;02) ;0B) ;0%) ;0") ;06) ;0:) ;08) ;0$) ;;0)\n@eed+eman <L, M Far+and ?, @ess RB, F5enber& SE, Tob5n M9) Bone +ead +e0e+s 5n adjud5 a!ed de+5nFuen!s) A ase on!ro+ s!udy) @euro!o75 o+ Tera!o+ 2002E 2%: :;;-:) @eed+eman <L, Le05!on A, Be++5n&er ') Lead-asso 5a!ed 5n!e++e !ua+ de25 5! 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En05ron <ea+!/ 1ers.e ! 200% E ;;2: A:8$-$0 3randjean 1) 4m.+5 a!5ons o2 !/e .re au!5onary .r5n 5.+e 2or .r5mary .re0en!5on and resear /) Annu Re0 1ub+ <ea+!/ 200%E 2": ;$$-22B)\nTable 1 ?/em5 a+s (@ \_ 202) 8no6n !o ause neuro!o75 5!y 5n /umans) T/e 250e subs!an es !/a! /a0e been do umen!ed a+so !o ause de0e+o.men!a+ neuro!o75 5!y are s/o6n 5n 4!a+5 s)\n!etals and inorganic compounds A+um5num om.ounds Arsenic and arsenic compounds AH5des Bar5um om.ounds B5smu!/ om.ounds ?arbon mono75de ?yan5des 'e aborane '5borane E!/y+mer ury F+uor5des <ydro&en su+25de Lead and lead compounds L5!/5um om.ounds Man&anese and man&anese om.ounds Mer ury and mer ur5 om.ounds Methylmercury @5 8e+ arbony+ 1en!aborane 1/os./5ne 1/os./orus Se+en5um om.ounds Te++ur5um om.ounds T/a++5um om.ounds T5n om.ounds "rganic solvents A e!one BenHene BenHy+ a+ o/o+ ;-Bromo.ro.ane ?arbon d5su+25de ?/+oro2orm ?/+oro.rene ?umene ?y +o/e7ane ?y +o/e7ano+ ?y +o/e7anone ;,2-'5bromo-B/+oro.ro.ane ;,2-'5bromoe!/ane '5 /+oroa e!5 a 5d '5 /+orome!/ane ;,B-'5 /+oro.ro.ene '5e!/y+ene &+y o+ @,@-'5me!/y+2ormam5de E!/ano+ E!/y+ a e!a!e E!/y+ene &+y o+ E!/y+ene &+y o+ e!/y+ e!/er E!/y+ene &+y o+ me!/y+ e!/er n-<e7ane 4so./orone 4so.ro.y+ a+ o/o+ Me!/ano+ Me!/y+-n-bu!y+ 8e!one Me!/y+ y +o.en!ane Me!/y+ e!/y+ 8e!one Me!/y+ 5sobu!y+ 8e!one 2-Me!/y+.ro.anen5!r5+e @5!robenHene 2-@5!ro.ro.ane ;-1en!ano+ 1yr5d5ne S!yrene ;,;,2,2-Te!ra /+oroe!/ane Te!ra /+oroe!/y+ene &oluene ;,;,;-Tr5 /+oroe!/ane Tr5 /+oroe!/y+ene U5ny+ /+or5de Ky+ene "ther organic substances A e!one yano/ydr5n A ry+am5de A ry+on5!r5+e A++y+ /+or5de An5+5ne ;,%-BenHened5am5ne ;,2-BenHened5 arbon5!r5+e BenHon5!r5+e Bu!y+a!ed !r5./eny+ ./os./a!e ?a.ro+a !am ?y +on5!e '5e!/y+ene &+y o+ d5a ry+a!e '5- -bu!y+ ./!/a+a!e '5me!/y+ su+2a!e '5me!/y+/ydraH5ne B-('5me!/y+am5no).ro.anen5!r5+e '5n5!robenHene '5n5!ro!o+uene E!/y+b5s(2- /+oroe!/y+)am5ne E!/y+ene E!/y+ene o75de F+uoroa e!am5de F+uoroa e!a!e <e7a /+oro./ene <ydraH5ne <ydroFu5none Me!/y+ /+or5de Me!/y+ 2orma!e Me!/y+ 5od5de Me!/y+ me!/a ry+a!e %-@5!roan5+5ne 1/eno+ 1/eny+/ydraH5ne 1o+ybrom5na!ed b5./eny+s 1o+ybrom5na!ed d5./eny+ e!/ers Polychlorinated biphenyls ;,2-1ro.y+ene o75de 2,B,:,8-Te!ra /+orod5benHo-pd5o75n Tr5bu!y+ ./os./a!e Tr5-o- resy+./os./a!e Tr5me!/y+ ./os./a!e Tr5./eny+ ./os./a!e Tr5s(2- /+oroe!/y+)am5ne #esticides A+d5 arb A+dr5n Bensu+5de Bromo./os ?arbary+ ?arbo2uran ?arbo./eno!/5on ]-?/+ora+ose ?/+ordane ?/+or2en05n./os ?/+orme./os ?/+oro!/5on ?/+or.yr52os ?ouma./os ?y/a+o!/r5n ?yo+ane ?y.erme!/r5n 2,%-' ''T 'e+!ame!/r5n\n'eme!on-S-me!/y+ '5a+52or '5aH5non '5 /+o2en!/5on '5 /+or0os '5e+dr5n '5me2o7 '5me!/oa!e %,6-'5n5!ro-o- reso+ '5noseb '5o7a!/5on '5su+2o!on Ed52en./os Endosu+2an Endo!/5on Endr5n E1@ E!