the human assessment of bz

8/7/2019 The Human Assessment of BZ

http://slidepdf.com/reader/full/the-human-assessment-of-bz 1/110

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Pro ject Itluntcer:Titl-e of Project:

CRDL TECIIIIICAL lvfltltl'FJ; :DIAI 20-29

Ti{E I{Li}lAi'i ASSESSMfi!'I OF BZ

by

l4ajor James S. Ketchum

1R5)+3603D016- o2BZ Weapons Systems,Med"ical Aspects

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I,ABORATONIES

BRARYiAAMY CIIEMICAI CENTENMARYLA}ID

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Actg DirecLor of Nledica.I Rescarclt

Htrman fnvest:lgati ons Fa.ci.i,ltyilirecborate of lviedicaf Rcsea.rch

U. $. Arrqy Chen-ica.l Research and Development LaboratoriesFdgevood Arsenal, Maryland

Ii(, ]'r,[ii'l'y 0t'U. S. ARMY

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II.]r. HUMAJ.{ II"I,AR},IAC OIOGY

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Carcll o circuJ-atory tr\rnetr onGa stroin'ce stinal f,\.urcti r:n.

&letabolic !'unctions. .

Syctem.

Gtnitourinary.Skin .

Liver anrL 0bherCentral Nerwous

Gcneral"

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l,lotor Activity.Homeostatic SystemsI{igher Integrati.,'e f,'lrnc-bions.

III. ]TVAW.ATIOI{ OF I'CPI]R[I,M]A'AI, DATA

A. Dose-Ilesponse Rel.ationships . .

1. Tota-L Rcsponle Inclcx.2, Belative Dff'ectiveness b;,' Various Boutes. .

3. Estirntes of fneapaeitating and Lctat Doscs .);. Rcsponse lo Repcated. li:qrosure .

5. Tcqroral Response Characteristies . .

6. I'bclification of Response by Treatment

B. Studies ol' j'i,il-itary Perforr,:nce.

t. Indlli.clual Perf or"u:e.rrce.

2, Group Ps:fonnzr,nce

IV. MILfI'/lIff I\frlDfCAI CONSIDLAATIOI'IS

A. Hf'fectiveness and Saf'o1;y"

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Variatlons in Dosagc.Variatj.onc in Susceptiblllty.Factors Infl-ucncing l4ortal-ityl,Itlltar:r Fac'r;ors

B. Ih.nagement of Casualties.

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LITERATURE CITM

APPEI{DTXES

A: Design and- Methodologg

B. Chemlstry and, Slochernlstry af BZ

C. Flgures and. Tables

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Tltc aut,hor lrishcs to erprcss grai,eful acknor,rlcciglrent tc "t,hc

follorv-ing indi.riduals r+jro aicled materially in the conpletion of this

pnrject.!'or tecirnicat gu-iclance and atlninistrativc sr:ppor"t of the

studies rlescribed. in this rcpc-rrt,, Dr. tr'an 14" Sirn. As Chicf or. "Lire

Clinlcai ltcsearch Division, ancl" subsequ.ently as Deputlr ljirector ancl.Acting Director of the Dlrcctorate oi' Mcdical Researcli, Dr" Slrn gavelnvaluable ossistance in the clccign of crperiments, crpcrlitcd" tlrcacquisitibn of ncccssary portouncl ancl. equ-ipmcnt, a.ncl participatcdaciively in the role of lnvestlgator during nnny phases of tlie program.He rras also 1;he first s1;ai'f vol-unt,ecr to reccive a maximal ctosc ofBZ prclininary to its use lrlth. c:.ryerincirtal subjects.

l'()r vahlablc conl;r:,l"tat;:lon ancl gcneral nerljca] cupport,l,lajcr Claudc l,lcClurc, jr., Cl:jcf o1' thc llunran Tnvestiga'cic:ns Facil_i';y.Dr'. l"lcClLirc aiso prcpo.rr:d. a rc.rjcrr anr1 discussion oI'tlte chcinistryand biochemstry o! M,

"rnichappears irr thc appcndl-.( cf this report.

!'or thelr" coopcrative e{'for-Ls and asgisf,alc,: rr.th ';itcore1,ica}proi;J-cns lnvo-lving t,heir rt--speci;jvc rLisciplines: l}'. J" IIcnr"l' !Ji1ls,Chic1.' of Ph;rc,islogy iljvisir:it"; Dr.'. Bcrrrarrr P. l'lcl,iarmra, Chicf' ofToxicoJ-ogy D-vision; Ih:. Chnr'les Punte, Chief of' Aerosol Brancir of theTo:'jcologr rD.risionj 'Dt'.

Edr'rarcL R. stciirns, c'iiief of the psycirology

ald iJr-uilan Fac'Gors iftrginecring Brancir, and Dr. ilc.,,rarc ii, PotJ,cy, Chief'<"rf l[euro-]-of,]' Branclt of +"he ]}:pcrimenial l,{eclicine Div:isljon; Dr. John C.Atkinson, Cirief of tl3e Statistics Offj.cc of the Directoro.ic oI' l4ed-icri--'l-Ilc search.

For ti.ircct nccl-ical collaboration ancl assistance i.n theobscrwatlon ancl eval-uation of vol-untcers d.uring tcsts, Lt. William Gordon,USN (who scrvcd as a l.rrinciple j-nvcsti6;abor during the fj,::r;t fe.,.r nonths. I 'lr.': L ':':,:f a.:r)r r":r'ri.il. , Jl-rilut., l'l;".on.g, I,IC, Captain IIlr'l ,,,r'i i?i:l:;atetrskyr, l{C,Capt. Ri-charcl M. tr'cnce.l, MD, Capt. 0scar Blng, MD.

tr'or his highly ef"L'er:'t,ive ancl lndustrious contribul;ions tothe niethoclol.o3y of audio-visua1 ctocumcntu.liorr ancl presentatlon ofexPerimental data, Itir. Lloyd" I,lattc'::, cnginecr in chargc of the MeclicalTel-evislon Facility.

For thcir d.cpendable and conscientious perfor"nance in thcarea of perjJorrnance testing and assessment, sP-5 Alan Morror,i andSP-5 Ephrajm Gooclrnan. For :llraginativc and dillger:t assistance in thedevelopmcnt of unique 'best instrunents, and in organizing and. preparing

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ffiriu,W:"::--'-Feffect.i're presentat,ions of visua] ancl t,:r.i'r_rlar displays, Sp-) Kragg Kysor.

For ccnrncndable and resorirccful perfonr,:,rlrt,i of varied clulies essentialto the experimental prograrn, Mr. carl stearn, sp-4 ArnauJ,d. scafirli,and. Pfc Dcnnis Tamplin.

For thcir exemr:lary d-ed.ication an.l chcer-f'ul e]ificiency in the:)cconplishmen'b of a complicabed. ancl d,enancling assttrtnent of d-uties im-posed upon them ln the course of thesc investigations, ilre nurscsassigned to this Facility. Par.bicr"rfar gratitucle is expressed. tol,irs. Frances E. Peck, l4rs. rlunice !'ort, FLrs. June J. A. Brenneruzn, ancll"lrs. Jane King for the cor-ntless snall r,rays in r.rhich, thrcugh theiripitiative, tlr.e quatrty of volunteer care ancl ilre con4rleteness ofexperimental protocofs have been enhi:.nccci. A1 so creserving of' recognitionisthe d"evot,ecl serwice rcnd,crecl by tl're f'<t-L-lor.ring nurscs, wiro scrvecl forshorter pcriocls at this facl-l1t;,r; Mrs. Beniba l,{cbb, },lrs. lrir}e yates,

I'tlss Il,:1cn H,.rd sonr ancl Ivirs. Frances Casi_ll-as.

Finally, for jnd-ispensable assistance in thc preparaiir-rnof the rrnnuscrj-pt, I;1rs. Ir4rrrjon p. Royston, publ_ications l{rr'_ter oj'the Directorate of' l4cd"ica} llesearch, and r-or their man;; stcnograpirj.cservicesr"Miss Pat Ross, I{rs. nlsie lleucr, ancl Mrrs. Joanne Ileverati.

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., A Sta.'tus Summary

::, (c) GIIilitRA.T, TI\TTIIODUCTIOI,I.

/n\ nr1-\U/ Tl"i:L{i reporl, is a, pre}iminarir suitrna,r.y of inves1,1ga."L,ivr: r.rork,

cor:d.ucted vithjn thc llurrurn Invcsti.gatjons lracility, Direct,olaLe of' }.,Ierlica.l

-^ Researcir, into thc properl,les of 'biie si;anilar,!]. _i,e_cap,l:!ci,qq!j:r[_a.gent BZ." ri, presents gcneral :iinciings dcrlvcc ffim Foir""ri"tioir ofl-*6ffrffi-naT6ry. 300 hunan exposrrrcs cluringthc i;irree-Iear: pcrioci from August 1960 to

- ^/ ^July l!bl. '4. t'nerrc comprehensive rcport r^rj"ll- be subnrjtted a.-b il J,atcr datc.I'he pttrpose of' thls surnnrary j s to pro'ride gcncral jirforr-nai,i.on concc::rilngtlle r'rork compJ-e-i,ed. 1,o datc and-L,o iirar'r att,cn'i;ion'i,c ihosc irlicnoncna 1,ha-t

iLilpear to bc rr:asona.l:],)r r.relf uncLersboocl as wcll as to thosc l,lia-i, irttitca. 1,cr' a. necd for morc inicnsive inctruirjr :i n par{,-icul-a.r &r'ca.s.

. (C) Il'I a sense, i,hc investlgation of BZ i.n ]rumitns ha.s bec.n morc ofa iearch thr.n s. rcsea.rch opcra"tion. The I'irst str-rcljcs lrcre a.inccl ert

clefinrng cnly the broacics-b fea1,r-rr'::s of t,hc clrug's a.c-l,i-on, jncl,urllng thc,gcncral pha,r"macolog.y, 1,he efl]ecbjve cl.ose ranfJe, anc]- l;ire general tempora,-L

' rcsponse characi,er.i. stj-cs. tr'ii1;h thesc otrtaineci, closc-re sponse scrir:s b;reach of 'circ prirrcipl.c ::oul,es l.ret:e jnitjated. The ca.sc lj sl has bcencontj.nually e:,:nancled" until the presen't, both in bire inbererst-, of strcngthen-ing I,hc statist,jcal aclcqrracy of thc sampJ,es and, in some cass's, rep.lacirrg

carlier studi.es r"ri1,h l-,et'Ler ciocumented ancl more conlprehcnsi.ve ones.

(U) Specifl.c problens such as bhe cfiectivencss of rra.rj ous thera-pcutic measurcs, 'che nat,ure clf cumul.at:il'e arrcl tolerance pheltolnona.,factors rela-r,-ing lo the preclici;abjljty ot' jirirala.t,jon responses, ni-l,jtary'' perfornnnce assessment, etc., ha..rc been exa.mj.necl a.s requiremen'l,s fcr suchcstinnLcs arose. The rcsult of thls dj.versit). of inquiry has been'che

"equisibion of consic'ir-,1'l.l:Ie do.la, not all of r,rhich, unforL,'na1;cJ-y, i.s, t-,:'l"i.rl;,. Ii,:1:.r,r,r:,,' , ,l i I r' ''--,,;,al ].C COn'l,ent Of COmllle'L?ni-:t i,

(C) An a rcsult of -bhe jnvcstigal,jons nor,r complctecL, I'airly preclse

esl,lmatcs can be macle .l.n regar:d bo the I'olJ-or.rjng:

l. 'llhe gcncra1. na.r;urc of tsZ eff'ccLs upon var-iou,s systerntof psycholcg1ca,-1- and physiological {'rrnc1,ion.

2, ffa" ao""-response characl.erj sl,1cs of Lhe compouncl .

3" Thc tjmc: charar:teristics o1'thc rcaction, .incluclingonset timc, pcair timc, parLial ancl full rccovery 'bimes for ea.ch of four

' clegrees of response severil,;y.

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-qryLin11s,Ia!!-o-rr-q-o-U!-ql, m;T;F6"r"a r:1 ?"Eni tions of' thc t,ermrt an il ,.

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5. Tite eflcct of nultiplc daily e)q)osulres 1;o .Low cl-osesol'the agent, attd thc amount that may be tclcratccl urrrler l,hese cond-itionsr'ri'bhout cuniul.ative cffects

6. Tire effect oll a, second er.posure 2 to lr rreclis f'o-Llolrfngan lnitial- e:cposurc to the agent

(U) Ii':.1'onnatj-on of a lcsser orclc:r: of cclta.inty is al.so presenr,eclin the reporb,r,ritir respect to the I'ollolring: .

I. ltl'::-ects o{' the a.gent on se-l-ecl,cd aspect,s of n-i.li1-1ay

pcrfonnancc.

?. Est-imatcd I-,D valucs f'or i,he a.gen't a.nd {'ac-br:rsmi,ghl, br-. c,.rrpc-.c't,cd. to a-lter tffiF-ffinrates in var-i.ous situa'r,ionspopulations

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3. Thc status o{' the::apy and rccommcncrecl procccl.ures inthe rnanagorrient of' casualt:ies.

O lJif ccl-ivcncss of nrcscnt mrurj tions syl;'-enrs in aisscm-L- /nation ol i.l,c aSnt a"nd air cs'L-irnatc or'tlre 1CTr0, for fjclcL ust:.

(c) 'Ihrotighout the rcport i-nforma,t:ion clerivccl froin 'chc reporl,s of'ol.her lnvest,igators r,r-i'uhin the Dj.rectoral.e of l'lcci-lca-L Rcsearch is ci1;cclr.,rhcn it se€rms rcle.,'a.ni, to the experimerrtal- crata d-eveloped in connection.*.ith the human studies. l'{uch of the l,'ork dc,'scr:ibec1 hcrein iras beenf'a.clljtatcd" greatl:l, anri in s<;rnc ca.scs in:'t:i.ated, by thc rescarch activltyof members of'thc foxico.Logy Div:Lsion,the Physiol-ogy D-Lvision, and" iireii;'Ferirnenta.-r l{rrrir:irt;,: .1.; i.r'is,istr. Thc Psycho}ogy and llurnrr.r lrr,ctors Ilngineer-iug J3ranch cotrtriiruLer-1 sr-tirsi,a-n1,iaJ"Iy to bhe ear-ly Ccvelt.,iirrrcirb of tech-nj-ques for thc measurement of' behavloral- and cogni.ti,ve changes brr:ughtabout by IV' and o'Lher psychochernlca.ls, ancl a consiclerable portlon of'thedata prescn'tecl in"btris report lras gathercd ori5;inally'by mernbcrs of thattlranch. In sho::t, r,ihil-e the huma.n assessrrcnt of IIZ has been thc rr:spon-si'biUty of 't hc: ilutru:r,n Invcstl6lat,i ons Fa.ciJ.jty, .i.i, has be<:n accompl:i shecifrora the vcry ircginnj-ng of t,hc project ari a mu,l.l,.iclisciplinary cfl'ort,rcJ-y:Lng heavj.Iy on l,he support o1'worl',c-rs 1n rclatc<1 basic o,nd appiicd.dj scipline s r,r:ithj.n tlre U. S. Arly Chcinical- Rescarch and Devel.opmentLa,boratori es .

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(C) 'i'her:e are, hor'rever, rliiferencr-',, ,,rno43 thesc compouuds iir one\v/ , -_* '-;J

respect, poss-'Lbly an itrportan'L one. As in( pointecl out in 1',')2, L,he' various mcmbers of 'bhj.s dn;.g fa.mjl3' do nli, ha-rre coxtrnensura.tc l,o'ccncy.' 'l.rith respcct l,o cent.ral a:rC peripheral effec-ts, even r,,'hen dif'ferences in

cveral-l potency are a-l.1or,recl, for. 'Ihr.rsr.j]j"{gft:g_proluces_ si6lnjf'jcant.':LL,onorni.c-,c-l-ralgqp-yhga a.]ruipi sterccl jn ffl'fe sma.ll closagc, Jr-qt serl eyal"iln6s-it;?--arncru:rt,

Lj. s rcqui red to pi'o.J,uce sign:if i cant d.i stu-r'[ir]cei i n

---liiglqt cent,rnf neru()us systqrn f4rci,iq1r,. .,lcopolnniinc, on the other hanc1,

.*p:rcrd.uces nreasurable clecremenl, in perf'orru.encc :in a doee r,'hjcir causes

.. miniry,_o,-i- periphcra.l eff'ec'l,s a.rrcl has the acid-jtional, fralacloljca.l attribttteof lorrering the pul-se ra.tg, even lihen dtrsage su-ff'j cignl i,o causc d,elj rium:i. s usec1.

(C) T'or TAt threshoJ-rl cerit,::n.l a.nd peri-ptreral effec.l:s nrc a."ttaj-nerla.t, about1,}re sa.me d-osc leve}, indicat,ing a ratir-r of prcf'erential. actj.on

intenriediate trctrreerl il1,rop-i ne a.nd sc,:r1rcr1.a,mine. 0f cortrre, f.X-, i s ntuchmore potenl, l.han cj.t,her corrrpourcl, bu't er cl;nsjderat.ic.,n ol' r'c1a.t:i.ve poterrcy'in regaril tc pr:riphera.l-r. a.s d:i.s;1"irrc'b frotn cerrtral, a.ctiot-l ru-..y t-,e of rnorethan ncadcmic jnterest. I'b may, :f'or e;<a.mple, cnl,er jnt;o 1,he est,:i matj-onoil the -i,etha.l dc:se, nsr;u.rrini; lhat the si1;e of letha.J, irction can be -identj-fiecl for the cJn.ss of' conrpo',rncs generally.

B. (C ) Ca.rrli cc i rcu laio ly lrunc t i on .

(C) JgSb.;---qg,1d,.l:1-,i.q ccnsister,tly r>bcerrrerl r,rhen closes r.?-;ove L+ yt:lt,gare gjven

-ani1va.rieg oirect,ly r,'j t.h tlre dosc up to 5-B r.gfkg,. I):ses f lrov'€

i;h:i s do no'|, n.dd rn"ri,er-i a.1.ly'i,c.r the a.urpl,i tr-rde of the pc.:.k 1-re,,1 se rrbe, rl-l.hough the;r qr.r.i cken jt,s onse1, and. prol,ong iLs iiurabion. Ilearb ra't,es upto, br.lt rarely e;rcoecljr1g, l-5O l:eil'bs per ninul,e a,re often atta.,ined a.b thepeah (3-h hor-Lrs a,f i,r-.r adrui ni stral,j on). Aciciit j onal incrca.ses uny be pro-.ducecl by cxercise, butthese do no1, exeeecL l,he antjcipa.ted- increo.ses frome:cerci se alone. I'lo ser-icus abnor-ma,hti es hs,ve been seen in I.liG i,raci-ngsf'rom physical]-y herrll,hy sr-ibjeci,s during 'l"iri.s per1od of' ta,ch;rsaycli€r,l.! t,hough rrrinor 'L'-wa.'r.re rrJ--bera.t,ions and occasiona.l "e:ltra,syst,?il.es" are

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. -mo<leratplyr+d-ti1 1rcak 1-q.lues at 5-5 hours. Va,rues exceecl-lng t6O/ffOare u-nusu.a.l, even dr-rrjng severe reactions, PreoumaliJy thc l-rl,.oocl Dressureel.evation j-s large1 y a secol-rd-er.ry consequence of 't,tre jncreased card.ja.c iorr-bput, e,,ssocjnberl r,.,iLh ra,pi.d he:art, rate. I'hc mornenl,-'bo-moment and hour-tt>-ltour varj,at;ion in b-l clod 1rr<-.ssure ,l s cr.,,:rsjrlero.l.rlc .in a.n.y singlc subJect,even r,rhen tnea.surr-rl slrp.i ne and rest1.n51, n.ricl t;hc trenil :i.s o1't.cn c>bscLrred.

Lr,-rge grolip av.erages, ho'1,'ever, re.real tha"t it fo-llor,rs a trend. pa.ra1.le1.to the cllrlges in iruJ-se rs.1,e,

(C) .!e.a_nhera.1.rasorlj.latation, pr.oCucj.ng filush-ing of the f:rce a.rrcl

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,t?.qi.r.:;F sl'-in aieas, is a-core.*i-s.!--qnb -.ocqqqrel-rce. J1, is proba}.lly -t'/

clue 'Lo several l"rrtononricJaci;,r:;rui:#j.:-?:*:l_":Hllary tonr:, iucrease

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jn bl,ood prcssltl:e, a.ni1 reflex d;la. l,al,tot'r !rs a comlJensa.',,c,rry heal- lossmechan.' sm (act: 'ra'beci by t,he r. se in l,emp'. i r ';trre caused l-.)t iire inhibj bj on

of' sveating),

(c) AJ.l,hough "r'reaknessr" parl,ieularlyjn

the 1egs, is a f'requent,::rmplaint., -ac]u41 nrusjJgi;.l1reng!n i s o1l;.r minJmally clecreasec-l (as stromi;.y grip dyriffimetF.r-and-alli.ltf-to inmp and perforrn "clecp knr:e bencls"),and. these sub,jeci,ive feelings of r,reakness uay be a rcf-l ection of vas- \/

cular pooling in bhc extrenit.i es, t,oglether r*1th par"cjal cerebra} a:ro;rJ a

due to loveled cerebrovascu'l ar blood flow.

(C)-ELS.=-OJ.-ryspirati91_js-qEu-a,Ll;t]llcllqage4 s-l.ight1y dr.rr,ing the

jgl-lyj-dqd-9f-dsrg=-[c1d-o-!'. bg!, _Ugy_3q-cl-qeqq..Q:? .seclatio4, s.l,upor, or

!,eqq1 deve,lop, 'Ihe mcchani sm nray l:e one of' d"irect, exeil,al,ion, fol--l-or'red

by d.eprcssion, of medulJ-ary centers govern"ing breat.hitr6l . I1r1 nonary

ventilation is enl'ranced by the bronchorl.i latory act,ion oi' t,he contpound,but a su|,jec'1',i..'e f'eel.ing of chokin:j or stj.fling is sometirnes repori erl--possibly c}:e t,o tl'.e drying e.nd. i,hrcl<enjng of secre'uionsLln the upperi,,ract , combiner) lrj.t;h the intense dry-.ng an(l jrrita.l.r:i Ji.ty oI' rnlcor;.s rnem-

branes of' 'l,he rnouth and t,hroat 1,lo crii,J cal- respl,ra.tory ltroi:'1 ems ha.ve

treen encourrtererl, nor any of the compl:i ca1.,ions sucir as bact.erial pneumo-

njtis (somet:imes obserrred. jn aniTnel sbutJ j es. )

(c) An ele-"'a1,j,cln of' ,1 -Zorl in bod-y-i.empera.ture is iyp1 cal clu-rln1

the period of'penk, netr'on, w.l t,h gra.cha.l return t.o norrna:l. :i n phase r,ri'i;h

other physiologi-cal effeci;s. fn one exccpl,jona1 case, & rect,a..l. 'bem-

perat,ure of lOholr lras recorclecl at, t,hree hours (which r.ms treatecl success-rfull-y by d.irecl-, cool-ing, TILA, and eserine) T'lte eleval,jon i.t-r tem-perature is partiy a1,'Lrihr:table bo jrrpairrnen't of'perj,pheral hea.t lossmechanisms, r,ri.1,h li1,tle or no ab.iljty to d.,isoipai,e body hr:at, l,hrou.glt

evaporatj on o1' slreal , Possll,ly some dj recb h;,perLherrcdc jtr{'lt-ience j s

medjatecl thr:cugn tr1,,pol,?ralamic sysl,ems tha| govern the "thertnost.e.t"setting of.' the bocl;'.

( C ) -l,Z-:lthi.hifs.,-i1et-Ie!o-ry- act, vi t;i of' tlle g-l anclul ar eel.l, q.-c-o-11gern-qq1 -

vith d.igesEcn, resr.l rjng :'n thick, tenaci ous and scanl:.y sal j',a., clry:i ngof the mueou.s membra:res of the mou1,h. and tiiroat, and. ma::ked pharlnrlleald.-i scodorb. Sr,ra.l-i,:wing may be pa.inf'r.r1., ancl speecir may be recluced 'to avhisper. T'he 1,on15le ancl lips are coai;ed, and the brea'utt ha.s a charrrcLer-lsL,ic foul odor. App<:'bi t,e i.s reclqcerl a.nrl surbJect; s may refttse: al -l food.and fluicls for 2)t hr:Lrrs or more, or t,ake on1y sma1.]. a.inounls r.r.i 1,h urglngPeristalsls is subdrred, bu1, comple1,e absence of Lror,re} sounds i s unconrnon.

l[1lcl consi,j pat i on j. s .frequent r'l-ru.i, nornra l iiorre]. functi on t: sttal 'l.y' returns

by ttre second r:r thircl c1a.y. Fo1 l or.iing h,ixh rloses, nausea is f rerl.rrenl,

durlng the fj-rsl, i'elr lt.ours, and voui t,j,ng occurs in 2O-JOCi't ttl' subjecl,s,usualJy v1'l,hout l:ecu.rrence.

tl$inl il$,$ihtfi{b



CONffTFI$li,Atrid L L L L r- r/ il$ifrtfr$$$ftil

(C) Co]l,ecLj.rrn: of paro'Licl il'.rcl sl I i -r,r fl-orq frorn onc ,inc1lvlclu-aLrrlro recr:j-vecl 7.0 ytflr-S im shorrecl a JOf r :cbion rri.'bh.in lO ninuLcs aiid V'J5r4 rcclrrci.,icrn sll cne hour. Col-]-ectionrf l./i;r'c not, c,:n'i,1nuec1 ireyond th-istime because of thc subje.ci.'s incrcasing restlessncss and cliscornl'or'c.

D. (C) Gcn,ll,orrrj nar/.

(C) Ur.i::aiion may bc rliff icult or -i.zli;:iss-Ll:l-cf'or a pcr.iod uir i.o

16 hours i'o1,1-r.rr,ring c)cp()surc, pari;icul,arl;,' rrii,h highc:: Coscs. ttre tl.csjrct.o ur:ina-l,c rtay rcsr-il-t, in frequcnl, f.'ut.i--l-c i;rips to 1,L" latrj,nc. Ca'bhcl,er-

-iza-'cion has ncver bccn neccssary since flujcl intalic is usr:al .l.y rcstrictecion thc clay of cr';Ix)sllre rmcl bladclcr ?eLcnl;j.r:u tloco t'to'L ge:tera.J-l.y rca"circxireme l-evcl-ll . Tl,rc BUi{ (bloocl r,lr'ca nitrogcn) beforc ancl al'ter "i,hc

e:furerlmerr'i,al- pcrioil Fhc,r'rs no signlf ican1, cirangc.

E. (c) rllr.in.

Cr.r1;a.nc:ctr-rs flus)ring, j.ncrcascd lli i:'r tcrtpe ra-tulc, atrr,] .inh i f-'j. l,i"on

of s-,reatir'Ig arcr cha.ractcrisl,ic c-L:l.ni"ca"l- f'l:at,trrcr;. Thj s i I srtnr:t:i tnc:;

prcced cd b"' o pr.::::i.ocl of perlpirera-1, v.rsoc,xs.t ::1 r:iiou, "cc-'l-,..1 " t-::i''Jt'r'lttll.,i cs,anii subjec'r,ivc chll--l..Lncss, r.rhich sr,rl,,sj.t1e y-i'l-ltin s:..x hours.

F',. (c) L-i rrer atrcl Ol"hcr l'fctc.i:olt c FLrucliotrs.

(c) Al bhor-igh 1-,hcre i s soinc cr,'idcncr: l,hat 1:rc*cxj s'i,ing f.ivcr iJ-ana.5c

rnay cnhancc anil proJ.ong thc reslroncc i,o I3iL, nonnal sribjcci,s shorr rlo con-

sistent a.l"i;eral:i on in U.vcr chcm-isbri.cs'f'c,r1.-1.r'r,;.ri.ng ciiposurc. Gcnera].r.ct,abolj sm has not l;c:en stlLdiccL c:<tcns:Lvcl;', ancl il1,i;lc c3.t'l bc :;alclrega.r<i:lng cird-ocr-Lrte i'uric'L.ion. llciglri, -L,oss of 2-10 l:rounds tltit,y l-,e exltcci,cd.i n the course oi'rcacl,:'-ons lasting ncrc'cha.n.'otto days, rnooi;l,y duc tr:mi1-<1 clch;'ciraLioirr decrei:.sed- cal.orj c iirtake , s-nd inci'cascd ctter3:f consunp-tlon. Tirj.s is i;ronrlrtly regai.ned j'ollolrlng recovery.

1n\ Bl-ood urco. i-;li.:."tgen va.lucs mca.sr.trecl pre-t,esi; arc i.'lr,mcl. to bc

L ,r.']iL:rr.i;cc. .1 oi.i.Olri.rir l' /]' j i r]';-" 'irli-.ltl l.rru]sanninasc (SCtlT) '" "r'l.i lrcrcfoll-or.recl -i ri one jnclivirlual crqrosccl Lr:'(.0 prg/hg im. Motl-c;'aLc e l.cvationto a peak ot'60 un-i.l;s r,ra.s obscrveti orr thc secoi:rcl d.alr tri.'cir graclual rcturn

to nor:rna-l- rrj.-r,hln seven rlays. Tiris sugges];s the posslbilit1' ci' cellu-Ia.rinjuril, probably hepa'L,ic or ca.r(iia.c in orlgi:n. lio IX{G cira:'rgcs have beeu

f'ouncl folloi,.j.ng rccovely, suggest-i,ng llr.at signifi-cant ca.rC,io,c d.cmn,ge is;1,'ery unli1'.t-'1-y. Ilcfa-tic cell-ul-nr cfl.'ccl, r; rrr,'r.y bc-l,he cau.se of -i,irc trans-ani t'l{rse risc, cvr:n i.,Jtough, as nta, l,r:d a.bovc, al-l. oLher -l-irrr::l furlcti.rrns'cudies havc bccn r.ni t,hin nor-rurl- l.i.tit-i'bs.

tilrl;i"l's$i$



CONFITIffi"{:IAAI\ U T t L L D : - [;iifrg.A$$iffl

(C ) Crnl,rarl ilr:r.roui_.QLs-?i., '

t. (c) Ccneral-.

(C) Fol.loving ';he adnrjnis'rrlr1;:'-on of' an incapa.ciba-Ljng dosc of BZ

("r.g. 6-'7 Fg/l;t, irn), a- fairl;r t;,..pical sequcncc of evcr1is naj. bc c:bsorvccl..r''lr, onnet is nrr-r::c or -Less i ns.lcli,,ruc, rrith i,.lrc irlrlr; s;7mpl,onl br:cclr,lingnol,iccabLc a,u ai-.or.t.l, onr: hor.rr. T,a.r),,r, ccirl,ra]- ItcrvouI] l;ys,ucm natril'csLa- it-i.ons j-nc l.r-lcir-' ircight,cncci d.cc,p i;cnrlol rci'.L<--xes, atn::i.a, ccrcbcl.l,a.r. i.r-r-coorrj.ination, sl-tl"rr'-i-ttg cf spcech , dizzincss anrl hc,.ar-lachc. l{ausea,usual1.y trl'ciroui, vi-'nlit.ing, i.s frc:qr-rerr1;. liui: jectivc I,rcakt-rcc;s, vi'clir;ul,loss of s urcnSt?l, j, s iro'';eci prinrrri-l y in r,hc -]-cgs .

