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From: Bryan, Rose (ELS) To: Subje !: 0"ART#$0$% Messa&e 'a!

e: "#2#2006 08:02

Tuesday - May 2, 2006 8:02 AM

From: 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

Manus r5.! subm5!!ed !o T/e Lan e! (a e.!ed 2or .ub+5 a!5on, 2 May 2006)

Developmental neurotoxicity of industrial chemicals A silent pandemic

1 3randjean, 19 Landr5&an

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Abstract @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)

Search 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)

>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)

Vulnerability 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

1ara++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

do 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

breas!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

adu+!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)

Manganese 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)

As 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! +eas! 6ea8+y en2or ed);0% T/e onseFuen es are +ar&e+y unre.or!ed) Prospects for Prevention T/e .andem5 o2 neurode0e+o.men!a+ !o75 5!y aused by 5ndus!r5a+ /em5 a+s 5s, 5n !/eory, .re0en!ab+e) 1remar8e! !es!5n& o2 ne6 /em5 a+s 5s a /5&/+y e225 5en! means o2 .re0en!5n& !o75 5!y, bu! /as been reFu5red on+y dur5n& re en! years) >2 !/e !/ousands o2 /em5 a+s urren!+y

used 5n ommer e, 2e6er !/an /a+2 /a0e been subje !ed !o e0en m5n5ma+ +abora!ory !es!5n& !o assess !o75 5!y)2% @ear+y B,000 o2 !/ese subs!an es are .rodu ed 5n Fuan!5!5es o2 ; m5++5on or more .ounds .er year, bu! 2or near+y /a+2 o2 !/ese /5&/-0o+ume /em5 a+s no bas5 !o75 5!y da!a are .ub+5 +y a0a5+ab+e, and 80N /a0e no 5n2orma!5on on de0e+o.men!a+ or .aed5a!r5 !o75 5!y)2% A+!/ou&/ ne6 /em5 a+s mus! be !es!ed more !/orou&/+y, a ess !o !/ese da!a may be res!r5 !ed, be ause !/ey may be +a5med !o ons!5!u!e on25den!5a+ bus5ness 5n2orma!5on) La 8 o2 5n2orma!5on on !/e neuro!o75 .o!en!5a+ o2 mos! 5ndus!r5a+ /em5 a+s 5s !/ere2ore a major 5m.ed5men! !o .re0en!5on o2 @''s) A e+era!ed !es!5n& o2 /em5 a+s a+ready 5n ommer e 5s !/ere2ore essen!5a+) 4n !/e =SA, a +e&a+ manda!e !o reFu5re !es!5n& 6as es!ab+5s/ed 5n !/e To75 Subs!an es ?on!ro+ A !, bu! 5s +ar&e+y unen2or ed)2% 4n !/e E=, o..or!un5!y e75s!s !o reFu5re more e7!ens50e /em5 a+ !es!5n& !/rou&/ !/e REA?< .ro&ram,2" a+!/ou&/ !/e urren!+y .ro.osed +e&5s+a!5on does no! em./as5se !es!5n& 2or de0e+o.men!a+ neuro!o75 5!y as a .r5mary obje !50e) To75 5!y !es!5n& o2 /em5 a+s needs !o e7.and urren! .ro!o o+s !o 5n +ude e7am5na!5on o2 neurobe/a05oura+ 2un !5ons) ?urren! !es! .ro!o o+s re+y ma5n+y on re+a!50e+y rude .arame!ers, su / as bra5n 6e5&/! and &ross mor./o+o&y);0",;06 R5s8 e75s!s 5n abbre05a!ed .ro!o o+s used 2or !o75 5!y s reen5n& !/a! neurode0e+o.men!a+ !o75 5!y 65++ be o0er+oo8ed, and 2ur!