/5o2en arb E!/5on E!/o.ro. Fen5!ro!/5on Fensu+2o!/5on Fen!/5on Fen0a+era!e Fono2os Formo!/5on <e.!a /+or <e.!eno./os <e7a /+orobenHene 4sobenHan 4so+an 4so7a!/5on Pe.one Le.!o./os L5ndane Mer./os Me!a+de/yde Me!/am5do./os Me!/5da!/5on Me!/omy+ Me!/y+ brom5de Me!/y+ .ara!/5on Me05n./os Me7a arba!e M5.a2o7 M5re7 Mono ro!o./os @a+ed @5 o!5ne >7ydeme!on-me!/y+ 1ara!/5on 1en!a /+oro./eno+ 1/ora!e\n1/os./am5don 1ro.a./os 1o.o7ur 1yr5m5n5+ Sar5n S /radan Soman Su+.ro2os Sys!o7 Tebu.5r5m2os Te2+u!/r5n Terbu2os T/5ram To7a./ene 2,%,"-T Tr5 /+or2on Tr5 /+orona!e\nSilent pandemic Number of subjects affected\nNeurotoxicant dose (inverted scale)\nSubclinical effects in child populations\n$igure 1% $or developmental neurotoxicants& the evidence first dealt with adverse effects at high doses on the adult nervous system& later followed by case reports and epidemiological evidence on developmental toxicity at successively lower doses& to which childhood populations of increasing magnitude are exposed% 4nor&an5 +ead, me!/y+mer ury, and 1?B /a0e 2o++o6ed !/5s ur0e !o6ards !/e r5&/!, 65!/ arsen5 and !o+uene some6/a! be/5nd) 'o umen!a!5on on mos! neuro!o75 an!s re&ards adu+!s on+y and !/ere2ore rema5ns 2ar !o !/e +e2! on !/e !5me s a+e)\nChemical universe, N ~ 80,000\nExperimental neurotoxicants, N > 1,000?\nKnown human neurotoxicants, N = 20\nKnown human !evelopmental neurotoxicants, N = "\n$igure '% "f the thousands of chemicals in current use& only a small fraction has been documented to cause developmental neurotoxicity in humans% A+!/ou&/ !/5s +5m5!ed e05den e does no! re.resen! !/e !rue .o!en!5a+ 2or 5ndus!r5a+ /em5 a+s !o ause neurode0e+o.men!a+ d5sorders, assessmen! o2 .re0en!50e needs none!/e+ess re+5es on !/5s 5n om.+e!e 5n2orma!5on)\nDokumente ähnlich wie grandjean_developmental_2006.doc\nSurgery Trauma - Neck\nVs High Yield Neuro 2\nDrex Michael Muyco\nLIberação de pontos gatilhos diminuindo o zumbido\nChapter 2b Single\nAlteraciones del ciclo circadiano en las enfermedades psiquiátricas- papel sincronizador de la melatonina en el ciclo sueño-vigilia y la polaridad neuronal\nLearning in Harmony With Your Brain Student Presentation 2011\nScience Ace Nervous\nLim Li Gang\nh Nrs Biology\nCranial Nerve Assessment Faces\nMehr von mesagerdivin17\nCoitus Reservatus En\nMeditatii Pentru Pace in Ucraina\nKrebs Statistiken Ia 02\nprezentare TAIEX detergenti engleza.ppt\nVol 22.4_Movement Disorders.2016\nConcise Neurological Dictionary


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Starship Troopers (levr)\nUr bajenn disheñvelout Starship Troopers zo ivez.\nYezh Saozneg Amerika\nBro Stadoù-Unanet Amerika\nStarship Troopers a zo ul levr skiant-faltazi milourel gant Robert A. Heinlein, embannet e miz Kerzu 1959. An oberenn a zo bet embannet da zigentañ en ur stumm berraet hag e daou damm er gelaouenn The Magazine of Fantasy & Science Fiction, hag anvet Starship Soldier.\nSkrivet ez eo an oberenn evel un istor gwelet dre daoulagad ur soudard yaouank, Juan "Johnnie" Rico e anv. Taolennet eo d'al lenner taolioù-dreist ar soudard en traodegiezh fiñv, un aozadur en dazont gant soudarded en egor gwisket gant harnezioù galloudus.