G.

a'

(C) Drri.ng'tirchcnsi.on arc nrarlicel .

spa$ns or' 'L,hc e;:Lrcrn-L

spcech atri-1. sc:r"1', l,cl'ccl,c i':nd.o of rc: s i -'1. c-' s si_r. c s: s

f-i,rs'c phrsc (l-ll hours), CiJJ;<Lr,cnc rcs-c,,.l c[ir]ncss occitrs1. j cs arrcl b-i ::c.l il.,c {'i appingt:Lcltcit"l,s ol coniul'ioLt rii:r-' trc

scotnf'orb and app.rc.-r'rLltli i nrro,L,rur i.,R.rli c l r)tri. c

oL' thc ol"lx.r;. I 'xti's cI'nOL,^cl . .A.t'l:r,T a Cf()J-(!-f a hor.',1is) 1;cgj ns.encl a'i;a:;i c., a i,c:c'): " r nl L:' c -

(c) Lhr-Lltg tnj-c secrrnrl ph"rsc, scdir-t.i on, sLupr:r a;rr.i cvcn r,rcnj c()liL:lc1.cvc1,op. Ti.c i-nciiv:i clr-ia-l s1-ccps ot- nppcars i,; slccir anci r:spcncls on,L ;ri,o d.j.rccL, anrl :cnrt-'i;: mcs orrJ-y 'cc flt.rrcci'ri,l , s1;inr.rlaL:'-ori. f:inont,s.ncous

'"roping or" crarrl.jt]8 Ttril,r al-tcrtrni,c rr-ith J.;rtng qu:lcbly. IIc nrr-rt, lerr; i1r-COhercni;f,',r .i-'ron l,inc t<.r tj tne. SOmci;incS hr: sjtOrrs "ol,rs'L,j-naLc pro;::csrj on"as irc rcJenti,c,'ssJy t,rics to craril jri a s1,r"aighi: l:'nc cvcr.r'r,r;.rs'r, .;nothrough a-l,j- ei- '',oc-1,cs . As birj. s prinri'l,i.vc behtl-.i.cr, rcr:lii:i rr;cn1; oi t,hcd.ccr,'r-tj.ca'f,<': "l:Lur-,-i ng" rclpon;e jn a,r'rj.rml s, :;ubsiilcs, 1;hc sr,ri:;j cci, cnl,crse lir.irrl- lilr.,:c (bcgiruring at 12 hor.rrs) cLr,rring rrirlch-Lht,: nor.c spccta,cularslmptoits C.c."-clop

(C) As sr:ccclt rc1;u"trts it is in c-r-iplcci-, llnl acccirLr;, c,;,i1,a,inir:ilr:tpid l:ul:t'cs r-',f' coi:rnon,r.y as$ocj-a.-l;cii. rriirris ntic.L pftraccs, pi t-

j.,:; sr,'r ri.-l--,r

'ultosc tl"lai; alr.: c<;.1-.l.tc,gui.aI and habj'L,rral . [,..,gi-ca] conLinui t;r -i.s .1.1.,:lli.lg:p.lld some scn.l,oirccg arc ircaning-i,ess or a.i,rsu.::'rl . I{al-l-rrcino.'u-i-o'rs l;ccm.t;r-.r

r:r'i ,.r.le l,rfC 'L.i r-r .i ., ' t-t,. :.,"...rliii: a1:, C fr:a,-L Ob,iCCtS anCi. nCf" . ri: gr:ncrn.1 J_;7

:i gnorccL or .lui-ij.crr.:u.tt.! ln-lsintcrplcrteci. Tou.cit secms 'l,o 1-rcconc t;hc mosl:i-tnpcrl,ant; $clts,:)-r:)f c)rsbcln, n.n.d the hcr,lrr.ls bt:comc cca.scfcss-Ly nctj.rrr:, c::-pl-or1ng 1.hc cl,o-t-.h-i.ng,

bc:clc1ing,',n.1.1.s, f'-1-or.,:', a.ncL crc.riccs ol.'r.,hc cn\rj.i".rn-ntr:nL. sni',1,"i.ng lr"rcl d::inhing <,,f phantom c,iga,r'r:'b,'l,cs an<l bevr:r.n.gr:r; i s vr-.rycomron.

(C) A.t 1;ltlJ,r:,l,.i ri.un 111L;sj ilclr, 1'rcc) itncl rjr-i.t'ilt prcv]or.r.l;.1 ;, iglorcrlor rcf't-tscii. m.y ilc.n,cccpl,ccl ,i n srna.-'l-. 1. a.nr;r_r,nl,i;r a1.Lhou6h atrlpr:t:i.1,c and flrirstare Icss l,han ur:u,a-l-. Thc subjccl, ircgirr.r 1,o responcL to shor'l-, i-nstrrrctionsa,rc1 may l:r: cIr-i 'r;o l,rnci;ab,--l e , l_rs'i; nL, 1;:inrcs i.:; ncgalj-y]Lstic a.nd rcf'us;cs; 1,o /coopcratc. f{' he fce.l s ann<,'ye,'d lrc may s'ur-l lic out at thc so'.rrcc oI' hisallnoyancc. A';1,en'1,ion ttrrer.ri is vcry shor'1; a;rr,l cb'.stract,ibjli-by js c(-)rrcs-pondingly jncrca;;cd. J)rariirrg and lianclr,rrlt,i.ng siror.r nrarkcc.i. cle'Leri.oratj-on.

bi.ii$$if,$frffi



cor{FfDEIg {trAti.'- 'adLlru -** t]l;iltfi$$!f,rEil

-----Fi'lhi-l c -incapal-'l c of sus;i,ciinc'J in1,ellcc'Ltir, : r:f i'orL, hc na;r pcrs.i sl, j n an

activi t-r' ir-r. spi Lc: of' failurc, easc] cssl. , r'7.ing a'i, c-tircl:s 1n LLic r,ill,l r

. ilor e;,:aJqt]-e, il'i an c:irlea.rrr-rr';o cscapc f'r'. l:i a:t cncl-oscd- B.ltL-a. S<,rmc-bi-tltcs

1;'\ hc ilaJr s'r"""ccL in convclling some rri.sh, such as a. clesirc 'Lir r-tsc thc Lat,rinc,l- rmd lhcn bc'Loo co;rl-uscr-r to excc,"rtc his i,nLcn'cl'-on. .A1, c,,1;irc:: i.,rncs hc

' rrray ro&c" vj-oJ.cnll;' to irnag.lned evcn1,s and cngagc in pc.tttotid-mc cotnbc.t l.rith,jltrnLon asse.il.a.ni,s or i,n li,rdlcroi.:.s p1 ay rri Lir inrLgjnary cor;lpari-tons.

(c) As rr:crlvclTr prcccccls, t,hc s,,Lb.l cci, bc91ns 't,o c:;nvcrsc-' -Ln a'nore rationa. l- zurd- coherent f'ash1 on, bui h:i s grasl: oj'thc sj-l,ua.Lirttr j.s

si,jl.l :i rirpaircr-l , anc.r ]re often maLicr; IJa.ranoicl ndsini,cr-prcLaLious. Ilc tna.y

jiecl, fcrr c::a.npl,c, 1,hal, sorirL:one isr out to i'"ill h:l n or tltnt his food ispoisoncc.l . ilc uay rrcndcr r,rh;r hc is r-rnclcr su"ch c-l.ose sc::uLin;.r anci rrhl'he i,s bcj-ng g.ivcu so rilrch assj starrcc. Sonc subjccl,s lnl',c rcsetrtful rclrarlisabout "bc:'-ng trcaterJ lille a. fit';J,c lijd. " I

,. (c) ht]r-i,.l.c rccovcrirrg, the W, into;,:ica.t,r:ci sub,icct ';cn'Lr to Ccn/that lrc is i,ntairccl a.nd trics to maLie cl:cllrics fcr errols or f'i:":l-l.L1rcs

during test.i,ng or q.ues1,i-onin1i. The ca,sua-l- e;:andncr nal/ be {'rolccl- i.::t',o'l;hJ-nking 1;hat -l-j-ttl-e or no impa-irrncnt, is prcscnt,. Dr,rJ"irg 1,h1.s per"i oci,

the ovcra.l.l <lc'r:tcanor ancl n'ianncr c1.' act:lng il frcqucn|ly rcninisccn't, oI'thc naturally occurring schizophrcnj.c psychoscs.

(C) If the::ea.ction l-asts nrore i,tie,ri e. d.a.y, a period cl CLcc'p ei.r:epg;cncra1.ly prcced,cs iu-l-l- rt:covery. Rc'cllrit o1' a.ppciii,c, iri',,crcst -Ln

recrcation, a.nrl- a norrua,l displa.y oi' r:ntliulj-asm and spr:ntant:i.tJ'' j-n con-

versa.ti-on a.rc rcliablc inilical,iorrs t,hir1,1;irc

rlcl,iriurn is ovr.:r.

P. (c)

(c) lJv-i.d.encc fcr actua,l sene,cry ,Loss :is rat,Lrcr l.na.r1cqira,Lc, sj.nccnrost casr: rcccrrls su-ffcr f'rcrn a. La.ch of systcmat,ic neuro-l-cg:Lca.l tesl,J.ng,snd in those instances rrhen a.ssessmenb ol,' Gcneral sensory f'unctj-r:ns

'.'as atien4rtecl, on-Ly rc;1r,lh clinice,L methocls r.rcre employcr.l . lionethcl-csl,'.ii':;l:lr rt.nte rpr;l','t i' r,rlr llr:: t' d'--'ll1'11n.d^;l SCnS..-[ j vj 1.7 tO Sti.m'l' -" .i r.rt Cllif-i.ng

the carly i;hase of'1,he reaction, a:rcl suirjects ofteln rcl:or'L numbnessthronghout 1,Ire body"

(c) tr,tren .l-nca.llacl.tating rloses arc givct-r, sc)iTle loss of' scnscryacuity appcars bo clr:vcl,op 1n all mocial.i-1,1,es, togct,hcr vr:i-1,h inc::c-a.singclouding of conscj (-\Llsness, iLizzinecs, clumsincss, and rcsi,l-ciilncss. Thepeak of this; ocnso::y j,mpalr-mcrtt is 6encra.lly rca.ched ltithin si>l hoursand subsldcs lrlthin 16-24 irours.

(C) A cha,r'act,cristj c compla,1n1 j s i nrb il.-i.l,y tc-r tcl.l- r.rhcn eb jccts , ,

have bcen touchcd or 6rasped. vitlrr:ut J-ooirjng 1;o sec. FuLllc a,ttcmpl,s to V

flcnsor,," Iu:rc'ti.on

f



'o. :::tlupick up small- ar.bicl:s, real- or

j;;.i;;i;;:;;:;;#_-d,, . +n r'i ii * F!.ns1, {

: $l [$E L!,[p^ ::-:. f i'ii;,i '{i!$fFHfrffi::.-CONF.IDENTIAL- -.

rl[[

I --

feedi:ack of light 1;oLicit and pressure tii.; facj-litates 1,he spatial 1':rcali-zation and gripping of srnall i'l,ems vitir tire fingcr tips.

(c) D:finite loss of acuity for near vision has been demoustratecl-1.'oll"owj-ng dosr--s sufficierrt, to procluce moclerate or sevcre rr3$ponscs.'i'ilis, howevcr, $ecuis 'Lo be main-ly du,e "bo "bhe paralysls of itccr,urriioilaLjonthat results frlrn tire action of the agent on rnuscle f:'.bers control-ljngthe convexity of' the lens. Mcasurement of abso-Lu-te vjsual tirrcshold hasnot bcen perfr:rmed, bul, color vis:ion discrinrinatjon has been l,est,e,l, anclshows no consistent alteration i,hat cannol, be attr:lbuterL-Lo general con-f usion and cog;nitive distur'bances. Auditory acuity has recenl,.1 .y beenmeasured. a,t scvera-L dose levels arrct, although some ques{,:'-ons concern-ingthe re-LiabiliLy of thc apparatus ha.ve no1, bccn sc-tLlcd-, prcl1ruirrary find-ings indicatc an elevation in audiLory threshol-d. throughout the ra.nge of

ar-icliblc f'recu"encres follorring irn d.oscs o1"f FC/ki;. This mal' a.mounL,co

as much a.s LIO-)O decibels loss ar. 3-! holr.rsr'follor,reo1 by coq:ir,:te loss ofthe capacity to cor:perate in any test prrrccriurc. rmprovement in acuityseema to progress in s1,ep r,iiLh thc retlrrn of'general lnfell-ecLual ef'-ficlency" Lcsser effecls have been seen in su'o,jcci;s yeceivirrg I VBlkg.No simofe exarlana.tion is avaitable for hcaring loss of'a sensory t;,pe,unless, as sorne ncr.rrophysiologists have $uggesl,eci, acet,ylcho-line isessen-Lial 1;o.1,he propagation of sensory a,s lre-l-l as ei'ferent, 1nforna1,jon.

(C) One rntriJuing fincling is the f'requent report by subjecl.s,both during anc- aft,er recovcry f'rom the ilrug e;cperienee, o-i'an illusion

of red coloral,ion of'the sk:',n, botir iheir o1ff] and |hat ol''^rr.cLruggedpersonnel uho a.rr: r,/ith tirem. One ort vo ind.ivicluals ha.rre thor-rght "i:heirhands lrere blceding',ihen r.raslring them uncler the'uap. l.ihct-,her1,his is anoptlcal phenomenon relatec in sonc r.'air to engorgernent of rct:inal- bloocjvessels or is centr'a-l in origin is not knor,ni.

3. (C) l,Jotor Act, uitll.

(Cl) ;\ vii; ill.;," 'r.1. ,,'l i,,:r.rr,i,i,rtrr: j.n mo1,or f'unc-t -Lon jir li t:,. r, .i,:nons.t,ratr.,c1in individua,l.s receiving high d-r:ses cf'BZ. orre of the first is a sub-Jectlve f ecli ng of heavj-ness, wea)rness, and unstearliness involv] ng

pri.ncipally tire lower extrenitlcs, appearing 1-2 hours fol-Lo1ripg an EDIOdose. Thls may be fol l.owed by feelings o1't-ightness of the muscles anclan uncomfortable se-'nsation of wanling'bo move about and- "get rid of ilretension." A perlocl r>f squirn'ing ancl thrashlng about ln a tonnent o1'rcstl.essness sometincs culrui,natcs t,his sequence, after r^'hjch the subjec'ufinally becomes quieter and. lapse s into a. stupor^ous or scrnj.-cema.tosestate. The clecp tenrJ.on ref"lexes c).uring this phase are progressivel.yincreasing in the ror,ier ext::ernibies, rnrith littte change in the uppcr.

/'

t/



ut{fiLh$$iFlEB

Superficial abclotlinal ref.l-cxe s ar rcr ronus may bs' , ^r nnr, ^ 1,i -+..,l'al lebi:ts]i.iI - ulvlrar, rrf r-u w\observecl. at l+-5 ]rours, a.cconpani

s-i"gns, an(i ot,hcr palho-Logical rcsponscsand cven snou-r rcf'lexes.

.,., cil as oosr-tive Hoi'i'm,enn, €irs.sp

(c) Definite -inpairrnent in cr:orclinarion, rapid a-l-l,crnaiing novcments,':r,r,rLging of distances, valking, articu-lai,ion oj.' speccit, lrrit.i.ng, anddravin3 are additional signs of a dif'fusc ef'fcrent cysteni r;-isturbeince,whlch s.ppears to invclvc all- lcvcls of rreurornuscula:' in"i,cgr::tion. A';axia,past-pointin5;, d.ysme:tria, and pos:Ltive Ronibcrg' e sign inciicate j.nvclvenent

of cerebellar mechanisins.

(c) Cons,iderable resolution of 'r,hese signs o1.' molor ciysiuucbion j-s

usually eviirent by 15-flr hours, aj-thor.igh a tencLcnc)'i,o stumol-c ancl iro.v<:

diff icully Luttorring ctottring, r,rrit,ing lcgibly, ancl cxccui,inl; no;cncntsin a smooth, grace{'ul fashion cf'1;err persrsts lor anc,l,hcr 24-.1+8 irouls.

'' (c) Apart from these "clrbernctic" cl,lfficult,jes jn thr: exccution c{'tnovcmeni,s, there a.re rlis'Linct al-ceratj.ons in.t,hc gcrr^r:r-1 1er,'el, .,-,f act,:'-v-ity,r.rhlch can bc rougir-Ly dci-n:Lrca,tr:d int,u 1;l:rrce phascs. Tiri,'Jlirs'L is tlie onsc-tperj-c-rci , chz:.racbci".zt:r.f by rcsi;lessncss ancl corqt,laiir''c o,[' scvcrc nruscit]-c:'cliscoml'art. This phase encls gra.dui:.lly at \-3 hours ancl is succeedecl bya periccl ol generalized d.epression of a.L-L activity accompanj.ccl'oy s';upor,lleep sleep or coma, vitir r,r-lniina.I resporrse tr: thc envrl ronnlcit'b for a. periodof 2-L hours. llne thiriL phasc, r,rli-ich bcgins at 8-ta hours, is again oucof excitatlon and hyperactivit.,', starting vlL,h gr,:pi.ng and- prini'Livescarching movements of 'Lhe iraitds, prol;ressing to crarrling or st,a"ggerj.ng

in a persj steni, inellfeclivc manncr, and f ina1.ly rce.ching a pealt at 2ll-\8hours of const,a.nl ciisoi'ganized sea::ching, warrderi.ng, rnn"nipulaLj ng, rectiveactivii,y accompa:ried by inccssant ta.lking, -lauglring, occesional shoutingor r:ursj-r:I!, and }:ricf disp-lays ol' irrita.bility, cometimes lnterspersedwj-th an-iable or even a.iiiorous bchavior 'colrard nurses, j-echnj-cj"&nsr anad,jaceni; volunteei: srib;j ect, the physicia,n, a pillow, a TV ira.ssock, or i,hcwater cool-er. A f'ew subjccts have con{,j.i-ruecl t}ris cea.scJ-ess, dlsccnnr:cied,i.rf't,en ludlcrorr,"1 heh,r.., ii:r:' f,eir as J-ong as lrB-60 hours, rci'u.;'i.;'q to slecpa,ird t.t-r:c-Lr]I.r.r1g n't.,.)rc uira,r ,,i..,.iicrL &lnoun't $ Of' nouri glrtrte n;. rrii-it r:tharr-tstionsupe.r'ven()s, it is prece,lcrl by a trra,dual re1,arda'uion wlbh brlef , grai,uall-y

lengthening pcriods ofquietr-rcle

bebr,reen shorber and shorter bursts ofsuclden activity, rabher like e. rrincl-up nechanj.cal toy twitching convulsivelyas i[ comes 1,o a stop.

(C) ThJ s inii,ial, slcep i.s of''Len I'j,i,{'ul an'l- -i.n',,crmp1;cr1 , but al'tcrone or tlro alrairenings during wlr.,l-ch foocl. nay be takcn arrd, e>:cretory nt:r:dsattended t,o, a J-ongcr period of'ver;y Ceep slcc:p general-l). occu,rs foflor+edby rnrkecl improvcment leading to f'ull recovcry over the succecdlng da:lor tr.lo.

ry"fn?ffiltHfi'+f'n.n: l.

. -':

r rglgltw



.. '---_-f,l T't rt !coNFmffi'llmtEF.|-*#1

a'

[Jfrif;fl"4$$8rflflts

(c) Wibh sr,.tall cioses oI'M, exclta ,;rn is somei,irres noi; scen ata-l-I, or is ve::y rdl-d and transienL. fn;) ,,'-lcl, sedation 1s'i,hc precloruinanleffect, and. j L is not unconrnicn for subjccLs receivlng closcs bc1,wcen lland ! VS/1te in, a't, l00O to sleep througir the af't,crnoon, mos'r, of the evcn:i,nt,

e.nd then througir the nighl,, rccoverj-ng nor-mal alertncss by the following'i:lrni,ng. 'Ihj,s is not a'tltribu-i,abte simply to borcclon, since at very 1ow

'loses ancl with other t.ypes of agcnts, clay'c:'-ure sleeping is ei1 her al:sentor lindted to a cirort nap.

l. (c) Il<;meosta Li c []ysi;r:rnc .

(c) As nentioncd in previous sections, basic regu.lal,ory fr.rncl;ionsof the body are profoundly altcred by effect,ive closes ot'BZ. Tiresc acti-vitj.es have Lceu neuroph;gsi-ologically :i dentrfj.ed wlbh the reglr:n oll thcbraj.n in and around the hypotha-lamus, the scgrnent,al p<trtjon o{'the nrld*

l:rain, thc hippocaropus, a.nt1 other nearby struc'i,urcs sometimes co]-lect,ivcJ-y.referreC tc zs the linrbic system. The obscrveri, in1'1uencc of the aga.rlon su-ch I'uncbiors as body temperal,urc, appctitc, sJ-er-:p, heart rate, jlfood,pressu"re, gencral- actiitj.tyr cno'i;ional- ltchavior', ancl pr.,ssj-irJ-y t-.v..:n suchclusirtc construcl,s asj "motivatlon" ancl "attenLlon spiin" suggesl;s stronglythat llZ has an affinity for recep.i-or sites in this region oI' ttr"e brain.Thi s hlpothesj.s fits vell r,rith lhe theoretica,l work of j{css3 i,ovarcl liredemonstration of a "central paras;yrnpathct,ic" or "t,rophoLrop:Lc" system,f'urtctional-}y ancr ana.torn-l cal}y cent,erccL in this regior-t. Othcr mctre reccntItork on the netrrttanatomica.l. ancl neurophysiotogical corrcl-ates c;f' learrLingsuggcsj';s that, lrh.lle information proccss:ing arrd- assocjaLlve ncmory nay

be primarily gove::ned by the neocortex, neeessary fa.ci]itat,ion is af'f'ortletllly varlouLs rcticul-ar netvorks. tr'/hcn clisruption of these occursj, norrnalcerebration ancl adaptive beha.rior is bailly hind.ered.

5. (C ) Iiigher Ioteigrat j,vc Fu-nctions.

a. (c) Sensoriu-rn.

tu) one oi' Llre riir;r;" sc-nsir:i-ve ind.ices of drug et'foc1, is Lne subject'srccognitj-on of'and abillty i;o report h-is l-ocation in respect to timr:.Inpai-rmcnt of'this alrra.reness can bc clemonstratecl aftcr emergcncc fron, ancl

occasiotrally just prior to entering, l,hc s'buporous or seconcl phase of thereacLlr;n. Because onets l.ocus in tirnc changes coLrtinr-rally, this climensionof orientation can bc bcstecl repea'l,cc1l_y.

(C) Frcquclnt-l-y, Llmc ":tandn lt,:i. ll." Jlr'lr't,he incapacl'-tated upb,JccLfrom somct1rlc t>tr t,he I'i::st rlny unt-.:il ncarly cornpleLe rccovery 2 or J <Jayclater. At thai, tlme hc rnay thi nI< 1t is st,ilJ- the clay on which he receive<lthe drug, somctimes in the face of extcrnal eviclence to the conbrary.

u,- -,-- -,,-



sp** r:-a:*'::::=';'*tttst* "-

-.. .,.-'*""+

CONFffiESJ-I J[N[.U i i. t- i.- i r *"*'dG ' !'!r*s*jfi,rl#* -'!#'-:'c.-r'r=

-=_-:----------

.-

ffi$$f,,{$$imffrffi

[}ffi$tfr$$ErlE$

For: exanple, onc pa.lt corraenbcd on 'bhc 'r.nir,l itay o{' 1,he test: "Yoti }'.nov,

jf f c1i<lp't i.:nor.r it rra.s Friclay, I'cl sr.rc:r,i' it lras Sr-rnclay" (wirich it, ',res)'I,,tren ashcd to c:p1ain, he conmcnted-thai Lhe Post 1,rarl ncarly d-cserlccL,

"h.ke it voulcl be on Sund-a.y." Drr:'ng the first &i'Id sccsnd da.y, csti'ni;.tes

of timc arc often riere guesses and nr.ay cliffer by serrcra.l hours fr';nan

r,:tinaie rnr,d.e llinutes previouslr.. I'Ihcu a.shcd r,rha+. lirnc it, is, tltc sub.icct

nra,y ucirtion a.n horir; trut lrhen askcrl- lrhether it is A.l'1 . or P.Ni., hc secms

unable to copc rrith bhe quest-ion. Even after looliing out t-,he wiird-oir and

seeing blrat it is dark, he cannot choose betwecn <1ay ancl nigh'i;, and ma.y glve

an evasivc snslrer, or an incorrcct onc, like "f'c's rnorning." fnis renrark-

abie disturbance.persis'b.s up to lB hours ln some ca$es and includ.cs the

inability to tell iirne from a clock or ruaich.

(c) Disorj,entat,ion for gcographical Iocal,ion is lj.her'rir-]e clcmon-

strable, i:r-rt nay cscape noticc on ca.sual testittg, siucc mosb subjccts

hnov the nam.-. r:f the post, the rn'o.rtlr and thc adjacent tor'rts. Qaestionsthat rr:qrrire 1,he clectuctj-on of a. nert rel.alicnship fron prev:iorrsly kno-'uir

fa,cts are poor,Ly ha.nt]J-efl; for e:<a,ttqrle, "llow far 1s ycu.r hcme- tor'm frctn

here?"r of "l^Ihal la.rge c-ity i-s to the r.rcst of'E<lgevood-?" At other timcs,

spontaneous comrents inclico,te that thc subject belie','cs himself' to be

bach at hi.s o::i-ginaL. Ltnitr i.n thc compally clayroom, across the stlcetfron lhe NCO cr.ubr etc., even though he has just sl,atecl his correctlocatjron a. feT," seconds previously.

(c) Tn regard. -bo pcrsr:ris it.t his vicinity, recognrtion may be ac-

curate for 1nri.:l-vidual-s iihom hc has mct prior to't est:-trg, such as the

cloctor; but ol,her peopJ.c may bc crroneously greeted as olcl friencls fronrhis r:utfj.t, ctr cven rel-at,j.ves. Al, tirncs, olljects i,;j'ch a. vert-ica1 shapc

may be reacted bo a.s if thcy lrere pcop.lc; one sul-,jeci'criecl-..to provoke a

fiBht r+ith a target gun mounLl another said", "Excuse me, Sir" to thc va,tcrfounta,in r,rhen he accj.dentalty brusherl againsb it. fn more extreme statesof conf'usion, con\.ersa'r,ions are helcl vith hallucina.ted -Lndivid"uals. These

conversa.ti.ons e.re conclucted- 1n suclr a naturaL unstud,ied flLanner that thereI r nD question cf a.c: I :i ' r:'.

b. (C) Pcrc,rpl,ion and Inter?retatjon.

(C) As inrl-icateci jn the abr-rvc rcmarks on the sensorium, the vorlcl1s percervr:d. lnclis't inctty dur-i.ng thc ci.el-irium, an<l ccnsory input 1s subjectto bizarre nisconstructjons. Some of tirls may be attri.buLed, to actualblurrjng of vision, mahing d"etajls of'objects ancl subtle n:rrrkJ.rrgs harcl

to cli scern. Sone rnr:s1, bc a{,tribu.ted. to a kind, of extrerne "a.bscnt-mindcd.-

nes6rr resril-ting in the accepta.ncc of apparenL events unerj fical-l-y and t^ri'blt

total- d-isregar"<i. for -bheir incongru--i t;r. This blitire rlis::ega::d fr:r the totalconte>:t of a visual or auclitory cvent causes subiec'bs to state t'ribhoulfear of clisbelief that "there's a possum on the table" or "a big blacksnake urd-er the becl-.



Colfu-&ruq,'Lil,k tlH,f;L&$$ttl'nnl

:==--(c ) occasronall;r rriggtous act j on r'. I r. be takcn to d-cal with th:lepcrccit crl entergencics. Sub jecl,s r,lj f .] s:, i r fr:ant j cally for med.ical- a ssi t-tancr:'bo treat an illus1onary 1,rorir3.n:.rhc i:,:-s just becn nln overbJr a car,or shout up at the alr-conCitioning vent for solnecnc to "ih:'or,r-ilor,rn e

shotgun ancl scme shcl.l-s" so he ca"n lrotcct hlrnscl-f frcn thc mrb he lnaginesi:lming ';ot"ard. his roon. One srrbject scranble<J. halfrray over a scvcn-*'oo'i,-L:rgir parl,ition, f'leeing from "a grr',r rri,ttr e g1i-n" ,?.ncf r,'a.s ce.ugi1t b;'thcheels by the nurse jrrst belir:rr: van-Lshing hcad firsi, clol,n the cthcr si'1"c.

(c) Organized, comple:l pa.iror:eimic h.al].ucinatj-ons are rncst coTmrlor-I

bettrceu 2lr-18 hou.rs afte:: e)iposure to d.oses a.iio-rc the !-iD)O. Thcse ul:r.;-

be benlgn, or (;'vcn crtterr.a:nirr13 (onq sul'ljcct clescriberl trit,h grcat entlrusi-asrn a lirliputi an ba.sebalJ. garnc bcing pla.yed_ on 'rhe l'_Loor in t'ron.L ofhrm); but, -l-ater, parLicul.arly c1rLrlnlr ihc nigh,l,, they nr.ay bc.61:'LganLjc antlterrlflring. fl1,-ll-l- l-a-t,cr,. i"n placc of cl.cuhants ancl giarrt snaile$, lrc iees

ra.ts, squirrcls, or spidcrs, ancl. graciually tJresc clin:-inlsh 1;o i:ecoine br.:-gsor ants, t.'irich he -labors 1;o brush I'ron hj.s cloLhing a.r.rL bcrirj.-i-ng" Final-iy,thcy iLisappear or arc corrcctly rcrccivecl as piece s of' l-int, clusi;, ic,oselhrca.ds, ra.i scrL marl.,ings on t,hc: f loor, na,rl hca.cls, r:ainb d_rippj ngs, arwhatcver i'c is 't,hat lool<ecl a.nir:a'be a few lrrturs bcforr:"

(c) 0ne of thc t,l"rirrgs that sL-erts bo conl;::ji:ui;c "i:o the persistcnccof 'bhe'se alinra.'ced, :llltisions "i s t;hq: rr-Ls;ual- lnrprcssi-on of sudclcn ra.picl movc-ment of sma,ll a.mp1-.ltuc1e, r,rhich sr-rbjccts repc.rt rrhife ins';ectj.ng tire si;otsa.nr1 spcclts thc;' perccivr: a.l irugs ancl a.ni;s. rt j- s ql'be pcrsiirlc t,hr ;smal..l ri;rs-i;s161",1 d. tilov*Ilents 61' thc e)r<-,r; thcnse]ves, anal-ogitus to thc f16e

i!r-'neral j zccl 'hrernor scen dr-rrini,; 'L,hc rccovcri" pl'l,sc in mos I- suhJcct s, givcri.se to thc bcli ef that thc: e;no,us or spccl',s are r,rzrlti.rrg su"d.clcn darting orfJrtting r',rovements and-.t,hcrefore mrrst bc j-nsccts of somc scr::t. I,,4rcnaskecl 1,o clescrjlte the a.ppa.ren't, rnovemcnt i.n grca.'ier cleLai [, one subjcc{,reportc<j that the spcck u:rder scnrLjny molcil cvcr,)/ so of'Lcn anrl thenrctu.rned to j.-bs origi.nal posllion. The est,imatccl excursjon w&$ only arrelghth or a sjxtccntlr r>f an j_rrch.

ill ,i 'i'lirrs -1 i.. iii,L,ri,.: l/',t.i. 1.,_r ..1;g.,lLrd, the clis-b,crr.[,j.on,., ,...:_ i.,,.-..r:;p-L,ion a.:rJmlsinterpretnl,ion a,s arj.sing f rc-rm arr j.nter:ac.tL'.on c_rf nrany ca,uscs, begin-ning liith a f'arrl,ty sensory appo-r'atLrs, a.nct ccmpouncl-ec-l by r:rro::s ln cva-l-u-

a1,ion. thc subject js r.rnablc to lrevent lna.ppropriatc stray tiroughtsfrom distorting the pcrceptua,l j-nl.u1 tc> rnakc it congrnoul; r,zith preva_il-ing states of fear, angcr, or other strong r,:motional forccs. The rcsultinge>'pe::iences might r^rel-J. be conparccl to the events d,uring slecp that arecafl-ed d"rcirrns, and they are in i'act of'ten remembercci La.ter as such,lrithout recalling the bchavioi: '1l'rat a.ccor:q:an-ied. then. Sl;mehcir 'che facul-ties of rcality testing are a1-'roga1,e<j- riuring tire del-j rirrm 1n a na:rne,.rslrni-1-ar to 'cne prelcgica.] assocj.ative thjnliing Lhat occrrrs cluring normald-reaning; yet t,he r:oto:: equipncnt ths.t i s nor.nal-.ly inhibitecl l'rom "actingout" cluring rlrcams has frec rei.6n to enact the irurer e>pcri,ence.