/er !es!5n& may erroneous+y be ons5dered unne essary) 1ro edures 2or 2un !5ona+ e0a+ua!5on are a0a5+ab+e,;0" and a /armon5sed .ro!o o+ 2or assessmen! o2 de0e+o.men!a+ neuro!o75 5!y 6as de0e+o.ed under >E?' aus.5 es 5n ;$$$,;06 a+!/ou&/ 5! 5s s!5++ under re05e6) T/e number o2 /em5 a+s !/a! an ause neuro!o75 5!y 5n +abora!ory s!ud5es .robab+y e7 eeds ;000, a number !/a! &rea!+y e7 eeds !/e a..ro75ma!e+y 200 !/a! /a0e aused do umen!ed /uman neuro!o75 5!y) <o6e0er, 5n !/e absen e o2 sys!ema!5 !es!5n&,28 !/e !rue e7!en! o2 neuro!o75 .o!en!5a+s o2 5ndus!r5a+ /em5 a+s 5s un8no6n) Tab+e ; 5n +udes on+y !/ose subs!an es 2or 6/5 / ausa+ asso 5a!5ons 5n /umans are 8no6n and /a0e been .ub+5s/ed) T/e ./ys5o+o&y o2 bra5n de0e+o.men!;2-;% and e7.er5men!a+ e05den e;%,26,2: su&&es! !/a! de0e+o.men!a+ neuro!o75 5!y 5s +58e+y 2or a++ o2 !/em, e7 e.! .er/a.s 2or some o2 !/e om.ounds !/a! reFu5re me!abo+5 !rans2orma!5on !o be ome neuro!o75 , 6/ere 5mma!ure me!abo+5sm may .ro05de some de&ree o2 .ro!e !5on);$,;0: T/e 2e6 subs!an es 5den!525ed as .ro0en /uman de0e+o.men!a+ neuro!o75 an!s s/ou+d !/ere2ore be 05e6ed as a !5. o2 an 5 eber& !/a! ou+d be 0ery +ar&e (25&ure 2)) Lar&e-s a+e, .ros.e !50e e.5dem5o+o&5 a+ s!ud5es, su / as E=-based b5r!/ o/or!s;08 and !/e @a!5ona+ ?/5+drenOs S!udy .ro.osed 5n !/e =SA 65++ be es.e 5a++y 5n2orma!50e 5n re&ard !o ear+y !o75 an! e7.osures and @'');0$ 'a!a 2rom !/ese 5n0es!5&a!5ons, es.e 5a++y 6/en .oo+ed 5n!erna!5ona++y, 65++ /o.e2u++y .ro05de dose-res.onse re+a!5ons/5.s !/a! an &u5de 2u!ure d5sease .re0en!5on e22or!s) T/5s resear / mus! mo0e beyond re.ea!ed assessmen!s o2 8no6n neuro!o75 an!s !o e7am5ne ne6er /em5 a+s, 6/ose !o75 5!y 5s jus! be&5nn5n& !o be re o&n5sed) T/e subs!an es +5s!ed 5n Tab+e ;, es.e 5a++y !/ose mos! .re0a+en! 5n 2ood, dr5n85n& 6a!er, and !/e en05ronmen!, s/ou+d .ro05de a use2u+ s!ar!5n& .o5n!) 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

.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)
References ;) 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! S!udy: +ead e22e !s on .re&nan y ou! ome and ear+y /5+d/ood de0e+o.men!) @euro!o75 o+o&y ;$8:E 8: B$"-%0;) ;0) '5e!r5 / P@, Pra22! PM, Borns /e5n RL, <ammond 1B, Ber&er >, Su o. 1A, B5er M) Lo6+e0e+ 2e!a+ +ead e7.osure e22e ! on neurobe/a05ora+ de0e+o.men! 5n ear+y 5n2an y) 1ed5a!r5 s ;$8:E 80: :2;-B0)

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Table 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)
!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

'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

1/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

Silent pandemic Number of subjects affected

Neurotoxicant dose (inverted scale)

Subclinical effects in child populations

Neurotoxicity In adults

Poisoning incidents

Time of recognition

$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)

Chemical universe, N ~ 80,000

Experimental neurotoxicants, N > 1,000?

Known human neurotoxicants, N = 20

Known human !evelopmental neurotoxicants, 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)