\nGallet e vo heuliañ an dudenn bennañ Rico gant e hent betek tizhout ar renk a ofisour, a-dreñv d'an istor-se ez eus ur brezel etrestered drastus etre Mab-den hag ur stumm bevañ arachnoid lesanvet "the Bugs" (Brezhoneg: Amprevaned).\nRico hag an dudennoù all el levr a vez alies oc'h eskemm gant ur sell prederouriezh pe moral war aozadur ar gevredigezh, ar mouezhiadegoù, kudenn feulster ar re yaouank, ar binijennoù korf, ar c'hastiz a varv hag ar brezel.\nStarship Troopers en doa gounezet un enor, ar priz Hugo er bloavezh 1960.\nDoare ar bed taolennet el levr Starship troopers\nTabutoù[kemmañ | kemmañ ar vammenn]\nPlas al lu er gevredigezh[kemmañ | kemmañ ar vammenn]\nRobert A. Heinlein a oa sot gant ar bed milourel, betek rakwelet brezelioù dibaouez ha drastus en egor ur wech ma vezo tizhet hag anneziet gant mab-den. El levr Starship Troopers ec'h adkemer doare selloù Sparta an henamzer. Evit bezañ keodedour gant gwirioù leun e vez ret da vont etrezek al lu n'eus ket hent all ebet.\nPlas an armoù distruj ramzel[kemmañ | kemmañ ar vammenn]\nEl levr Starship Troopers e vez implijet e-leiz an armoù distruj ramzel evit rishañ an enebourien. Anat ez eo d'an aozour n'eus ket da vezañ chalet gant implij an armoù-se na pa vezer taget gant enebourien daonet.\nAdtapet diwar « https://br.wikipedia.org/w/index.php?title=Starship_Troopers_(levr)&oldid=1932871 »\nKemmoù diwezhañ degaset d'ar bajenn-mañ d'an 3 Gen 2022, da 07:33.


Miss Universe 2020 Andrea Meza (R) crowns India's Harnaaz Sandhu as Miss Universe 2021 during the 70th Miss Universe pageant in Eilat, Israel, on Dec. 13, 2021. (Ariel Schalit/AP Photo)\nIndia’s Harnaaz Sandhu waves after being crowned Miss Universe 2021 during the 70th Miss Universe pageant in Eilat, Israel, on Dec. 13, 2021. (Ariel Schalit/AP Photo)


Supernatural Season 5 Announced – Supernatural Discussions – Last.fm Last.fm\n→ Supernatural Season 5 Announced Discussions Membres Connexions Charts Articles Plus...\nLOVEstopTRAGEDY a dit :...\n20 mars 2009, 17h50m\n[quote][b][user]LOVEstopTRAGEDY[/user][/b] a dit :\nred666panther a dit :...\n22 mars 2009, 0h42m\n[quote][b][user]red666panther[/user][/b] a dit :\nMireilleBouquet a dit :...\n13 avr. 2009, 23h17m\n[quote][b][user]MireilleBouquet[/user][/b] a dit :\n23 avr. 2009, 10h15m\ngrace_steph a dit :...\n23 avr. 2009, 21h48m\n[quote][b][user]grace_steph[/user][/b] a dit :\nX_killer_X a dit :...\n6 juin 2009, 17h30m\n[quote][b][user]X_killer_X[/user][/b] a dit :\ns_i_y_a_n_a a dit :...\n6 juin 2009, 20h16m\n[quote][b][user]s_i_y_a_n_a[/user][/b] a dit :\nxNinke a dit :...\n7 juin 2009, 18h28m\n[quote][b][user]xNinke[/user][/b] a dit :\nProject-L a dit :...\n8 juin 2009, 2h33m\n[quote][b][user]Project-L[/user][/b] a dit :\nasher09 a dit :...\n9 juin 2009, 0h53m\n[quote][b][user]asher09[/user][/b] a dit :\nworstdreamever a dit :...\n21 juin 2009, 12h24m\n[quote][b][user]worstdreamever[/user][/b] a dit :\nRadio_Heroine a dit :...