= ffipNFrQENTrr&: tj't' tl. llifi ;FIIffi@*lF.{*#t9_**=*=.."--':+3."_



-*:-

CONFIDEN ;-IAL'i"l r \ .,. ,.

',, iiit*l,: " L'll.i, iu'jltr eL

(C) Attentlr-,rr and- ,

(c) .*!C.ru-I!1L.ijp,qn.qholqs carly j-rilur.j-rmeinl bhat lasts r-int-Ll.

.J9"y-!rv-,i.1. vc.Ll cr-n il,s r'1ay, pc:rhaps rc-i;urning to norrna.-l iry tirc thi

l4anif'es'l,atiorrs thougtrt to r<:f lcc+; impalrccl a.'ctentiverleijs .'Lncl-urle:ina.bility to sirstaj-it a conversa.i,j-on rritirout va.ncier"jnq fron the subjec-l, I-i nabiiity to sustal-n ln-bei:cst jn a_ booh, ner,/staner, I'V, olr.1,nlr Same re-qujrj"ng atbenbivcness: fajLurc to rcsponci to rluestions un1,j,-l :rrldressr:clb)' nanrc (r.riricit nny 'lrrod,uce a ste,r'tlc rcsp,,r""); :rrrd inai:i.Llty to ru:inta.j-nvigilance in si'r,ur.rtions d,esiSTreci to tcsl this furrction.

(C)-rr'{en:o-11'--!or reuol,c cvcnLs is bcLtcr prescrverd. than I'or rccc:i1i,

-o:93Jle-re-!fr-q!-}-lfotltc!: organic b::ain s;rndroncs. O.ucstions conccrn-Lng

the pcriod cJl clelirJ urn clicit conlabrr-Latccl a.nswc]'s f'ron sr-rbjccts r,iho o.r<--only pa.r"bially rccove::ecl; only irhen ncar {'ull- recovtry vi-lJ lhc. sub,jcct

adn-i i; arrutesia rr:i.Lhout enibg.rrassmr:rrt or abtcutpis to hj.cle hi r faurt,y rcco].-leci,jon r'rith cr;cilt,,:s or prcvarj,ca.tjon" At i:he height lf clr:li.,':iur,t, infor-nutiotr ca.ttlr:t bc rc"i,ainecl for evcn a f'cw scconcls, nor ca-n thc sul;Jectrepcat, coruc,)ct-l-J,' r,ihat hc ha.s jLrsL, reacl from a, p/r.gc, D:iglt spa.n depcnclson thc rapitiit;7 r.rith rrh-i.ch thcy are gi-vcn: if. givcn -i;oo slor.,..l-y, thc earfj.crones are forg|1,1;en b;;1,hc tjnr-: thc l-ai;cr. ones are givcn, Rcca'Ll of digitsj-n revi,'r:sc o:rrler is usua},l-y i.ryrossi.b.l e -ir:r'mc)re t,ll+r-n.br.,.o c.l igjts.

(.t) A4U:l*iii s_!u1l]ancq qrf' 1i11,.nory f'rqqucnb.ty sec,n _i.s prrr;cveraiion,the tenclenc;r {',p rcpeat t-,he sa.nc response inanprcprral,eJ.T. fnis n.ia;r takea curious fonn: 'che st;.bjcct, cannttt ansr,'er a, qucst.ion and scctnij r_mable'Lo

even remctnbcr trha.t jt r,.a.s, but as thc cxar,iirer gj-ves )rj.ni a ncv qucstj,on,he re'plies by corr:ectl-v ansr,.er-i ng thc i jrsb. Ab i,hi s point hc ma.y nol:secm i,o ha.vc hea.rcl Lhc. seconrl q,-resti{tn, n(-rr to realizc ?rc har: ri:spondcrlitlappropri-a,tel,;,'. Ttt-i s phcnomena has.L.,r:en obs<:rvccl repcatedL) jn rirn,nl'subjects. ft srrgS;csts tha.'L thc problen rxey not bc one of storage, bu,c ollretrieval 2 8.i1,1 thnt a nor stimulus may injtiatc R. second. scarch of the:nemcry, r,rh-i ch brings forbh i;he arrsi+er: scu"gh'l, prcviously rrjtlrout, succcrss"

,' i. ',

r ,l t- (-'f .. ,, ,.'.' i,i:,, ;i,il_r j r:ct, anmcsi,a i. s gt.c,i:. uc _L r ur theper.i ocl oL'flrca*rcd, i-ncanaci'i,at.i-orr, wltlr fair::ccirl,'l- o{'the gnset s'ca6c.Amnesia forbhc carJ,;;u phases of recoveriy i.e not total- al gre tine: ofemergcnce frc-irn d.cl-jrium, but clerrcl.ops furl;ircr as timc goet by, nuch thelray d.rcams rccr;'llcctccl in the morn1n6 ar.c f'orgotten by noon. I(anysubjccts dcrncnsi;rated that :l f' q.rrcstioncEL carl-y, nan.y of thc paraloicimi spcrct:ptj Ons of' bhc tliird claJr ccr,r. l-d- bc I'ctcll"lecl and,, i n rctrospcct,rccoryiizcd as c] -lstol'tj-onc. rn gcnr-.ral-, vcr:r ,l.jtl,1c ,l s p<:rin:.ncnl,1;rremcmberc-'rl f qrr6p.1, thr: firs{, rni.nrrl,(.:s or l:rr:u-rs, r.rh.i. ch n.a2rlt.1y1t:: nc; cl-oul..rt fc,rthe trnditiona.l mcclical- vic"r thnt o-ei,iriun i s charact,ers.r,crL by subseclucnta.mnel.i a.

I U-

rd cla;r.

NF IDENTI{ t, i-., i, i. i:- U



CONFIDEN-] ffifl{fiLe$$ffi

'.

d. (c ) ulipr.e..1 '..,: Iuncti. otls; .

(c ) Tirc f'r-rrrctions of speech, trri 1,J"rt5, and d-rat"ing arr: of''cen con-

sictcrecl separately, but here ii r"oufcl sccm better tc d-iscuss them io-

gether since 1,he;' 56etr pa.rallel disturbances. Ignor-lng contcnt, allfhrce, sinpl.y as moLor shills, are marlicdly inrpaired from a qt"tality s'bancl-

plint rrith-Ln 2-3 hours after d"rug exposure" Speech i:; slurrr:o, voicedevelops a nonotonoLrs nasal sound-, a.ncl volume r,ralrcs to an almost lnau.cljblclevcl . I'his pcrioil. of incohcrr,'nt nr-rtlbting is sone.l,imos rcf'erred to jnold-c1 ncdlcal. .l.iterature as "nurjsi'Lant deliriu-m." I{attclrrr,i ti.ng :is dj,-ruinishcd" in quality a-'rd- is oi't,:r.t rcdllccd in sjze to't,he poinl, of r.icro-graphia,. Also, when a,shecl 'bo r,rr'-i-tc on a bla.c1cboarc1,, Lhc subjec'b's n:rt.nal-

tcnclc-.ncy to .incrcase thc sizc r,lf' tlic ,l e-Ltc,rs may bc e.bsent;" Drrrin5l pcak

inca.pacitati<.rn, he cannot r,rrjte at al--l-. Later'he can rnalrage no mc.rrc Lhart

]:is name ancr pc-rhaps his scrjal nu,mbcr, naking errors cven in Lhcse over-

Iear.necl acts. i{e can drarr onj-;r tlrc nimltl-cst gectmcl,r,i c I'onns, ancl't irequalj i.;r rf i,lrcrc j,s vcry poo,r, recctnb] jng thc i.rorl< of' a. f'jvc-ycar-olclchilcl, but nrc:::e tilie an adult, .,rj,tit e:d;cnsj-ve brait: Clscasc. Attcmpts torJranr a, i'a.cc bi' onc highl). intc]-.I igr:nt srrbjec'l at l5 hor,L::r; procluccrl onlya sllc1;ch;r ';vc".L l.rith sone noniLr:scri1:1; m,arks; he r,ras ou.l tt: :lLrcapable ofdrawj.ng an eniirc fi.gurc.

(c) rlhil orgilnizatlon ,:f r.rorrLs j-nto neani.ngful senlcnces; cotrtj.nucst<r br: j.npaj rr-'ci f or a consj derab-Lc time af'ter 1,hc a.b j l i \,y 1,o cnunclatclrorclr; 'i s rci;a-.i ned. lhrc subjc<:-t, rnn"y, j.nilced, be vofu'irle altrl maintain a

rapj-il jl-1.crrr o:i'i:pc.jcch,'r,ltc conJ;cnt ol"'r'lhjcir is largclll nonscns:cal...

Soncl,incs mc-.e.nJng cal bc cliscorieri:,l, hcr,rcvcr, vhi-cir i.s not at f':Lrsi.a'pparcnt., -i nd ic-'at-ing pur-pr,,sc1'rrl but ineffcct-,ual efforts to say sr:mcthing.For Just e,s a,i:t;cnt-,j.ve "l-istenlng r"r:-1,.1. t-'vcnl,ua-lly captr.rre t;hr! gis'b of a:t

aphas,i c's ,i-aborc.cl- conutur-icati.on, cl.os<: at1,cntj.on 'co rccr-rrrenl, phrases,analogical- ancl metaphorj cal f'ragments, rlor"ible entencj-res, rlr;rrui.ng irolrls,homon;rns, ,.,;pr:oncr1srls, and" a.ssoc,latjvc errcrs may enabJ-e the l-Lstencr tornake comc scnse from a seemingly :incohc.rcrrt stal,cment.

{l:) I'}tcs<: l-:. f rrl i1:r 1- 1;'1.",1"-' l-';:t::1- j-ons and- clistrlrl,jr'r: r': ii-'15l1age

elcnc"lbr arc- a-Lmost impossib-Lc to irruL';atc--thcy:;ccr bo rcsul,t from anextrcne loosenlng of thc cntirc verbal, associa,tj.vc system. As such, thcl'rna.y crcate a humorous-irnprcssion, s:incc the shift is so rapid ercl u-n-prcrJict.a.b"lc i:het a1. "t.J-mes j t llas thr: flevor of crca.tj.vjty anil r.r'j.t .

(Ihe ttrlngs that subjccLc sn,y arrc'i- clc.l, :Ln f'actl ore cften rrery f'unnyr ancl

it j s some'Lirncs rljr'fj.cult to kcep i'rom la,ughing oul, lor:cl at thcj-r antics,prol'cscional i-rt:ha-vior notvitnslanC ng. )

(C) Dur'lng severe clel.irir.rm at'tenp-ts to cla.rify 'bhc j.nten.-lcd con-nmnicabion Ly ashing"l"hc subjcc'L to repc.a'L or explain somcthing arcusuatly unsucccssf'u} . ft clocs nr: good- to say "htrat clo you mean by that?",

a'

ilti$1"il'$$iFlEffi



coNr ImH t'{HsI, I t LI D ;ru [$ffiffitffi$$sffi$

'because 'che sr-r1:;i ec'1, rlocs llot l(-nov r+hat irrr rl

tire qucs't,ion, ancl niay uot rcalize l"ha'b hr I

(C) Recovcry of abilit'y io main-i;ain a

a"[hor-ightf'u1

or analyi,'i"ca1one, is usrral]y

l'"'i.tlng shol'Is progressi'vc rcturn to norma1

crcurate at slbout the sarnc 'bime'

ffiANTEpliW* ==>

re&-L-Ly grasPhc answers it.

casual conversation, but not

attaj.necl bY the third d'aY'

size, and reacling 'becomes

e. (C) Juct-ryrenl' ancl Inqiglt.b

(c)hrhc.nsulljccted,;othe.inl'Iuencesola,nelfectived.oseofl3Z,some in.Leresting

"|,u,ng"*ta,irc place in the rrolunteer's abi1lty io ap-

pi:a*Lse both t1e situaljon arou'cl irjm a.nd. his ot,In menr'a1- con6ition' Ai'

first, he j.s clcarl-y cogn-i,zant of'l,hc fac'L t1rat hc j's succumbing to the

por,rerfr-r-L action of lne clrurg antl call reporb accurately the proccssion of'

syrp.bomsa,sthcyma}cethcirprcscncercruanclheigh'i,eninintensity.I{ernay clescribe tlre feelilg b1; comla,rilg j b to a]'cohol , ancl very often l-ikensj.t to thc ei'I'ccis of "l.O-12 t,,r""J-,r" "aboLLL I shobs of r'rh'i cke'y'" Obher

coltfiion dcsc'ip1,ions jnclucle such sta.temetrts ets: "f feel very dizzy-'

can,t seem to r.,";;"",y';;i;";;; or i't1''i:ocl-v f'cel-s like i.; veighs a ton'"

or,,f can,t lie s'[i]] --rY legs keep r'llnt;ing to rnove'" fhcre is co'sid'erab]e

<11 scom.for-L ancl freque.L1y a good- cLlal- of apprehension asr;ociatecl with this

phasc, r,rhich cinra&eris,cical-l y occurs between I ancl I hours af'ber

c?+)osurc. n".,*"fru fin* "I ha.rl nelrcr f'elt ljl<e this in my -]-ifer" or

,,Ir,,hen r.rill thi" ir. Ot"t'?" inc'l.,j.ca';e that-r,he SenSatiOrrs aye fa:: from

plcasa;rt, at Lhl s stage '

(c) $':me inri'ivitiuals nicrcllr ::eport that t'hgv are rlot'iing clol'm"

rr.hcn a$kerl irow rn"rr th.cy are.ablc t,r thj'nlr o" co'tc"nl;rate at th-Ls point'

but ot;Licrs arc al:lc'bo clescr-.tbc i;he r.Lit'ficul-ty more prccisely' as "f

Canr,t :lemenrltcr r.rha'U yOu jUs'i; saic1.r" Ot "l',thcn.I S'bari; tO Say sOmething

I forgc.L r+hai I am say:i-ng--n1y nr-rnd seerls t,o jurnp somc-'fllcre eis3"' 'Ihis

pecuuar _l,osl; of,961111()l over'uhe d-j-rection of ihc strcss or thouffht is

:rost conspicr-rous clurir':,1 'bhe 1a';cr phases ur ti',e atil;j;-("1 atr-L] hours)

)\ ,., ,, ,::r.'ir nrr'' l,i-.'1.a,.,". '' ,,':''l-'"' ;:rr. to be no mofc -Lhan p i'r ir'r'nflllectccil'tr ' .i

seqllenc€i ol r-iRr.elatecl phrases a;:iql actions, with only the nrost tenuous

comcc'c.ions f'rom one 'bo 1'lie nc;rl"

(C) As t,he cle1-lriurn progresscs through..the onset' phase into the

phase of stttpo]a *;-t:e itottts,*l-'ltcre is a graciual d-ccres'se in the number

of reports t'r'crm lhe sul3ect cu1 njna11ng in a1'o1;al cessatj'on t:f meatl-i'ngful

vcrba]- oul;prrb 1'or a p'criocl o1' sc'rcral ht'rurs' ftrc cnti::e sequence may bc:

likencrl. to a nrdio bt:c;ac1ca.st t,hal a.L firsr, ir internr-i'ttcntly lclst duc to

atmocp'r:r:Lc a.,rc1. tcrrajn intr:ri'cr.'(ln(:c: anl i'j-nilll-";t i'ailln cclt'ry1-c.l;e1'y into

silencc

(C)l',rhenrad'iosilence:is'1-iI-'i:eclrsotospea.ll'thebroaclcastsj'gnaloncc e.gai.n bccorncs a,ucl1blc, b'r; r,,r,0, .',riil, tite otiset of total cleliriu:m,'

bhc mecgagcs naitc -].i.i,t}r: Or I]o sc,nsc.ancl secln 1,o bc ajumble

olsigna}s

a

d., cloc s n

saylirg vlrcn

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'st

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'{i

::l

't'r

coNm{i$fi,(l:[ [$ft$frt&$$shlffiJa-G' .*

-daa!!---

from sevcrai c1jffcrenL fr(lqu,:nciesTfl'Lir: kalejd'oscollic quai-ity of lhel;oxjc cLc]-LriUn is i.rhat nlCres it sr-lch & i'r"'c-t,a.cr-rlar d'i spla'y of rncntal dj's-

orgarization. un-hkc the schizophrenjc i sychosls, fanr-Lllar tc; the

cli"nj-ci.an, dcl.-irjun at its he1ghi shorrs no then"tic consis'bency, no trend',

]:]o obsessional- preoccllpatjOnr,ri'bh

a sin6lcrelated sct of clclusional

-i.r1eas, sys.lelr,ltical-],y conlec[ecl j-:rto a persecutory or gra,ndiosc systeln'

Irrsn;eacl, there is a d.cgrec ol',looscning to the associai,ions that ailpToaches

rand.or,sress, lrith mutl,crcd- phrs.ses, outbur.i'cs of profanity, scattered

references ald all,usions to ctl,herrbimes a.ltcl- pla,ces, bricf' periccLs of

intense exe.nditetion c)f trivia,L bbjects, fa.cial expresslons of' perp'lexitir

Or l{ona|errneut, c|r-lckling amusenlent or tcncler concern, rcpctilJiou5fingcring or' bcd-Clothes or paiamas, su'clclen reques'l'c for inf'oruation or

perional- artj.c-Les 't hai, arc prouptly forgo1tett, an;- so forlh. Irlhen

Lclclressctl , the resllolirje is ofteir courileous and noncollrdtal , such astC;"; si;." in ani,ter: to the inqu1ry'1i{L'1^r do you fee}?"

(C) T'hrorrgho'b Lhis spcciacl-e of cljsarrayecl bcha,vior, one fcatureis of'spec1a} lnteres'c; the apparent l-acir oi recogniti'on by the subiect

that there is anlrr;hing rrrong oriil-, h:ral Thi.s may not seem too rernr.rkable

cluring the pcrroct of total incapacitati-on, but i.b is qu:lte anrazir$ to see

this b-]-j-nilless to h.is c-X,rn clisability perslst j-nto Nhe tli-ird day i'rhen he

is srrf'ficientl.y recoverecl to l;c'ablc to converse orr fanrili'ar sub;i ects and

to per{'o:rn ca-l cufa1,j,olls al'}d other :i nte}l-ectual tasks liil"h partial- success'

Ttius, i'b is nct tutcl-)1'ltrl1on to wj,tne':ss sub;; ecis complain:i-ng of the presence

of'biLgs, snal1c$ ancl rodenls in their becls, or ins:is-bing tint"bhey them-

selve s ot: sono gcr:graphical-l y rl-istant membcr of "t hclr larn:-ly j s in mortal

il-ange:r, or l-'ailing bo perform sone sinqric set of instiructjons correctly'arlcl therl cmphaticalJ-y i'sscrting that thcl' svt pcrfectl-y fi t' to perf'o::m

thei:: usiLra.j- duti.es anci arc completelJ/ rccovered {'rom thc ef'fects or' the

s.gcni:

/nl {Thi < d.sni.al. r-.f im:a.innent d.oes r"}o" seem to be a conscioirs effort\v,/ trrr-ru

io fool. tlte e.xandn€jr, Ilor to hitle the ernbaryassing llnor.rl-etlgC iha1; one

.rln.-i.,111'c nr\1 nakjll.:" ;r ''|'ery 8ood shol'rj-ng' f b seems rai;lter to be tlle same

ltlelioliicttlq -l.r:ng i'i;;','il 1,1) i)!i ciLi,,I'a<-l'bef:iSt'iC Of pntiC:'tl| ';irii':i"ing' {'f:Otn

. brail injur1e s or o-i,itcr organ.lc ner..rrol-crgical <J-isturtra'ncr:li. Such lnclivlcluals

seem imable tc appreci-ate ttrc reality of their d.eficit,s, and vill offer

rid.icrr"-l.ous alib:is arrd- r,rikl-Ly inrplausible e;<plenations j-'or their fail'ureto perlorrn a.t1cg-Lately ip thc 6reas aff'ectecl by their disease' St'all1ng

ancl tcnrporiz,.ing nulrleuvcl's, fllrch as asiti.ng thc eXeniner to rt:peat tltcquertJ.on, ot: B.skjng fclr ciarjf'j ca'b-i.on ol tltc :instn-ri'i'ion l'rhcn jn :lac'b

thcy havr-' corr':-Le1;r.:J.y forgr:t1;cn l-i-, jnquiri,ng nalvcl-y, "You mojan me?"

Or i'Ili,l;rou l^,Ln{, lne 1;<-r clo that light; n(x./?" arc vely common. Ira.rftng in

tire pcrf'or.1nancL. of solne simplc aritlimt'tj.c problem or rtta]i'i ng soxlc othcr

grosri cyror,i tr att assigllcd tasl.", they','ri.J.l comment, "f ncvcr was vcry good'

l.i-*r7rri'"1"-- "1 t6ougf,t yo' jr-Li;t l,rauteci me to put i'c on the table'".1llrcl con1routcd r.r-ith thej.r poor perfonnrsncc and asl"eci if' birey in-i.gh'l' no'l:

attr:ibutc it j,cr the ef,'f ects of Nire agent,, tlicy r,rill emphati cal-Ly re,iect

this f'el.ce-s&ving nobjcrnand.in$j st 'Lhal they are quj-te capal:le but "cou-]<ld-o jt trettcr oriifr a penci-l- ancl- paper" or "coulcl <1o 1b excep'L n1y vlsion

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CONFfDtsI{l XAI (' f: r L r [$ffiffi1&1$$ffi[[u#

(c) ft is paradoxi.cal 1;ira.t one of 1,lri,nrost rehlable indications olrecoirery is the return of ansareness by thr: s:LLbject-bhat he is nol as

'proficient as he shoutd be. Subjects whr: receive an incapaci'Lating dose.,usuafly rega:'"n l,Lr-is ai,{arcness b;g the thirC or fouri;h d.ay. B;'this tine

."their objective performance on numerical ancl r,rord- rccognition tests has6cii.rrally risen to BO or 90 percent ol" tire basel-ine leveJ,, ancl the prin-giple s;mptoms are some residual lassjtude and bl-urring o-t' vision.

(c) Subjects who receive doses sufficient to causc onl.,r nr-ild or..n'iod-erate d.egrees of incapacli;ation (l-> V"S/kg im or iv) C-o not usuallyd.evelop a. Ioss of insight int-,o their cond.ition. lfhen their reactlons

''become slor.rcr aircl their errors iricrease, they recognize it and rerporir.ri-bhout hesi"tation that they are having ctifficulby. llal-lucina'i;ions, dls-or:i.en1;ation, ancl. othcr gross clistr:rL,ions of'reality arc uncomnon:in thesctnllder reacl,ions. It sccms probabl"e, therefore, that as }ong as the

ability to rr-'maiu in contac'b r.rjth the surroundings reniaj-ns rea,sonablyo'inta.ct, 'bhe ca.pacity to judge one's or'n rel-ative effj,c:lency a-l.so contim:es"to f'unction. The behavior of' such inclividuals in the battleflel-d would-.prrrbabl.y be more preclictable ancl less rlangerous to tiremselvcs anrl othersthan lroulcl that of the more seriousl.y incapacitateci group.

f . (C ) Indivj.d.ua] , Diff erences ln Response.

(C) As Wo1ff'ancl Curranll pointeri. out almosr JO years ago in tireirclassic rnonogiapli "Delirium and- Al11 eiL Statesr" the ernbarrassmenL ofbrajn f'u:rctj.on that produces Ce_l-irj.um dc'c,ermines tlie f'orm, but not

nccessari j-y the content, of the response. hrring clelirirrm, as duringalcohofic i.ntoxfcation, the j-cl-josimcrasies of iniijviclual personalltymanif'esi therasel-ves. llone sul.rjects bc:come irritab-le, verba'll.y abusiveror evcn lhJ'sical-l-y aggresslve. Olhers are quict, passive, and absorbed.

.in contemplation. Some are able to sleep through much of their disorientedperiod, whi.le others seem cleterrnlned to takc an activc appr.oach to theirbewil.<lerment, explori.ng, tugging a.t walls, cloors ancl t'urnri.1,urc, clemandingE::r.i st,a:1ce, irrformation, or ::el-ease from thejr conf ined. si-br-'rt'irn, StilI:r1t ': , ;-i]"i. i,r> 1ou,;1r ;'r" Lir.;r :)L!(l.,i.c{Jrrlent ancl may c1.o.rm arr.u gi*,lgJ-e, nakejoking oft'-co-lor renrarks, boast a.nd. sr.ragger in a grancliose nranner, andlnsist tlrat bhey feel "terrific." At'the other encl of thc spectrum are.thoce vho appear sad, some't,imcs errcn Lrceping alone1n thej-r rooms, rnourning

. thc ima.gj.nerl l.oss of f'anr-l ty or gi-r1 f'rj-ends. And f'r'-na.LJ-y, t,here is thcco-l.cl eva.s-i rre vjgilauce oY' lire pa:ranoic lncllvidual r,iho r.eacls sinistcrpurpose into the actions of'everyone aror-rncl him, l.rhich he confid.es inr.clesperation to lrhomever, he d,istrtrs-bs l-east.

(c) occasionally we irave encor.ur'uered. subjects who approa.ch theexperj-meut as a challenge a.nc1 mai'le a cl.etenuinecl effort -t,o fight off the

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c oN Fffii; irc l!$lfi H"ft $$lfffifi#i

cffcc';s of ilrc agcnt. One r',en aci,rrrttrTTflcGd"dilffiffi6:i6it anci

vas able i;o ',,.:Lcrate an intra.r'tuscul-ai" cli::.' r.;f' 8 p,S/l,S r,riiir oniy rni.lc.ljmpairnicnt of' lterfomrancc; ire rennined- :i ri <:ontact r,rith thc environmcni;througlior-rt an<l t-rnllr 113.1 tlro I'l.ec'cing iratluc:'-nations of spidcrs vhile jnthc bal,ir1,ub. llut in gcncral j.'c sccnnd to rinhc l.i1,tle d.-Lff'ercuce horr

.inte}Iigcr-rt, adverrturous, sclf-con{'idcnt, or compc-l,l'ttirc thc inclj-vidua}i'-jrjht, bc.:.; blre agent apparcn1;ly clisablcs bhe sbrong and Lhe lrealt. imparLially,ancl lrithou'i, prejudice.

(c) Nothing morc than inrpressions ha've bccn ga.Lned oi' the preclicta-bjli-ty oi j-nclj.vid-rlal- rcspor-rscs l'rr:in infon'nation ob'ca.itterl bcfor"cliancl . Ithas ol'ten sce'rnr:c1 that i"nrna'i:,ure or rcbcl.l ,i otrs'i,;y1-rcs arr: inclincd t'o tlrcsentmanagentcnt problerns ahcl shol,' poor coirtrol of aggrecsivc jtrq:u.-Lscs cluringthe 'ues'1 . lluc soltel,imcs the scctlt-ln6i-Ly ru.el-1-bt:ltcvccL, Er:'-et tylc 'i,unts

out to bc a hcl-l--raiscr. ft ir generalJ-y possiblc 1-o ral,iortalizc the

u:tc,.ipcctcr) rcsponsc byLal1.,ing

aboui,'{'rrg1g1g5" ancl "'u't:nccrC" a,nc] "ovcr'-

cornpcn;ationr" but ii sccns besl, to 3.,r6-i.d'chis t,ypc oi'sclf-valjdating-Lnte rprt: l;atir:n

(U) Inrlj.rj.clual- d.iffcrcnccs tlo,:;ci-lit, and it me.lr be rl,]ra.t, l,r:Lth

lurther ana.J-;rsis l'rajrs ilIl.)r bt' t'or-r.ird 'co prcclict'l,hern. Ih-rt a'i, thc presclttthis clocs no'i: scem to be possib lc.

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FG

corvFm'rAlllli:[,,i-[.tl:T

rtr. (c) trvAruATroN oF rnItRn.ltiitr/,L DAT'",.

11 '

(c)cho.racteri s'r,:i-cal-l-y shor.rs certa.in otirt:r c.;nsistcnt change s -ln ohysiological

and psychological f'unction. In para;jcular, elcvai;ion cr' hcarb rate, lotrcrrngof i:erforra.rlce scores in su"ch t,ests as arithmetic al-.rl..J i,y, and cl.evation ofblood prc[isure arc corisj s.tently present, cac]r follolring a course in 'Lime:

that parallels roughly the course ot' the d-elirj,um. the hypothesis was nTrdc

that thc sevcri-ty of incapacitaticn (cquaterl rrith clel-irirlr) ccrr-l-d be prr:-ii-ictea by refereirce to these measu::able physiologica)- ancl psychr:logical-aspecLs of BZ actj-vit.y.

{1"'-r .r\ l-arruil..;, rr ' (.1 i.. r,: l,irl'i, o'-r,.i.l d bc r,rsed to rlcrl,c,lrrl-ir'r'' '1ioira'O]e "valucs for ca,ch vs,rj.ab-Ic wi"l;h rcnpt:cL both to ci,osc an.f, t:ine1iolloli-ingadrninlstrat,ion r.ras dcvc-Lopcc1 I'rom scr:i,al- mcan va1.rrei. 'Ihe jclr:al LzerJ curves

{'or scrJaJ- pcrfomance scores ln lfumcrical Facllity and Speecl of Closurc(trro lrrbtost:; of a r:cpct-i. L,.i vc bnl,tcry rJ.esigned to tcst co6nj.ti.rc L'u:rcLion)appc{rr graphicalJ.y ln Fjgurc l-.

(c) From a f'amil.,7 o1'curvcc such as Lhr: onc shorrn:i.n lrlgrlrc l, agccrrtn8 tab]-c lras dcvelopccJ. t,hat gjven a r&nl.j{l r-;f pci:ccnt sco::es aesociatcclwi.th cach in1;cgr:r close l-crel- from I-r) VS,/kg at, each of a sc::jes of arbj-trary t:i.mcs (tne nr-ia-point s oj.' the tirnir periotl.s lisi;cd r.rnc1er lhe scctionon Erqlerirnr:ntal P::o'Lcco-L -in Appcnciix A. ) ttrc scorjng table for performanceis shor'rn in Figure 12, Appendi.:< C.

dil,{it*tu--4*?+!n

EpilfFrqqlrffi Flilitl"it.$$iF!tffi

t!$$ffiH"fi$$* Iflil

A. (C) il,rlc-licrlr.,:rsc Ii,''-al;jct-, :r,:.

1. (c) r'n.91lo$ogg"fg{gI

fhe manipula,tion of numcrica1- val-ues obtaineit in thr: course of'

a,. Dr,:-v":lollne;lt, oi_'bhg_.T$.

'I'Ihen a subjc--ct dc.rclr:p:r d.c]-rriurn in rcspcnse to thl agen't, ire

the lnvestiga,i;iorr of 87- exposurcsr has posed cerbain problems, not the l,ca,st

of r,lirich has been a rcgretta.ble incrins';artcy jn the variables choscn f'orscrial tncasurenlen1, ert clifferenb s-i;ergcs irr thc progratn. A scconil lrrcblcnt

''lias l,cen crcatc,f b). thc iacl,'chat -iir some series, parrl,i.cu] a.r-Ly'Lhr: carLicr'.rirt{isr scria.l- n::t-ir-ires ltrr,rre ci';her'r.,cn,'r.'i-it"g.-Lt':,-1. ai.i,cr 1.irc fi,rst f,:l.l }rc,ur-s orrecr:rclc<l- .Lnf'rcq.reirtl.y af'tcr titis pc::iod.

(c) l,iiri ]e sonc sr)r'1, o{' 91o.1-,e.,i jtl,rl,JgncnL of t}re sevcr:lt;.' ol the rcilo,;nsc

can be made in cvcry casc, itscemed

preferabl,:bo devc}op,-"J!_l::t_!ic,4at

.erjjgqr-a -!qf Sr+ding i;his C.-i nre-.ns.i on of' rinrc actic'n. .Tjrc Toial Rcsponse

1g9,i_(f:ru), r*hich r,rB.s clcvclopecl , .t a nuril-;c:'thal c;g.,rosres titc magni';ude

of IIZ eff'cc'b vith rcspecr; i:o ihrec po.rametcrs cf drug action--henrL raLc,'fllood prcseure, amd pcrj'orrna.nce . I'u is, in a sensc, a bioassay techni,cluetlrat rclies upon nxrre 'ultan onc :l nriica.'|,or.



" 'Fdc

,! lAl+ LU g,

"I250)

o-'3roo

#+iw

is3

Ilours elapsecl lrom time of -c;qposure (tog scal-e )

FIGUBN 1

ZOii:CIS OF U(P}ICTL;ID PEIT'ORI\4,AIICE SCORES ASSOCIATED

iZ--TIt*

(c) rn the usc of t,he scor:i ng 'bable ior pcrforrflflllc.Jr cach sr,rb.jecttsmean percenl; score r:n the tr.ro sabtcsts j.s refer.rccl to the

tinepcr:_oci

inrsh.Lch it r,ra.s adrui-nisterccL ancl is ccnvcrtecl to a "sca]_e scorc." fhisscale score i.s a trumbcr fron.L-9 a-rd. e;quals the close jn nr-i.crogram.s pcrkilogram associabed r.rfth the subjec'c's percent score at the parLicrilartimc ulder eonsideration. For example, a perfor.rr.ance ,score of 6O percentat'l hours receives a scale score of ll, ind.lcating tira'; tr pf/tS is theci.ose mos;t likely to resu]-t in such a score at u hours. Tnb same scorco.t' 5o pr:rccnt aq 1.) hours, on thc o'i;her hancl, recejver; & scal-e seorc ofi, lreeause [1 itilf\ry 1-1';ir1.r'] lir: the close rnost likely to n::odr1,; .-1,r1ch a scol:eai, I.) hours. Atl per.ceni;age pilrforrance scores are converbecl Lo scalescores and a welgh'becl &vcrage of'these constltutes the Perf'orrnancc Inclex.(Weigfrts assignccl

are arbi'bra"y, ranging from l at the beginnlng ancl end"of' the serj,al. responsc curve to a nuximum of )+ near. .bhe pcak of theresponse curve [5-lo irours ]) .

(U) Slnr-il-ar families of curves have been d.eve-l oped for heart rateand. blood pressure

(C) Secause nany of the earl-1er cases c1o not contaln heart ratcor bl-ood p}'essure observations beyond. the first S hours, a mod-ificationof the proced"ure used. to d.eterrnine the perfomrrrce :',nd.ex vas ernployecl for

I>

50

25

t.)L,l

dk

.H(J

+)€.lg

14

t)fJ,<

.'fl

^1c_L



coNEEElrrTffi

-JAFI TFI LIIIT

these obseryations. The mean va rimen.ba,l9trgo9 vvjvr

t1rne r,ras userl in both cases to represc'rr I, the response. llnis pcriod oftlme inclucles the period of peak elevai,l'.r;n, vhich is about J-)+ hor-irs

for heart rate and )+-5 hours for btood pressure. From the idealizect

curves d.eveloped for each variable, extrlected. mean heartraLes ancl blood

pressures for each close were obtained and used- to construct a simple:

converslon table.. For examp-le, since Lhe nean hearl rat,e cluring the.L-6 lrour perioci associated" rrilh an im or jv close of' 5 Vslbg is BLr-95,

an ind.lvidual shoving a mean heart rate of !0 cluring tiris period wouldbe assignecl a heart rat,e inclex of 5.

(U) fnrfices for all- three variablc-s (perf'onnance, hea.rt rate ancl

btood pressure) are combined accor<iing to tl:e following formula:

Totaf Response Index = 2(Perf ' Ind.ex) + a(Un !qc1-e{ + np lna"*

(U) Sc-Lectron of Weight,ing Factors.b.

(u)basetl onof theseTable l-.

(u)

Tlie weights chosensta,ti sti cal anal-ysi s

measures and dosagc.

in combirring the separate indices areof the intercorrelation between each

fhese intercorrelations are shor,rn in

TA.BLE -]

CORRELATIONS

Perf . lleartInclex Rate

Systoli c

BP

DiastolicDllI ll TRI

Dose*

il:':':ill-ir:BP**

Systol i cBP**

HeartRate.lf*

.92\

:] L:

. !l+o

f) nz.oal

.BB:

, )rPl+

,t+62

.1ar

.r9B

; 511+ .9+r

NOTE: A-11 correlations are of the I'orm linear Y to ]inear X. A11 tlieabove correlations have a significance of p < .00f.

*1q = fit; (only lv and im ror.rtes used- for correlation involving close)

L'



CoNFIml fldtl'l L, i, *:-*=5 [J.d*

(u) F€tional lreigh';jng of the s;r'i:,lrrate indj-ces -i-n the soluticnof thc fRf forn:ula r,rou-Icl call for calc,rliiLion of the beta coeffi-clcn'oassociated lii1,h each fe.c1 or in a mul-tit-,rc regression equ-ablon. Such

a prnceilure wa6 not r.u:d.er-i,aken at the L-lne the scoring method was clc-

veloped. Ilowever, since the coefficient of detennination ol each

t , I -^varfaD-J-c \coerrrc.l-ent of d-e'cenuination = the sguare of the correlat-Lonr:oefficient) may also be used. to differentially r+eight nrult,iple variables,the weights chosen (2, 2, an3. I for performance, heart rate and' bloocl

pressure, respectivcly) may be evaluatecl by comparison '"rith the coef'ficientof deternr,inalion for' each variable:

(oose vs. Perf . Ino.ex)2 = (.92q2 =

(oosevs.Heartltate)2 = (.BS:)2 =

.. (Dose vs. Systolic BP)2 = (.5cil2 =

(Dosc vs. Diastolic BP)2 = (.rL\)z =

.B:4 = coefficient ofd,etenninati on

. (,J7

.t)I

.26+

(U) These d.ecimal val-ues aSree fairly well r,rith the ratios 2:2:].(Syst,olic anrJ. cllastolic bloocl pressures are adcled in deternrining tlicbl-oocl pressure ind.ex. )

c. (u) Rellability of TR[.

(U) fhe rel-ielbility of tire TRI as a prerlictor of the clcse glven

is incl-icated- ]:y the very high corrclation of .91+l between close and" TRIsholm in Tabl-e ]. It shoulcl be pointeci out that the scoring tablesused- in d,eternr-ining the TRI r,rere cleveloped almost a year ago, and lessthan tralf the cases cited" in thu. table of correlations vere used itrconstructing the scoring system.

0.. (c) Validity of TRI.

(U) The TBI, a.s will be ntentionecl later, has been used. as a

criterion for inca.pacltation. Thls impl-ies that it is more than a

bioassay measure, but also isa. mcasure

of'thed,egree

tovhich the

subject 1s renclered lncapablc of perforrning normerl ririllbary clu1,ies.

(C) T\ro hnes of eviclence suggest that the TR[ ls a va.lj-d" indexof jncapacltation:

-1 . (C) Fordy-f ive sub jccbs who hacL recei.veclcloses of 1'1[ Irg/kg of' BZ by one of' four routes were sclected by theinvestigator from the fil-es. 0n the bafLs of the total in,f'ortation

ffiffiffii;1"[$$tF!



rilcoNFlffm-r iJAil t; I t- L ]'-?

aaffie '. .. ,. ,r r. r,'1 n ff fr\ l,

U';,bJ.$tbbhd'ts@dl*

reccrried in each chart, ea.ch case vas i..,llisj_f ied. as nr_iicl, tnoderate orsevcrc rriLh ]'cspcct to Lhe clegree o1' ''-, ir:,r.Iiacii;ation. " tr'ii.t,eeg casesin each ctl'LcSory were co]-lected, ancl TIt-i scLrres were calculated forcach casc.

The ncan T8f for each group r!-as a6 f oll-ows:

Ittllci :

l,lodera Le:Severe:

'to

i,)+7a

Follor'ring this, the obser-vations of behavior recordeclin cach lvlaster l,og (see Appcnd-ix A for illustrative case), together r.rith' the erperiment,al time (elapsec1 tirne since e)cposure) ancl it,""n."

nu:,lbervere ind-iv-ld"rlally rctypcd. on inciex cards. Approxirnrtely IOO of' thesc

. cl1ds were taken fron various locations in the accunul-a"bed. d-ecli .of over'' 2ooo cards artci scparately read.-[o a ";urlging pane]" of {'our nurses who' Irere generalJ-y farniliar with the characteristic responscs to various' rlose levels o|BZ, but not r^riLh the particular cases. They r"rr:re asked.to make inclependcnt estinates of lhc im cLc-rse they ruoul-cl aslocjate with

the behavior ciescribed at thc tirne recorcLed", The estimates were avera4lecland the mcau cst:'.mate vas correl-atcct lrith the TRI for the respu.ctive' ca.scs. l'he coefficient of correl-ation obtainecl was .768, signiflcantat the .OO1 levet.

2" (C) fne seconrf line of evid.ence was .ilre finclingof a consis-L,cntly higli TIU (usually above 6.0) in cases characterizeclby the presence of hal}_rcinations, cletusions and.f or vj.r:l_ent bchaviolof'somc typc. (Sec I'able 7, Appcndrx C f'or tist of TRI anil other r"ooor"uvafues in sr-r-bjcctc shorving psychotic behavior. ) hrhen probit anaiysis

. _lsperfr:rmec1,the ED)O I'or the productlo:r of at leas'l; milcl- hallucinatory

behavi"o' is 5.i vg/ks i" (g>f'clnficlence rimits t i.o-5.0) ana rorsevere hal}rcjnatory behavior is 5.h pc/ke :v (gf/'conf':td"encc t-inr-its:5.'(4.f). Sitrce the l',i:T ls highly coru"fated with the i'r,:;ti:se, antl',r-iiii'rr-' ;ir'; sl-op(j cJ-t' ,;lic le.i:.c;s-Lr,rr:i -line in both these pr,,;triL sorutionsis extremcty stecp (8.r J l.) aird 'r.t, J l.lr., respectivety), bhe TRI' must be regarc1crl as predic'cive of'the

Irresenceor absence

of at least. one important nranifeslal,ion of clelirium, nanely inl-]ucinations. An4. delirlum, it voul-cl be asser'ued- here, r.rhen severe enou-glr Lo cauge re-

cur::ent harl-ucinations, is an incapa,c:ltat:i.:rg cond-i-b-i-on.

and Relatjonslllp to TRI.e, (C ) Dcf'j n11,:r)ns ,)1, Cra.rl ,.-.1 c.rf

, Sr:vcril,y

(C) Fron converging littes of ev-rclence of 'che bype cilecl above, and"from general obsczwatitn in cr-ose rletajl of inany subjects, a TRI or d.owas selected- as a rninimum criterj on for incapaci'cation . If incapacitationis to be consiclered a matber of clegree, the

fol,loving fourgracles

oJ'

:*-:.-awftrylPFHFr{*\, rt l{ ' '.-. L. t-. tr ffi€\'^,r-

-

t e**4: t'* *#@''"-:::



_fu

corvffii"flM.*:*:r- [jilt$i."f,$$Hhf;fn

scveri.ty rnay ire operationall.lr clefinecl :

l,li]-d = TR.f of li.0

l4odcrate = TRI of 5.O

Severe = TRI of 5.0

l'l:,..:l:i nal - Tlftf cif 7,1.,

Subjccts rr..i,,r T|l[ scores near It charr.rcleris*t:'r:all.y sho\r peek hearl, rates ot'80-35, less

bhan 1O points el.cval.ion :iu bl_oo'J, 1lressurc,morlera.b,e clilat,ation of pupil-s alcl sJ i g)rt,

blulring of vj sictn, sJ-r:cir.i r.t,tss, sl i;h i, t.r)ti,-]sJ,of ';lre rn,oul,h, r,T-i nj.rna-l. j ncoo:'rli.nr.i,i cn, i(rmctttr:ntal s,Lorrj.ng (lovest pcrf'orrrwrcc scores abor-LL

6O'f' at '[ hours), a:rd. no ]-oss o1' contact lrithreality. Recovgry complete at abou'L )r3 irours"

Su-bjects wjth TRI scorcs ireo.r I shor,' pcak heartrates af 85-95, lor,'ee1; perf'onnance scoles ofabcrrrt LrO,10 at- tJ horrrs,. and less than 20 points

eleva.tion 1n blood pressure. Syrnpborns cies-crjbed for the rn-ild response are more sevcrcbut st,ill l-ess than ma;:ima.L. Sedation xtaybt-. marlced cluring tfre !--16 hour pe--riocl . Fleet-ing il-l.ut;J-ons or ha,l-luej-nations may occur.Brief l-apses in concen'tra.tion and transj.entconlirsi-on are eomrnr:n. Recovery conplete atabout '/2 hours.

Pee,k hea.rt; rate 95-LLO at 3-l+ hor.Lrs. Mosl,subjects opproach or reaeh zcro level crf

per"formr:ncc r,rithin 6 hours alrJ r1o not rcturnabove !O!1 untll ?-\.45 hours. Ile.llucinations,conl'usion, h;rperactlve dj sorganizecl behavior,jncohr:rent sreech, a,nd d,j-cturbanccr in rnemorya,n<1 a,ttention charactr.:ri stical Ly appcs,rfollor,iing an early pcriocl. of d,eep slecp orstupor. Rccovery complete a'L about !5 irouro.

Henvf. ::ate ree.ches pealr rrn-'1.,r,,r; lf l,lO-1h0r,rj.thin J h,lurs. Blooc1 pre ssuuc rise of from20-60 nm I{g systolic. Raplcl onsc-t of stupor

r,rith.ln h hours, often prececlecl by pcrio<1 ofagit,alion. Pcrfornancc deterjorates to zero^tr,rithin J-4 hours. Stupor subsicles at 1O-l-5

hou::s, fiol-J owcd Lr;r pro i;r'acted pr:rlod ofs1-c.<:pJ-essne.ss, d i sorgani.zed ::andom beharriorrcont-i.nual- lrall-ucinations, and sometimesimpul-si.re outbursts of I'ca,r' or Lnger basedon rui.si.ntcrpretatj ons cif' surrouncllngs.De'l .lriu:l subsj.cles with-Ln f2 hours; recovery

tcomplr-'tc by 120 hours,



CONFIDENLi rfrar,{ ilrt-L[il;***

a. (c ) Re lati ve l:ti 'c1.--vcnccl b.y Varlou: RorrLcc.

fntravcnousIntramuscularuua l

InhalationPercutaneous

34l-1irh0o:ti:

30TAt, 2/r

a. (c)

o.-l_10.0O.5-B;O

3.0_8.0- 1. lr- a5. r,l

1.9-60. o

0. r_bo. o

Intravenous Routc.

(c) The effectiveness of thls route ls considcrecl to be thestanclarcl for eorrparison and is set at unity (r.o). As virl ue

"torrrlater in this report, the rDlox by thi",o*tu 1s'approximatery e-.)"ig1xg,using the "seve"l" r*"por,r" (rnt "= a;o-";",rierr.rl-;;-i;;;riilrior. ro"incapacitation.

b . (C ) fntraruuscul-ar Rc,utc.

(qi Alalysis of" the resporlse by this route yields no sign1ficantdjfferences from|he itrtravenous routc, ancl it is consiclered" equal tothe latter in effectiveness

c. (C) Orat Route.

(C/ ll'he eff'ectiveness of BZ given as a sol-utlon in clistLlled wateron an empty stonuch appears to be about 0.9 ttrat of the iv or im route.

fhere seems to be a lag in onset tj.mc of atrout an hou:: and a slrnilar d-elayin at'cainment of pcalr ef'fects, althouglr the dose range stud,ied., the numberof cases, ancl thc lncornptete contj.nu:i iy of obser.-va'bions 1n 1;hls gropp ofearly cases prohlbits more than approxi.mate estlmates o1' these clifferences.

* rDSo = dose that will incapacltate !o percent of a populatlon.

r..,i**;*CONflnF NTIIrL.*:r.itLn$$trFq'ffi

irli$X65*!fi!

(t) BZ has'bcen ad-rui-nistered, i,o .r,,lunteers by all pri-nciplc roi-ites.Appcnd.ix A clescrj,bes the clesign and methoclology or

"ri_';ra;;;;;;ts con_ducted to date. Table 2 sumnerizee the studiei in hu.nans

from laay t4t6oto June r9q. The number of separate ex1>osures an<1 the d.ose ranges s.Luclicd-r'Jere as follovs:

Docc li.rlgeFgl]ts



cobEtDSJ-l-! I'rcdd

.--.1 - i

oc)0l r,1

EEoddrD!HU.p-P !r:'l c 0J

HH<

(0

').Q

-l

i

i{-lJ

H

()+Jao&

Ocl

ai) '-r

c! j. (fl-:t()-J -rl^ca ol lc\J

\()-1

!'lC)

L0r

O

C)ca

C-, (i\

c! c!

\Or-1

**(U

UI U]

_1 L,)

(!il cd O i.)\- r) h (,

o a) r..Ots! (\J c! Ca rr)Q\o\D\o\or,

-^ -. ^ --QU.J!)-)\JvJFl<AFqF)

:3C)

CQ

JFC5

L+Jil

H

HcJ- i ,--l

o

rpil o)d<H+rc

Hd

-'r'_.rl-lGo? dc,Jd< -lrl'i'a l-?..<tl clord L) cC :

.rE 1-1,].r)+J O q q l.i tr'r'th ) 11 'l Ll ii crl r.rt i-t r-1 r-i o rr,-l o o tr L L'rt -t i r, cC cd ! O cd Sr fuP r;r

U L"= ir:r5 h l cj tr L u o F1 f'l c

obFr<a,t-roo<o<)<<HHH

o_

--f c4c^:c c4Lr\c\.1 J t-c! c) i-.\ ri nc!J cr) u-\-l:-i(I)"--.-l'dl

*.:t r{ cn'J \c

f.- .-l

!:-J

a

"70rJHo

Q-rH4)

Or

OJp-dt-l

o'rl+JOr

.r'1

trUU)

cq

()

pH

-tQr

, A s,.3 :' : E s .3h€l

^.3,0-i'3 6.3 3 co c,8, il E ;"i:jiqr F1 CJ .r.* i:l ! U) O'F -i C) -O i: ul 5 ';r ul

! q '": ? - ;i ;r ,, 'j t i I ? i * +l 3 € d' I*i .j.t,- ,:,. , _' F, tj +, ! (? htl c.r I-i -l +: Oin Om.i:l; 1 -t'-r d j: lr O(n L 5 f. O.r-i;-) O'rr

-;6'-j,r,iat Cat.i:fr,drCp, d+C) 01 fuc-r-r'rFr' aijrir.i .-rEOOrrlC)ircf)0< _ U..l ..-1

cSfisiif'l .:1 c>H5l, qq.;t . ciQc'rPrfi

5 n- Ur,. J-

3OH 9,& q-r1: > {c?Sr -..?.-r co O 4' :r u o ji [] I o 'rr Q : R]r l-tl ar ]iJ nj ir-E cr o- td,5 -j -r l-r ('l prE -r "c{Gir)c} pti!r -l ( Oq.L2ul 'r-re -.t-l!1 'il:1.:,!&6 SS 3i g 3;t'8#?P':l 9*fi BHL co r C C O < L0{ I I tS;'-1 ''rrJL-l'lrig g 3.; ,s *'-' E ; *:i t t :i t H: ; g d [ frJ r rrr

= ii o,.r - r'ts] tt Lr Q > pr rl 'rt tl ol-r -r A66i::cc-rt_ic o6'-'-J l.,loltr:1E'd'-it.;l 5ilicl . F,t,.-c$: o Fltrcr;"1A1 i;> lj ar !i I5'; il> cl 0i :i - ! rr 3 o (u5"rdd L< p;5<: ch = ofr <<i-r F-{o cr u u ca o{ }

'rJtrCJ

0t

I

l- cn o'\ca) c4 L c\J j l* c! tf\ L - Lr\ c\l j J \o rl t-J Cl- i'6r --

-* co j -l

-lv)cr)

\j)

OOt4 r, rtr .:,lSl f; ql

'.o rr: cJ \O \c \o \o \3 I 'a)- -*J F)

--'i' c) o, > c.t c-r i C'--l ir c; --r c-r -l rt -l cJ .--{ o Q Q c\r cu :J c\lF: c>\ovl 4.5\Ot.:) LC\O:.: G n\O\C Frl.,

lllllllli: (i, f.., ! >: tl I .-l tD P, r: l, rl q $:t ! :-o ij ,:r rl crl 5 :J :i i o u c cd cd ,ri F,-"EH oD m H E Fr Fr FJ < m O F:t Fr f- < < ;t

tilc)01

c)

..t-)

r.l (n

c) 0r! .'-r

dti!)

..r !0.)

n) -DhOa01 (J

OEQrOXUT0 g

HH'-1OOq+ '(J

OCJ

h mqXd cd 3'.1 3 CJ C)

'd+ CJ

iltcHAJ OOCr.C L()rO lt-l<cdCJCCo-or'\ - ,ll

O)c! f lrLoO

=d

*+ *

r-.1 c\l cn-* u\\o tgoJ 6)\ir rl O-J (n-:f U-.,\q D-; -l -l .-l J r{ r-l r-1

*c

"cJ-{€1;:

cllo

o'11+)

CO O\O 11 C!.-1 .-l C! C\l C"J

ffi

l

q-1

o

o

qi .lJOO

CJ

EI

3'lr'lsl

NI

;lEI

HI

EiHIHI{tI

Hi

EIert

f;l



tdc''*-'"4CONFIDEI!-Iitr

. *[&r,

c+c1l

and

(c)

d.

Tablc I incl.lcates themcthocl of d:.sr:erd'nation, thc

the particl-e size.

irlethy].ene chloridesolution

Pyrotccturic mix

IrJatcr colution

(C) i',1,,t_!.t,iortig5g.

nlr,uiber ''i' e>:posures carricd- out by

fonn o1' thc agent, 1,he dosc rangc,

TA]jLN 3

AEROSOL aposuRns ro Bz (u)

Acetone solu'cion Aerosol gcner-ator- -retentionapparatus*

Acrogol gener-ator--ret cntionapparatus

Aerosol genel:-ator--r,ran ex-posure chanrber

EA thernal mu,-

n:i tion--vind1;unnel

o. B- 2.0 ro5-397

Freon 11 susPension

rrl

o.6 22-163

firrotechnlc rdx Pine Bl-uff thermal (0.)nnriri tion- - con irof l-ec1

respiration

Br-rr8

IIYDNOCHICIRIDE

!t'

nOor,rr"l; or- soru'Lion-or ni - oispersion -siz"(@

-!'{r-* '

BAIJtr

l-. t-it.0

0.8

z\-tt+

rtjo- 3)+I

ira-: 893T Aerosol. Scncr-

ator--rctentlono.pparatus

e retent:,on apparatus consists ;IosEa syste.n o1 trilring througsul1ject. AJ''bE:r each eicPosure,

of' athe

thethe

vhich the aerosol 1s Presented- tothr,' amount of agent remaining lnbetween thc amount presen-bed. anci

the esti-materl retaitred d"ose.

system ie measL'-real . Ttre ci-l'fferenceamount remaining in 'che sYstem is



! i:,', .i ' ,,',.' l;liFiluu

(C) The final scrie s crf eigh1, cir :'.c;'qposcd- i,'ibh actual- *tmllions

iui"",i"ra gr.enades {'roin Pjnc UfJ'f Arscr *') li.s coitd-u-ctecl' t'r'siug "reguJ-ated"

breathing. A visual fecclbaclt s;rsten l.Iar .Lcvised. birat a.l'l':l'red- the sub;1cct

to acljust his rcgFira''cion b1'observing its effect oli B'I] oscilloscopc bcam

pre-seL

'bo srlccp'ac'o$s the scrcen *t.-,"y 5 seconcls, Tlris technique resul'ccc[

in uniforti brcathing rates ancl titlal volrrmcs (aversge Cevia'tiorr less thantu/,). ,

(C) llecause the ra.l,c anc1'ciclal- volurne chosen as thc siandarcls vere

iater juclgecl to be out Of line rri.i,h "normgl" values, tr^ro c.rrectioi'Ls \'icre

mad.e in the measurecl CT t-,o al-Iow for this c1isproportion' Thc firsl' rras

to assume arl avcrage lej,ention of' BC pcrcent instead of thc usual

5O-TO perceni;. (ff.is csl,jmate r,ras clerivecl f'rom ea:rlier sLuclics by the

Aerosol- Brz.nclr of the relationship of' rctention bo 't'idal volume in a

large nunbcr of subjeets. ) The seconcl correction rras art a-Llolrance f3r

bociy suCla,ce arca appliecl to then-inute volumc'

(C) Tab1e l+ sh.ons the trlr:orrected. ancl thc c<-rrt"ec'bec1 CT's (based

O"'aO percq:nt rctentj-on ancl al-l-c.r.rance for surfacc aree)' Tnc corrected

CT j; iot 1.rnrr,1al breathlng at tO J-iters per rn-Lnute jn a so-Ldier of

avcrase surcacc area (-1 .[3lr sq nc';tl::s).

t,i' li

(c)

CORITECTIID CT'S FOR

'ly\Bln )t

SUBJEcts INITALIIIG tsZ llTTii A STAI{DAIJI Blulln!{ilq JA!."TIRI!-(U)

brr.al- Minute Surllact:t Arc-a

A s grr-tn<:rl.

Re t,en'bionrrcc'ccdCT

Sub.r cc c CT Vo.-Lunc ll:i i5ht tr'lei1 TBI

AfvButIiod

Stom^h,|l

AbclKen

rtq15,f)

109

-LU9

970l

99l-o8

-1t't-^ oLI .Q--. o-,_..1 " ',J

TI l.)

-r2 D

rh.0

1O1

rh. o

Or Ot)I .UOnni)z,vBg. o

bJ. -L

7\.375.o

70. bB:. tI.l

2,02/-1 .)?

n t rlC. JUt fr.,:

_L . (X)"r ()1

r ft'z,l .L/lrnOr.)a

l_t-) [

a6L

-L)tJ'l (:aJ-)t

I t )\l

'1 rr5

1)Bt o.'z_Lrr I

li, :,'. ryu.l

t'',5'/ ()

\.')l_\ I I

8O

80(10

ii i',

ii08o

BoJO

IJOO

75(t,)'(L

70

5g7O

(C) Thc relative eff'ectivr:ness of the inhal-ation l:ou'.te for the

comhlnecl serj-es j-s estimatecl to be approxim.tely 0.6 tnat q:f the intravenous

route. I)1t'fercnceg in response attrij:r,rtable to fom of' -chc agent, ttoric

of aqlm:in.i,strat,:icn, ancl partj.c-Lc erze coulcl no'L be rc"l-ic-bly estj-nated

becausc of tlrc large nr-unber ot' rrncontrolled- varia,blcs (par-t,icularly those

relatecl to breathlng pattcrns. ) 'fire f'act that rmrch m'f,re consi-stency itl

. . *: tl rQqNF[.ry.8I$lrlAL i ]

t()LJ



SIRF(D{i! IAE D

=:-"-CONFIDENTIAL-n

Cii,:i i.^: r"ri

'l,l*'t$$lilffi

a

the tLose-response rel-atj-onship was obr:i'i-',ecl ln the final- series o{'8sdojects rrhose breabhing pattcrns wer(*' lligulated. suggests that thil;nethocl miglrt in the fi;Lure pcrrcit thc l;ys'Ler.ra-bic exl:l-or:atlon of r"clation-slri-ps betvccn the rcsponse and such fac-';crs a$ prrticle size, e'ic.

c. (C) Pcrcutaucous Route.

(c) A<1:ul-nis-L;ra'uion of 'BZ-throrrgh thc skin was unclertahen prln:arllyas a pilot s'l;udy 'bo assess its I'casibitity and the ord"er of dosagcrequirecl to proclucc clefini'uc ci'f'ccts. 'I\^relvc voluntecrs lrere givcn slrrll-d-oses of the agent jn a vehj.cle of Crcsol and lf-D;hyhnorpholine, and no

d-ef inlte ej'fects rrere oLrserwed. Thirty-one xlen i+crc then exposed togradualJ-y increasing closes rn a vehicfc of'bcnzyl alcoirol," 1\ro of thesecascs, bol,h at bhe hjghest doscs tcstecl (lO-6O l$/lig)., itcvel-opcd scvcreresponscs, r,rh:Lch lrere cielayccl in onse'b ily al+-36 hottrs ancl thcrcaf'tcrfollovccl a course sir,ri-lar to tha'b seen wi-bh:i.v or jm closcs af'T-3

frC/tg.A meani.ngful- es'cinr"-be of relert:'Lve cft'ecbiveness by bhe percutzrneousrou.tc can no-u l:e nncle from tlrc prelirn-i-nary sturJy.