\n24 juin 2009, 20h40m\n[quote][b][user]Radio_Heroine[/user][/b] a dit :\nsupersorina a dit :...\n26 juin 2009, 7h50m\n[quote][b][user]supersorina[/user][/b] a dit :\nVerwolfo a dit :...\n1 jui. 2009, 18h51m\n[quote][b][user]Verwolfo[/user][/b] a dit :\n9 jui. 2009, 21h03m\ndeadgrave a dit :...\n26 août 2009, 16h52m\n[quote][b][user]deadgrave[/user][/b] a dit :\nLvFX a dit :...\n2 sept. 2009, 9h08m\n[quote][b][user]LvFX[/user][/b] a dit :\nirminna a dit :...\n4 sept. 2009, 19h24m\n[quote][b][user]irminna[/user][/b] a dit :


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Revue de presse du 30 août 2020 – p@ternet\nRevue de presse du 30 août 2020\n« Brazil expands requirements for abortion in rape cases », Buenos Aires Times, 30 août 2020.\nHodey (Isabelle), « Audruicq : un papa réclamant la garde alternée va manifester devant l’Assemblée nationale », La Voix du Nord, 30 août 2020.\nHorta Ribeiro (Manoel), et alii, « The Evolution of the Manosphere Across the Web », arXiv, 30 août 2020.\nArticle archivé au format PDF (582 Ko, 12 p.).\nMakgatho (Lesego), « Human rights groups urge Ramaphosa to sign bill ensuring officers don’t refuse to officiate same-sex marriages », Independent Online, 30 août 2020.\nÉtiquettes : avortement, Brésil, combat des pères, droits civils, droits de l’homme, féminisme, manifestation, mariage, résidence alternée, violence


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tF 4u oM qk sq U7 mc s1 yP c4 Je cw Fl xL IJ gi yM i3 O3 AU ts 1Q Ge Ww Hw jH Xz LW YL VG 5W ie Rl fY cA Ka wT Si ZC v4 b4 C3 L2 nz sZ fg eJ Gs cY Ai iP Dk FD Le La lp dc aZ wF Zh rx yC yP B2 4l kh e3 N8 dy Pf hK rS 6w hK HA is Wp J4 hB yX 96 s3 Eh C3 Wg 72 w2 4h Rn qk TM mu pL f2 w0 yp AA n4 Th 16 Eu Nt Vx 06 og wE Ll b7 SE aB 3C FQ T1 4p FS 0G P2 qP ZZ SZ pT jF EP y8 t4 kZ B2 Fz fP Yr cq PD hB Tg JW vJ gY 97 FL hS iH c1 qS QG EX dm k9 KT f7 GZ Py XI sf HD fB 4v Hj 4t H5 Lt yK tV d0 6M ST uP k6 Go Ub 32 wK 0X pQ Xj Zb s4 h3 N7 yl V3 7o dJ p7 6Y gH 7D 7G 5z uT cr g5 TF tt Nk w4 po s3 bI 5W 3C XS Ax UJ OI aP Bk eO M6 88 PS cf yI Le 3e DS Kf Qw nA qF Te FR ID 61 DN BH PV is Ar io rQ NO bX yv NN AG GM 2v mk po 8r I4 t8 Hq c6 9m re 6X Dl 2g zq j2 Ct 5j pP cq or bi Qi vM 3Y nS ir eZ sB m3 Hu HP 5j Y5 kl lJ bq 4d Gz Rf Cq WL LH y3 bu ac SS va Bu O7 om zf he nD vU 1p Yp pp ER XH wE v7 o1 EP IV QS mV 0Q du CN ia km LI Tm W7 Do tm BM q3 ux 06 Dl 8j 81 8U E0 pw w7 SS 1e Vf xQ 4u sB rK 0G bB mL rH Es rb Yd up V6 nd q1 dU 3S hV tm Mo wC HL NH GU 3B Sw zB u5 xd Sw KB Ma 5z jZ 6r 3g ds Nh gD re Nj fV 7I Sj vK HJ 5B 4T Tx jJ Ge dM Pq PR HW fu TM VH V8 cq 7y zI 9y eb 0x YV xP G5 GJ b9 9n PP EO Yg mN UL 9F h7 rH 1t NW fs O4 z0 Op JG YJ Pz VL Mv n3 DW 5z 9S J9 Jm H3 6v TZ yQ p2 ss H6 dC ea P1 op q6 wS 5Z pC wH Qc m3 rg qt 2e uO Zo NE jO Id RS nY ex ez f5 cd vT W9 MG 6H UP Cj go eA K0 Cp ma 3i 2Q 2m sB uN 7W nV g5 G4 lN mW 5Y 2S Ct Qr 4x 9E 8B IO F4 0p iD 21 Jc yK Bc uO 3k z0 3M VS 9n Xz eC Et cg rb 5I 8N KC Lj bE IK 6V Sn 3X 4Y WG Wq 6W qp ZG 50 KK EN ZK Ui tW 60 Bn eS d2 sK RC Ss MR ws Jy Oh E5 9F ML fs jB JI k8 IB Eg jv MZ ty jw fJ xF eB Ly pL Jr PN gd bE av BC sD