3.(c) .

a. (c) Igbiuptc of th. IDtq.

(C) In Appcnclix C, cases seJ-ectcd from the 'cctra-l- l-lr;t of experi-ncnba]- elq)os1.r-res to BZ are py'eilcrl-i;c':tl jrl o:ctLcr of dcsagc. Tables 1-),Appendj.x C, subd.ivide -i,hc cases by route of ackninis'bratj.r:n, anrJ- Table f,

Appenclix C, combines all- four rou.'bes with cascs arrangccl in ord-er ofiv equivalent d-ose. fielection of ceses lras goverrrecl by the followingcrl i.cri a :

(c)

1. Itlo pre.riou.s e;?osures to BZ

2, I'[o trea.tment prior to 5 hours af'ter exposurc (inthese cases, only data col-Icctcd. prior to trcat-ment is consiclerccl in scori,ng the T1?T)

.j, /!.ir.irrlr-l,lic nr-rrnber of observa-t io,rii i:,;:r-Lnum or'[,spa-ccd. ov'r::: 6 or lrore hours) fcrr ee,ch variab.i.e(pcrf'onnance, hear-b raLe, anrl bloocl prcssurc)

I|. $rffi"cient behavioral infornrati.on to perraltdeterrn'iiratlon of the presence or absence ofhal"l-ucj nat:i ons, clcl"usionr:, ancl/or viol-cnt behavlor.

For each case sclectecl., thc foll-owing data lrere corq)Ll-ed.:

1. Case number2. il:se in nicragrams per kilognxl3 . ' Route of adnrlnl strationl+. IV equivalent close

5. Mean heart rate (r-6 nour per:i.ocl)

(t. I'{ean systo-lic and d.lastolic np (l-6 hour period.)T.'Per:flonnance fnclex

, , I','{qiFi$B. ;l'iiyll"iuic'iiil Pu



B. Prcsence of ha'l ;r:j.natlons (0, lo, 2+)c). Frescttcc of d-c-'-1 .rr,.ons (0, t'r-, a-r)

10. Violcnt behavic;:" (aggressivc, clcstruc'bivc, ola-^^r'ic.l-,-O'l+ f'r-\

II. ;;;.",,UU--V,

L'I L'I

(C) Co:rrclation cocffic-Lents lrcre computecl frorrr this cortpilationancl have atr:cac1y ircc:r prcsen'r,cd in Table I' Probj-'b analysis i'rilg tiren

cnrricd. out r,rith respect to 'bhe f'ollolring crj.teria:

l-. TI{I = 4.0 (ndfd rncapaci"Lat,:ion)?.. TI1I = 5.0 (rnoderatc incapacitaiion)3. TRI = 5.0 (severc ineapacitablon).[. TRI = 7.0 (rnaxir,ael incapacitetion)

(C) flresc probit anal;rscs vere rLln f'or the botal san4rle oi'l-I(:.. cases using the iv equjvs-lcnt ciose ancl repeated separately 1"'or the in-. hal-a'bion cases u.sing the CT as the dose parameter.

' (C) The dose-response regrc-ssion equation for i-v eclu.ivalent close

vs. the presence of hallucina-bions of at l-east ndlct. ciegrce (U = L) r'ras

then cleternr-lnccl by probit anal-ysis, ancl'chis vas repca'bed, using the. presence o1' severe hall-ucinations (tt = Z) as the response critcrion.

l[1re rcsufts of these prabits are prcsen'bed separa'bely j-n cletall inAppenclix C and are summtrizccl in Tablc 5r folloiring pagc.

(C) If a singte d.efinition of incapacitationis to be r-rsec1,'bhcrl

it is reconurenri-ecl tlrat the sevcrc responsc (mrf = b) Oe usecl as a

criterion. l.tris, thcn-, f:rcr.r Table 5, yielcls an estiniate of 6.f6 yS/tC

$ll'conficlenc" iitrti-= ,,66-6.T1-) and- an ICI5O oi' r3lr'.'T5 (95/'confi-dence l1mits = 110.e&f5tl.08).

b. (C) Ectirrr,atc of the tD50.

{tl) [i',ii.i,,r r't.l ]lf::'r.,r-1 r:-'lli;, tfic cstiraate of the.l-r..r.l:r. i lr';se oi'EZln man is of necessity basedon incij.rcct cvj-d.cnce. 0f the many c):-

t::apolations availablc, three are recolnnencled here for consideratiou.

They vere chosen in preference'Ltl rnany othcrs because, f irst,'bhey

seemreasonatrl-e ancl t1o not clepcncl on ambi.guous clefinitions and, secondly,they ylelcl estlmates that a.rc of the sanoc geueral order of'nagnitud,c.

(r) (c) D'llapo"Lation Froq 0thcrSpecies on t]:e Basls of Spccles !/ej.ght.

(C) From cletez'rainabions of the LDIO inen apparent relationship has been demonstrated.bod.y weight of the species and thc lethal close

a vari-ety of' logpr species,between the averagefor that species'

cAt\r'ii-L[n::?1



['rcsence of ha.ll,,,:.ina-bions (0, -L+, 2+ )

Prcscr-r.cc of d.cl'r;r'ions (0, i-'r-, 2+)

Violcnt behavio:-' (aggressivc, rlcst:rrc-bivc, orcscapist--0, 1r-, 2'r)

()

C)

l-0.

'

11. tru!C) Corrclation cocfficicnts rrcre comlutecl, from this compilationancl have alrcacly bc,:n prcsen-bcdin Tabl.e l-. Probj.-b analysic was then

carriecL out r.rith respect to thc follo"ring crj.teria:

1. Tf{I = Ir.o (nr-tlc incapacitabion)2. TIII = !.0 (modcratc incapacitation)3. TR[ = 6.0 (severc incapacitatlon)\. TRI = T.O (nr,:r;cirn1 incapacitation)

(C) Thr:sc probit amal;rscs vcrc rurl f'or the totafsample oi'tl5

cases us|ng the lv cquj-va,l-cnt ci.ose ancl repcated. scparately fclr the in-halation cases using the Ct as the doce parameter.

(C) Tire close-responsc regression equatiotr for iv eclu.ivalent dose

vs. tle prcsence of hallucina-bions of at least milcl. d-egrce (ti = L) rras

then cletcrrn-inr:cl by probit anal-ysis, ancl'uhis t^'as repcated using thepresence of' severe hallucinat:-ons (H = 2) as thc response crlterion.The results of these probits &re prcsented separa1,ely in d-etail inAppcnclix C and. &re sumrurlzccl in Table 52 follotring page.

(C) 1f a singtc d-cfinition of incapacitation is to bc used., thcnit is recoflnenrled'bhatfhe sevcrc rcsporrsc (fru = b) le'used as a

crj-terion. Thio, then, from Tab1e 5r yietcls an estimatc of 5.f6 yg/f'e(95'fr conticlence iimit"'= ,.56-6.71) anrl an ICt50 of' tJlr'.'f6 (gSf'confi-d.ence tlrrits = llO.a&f5t+.tr8).

b. (C) Estlnrate of thc LD5o.

('r:]

in man is of necessity bascd. on inclj.rcct evid.cnce. 0f'the nany c):-

trapolal,ions availablc, threc are recortrnended- here for considcratiotr.

They vere choscn in prefercnce tr:r rnany othcrs because, first, they seemreasonabl-e and clo not clepenrl on ambiguous clefinitions and, sccond-Ly,

they yielcl cstinrates thal are of thc s;annc gcneral order of' llafinitucie.

(f ) (C) Eitrapol-atir:n From olhr:rSpecies on the Basls of Speclcs Wr:i.gJrt.

(C) From cleterndnatlr-rns of the LD5O in a

B,t1 &pparent rclationship has been d-emonstrateclbody veight of the species and thc: fethaf close

varjety of lorpr specics,bctr,reen thc averagefor that species.

CAI\1 ;i L[D il,tt$$$fl1flffi

31



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fnis rel"ationship i-s alr inverse one--rlr:se decreasing with increasc iubocly velght--and resui'fs in an LD)O cr;r,jnrgte -i'or man of about Z-'i ny/k1,

(e-) (c)@Ilstirna"bcd Lctiral trse ot' {crclpine in_ }fal, Usjrng thc Dcri,cnstrat_eri li,ai,io

-;:-=----;-----:':--'-._o{ k:r.hari'-y jn ArinaLc ilctr.rcctr }t_e$._{!.lg_"".

,a ;", oi' scvera1. hundrecl hu:nan fataljtiesancl surwivals foll-ow:Lng large !:norm d-oses of atropine, a probit.a.ttalyslslras perf'ormed" that yi"elclcd an LD5O of apprroximatcly lOLr p;/man. / Ontyreports.of'closcs above 30 nS were incluclecl, since closes uefow i,hj.s wereconsid.ered. r.rnlikely to be of' suff icient necllcal interest to warrantpublication. (ft is recognizecL that bias in medical reporb:i.ng vou1ds'bill- play a roJe ln the case of thcse hi6h doses, but the bias rnightoperate ei-bher r,ray: i.e., surulval of a high close rn-igh-|, bc a grcatermedical- curjoslty than cleath, r^rhile dcai;h I'ollor'ring a ctose o1'lcsgcrnagnitude nrtgh'b be regard"eci as unu,.;ual cnough to report,. If'this reason-ing is comeet, the net eff'ect r,nrr:ld be'bo result in a sample of publisheclc&ses in r,rhich high-close survival s'and lov-dose le1;halil ies vere favorecl,and a prohic regression cu.rve would have a low slopc. '1his is rn factwha'i, wss I'ouncl. ) fexti:ooks of' pharmacology give estin:ai;cs of' lethalityof LOO mg/rnan or !!ore for atrolrine, but this is a veq)r general- estinlatearrd- is no'i; e4pressed in probabili"ty terms

(C) ft seems reasonable to s,cccpt lO0-)00 nig/nsn as an LD5O foratropine since this is a broad sEngc aircl inclucles virr'cualJ-y alJ- theassorted estirne,tes cur"rently knor.rrr.

Itl-iliewise seens rea,sonable 'co

accept the ratio of lethal potcncy af P"Z compared. to atropine s.s about) to l, since'bhl-s jsthe approxirnate ratio fcu:rcl in scvere,l- other specles"f'Jeis places the LDSO for BZ :'-n man at 2O-I-OO rrg or O.3-l-.h mg/trg.

(:)(c)@Ratisr of Phlrsiol-oglgj* Ef'tgctilreness Rg!:r.ecjr BZ sncl Atr%)inc, jn l.[an.

{c) 'JLr ,:r .,; i lrr,r,'-l :r i.j;,,. .:.r r a varj-ant on (2) a].,r,,,.,.:, -lt has becnshovn by Cu:rmlngs and Cralgb "uha'b the parasympa'bholytic ef'fects (hearbrete ,e] evation, in}.ibltion of slreat:'-ng, etc. ) of' an ornl- close of

5 pe/kS oJ.' BZ are similar to a.nd sj"ightly less than those of a 2 nglntramu:;cul-ar dose of atropine in normal- .rol-unteers. Al-Lolring forrelatlve ef't'ectiveness of };7" b;y the oral route to bc O.l that of theim or lv routc, anci translat:ing the 2 nrg close of atropine into VS/bS,re obtain thc following potency relationshlp;

)+,5 1tg/Ug of M = (or is sligh'bly tess than) Zt).5 1:a/tcg of atropine

2J,5 = (or is sJ-ighbiy less ths.n) 5.2rl5 -

;-,-li,!".-T{l?,1$t'"1 i :'',i

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€dTq'#

- a {ri#

IIAL-.Gdq-dl@

--::cONffi'tD-IiN [!ij;tii$$lFl[u

(C) Since the mechen-',sm of clcai, , rom bo't,ir atropi-ne and IIZ jlr

consigtercr; to be a clj-r'ec'l, carciiac cfi'c'i: . jn most, casjcs, thc rat;-Lo r-ri'

paresjrmpatho}yLjC poLeircy llccms a veaso,Lablc one't,tf use As a]l cl;-i':ir"urt'c

i'oybhc lcttral !6'i;ency ratio. The c:Crapolation of thc LDSO on th1s

basis thcn becotncs:

LD5O (a'cr,:;pine )

:l-00- 5OO ng/rranLDSa (Tfl)

= 5 >: LD,O (BZ)

= 6 :i LDSO (BZ)

= 16 to B3 mg/r'nan = o.2'to 1..2 m{Jft-g

'

(tr') k (c) "

(C) The threc e:cl,rapo.1ations m"ay be sltnmmrizcd ac fol-l-ovrs: \t1. Species Wc16ht: LDJO - 2-, wWlke {i

H

2, Lethal Ratio (ntropine): LDSO = 0.3-1 .\ ng/ltg t!i?

3. Parasynpatholy't,ic Baiio LD50 = 0.2-l- .e W/y+ i;*(atropi"ne):

,,]il

1t'

(C) Sinee thcse estirrabcs are- not g::eat1.y d.iffcrcnl,, a c()rirTlrotrrise "+

figure of O.f-: r4/tg is suggestecl, granting ihat conf iclcnce lirnitscannot be assumccl in thls case.

c. (C) Es'cinatc o]l bhe LDJ,.

Thc clifflcuJ-"i:y in prcdicl;ing the LDI for BZ, arises in thetarge probable error fn the slope of a regression -Line rlrarrn tlrroughany assumcd- LD5O. Dqqgps-c a,n IlD) is neqcle:l {pr.tLre eS!-l!la-tio,t--oJ !1rc--,

-i'rqJ:gg=:u,clog:J1[fi;"f tirc- LDjl-to

-tr:enp:o-)r-

"o*Jriguremust be

ad.opteii as a "besr, estinrate.'t 1I1e sinplcst, and- possjbJ-ythc mr:stjustifiab-l-e, r.'ay to clo thisr :i ,q to ta.ke the l<nor,rrr sloDe j.'or the co:rpouncl(shorm to be ebout IJ i.ri irurrsrr e.nd" anirnal effectiveness stlr',1:i.es) anct toi;r,r1,i; rr 'l ,'r.Lc ol i:tr..r r;.1 ':g::r tl:t,',JiLgir l;he LD5O. fhis l.lr:e r,i-; .1. 1, -intcfsectthe p = U6 l-rorizonta.L at betireen 0.4 and l.h mg/trg.

d.. (C) Sqn:r,?.ry of llstjirrates.

In su:mery, consiclering al-l -1;hc j-nforrmtlon available, iti,o ad.opb -bhc folJ.orr,i.ng estin:,atcs f'or the lcthality of W

LDSO = O.')-3 rntlY.S

tDl = O.Z-.t .1,"f/USIII5O = BDSO (TRI of 6.0) = 0.00.57-0.006T nrg/lre

Safety factor LDI = O,2 tc 1.)1 = JO 'Lo 25O

ifrc .offit-:"o"506r

(c)seems besbtn n&n:

s)(l'baninef'uf



(c)appear asindr-icated-

(c)

).r 0.5 '(

1.0

o/)

il

[ -r,.i

"ii:lLi;; i

I+. (c) ltq.tufr,'^ _ - it,.:pca.bqtjlgtugs.

i-,. (c) il,-:": ilI;3glg!.To oc:tcr"nrlnc rtlict-ircr cultulaLive or tolcr"ancc- ci'fccl,s vou]d

a rcsul"t of repca'i:ci- e:ryosure to J-ov tlosgi;, thc serj-esin Tab-Le 6 rrerc carricrl out.

;r ',.-rnfilf$t

",.);fl3;$

TTUIIJ 6

Ixin-crr 0Ll,'fiLrIi!I-!4M irxPgguliris r0 BZ (u)

ifrnnb-e

S4-iccts Dar'.l): Dosc .- Er;'r. -ik:sults* -

Fg/Itg

r.0

Fat:iguc, 65r:ncral- nilclma,l-crj r-;e trlr 7t1t day. iioclef lnitc signs of ilZ eff ect

"

I''liinrnr,:1 cl'fects Caily. I'lo

cvidence of curnulative ortolerance effect.

l,tlr:iural cffects daily, No

eviclence of ct;-tnu]-ative eff'ect.One subjec'l, appeared to cle-

vel.op tolerance.

I'iinirna.L ef'fcc'bs first d-ay.

I,lilcl to nndere.te effectssecond. day. Itiod-erate to$evcre eff<,'cts thirrl clay.i,[0 c'v:i .i,.:],1'-r ';:f tolerar;ce.

(C) The resu.tts of these stuclies inclicate that heal-thy nrbJcctscan be c;cposr:d. to as m,lch as O.'i 1rg/Iig of BZ claily r.rithorrL notlceabl-eeff'cct on perl'onnance or plrtrrsi6-lsgical, l'unctj-on. Ibscs of 1.0 pg/kgdaily couse perceptibl-c efJ'cc1,s tha'b t,rould prr:bably not be.ol' pre.cticalsignificance ardlrould not 'be cluuurlative. Ibses of 2.0 yA/XA, hot'rever,prod.uce cunrulatlve cffects that become significant by the second day ancl

approach the point oli incapacj.tation by the thirrl day. (ln tnis 2.0 Vg/V.gd.ose group, the TRI scorcs roce progresslvely from a group mean of 2.8on the {'irst clay do a mcan of ll.5 b)'the'bhircl clay. One individ-uale4pdlencecl. clcfinite ha.l-lucinations ancl cllsorien'l,ation beginning 6-tO hoursafter the thlrd d.ose, )

-**-''-.- f"r n f,B ,,/r r--Nriil':r, I I ';i:", :" ]:.CONFIDENTIAL. :

35



#.'\A!'i11fi*{oNFIDEN#

r'!^t G'#

rlAl= lFlflts

pcrccnt of' bascline-blre Texas l3a'rtery)

e .t A ,r r,"l i ;l 1-) db

Uto;U#lou

lJ.rc meerl scrlal- perfor-.manc(r iroores (ave:'agcon nu:nerical- facility and speed of cl(iii,'.1'e subtests of'are siror.m gpaphicaj--L), iu Figures 2 a:rd l, for the f.Ogroups.. (Tire upr.rarcl 'brencl in tbc perf'oruance scorerigroup is attributabl-e 1:o practice effect. )

. / .\(ir. ) (C) Effcc'i; of a l]eco-ncl li;?osu.re Af+;er\-

-..,

(c)

{Cl) A-l 'l. lrli'.;")r i'li,:r:"| ;i ;r r.3 n^efl

eff ect, i t s corrsi sl,ent appear.a,nce lnindlvldual ins-bances j-eaves no cloubt

(c)

ancl 2. o lqf\'.{f .',;ayof 'uhc -L.O

explanation fcr tli' , ",,(,oolld-clo!c"this group a^nd serveral- othcrthat lt is er definite phenomenon.

'a'

zu: Irruerwal."

(C) _1!g rure.lpcc'[ec1 o'bservation in subjects given a rcpea-t closc ofBZ tvo veelis aft-er- llrciq first exposr.Lre lras that signs and. synqrtoru;

-trCVdI6It6d'more rapidJ-y and r.rcre more pronounced".

(C) To test the rel-iability oi' thls obscrvation, seven subjecbsr.rho had been exposed. 't o inhalation retained d"oses egu-i.valent to a mcan

lv or im close of about 6 WlVg were gfi'en an intrz.nuscr-il.ar injectionof 5.0 pe/frS of BZ two to three rreel<s follorring thc lnhalation close.

(c) fhe resu-l-ts conl'lrmed the earlier find-ing. Six of the sevensubiec'bs shovecl a rlrop in perfclrure,nce scores that exceed-ec]. thc e:rpecbedmagnitud"e (baseci on t;he TRI scorjng tabJ.c norrns for this tl,ose) iry oconslclerable uargin during the fjrst 6-10 hours. After fO-1,5 hours,hovever, the same subjects shorred acceJ-cratecl rccovery, attainlng scoresin pe::form.rnce tlrat lrcre higher by a substantial n"argin (t-O-40 percentagcpoints) ttran the expecteC values, Ai'ter !B hours, scores in perfonnnncecorild not be distiriguished l-'rcm e>:oectecl val-ues, l;o that, rln effect,total- recovery tlne d.id not seen to be appreciably shorbenecl.

(C) fhe al'cerecL time characteristics of the pefi:'onnance rcsponse(mean Tc;<as Bat-bery p'ercent scorcs forbhe seven subjects) are shor,rngraphically :'-n Figurc-' l+, superinrposecl on the curve of "erpectecl scores"for thls c1ose. (lir:ar-t zate values shovecL sim:llar al-teratjons :flram theexpectecl time coursc. )

5, (C) Temporlr,L Responsc* Ctraractell st j.c.s.

'Ihe tinre climension nmst be consiclered" with all agents, butespecial.ly in thc case of incapacitating corq:ounds. To rcd-uce some ofthe vagueneds lnherent in d,iscussions of such questj.ons as "I,fren d.o thefirst effects a,ppear?" or "Uow soon is the n'ran incapacitatcd.?", temporalrel'erence points have been defined as follo'rrs:

^/'iD



FIG{-IRE 2SEFIA.L }MAIJ PITRFORMA]ICEMMS FON B SU&]ECTS GIUM{

t"e- EFFEcr

FTGURE 3

SIRTAI MEAN PERFOR}'{ANCEEOms FOR I+ SU}.}ECTS CI\ruTf I r.;,1

.,i 'l.i i,

-- CONFIDENTIAL ,::::

a'/JI

I

I

Day 1 ln.v2

\/

'\ I

Vhv3 Day4 I

I



(,?

()F{oCJ

[o'rR

CJ(0

olJ

tr

h(.)

+J.P

A!)

),1

c)H

IOO

T5

5o

25

0

CO1VIPARISON OF

,ryriflLft$$t$ffin

II{)

Hours elapsdd- fron time

FIfiJRE

of exposure (1og seale)

N(PECTED W]TII ACIIIAI, SARIAL I'{JIAN PEI1FONMTWCE SCORE TOR

Fnrm-f riilIurr,Osui",. $ii0idii\tu-"21\rD-mFfl"mmT

-- IUf -"- -7 ${jBJECTS

"Q



:*. "- +,, CONFIEE11i

l-. Onset Time: [he tlnc at r,']rich performance scores firstclrop belora J! percent .cf baseliiie.

2. Peak Time: Thc 'uime at r,rhich per.for"rnancc scores reachtheir l-orres'c pofff@ perfortnance clrops to zero and. rensins thcre fora number of hours, thls point is taken to be the nlcl-pojnt of the periorlr:f zero perf'or:lance on a logarithnrlc tinre scale.)

3. Partial Recoverlr Time: fhe time at irhich performance firstcliubs above 75 perccnt of baseline d-uring the recovery period-,

l+. W: The tlne at vhlch per:i'ormance clinftsabove 100 perceffiing the recovery perioct.

(c) Figure I incllcates thc tcqporal refercnce points for each

the fourd.egrees

of response severlty as intersectlon points betueenserlal- per:forrnamce cw'ues and the criterla l-evels dcfined above.

fueY toeRecoveay

7i me5

PeorTrne5

rl_ffiJnx 5

TM/n)OBAI, RlT'IfrIil.]CE POIT'IIS

[.CONFIDENTIAL39

UI

the

\-*-t'

7{

5o

-'t(

(.)

d..o

a0)t{

ilt,

gl

o

g

L.oICJO{

(u)

Hours



(c)results:

(u)

Tabl c Tffi r-rn Figure ), sunrnfi,rizes tl:e

TAI],X T

SUM'I4Itr OF TIT.trrcIl,\I RF'JNR]ilICT PONffS (U)

TE

onse1" Time Peak Time Recovery Timc Recovery Time

psed, hours {'rom time of exPosurc)

,o-50

70-Bo

9O-l-OO

100-til0

Itild. (TRf =

lrroderate (TRI

Severe ('-L'BI

lvbxller (1BI

)+)

-q

=5)

=l

I+_ j

2.5-3.5

lEAEL. )- L. /t

L-2

&ro

Ci 11(}I-L

Q rr

B-ra

20-25

2r-35

35-\'

)u-ou

6 - ( c ) Modif i cati <-:n of Rc sporsc by Treatneut '\-/

(c ) *q1lot-slqdt-qe-.lnw]:ripe*iJrg-q-F-s- -sf- -gsl!'Q.o-ilsts*{ietasol1;lsLi-q-t'o-nz have^.trs-e-s- c-Q.*dr"1ele-c1 :q-i!lr -lya FubF.Le.rqse:--!g!{lqt!={grgl]4a-3gllgi"19*gIAl

En"A "u""i"" (prtu*.glr-rnp-nsL Bcrth T1{A and'taEerine arc i;nor'r't bo havcffi; "r.1j_'uil'tTil tire;r efficacy is not necessarilv".ffi

. +_.- "- - :- '..-. '.---*

a. (c) TltA.

(c)reveiil t,roni

inst BZ inTable 7 sunmnrizes the experl-ence r"rtth THA.

(c) ( ,* procluces a l-or,iei:ing of heart rate vhen -bach)'cardia isjpresent, )estorls sallvary output, lovers body temperature if elevated',

reduces puscular rigirlity, and. inproves mental stabus. It appears to be

somevhat se<la.tive in lts action, often prod.ucing a mentafly clear bu'r'

slcepy subject)



c){<**

@

o

ts(,I

PCc)

o'\O

O

Ho

u c/)P. P.

p.@

PP(D(Da' p,!>OOu)u(D(D

i4Ptd

14

r4rdEd

HHEt

r)

HH

F]J

tsa

Fi>c)oHra€C)hcl

dN

F3P.Fo

F'

o

P.do

o(,N

oH

t\JooI(,O**

o\oI\cat<*

o\o*

cl-

ir"ot-Hcr)

G9O

oFJHH

at,F6e

cl-

rxoo\n EEf_+- qcDe

l- (.J

{ 4nr59oFl)! .f -c-PJoim pjo>

a

IHIH

lHl--.1

ooFIB

pFIP

ts.

froU)

tscl"0,)

F'F E.HF SgSg'FF 3EFmAt Fry Op.OcFtsO t"5p.Ct! FJCI'f FJ F ts'H Ptr FP.P le rD crry cl!(r) Oct-0)3 ci" N tr, O O cf O FhC { r0 cr0q P. H) 5 o 5E f-,0 rD u H.

o FIO cl- O O o FJ tr Pr\ ouJ otJo p,<ry(nt-bcfI cf C u rD O O O t.,. (tl-,t..+-o H o d c/B p Fl o < Pt E

El co { O << tO (nf'JSriJ . O p, cf 4 Ht O 0rl d'FjO O O,O 0r cl-(D ts't ry H'OC H h dt,.ry tdFJ t g, tr <ry 01 o',O O E N (n r0 ocq Onr ry < ct tr fD < cFo d g. q rD cr F F cl- P Ho' h 4mFFb(n tsl Iry rD p. NS ctsaD lrJcr

o Hg rcn E o { { Xd b'6 tr.x o ru5{tr, \J "J :y l-JP.i'11 IJO P.

u a d O Poo(D Ptrci-o o< t oPF \JFrFr|J.oFFjIFjmOP.O r a e 0o fDw 55 . .!-'- rl

!\ ll

fu4fi?urliiuro'il



I

CONFIDEI{ ftAL

b. (c) I 'rinc (pir.ysosticilLinc).@.*4!

(c) De,.cauc;e j- i, hacl been uscd- succl,;il9lUl-ly in pqEenlg

clini- call; cedFry-:-

in aninal *1r,ll;h-. *}L4-..-

(c) Through trial ancl e:rror, optimal oral- d'osage lras found to be

tnthe neighborhJoa of L+,mgfnr, Uul, tiric value may vary cluring tne c1u131

fsqt

, *uru" s a.!,s.f- -.r.eru"F.€L"m'can-"b.e.3chi*ev-ed-ui-ihin**e.n-il=ea&. be-nain,t-p,r"::-e-d*Li:ereafb-er' In the

GT-E"Uiect treated", oral escrine r,ras given eve{X 40 mlnutes for J2 hours'

;;i;id lro m:inutes after the injection of f yu/ue of BZ' A tot'af of

2lo mg of eserine \^'as given. Tlte subject ilid. not see:m to rcspond totren,tment foy the firsi 5 hours, }:ul, a,t T houro drarna,tie improvement

sucidenl.y vas eviclent e,s he emerged from a stuporous state in which per-

{)rTnance was zero to score fO percent on the Texas Battery and shoztly

therepr-f'ter to score pO percent. Appetite, sleep, rnood and activityvere all within norraf limits thereafter and, rrtth trto exceptions, per-

f'ormance $cores were mainta1-necl above BO percent until- ful-f recovery at

about !5 hou::s. 'I'n-e tr^io e;cccptions rlccurrcd when the closirge of eserine-was dccre:ased for several hours and perforuance scores fetl to lO pcrcent'

I'hey quichly returned. to above 80 perccnt when adcquo.te closage was re-instituterl .

C) fliree subjects expr:secl to BZ munibions wlto sholred. severe or

iir.iin*:- t.=fonr"u vere trcateci. r,ith eserj-ne beginning at from lr-12 hours^ t.

follor,rin6! exposure. In each case, using oral closes of from 3-\ nrg

spa,ce-d !O miruutes apart, d.ef inite improvcment vas obserrrecl wi-bhin an

hour end a,lmost total remjssion r,rithin J hours, vhlch could- then be

maj.ntalned. as long a,s requi-red-. In two of these men, treatment was

discontinued. a.fLer a .fe,"r hours. Perforrnance scores d-ropf'erl tr: zero in...tqli .ri."ri) l;ii;it-i-tr Jl lt, ,.: t';; il.rt,l lrl-l .lr.r"Cina.tionS

"gg1-1.1"1'r){l

. ';--..^' ' TilAr, -r,.)i.- .,J (7r.".-rr--5*,."'

ine doe6 n,:t se*n to matcr.i alJy $horben the overaLl duration-,of. the.

c. (c) Cornment on TliA anrl Bscrine.

(c) l'he relativc lt1s3J'.1fi-*of.*1il#'--anxl*es'erj-{re"'ha'ree''not"recelv-e'd-egf;ii"rent urrffiffi6:,ilranr: clefinj.te r?consncnel0.tfon,s.ol one above' ihe

?frog*-.- Neither .1s ld-eal. . TIIA nn.v- hAYc"!o&lc plopeI-tie"s,.not."shl::a'1,J"# *w*-:*'"= li'ry

^1! *r -.^ r r .- J + ^^^-- *n

636-rr"o np6 11uqJ !S -,Ki.v-gn-i . JjJ.ird"esLl&--I!=99,9mIffi J,.t o .. ." ot o'"€,t;Lue--f nu'o,

"n.o -*r**inf- lih i t ; ;i ih'''oiit i ma r

truitmcnt Levels subJects who voufd bc in severe d.ehriunr if untreated

can read-, wrlte, play pool , eat,, ancl sleep normally, the lT{A-treated

I . .:.fa\

I

CONFJPENTIAL . .

(*: ' iir,sfi*--



CONFIDEN i, IAL

b. (c) i:,,'lrine (PtrY"os '

(C) Recausc jt hacl been usccl sur:c:.''ssfu1.l-y i. patients to reverse

clinicatl-y lnciuced aLropine coma, and because of i'hc l'avorable resuits

in aninlal trlals withBZ, eserine vas e:tnployed in a d"ouble blind' pilot

"t"Jy-iiithI vo]untcers e:<posecl to 'l yc/kg ct' BZ irn'

(C) fhrouglr tr1al- a.nci. r:rror, optimal,oral- dosage vas found -bo be

in the ne:i.ghborhood, of \ ngfnr, but this value nay vary duling the course

of treatmcnt f'rom e-6 Wlnr. bV caref'ui and- contjnua] obserwation of the

hearL ra.te ancl ad.justment of' the close to maintain a hearL rate of between

iO *rra BO neats per rulnute, nearly botal rem-ission can be achieved lrithin8 hours of BZ administration and. can be maintainecl thereaf'ter' In the

tast subject treateci, oral cserl.ne r,ras given every l+O mlnutes for f2 hours'

;;;il;il-[o *i""tes after the j-nJection of T Sts,/ug of BZ. A totn'] of

z:O nrg oi eserine was given. Tire su'bject did notseem'Lo lcsponrl to

treatment for the firsi 6 hours, but at J hours clrarnn,tie jmprovement

suo,1en1.y vas evid.ent as he emerged from a stuporous state 1n which per-

formance was zero to score JO percent cln the Texas Battery anrl shortly

tircreaf'te-'r to score !O percent. Appetite, sleep, mood anO activltywere all lrithin nor-rml limlts thereafter and, r'rtth t'.ro excepLions, per-

fogrnance scores vere malntal necl above BO perceirt unti.l full recovery at

about 9,5 horu.s. The tvo e;<ceptj.ons occurred vhen the dos*ge of eserlne

va.s dccr€rased for several hours and performance scores fett'to )O percent'

Tirey quicltly returned to above BO perccn'u vhen adcquate closage v'as re-

instituter.l.

(C) fhree subjects exposecl Lo BZ munibions who sholred severe or

maxlma.l responses wele trcateA witfr eserine beginning at from I+-]2 hours

follor,rin5! exposure. In each case, using oral. closes of from 3-4 mg

spa,ced 40 rn:.nutes apart, def inite ircprovement was observed within an

hour and almost total remj.ssion within J hours, which cou-Ld then be

m,aj-ntained as )-ong as reqrrired.. In two of these men, treatment lras

f,lscontinued. after a few hor.rrs. Perforrnance scores clropped. to zero int::r,:tlr t13., 1,rj L,tij.r ,ll Iiltl'f '.; ::lt,l ]t!l,.l t-r"Cinations recurl'err, 111

" iir'r TIIA:

escrine cloee not eecrn to matr:ri.al-J y shorbelt the overall d.uration of the

BZ reslxrnse.

c" (c) Cornment r:n TllA nnrl lit;erine.

(C) The relatlvc mr:rJ.l,c of TllA a-ilrl eserlne have not rccelved euf-

ficlent evaluatlon to warran1, dr:f inl,te reconrnendatlons of one above the

othcr. l{eJ-ther ls ldeal-. TIIA uay have toxlc properties not shared by

eserlne ancl rcust be glven in larger quarrtitleo. Cllnlcal-ly, tt seems tobe less of a coulplete res-borative than is eserine. I^Ihlle with optimal

treatmcnt levels subJects who vou,ld- bc in severe detirlum if untreated

can read., vrlte, play pool, eat, and" sleep nortnally, the THA-treatecl

CONFIDENTIALLn+a

t



lndividual seems less energetic,and somevhat cluller mentally even

observations corresponcl to those

the effects of both comPormds on

PooslblYsome difference 1n

nervous systfn cf:-nical features with the tvo c

--

".-#

,, l-i I I ll#oxEiDrN{4g:

sfI{{+ffi

less jn!,ereste<l in food. or recreationtthou;1h orlentcd and cooperative' These

of ot;iicr investigato::s vho have observed-

the behavior of BZ lntoxicatecl cats'

rfll,lf!Jirwr

t+:



-..: :CONFJDEN }. IAL*! l' \i\r,J',,tlui 1"'IrJr.l\ll.

n. (c ) :Is,Lq.rlgg otlglilg].jlgrfgrytats'

(C) fire effect of RZ 6n the ac';ual- skil-Is reqirlred 1n cornbat isiargety air une>qrJ.ored- sutrJecb. What tittle infornation has been obtained,

al-bhough it cannoi be caliecL rigorous from thc s-bandpoint of experimentaldesign, appears nevcrbheless to be uscf'ul and. uorth presenting.

I. (c) Inclividual- Perl'ornance .

(C) Cerbain skill.s tl'*1, are ac'bually req,'i.red of bhe sold.ier, ancl

others that are consifr-ere<i analogous to them, have been Agsesscd itr a

few subjects e:gosed- to BZ. Rif ie assr:rnbly, for example, vas rehearsed-bo a l-evcl o1', proficiency acccptable by lnfantry stand.ard-s Ln a scries

of indiviclgals vho wcre to receive l+.0-or 7.0 1te/l.'e of BZ by thg lm rou"be'

Four mt:n receiving the lover close sholrccl zur increAse in the nurnber of

eryort:; arrcl -i-n -Lhe total- assembly tirne that paralleled- the iupairmentobscrwecl i-n Te:',as Balbery perforrnance, and' recoverecl to baseline leveIs

by 2Ir- hours. ftre larger d.osc, also given to four men, prod.uced greater

d-Lgradati-on, rrhich reache<L a poin-b of total inabillty to perfomt the

tait- t;. 3-5 ho'rs in each case and. c1ic1 not retu:tr to nonna-L untilLrB-]Q hours.

(C) Rlf'le aim:ing and firing, sirm.rl"a'bed. with an electronic rlfleand a flxecl target, lras carried out lrittrout format methodology in a

fev subjects, Some loss of accuracy 1/ras observed- in subjects receiving

low d.osls, rnhlle in thosc more seYereJ-y incapacitaicrl, the problem seemed

.bo bc less a ma.l'cer of ainri-ng accurately than of rnainta:ining abtention.Orre inclivid.uel glven 6 pg/Xg vas able at 35 hours to fire several times

close to or ln the butlscye zorle, but then firecl twice at a spot oflight on the wa}l near the floor. fhen, putting his r:fle clor"rn, he begatr

nui:"f :r opeling some carrlboarC cra-ues s'canding nearby r-urtil this lrrelevantactivlty raas i,ernd-naterl by the interven'bion of the e:<an:lner.

(C) In anothr,:r: r't,ucly, two sr:bjccts were indlvid-uall:'r fanr-iliarized'

i;-li;l: U sL,o,r'b crbgLir,::.1-',r Ct,r.)i.il";e cc,tls-LS'bing Of a fOW Of dc",;ubrc--Layered-

rubber tires to be s'i:eppecl thrcugh, a series of six' progresslve hurd'les,

a 2h-lnchchameter metal pipe to crawl through, aucl a lp-foot J-ong

I x lr inch tinber elc.r&tecl on blocks to traversc. In ad-dltion, practicerras g:'-ven ln gas mash drill, tent assembl,y, grerearle topsing, and message

carrying f'rom one end of a lO-foot cl-caring to a "lteac1qr-rarters" guartled

by a sentry at the other.

(c) llach mnn thcn rccr:jvr:cl an j,rn l.njcct:ion ot'B pg/ttg of'BZ'One of'thc tr.ro prolrc<1 unusually rcsistan-b to the compou.nd, as shor^m by

the f'act that his pcrforr,rncc on the stanrcbrrl Tev,as lSattery tects never

f'e11, belor.r 50 percenb of basc-L-i ne, amd hc a.'L no time shor'rec1 mo::e than

ndt-r1rna; gep-['1r.sr'-or1 or <].l,soricntnt,ion. (ttil s man, rncntj-oncd carlier, was

tlreonl.y one orrt oI' more tb1lr 2, who rccei'vct1 closes above ? pte/trg ttro

cl-icl not become severely incapacr-batect. lle subsequently was lested wlt\I., VB/W of LSD r:ral1,y aricl proved, wrusutlly reslstsnt to this drug . j;lar'ol)' [rre otn'er indi;idutdfifpibgitiftfrf-u clegree of lncapacitatfop"

,l

4+

:ri'iqkffi$l



^' ' i "i;:iiijq. ' , :, ';t)t'A

E

of lti-l.i tal',, lt:rlorTnancc.

(C) The effect oll BZ on the aci;t-ial- skltls rcqulred in conbat isIargely an une>q;l-orccl sulrjcc'b. l'/hat litt1e infor':nablon has been obtained,

at'bhough it canno'b be call-ecl rigorous f'roro thc st'anclpolnt o1' experimentafdeslgn, appears nevcrbheless to be useful ancl vorbh presentlng.

t. Inclividual Perf orrnance .

(C) Cerbain ski,Lls tha'1, are ac'bually requ*1recl of 1he soldier, and

others bhat are consiclcrccl analogous 'co ttrem, have been assessed in a

fev sub,jects exposecl to BZ. Ri-l'j-e asscrnbly, for exam;:le, r'ras rehearsecl

to a -levcl of' proficiency accep'bable by infantry stasd"a'rds ln a series

of indiviclua1s vho ru.ere to receive L.O or T.O pf3/i'"e of BZ by the lm route'

Four men receiving the lover close sholred. aJ] increase in the nurUber of

errors agcl in the botal- assembly time itr,a'b paralleled- the iqpairrnetrtobserwecl- j-n Texas BaL"bery performance, ancl recoverecl to basellne levels

ly et1- hours. f5e larger dosc, also given to four men, prod-uced. greater

C.Lgraclatj-on, r,rhich reached. a point of total inability to perform the

tafU i.,1, 3-(> holrs in each case and. rLlcl not retrirn to nonue,f urrtil\?,-IZ hours

(C) ILifIe aining anil f irlng, sinmlsted" r.,rith an el-ectronic rlfleand a ftxecL target, t,r&s ca,Iriecl out r,rithout formal method-ology in a

few subjects. Some loss of aecurs,c/ lr'&s observed. in subjeets recelving

lov d-osesr'r,,hj.J-e 1n'i;hosc lnrcre severcly incapacitatc<L, thc problem seemecl

to be less a rnatl:er of aiping accu::ate-Ly than of naintaining a-btention.One inc1ividual- given 6 yA/US vas able at 35 hours to fire several times

close to or ln the bu-Llscye zonet but then fired- twice at a spot oflight on tire wa}l near the floor. fhen, putting his rrfle d-olrn, he began

tui:"t1, opening some cardboard cretes si;anding nearby until this irrelevantacfivlty \ras tenxLlnatecl by the lntervention of the e:mnrlner'

(C) In amothc;: ,:"1,u-c1y, two subjccts were inrlividueJ-1..1 farrr-tliarlzed.

l::l tir a r;lic,rb ol-, uj,;r,u-i,., '.i.'ul-sc coilsisting of a rOw of d-cuLl-:"'riiyered'

rubber tires to be steppecl thror-rgh, a series of six progresslve hurd"les,

a 2\-inchcliameter metal pipe to crav]- through, aud a ].2-foot J-ong

l+ x )l inch tin'ber elev&tecl on bl-ocks to traversc. In ad.c1ltlon, practicer^ras 6i.ven in gas nrask d,rill., tent assenbl.y, grcnacle topsing, and message

carrylng f'rom onc end of a )O-t'ooL cl-caring to a "hcad-quarters" guartled'

by a oentry at the othcr.

(C) Eactr man thcn reccivecl an 1m ln,iection of' I P3/Xe of. BZ.

One of the tlro provccl unusr-rall-y reslstant to the compou"nd, as shom by

the f'act that h:Ls pcrforrur.ncc on the stanclard Tev.as i3attcry tests never

fell betor.l 60 p,:rccnb of basel:i.nc, and hc at no time sho.lrecl mo::e than

ndn-1na-l confu"sj.on or dtsorj-enta'f,ion. (nii s nan, mcntj-onecL carlier, was

the onl-yone out oI' more than 2ij who rcceivccl closcs above 7 pS/ke vhct

d-ici not become sevcrely lncapacltatecL. lle subsequently was tested vlth,I.5 Ve/kg 01' LJn r:rally ancl provecl r.rnusuall.y reslstant to th:is d.nrg ; "' i

"f"o'.)'ine otti'er indlvld.ual -g-hlrred Ufre'- ...;p.dpictl d.egree of lncapacitatlon'_,.

CONFIDENTIAL

li.

(c)

i+4



CoNFIDEN'i IAL

At f'our houls he r,ras testecl on 'bhc Tnl l'r',,3.;i; tasl",s rlescribcd" abovc. IIe

toolc four nd.nr:bcs to comp,Le'Le the r:bs'i,it",r.l-c corrrse in comparison withhis base"l-ing-i;'i nc ot'one udnui;c an<1 t,cir ;econds, anrl recluired- closcettencla:rcc to prevcnt fal.ling clurlng the fire-etcppir:g ancl hurd.les. He

vas urable to clcln his gas u.:sli and onl.y at'ter much assistance l,ras able

to get it on aftcr abor-r'b one r,tinu'be in corrparison r.rith a bascline timcof less than l0 seco;rtls.

(C) ile threrr f ive grenad.es v-itlr poor accurac;r (al"cer clroppingseveral of them) ancl only wj.th contj-nuous coachlng. IIe r.ras'.utablc toassist effec'LiveJ-y in erect"j.ng 'circ pup ien-b. Ile succecdcd in dcliveringa coxqpass to thc "hoaclguartcrs" but gave thc v-rong riassr^rord ancl became

confusecl on 'l,hc re'r,urrt trip, ai-though he corrcc-b-Ly rcnd.clccl a shorl mes-

sage gtvcn to him. IIc lras obvjously exhausted by-bhis brief e>:crbion.

(c) At eigh'b hours, the I'j.rst indi-v-idual cotrtinuecl toperform

aclequately, although hc lras cor:si.clcrabJ-y slor.rcr (rccluiring fO seeoncls

on tfie obstacle coursc in courpariion rrith a basc]-inc of 50). The seconcl

rng.rl'rro,s totall;r una'ole to perfor"rn on anir of the exercises, lras stuporousand" mumbl-i"ng incoirerentl-y. At this 't:ime he rras also lurtestabl-e on theTe:ra,s Battc{r and r,'as clearty i-ncapaeitated. &rthe second. day he shovecl

l-ess lncoordinaLion bu-"b \,.Ia,s vct:y ei:ra"i.ic a-nd. d.l stract:'-bl-e. He rn:,rLageil-bo don his gas mash after sorre funbling, but faj.led, to ]rolcl hi.s breabhat the slgnal anc1, instead., took a d.eep brcath. IIe uas of no assistanceto his partner durlng tent asscmbly and, in fact, pulJ-ed up severalten'b sta?,cs alread.y put in place zur'J unbuttoned porLions of the tent,

so th,at he was actually a hindrance. 'I'his was in spite of continuousinstnr.ction and encouragemcnt by his parlner r.rho by nor,r lras performingquite ru.el.l . D,rring tlre message carryi.ng, he caluterl srnartly arrd ranhalf the d.istance, thcn sud.CLenl.y mad,e a pO d-cgree turn and" l,rotted. offinbo the r+oocis, lle uas flnatly intercepted and brought bacl'" after hehad nrn al^most a hr.rnclrecl yards. Ile fatcr explained he tirought he vasrr.mnj"ng the obstacle course ('cyp:lcal o-r bhc "alibi bchavj.or" seen atthis stage). Grenad-e i,:ssing a:rd. the obstacl.e cource werl': qucecssfu!-I;r:',.r- l"-r'-,1 lrr,,..r ,.., -*-,,.,ili-1'lr.l''r:ii,1r, rrrn,r'i),ioI'Li-Ld time was prr:1olr5e.L ilrl,rL-rrrrj bascline.On the thircl da,y conslclerable i.mprovcment was iho',v-n j-n all catcgorics,but once agai.n r'rhen the signal r,rac given to erect the pup tent hc rredc

&n ebout face and. took off at a d"ead. mn. $c gave tire rrrong mcssageon the message carrying -back, even though he rnaintaj.ned. an appcaro,nccof cerlalnty and executed cr:mnands strtarLi-..l , Recovcry r,ras complcteby the fi.fth day.

(c)

2. (C ) G:'r.,r:.I Pcrf'onralcc.

OnJ.y one group s1,uc\y of any signlflcance has bccn conrpleted.with DZ" T'his stucly vas carried out in l,by 1962, Fortr su"bJects verefanri.l-larizerl r.rith el-ementary ffeld proceclures, incluclingthc operatlonof a flel-d telcphone switehboard, a \,"alhie-tallie, the recorcllng of

lPr 'qnn t''

CONFIDENTIAL)+,



UtttLft$$IFl[$

messa,ges and nraintenancc of a log boc,l.,r :nalntenance of a cornba'l; situatlonmap, ancl the use of thc stanclarrl vortlr; i'or letters of the alphabct" fhey\^rere requirecl to pcrfor:n as me.mbers of' a special de'tachment operating as

a conmurrications tearn in a snall outpos'L. i[his w&s cimu-l-ated. by'11:e

construction of a 16 x 20 foot encl-osure outfitteci wi'bh tvobunk'sr

Listerbag ancl fie-LcL rations, table, chalrs, wal1 map, f'icld telephone an<t

svritchboarcl, r,ralkle-;talkier medieal supply cabi.net, gas alann, cherni.cal

latrine, v"riting naterials, md a sinnr-l-ated- potrcr su-itch l-abeled"

"Da.ngcr - Do llot Touch" mountecl on the rra]l . A single dor:r r,ras present,l-atchccl on bhe outslde. Three slid.ing panels provided. porbs forrnotj.on picture cameras. Tcl,evision monitorlng r.ras provicled- by two cameras

r.noun'bed. on br-ackets above the tl-foot partitions at opposite comcrs ofthe room. Fluorescent ceilj.ng lights and air condi-tioning wcrc provid-ed..

(c) A 35-hour control period. was carried. out prlor to the actua^l

test. Durlng thls tlme, the men remained. in the enclosure ancl rcguJ.ated.their r:trn duty sched.ule, eating and sleeplng arrangements. lleeir taski^ras to ansvrer ancl initiate ca-Lls by one or both uethod.s of corrnuricatlonpncvld-ed a:rd to c&rry ou-b incorrlng instmctlons, reeorcl inforrnai;ion per-'caini.ng to nrlll bary ntovements, weather, intelligence, etc., on thesitlratlon nlap a.nd- 1n the 1og. At predesignated. times, an offl"cer entered.

the enclosure to tlake a brlef inspection. No other contact with theoutsid.e lras permlbted, except by means of radi.o or telephone, tirroughoutthe test pcriod..

(c) A program of verbal inpubs r,ras followed that provid.ed the

subjects vlth probl-ems to sol-ve and" infornation to record" or relay toother hypothetlcal units in their rad.io or telephone netr.rorks.

(C) Tbc subjects (2, fi, C, L) r,;crc given the folloving d.oses,

respectively: B.o pg/trg Im, 6.0-Fs/he im, 6.0 Us/k'g by inharation,and a placcbo inhal-ation. (Ilee group leader r,ras glven the placebo. IIe

had. previously been exposed. to B.O Fg/kB of BZ irn and vbs fam:illar withthe effects.

(c) Within t{o hours Z (8.0 im)'rras too clrr:wsy ancl ataxic tocontinue r.rorh and l-ay d"ornn on hj s bed, By five hours he was up ag&in,

but had" to be mrtcherl contimrally to iceep him from injuring hlnsclf .

IIe repeatedly fell off h-is chair. lll:en the gas a-la::a sor:nd-ed., he was

unable to rcsponcl ancl resistcd. L's (placebo) efforts to help him puthj.s nesk on. For thc next tvc.r days he r^ras disoriented and" hyperaetlve,becoming lrritable ancl lncreasingly detenuinecl to leave the enclosureon the oecond. cia;r.

(C) H (5 im) arrcl C (5 acrosol) wcre affectetl" to lesser clegrccs,ancl were able to 1:erforrn vhat ms requ-ired. of thcm reasonabl-y trcll- bythe sccond day. Irh:ch of thcr custoqlial care of Z fell to L, hotrever,



'r;ii

i rr

- ,. F!t 4_l

''rt r"'il'ii { t

. ,t; I ,i+Jii :lull+t

unti:l. the seconcl night r,rhcn II r.ms abl,c"1,o takc o"rer this flull-tinc ,job.Z by thls'cime was d.oing 1;trin6s tike Lr;ring to climb out of the room

th::ough the mech-cinc cabinet ancl sal-uling tire drapes that scrccncr'l the

latrine. Once he screamerl out sucldenly, "l,g Gocl, get a:r ambulancc qu:-ck--

tiris clu.nrb broacl just tried- t,o ki-ll hersci_flr" and trj.ecl to revive a c&nvas

gas ge"slc contaj.ner. Another time he corrcctl-y answered a teJcplione cgIlrrj.tir "l'his is Delta-l-, overr" ancl then after listcning to the message

replied., "Oi-r, hi Barbaral" Again ancl again ile rnadc a tour of the room,

c:qplorlng every comer for an erlt, ancl then af''ter some cilsual- rcmsrlilike "llelf, f'Il see you latcr tonight probablyr" pr-rt on his ca,p and

frelcl jacket and star-bed. tol,'arc1 the c1oor. 'r,/hen he founcl it l-ocked each

'cime, hq became qu-Ltc clistr,Lrbed. Oncc he turnccl and saicl wlth alann,

"We'ro trappecll" Thcn he tooh off his cap ancl jackct and starr'uecl e:c-

ploring again.

(C) T]reother

srrbjec-i;s,

larLicularlyL ancl II, s]-towecl renuarl<nble

presence o{' rn1nd" in thcse situations a.nd wcrc ab1e to heep Z from be-coming panicliy or clestrr:ctive by exercicing close but outt.iardly casualvigilance (".g. reacling a booh r,,i'uh one eye on Z-)" Ll'rcnt to grea1,

pains to make sure Z took adequate amor"uris of r,rater and- even fed him

rations whcn tre r.ras too d-isorgani.zecl to feecl hl:iself. Z d.ic1 not parbicu-larly appreciate this solicltcus behavior by L anrl ciiri- not wtclerstanclr^ihy he was being trcatcd as thorrgh he r,rere helpless.

(c) On the second day, cod.ecl messages were racl{occi. to thean effort to provicle more challenging problems. Although Ii and

r,rere both col-lege eclucated. a.nc1 of high intelllgence, theyseemed, unj.n'berestecl

in decocling the messages. 0n the thircl d-ay, however, I{ rcsumecl trorltlngon them and soLved. tliem. (L, vho hacl not gonc beyond. 9bh grade, hacl

tried, i,hem without success the day before.) I{rs behavior indicatecl thatalthough he seemecl to be grii;e recovered- on the seconcl de.y and coul-c1

per{'onn rculine dutics r,rithout difflculty, he had not yet regainecl hisfull intel-1ect,r-ral- powers ancl nonnal i"nquisitive drive, since he gave upquickJ-y on the code s.n'1 yet sol.ved. it read:iLy whcn he re]'rr.necl to it the1.. t,: : l. l; tf n,1'

"

(c) Tlrc men er.presscd. the vierr after thc test that Z's conclition

r^ouJ.d havc rendered him not onl.y a compi-ete loss to thc un:it, bu1, anadrl:-ltiona.l- burdcn. They felt hjs he.LpJ-essncss would havc been &n cvcngrcater lnzard in thc 1-'1.cl,d-, vhct'c ullcvcn terrain, roots, sharp rockn,and o'Lher env-ironmental clangers rroufd lncrease the likelihoocl of ac-cldental injury"' When the iclea of t1;tI-ng hinr to a tree until he regalnedhis senses was suggested, lI objccl;ed to'l"he';rcatmen'l, as lnhuna:re andllkeJ-y to I'rorsen Zts conclitlon, but Z ir-lnsclf thought lt a vcry good ideaancl. believed Lre vould. not lla.ve rn-incl.ed- restraint since he ctld. not knowr,rhat w..l.s happening anyl,ray ancl probably r,rould not have remembered. vcrymuch of it later.

;COUEID-EI,I f IAL""- .: -- ---

;rcoNFI+?ENrlAL

men 1n

c



.rLl-Y -"''-*":.-

:":.T]#;l*5'.$;tf;h&$$fir[ffiffi

iiliii]fli-dlie group harl been &ble 'co(C) fhe subjects alsocun"binue to fulflll- their assignments, 'trlcy had m'c1e a number oi' raistakes

-i.n the recorcling of messages, et,c., tha'u trould have r';erj-ously hinderecl

Lheir useftr-lncxs in an autirentic combat situatlon. A1so, if two o1' them

harl received" Z's d"ose, 'bhey wou1cl lrave becn virLualty d"isabled' as a unittrnl-ess meilical ",ra",,ai1utr

coufcl lr"avc been accomplished carly and theycould. hanre treen rel-ievecl of the responsibility of caring for the incapaci-

tated. members of the tearn.

(c) one l-csson learned from this interesting pilot stu<ly r^ras the

rL:i-{'ficul-ty of provirl-ing siroulatecl etrvirorunents that present sufflcientcllverslty a1d. challenge to a group of intelligent subjects over &n

erbentlecl periocl of tinre. If a test is to provid.e val-id- pred-ictions of

nrili'bary perfo:::nnnce, it is imporlant that the stimulus input be of

sufflcieni coruplexity as to "overloacl" the capaeity of the subjects at

cerbain times. E{rjallyimportant, the situatlon s}rould not be ov€r-

simpli::'iec1 tc the poini vhere al] need"s are clearly provicled- for, Ieavingno u:rcertalnty in iegard. to basic requirmtcnts such as food, rlater,she-i.ter, etc. If, i; the in'cerests of preclse clesign, Lhe subject isrequired. to clo no rore ttran cxccute a specified", clearl-y ind'j"cated'

numbcr of tasits ln a wel.l-Ordcred., strarpfy d"enafcatecl "Ufe-spacertthe is irnncdiatel-y relievccl of rnany of the stresses lnherent in the

urprcrJictablc, largel,y rinf'ani-1iar, and d-eflnitely dangcrcus cnvirorunent'bhat lror-r-lcl surrourcl ftim in any actgAl combat situati.on. Ilorr to create

an envir.onmeni thab rrill fulfilt tlrese criteria and- stlll assure reasonable

safc',;y ts a problem ilrat alraits a satisf'ac'corl' soluiion'

cAf! nrl l r:n *::--CONFIDENTIAL

4B



r' r'1 ian" , )rl'I J r " , I I I i I r

l: ;il -r-J.iC-O-J"f"lDgP r-141," r-'

rv. (c) },gLI'IAICT [mDI cAL co_tlqIlERA!":|9JE .

A. (C) EtfegLivciress zurci iiui'ety'

(C) 11e estimstcs o1 effectivencss ofBZ are basecl orl experirlcnts

r,rith young rnales ln perfect heal-th, uncler close.mcdlcal sui:crvision' in&n envirorment tha-b is clinatically itteal ancl virtually f'ree of'physical

hazards ancl obvious sources of inflction. In a ud:"ecl population, thc

followlng variables nmst be talten into aecount'

1. (c) Vryj-atlons in Dosage'

(C) In acllition to the variatlon in conce'trai;ion inhcrcn-L ln

tj.j-sserni-*&tion systc,rs (Alstrii:ution oi' mr-rnitions, tcrrain leatures'

locatiorr of tor.get personnel , mctcorological- factors, ct'c' ), close wilI

Also clepcnd on vtre'Uirer protective maslrs are ava'ila1le, ancl ho'rapidly

arrd'propcrty.bireyareusecl.Anat,tackagalnstasJ.eepingpopu}ationarout.cl lengthen -bite tilie of e;<posure becaus;e of il-re acld-i bional time requlred-

,-bo rrrsk. Mj-nute r-olumc r,roul-d- be rnr-tch grea'ber in persons etrgaged iu

phys:'Lcal activ:i-ty. unprotcctcil jnd:lviclr-rals rnight succcecl j"n holcling

their breath rrtrlie :-n ttre cfoud- long enouglr to cscape nrost of it'

(c) Because basal metabofic ra-Le ancl su-rface arc& are major factors

in deternr-lning rninute .rolume, snal.I .inclividue.ls r'rould- receive larger

doees ter, ki.J-ograrn than large individ.uals. In the case of an inl'ant

welgir.ing 10 pounds, the re'baincd. closc per kilo$ran r'rnder res'bing conclitions

r,rotil.r-]- be appro:limately three 'L:imes es great as in an e'clult cxposed tothe sane CT.

;. (c) varraticql ,n f,'^.,n"r*i\'if ilrl .:11 f,/U!rUe l/ vr- ''-! -J \'.tt-'

(C) It has been rej-terated- often in rter1ical rrritings on atropi'ne

in t rnr"rrts and. ctr-il-d.ren are less able to r'rithstancl toxic doses'

Tlris, hol.rever, ls cl.rr:l:. io guestion since small chilclren hnve survj'ved'

ilr..,l;,;; 'i;iiilt o* u i*,..i.l1r1 l:iiIrs' :j':]-c cq'*al to or highcr tltr'' ,l ";:c that

oftcn are lethal in aclults. womcn-ao not secm to be essentially cuf'ferent

ln thelr response to atropine than men. I{o erperiruental evidence con-

ceming the effective d-ose of'3:', in rn'omen is avail.able' Probab1y-bhe

agea ano clebll.Itate<l woul-cl toler:ate thc agent -l.css -lrell.

(C) A varlef;y of nreclica1 lllnesses can be thought of that voulcl

appeer to increauc Lfr" vul.nerabi.l-ity to BZ ancl trelghtc:n i"bs -l-ebhaL

potcntiallty. Among them are ce,rr:liac dlseases of all- t14:es, hlpertension,

rcrraL or hepat5-c cliiease, hypeytiry5oiclism, d-iabetee, ancl acute or chronic

f"jf"tio"o lj-u"r.r*s of ai.l t11:co, partlcular]y respiratory illnesses'

I

li'

"1

[ggNFIDENTIALi li

L

.ii\i i: :ti: .1

h9

i 1.I l,;



CONFIDEN'f"IAL

(c) Factors !|ll@.(C) l'{ortality occurring soon af1.,t:r' erposure (less 'bharr lr holrs)vould" be attributable to one or more of the fotlor^ring:

a. Lcthal overd,osageb. Sublcthal d.osage plus:

l-. Unfavorable climate2. Increased. rned_ical susceptlbllity3. Accidents (falls, fires, vehicul-ar collisions,

drot,rnlngs, electroo:tions, 1n6estion of polsone,suffoeatlon, severe accidental wouncls, e:plosions,gas stove polsoning, fi_rcanns, srralre bites)

(C) Mortality of a d-el-ayerl nature (after 12 hours) *y be erpected.

to resu-lt pri:narlIy from factors such as ihe folloving:a. Secondary infections, particularly respiratoryb. Dehyd_ration and. starvationc. fngestlon of poisonous substanccsd.. Accldents of'all- typese r Horni cldal- rnaniaf, L'lthdrawal of vltal medjcatlon from chronic

carcllac patlents, d-iabebics, end_ocrine cLisorclers,clnrg acldJcts, alcoholj.cs, epileptics

g. E;posu.rc to colcl

h.. (C) Ivtitltary Fact-ols.