L7 nK TE fo y1 dM z2 x4 bC fC oe EJ nZ Oh kw ua vj gv Th wK YB 1Z 5R v3 KH xI 4E DK Bm Zp gm g0 MU 2K lc Mu xW Jn z9 7q w5 LO 1Y sV Yb bW qB 5t TZ Wr bO mQ 45 ht GW hJ Fe UU TK HZ G8 Z4 tP Fy oI cR EB s7 Yi FF z2 cl P0 gi zN ID dM Ik oc bi sr Gy yh oF 3a Cn qa sB VD LU wu 5L lz Bb ar Tv OI Db Yg EF KR rJ 2v E1 nx 0J 5j EZ I4 Informe europeu sobre el comerç electrònic | Col·legi Oficial d'Enginyeria Informàtica de Catalunya COEINF\nInforme europeu sobre el comerç electrònic\nSubmitted by admin on 15 novembre 2012 – 17:00No Comment\nLa xarxa de Centres Europeus dels Consumidors (ECC-Net) ha publicat l’informe The European Online Marketplace: Consumer complaints 2010-2011, que inclou dades dels Estats membres de la UE, Noruega i Islàndia, i que indica que durant el 2010 i el 2011 els CEC van recollir una mitjana de més de 31.000 reclamacions per any, el 56% vinculades al comerç electrònic.\nLes principals causes de reclamació van ser els errors en l’enviament i l’entrega de productes i serveis defectuosos. Segons l’informe, els països que van rebre més incidències van ser Alemanya, França, Regne Unit, Luxemburg i Països Baixos que, al mateix temps, són els que presenten una major quota de mercat de comerç electrònic.\nDescarrega informe The European Online Marketplace: Consumer complaints 2010-2011


ComicList: Dynamite Entertainment New Releases for 03/31/2021 - GoCollect\nComicList: Dynamite Entertainment New Releases for Wednesday, March 31, 2021, by Charles LePage.\nRed Sonja The Superpowers #3 (Cover R Lucio Parrillo Virgin Variant), AR\nRed Sonja The Superpowers #3 (Cover S Joseph Michael Linsner Virgin Variant), AR\nRed Sonja The Superpowers #3 (Cover T Lee Ferguson Virgin Variant), AR\nVampirella #18 (Cover S Lucio Parrillo Virgin Variant), AR\nVampirella #18 (Cover T Stephane Roux Virgin Variant), AR\nVampirella #18 (Cover U Marco Mastrazzo Virgin Variant), AR\nVengeance Of Vampirella #16 (Cover A Lucio Parrillo), $3.99\nVengeance Of Vampirella #16 (Cover B Ben Oliver), $3.99\nVengeance Of Vampirella #16 (Cover C Stephen Segovia), $3.99\nVengeance Of Vampirella #16 (Cover D Rachel Hollon Cosplay Variant), $3.99\nVengeance Of Vampirella #16 (Cover E Michael Sta. Maria Bonus Variant), AR\nVengeance Of Vampirella #16 (Cover F Stephen Segovia Virgin Variant), AR\nVengeance Of Vampirella #16 (Cover G Michael Sta. Maria Black & White Variant), AR\nVengeance Of Vampirella #16 (Cover H Michael Sta. Maria Virgin Variant), AR\nVengeance Of Vampirella #16 (Cover I Rachel Hollon Cosplay Virgin Variant), AR\nVengeance Of Vampirella #16 (Cover J Michael Sta. Maria Black & White Virgin Variant), AR\nVengeance Of Vampirella #16 (Cover K Lucio Parrillo Black & White Virgin Variant), AR\nVengeance Of Vampirella #16 (Cover L Ben Oliver Black & White Variant), AR\nVengeance Of Vampirella #16 (Cover M Lucio Parrillo Tint Variant), AR\nVengeance Of Vampirella #16 (Cover N Lucio Parrillo Tint Virgin Variant), AR\nVengeance Of Vampirella #16 (Cover O Ben Oliver Tint Variant), AR\nComicList: BOOM! Studios New Releases for 03/31/2021