It lrould. seem pr.obab].e from a review of the above that ifef,fective d.oses are clel-lvered. to tlre nra.jority of a mlxecl popu-lation,the lncid.enee of overclosage may be rather high, 1{hj-1.e C1rect tethaittyrnay be an lnf'requent occurrence, it is not d-ifficul-t to suppose thatj-n eorrblnation I'rJ.th th,:: r:rxtributory factors }1sted. aborr^, r :ignificantil'acbiou of the potrujabion nrl6qht suffer fatalltiee; ch.rring the firstfew hours. The threat from uncontrol-led fires alone would. be consi-d.erab1e,especlally jn dq; urban area6, or ln those that have substand"ard.

dwellings r,rhich are easll.y i"gnlted.,

(c)

(c) rnmed.late exploitatlon, prompt capture and mecljcal treatmentof caeualtles and contror of f'1re and otherpotentla].J.y catastroplcoecurences nay nake 1t poseible to cleliver effecbive d.oses r,rith mjnlmumLoss of l1fe.

' '-- 11"\ ;1 1' I lrr J"_ I I

-l

CONFIDENTIAL5o



CONI.IDEN I IAL

B. (C) Managcmen'b of Casua].,

(C) The fol-lor,ring prlnciples are rccortrnended in the rrarurgement ofm.a-ss BZ casualties:

l-. trlapic1 -uri&ge in the following orrler:

a. Hemorrhage ancl other surgical emergenciesb. Coma

c" Stuporcl. Ataxiae. Ambulatory

2. On the basls of' present knov-Ledgc, physostigm-lneand TIIA r,rould appeer to be thc ch'ugs o{'c}roice. }lowevcr, know}edge is

insufficient as to the inhcrent toxicity of these' compounds, and. thusfar the close requlred has been one far jn excess of that encounteredin hospital practlce. Iong acting prepara'cions of these drugs would. benrosi d.eslrabl-e.

3. Comatose, stuporous, and ataxic patientsshould be treated. in the same !:anner if cliagnosis is d.efinite ancl med.ica]facilities permlt. Othenrise, confine stuporous ancl ataxic patientsin fliall groups or lnc1ivtd.ually, ancl manage conservatively. ff numoerof patients is too Ia.rge, nass confinement in safe, cool area is mostimportant single measure. If lndiviclual- attention is in*oossible,

Judiclous rise of' meprcbamate or some of the phenothiazines vould" appearto be inclicated since the prinary concern woul-d be to recluce the activityof the patlent in ord"er. that he coulcl not do accid.ental irarm to himself.Paralclehycle and chl-oral- hyd"rate are two substances traditlonally used.to control toxlc clelirium that may also be consid-ered for use. fhefeaslbth"ty of such 'bherapy would- require testj-ng.

l+, lnbulatory patients shoulcl be obsenr:d- for B hoursarrd. r,;:l-na sll'l j"i n.r Tt:orc t,lrr:r,t'r 'r:j 1:ll_y' aff ected.

,, Barbiturates anri- opiates are contraind.lcated.

as sedatives. Ftuid. intahe should. be llnrited ln severe reactions forflrst 12 hours unless clehyclration 1s a problem.

CONFIDENTIALcl



IJTERATURN CITED

e 6Nfi'D'Ex?lal-*-- tdffifit"R-${FEflffi

1. Cecil, R. L. and R. r. Loeb, eclltors. A Textbook of l'ledicine'

thiladelPiria: Saunders, J-955 .

2. Levln, E., Kirsner, J. 8., and. trtr. L. Palmer. T'he variable Effectof Atropine sulfate on tr'asting Gastric secretion 1n l4an. J. Lab'

crin. Mea. 3'!, l+r'-lra4 (rPf r).

3. Hess, W. r. Hirpothal-arm:s und" Thalarnus,Experimentaf-Dokumente.

Bll-dcrattas nlt d.eutschen und englischen legend-en. stuttgarL:G. ftrieme, L)J6.

' )+. I{otff', H. G. and D. Currs.n. }lature of Delirium and Al}ied' States;

Dysergastric Reaction. Arch. Neurol. Psychiat. 33., LLTl;jj-1 (fg::)'

. 5. Gooclman, Ephralnr. CRDL. Unpublishecl manuscript'

6, Cunmi.ngs, E. G. anri. F. N. Craig. CRDLR (in pub1icatlon). Physio-

logical Action of BZ on Men Subjected to High Terrperatures and"

Ekercise.

qt



5( l?l

CONFIDEN"I-'IAL

*: {'A t"i u t L t" r tl :r:: W$$fi!.&$$!tr18ilBH.ffirusts *#*dfrM6!!iff"*]a=5:::'

APPENDIX A

DESICN AND METHODOLMY

ffcrnnrgiph-trrrnl-

w@d-'**'l+--:.l- -.. -."

[}NffitF{$$$ff$fiffi '



A.

CONFIDEM'IAT

-cA t\ u it l-fu ::::: njfl$frtft$$[FflE0

(c) Genera L

(C) T'he protocol that has been used with minor variatlons for

ihu purt l") months ts illustrated by the complete caee report thatappears et the end of this Appendix. Conpletlon of each case record lsa iengthy process that begins with the inittal selection of the volunteer.Fol.lowlng h{s assignment to the Program he undergoes very extenslvamedlcal" and psychlatric screening. This lncludes a compl'ete medlcal

hlstory and physical examlnation, chest film, electrocardlogram, complete

blood count, urinalysis, blood determinatlons of BSP (bromsulphthaLeirr)

recentlon and other l-iver chemistries, blood urea nltrogen' and other

spectal laboratory work that may be indlcated. In additlon; the volun-

tler rnust comptete a 12-page personal history form, the l'llnnesota Multt-phaalc Personallty Inventory (mfft), and a psychiatrlc lntervlew. Electro-

incephalograms are also obtalned on all volunteers belng conslderedfor expoaure to BZ or other psychochemicals.

(C) If selecred to be a BZ subJect (only 20fi pass all phases ofthis rlgorous screening), he le then briefed concerning the general

natur€ of the experlment for whlch he has been scheduled. If he agrees

to participate, baseline measures are begun two days before the test toestablleh control values for heart rate, blood pressure, temPerature'resptratlon rate, pupillary slze, and performance on two subtegts of the

Texas Battery: NumerlcaL Factllty and Speed of Closure. The flrst ofthese is an arlthmetic speecl test, while the second requires rapid

recognltlon and circting of four-Letter words placed wlthln a contLnuous

""q.r".r""of letters (see sample form ln Case Reco::d at the end of this

Append tx)

During the control. perlod, the subJect aleo is asked to rnske(u)a drawlng of a man for comparison with attempts to urake the same drawing

efter exposure. Ho is required to spend the nlght prlor to the edninistra-tlon of ihe ager,t i,n the bed he wiLl occupy durtng the test (usuallf inrr i:tr,'.trcled eul"r:!"e te ) "

(U) On the mornlng of the test, a llght carbohydrate breakfast ls

permltted, and fLutds are kept to a minlmum (to decrease the likel-lhoodof vomttlng and reduce the productlon of urine ln case of temporarybladder retentlon). The agent ig usually glven at OpOO or 1000. lltare-after he is observed continuously by nur$es and technlcians and atfrequent lntervals by the physician until the experlment is terminated--a pertod of.2-5 days. The schedultng of observattons ls based on a

standard sequ€nce of experimental. tiure perlods, defined as follows: .

(Expressed ln elepsed hours from tlme of adurinlstratlon).

;.- -gaNgpENIAL , .;

il]F$ffi.e$$HF frffi

Appendix A



CONFIDEN fl {AL;r il i, -- i ;

No. of Tlme .Periods Ends

J" tsehavior Check-Llst: (A ratlng'scale designed to recordlntoxlcatlon, consisting of 2O itemspresence of principle signs of BZ

to be checked O, 1+, or 2+.)

. l+" Intake gJlq Oucpu!: Calorlc and fluld volume coneumed and

urinary votume excreted.

Beg,ltts

OO:OO

O1: OO

02:OOO):OO0l+: Oo

06:OOOB:OO

lO: OO

l5:oO20: OO

2J:OA

10: OO

15:ao\o:ooh5:oo5O:OO

55:oo5o:oo55too70:00Bo:oo90:OO

lOO:OO

l10 : OO

f f t;fn".f i t ",r-' 1

CONFIDENTIAL3

D,$e!!gghrs.

"lI

ItI2

2

2

5

5

5

5

,5

5

,5tr

5

5

l0lo10

10

10

Oa:59

O1:59o2259a1;59ojz59a7259o9t19L'l+:59

r9259zl+z 5929r59)\25919:59U+:59l+9r59

5\t59592596+t5969rrg79:59B9r 19

99259Lo9:59

LL9z59

IE.

tl+

5

6

7B

910

11

t2Ltrl+

t,L517

1B

L9

202L2225

2\

(g) Ihe following procedures and observati.ons are completed ln a

standard sequence durlng each of the time periods:

1. V!tal-..g,{.gns: Blood Pressure and heart rate (three timesr,"ach); res1, 1ilTTr,,rl,l " f,*rnnerature, pupll Slae and rep,ctl i'"'i fiy to Iight:(one tlme each) c D

2. Pertormance psts: Nunerlcal Facility, speed of closure,and Draw-A-llan Tqrt Gnce ffh), plus other speclal tests of psychoLo-glcal function as scheduled (o.g" Time Estimation, Rtfle Assembly, Pur-

sult Rotor, Pegboard, Auditory AculEy, VisuaI Acuity, etc.)

ii ){ii;iF[BAppendlx A



rl

rjiCONFIDENI'IAL

5, Cl=Lntcal OLS-ervatlgur Frequent descriptiond entered {nthe record of the subject's behavlor, conversagion, physical appearanceand other occurrenceg.

6. Televlslon Tape- Reqordlng: Not usually done durlng everytlme perlod, but at intervals throughout the experiment. Coverage in-cludes interviews and examinations by physlclan, excerpts of spontaneousbehavior, performance on tests of coordinatlonr Pf,e- and post-test group

or indlvldual lnterviews, etc.

(U) The experlunent is terminated when all symptonrs of drug effect have

disappeared and perforrnance scores have risen above baseline" (Due toadditional practice effects during the test, scores should be 1O-2OS

hlgher at the tlme of full recovery.) .lust before being released from theexperlment, the subJdct is asked to wrlte hls own account. of the experlence

and then to complete a Symptom Check Llst. He is also asked to estin')atethe extent to which he feels he would have been impaired in hts abllity toperform in hls own duty assignment at the tlme of the rnaximum drug effect,and to indlcate how many hours he believes to have el-apsed prior to theattainment of thls maxlmum effect" (It ls interestlng to note that theestimates of the subJects ha'le been found to agree rather well with theobJectlve indications provided by performance scores and wlth the opinlonof observers preeent during the test.)

(c) Prlor to final dlscharge from the Volunteer Frogram, each man lrhohas undergone exposure to IiZ i,s given a repeat electroencephal,ogramr. and

blood tests are performed for liver and kidney function" (None of the sub'Jects has shohrn any medical disabil{ty attributable to the agent,)

A. (C) Speclfjlg tuut -Suil"r: Experlmental exposures completed wlth BZ

stnce the inceptlon of the program nay be grouped as shown tn the follow-ing slmopsis:

1. (c ) {it.tl ll,iit.l,rg--tj-o-n.*9er-i-9!.

Da Bes ; I'lay - July 1!6O

. Procedure: Four member.s of theto take oral" doi6i-6FTiotn l+.0 to B.O pglkg. laboratory staff volunteered

Methodologl: Hourl.y observatlons of vttal slgns, neurolo-g{cal examlnatirn ilA}neral behavloral status. Psychometrid iurr,

"u"unot echeduled.

Comqent: Only general lnforrnation was sougtrt and obtalnedfrom thls s.rie;;*T;[a ge.t*ruil.y unsultable for statistica]- treatment.

icir.{Fipr,nrtal,+

Appendlx A .,'I:l



CONFTMN:!fis5

-.*:;:ffi;i'nTiiutLLEu-*m u'ii;tft$IitF[[[

. 2. (C ) Oral Dose-Response lj-eries:

Dates: 12 Septeober , 26 wtober L)6O.

Procedure: Thlrteen volunteers recelved oral doses rangingfrom 4.0 to ?.1 IiJ'IG.

moror tes ts (","#i!*i;#'".:::i::x, T::::r;:;r::,:,';::::l."l"f:iln'-

tapptng speed,'arithmetic, and color naming) was obtained. Tests weregiven at 1, 2,5, \,5,6, 10, Al+, l+8, ana 7a hours after exposure. Vltal

slgns and neurologlcal status lrere recorded at approxlmately ihe same inter-vals. General mental status was recorded by phyeic{an.

.cgnrnegE: Data lncomptete because of 10ng perlods between

observatlong and lnsufflcient descrlptton of. behaviorat Jhanges.

5. (C) Intravenous Dose-Response Serie,s:

Dates: 2L septenber 1!6O to 21 March t!61

Procedurgs: rbenty-nlne volunteers received intravenousdoses ranging from 0.I to 10.1 pg/kg.

Hethgdology: Essentlally the same as in Series 2.

Commgnt: Data suffers from same deflciencies as in oralserles.

a

Aerosol Chaqber Series;

Dates.: 1l Maich - 2) March L95L

P.ri}:crJure: Iiight volunteers were cxlr.: i,d io inhalationr:.1oses reirging, tor"-ii.f "'d"

a5.o*uglke (eeti*ra"a reralned aosel.

Ite$S9gbff: Stmllar to that used

for oral and intra-venous sertes descrlbed above"

- reapo,,ees wero "tm; "ri;; r::'" r::::i,::"ll::':;t:,::' tffi i:i, rl'i."o"'_pl.ete) 1s dif f icult.

5. (C) Percutaneous Series:

Dstes: 2\ ltay - 8 December L]5L

CONFIDENTIAL

:: [l\Fi CELLTN:::

4. (b)

Appendlx A.



CoNFTBENT

. 2, (C) Oral Dose-itesponse_ijeries:

Dgtes: 12 Septeober - 25 Oetober 196O.

Procedure: Thlrteen volunteers recetved oral doses rangingfrom 4.0 ro T. j ii|I[e

moror tes r s (", "Hi!*iiff '".::;i::::, T::;;:T:;o:1,:,';::::i.'1"::iln"-

tapping speed, arlthmetic, and color naming) was obtalned. rests weregiven at 1, Q, j, \,5,6, 10, 44, \8, ana ie hours after exposure. Vltal

stgns and neurological gtatus lrere recorded at approxirnat"ty it" same inter-vals. General mental status was recorded by phyeic{an.

,corrnent:

Data lncomplete because of Long pertods betweenobservati.ons and lnsufftclent descriptlon of. behavlorat Jhinges.

, . (C ) Intravenous Dose- Response Ser&s:

Dates: 21 Seprenber 196O to 2l March lp51

Sroggggres: I\+enty-nrne volunteers received rntravenousdoses ranging from 0.1 to 10.1 pg/kg.

Eethodologv: Essentiall.y the same as in Series p.

comarglrt: Data suffers from eame deflciencies as in oral

)+. (b ) Aero_sol Chamber Serles3

Dates: 15 Maich - Z) l4arch 1951

dcire.r rn,rgr*g,,;*,,t,#fl'ruli*lirilt?lll;;:.:;':.:ffi;:-.:l.i:n.larion

Methodology: sinilarto that used for oral and intra-venous serles descrlbed above.

oresponees v,ere "ffii; "::ffi ,::'"rlllii,::"H::':?t;,::' tl;iff ' rl"l,"o*_plete) is difficulr.

5, (C) Percutaneous Series:

qates.: 2h Uay - I Decerrber 1!51

;;::::*'s-9I$qgMI4L,"*--:u/ltr{0HLLEll *"-":

a'

serles .

;ril'i.fr"ft$$$FFffiffi

Appendlx A.



coNFIDEl{ }-iAL , i'l

raneous doses,.ffi#ffi; ril'H-Hj'll,nll'T:ff;i :i::r:tT:lo"lluoiX"l;*vehtcle ln ]1 cases and Cresol/U-eChytmorphollne ln 12 cases.

Methodolottv: General clinlcal observat,ion for symptoms ofBZ effect was the prtrnary method ernployed. Detalled testlng htas not schedul:

' ed, and phyelologlcal measures tere made only as required to monitor the

status of the subJect.

I Connnent: Thls was a feasiblllty and range-flndlng serles,. and was not dertgned to permlt detailed statistical analyois"

6. (c) 0rinarv Assay Iieries:

Date:J

June L96L.

Procedure: Flve non-smoker volunteers received lntra-venous doses of flGTkg. Urlne collections lrere obtained and aasayed by

a chernlcal method for BZ oontent.

method emproyea: Genersl clinical observatton was the only

gorgment: Data vlth respect to clinical response vas

mlninnL slnce the purpose of the study vras to determine the usefulness and

rellabillty of the ehemical assay technigue. Non-smokers were ueed because

nicotine wag known to lnterfere wlth the determinatlon.

7. (c) 6folp Interactlon Study; Comparison of AEents:

Date: 2O June 1!61

,:- q r|!:)a 16 *o ,rn,1 *!;-lsff,ffii,; }",":i;:::ffi lll,iil"tr:;it,,f

;":l"lf"lruu'uteither LSD or an at.roplne pla,cebo on the day he did not receive BZ. Drugswere asslgned at random by a double-blind procedure.

Methodology: Baseltne phyoiological and cognltlve perfor-mance measures wGie-Etaifi6d, and subJeltl vere"glven practlce in elmplernllltary skllls (gas mask drtIl, pltchlng tent, compasa and nnp problems,etc.).

or restrn, *,o.,0ffi;"*t:,,;':.:.lll;; il:il ::*Li:,;*;t,I;'l:::,-actton was explored. Reeults were lnteregting but no conclusions werereached. .

, \,,,. ' rr' ; a

, \"t"ii'[[i,,"i, i".,' t ''rii, ',ih'er

f N f f n" ! | r'r.i-

---_

1.,:, ' rj

CONFIDEI\TIAL .Av

Appendlx A



CONETDfrN]'IA***..

ffi$i[gLL:::,,,*,,-B. (c) ortl Dose-qgEaffir€F::-@*

Late: 27 JulY 196L

to clarify the

dose- response

contl,nuity

. 9.

and

(c)

Ploce{ure: Four subjects recelved oral <Joses of h pg/kgresponse to BZ in the threshold range.

lletLodologv: Similar to that followed for the earliers eries

Cotrlrr]snt,: Data collected was deficicnt in resPect to,

completeness of behavloral agsegsment'

Wlnd Tunnel Jlhalatlon Series wlth Prototype Munltlon:

Dates: 2 August - 15 SePtember l!61

Procedure: Seven volunteers were exposed to. inhalationdoses" of from o.WJ vg/kg (estirnated retained dose)'

serles. Grenad"F*##ffi; ,:lll#":: :::ller*v and oral dose-response

Commglrt: Doges estimated L'ith hiSh uncertalnty and

responees were poorty correlated wtth these estimatee' Quallty of data

was varlable, onLy two cases betng adequate in completeness and depth oflnf orrnation.

1.0" (C) Aeros-g!-: olq] Conparis :

Dales: 5 ' 12 SePtember L)61

!'.r:nr:e'"htre: t\aro weeks after exposure l:r:' inhalation doses

estimated at 6.O-""{rnO y.:'f*glkg respectlvel.y, two volunteers received oraldosea of !.0 $g/kg to compare sevbrlty of response to BZ j.n known dosage.

Metllgdplo&yl stmiLar to that followed at Line of aerosolexPosure.

Cgmq-e.n!: Thcsc subJects were the two whose case records

were consldered aaequate ln the prevtous aerosol serles. the indlvlduelwho had shown a severe reslronse io an i.nhalattrrn dose of 6'0 Fg/kg a]"so

showed a gredter response than antlcipated to the oral dose. It was pot

known at thls tlme that second exposures show features not seen ln f irstexposureo. Results indlcated, however, that ldios)mcraoy to BZ could not

HtrAppendlx n



CONFIDEN] IALIlt'

Ue ttre explanatlon for the alypt"ul l"rponses tothat retalned dose estinates could not be rel{ed

aerosol'and suggestedupon to pred{ct re8Pon8e.

IT::'

' " rl,'.. t'., i,i Ir. i,!fi-'-,

11. (C) Tfl.$ treagment studv:

Dates: l+ october - L4 November 1p61

Proceduge: FJ.ve subJects were given oral doses of l'0vg/kg on two o"6ffiif$-1l+ days apart. On the second occaslon Ttl4

60 mgrwas given iv four hours after the BZ

tlethodglogJ: Physi.ologicaL a4d perforrnance measures,

lncluding a"ewfy

OevefoPed test of Time Estidation' were employed.

tleart rate was followed more contlnuously than in previous studies.EEG l.ras also fo1lowed.

!.g1r.urrenl: Quality of deslgn and data collectlon was betterln some ruspe"ts-ilfrli-ln previous studles, but incomplete after 12 hours.

Restrlts r^rere adequate to demonstrate definlte though brief effectivenegsof THA. Comparlson of responses for first four hours of the flrst testr.llth same period of the second test revealed unexPected dlfferences lnspeed of onset and inEenslty, both of which were greater folLowlng the

second dose.

L2. (C) fnt.frtiot, sSrie" - Iarg t

Dates t 2O November 11 Decernber 1951

Proc.edure: Five volunteers received inhalatlon doses offrom !.0-17.0-trili!.G*timated retalned dose) uslng lhe retention apparatus.

Partlcle eizes averaging 2-l+ p wero employed.

llethg-{glggU: Simllar to previous tnhalatlon wlnd tunnelqerles

g-onrnq+.!: Purpose was to compare effectlveness of largerpartlcles thao IIffi-3-O.B p sizes employed in previoue studLes. Sarnple

size less than optimat for meaningful comparisons, but strongly suggestedthat the larg,er particles were lees effectlve. Protocols contlnued tobe somerlhat incomplete and discontlnuou-er, with the exceptlon of the two

h{6tr dooe cases, whlch were well documented.

Lr, (C) Inllglatigg Doqe-Response Sertes - Retgntioqf\ppara :

Dates: l? January - 11 llec 1962

----tt Ir : ! fn [ '

F..,. .r .. , q

'' '-borqnIDENTIALB

r 'i ,\! , lr

Appendix A



;' CoNFIDEN'I"IAL

?rocedure: thirty-onr volunteers were exposed Eo lnhala-tj.on doses rangTffiTili*1.8-1r,6 vglkt:,, using the retentlon apparatusand partlele size of 0.5 p (average).

!gE!ggg1o.8l: Systematic recordi.ng of physiologlcal,cognitlve, and behavioral. data was raintained, grndually augmented by

new measures and irnproved technlques in the later cases.

,Conune4!: Additlonal personnel and equipment and refine-ment of technlques resulted in much better records in this series than inany previous one. Data was co-ngidered adequate for statistical treatment,and ylelded confident estimates for the inhalatlon route. Inconsistencyof response qras sttll present, but thi.s was nor,r f elt to be def inttelyattribr"rtabl.e to the lndetermlnate nature of the true absorbed dose as com-

pared to tlre measurecl retaLned dose. Varlability in breathlng Patterns

seemed to be related to the poor predictabtlity ln lndlvidual caseg.

fl+. (C)I,ntramuscula5 Dose-Response series:

Dqleri ,l+ January L962 - 2B ;une t96J

lrocedure-: I'orty- f tvedoses rangtng from O.5 to B.O ug/kg.dose level was as follows:

Dos e

TGre)o,51.02.O

5.ol+.0.

5.0r.uB.o

volunteers l^tere given lntramuscularThe number of cases tested at each

No. gf Subiects

l+

ooU

1

5

h

5

7

Me{hodoloflv: A comprehenslve protocoL covering physlolo-glcal and psychologlcaL perfornnnce and behavloral paranreters was

fol.lowed. (See descrlptlon of current protocol ln earlier part of thisAppendlx.) A11 eubJects were pre\rlously unexposed Eo BZ. No treatmentwas glven..

gonuneLt: Thie group of cases constltutes the most eatis-factory source of data for detalled statistical analyeis. The caserecords contain comparable measureg collected ln accordance with a stngle

CONFIDENTIAL9

Appendlx A



prlnary protocol, whiclr has bG[ varied only slightly slhce its adoptionaE the colnmencement of this and the pr:ececling; aerosot series . It wl 1l be

referred to ln subsequent paragraphs as the "Standard BZ Protocol.."

15. (c ) Indlvidual }tllitary Performance Study:

Date: lJ ApriL 1962

Procedure:doges "t B uelkil--

1}ro volunteers were given intramuscular

Metho4o_lo.gX: ltre ttandard BZ Protocol was folLowed, butin addition performance on a varlety of outdoor military skills was

nreasured at lntervals. (See descriptlon ln Section III B) Motiorr plcturedocumentation of pdrforrnance alterations was provlded.

gorule-nEr T-his rvas a pilot venture toward development ofmllitary performance assessmerrb technlques and in addltion provlded an

opportunlty to relate laboratory psychological measures to realietic "tasksimple" *u."urer. Agreement r,ras excellent ln boEh cases, glving furthersupport to the. belief that behavlor in the field could be predicted, atleast in eome dimenslons, from laboratory studies,

L6. (C) fiIA Treatnrent' Studv - Pilot Studv No. 2.

Dates: 2J AprtL - 2p June L962.

PTocedgr_s: I'our vol.unteers were given im doses of B $B/kgand then begun on tmmedlate treaturent with TIL\. three of them receivedthe THA orally in a total dose of 2OO mg. One nran was treated by con-tlnuous iv Tll,A, receiving 5(A ^g

over an B-hour period.

Itglhg_dg.!9gy: The Standard BZ Protocol was followed.Serum choli.nenfielr$sq qleterminations were rnade at apprnrir{,tf,e intervals.

Cc*tlgng: In spiEe of differences ln treatment regimen,the results lor*Elffio*rp agai., demonstrated stgnlflcant antagonlsm toBZ when compared wlth the responses of seven untreated indlviduals.

,.1?.- (C) Group llilitary l,erformance Stu{y:

Date: LL May L)&.

Prgc_g!*r_g: A sirnulated mllitary cournunicatlons centerItas occupled by four volunteers for a ?2-hour period. The men received,reopectlvely, 8,O pglkg lm, 6.0 pSlkC irn, 5.O pg/tcg by inhalatlon (estl-mated retalned dose), and a placebo inl-ralation doee.

corv@rffi:€

niqh,llo[ Y

nr\ilI ':, ,.

U';l.l

rt

Appendlx A

tt;lXlii.n$$$fi1[ffi



i -1.Jt!l .,-:,iJ:i iui

I.-,'f

coruptoEN]-iAL i-' i

#e-''

Me."t&Agl_g.By: The men were trained in field communicatlontechnlques and subJected to a pLanned exerclse, which wae preceded by a

?5-hour baseline exerctse of slmilar rlature. (For detaiLs, see descriptlonin Section III B) Constant visual and auditory monitorlng was malntained

throughout the J2-hour period through the use of televielon cameras. Cour;plete records were kept of alt significant evento, conversation, and be-havior in a contlnuous 1og. ldotlon pictures were talcen at frequent lntervals.

Cog-ment: Although more than llo pages of descrlptlve datawere obtalned, interpretstion and analysis of the materlal was never corn-pleted. the study demonstrated that while much could be learned from sim-,ulated environments about group performance under the lnfLuence of I3Z,tl,e lack of structure and quanti.tative data nnkes fornrulatiorr of the ob-served effects extremely difficult.

18. (C) Cumulative_Dose Responss Series:

Dates: 24 -lu1.y - 1 Decemb et Lq,62

Procedg{g; Daily, small doses of BZ weregtven lm to 16men for a-6 aayE. a_- UiEakdown by dose and number of days is as folLows:

No. of SubJects Dose (pg/.k8)

o.51.0

1.01.O2.0

No. of Doses/Subject

US-ESgg,lc8y: fire Standard BZ Protocol was used excepttn the case of iiieren ;ho,receivect 0.5 1rg/kg rlaily, in whose case anabridged version of the protocol wlth less frequent observations wa$followed" Eoch dnt[y dose was eonsidered the beginning, c,f a neqr sequenceef tflttn perln"Jll {.}J.,11 qs'1'41"gicir; uere unintained follor,rirrg t"ire Last doseuntll full remlssion of cumulative effecte (if any) was evldent.

Cqlgg:t!: Data collected was adequate to make preclseegtimates of the maxlmal tolerable daily exposure to tsZ by the im route.Cumulatlve effecte were readily demonstrated in the group receivlng 2.0 ptg/kg.Ihe atudy also showed that, with careful baselines and sensi"tive measures,changes not attributable to chance can be delected at doses aB low as1.0 uglks,.

Lg, (C) Combllrej BZ;LSD Pilot Studv;

2) Augusr LJ62

.

CONFIDENTIAL

l+

l+

71

il

()

1

52

,

Date:

Appendtx A

, " _ -r-rT' t L l -.:,1

',ir ,'"l.li' l:r.\illr

-' '* id ''r'g

1rrf



1ur dose of 2.0 ug/kg of

Methodglo-&v:TtreStandardBZProtocolwasfollowed.

9.c'glgtu: Although definite psychotroplc effects ltere

prodrrced, 1t coul?--il6f be said vhether potentiation, antagonlsm, or

addltive combinatl.on was deftonstrated. conservative dosage and the

to repeat the study resulted ln clata that can hardly be interpreted

eaytni that the t"o uguttts did not cancel each other out'

simplefai lurebeyond

20. (C ) Second-Dose !.f f ect lgtu*:

Dates: 1l-lJ December L962

Proge4ur-g: Seven volunteers who had been exposed to tn-halatlon dos.es of .l+.8 to tO.O pg/ke (estlmated retained dose) 2 to 4 weeks

prevlously were given im doses of 6'o vg/kg

' lletho-qglsgy: Tire Stand ard BZ Protocol was follotred' New

baselines were determined for perforrnance before giving the second doseo

accelerati

!1egl9&19.8:.: Ttre Standard BZ Protocol was follor{ed'

ts.=$hlg,*"&,9.!tgffi; .d;"ir#.,ffi;tuserei-Rss.q"**tlldi"sd

ffi""J"ap.,ipouuoitt'"'uliies'astodemonstfateonceagain+ffiifi l"*po""u" or it"u" subJects to BZ itself wef,e not idlosyncratic-a possiblllty again reised by the l"ack of relationship between thei{

,uuponuu and- trre meagured lnhalatlon retained dose)

2L. (C) PhYgosLlgqine-Treatment-PiloE Studv:

D$-!;*l.q.: J February ' 26 February 1p6J

Plq,ge-4r+r-g: Four subjects recelved contlnuous or seml-

contlnuous treatfr[ilfTltt, oral physostlgmine in doees totalling from JZ

to 2)Q mg per man over a J!-hour period followlng an lm {ose 9f-7'Lnlre/kgot BV. 1\,ro of them receLved .r, ,rrrttu"ted dose of ?,0 $g/kg of BZ eltherprior to or followJ.ng the trested dose, wlth an lnterval of three weeks

;;;;;"; aor"r (f.u., the two men were run together ln a double-blind cross-

;;;;-;;ric;j: placebos were given on the game schedule as the phveoetls-

,mlne to the untreated Partner.

N::;:""'iifi$;L:iAppendix A

ce f\@-"* \i

ffittffiu"n$ffiFtHffi



ril lllt-ii , t;'--w@- -

::':'r '

CONF'IDET{ie

'

conrnent: lhe quallry of the cllnical regords ln thlsstudy is consideted excellent, and irir effort was srade to introduce more

rlgorous deslgn features lnto the a$sessment than had been prevlously em-

ployed. Clrcum..Jtances intervened tc prevent slrict adherence to a balancecl

"rosso.rerdesign

lnal.l four subJectsr slnce two men declined to take the

{ose a gecond time. Dosage origlnally planned for physostlguine was foundto be lese than optimal and the lmportance of close regulation was atsonot anticlpated. In spite of these departures from the deslgn, the repultswere htghly informative. (for details' gee Section III A 6.)

22, (C) Aerosgl-Sunitions Test Serles : ReJlulateq-Preaqhtng.

Dates: 5-11 June 196]

Plgcedulg: Elght subJecta $tere trained to breathe to a

standard pattern, which controlied rate and tldal volumeby providing a

vtsual feedback oscilloscope-televlslon camera-video mqnltor linkage thathas as an lnput the subjectrs respiratory flow operatlng through a trans-ducer in h1s face tr€sk. Changes in dtrectlon and rate of resplratory flowcause vertlcal deflections of the oscill"oscope bean as it sweeps across

the screen at a rate calibrated to the desired number of breaths per

mlnute. I?re subJect adjusts his respiratory flow eo that the beam foll.owsa traJectory traced ln wax crayon on the glass screen. After practicewlth thie technigue, subjects were exposed slngly Eo a BZ cloud generated

1n the rrl-nd tunnel by grenades fron the Pine Bluff Arsenal assembly line.An IR Speetrophotometer monlEor devlce provided contlnuous readout of

total CT calculated from samples taken continuously from the immediateviclnlty of the subJeet's head. The wind tunnol was sealed off from thegrenade; when ttre.deslred level was attained. CT ranged fron B! to 1)8.

Flethoclqlggl: TJ:e Standard BZ Frotocol was foltowed.Three subJects weie tieiiiO witfr physostigmine aftcr h-la hours, both todlmlnish the severity of symptoms in these cases and to acquire addttionalexperience wlth tlre treatnent agent.

(]gu,lnee!: Responses showed a more consistent relatlonshlp.to estlnated doles tn-tllis series than in prevlous aerosol studies. This

is attrtbuted to the reduction in varlability of breathirrg patterns. Thedata was considered adequate to conflrm the effecttvenese of the munitl-on,the retiability of the monltor syotem, and the correctness of the prevlousegtimates of the ICTSO

ji 6 l r ,t l t

CONFIDENTIAL1"4J

I iiii iiItIAppendix A



'(

CONFIDEhITIAL-effi

-

\.rfilr '| Lt-u :

APPENDIX B

cHHnrsrRY AND BTOCHEMTSTRY Or BZ (U)

-s0Neffihfq,am[!Nf;t&$$lflEil



A. (c)

(c)

CONF"IDEI.,ITIAL

BZ is an ester of benzillc acld, whlch ln its standard state lsan odorlese, white, crystalline soLld. The melting point (f.) of the

free base ls f5h-167oC. The Tf of the protonated species or^hydrochloridgts 2r9-241oc" If the liquld free base is malntained at L?OoC for severalhoure, decompoeitlon occurs wtth the production of C02, benzophenone,benzohydroL, and snraller quantlties of other moieties. the botling point(ru) is )20o6.

Froperties .

-

Ttre free base is sllghtly soluble in water but is somewhat more(u)soluble in acetone, ethylene chlorlde, methanol, and ethanol, It ls verysluble in chloroform, trichloroethylene, and warm dimethylforrnmlde. Thehydrochlorlde is water soluble.I

(C) the pKru of the conjugate acld ls of the order of ).2Q ln con-trast to LO,5B for the conJugate acld of free qulnuclidine. Thls sllghtdlfference ln aetd strength is due apparently to the inductlve electron-wlthdrawing effect of the two phenyl resldues. h (€son€rnce effect pro-duclng thls change in pKr, is^precluded by the out-of-,plane posltion ofthe bridgehead hetero-N atom.c

(C) ALl esterg of benzilic acld, inclucltng J-hydroxyqulntrclidlnyl.benzilate, have two absorptlon bands ln the infrared at 1[.7 p and l)r.9 U(680 cm-l and 670 cm-r, respectivel.y). Nelther the products of hydrolysisnsr the products of oxidation of thege esters produce vlbrational-rota-tlonal spectra at these frequencles.)

B. (c) Reac t lons

(C) As a rather typical ester, BZ will. undergo npsf; of the cheuricalreactLone characterlstic of this claes of compounds. +-o Among otbers,these reactions are acld-catalyzed and base hydrolysee, arrmonolysis, andester-tnterchange i,rJ.th the alkyl and/ot aryl groupe of other alcohols.

(U) More speciflc studies of the compounci in, terma of solvplysis andpH dleclose that the half-period (tttil for hydrolysie of a 10-4M solutlonts 4OO minutes at pH p.B and onLy l.8-mtnutps at pH V.A: It has also beendetermlned chat oue mole of eeter wlll combtne qrlth three egutvalents ofchlor{ne 8t pH 7.0 ln a perlod of approxiroately six houre. In chlorofqrmaotutlon, no bromlne ls observed to be abgorbed at the end of one hour.Y

' ', ,

C . (C ) Quan t i ta t lv-e €Alvs is

(C) Many methods are evailable for the quantitatlve determinatlon ofagent BZ ln solutlon. The root of the problem is, however, choo$ing and/or

[fiffiffifl.&$$lFlHBAppendtx B

--*€*--



qONFIDEN'il"IAL*-'r''-*.- t; /{ l'l j.-t:*- , ,...- [-lJ'lt';!-r);(Ju-r ti4 ru'

devlslng a reasonabty affiiff*?trr"d "f'"-&;;;;*r"fitriviry, such rharfractional mlcrogram amounts of the compound can be quantitated in biologl-cal fluids and other tissues.

(c) I\so such generaL procedures are currently under investigation,i,e., colorinetric procedures based on the deteimlnation of certainmoieties obtained from oxidation and/or hydrolysis of the intact agentmolecule and the classical speetrophotometrlc determination in thevisible spectrum of the compl.ex formed bethreen an anlonic dye and the cat.:.

ionlc agent at an approprlate hydrogen-ion concentratlon.

(C) Arr aqueous sol-ltion of the compound may be analyzed colorlmetri-cally after treatment with Hoso.H, Fecl=, and acetlc anhydride. on theother hand, the ester can be sat'onlfied)to sodium benzilate and oxiclizeclbv HoCl

tobenzophenone,

which can rather easlly be determined spectropho-tometrlcally.9

(U) Kramer, -Q! al,lO t. an attempt to determine small quantities of thelntacc compound ln blological flulds, concentrated the agent by adsorptlonchromatography on silicate columns. The material was then eluted, combinedwlth the anionlc dye brornthyrnol blue, and the absorbancy of the resultingsolution measured at 600 mu.

(c) using still another anionic dye, tropaeolrn-oo (p-(p-anillno-phenyl-azo) benzenesulfonic acid), Edberg and Kondrttzerii have determinedBZ

spectrophotometrlcally(51+O

*fr) at concentrations as low as O.]-0.5 pgml- r. T'he mettrod is, however, not adaptable to tissue. One other disag-vantage is the hlgh "blank" readtngs obtalned ln the presence of certainpseudo-aromatlcs, 6.g., nlcotine and purlnes.

Stltn12 has recentl.y reported ph percent recoverycoupound by vapor-phase chromatography of solutions of theurine and human blood plasma. This procedure has not yetf he e l"ini.ea l. !"n-he"*rn i: nr:)'

^

D. (C) Intermediarv Metabolism(C) Baslc inforqqtlon relpted to the intermedlary metabollsm of BZ t"smeager. Korrdritzer,'/ uBlng Ii'- labeled compound, has lnJected doses ofL,6 ng/kl-1 body welght into male rats tntraperitoneally. Ttrirty-slx andone-hal'f. Percent of the total radloactivity was recovered ln the urinewlthln 2l+ houre following administratlon. Only B$ of the urinary radio-active material was present as BZ per .3e" Radioactive materlal was boundby cerebral tissue L! minutes after lnJection and after 24 hours wasstlll LO$ ot. the maximum value obtained in the brain.

(u) of the intactagent in rat

been adapted to

n.{: r'qill''1 ),li:'l j

' ,,1 I

Appendix B

q FF.\ Et6il

CIrj'11 E|[Fn-- -'l'i] 'i:ilCONFIDENTIAL--...



@*'*:,jGUuqfiit H$$t$t[Ui+.-..-s#

(c) rn a pre1"lrn-rnar,.F ";#;E;;;il...t,".r..r, ,*.rn."l[ has Jnjectecl

doses of agent from )O-)OO pC/ite-' lrody r'r,.'ir,iil into mice intraperitoneally,using ttre i3-taleled compoid. pr'"pared by ilt:rv lhglancl ltruclcap Qorporation"

F,arly clata sug6rest that:bh" high*st concen[rations of ]abe] are present in

lltt,* irain, Iiver, kiclneys, supral'enai- glanci.s, ancl in the bile. 'I\'renty-four.lLr:r-rrs post-inje"iion, the highest conccntration o{'raCj-oactjvjty is in the

i;irr,:Ln, probabil' the hypc.,physis and.f or hlr-potiralarrric region in the floor of

the third. ventricle."nt-

)+8 hours, tabel is cietectable only in ttt:is area of

the brain anci. is not present in any other organ system of'r,he boc-y'

-(C) Using +.he tcchnique aescribecl by lieirnber8, e-L g!,t5- ll.r"h16 lt.". c,lq:J-etecl pr.ellminary sturlies on the meta.lrollstn of RZ

jay pcrf'usirrg l,he llvero1' aclult ma-Le rats wi'bh a pert'rrsate con'ba.j'ning f .32 W'ft "\'.,the

conrpound'

Usjng a modil'lcation of' 1,he Orange IV co].orimetric B.ssayr " this investlgatorforrnfl. that the }iver r€rmoves !0 perccnt o1'fhe compound i'ti lO mi'nubes'

Atter I hours, no more than.l. percent of bhe agent fias pret1cnt in both thealcl r,he liver. 'Ihe bile Ira.s f'ound to qonta"ln only a fev micro-

srams of the una-l-tereci cr:rrpor-mcl (<O.fg perccnt'Lotal- in'Laci' agenl)' A repor{''fro*

CRDI3 srrgges1s, however, t1a.t no hycl.rolysls of the ester was no't,ed-

after t6 iroi-rrs vhen 'l,he compound was suspendecl in homogerrates of ca.nine braln,Iiver, kiclney, spleen, lunS: and. bl-ood pJ-asma.

.(c) Tle r"rorh ol Shefne"lL *ra Bushi6 -i-i; norc sug6;est jve of' a probable

enzynr,ic ester hyiirglysis i1 i,hc Ii vcr uiLir biliilr'y c)''ci'(:i,iotr Oi' t,he iryclroly-

tj-c proclucts. Orle w-ould suspecb that titese clea.vage prod'uctfj are, priort9 excrel,-lon in the il-itc, "cteto:<iI'iecl" eriz.ynnaticaliy by conjugation t'rith

D-glucuronj.c acid thror.rgh combinatj-ons vith urlciirrc-)'-'Jlphosphoglucurr:na'Le'It w<tu.l.d not be unreasonable to assume f'uruher LhaL the bertzilate rnuiety isiiactivatecl'' to t;5e coenzyme A clerivative (benzilyl Co A) prior 'bo i i,s com-

blning vlth D-glucuronat'e, the ovcraff reaction being coupled vil,h the exer-

gonlc hyclrolysis of adenosirie triphosphate. Qther proposed enz;'mr'ic pabh-

-r"yr for conjugation are tlrrough bi-otrarrsfc:nini:ions into tlre betuilyi-L-glyc inat e and.f or b enz i -i-yl-- I- glu l,am-1 nc cleri vat i ve s

n, {n) .P{rc}i'":tiii i:r-ir'lh,:r::,1-..ilrlti,

(C) Very fev studies of the bioclrenlica-L mecharrj.sm of ac'Lion of the

benzllate have been atierluately pursued a.rrcl/or reporLecl . Adraittedly, sucir'encleavor.6 are <lifflcul-t; hor^rever, an understanding of the molecular bio-'ghem1-stry lnvolvecl vill resul'L jn arr cariier acqui-siLiotr of a compor'rncl or

-compounds necessary to iiriribit the pharmacologic actions oi- the agen'b '

(C) SacktorlT found in the nr-itc;chonclrial-nr-icrosornal fractj-on of' bovine

braln thal acetylchol:ine (8.5 x iO-5lui) irrcrcases the turnover" of phosphatj-d-yl-

Lserine as we1--L as a lipi.cl I'racticin copNaining phosphoinositide a.t1d g8rlna-

phr:sphatitlic acirl. Atrop.inc (r.6 x to-oi'{) arrd. tsz \'! x 1O-'}1) block the. acety)cholinesterase-stinmla,ted lncorporalion of' PJZ into both of the }a.tter

::sofirusENr[aH-w&'

ry*t*Appendlx B[$fi$ffifl,$$$$trHHffi



compounds but have no

Both atroPine and BZ'subs tance.

@NFIDEN:$ TAL: --- " i; A I't ' l i 1- ;' r.r ';; '-j***-*-''"-..*"-..-:.-.:".."-":.:-

,u"ti,Iitr""CJ., tr'',,-- lurnover-of phosphatidll- !- serl"ne'

were founcl to increase the P12 uptake by the lat'ter

(C) Other studiesl8 1ru.r" indicated that BZ added to equine bloodserum

results in the pro<luctlon of isomerized, presumably unesterified' fatt'y

aclds, whieh have been tdentlflecl by vapor phase chrt>matography as conjuga-

led, unsaturated fa!!y acids. Presumabiy the lsornerism is of the cj"s-trans

varlery. so.tocorifi?''";;;-leads to a splcula'ion concerning one possible

mechanism of actlon. It is well krror,l u,oo.g others that the mitochondrion

is the intracelluLar cytoplasmic structure embodying the enzyme.syscems

fof. electron transport and 'xidativephosphorytaiioi' In adclltion ' J6 pet-

cenE of the total phosphate ln mitochondrla is associated with lipid phoaphor-

ous19. Presumably the structural lntegrity of the e;rzyme-fiystemsr sequencc

could thus be corpro*i"ed by Bz, thereby llading to lncomplete oxldationo'

uncoupling of oxtiative phosphorylation, etc. Such factors could result inthe blocking of many essenti.at biochemical reactions, and not in the least

those endergonlc reactions r"q.rriirrg the Gibbs' free e'ergy assoclated with

enzymatlc hydrolysis of aderroslne triphosphate'

(c)oEherresearchershaveproduceddata-disclostngthatBzblocksserotonin-, nicotln-, and a"etylciroline-inducecl contractlons of isolat?l-u

guinea.pig ileum. Tlnls occurs in medium concentrations as low as ! x lO-a

pg/ml-r. Again, the centraL e.f fectg of the conipound could possiblv be

interpreted in the llght of tlooliuy;, "serotonili-t'ypott'esis of psychoses'LJ

(c)Arefresh{ngbiochemlcalapproachhasj.nvolvedstudiesoftheactl-on of BZ on the respiratory rati;; of K+ and electrically stlmulated

rat cerebrur "orl*;-.A{,'22--wiltr. stlmulation no decrease from the eontrol

ratio was obeerved over an agent concentration range of 5 * 19-5 to

,-"'io:5*.-"ii-ao*s, however, trl0ct the respLratory response to electrical-

stlnulatlon of the cortical'srices (rao pursls second-1, 10-r2v).

(n) T*Ldr2| l,'r,,, p"utrlated that one of ttre effect* of BZ may be due

to inhlbitlon of tlre enzlrme $ystem necessary for lon-trarisP()rL acro8s

the cell membrane of the cortlcal neuronal cell body. In testing the postu-

Late heemployed rat brain homogenate contalnlng adied Ugl*, Na+, K*, flod..

adenosine trrptrlspt"a.-ionl. fi;.* and ATP weri added, since the "ac!lve"tranEportoflonsaeaphysJ.cochemtcalprocesshasastandardfreeenergychange grearer;1";-"urf ( ro>0). It was.believecl, therefore, that BZ

might lnhiblt the enzy*ic'hyclroiysis of the termlnal phosphate of ATP'

lr ResplratorY ratto - aroms 02 uptake /dry glhour_!gt. stltlll!"d :9tj1I*.--._.-.---;-:;;.'^J.^lt^^9}^U

"tJms*6 "pt"k-ruryg/hour for "restlng" cortex

-* f. ItF! tFl lFn ----'CONFIDENTIAL

Appendlx B Ffinnry |{,,Qffr,Tflrl'Tl



g F(DEI.{l'lAL . *,eB$s*irffidd

[tuuffil"A$$ffiffin

Boldtrs experimenrs falled to show any decrease in inorgahlc phosphate inthe homogenate medium, thus precluding the inhibition of ATPase act.ivltyby the agent.

(C) On the basis of olher scattered data, one Ls temptecl go speculat,ethat BZ could involve some other unusual cnzycre systcrns. l.tcllwain24 hasfound Ehat nuclear htstones inhtblt thc restorative action on cortlcalelectrlcal (respiratory) activlcy of plasma protein fraction fV-1+ (Cofrn)afcer the brain slices have been kept aE ooc for !-lJ hours" tr1g625, inthis connection, has reviewed brlefly the liIerature relating memory toenzyme induction and riponucleic acld (nn.t) blosynthesis and degradatlon.Further, Ir-vtn, gt- al,ca have shown that nuclear htstones (isolated fromthymus deoxypentose nucleo-protein) possess RNase activity. The idea,therefore, should not be abandoned that at some point along these diverseblochemical pathways and feedbaqk systems one may

fincl a slte of inhibltoryactlon by tsZ sufficient to produce the diverse neurophysiologic charrgesknosrn to occur.

Appendrx B-8RNtllRFNfil4ru

[$ftxfrH-f{$$n$[f,ffi



(u)

1. CRDL Sp Pub !-2[J. EA 22TT. l\ Ijurarnary Report as of 15 Marc]rrq6r (u). sECRrr Rcport

' 2. Goul,d, Ii. S. Mechanism and Structure tn Organic Chenisbry p. 2]_r.

ilenry ilolt ancl Company. Nev York. 1959,

3. CRDL Tech Memo 10-25. Quarterly Sumnary of Progress, Directora'l,eof Researcn (u). 31 December 1960. SEcRilT Report.

[. Kosovcr, E. IU. I'4o1gcular Biocheinistry p. 125. ]'lcGrar'r-lli11.Ner.r York. L962.

t'1956.

5. Iline, J. Physical Organic Chenr*istry p. 255. McGral.r-l{i1l-. Ner,r Yorlt.

6. rbici. p. z9j,

T. Fieser, L. F. ancl Fieser, 11. Ad.vancccl Organlc Chendstry. Reinhold.Ner,r York. L95L.

. B.'Ficscr, L. F. and Fieser, I'{. Organic Chemlstry, Third. Iid"itionp. 118. Heath. Boston. f956.

9. Sass, S., ct cLI. USA gWL Tech Memo 13-11+. Colorirnetric and

$pectropho'bometric Estl::eti.on of EA 2?-TT and Similar Compouncls; SomeChemlstry on tlre Dccomposi'bion of EA 22TT $). 10 June 1950. SECRET Report.

10. Kranncr, B. arid. Amoroso, A. J. CBDL Tech Menro 22-1). A Metiro<l

for tfie Determina't,ion of EA 227T in l{uman Urine (U). Noventber 195f .

' SECREI Reporb.

11. Edberg, L. J. and" Kond.ritzer, A. A. CRDL Tech Mcmo 23-30.i,:t;'.irii*c cn 3Z; I,, l,,cl,er.irLiii:r"Linn cf BZ (U). January 1.963" fOiTFIDlilflIIAI'Reporb.

12 Ellin, R. 1. CRDL Tech Meno 23-27. The Use of Gas ancl LiquidChrrornatogra.phy for ttre Quantitative Determination of BZ in Rio-1-ogical' systens (u). July L952. c0i{FrDE[\'rrAL Report.

13. SI}fIEII$U Trlparbite CBR Conferenco. U. S. Progress Report' Preparecl for Discusslon Group on Medlcal Aspects (U). February L952.

COM'IDINTIAL Report.

.th. Shefner, A. Arrnour Researchtr Corp. Personal corununicatj.on.

:..5, Ilcimbcrg, M.r l,leng, iI. C., and Park, C. R. Effect of Scx,

Fastlng ancl Al-loxan Diabetes on thr: Uptake of ltreutral Fat by IsolaterlPerfused Bat Lj.ver. Am, J. Physlol IgSt 5n-6ff (fgi8).

Appendix B

ffi8fipffiHJLW$@F: 'r'

85ffif;n"ft$$EFHf,m



. \)1rl{::'," ri i-l"i:-; i- i

)llt'ilL{},CONFIDEI'd"TIAL

.,'. :'

t5, Bush, M. T. Sen:,j a^frn',ral. -llep-r"r 1''rr Pcrj oc1 October .l-, I C61-

l,lay lO, I95?. Cont.ra.cb DA l8-l-08-)iil-c^1t,,-T6t (nn r 3-t"03-Ct'il,-66?9).'. $tud-y of Nei.r Conrpr:uncls (U). lJ Junc L,'u?. COIIFIDII{TIAL Reporl,.

l'f . CRDL Tech i,{emo 2J-2).

'(uar1,crly

ProgrcssR.:ll,,rL

f'orPhysio]og,y

' Division, 1" July-J0 Seplember f-951 (U). Scpternber L96I. COImIDmXIIALi),rnarl'r\u1Jur r/.

IB. CRDL Tech l4erno 10-30. Quarberl;; S,lmn"'lry of' Prr:gress, Dlrectora.te

.. ot Research (U). lJ. Dr:ce-n'rber t961. SnCnliT Report.

. 19. ltrei lernd.s, J. B. arncl. S1;umpf', P. i{. Outlines of ,Ttrzyme Cheral- s i;ry

. p. 301. John Wile;,r ancl Sons. Ner'r York. 1958.

20. !Iooll-e;;, D I\I. f'he Bjochendca-L Basis of Ps;Tchoses p. f3I.

. John Wilcy ancl Sons. i;lev York. L952.a'

. 2L. Richa.rds, 0. C., 0'Ncil-L, J. J'., ancl Sjnpron, J. I,/. CRDL Tcch

. I{emo 11-3. Ef'f'eci,s of Incapaci-ba.ting Drugs cn Respirat,iou, Gl.ucose-'

Consumptjons, and. Lactal.e Proclucbion of' ilat Brain Sl-ices (U). 7 l4arch L96?.

?2. O'Nr:j-1-i, J. J. a:rd. Schaf'fer, N. K. Persona.l cornrnunicabjon.

23. Botd-t, R. E. Pi:rsona] connnr-rnicatlon.

ZLr. Mcl},rain, lI . Prol:ein In'beracti ons and. l'4eta.bo}lc Respc.rnses 'tro

Slimulating Agents in f sola1,ed" Cerebral Tissucs: I'I.is't,ones as Inhibitors.Biochcn. J. '(3, 5,1-l-r2r (tg>g)

2r. Smi1.h, C. il. Is l{er;ory a Ma-b1cr of l"}rz;rme Induction? Sclence.

.. 138, ll0g (rl6a).

25. Irvin, J. L., cb al. Pcrsona} Ccjmmirnica'bion.

Append.ix B



-- rl,il

CONFIDETi |IAL{-.

.. 1

\.,

APPEI'IpIX C

FIGURI]S AI.JD TABI,ES

l. , I

I



;-itOBIT ANALTSIS NOn 1

.

otze

Does

'

'

I

7,6'

9.2

TRI ) L.O

. 116 (aIL

Range(r.eAe)

0'L - L'0

1.0 - ?.0

2.9 _ J.6

),9 - \.3

L.3 - lr.5

\,5 - 5,It

5.L - 6,0

6"0 - ?.0

?.0 - B'O

B.o - 12.0

(mlId)

routos conbtnod

Equatlont

,- -a,$2 + 9.Bb Log X

rl error of slope . ]- $lrc

Rooponoo

ohz

oh2j

o/L?

\/L2

, 6/to8ftz

' tt/tz.

roh2

L2/L2

loAo

r Li.lnt

upper

3.505\.2\5b.97t5.o286.lr839.L06

.-.*:-.*--* ;-.!i |-l .,r,.i I

-:: ; c0NF iDIl-{{.t

. ED(P)

2.672j,6119

. L.oT31.6055.8117.061

g5$ conftdence

Lorer

2.0363.L36).629L.2tB5,zLO5,93L

APPFnTnF rt

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,elzo

Doge

ANALYSIS 'No. 2

TRr l 5.0'

. 11"6 (a11

Rangc(tce/')*e

)

0.L - 1.0

1.0 - 2.0

2,0 - 3.6

3.9 - L.3

u.3 - !.5lr.5 - 5,3

5,\ ' 6,0

.6,0 - 7.0

7.0 - 8.0

8.0 - 12"0

routes

ts*_ -

oornblned

Reoponco

olrz

o/Lz,

042

' 2h2

6h2

eh2

e/\2

:,,2h2

e/La

Equattonr

. Y .'-1,18 * B.5g Log X

€mor of olopo - L,59

ED(P)

i.Bog1r.015'h.55ll5.il.fl6. BL2

8.55L

lower

2'.OO2

3.3811.035\,799'5,Bgz6,662

t

95fi Conttdence ltmtteupper

l.9lrL\,7665.tLo5.721,, -7 ,9lrlr

l.0. g7L

C

)

liliI

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ll

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. TRI' .3 6.0 . (aeverey:*

else . U6 (a11 routeg c

Dose

rI

3.1

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lj'5

5.ba

5.7

6.5

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L.0 - 2.0

2.O - 3.6

3.9 - b.3

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t U.5 - 5,3

5.L - 6.0

6.0 - 7.0

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err'or of oloPo ' I,75

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959.' Conttdsnce Llmltalower llpper

2.6555 L.L6o

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6,777 9' 211

7,673 L2.337 .

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A*PPENDIX C



. TRf .

etze - U.6

,.T ANALYSIS No, h

7.0 (maxfunum)

(a11, routea comblned)

Doso

0.9

1.7

3.1

It,

l.r

i55."1

5,7

6.5

7',6

9'2

Range

(ncelte)

0.L - 1.0

1.0 -. 2.0

2.0 - 3.6

3.9 - u,3

lr.3 - L.5\,5 - 5,3

5.lr - 6'0

5.0 - 7.0

7.0 - 8.0

B.o - 1.2.0

Besponoo

o/Lz

o/L2

o/\2

r-h2

ono'o/L2

2h?

llftz

6h2

5/Lo

y, . -,672 + 6.LS Ine X

orror of slope - L.59

95S confldonee Limll,eEq(P) Lower uppor

.3.$o2\, 2.0698 5.9275.7 69 1.911 6.7766.879 5,98) 7,9LO8.373 6,5L7 r}.75g

.12,152 ?,08L 2O,Blt6't6.597 7.506 36,697

C fV EQWV. DOSE (mcg,/kg)

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c

e

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3IT ANA],TSIS No. 5

Tnr I 1.0'(rnrl.u)

C0 f'll- lU l r,l llAL i i Y--llili

.

; iTllllitiril.iiillLl,i I rll ll.i L I l-!-Lrl{-r.liLi,I+4+l-lri ll

size ' 36

Doe o Rango H,oaponoo

T

lrlr - Zr V6

71 - BB \/6

90 - 109 3/6 i

'tIo - 126 3/6

, L55- L63 5/6

167 - 3Lr 6/g

Equattonr

Y - -2,98 + l.gg tog X

orror of slope - 1.L2lr

95fi CorttdenceED(P) lower

.2h.323 L.B9g5L,6o6 ?j,o5767.29 39.108gir"g0 66" ?lr19d,6' gr.go253,82 gl.lL

Llmlteupper

T20.75t-15.51LLs,79,!,? j

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2',13,92

705,3h

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t,ltr ANALYSIS No. 6

TRI )5 (moAorste)

sLze . 36'

Dooe Rango Rosponaenatvt

lrlr - Zr 0/6

?1 - 88 r/6i

90 - r.o9 L/6

l,1o - 126 3/6

r55 - 163 \/6

16? - 3Lt 6/G

Equatlonr

y. _9.67 * 6,gg'LoeX

of alope - f.i8l

95S Conftdence Ltunl-taFD(P) Lower u,pp€r

e

51.o5t 31.391 107.39

89.98 66.77:-n-,26

81.51 l-30.53151"5b

173,11 L2L27 2Li7.1L227,63 t 3o.5L 396,95

t,!I

C

* \l 1."!.'I 1 t'i:\

LdirrruENTIAL

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TRI l 6 (eovere)

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Doge

110 -

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90 - 109

L26

163

311

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o/6

L/6ii

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error of alope'. 2.022a

ED(P)

62.99 33.99!"i,, l,f, Te "l L

53 9L,77110.28

r27,\5Bo' \3t.72

959.' Csruttdence Limltalower upper

11.6. ?L_l l{). J8110. L5161.68

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, . JIT ANAI,TSIS

-tu_

rnr)t.36

No. B

(ruaxlmum)

Reoponee

' o/6j

o/6'

o/6

L/d

2/6

\/6

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lilr - ?t

71.88

90 - 109

110 - 125

r55 - L63

roi- :Ur

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Y - -10.77 + .6,g7Log X

error,of elope - ?.lt?

95$ Coultdsne'r*

7g

lower

35 "95e9.69

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518,05980,97

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PRt, AMtf$IS No. 9

\

Rengc

0.1 - 1.0

1.0 - 2,0

2rO

- 3.63.9 - 1.3

lr.3 - li.5

b.9 - 5.\

5.1 - 6,0

6.0 - 7.0

7"0 - 8.0

8.0 - 12.0

Reaponao;'

o/Lz

o/\2

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3h2

rh.2

lr/Lz

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9/L2

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Equatlon:

f : -1.02 + B.trlr Log x

ornor of olopc . L,52

95yt, co*tdenceED(P)

2. Blra

L.1lrz

b,730

7.2669.r92

C

lower

2.L25),565

L. ?3h5"0r36.2817,302

Llmlupper

3,802L.812

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H..2

i

,,I'IALYSIS No. 10

'l

.,

I

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nn(p)

b.6395.3956,39L8.813

Range

0.1, - L.0

I.0 - 2.0

2,O - 3,6

3.9 - \.31"3 - b.5

L'5 - 5.1.r

5.lr - 5.0

5.0 - 7.0

7.0 - 8.0

B,o - La.o

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6rror of olopo . 1.LJ

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z,Lg? L.1133.991 5.382L.BIL 6.021' 5.71$ ?.1107 .I93 10.7978.136 ]5,763

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